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IL151428A - Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same - Google Patents

Azetidine derivatives, preparation thereof and pharmaceutical compositions containing same

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Publication number
IL151428A
IL151428A IL151428A IL15142802A IL151428A IL 151428 A IL151428 A IL 151428A IL 151428 A IL151428 A IL 151428A IL 15142802 A IL15142802 A IL 15142802A IL 151428 A IL151428 A IL 151428A
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IL
Israel
Prior art keywords
radical
methyl
compound
formula
chlorophenyl
Prior art date
Application number
IL151428A
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Aventis Pharma Sa
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Publication date
Application filed by Aventis Pharma Sa filed Critical Aventis Pharma Sa
Publication of IL151428A publication Critical patent/IL151428A/en

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Description

15076/02 151428/2 AZETIDINE DERIVATIVES, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME The present invention relates to derivatives formula : which R represents a radical selected from CRi R2 C=C(R5 ) S02 R6 and C=C(R7) S02 alk, either Rx represents a hydrogen atom and R2 represents a radical selected from -C(R8) (R9) (R10) , -C(RB) ( Rn ) (R12) / -CO-NR13R14, -CH2-CO-NRi3Ri4^ -CH2-CO-R6, -CO-R6, -CO-cycloalkyl , -SO-R6, -S02-R6, -C(OH) {R12) (R6) , -C (OH) (R6) (alkyl) , -C(=NOalk)R6 -C (=NO-CH2-CH=CH2) R6, -CH2-CH (R6) NR31R32, -CH2-C (=NOalk) R6 , -CH (R6)NR3iR32, -CH(R6 ) NHS02alk, -CH (R6) NHCONHalk and -CH(R6)NHCOalk, or Ri represents an alkyl, NH-R15, cyano, -S-alk-NR16 Ra7, -CH2-NR18R19, or -N 20 21 radical and R2 represents a -C (Re) (Rn) (R12) radical, R3 and R, which may be identical or different, phenyl or indenyl, these aromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl and -alk-NR24R25 radicals; or a heteroaromatic radical selected from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2, 3-dihydrobenzofuryl, 2, 3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1, 2, 3, -tetrahydroisoquinolyl, thiazolyl and thienyl rings, these heteroaromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR24R25 , -CONR22R23 r -alk-NR24R2s, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl and hydroxyalkyl radicals, R5 represents a hydrogen or alkyl radical, R6 represents an Ar or Het radical, 151428/2 R7 represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical, optionally substituted by a -CSO-phenyl radical, Re represents a hydrogen or alkyl radical, R9 represents a radical selected from -CO-NR26 R27- -COOH, -COOalk, -CH2 OH, -NH-CO-NH-alk, -CH2 -NHR28 and -NHCOOalk, Rio represents an Ar or Het radical, Rii represents a radical selected from -S02-alk, -S02-Ar and -S02-Het, Ri2 represents a hydrogen, Ar or Het radical, i3 represents a hydrogen or alkyl radical, Ri4 represents an Ar, Het, -alk-Ar or -alk-Het radical, Ri5 represents an alkyl, cycloalkyl or -alk-NR29 R30 radical, R16 and Rn, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, Ri6 and R17, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one 151428/2 -4- or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, Ri8 represents a hydrogen or alkyl radical, Rig represents a hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02 alk, -CO-NHalk or -CO-alk radical, Or, alternatively, Ri8 and R19, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, -NR20 R21 represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle ring, optionally containing another heteroatom selected from oxygen, nitrogen and sulfur, R22 and R23, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, R22 and R23 , taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, 151428/2 R24 and R25, which may be identical or different, represent a hydrogen, alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or, alternatively, R2 and R25, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2 radicals, R26 and R27, which may be identical or different, represent a hydrogen, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl , -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2 radical, or, alternatively, R26 and R2-;, taken together with the nitrogen atom to which they are attached, may form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing one or more other heteroatoms selected from oxygen, sulfur and' nitrogen, and optionally substituted with one or more halogen, alkyl or alkoxy radicals, R28 represents a -CH2 -alk, benzyl, -S02 alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO-(CH2)nOH radical, n is equal to 1, 2 or 3, 151428/2 R29 and R30, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, R2g and R30, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, and being optionally substituted with one or more alkyl radicals, R3i and R32, which may be identical or different, represent a hydrogen, alkyl, Ar or -alk-Ar radical or, alternatively, R3i and R32, taken together with the nitrogen atom to which they are attached, form a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, alk represents an alkyl or alkylene radical, Ar represents a phenyl or naphthyl radical optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22R23, -CO-NH-NR24 R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl , alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR24 R25, -NR24 R25, alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl and S02 NH2 radicals, Het represents a 3- to 10-membered unsaturated or saturated mono-or bicyclic heterocycle containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen, alkyl, alkoxy, alkoxycarbonyl, -CONR22 R23/ hydroxyl, hydroxyalkyl, oxo or S02 NH2 radicals, the alkyl, alkylene and alkoxy radicals are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, the cycloalkyl radicals contain 3 to 10 carbon atoms and the heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms, their optical isomers and their salts with an inorganic or organic acid.
Among the alkyl radicals, there may be mentioned the methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl and hexyl radicals. Among the alkoxy radicals, there may be mentioned the methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and pentyloxy radicals.
Among the cycloalkyl radicals, there may be mentioned the cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl radicals .
The heterocycloalkyl radicals are cycloalkyl radicals in which at least one of the carbon atoms is replaced with a heteroatom chosen from nitrogen, sulfur and oxygen. Among these, there may be mentioned the pyrrolidinyl, imidazolidinyl, pyrazolidinyl , piperidyl, piperazinyl and morphplinyl rings.
The heterocyclenyl radicals are cycloalkyl radicals in which at least one carbon atom is replaced with a heteroatom chosen from oxygen, sulfur and nitrogen and which contain at least one carbon-carbon or carbon-nitrogen double bond. Among the heterocyclenyl radicals, there may be mentioned the. 1, 2, 3, 4-tetrahydrohydropyridinyl, 3, 6-dihydropyridyl, 1, 2-dihydropyridyl, 1, 4-dihydropyridyl, 1, 2, 3, 6-tetrahydropyridinyl, . 1 , , 5 , 6-tetrahydropyrimidinyl, 2-pyrrolinyl , 3-pyrrolinyl , 2-imidazolinyl , 2-pyrazolinyl, . 3, -dihydro-2H-pyrane, dihydrofuranyl and . fluorodihydrofuranyl rings. Those preferred are the 3 , 6-dihydropyridyl rings .
The term halogen comprises chlorine, fluorine, bromine and iodine.
Among the heterocycles representing Het, the following heterocycles may be mentioned: benzofuryl, benzothiazolyl , benzothienyl, benzoxazolyl , chromanyl, 2 , 3-dihydrobenzofuryl 2r3-dihydrobenzothienyl, furyl, indolinyl,- indolyl, isochromanyl , isoquinolyl , . piperidyl, pyrrolyl, pyridyl, pyrimidinyl, -:.quinolyl, 1 , 2 , 3 , -tetrahydroisoquinolyl , 1 , 2 , 3 , 4-tetrahydroquinolyl, thiazolyl and thienyl .
When R3 and/or R4 represent independently a substituted phenyl, the latter is preferably mono-, di- 5 or trisubstituted .
When Ri6 and R3.7 together form with the nitrogen atom to which they are attached a '3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, 10 piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When Ri3 and R19 together form with the nitrogen .atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, 15 the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
The heterocycle formed by NR20R21 is preferably -" ' azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 20 thiamorpholinyl, piperazinyl or imidazolyl.
When 22 and R23 together form with the nitrogen atom to which they are attached' a 3- . to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, 25 piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R24 and R25 together form with the nitrogen atom to which they are attached, a 3- to 10-rjnembered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl , piperidinyl ,. morpholinyl, thiamorpholinyl or piperazinyl ring.
When R26 and R27 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, -morpholinyl, thiamorpholinyl or piperazinyl ring.
When R29 and R30 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated' mono- or bicyclic heterocycle, the latter is preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
When R31 ' and R32 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated or unsaturated mono- .or bicyclic heterocycle, ■ the latter is. preferably an azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl ring.
Preferably, R represents a radical CRiR2,. either Ri represents a hydrogen atom and R2 represents a radical -C (R8) (Rn) (R12) or C (R8) (R9)" (R10) , or Ri represents an alkyl radical and R2- represents a radical -C (R8) (Ru) (R12) , R3 and R4, which are identical or different, represent either a phenyl which is unsubstituted 'or substituted with one or more halogen atoms or alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, - -CONR22R23 hydroxyalkyl or -alk-NR24 25 radicals; or a heteroaromatic chosen from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, it being possible for these heteroaromatics to be unsubstituted or substituted with one .or more halogen atoms or alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -CONR22R23 / -alk- R24R25 or hydroxyalkyl radicals, R8 represents a hydrogen atom, ' R9 represents a -CO-NR26R27 , -COOalk, -CH2OH, -NH-CO-NH-alk, -CH2-NHR28 or -NHCOOalk radical, Rio represents a radical Ar or Het, Ru represents a radical -S02-alk, -S02-Ar or -S02-Het, R12 represents represents a hydrogen atom or a radical Ar or Het, R22 and R23 , which are identical or different, represent a hydrogen atom or an alkyl radical or alternatively R22 and R23 together form with the nitrogen atom to which they are attached a 3- to 10-membered saturated mo.no-or bicyclic heterocycle, optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R24 and R25, which are identical or different, represent a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or alternatively R24 and R25 together form with the nitrogen- atom to which they are attached a 3- to -membered saturated or unsaturated mono- or bicyclic heterocycle optionally containing another heteroatom chosen from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or -C0-NH2 radicals, Ar represents a phenyl or naphthyl radical optionally substituted with 1 or 2 subtituents chosen from a halogen atom or an alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR22R23 / alkylsulfonyl, hydroxyalkyl, -alk-NR24R2s, -NR24 25 , hydroxyl, CF3/ 0CF3, -O-alk-NH-cycloalkyl or S02NH2 radical, Het represents a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1, 2, 3, 4-tetrahydroisoquinolyl, 1, 2, 3, 4-tetrahydroquinolyl, thiazolyl or thienyl ring.
The compounds of formula (I) may be provided in the form of enantiomers and diastereoisomers . These optical isomers and mixtures thereof form part of the invention..
The compounds of formula (I) for which R represents- a radical CRiR2, in which Rx represents a hydrogen atom and R2 represents a radical C(R8)(Ru) (R12) in which .Re represents a hydrogen atom, R represents a radical -S02-Ar, -S02-Het or -S02alk and Ri2 represents a hydrogen :atom or a radical Ar or Het, and the compounds of formula (I) for which R represents a radical C=C (R5)S02R6 or C=C (R7) S02alk may be prepared according to the following reaction scheme: in these formulae,, either Ra represents an alkyl,. Het or Ar radical and Rb represents a hydrogen atom or a radical Ar or Het, or Ra represents a radical Ar or Het and Rb represents a hydrogen atom or an alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl . radical optionally substituted with a radical -CSO-phenyl, Rc represents a hydrogen : atom or an acetyl radical, R3, R , Ar and Het have the same meanings as in formula (I) .
Reactions d and e can only be used when Rb is a hydrogen atom.
The reaction is generally carried out in an inert solvent such as an ether (for example tetrahydrofuran) , in the presence of a strong base such as tert-butyllithium,. n-butyllithium, lithium diisopropylamide or potassium tert-butoxide , at. a temperature of between -70°C and -15 °C.
The dehydration reaction b is generally carried out by any . dehydration method known to a person skilled in the art which makes it possible to dehydrate an alcohol in order to obtain the corresponding alkene. Preferably, the acetyloxy derivative is prepared by the action of acetyl chloride, in an inert solvent such as pyridine, tetrahydrofuran, dioxane, a chlorinated solvent (for example :dichloromethane or chloroform), at a temperature of between 5°C and 20 °C and then the -medium is treated with a base such as- an alkali metal hydroxide (for example sodium hydroxide), an alkali metal carbonate (for example sodium or potassium carbonate) , an amine such as a trialkylamine (for example triethylamine, .4-dimethylaminopyridine, 1 , 8-diazabicyclo [ 5.4.0 ] undec-7 -ene , at a temperature of between 0°C and the boiling point of the reaction medium. The acetyloxy intermediate may be isolated or otherwise. The acetyloxy may also be prepared directly, in the reaction medium of reaction a.
Reduction c is, generall . carried out in an inert solvent such as a (1-4C) aliphatic alcohol (for example methanol), a chlorinated solvent (for example chloroform or dichloromethane) or a mixture of these solvents, in the presence of NaBH4, at a temperature of between 0°C and the boiling. point of the reaction medium.
Reaction d is carried out by the action of trimethylsilyl chloride, in an inert solvent such as an ether (for example tetrahydrofuran) , in the presence of n-butyllithium, at a temperature of -70°C.
Reaction e is generally carried out in an inert solvent such as an ether -(for example tetrahydrofuran) , in the presence of a strong base such as tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between -70°C and -15°C.
Reaction' f is generally carried out in a chlorinated solvent (for example dichloromethane or chloroform) , at a temperature of 0°C at the boiling point of the reaction medium.
The hydrolysis g is carried, out in an inert solvent such as an ether (for example dioxane) , by means of hydrochloric acid, at a temperature in the region of 20°C.
The reactions h and j are preferably carried out in an inert solvent 'such as acetonitrile , in the presence of a base such as an alkali metal-:. carbonate (for example potassium carbonate), at the boiling point of the reaction medium.
Reaction i is' carried out under a hydrogen atmosphere, in the presence of a catalyst such 'as palladium or one of its derivatives, in an inert solvent such as methanol or ethanol, at a temperature of between 15°C and 60°C.
Reaction k is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or chloroform) at a temperature of between 0°C and the boiling point of the reaction mixture The derivatives R3CH (Br) R4 are commercially available or may be obtained by application or adaptation of the method described by BACHMANN .E., J. Am. Chem. Soc, 2135 (1933). Generally, the corresponding alcohol R3CHOHR4 is brominated by means of hydrobromic acid, in acetic acid, at a temperature of between 0°C and the boiling point of the reaction medium.
■ The corresponding alcohols R3CHOHR4 are commercially available or may be obtained by application or adaptation of the methods described by PLASZ A.C.et al . , J. Chem. Soc. Chem. Comm., 527 (1972) .
The intermediates of formula 2 may be obtained by application or adaptation of the methods described in the examples. In particular, the procedure is carried out according to the following, reaction schemes: RaSNa Rb-CH2-Hal Rb-CH2-S-Ra Rb-CH2-S02-Ra RaSH ICR, RaNH isoamylnitrite » RaSCH3 RaS02CH3 eSSMe 4 ' nBuLi d f eSS02 e RaHal in these formulae Hal: represents a halogen atom, and, preferably, chlorine, bromine or iodine, Ra and Rb have the same meanings as previously mentioned for derivative 2.
Reaction a is generally carried out in an inert solvent such as dimethylformamide or a 1-4C aliphatic alcohol, at a temperature of between 20°C and 30°C.
Reactions b and e are carried out by any known method which makes it possible to oxidize a sulfur-containing derivative without affecting the rest of the molecule such as those described by Μ.· HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263 (1990) . For example, the procedure 'is carried out by the action of an organic peroxy. acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, -nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or monoperoxyphthalic acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid) , in an inert solvent , such as a .chlorinated solvent .( for ' example chloroform or dichloromethane ) , at a temperature of between 0 and 25°C. It is also possible to use hydrogen peroxide, optionally in the presence of a metal oxide (sodium tungstate) or a periodate (for example sodium periodate) , in an inert solvent such as a 1-4C aliphatic alcohol (for example methanol or ethanol), :' acetic acid, water or^a mixture of these solvents, at a temperature of between 0 and 60°C. It is also possible to carry out the procedure by means of tert-butyl hydroperoxide in the presence of titanium tetraisopropoxide in a 1-4C aliphatic alcohol (for example methanol or ethanol) or a water-alcohol mixture, at a temperature in the region of 25°C or by means of oxoneR (potassium peroxymonosulfate) ,. in a 1-4C aliphatic alcohol (for example methanol "or ethanol) ,, in. the presence of water,, acetic acid or sulfuric acid, at a temperature in the region of ,20°C.
•Reaction c is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (for example methanol or ethanol) , at a temperature of between 20 °C and the boiling point of .the reaction medium.' Reaction d is carried out under an inert atmosphere (argon) , at a temperature of between 50°C and the boiling point of the reaction medium.
Reaction f is generally carried out in an inert solvent such as tetrahydrofuran or an aliphatic ether, (for example ethyl ether), at a temperature in the region of -70°C.
Reaction g is generally carried out in an inert solvent such as dimethylformamide , an aliphatic ether (for example ethyl ether) or a 1-4C aliphatic alcohol-in the presence- of ' a base (for example sodium hydride), at. a temperature of between.0°C and 60°.
The derivatives of formula Rb-CH2-Hal are commercially available or may be obtained by application or adaptation of the methods described in the examples. In particular, the methylated derivative or the corresponding alcohol is halogenat.ed using a halogenating agent such as hydrobromic acid, in acetic acid, at a . temperature close to 20°C or N-bromo- or N-chlorosuccinimide in .the presence of . benzoyl peroxide, in an inert solvent such as tetrachloromethane, at .the boiling point of the reaction medium. The methylated derivatives or the . corresponding alcohols are commercially available or may be obtained according to the. methods described by BRINE G.A. et al . , J.. Heterocyl . Chem, 26, ,.677 (1989) and NAGARATHNAM D., Synthesis, 8, 743 .(1992) and in the examples .
. The azetidinones of formula 3 may be obtained by application or adaptation of the methods described by KATRITZKY A . R . et al . , J. Heterocycl . Chem. , 271 (1994), or DAVE P.R., J. Org. Chem., 61, -5453 (1996) and in the examples. The procedure is generally carried out according. to the. following reaction scheme: In these formulae, R3 and R have the same ' meanings as" in formula (I), and HAL represents a chlorine or. bromine atom.
In step A, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol or methanol for example) , optionally in the presence of an alkali metal hydroxide, at the boiling point of the reaction medium.
In step B, the reduction is generally carried out using lithium aluminum hydride, in tetrahydrofuran at the boiling point of the. reaction medium.
In step C, the procedure is preferably carried out in an inert solvent such as a 1-4C aliphatic alcohol (ethanol -or methanol .for example) in the presence of sodium hydrogen carbonate, at a temperature of between 20°C and the boiling point of the reaction medium.
In- step D, the oxidation is preferably carried out in DMSO, using the sulfurtrioxide-pyridine complex, at a temperature close to 20°C or using dimethyl sulfoxide, in the presence of oxalyl chloride and triethylamine, at a temperature of between . -70 and -50°C.
In step E, the procedure is carried out according to the method described by GRISAR M. et al . , in J. Med. Chem. , 885. (1973) . The magnesium compound of the brominated derivative is formed and then the nitrile is reacted, in an ether such as ethyl ether, at a temperature of between 0°C and the boiling point of the reaction medium. After hydrolysis with an alcohol, the intermediate imine is reduced in situ with sodium borohydride at a temperature of between 0°C and the boiling point of the reaction medium..
The R3-CO-R4 derivatives are commercially available or may be obtained by application or adaptation of the methods described by KUNDER N.G. et al. J. Chem. Soc. Perkin Trans 1, 2815 (1997); MORENO- ARRAS M . , Eur. J. Med. Chem., 23 (5) 477.. (1988); SKINNER, et al . , J. Med. Chem., L4 (6) 546 ■ (.1-971) ; HURN N.K. , Tet. Lett.,.36 (52) 9453 (1995); MEDICI .A. et al . , Tet. Lett., 24_ (28) 2901 (1983); RIECKE R.D. et al . , J. Org. Chem., 62 (20) 6921. ( 1997) ; KNABE J. et al., Arch. Pharm., 306 (9) 648 (1973); CONSONNI R. et al., J. 'Chem. Soc. Perkin Trans 1, 1809 (1996); FR-96-2481' and JP-94-261393.
The R3Br derivatives are commercially available or may be obtained by application or adaptation of the - methods described by BRANDSMA L. et al . , Synth. Comm., 20 (11) 1697 and 3153 (1990); LEMAIRE M. et al. , Synth. Comm., 2_4 (1) 95 (1994); GODA H. et al . , Synthesis ,.9. 849 (1992); BAEUERLE P . et al . , J. Chem. Soc. Perkin • Trans 2, 489 (1993) .
' The R4CN derivatives are commercially available or may be obtained by application or adaptation of the methods described by BOUYSSOU P. et al . , J. Het. Chem., 2_9. (4) 895 (1992); SUZUKI N. et al . , J. Chem. Soc Chem. Comm., 1523 (1984); MARBURG S. et al . , J. Het. Chem., 17 1333 (1980); PERCC V. et al . , J. Org. Chem., - _60 (21) 68.95 (1995) .
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri represents a hydrogen atom and R2 represents a radical C(Ra) (R9) (Rio) in which R3. represents- a hydrogen atom, Rg represents a radical -CO-NR26R27, -COOH, -COOalk, -CH2OH, -NHCOOalk or -NH-CO-NH-alk and Rio represents a radical Ar or Het may be prepared according to the following reaction scheme: in these formulae R3, : R4, Rio, 26 and R27, have the same meanings as in formula (I) and alk represents an alkyl radical .
The derivatives of formula 4 are commercially available or may be obtained by esterification of. the , corresponding acids, optionally in an activated form such as the acid chloride. The acids are commercially available or may be obtained from the corresponding methylated derivatives according to the method - described by JP. HANSEN et al., J. Heteocycl . , - 10 , 711. (1973) .
Reaction a is generally' carried out in an inert solvent such as an ether (for example tetrahydrofuran) , in the presence of a strong base such as. tert-butyllithium, n-butyllithium, lithium diisopropylamide or potassium tert-butoxide, at a temperature of between -70°C and -15°C Reaction b is generally carried out by any dehydration method known, to a person skilled in the art which makes it possible to dehydrate an alcohol in order to obtain the corresponding alkene and in . particular the methods previously described.
The. reduction c is generally carried out in an inert solvent such as an aliphatic alcohol (1-4C) such as methanol, a chlorinated solvent such as chloroform, dichioromethane or a mixture of these solvents,, in the presence of NaBH , at a temperature of between 0°C and the boiling point of the reaction medium.
Reaction d is carried out by any m-ethod known to a person skilled in the art which makes it possible to pass from an ester to the corresponding acid without affecting the rest of the molecule . The procedure is preferably carried out in an inert solvent such as dioxane, in the presence of hydrochloric acid, at the boiling point of the reaction medium.
Reaction e is carried out by any method known, to a. person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule. Preferably,, when the acid is used, the procedure is carried out in the presence of a condensing agent which is used in peptide chemistry such as a carbodiimide (for example N, N' -dicyclohexylcarbodiimide) or Ν,Ν'.-carbonyldiimidazole, in an inert solvent such as an ether (for example tetrahydrofuran or dioxane) , an/ amide (dimethylformami.de) ' or a chlorinated solvent (for example " methylene chloride, 1, 2-dichloroethane or chloroform) - at a temperature of between. 0°C and the reflux temperature of the reaction mixture. When a reactive derivative of the acid is used, it is possible to cause the anhydride., a mixed anhydride or an ester (which may be chosen from the activated or nonactivated esters, of the acid) to. react/ the procedure is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogen-containing organic base (for example trialkylamine, pyridine, 1 , 8 -diazabicyclo [5.4.0 ] undec-7-ene or 1 , 5-diazabicyclo [ 4.3.0 ] non-5-ene) ,. in a solvent as cited above, or a mixture of these solvents, at a temperature of between 0°C and the reflux temperature of the reaction mixture, or in a biphasic aqueous-organic medium in the presence of an alkaline - or alkaline-earth base (sodium hydroxide or potassium hydroxide) or an alkali or alkaline-earth metal carbonate or bicarbonate at a temperature of between 0 and 40°C. - Reaction f is carried out by CURTIUS arrangement, in the presence of diphenylphosphorazide azide and triethylamine, in toluene, at a temperature in the region of 50°C.
For reactions g and h, the procedure. is carried out. directly in the reaction medium of step g at a temperature in the region of 20°C.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -C(R8) (R9) (Rio) for. which R8 is a hydrogen atom,. Rg is a radical -CH2-NHR28 ' and Rio represents a radical. Ar or Het, may be prepared according, to the following reaction scheme: In these formulae, R3, R4 and Rio have the same meanings as in formula (I), Rd represents an alkyl or phenyl radical, Re represents an alkyl radical, Rf represents an alkyl radical, Rg represents an alkyl, cycloalkylalkyl, cycloalkyl, -(CH2)nOH radical, n is equal to 1, 2 or 3.
Step a is generally carried out in an inert solvent such as an aliphatic alcohol (1-4C) (for example methanol), in a ■ chlorinated solvent (for example dichloromethane or dichloroethane) or tetrahydrofuran, in the presence of a base such as NaBH (OCOCH3) 3 , at a temperature in the region of 20 "C.
Step b is generally carried, out in an inert solvent such as a halogenated solvent (for example dichloromethane) , in the presence of an organic base such as triethylamine or dimethylaminopyridine, at a .temperature of between 0°C and the boiling point of the reaction medium.
Step c is generally carried out in an inert solvent such as tetra.hydrofuran, dimethyl formamide , a chlorinated solvent (for example chloroform or 1 , 2-dichloroethane ) , an aromatic solvent (for example benzene or toluene), at a temperature of between 10°C and the boiling point of the reaction medium.
Step d is carried out by any method known to a ■ person skilled in the art which makes it possible to pass from. an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
The' derivatives 6 may be obtained according to the following reaction scheme: In these formulae, R3, R4 and Rio have the same meanings as in formula (I) and Ms- is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of triethylamine, at a temperature of between 10 and' 20°C Step b is generally carried out with liquid aqueous ammonia in methanol,, in an autoclave, at a temperature in the region of 60°C.
The compounds of formula (I) in which R represents a radical CRiR2 in which Ri'is a hydrogen . atom and R2 is a radical -CONRi3R14 may be prepared according to the following reaction scheme: H2OH In these formulae, R3, R4, Ri3 and Ri have the same meanings as in formula (I), Ms represents a methylsulfonyloxy radical and . Et represents ethyl.
Step a is carried out in the presence of triethylamine, in. an inert solvent such as.; an ether (for example tetrahydrofuran) , at a temperature in the region of 0°C.
Step b is generally carried out in an inert solvent · such as a mixture of water and dimethylformamide, at a temperature of' between 30 and 75°C.
Step c is carried out by any method known to a person skilled in the art which makes it possible to · pass from a cyanated compound to the corresponding acid without affecting the rest of the molecule. Preferably, the procedure is carried out by means of potassium hydroxide in an aliphatic alcohol (1-4C) (for example ethanol) or in an aqueous medium, at the boiling point of 'the reaction medium.
Step d is carried out by any method known to a person skilled in the art which makes it possible to pass', from an acid or a reactive derivative of this acid to a carboxamide without affecting, the rest of the molecule molecule and in particular the preferred methods previously described.
The compounds of formula (I) for which R represents a radical CRiR2 in which Rx is a hydrogen atom and R2' is a radical -CH2-CONRi3Ri . In these fprmulae, ■ R3, R4., R13 and Ri4 have the same meanings as in formula (I) and Et represents an' ethyl radical .
' Reaction a . is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of a base such as sodium hydride, or an alkali metal · carbonate (for example potassium carbonate), at a temperature of. between 20 °C ' and the . boiling point of the reaction medium.
Reaction b Is generally carried, out by means of NaBH4, in ethanol, 'at a temperature in the region of 0°C.
Reaction c is carried out by any method known to a person skilled in the art which makes it possible to pass from an ester to the corresponding acid without affecting the rest of the molecule. The procedure is preferably carried out in an inert solvent such as dioxane, in the presence of hydrochloric acid, at the boiling point of the reaction medium.
Reaction- d' is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this, acid to a carboxamide without affecting the rest of. the molecule molecule and'in particular the preferred methods previously described.
The intermediates. 7 may also be obtained by malonic synthesis according to the following reaction scheme: . .. in these formulae, Ms represents a methylsulfonyloxy radical, R3 and R4 have the same ■ meanings as in formula (I)..
. Reaction a is generally carried. out by the. action of diethyl malonate, in an inert solvent such as tetrahydrofuran, in the presence of freshly prepared sodium ethpxide, at the- boiling point of the reaction medium.
Reaction b is generally carried out in an aqueous solution of hydrochloric acid at the boiling point of the reaction medium.
The compounds In may also be obtained according to the following- reaction scheme: HNR13R14 PO(OC2Hs)2-CH2COOH PO(OC2H.)2-CH2CONR13R In .these formulae, R3, R4, R13 and'R14 have the same meanings as in formula (I) .
Step a is carried out by any method' known to .a person skilled in the ■ art ' which makes it possible to " pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest .of the molecule molecule and in particular the preferred methods previously described.
Step b is generally carried out in an inert solvent, such as tetrahydrofuran, . in the presence of a base such as sodium hydride or potassium carbonate, at a temperature of between 20°C and the boiling point of the reaction medium.
The reduction of step c is generally carried ■ out by means of NaBH4, in ethanol, at a temperature in the region of 20°C.
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents a radical -SOR6 or -S02R6 may be prepared according to' the following reaction scheme: In these formulae, R3, R4 and R6 have the same meanings as in formula (I) and Ms is a methylsulfonyloxy radical.
Step a is generally carried out in an inert solvent such as tetrahydrofuran, in the presence of an inorganic base such as sodium hydride, at a temperature .of between 0°C and the boiling point, of the reaction medium.
Step b is generally carried out by any method of persons skilled in .the art for oxidizing a sulfur-containing derivative, such as those described by M. HUDLICKY, Oxidations in Organic Chemistry, ACS Monograph, 186, 252-263' (1990) . For. example, the procedure is carried out by the action of an organic peroxy acid or a salt of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in : particular peroxybenzoic acid, 3-chloroperoxybenzoic acid, 4-nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, peroxyformic acid or. monoperoxyphthalic . acid) or inorganic peracids or a salt of such an acid (for example periodic or persulfuric acid) , in- an inert solvent such as a chlorinated solvent ,(for example chloroform or dichloromethane) ,. at, a temperature of between 0 and 25°C or alternatively by means of oxone in. a water-alcohol (methanol or ethanol) mixture..
Step c is generally carried out by any. method of persons skilled in the art for oxidizing a sulfinyl derivative. Preferably, the procedure is carried, out by the action of an organic peroxy acid or a salt .of such a peroxy acid (peroxycarboxylic or peroxysulfonic acids, in particular peroxybenzo.ic acid, ; 3-chloroperoxybenzoic acid, -nitroperoxybenzoic acid, peroxyacetic acid, trifluoroperoxyacetic acid, . peroxyformic acid or monoperoxyphthalic acid) or . alternatively by. means of oxone, in a water-alcohol (methanol or ethanol) mixture.' The compounds of formula (I) for which R ' represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -COR6 or -CO-cycloalkyl may be prepared according to the following reaction scheme: In these formulae, R3 and R4 have the same meanings as in formula (I) and Rh has the same mean as R6 or represents a cycloalkyl radical (3 to 10 carbon atoms) .
Step a is carried out. by any method known to a person skilled in the art which makes it possible pass from an acid or a reactive derivative of this to a carboxamide without affecting the rest of the molecule molecule and in particular the preferred methods previously described.
Step b is generally carried out in. an inert solvent such as an ether such as tetrahydrofuran, at temperature in the region of O'C. The organomagnesium compounds are prepared according to methods known to person skilled in the art, such as those described in the examples . 151428/2 38 The compounds of formula (I) for which Rx is a hydrogen atom and R2 is a radical -C (OH) (R6K 12) -C (OH) (Re) (alkyl), -C (=NO-CH2-CH=CH2) Rs or -C(=NOalk)R6 may be prepared according to the following reaction scheme: In these formulae, R3, R4 and R6 have the same meanings as in formula (I) , Ri has the same meanings as R12 or represents an alkyl radical (1 to 6 straight- or branched-chain carbon atoms) and Rj represents an alkyl radical (1 to 6 straight- or branched-chain carbon atoms) or -CH2-CH=CH2.
Step a is generally carried out in an inert solvent such as an aliphatic alcohol (for example ethanol) , in the presence of sodium acetate, at a temperature of between 20 °C and the boiling point of the reaction medium.
Step b is generally carried out in an inert . solvent such as an ether such as tetrahydrofuran, at a temperature in the region of 0°C. The organomagnesium compounds are prepared according to methods known to a person skilled in the art such as those described in the examples.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents .a radical -CH (R6) NR3iR32, in whic R3i and R32 are hydrogen atoms or radicals -CH (R6)NHS02alk, -CH (R6) NHCONHalk or -CH (R6) NHCOR31 may be prepared according to the following reaction scheme In these formulae, 'R3, R4/ R6 and R31 have the same meanings as in ^formula (I), Ms represents a methylsulfonyloxy radical and alk represents an alkyl. radical.
Reaction a- is generally carried out by means NaBH in ethanol, at a temperature in the region of 20°C.
Step b is carried out in the presence of triethylamine, in an inert solvent such as an ether (for example tetrahydrofuran) , at a temperature in the region of 0 °C .
Step c is carried out by means of liquid aqueous ammonia in methanol, in an autoclave at a temperature in the region of 60°.
Step d is generally carried out 'in an inert solvent such as a halogenated solvent (for example . dichloromethane) or tetrahydrofuran, in the presence of an organic base such as triethylamine, dimethylaminopyridine, at. a temperature in the region of 20°C. .
Step e is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the rest of the molecule and in particular the preferred methods previously described.
Step f is generally: carried out by. means of an inert solvent such as tetrahydrofuran, dimethylformamide,. a chlorinated solvent (for example chloroform or dichloroethane) , an aromatic solvent (for example benzene or toluene) , at a temperture of between 10°C and the boiling point of the reaction medium.
The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3r.R32, R3i is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical may be prepared by' the action of a halide HalR3i on a compound of formula. (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R~ represents a radical -CH (R6) NR3iR32, R3i and ί½ are hydrogen atoms .
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine) ) , at a . temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R2 represents' a radical -CH (Rg) NR3iR32, R3i is a hydrogen atom and', R32 is an. alkyl radical may also, be prepared by the . action o . a corresponding compound of formula (I) for which R represents a radical CRiR2 in-which Ri is a hydrogen atom and R2 represents a. radical -CO-Re on an amine . HNR3iR32 for which R3i is ' a hydrogen atom and R32 is an alkyl radical.
This reaction is generally carried out in an inert- solvent such as a chlorinated solvent (for example' dichloromethane or dichloroethane ) , in the presence of a reducing agent such as sodium triacetoxyborohydride, at a temperature of -.between 0°C and 70°C.
The compounds of formula (I) for which R represents a- radical CRXR2 in which R'i is a hydrogen atom and R2 represents a radical -CH (R6) NR31R32, R3i arid R32 are. alkyl, Ar or -alk-Ar radicals may be prepared by the action of a halide HalR32 on. a compound of formula (I) for which R represents a radical CRXR2 in which Rx. is a. hydrogen atom and R2 represents a radical -CH (R6) R31R32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical.
This reaction is carried out in an inert polar solvent, such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for 'example triethylamine or dimethylaminopyridine ) ) , at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.' . The compounds of formula (I) for which R represents a. radical CR]R2 in which Ri is a hydrogen atom and R2 represents a radical -CH (Re) NR3iR32, R3i is a hydrogen atom and R32 is a' (2-6C) alkyl or - (2-6C) alk-Ar radical may be prepared by the action of an aldehyde-RaCHO for which Ra .is an alkyl or -alk-Ar radical on a compound of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3:LR32, R3i and R32 are hydrogen atoms'.
This reaction is carried out in an inert solvent such as dichloromethane,, dichloroethane, toluene or tetrahydrofuran, at. a temperature of between 0°C and 50°C in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride . , .
The compounds of formula (I) for which R represents a radical CRiR2 in which Rx is a hydrogen atom and" R2 represents a radical -CH (Re) NR31R32, - R31 is an alkyl, Ar or -alk-Ar" radical and R32 is a (2-6C) alkyl or - (2-6C) alk-Ar radical may be. prepared by the action of an- aldehyde RaCHO. for which Ra is an alkyl. or -alk-Ar radical on a compound of formula (I) for which R represents a radical CRiR2 in which Rx is a hydrogen atom and R2 represents a radical -CH (Rs) NR3iR32, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar- ' radical.
This reaction is carried out in an inert solvent such- as dichloromethane, dichloroethane, toluene or . tetrahydrofuran, at a temperature of between 0°C and 50°C in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride .
' The compounds of formula (I) for which R represents a radical CRiR2 in which Ri is a hydrogen atom and R2 represents a radical -CH (R6) NR3iR32, R3i and R32 form with the -nitrogen atom to which they are attached a heterocycle chosen from aziridinyl, azetidinyl, pyrrolidihyl or piperidinyl may be prepared •by the action of a' dihalide Hal- ( 2-5C) alk-Hal on a compound of formula (I) for which R represents a radical CR1R2 in which Ri is a hydrogen atom and R? represents a radical -CH (R6) NR31R32 , R31 and R32 are 5 hydrogen atoms This reaction is carried out in an inert polar solvent such as .acetonitrile, tetrahydrofuran or dimethylformamide , in the presence of an organic or ■ inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine) ) , at a temperature of between 0°C and the. boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes. •1:5 The compounds of formula (I) for which R represents a radical CR1R2 in which Ri ' is a hydrogen atom and R2. represents a . radical " -CH2-COR6, -CH2-CH (R6) -NR31R32 or -CH2-C (=NOalk) R6 may be prepared according to the following reaction scheme: d R.MgBr R HNR3,R.
In these formulae, R3, R4, R6, R31 and R32 have the same meanings as in formula (I) and alk represents an alkyl radical.
Step a is generally carried out in a solvent such as tetrahydrofiiran, at a temperature of .between 20 °C and the boiling point of the reaction medium.
Step b is generally carried out in an inert solvent such as .an aliphatic alcohol (for example methanol) , a chlorinated solvent (chloroform or dichloromethane) oir a mixture of these, solvents, in the presence of a reducing agent such as NaBH4, at a temperature of' between 0°C and the boiling point of the reaction medium.
Step c is carried out by any method known to a person skilled in the art which makes it possible to pass from an acid or a reactive derivative of this acid to a carboxamide without affecting the .rest of the molecule and in particular the preferred methods previously described.
Step d is generally carried out in an inert solvent such as -an ether such as tetrahydrofuran, at a temperature- in the region of 0°C. The organomagnesium compounds are prepared according to the m' yhodes known to a person skilled in the art such' as those described in the · examples .
Step e is generally carried out in an inert solvent such as a 1-4C aliphatic alcohol such as methanol, in the presence of sodium acetate, at a temperature of between 20°C and the boiling point of the reaction medium.
Step f is carried out in an inert solvent such as a chlorinated solvent (for example dichloromethane or dichloroethane) , in the presence of .a reducing agent such as sodium triacetoxyborohydride, at . a temperature of between 0°C and 70°C.
The compounds of formula (I). for which R represents a radical CR1R2 in which RL represents a cyano, -S-alk-NRisR.?/ -NHR15 , alkyl or -NR20R21 radical and R? represents a radical -C(R8) (Ru) (R12) in which Rs is a hydrogen atom may be prepared according to the following reaction scheme: - In these formulae, R3, R4, Ru, R12., R15, Ris and Ri7 have the same meanings as in formula (I), alk represents an alkyl radical, Hal represents a halogen atom and M represents a metal and preferably copper.
Step a i's preferably carried out in a polar solvent such as dimethyl sulfoxide, at a temperature of between 20 and 50°C.; Step b is preferably carried out in an inert solvent such- as dimethyl sulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20°C and the boiling point of the reaction medium.
Step c is preferably carried out in an inert solvent such as dimethyl sulfoxide, tetrahydrofuran or acetonitrile, in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20°C and the boiling point of the reaction medium.
Step d is preferably carried out in an inert solvent such as an ether (ethyl ether) or ■ tetrahydrofuran, at a temperature of between -78 °C and 20°C.
Step e- is preferably carried out in an inert solvent such as dimethyl, sulfoxide, tetrahydrofuran, acetonitrile, dichloromethane or dichloroethane . in the presence of a base such as an alkali metal carbonate (for example potassium carbonate) or ammonium hydroxide, at a temperature of between 20°C and the boiling point of the reaction medium.
The compounds of formula (I) for which R ■ represents a radical CRiR2 in which Ri represents a radical -alk-NRiaRi9, Ris and R19 represent a., hydrogen atom may be prepared, by reducing the corresponding compound of formula (I) for which R represents a radical CRiR2 in which Ri represents a cyano radical.
This reaction is generally carried out in an inert solvent such as tetrahydrofuran, ethyl ether or toluene, at a temperature of between 0°C and the boiling point, of the reaction medium, in the presence of a reducing agent such as aluminum hydride .
The compounds of formula (I) for which R represents a radical CR1R2 in which Ri represents a .radical .-alk-NRisRig; Ria. represents a hydrogen atom and R19 represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical may be prepared by. the action of a halide HalRig, Hal represents a halogen, . on a compound of. formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Rj.9 , Ris and R19 represent a hydrogen atom. . ■ This reaction is carried out in an inert polar ■solvent such as acetonitrile-, tetrahydrofuran or dimethylformamide , in the presence of an organic or inorganic base (alkali metal (for. example sodium or potassium) carbonate, trialkylamine (for example . triethylamine or dimethylaminopyridine)' ) , at a temperature of between 0°C and. the boiling point of the solvent, optionally in the presence of palladium or one of its salts or complexes.
The compounds of formula (I) for which R represents a radical ' CRiR2 in which Ri represents a radical -alk-NRiaRi9 , Ris represents an alkyl radical and Ri9 represents an alkyl, cycloalkyl, cycloalkylalkyl , cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical may be prepared by the action of .an alkyl halide on a compound of formula (I) for which R represents a radical CRiR2 in which Ri represents a radical -alk-NRi8Ri9, Ri8 represents a hydrogen atom and Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02alk, -CO-NHalk or -COOalk radical . . ..
This reaction is carried out in an inert polar solvent such as acetonitrile, tetrahydrofuran or dimethylformamide, in the presence of an organic or inorganic base (alkali metal (for example sodium or potassium) carbonate, trialkylamine (for example triethylamine or dimethylaminopyridine) ) , at a temperature of between 0°C and the boiling point of the solvent, optionally in the presence of palladium, or one' of its salts or complexes.
The compounds of formula (I.) for which R represents a radical CRiR2 in which either Rx represents a hydrogen atom and R2 represents a radical •-C(R8) (Rg) (Rio) or -C(R8.) (Rn) (Ri2) , or Ri represents an alkyl, NH-R15, cyano, -S-alk-NRiSRi7, -alk-NRi8Ri9 or -NR20R2i radical , and R2 represents a radical -C(R8) (Rn) (Ri2) and R8 represents an alkyl radical may be prepared by alkylation of a corresponding compound of formula (I)· for which R8 is a hydrogen atom.
This reaction is- preferably carried out by means of a base such as an alkali metal hydride (for example sodium hydride), an alkali metal amide (for example sodium amide) or an organometallic derivative, in an inert solvent such as an aliphatic ether (ethyl ether) or tetrahydrofuran,. at a temperature of between -78 °C and 30°C, by means of an alkylating agent such as an alkyl halide or an alkyl sulfonate.
The compounds of formula (I) for which R represents a radical C=C (R7) S02alk may also be prepared according to the following reaction scheme: In these formulae, R3, R4 and R7 have the same meanings as in formula (I), alk represents an alkyl radical and Hal represents a halogen atom.
Reaction A is generally carried out in an inert solvent such as an ether (for example ethyl ether) , in the presence of a strong base such as tert-butyllithium or n-butyllithium, ' at a temperature of. between -70°C and -50 °C, followed by the addition of sulfur and then an alkyl halide (for example iodide or .bromide) .
Reaction B is generally carried out in an inert solvent such as an ether (for. example tetrahydrofuran ) , in the presence, of a strong base such as t.ert-butyllithium or n-butyllithium, at a temperature of between- -70°C and -50°C, followed by the addition of azeditin-3-one, a return to room temperature and hydrolysis .
Reaction C is carried out by any known method which makes it possible to oxidize a sulfur-containing derivative . without affecting the rest of the molecule, such as those previously described.
It . is understood for persons skilled in the art that, to carry out the processes according to .the invention which are described above, it may. be necessary to introduce groups protecting amino, hydroxyl and carboxyl functions in order to- avoid side reactions. These groups are those which allow, removal without affecting the rest of the molecule. As examples of groups protecting the amino function, there may be mentioned tert-butyl or methyl carbamates which may be regenerated using iodotrimethylsilane or allyl using palladium catalysts. As examples of. groups protecting' the hydroxyl function,, there may be mentioned triethylsilyl and tert-butyldimethylsilyl which may be regenerated using tetrabutylammonium fluoride or alternatively asymmetric acetals . (methoxymethyl or tetrahydropyranyl for example) with regeneration using hydrochloric acid. As groups protecting carboxyl functions, there may be mentioned esters (ailyl or benzyl for example), oxazoles and 2-alkyl-l,3- oxazolines. Other protecting groups which can be used are described by GREENE T . W . et al., Protecting Groups ' in Organic Synthesis, second edition, 1991, John Wiley & Sons.
The compounds of formula (I) may be purified by the customary known methods, for example by crystallization, chromatography or extraction.
The enantiomers of. the compounds of formula .(I) may be obtained by resolution of . the racemates for example by chromatography on a chiral column . according to PIRCKLE W.H. et al ., Asymmetric synthesis ,. Vol . 1, - Academic Press (1983) or by formation of salts or by synthesis from chiral precursors. The diastereoisomers may be prepared according to known conventional methods (crystallization, chromatography or from chiral' precursors ) .
The compounds of formula (I) may be optionally converted to addition salts with an inorganic or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a · chlorinated solvent. These salts also form part of the invention.
As examples of pharmaceutically acceptable salts, the following salts may be mentioned: benzenesulfonate, hydrobromide , hydrochloride, citrate, ethanesulfonate, fumarate, gluconate, iodate, isethionate , · maleate, methane sulfonate, methylene-bis- -oxyhaphthoate , nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllineacetate and p-toluenesulfonate .
The compounds of formula (I) exhibit advantageous pharmacological , properties . These compounds possess a high affinity for the cannabinoid receptors and particularly those of the CBl type. hey are CBl receptor antagonists and are therefore useful in the treatment and prevention of disorders affecting the central nervous system, the immune system, the cardiovascular or endocrine system, the respiratory system, the gastrointestinal apparatus and reproductive ■ disorders (Hollister, Pharm. Rev.; 38, 1986, 1-20, Reny and Sinha, Prog. Drug Res., 36, 71-114 (1991), Consroe and Sandyk, in Marij uana/Cahniabinoids , Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds, CRC ■ Press, 1992) .
Accordingly, these compounds may be used for .. the treatment or prevention of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders, cognitive disorders, cranial trauma, panic . ·. attacks, peripheral neuropathies, glaucomas, migraine, Parkinson ' s..disease, Alzheimer's disease, Huntington's , chorea, Raynaud's syndrome, tremor, obsessive-compulsive disorder, senile dementia, thymic disorders, Tourette ' s ' syndrome, tardive dyskinesia, bipolar disorders , ' cancers , movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting., asthma, appetite disorders (bulimia, anorexia) , obesity, memory disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, ■ phencyclide, hallucinogens, benzodiazepines for. example) , ■ as analgesics or' potentiators of the analgesic activity of the narcotic and nonnarcotic drugs. They ma also' be used for the treatment or prevention of intestinal, transit.
The affinity1 of the compounds of formula (I) for .the cannabis receptors has been determined according to the method described by KUSTER J.E., STEVENSON J.I.., WARD S.J., D ' AMBRA T . E ., HAYCOCK D ..A . in J. Pharmacol. Exp. Ther., 2_64 1352-1363 (1993) .
In this test, the IC50 of the compounds of formula (I) is less than or equal to 1000 -nM.
Their antagonist activity has been shown by means of the model of hypothermia induced by an agonist of the cannabis receptors (CP-55940) in mice, according- to the method described' by Pertwee R.G. in Marijuana, Harvey D.J. eds, 84 Oxford IRL Press, 263-277 (1985) .
In this test, the DE50 of the compounds of formula (I) is less than or equal to 50 mg/kg.
The compounds of formula (I) exhibit low toxicity. Their LD5o is greater than 40 mg/kg by the subcutaneous route in mice.
The preferred compounds of formula (I) are the following: (RS) -1- [bis ( 4 -chlorophenyl) methyl) ] -3- [ ( 3 , 5-difluorophenyl) (methylsulfonyl) methyl] azetidine, ' (R) -l-[bis (4-chlorophenyl)methyl) ]-3-[ ( 3 , 5-difluoro-phenyl) (methylsulfonyl) methyl] azetidine, (S) -1- [bis (4 -chlorophenyl) methyl) ] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) methyl] azetidine, (RS) -1- [bis (4-chlorophenyi) methyl) ] -3- [ (pyrid-3-yl) - (methylsulfonyl) methyl] azetidine, (R)--l- [bis (4-chlorophenyl) methyl) ] -3- [ (pyrid-3-yl) -(methylsulfonyl) methyl] azetidine, .
( S) -1- [bis ( 4-chlorophenyl) methyl) ] -3- [ (pyrid-3-yl) -(methylsulfonyl) methyl] azetidine, (RS) -l-[bis (3-fluorophenyl) methyl] -3--[ (.3 , 5-difluoro-phenyl) methylsulfonylmethyl ] azetidine, (R) -1- [bis (3-fluorophenyl) methyl] -3- [ ( 3 , 5-difluoro-phenyl) methylsulfonylmethyl ] azetidine, 53 (S) -1- [bis (3-fluorophenyl) methyl] -3- [ ( 3 , 5-difluoro- phenyl ) methylsulfonylmethyl ] azetidine , 1- [bis ( 4 -chlorophenyl) methyl] -3- (RS) -·{ [ 3-azetidin-l-yl phenyl] methylsulfonylmethyl } azetidine, l-[bis (4 -chlorophenyl Vmethyl] -3- (R) -{ [3-azetidin-l-yl-phenyl] methylsulfonylmethyl } azetidine, 1- [bis.(4-chlorophenyl)methyl] -3- (S) - { [3-azetidin-l-yl-phenyl ] methylsulfonylmethyl } azetidine , (RS) -1- [3 ( { 1- [bis (4 -chlorophenyl) methyl] azetidin-3-yl } methylsulfonylmethyl ).phenyl] pyrrolidine, (R) -1- [3- ( {1- [bis (4 -chlorophenyl ) methyl] azetidin-3-yl } methylsulfonylmethyl ) phenyl] pyrrolidine, (S) -1- [3- ( {1- [bis (4-chlorophenyl)methyl] azetidin-3-yl } methylsulfonylmethyl ) phenyl] pyrrolidine, (RS) -N-[3-( {l-[bis ('4 -chlorophenyl ) methyl ] azetidin-3-yl } methylsulfonylmethyl) phenyl] -N-methylamine, (R) -N- [3- ( { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -methylsulfonylmethyl) phenyl] -N-methylamine, (S.) -N- [3- ( { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl} methylsulfonylmethyl) phenyl] -N-methylamine, (RS) -1- [bis (4-chlorophenyl) methyl] -3- [ (3, 5-bistri- fluoromethylphenyl) methylsulfonylmethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3- [ ( 3 , 5-difluoro- phenyl) methylsulfonylmethyl] -3-methyl-azetidine, (RS) -2-{l-[bis ( 4-chlorophenyl ) methyl ] azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-cyclohexylacetamide, (R) -2-{l- [bis (4-chlorophenyl)methyl] azeditin-3-yl } -2- (3, 5-difluorophenyl) -N-cyclohexylacetamide, (S) -2- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -2 (3, 5-difluorophenyl ) -N-cyclohexylacetamide ,.
(RS) -2-{l- [bis (4-chlor'ophenyl)methyl]azetidin-3-yl}-2- (3, 5-difluorophenyl ) -N-isobutylacetamide, (R)-2-{l-[bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2 i (3, 5-difluorophenyl) -N-isobutylacetamide, (S) -2-{l- [bis (4-chlorophenyl)methyl] azetidin-3-yl } -2 (3, 5-difluorophenyl) -N-isobutylacetamide, (RS) -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -(3, 5-difluorophenyl) -N-cyclopropylmethylacetamide , (R)-2-{l-[bis ( 4-chlorophenyl) methyl ] azetidin-3-yl } -2 ( 3 , 5-difluorophenyl) -N-cyclopropylmethylacetamide, (S)-2-{l-bis (4-chlorophenyl) methyl] azetidin-3-yl } -2 -(3, 5-difluorophenyl ) -N-cyclopropylmethylacetamide, (RS) -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -(3, 5-difluorophenyl ) -N-isopropylacetamide , ( R). -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2 ( ,.5-difluorophenyl) -N-isopropylacetamide, (S) -2-{ 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2-■ (3, 5-difluorophenyl) -N-isopropylacetamide, (RS) -1- [bis (4-chlorophenyl) methyl] -3- [ 1- ( 3 , 5-difluoro- phenyl ) -1-methylsulfonylethyl ] azetidine, (R) -1- [bis (4-chlorophenyl) methyl] -3- [ 1- ( 3 , 5-difluorophenyl) -1-methylsulfonylethyl] azetidine, (S) -1- [bis (4-chlorophenyl) methyl] -3- [1- (3, 5-difluoro- phenyl) -1-methyls.ulfonylethyl] azetidine, (RS) -1- [bis (4-fluorophenyl) methyl] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl] azetidine, ' . .. .· ' (R) -1- [bis ( 4-fluorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine, (S) -1- [b'is ( 4-fluorophenyl) methyl] -3- [ (.3, 5-difluoro- phenyl) methylsulfonylmethyl] azetidine,. ' .
(RS) -{1- [ (3-pyridyl) - ( 4-chlorophenyl ) methyl] -3- [ (3,5- difluorophenyl ) methylsulfonylmethyl ] azetidine, (SS)-{ 1- [ (3-pyridyl) - ( 4 -chlorophenyl ) methyl ] -3- [(3,5- difluorophenyl) methylsulfonylmethyl] azetidine/ (RR) -{ 1- [ (3-pyridyl) - (4-chlorophenyl) methyl] -3- [(3,5- difluorophenyl ) methylsulfonylmethyl ] azetidine, (SR) - {1- [ (3-pyridyl) - ( 4-chlorophenyl ) methyl] -3- [ (3, 5 difluorophenyl) methylsulfonylmethyl] azetidine, (RS) -{l-[ (4-pyridyl) - (4-chlorophenyl) methyl ].-3- [ (3,5 difluorophenyl ) methylsulfonylmethyl] azetidine, (SS) -{ 1- [ (4-pyridyl) - ( 4-chlorophenyl ) methyl ] -3- [(3,5 difluorophenyl) methylsulfonylmethyl] azetidine, - ' (RR) -{1- [ (4-pyridyl) - ( 4-chlorophenyl ) methyl ] -3- [(3,5 difluorophenyl ) methylsulfonylmethyl] azetidine, (SR) -{l-[ (4-pyridyl) - ( 4 -chlorophenyl ) methyl ] -3- [ (.3,5 difluorophenyl) methylsulfonylmethyl] azetidine, i (RS) -5- ( (4-chlorophenyl) -{3-[ ('3 , 5-difluorophenyl ) -methylsulfonylmethyl] azetidin-l-yl }methyl) pyrimidine, (SR) -5- ( (4-chlorophenyl) -{3- [ (3, 5-difluorophenyl) -methylsulfonylmethyl] azetidin-l-yl }methyl ) pyrimidine, (RR) -5- ( (4-chlorophenyl) -{3-[ ( 3 , 5-difluorophenyl ) -methylsulfonylmethyl] azetidin-l-yl j.methyl) pyrimidine, (SS) -5- ( (4-chlorophenyl) - ( 3- [ (3, 5-difluorophenyl ) -methylsulfonylmethyl] azetidin-l-yl } methyl ) pyrimidine, (SS) -{ 1- [ (2-chloropyrid-5-yl) - ( 4 -chlor.ophenyl ) methyl ] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine, ( RR) - { 1- [ ( 2-chloropyrid-5-yl ) - ( 4-chlorophenyl )-methyl ] - 3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidine, . (.RS) -{IT- [ (2-chloropyrid-5-yl) - (-4 -chlorophenyl ) methyl ] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine, (SR) -{1- [ (2-chloropyrid-5-yl).- ( 4-chlorophenyl) methyl] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine, their optical isomers and their pharmaceutically acceptable salts .
The following ' examples illustrate the invention .
Example 1 ( RS ) -1- [Bis ( 4-chlorophenyl ) methyl]' -3- [ ( 3 , 5-di- fluorophenyl)' (methylsulfonylmethyl] azetidin may be prepared from- 1.0 g of 1- [bis ( -chlorophenyl ) methyl )] - 3- [ ( 3 , 5-difluorophenyl) (methylsulfonyl ) methylene ] - azetidine in 40 cm3 of methanol, 96 mg of sodium borohydride are added and the mixture is stirred for- 3. hours at 20°C. After, addition of 100 cm3 of dichloromethane, the reaction, mixture is washed twice with 50 cm3 of water" and dried over magnesium sulfate, - filtered and concentrated to dryness under-.reduced pressure (2.7 kPa) . The crude product is chromatographed on' a silica gel column, (particle size 0.063-0.200 mm, height 6 cm, diameter 3- cm), eluting under an argon pressure of 0.8 bar with dichloromethane and then the mixture dichloromethane + 1% methanol and collecting 80-cm3 fractions-. Fractions 13 to 15 are combined and concentrated- to dryness under reduced pressure (2.7 kPa) . 0.55 g of a white solid is obtained which is taken up in 50 cm3 of diisopropyl ether, filtered and dried to give 0.47 g of (RS) -1- [bis ( 4-chlorophenyl ) methyl) ] -3- [ (3, 5-difluorophenyl) (methyl-sulfonyl) methyl] azetidine in the form of a white solid [ Η NMR spectrum (400 MHz, (CD3)2SO d6 with addition of. a few. drops, of CD3COOD d4, at a .temperature of 353 K, δ in ppm) : 2.46 (t J = 7.5 Hz : 1H) ; 2.77 (s : 3H) ; 3.15 (mt : 2H) ; 3.40 (mt : .1H); 3.49 (broad t,- J = 7.5 -Hz : 1H) ; 4.46 (s : ■ 1H) ; 4.81 (d, J = 9 Hz : 1H) ; from 7.05 to 7.20 (mt : 3H) ; from -7.15 to 7.45 (mt : ' 8H) ] . 1- [Bis (4 -chlorophenyl) methyl )] -3- ['(3, 5-difluoro- . phenyl) (methylsulfonyl)methylene] azetidine may be prepared according to two methods : Method 1- ' 0.65 cm3 of methylsulfonyl chloride, is added to a solution, of 2.94 g of 1- [bis (4-chlorophenyl)methyl] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS) ] -azetidin-3-ol in 250 cm3 of dichloromethane at 22°C, followed, in small portions over 15 minutes by 2.42 g of 4-dimethylaminopyridine; the orange-colored solution is stirred for 2 hours at room temperature. The reaction mixture is washed 3 times with 150 cm3 of distilled water and once with 150 cmJ of a saturated' sodium chloride solution,, then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is chromatographed on a silica gel column (particle size' 0.04-0.06 mm, diameter 5.5 cm, height 15 cm), under an argon pressure of 0.5 , bar with- a mixture of ethyl acetate and cyclohexane (1/9 by volume) as eluent and collecting 70-cm3 fractions. Fractions 15 to 36 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 1.86 g of a white foam are obtained, which foam is crystallized from isopropyl ether to give a solid melting at 190°C Recrystallization from 45 cm3.of ethanol gives 1.08 g of 1- [Bis ( 4-chlorophenyl) methyl] -3- [ (3 , 5-difluoro-phenyl) (methylsulfonyl) methylene] azetidine, melting at . 206°C [NMR spectrum in D SO-d6, T=300K, δ in ppm (300 MHz) : 3.00 (3H,s, SCH3) , 3.87 (2H, s, NCH2) , 4.20 (2H, s, NCH2), 4.75 (1H,. s, NCH) , 7.15 (2H, d, J=8Hz, 2CH arom.), 7.30 (5H, m, 5CH arom.), 7.45 (4H, d, J=7Hz, 4CH arom. ) ] . 6.75 g of 3- [(3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS) ] azetidin-3-ol hydrochloride are added to a solution of 6.8. g of bis ( 4-chlorophenyl ) -bromomethane in 300 cm3 of acetonitrile , followed by 2.97 g of potassium carbonate. The reaction mixture is heated for 1 hour under reflux, cooled to -room temperature, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is chromatographed on a silica gel . column (particle size 0.04-0.06 mm, diameter 8.5 cm, height 22 cm), under. an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) as eluent and collecting .250-cm3 fractions. Fractions 11 to 48 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 5.3 g of 1- [bis (4-chlorophenyl) -methyl] -3- [ (3, 5-difluorophenyl) methylsulfonyl ) methyl- (RS) ] azetidin-3-ol are obtained. [XH NMR spectrum (300 MHz, (CD3)2SO d6,. δ in ppm) : 2.00 (s : 3H); 2.94 (s :. 3H) ; 3.25 (mt : 2H) ; 3.48 (d, J = 9Hz : 1H) ; 3.80 (d, J = 9 Hz : 1H); 4.54 (s : 1Ή) ; 5.34 (s : 1H) ; 7.15 ■ (d, J = 8.5 Hz : 2H) ; from 7.20 to 7.40 (mt :. 8H) ; 7.50 (broad t, J = 9 Kz : 1H) ] .
Bis ( 4-chlorophenyl) bromomethane may be prepared according to the procedure, described. by BACHMANN W.E., . J. Am. Chem. Soc, 2135 (1933)'. 3- [(3, 5-Difluorophenyl) methylsulfonyl) methy1-(RS) ] azetidin-3-ol hydrochloride may be obtained in the '-following manner: 160 cm3 of a 6.2 . hydrochloric acid solution -in . dioxane are added to a solution of 37 g of 3- [ (3, 5-difluorophenyl) (methylsulfonyl ) methyl- (RS) ] -1-(vinyloxycarbonyl ) azetidin-3-ol in 160 cm3 of dioxane. After 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is taken up in · 320 cm3 of ethanol, heated for 1 hour under, reflux and cooled on an ice-cold' bath . The solid which appears is" filtered, washed with ethyl ether and dried at 40°C under reduced pressure (2.7 kPa) . 29.85 g of white crystals are obtained whose melting point is greater than 260°C. 3- [ (3, 5-Difluorophenyl) (methylsulfonyl ) methyl- (RS) ] -1- ( xnyloxycarbonyl) azetidin-3-ol may be obtained in the following manner: a solution of 14 cm3 of vinyl chloroformate in 35 cm3 of dichloromethane is added at 5°C -to a solution, of 60.18 g of l-benzhydryl-3-r .[ ( 3 , 5-difluorophenyl ) (methylsulfonyl ) methyl- (RS )] azetidin-3-ol in 100 cm3 of dichloromethane. After 20 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is chromatographed on a silica gel' column, (particle size" 0.04-0.06 mm, diameter 11 cm, height 32 cm), under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (3/7 by · volume) as eluent and collecting 1000-cm3 fractions. Fractions 8 to 18 are, combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 37 g of 3-[ (3, 5-difluorophenyl) (methylsulfonyl ) methyl- (RS) ] -1- . ( vxnyloxycarbonyl ) azetidin.-3-ol are obtained in the form of white crystals melting at 195°C. l-Benzhydryl-3- [ (3, 5-difluorophen.yl) (methyl-sulfonyl) methyl- (RS) ] azetidin-3-ol may be obtained in the following manner: 29.5 cm3 of 1.6 N n-butyllithium in solution in hexane are added to a solution of 6.73 cm3 of diisopropylamine in 110 cm3 of tetrahydrofuran, under an argon atmosphere, cooled to -70°C. After 30 minutes, a mixture of .8.7 g of 3 , 5-difluorobenzyl methyl sulfone in 200 cm3 of tetrahydrofuran is then added and the stirring is maintained for 45 minutes at -70°C. 10 g of l-benzhydrylazetidin-3-one dissolved in 60 cm3 of tetrahydrofuran are added and then the medium is stirred for 20 minutes while allowing the mixture to return to room temperature. The reaction mixture is hydrolyzed with 400 cm3 of a saturated ammonium, chloride solution, extracted with dichloromethane, washed 3 times with 500 cm3 of water and then a' saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) . The residue (19 g) is taken up in isopropyl ether from. which it crystallizes. After filtration and drying, 15.35 g of l-benzhydryl-3- [ ( 3 , 5-difluor'o-phenyl) (methylsulfonyl ) methyl- (RS )] azetidin-3-ol are obtained in the form of white crystals. l-Benzhydrylazetidin-3-one may be prepared ' according to the procedure described by KATRITZKY A.R. et al. in J. Heterocycl. Chem., 271 (1994). 3 ,5-Difluorobenzyl methyl sulfone may be. prepared in the following manner: starting with 33.46 g of 3 , 5-difluorobenzyl methyl sulfide in 318 cm3 of . water,.318 cm3 of acetic acid and 318 cm3 of ethanol, 129.9 g of oxone are: added at 5°C. After 16 hours at room temperature, the reaction mixture is diluted with dichloromethane, washed with water and with a. saturated sodium chloride solution, dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . 35.57 g of 3 , 5-difluorobenzyl methyl sulfone are obtained in the form of white crystals, m.p. = 135°C. 3 , 5-Difluorobenzyl methyl sulfide may be prepared in the following manner: starting with 40 g of 3 , 5-difluorobenzyl bromide and 16.25 g of sodium methyl thiolate in DMF at 60°C, 33.46 g of 3 , 5-difluorobenzyl methyl sulfide are obtained after treatment in the form of a yellow oil.
Method 2 0.80 g of crushed sodium hydroxide is added to a solution of 2.2 g of 3-acetoxy-l- [bis (4-chloro- phenyl) methyl ].—3- [ ( 3 , 5-difluorophenyl ) (methylsulfonyl) - methyl- (RS) ] azetidine in 25 cm3 of dioxane at room temperature. After 16 hours at room temperature, 50 cm .of water and 100 cm3 of ethyl acetate are added. The mixture is separated after settling, the organic- phase washed again with 100 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . A white foam is obtained which is crystallized from isopropyl ether to give 0.85 g of a solid melting at 190°C.
Crystallization from 20 cm3 of ethanol gives 0.70 g of 1- [bis ( 4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) - (methylsulfonyl) methylene] azetidine melting at 205°C. 14 cm3 of a 1.6 N solution of n-butyllithium in • hexane are added at -70°C to a solution of 4.77 g of ( 3 ,.5-difluorobenzyl ) methyl sulfone in .70 cm3 of tetrahydrofuran under an argon. atmosphere . After 1 hour at -70°C, a solution of 6.8 g of 1- [bis ( 4-chloro-phenyl) methyl] azetidin-3-one' in 30 cm3 of tetrahydrofuran is added, followed 1 hour later by a solution of -2.34 cm3 of acetyl chloride in 20 cm3 of tetrahydrofuran and the temperature of the reaction mixture is increased to 20°C for 1 hour. 50 cm3 of water and 200 cm3 of ethyl acetate are added. The mixture is separated after settling, the organic phase is washed with 100 cm3 of water, 100 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . 14.4 g of 3-acetoxy-l- [bis ( 4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl.) (methyl-sulfo yl) methylsulfonylmethyl- (RS) ] azetidine are/ obtained in the form of a yellow oil [1H NMR spectrum (400 MHz, CDCI3, δ in ppm) : 2.79. (s .: 3H) ; 3.04 (AB, J = 9 Hz :. 2H) ; 3.27 (d, J = 9 Hz : 1H) 3.45 C.s : 1H) ; 3.81 (d, J = 9 Hz : 1Ή) ; 4.32 (s : 1H); 4.49 (s : 1H) ; 6.88 (tt, J = 9 and 2.5 Hz); from 7.20 to 7.35 (mt : 10H) ] . 1- [Bis (4-chlorophenyl)methyl] azetidin-3-one may be prepared according to- the following procedure: a solution of 8.1 cm3 dimethylsulfoxide in 17.6 cm3 of dichloromethane ' is added to a solution of 5.0 cm3 of oxalyl chloride in .73 cm3 of dichloromethane cooled to -78°C. After 0.5 hour at -78°C, a solution-, of 16.0 g of 1- [bis ( 4-chlorophenyl) methyl ] azetidin-3-ol dissolved in 50 cm3 of dichloromethane is poured in.. After 5 hours at -78°C, 26.6 cm3 of triethylamine are added dropwise and the reaction mixture is allowed to return to room temperature. After 16. hours, the reaction mixture is .washed with 4 times 200 cm3 of water and then with 200 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced, pressure (2.7 kPa) . The residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter' 9.2 cm, height 21 cm), under an. argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (40/60 by volume) as eluent and collecting 200-cm3 fractions. Fractions 15 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 8.9. g of 1-bis (4-chlorophenyl) methyl] azetidin-3-one are obtained in the form of pale yellow crystals melting at.lll°C. 1- [Bis ( -chlorophenyl) methyl] azetidin-3-ol may be prepared according- to the procedure described by KATRITZ Y A.R. et al . , J. Heterocycl. Chem . , (1994 ) , 271 starting with 35.5 g of [bis ( 4-chlorophenyl ) -methyl] amine hydrochloride and 11.0 cm3 of epichlorohydrin . 9.0 g of 1- [bis ( 4-chlorophenyl) -methyl] azetidin-3-ol are isolated. ■ ■ [Bis ( 4-chlorophenyl) methyl] amine hydrochloride may be prepared according to the method described by " GRISAR M. et al . , J. ^Med. Chem., 885 (1973) .
Example 2 (-) -1- [Bis'( 4 -chlorophenyl) methyl) ] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) methyl] azetidine and (+) -1- [bis (4-chlorophenyl)methyl) ] -3- [ (3, 5-difluoro-phenyl) (methylsulfonyl) methyl] azetidine may be prepared by CLHP separation on a CHIRALPAK AS chiral column (particle size 20 um, height 23 cm, diameter 6 cm) of 0..52 g of the racemate prepared in Example 1./ By eluting with the heptane/ethanol (90/10) mixture at a flow rate of 80 cmVmin. and after having concentrated the collected fractions to' dryness under reduced pressure (2.7 kPa), there are obtained 110 mg of (-) -1- [bis ( -chlorophenyl) methyl) ] -3- [ (3 , 5-difluorophenyl ) (methylsulfonyl ) methyl] azetidine [aD] = 6.3° (C = 0.5. M in methanol) in the form of a white solid melting at 178°C and 134 mg of ( + ) -1- [bis .( 4-chloro-phenyl) methyl) ] -3- [ (3, 5-difluorophenyl) (methylsulfonyl ) methyl ] azetidine [aD] = +5.8° (C = 0.5 M' in methanol) in the form' of a white solid melting at 178°C.
Example 3 The mixture of the 2 A diastereoisomer forms 1- [4- [ (R*) - (4-chlorophenyl) -{3- [3 , 5-difluorophenyl.) -methylsulfonylmethyl- (R) ] azetidin-L-yl }methyl] benzyl]- -pyrrolidine and 1- [4- [ (R*) - (4-chlorophenyl) -{3- [ (3, 5-difluorophenyl) methylsulfonylmethyl- (S) ] azetidin-1-yl Imethyl] benzyl] pyrrolidone may be prepared by carrying out the procedure in the following manner: 20 mg of sodium borohydride are added to absolution of 60 mg of 1- (R*) - [4- (4-chlorophenyl) -( 3- [ (3, 5-difluoro- phenyl ) methylsulfohylmethylene] azetidin-l-yl } methyl ) - benzyl] pyrrolidone, A: isomer form, in.2 cm3 of ethanol and 2 cm3 of dichloromethane . After stirring for hours at 20°'C, 0.25 cm3 of- water and 20 cm3 of dichloromethane are added and the mixture is stirred and dried over magnesium sulfate and then filtered and' concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm) , eluting under an argon pressure of 0.1 bar with dichloromethane and then with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 5-cm3 fractions. Fractions 13 to 18 are combined and concentrated to dryness under reduced pressure ,( 2.7 kPa) . 38 mg of the mixture of the 2 A diastereoisomer forms 1- [ 4- [ ( R* ) - ( 4-chlorophenyl) - { 3- [ (3, 5-difluorophenyl)'methylsulfonylmethyl- (R) ] azetidin- l-yl }methyl] benzyl] pyrrolidine and 1- [4- [ (R*) - (4- · - chlorophenyl) -{ 3- [( 3, 5-difluor©phenyl) methylsulfonyl- methyl- (S) ] azetidin-l-yl }methyl ] benzyl ] pyrrolidine are obtained in the form of a white foam [XH N R- spectrum (400 MHz, CDC13, δ in.ppm) : 1.77- (mt : 4H) ; from 2.40 to 2.60 (mt :5H); 2.67 (s : 3H) ; from 3.10 to 3.25 (mt : 2H)'; 3.38 (mt : 1H) ; from 3.50 to 3.70 (mt : 3H) ; 4.24 (s. : 1H)-; 4.25 (d, J = 11 Hz : 1H) ; 6.83' (broad t, J = 9 Hz : 1H) ; 6.94 (mt : 2H) from 7.10 to 7.35 (mt : 8H) ] . 1- (R*) - [4- (4 -Chlorophenyl) - { 3- [ ( 3 , -difluoro- phenyl) methylsulfonylmethylene] azetidin-l-yl }methyl) - benzyl ] pyrrolidine , A isomer form, may. be prepared by carrying out the procedure in the following manner: 50 mm3 of pyrrolidine are added to a solution of 0.32 g of 1- { (R*) -'[4- (chloromethyl) phenyl] -( 4-chlorophenyl) - methyl } -3- [ (3, 5-difluorophenyl) methylsulfonylmethylene] azetidine,. A isomer form, -and 5 mg of sodium iodide in- 10 cm3 of .dichloromethane. After stirring for 20 hours at 20°C,- 50 mm3 of pyrrolidine are added to the mixture, the mixture is. stirred for 8 hours- and ' - then 50 mm3 of pyrrolidine are again added and the mixture is stirred for 20 hours at 20°C. The reaction mixture is washed with water and then the organic phase is dried over magnesium sulfate and concentrated to dryness under vacuum (2.7 kPa) . The residue obtained is ' chromatographe.d on a silica gel column (particle s.ize 0.06-0.200 mm, diameter 1.2 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with dichloromethane .and then with a dichloromethane and methanol (97.5/2.5. by volume) ..mixture and collecting 3-cm3' fractions..
'· Fractions 12 to 40 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 0.18 g of 1- ( *) - [4 - (4-Chlorophenyl) -{3- [ ( 3 , 5-difluorophenyl )' - methylsulfonylmethylene] azetidin-l-y1 } methyl ) benzyl] pyrrolidine,' A isomer form, is obtained in the form of . a white foam [a]20365nm = -22.5° +/- 0.7 (c = 0.5%; dichloromethane) [lH NMR spectrum (300 MHz, CDC13, δ in ■ ppm) : 1.78 (mt : 4H):; 2.51 (mt : 4H) ; 2.,81 (s : 3H) ; 3.58 (s : 2H); 3.84 (mt : 2H) ; 4.33 (mt : 2H) ; 4.50 (2 : 1H); 6.84 (tt, J = 9 and 2.5 Hz :. 1H) ; 6.98 (mt : 2H) ; from 7.20 to' 7.40 (mt : 8H) ] . . l-{ (R*) - [ ( 4-Chloromethyl ) phenyl] - ( 4-chlorophenyl ) methyl } -3- [ ( 3,5-difluorophenyl ) methylsulfonyl-' methylene] azetidine, A isomer form, may be 'prepared by. carrying, out the procedure in' the following manner:' 12.4 cm3 of methylsulfonyl chloride are added to a solution of 28.0 g of the mixture of the 2 diastereoisomers (A forms) 1- { ( R* ) - [ ( 4 -chloromethyl ) - phenyl] - (4-chlorophenyl) methyl } -3- [ (R) - ( 3 , 5-difluoro- phenyl) methylsulfonylmethyl) ] azetidin-3-ol and 1-{(R*)- [( 4-chloromethyl) phenyl] -( -chlorophenyl) methyl } -3- . [ (S) - (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin- 3-ol and 32 g of 4-dimethylaminopyridine in 500 cm3 of dichloromethane. After stirring for one hour .at 10°C . and then one hour at 20°C, the reaction mixture' is ■ washed with 500 cm3 of water, the organic phase is .dried, over magnesium sulfate and .' concentrated to dryness under reduced pressure (2.7 kPa) . The residue ■ - is chromatographed oh a silica gel column (particle size. 0.06-0.200 mm, diameter 6 cm, height 30 cm) , under an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 250-cm3 fractions.
Fractions 9 to .25 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 6.3 g of 1- {. (R*) -[4- (chloromethyl) phenyl] - ( -chlorophenyl ) methyl } - 3- [ (3,-5-difluorophenyl)methylsulfonylmethylene] - azetidine, A isomer form, are obtained in ^the form of a white foam.
The mixture of the 2 diastereoisomers (A forms). l-{ (R*) - [ -chl.oromethyl) phenyl] - (4-chlorophenyl) -methyl }-3-[(R)-(3, 5-difluorophenyl') methylsulfonylmethyl) ] azetidin-3-ol - and 1- { (R* ) - [ 4-chloromethyl) -phenyl] (4-chlorophenyl)methyl}-3- [ (S) - (3, 5-difluorophenyl) methylsulfonylmethyl) ] azetidin-3-ol may be' prepared by carrying out the procedure in the following manner: 6 cm3 of thionyl chloride are added-to a solution of 0.20 g of the mixture of the 2· diastereoisomers (A forms) l-{ (R*') - (4-chlorophenyl) [4- (hydroxymethyl) phenyl] methyl } -3- [. (R) - (3, 5-difluoro-phenyl) methylsulfonylmethyl) ] azetidin-3-ol, and l-{ (R*) - (4-chlorophenyl) [4- (hydroxymethyl) phenyl]-methyl}-3- ["(S) - (3, 5-difluorophenyl ). methylsulfonyl-methyl) ] azetidin-3-ol in 10 cm3.of dichloromethane .
After stirring for 2.0 hours at 20°'C, 5 cm3 , of a saturated aqueous sodium hydrogencarbonate solution are added to the reaction mixture and then stirred for' 15 minutes.. The mixture is. separated after settling-, the organic phase is washed with water, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) . The residue is ■ chromatographed on a silica gel column (particle size 0.04-0.06 mm,, diameter 1.0 cm,' height 20. cm), under an argon pressure of 0.2 bar, elutihg with a. cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 20-cm3 fractions. Fractions 4 to 7 are . combined and concentrated to dryness under-- reduced pressure (2.7 IcPa) . 0.17 g of the mixture of the 2 diastereoisomers' (A forms) 1- { ( R* ) - [.4 - ( chloromethyl ) - phenyl] - ( 4 -chlorophenyl ) methyl } -3 - [ (R) - (3, 5-difluoro- phenyl ) methylsulfonylmethyl )] azetidin-3-ol and ■ 1- {. (R* ) - . [4- (chloromethyl) phenyl] - ( 4-chlorophenyl).methyl } -3- [ (S) - (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin- 3-ol, are obtained in the form of a white foam.
The mixture of the 2 diastereoisomers (A forms) 1- { (R* ) - ( 4-chlorophenyl ) [ 4- (hydroxymethyl ) phenyl ] -■ methyl } -3- [ (R) - ( 3 , 5-difluorophenyl) methylsulfonyl- methyl) ] azetidin-3-ol, and 1- { (R* ) - ( 4-chlorophenyl ) [ 4- ( hydroxymethyl) phenyl ] methyl } -3- [ (S) - (3, 5-difluoro- phenyl)methylsulfonylmethyl) ] azetidin-3-ol may be prepared. by carrying out the procedure in the following manner: 1.6 .cm3 of a 1.5 M solution of diisobutylaluminum hydride in toluene are added. to a solution, kept under argon and cooled to -30°C, of 0.58 g of the mixture of the 2 diastereoisomers (A forms) 3-acetoxy-l- { (R*) - (4-chlorophenyl) [4- (methoxy- carbonyl) phenyl] methyl } -3- [ (R) - (3,, 5-difluorophenyl.) - methylsulfonylmethyl) ] azetidine and 3-aeetoxy-l- { (R* ) - (4-chlorophenyl) [ 4- (methoxycarbonyl ).phenyl] methyl } -3— [ (S) - (3, 5-difluorophenyl)'methylsulfonylmethyl) ] - azetidine, in 10 cm3 of anhydrous toluene. After stirring for 15 minutes at -30°C, 1.0 cm3 of the same hydride solution is again added and the mixture is allowed to return ' to ' 0 °C . After stirring for minutes, the stirred' mixture is supplemented with 3 cm3 of water and 6 cm3 of 1 N sodium, hydroxide and then extracted with 25 cm3 of dichloromethane . The organic phase is washed with 5 cm3 of water, 5 cm3 of brine and then dried over magnesium sulfate and concentrated to dryness- under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 1.2 cm, height 30 cm),, under an argon pressure of 0-.1 bar, eluting with a cyclohexane and ethyl acetate (50/50 by volume) mixture and collecting ■ 30-cm3 fractions. Fractions 4 to 12 are combined and then concentrated to dryness under reduced pressure- (2.7 kPa) . 0:42 g of the mixture of the 2 diastereoisomers (A forms) 1- { (R* ) - ( -chlorophenyl ) -· [4- (hydroxymethyl) phenyl ] methyl } -3- [ (R) - (3, 5-difluoro-. phenyl) methylsulfonylmethyl) ] azetidin-3-ol and 1-{(R*)-· ( 4-chlorophenyl) [ 4- (hydroxymethylphenyl ] methyl } -3- [ (S) - ( 3 , 5-difluorophenyl) methylsulfonylmethyl). ] azetidinr3- ol, are obtained in the form of a white lacquer.
The mixture of the 2 diastereoisomers (A forms) 3-acetoxy-l- {. (R*) - ( 4 -chlorophenyl ) [4 - (methoxycarbonyl.) phenyl ] methyl } -3- [ (R) - ( 3 , 5-difluorophenyl ) methylsulfonylmethyl) ]. azetidine and 3-acetoxy-l- { (R* )-( 4 -■ chlorophenyl ) [ 4- (methoxycarbonyl ) phenyl] methyl } -3- [ (S) - ( 3 , 5-difluorophenyl) methylsulfonylmethyl )] azetidine may be prepared by carrying out the procedure in the following manner: 3 em3. of a 1.6. N solution of n- butyllithium in hexane are poured under argon over 5 minutes, into a solution, cooled to -60°C, of 1.0 g of ( 3 , 5-difluorobenzyl ) methyl sulfone in 30 cm3 of tetrahydrofuran . After stirring for 1 hour at -60°C and 142 then added to the mixture, filtered and then evaporated to dryness under reduced pressure (.2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 15 cm, diameter 1 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 5-cm3 fractions. Fractions 12 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 29 mg ο·ί l-[bis(4- .. chlorophenyl) methyl) ] -3- (phenylsulfonylmethyl ) azetidine are obtained in the form of a white solid [ 1H N R •spectrum (300 MHz, CDC13, δ in ppm) : from 2.75 to 8.90 (mt : 3H) ; 3.32 (mt : 2H) ; 3.37 (d, J = 7 Hz : 2H) ; 4.22 (s : 1H) ; from 7.20 to 7.30 (rat : 8H) ; 7.57 (broad t, J.= 7.5 Hz :.2H); 7.67 (tt, J = 7.5 and 1.5 Hz :. · 1H) ; 7.88 (broad d, J = 7.5 Hz : 2H) ] . ' .
Example 19 1- [Bis (4-chlorophenyl)methyl) ] -3- (phenylsulfonylmethylene) azetidine may be prepared by carrying out the procedure in the following manner: 12. cm3.of a 1.6 M solution of n-rbutyllithium in hexan.e are poured, over 5 minutes, into a solution, cooled to -70°C, under argon, of 4.34 g of (phenylsulfonylmethyl) trimethylsilane in 40 cm3 of dimethyl ether.
After stirring the mixture for 30 minutes at -60aC, a solution of 1-.[bis ( -chlorophenyl) methyl] azetidin-3-one in 30 cm3 of dimethyl ether [produced in the form of a base prepared by treating 7.35 g of 1- [bis t.4 -chlorophenyl) methyl] azetidin-3-one hydrobromide dissolved in 79 then for 30 minute's at -30°C, a solution, . previously cooled to -60°C, of 1.45 g of ■ 1- { ( * ) - ( 4-chloro- phenyl) [4- (methoxycarbonyl) phenyl]methyl}azetidin-3- one, A isomer form, in 15 cm3 of tetrahydrofuran is added dropwise to this mixture. After stirring for 30 minutes at --60°C and then for 30 minutes at -30°C, . 0.43 cm3 of acetyl chloride is added and the reaction mixture is allowed to..return to 0°C. 40. cm3 of water and 40 cm3 of dichloromethane are then added to. the . medium, with stirring, and then the medium is allowed to return to room temperature and it is separated -after settling. The organic. -phase is washed with 20 cm3 of water and is ' then dried over magnesium sulfate, filtered and concentrated to dryness under reduced ■ pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, .' diameter 3 cm, height 30' cm) , eluting under an argon ' pressure of 0.5 bar with a cyclohexane and ethyl acetate (75/25 by volume) 'mixture and collecting 30-cm3 fractions. Fractions 21 to 35 are combined and then concentrated to dryness . under reduced pressure (2.7 kPa) . 1,28 g of the mixture of the 2 diasterisomers (A forms) 3-acetoxy-l- { (R* ) - ( 4-chloro- phenyl) [ 4- (methoxycarbonyl) phenyl] methyl } -3- [ (R) -( 3 , 5-, difluorophenyDmethylsulfonylmethyl) ] azetidine and 3-acetoxy-l- { (R*.) -( 4 -chlorophenyl ) [ 4 - (methoxycarbonyl ) - phenyl] methyl }-3-[(S)-(3, 5-difluorophenyl) methyl - sulfonylmethyl )] azetidine are obtained in -the form of a cream-colored, foam. 80 1- { (R* ) - ( 4-Chlorophenyl ). [ 4 -me hoxycarbonyl ) -phenyl] methyl } azetidin-3-one, A isomer form, may be prepared by carrying out the procedure in the following manner: 0.90 cm3 o'f dimethyl sulfoxide is poured over 10 minutes into a solution, cooled to -60°C, of 0.55 cm3 of oxalyl chloride in 5 cm3 of dichloromethane . After stirring for 30 minutes at -60°C, a solution of 1.75 g of l-{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl]methyl}azetidin-3-ol, A isomer form, in.20 cm3 of dichloromethane is added to the mixture over minutes. After stirring for 3 hours at -60°C, 2.7 cm3 of triethylamine are poured in and then the-reaction medium is' allowed to return to 0'°C.' 20. cm3 of . water are then added, the mixture' is stirred. and then separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated, to dryness at 50°C under reduced pressure (2.7 kPa)' . The orange-colored oil obtained is chromatographed on a silica gel column (particle size 0.06-0.20.0 mm, diameter 2 cm, height 30 cm) , under an argon pressure of 0.5 bar, .eluting with a cyclohexane and ethyl acetate (75/25 by volume) mixture and collecting 30-cm3 fractions. Fractions 2 to 15 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 1.45 g of l-{(R*)-( 4-chlorophenyl ) [ 4-(methoxycarbonyl ) phenyl ] methyl } azetidin-3-one, A isomer form, are obtained in the form of a yellow foam. 1- { (R* ) - ( 4-Chlorophenyl) [ 4-methoxyearbonyl ) -phenyl]methyl}azetidin-3-ol, A isomer form, may be. 81 prepared by carrying out the procedure . in the following manner: 0.605 g of sodium hydrogen carbonate is added tea suspension of 2.0 g of methyl (.+) -4- [ (R*) -amino- ( 4-chlorophenyl ) methyl] benzoate in 30 'cm3 of ethanol followed by 0.60 cm3 of epibromohydrin . After stirring for 20 hours at 60°C, the reaction mixture is concentrated to dryness under reduced pressure ■(2.7 kPa) . The . residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, .height 35 cm) , . eluting under an . argon pressure 'of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30 by volume for fractions 6 to 10 and then 60/40. for fractions 1.8 to 27, and then 50/50) and collecting. 60-cm3 fractions . Fractions 15 to 40 are combined and then concentrated to dryness under ' reduced pressure (2.7 kPa) . The residue is taken up in 30 cm3 of. ethanol and is then supplemented with 0.20 g of sodium hydrogen carbonate and 0.2 cm3 .of epibromohydrin. After stirring for 48 hours at 20°C and then 24 hours at 35°C, the mixture is filtered and the filtrate is' concentrated to dryness, at 60°.C under reduced pressure (2.7 kPa) . f 1.76 g of l-{ (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl] methyl } azetidin-3-ol, A isomer' form, are. obtained in the form of a pasty solid.
Methyl ( +) -4- [ (R* ) -amino- ( -chlorophenyl ) -methyl] benzoate may be prepared by carrying out the procedure in the following manner: 2·.51 g of -D-(-)-tartaric acid are. added to a solution of 9.2 g of methyl 4- [ (RS) -amino- (4-chlorophenyl).methyl] benzoate in 82 cm3 of methanol. The solution is concentrated to dryness under reduced pressure (2.7 kPa) . The cream- colored' foam obtained is. dissolved in 50 cm3 of ethanol containing 5% of water and the resulting solution is allowed to crystallize for 20 hours at 20°C. The crystals are filtered, washed with ethanol containing 5% of water, drained and then dried under reduced pressure (2.7 kPa) . 3.(4 g of white ' crystals are obtained, which . crystals are named "A crystals". ■ [and which are stored for the subsequent preparation of the second enantiomer methyl ( - ) -4- [ (R* ) -amino-.( 4-chloro- phenyl) methyl] benzoate) ] . The mother liquors are concentrated, to dryness and a white foam is obtained (8.1 g) which is dissolved in 100 cm3 of .ethyl acetate. The solution obtained, is supplemented with 50 cm3 of I N sodium hydroxide, > stirred and separated after .settling. The organic ■ phase is washed with 50 cm3 of water and then, dried over magensium sulfate and- ■ concentrated to dryness under reduced pressure (2.7 kPa.) . A yellow solid is obtained which is dissolved in 100 cm3 of methanol. The solution obtained is supplemented with 1.85 g of L- (+) -tartaric acid and the resulting solution is concentrated to dryness under reduced pressure (2.7'kPa). A. cream-colored foam is ■ obtained which, once dissolved in 27 cm3 of ethanol containing 4% of water,, is allowed to crystallize for 20 hours at 20°C. The crystals are filtered, washed with ethanol containing 4% of water, drained and then dried under reduced, pressure (2.7 kPa) . 3.4 g of 83 crystals of methyl' ( + )-4- [ (R* ) -amino- (.4-chlorophenyl) -methyl ] benzoate L- (+) -tartrate are obtained which are recrystallized -from 60 cm3 of ethanol containing 5% of water. After draining and then drying, 2.78 g of white crystals are obtained which are dissolved in 50 cm3 of ethyl . acetate . The solution obtained is supplemented with 100 cm3 of 1 N sodium hydroxide, stirred and separated after settling. The organic phase is washed with 50 cm3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . 2.1 g of methyl . (+) -4- [ (R* ) -amino- ( 4-chlorophenyl) methyl] benzoate are obtained in the form of a white solid.
Methyl 4- [ (RS) -amino- ( 4-chlorophenyl ) methyl] -benzoate may be prepared by carrying out the procedure in the following manner: 3.9 cm3 of hydrazine hydrate are added to a suspension of 16.3. g of methyl 4-[(RS)-phthalimido- (4-chlorophenyl) methyl ].benzoate in 200 cm3 of methanol. After stirring for 5 hours at the reflux temperature and then for 20 hours at 20°C,.the reaction mixture is filtered and the filtrate is concentrated t.o dryness under reduced pressure (2.7 kPa).. The residue obtained is ,taken up in a mixture of 200 cm3 of water and 200 cm3 of ethyl acetate. After stirring for 15 minutes, the resulting suspension is filtered, the filtrate separated after settling in a separating funnel and the organic phase, is washed with 50 cm3 of water, dried over magnesium sulfate and concentrated to dryness under 'reduced ' pressure (2.7 kPa) . 8.4 g of 84 methyl 4- [ (RS ) -amino- ( 4-chlorophenyl ) methyl] benzoate are obtained in the form of a pale yellow .oil.
Methyl..4- [ (RS) -phthalimido- (4-chlorophenyl) -methyl] benzoate may be- prepared by carrying out the procedure in the following manner: 12.6 g of potassium phthalimide are added to a solution of 11.6 g of methyl 4- [ (RS) -bromo- ( 4-chlorophenyl) methyl] benzoate in 70 cm3 of N,N-dimethylformamide . After . stirring for 3 hours at the reflux temperature, the reaction mixture is. cooled to 20 °C and then supplemented with 300 cm3 of ethyl acetate and 300 cm3, of water. After stirring, the mixture is separated after settling, the aqueous phase reextracted with twice 100 cm3 of ethyl acetate, the combined organic phases are washed with twice 400 cm3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . 16.3 g of methyl 4- [( RS ) -phthalimido- ('4 -chlorophenyl) methyl] benzoate are obtained in the form of a. pasty yellow solid.
Methyl 4- [. (RS ) -bromo- (4-chlorophenyl ) methyl] -benzoate may be prepared by carrying out the procedure in the following manner: 10.18.g of Ν,Ν' -carbonyl-diimidazole and 54.3 cm3, of allyl bromide are added to a solution' of 17.4 g of methyl 4- [ (RS) - ( 4-chloro- . phenyl) (hydroxy) methyl] enzoate in 200 cm3 of acetonitrile . After stirring for 30 minutes at"20°C, . the reaction mixture is- heated under reflux for 2 hours, stirred for.20 hours at 20°C and concentrated almost to dryness under reduced pressure (2.7 kPa) . The 85 mixture, taken up in dichloromethane, is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 7 cm, height 30 cm), under an argon pressure of 0.5 bar, ' eluting with dichloromethane, and collecting 500-cm3 fractions. Fractions 3 to 6 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 11.6 g of .methyl 4- [ (RS ) -bromo- ( -chlorophenyl) methyl] benzoate are obtained in the form of an- oil which will be used as it is in the next step.
Methyl 4- [ (RS)- (4-chlorophenyl) (hydroxy) - methyl] benzoate may be prepared by carrying out the procedure in the following manner: 1.21 g of sodium borohydride are added slowly in small fractions (the \ medium becomes slightly warm up to 50 °C) to a suspension of 2.75 g of methyl 4- (4- chlorobenzoyl ) benzoate in 200 cm3 of methanol at "20°C. After stirring for 20' hours at 20°C, the reaction mixture is concentrated to ' a reduced volume and then 'supplemented with 150 cm3 of dichloromethane and, with stirring, with 100 cm3 of 0.5 N hydrochloric acid.
After decantation, the organic phase is dried over magensium sulfate., concentrated to dryness under reduced pressure (2.7 kPa) . 2.5 g of methyl 4-[(RS)-(4 chlorophenyl) (hydroxy) methyl] benzoate are' obtained in the form of a colorless oil which crystallizes slowly at 20°C and which will be used as- it is in the next step. . -·· 86 Methyl 4- ( 4 -chlorobenzoyl ) benzoate may be prepared by carrying out the procedure in the following manner: 27.4 cm3 of tri-n-butylphosphine are added, under argon, to a solution, cooled to -22°C of 19.3 g of . terephthalic acid chloride monomethyl ester in 200 cm3 of tetrahydrofuran . After stirring for minutes at -22°C, a solution of 4 -chlorophenyl- magnesium bromide (prepared from 19.15 g of 4- bromochlorobenzene, 2.43 g of magnesium and one. iodine crystal in 100 cm3 of diethyl ether under reflux) .is poured in while maintaining this temperature. After stirring for 30 minutes at -22°C,-150 cm3 of 1 N - hydrochloric acid are .added slowly, the mixture is allowed to return to 20 °C and then the medium is diluted 'with 200 cm3 of diethyl ether. The white ". suspension obtained is filtered, the solid is washed with twice 50 cm3 of. water and then with twice 50 cm3 of diethyl ether. After draining and then drying under reduced pressure { 2-.7 kPa) , 16.2 g of methyl 4- (4-' . chlorobenzoyl) benzoate are obtained in the form of a. ■ white solid melting .at 170°C.
Example 4 The mixture of the 2 B diastereoisomer forms 1- [4- [ (R*) - (4-chlorophenyl) -{3- [ ( 3 , 5-difluorophenyl ) - methylsulfonylmethyl- (R) ] azetidin-l-yl }methyl ] benzyl] - pyrrolidine and 1- [ 4- [ (R*) -( 4-chlorophenyl )-{ 3- [( 3 , 5- difluorophenyl) methylsulfonylmethyl- (S)' ] azetidin-l- yl }methyl] benzylpyrrolidine may.be prepared by carrying out the procedure as .described in Example 3, starting 87 with 50 mg of (+■) -1- [4- (R*) - ( 4-chlorophenyl ) -{3-[ (3, 5-difluorophenyl ) methylsulfonylmethylene] azetidin-l-yl } -methyl) benzyl] pyrrolidine, B isomer form,.1.5 cm3 of ethanol, 1.5 cm3 of dichloromethane and 18 mg of sodium borohydride, with stirring for 8 hours at 50°C and then for 48 hours at 20°C. 50 mg of the mixture of the 2 B diastereoisomer forms 1- [ 4 - [ (R* ) - ( -chlorophenyl ) - { 3-. [ (3, 5-difluorophenyl) methylsulfonylmethyl- (R) ] azetidin-l-yl Imethyl] benzyl] pyrrolidine and 1- [ 4 - [ ( R* ) - 4-chlorophenyl ) - { 3- [ ( 3, 5-difluorophenyl ) methylsulfonylmethyl- ( S) ] azetidin-l-yl }methyl] benzylpyrrolidine are · obtained in the form of a white foam [XH N R spectrum (300 MHz, CDCI3, δ in ppm) . A 60/40 mixture of diastereoisomers is observed, * 1.79 .(mt: 4H) ; from 2.45 to 2.60 (mt: 5H) ; 2.67 (s : 3H); from 3.10 to 3.30 (mt : .2H); 3.40 (mt : 1H) ; 3.57 -and 3.60. (2s.: 2H in . . total); 3.65 (broad t, J = 7.5 Hz : 1H) ; 4.26 and 4.30 (2s : 2H in total); 6.84 (tt, J = 9 and 2 Hz : 1H) ; 6.96 (mt : 2Ή") .; from 7.25 to 7.40 (mt : 8H) . (+) -1- [4- (R*) - (4-Chlorophenyl) -{3- [ (3, 5-difluorophenyl) methylsulfonylmethylene] azetidin-l-yl } methyl ) benzyl ] yrrolidine, B isomer form, may be prepared by . carrying out the procedure as is described in Example 3, starting with 0.50 g of l-{(R*)-[4-(chloromethyl ) phenyl] - ( 4-chlorophenyl ) methyl } -3- [ (3,5-difluorophenyl) (methylsulfonyl ) methylene] azetidine, B isomer form, 5 mg of sodium iodide, 15 cm3 of dichloromethane and 0.190 g of pyrrolidine v. The crude product is chromatographed on a silica gel column 88 (particle size 0.06—0.200 mm, diameter. 1.5' cm, height 20 cm)., under an argon' pressure of 0.1 bar, eluting with dichloromethane and then with a dichloromethane and methanol .( 95/5 by volume) mixture and collecting 25-cm3 fractions. Fractions.20 to 40 are combined and then, concentrated to dryness under reduced pressure (2.7 kPa) . 0.28 g of (+ ) -1- [ 4- (R* ) - ( 4-chlorophenyl ) - { 3- [ (3, 5-difluorophenyD.methylsulfonylmethylene] azetidin-1-yl }methyl) benzyl] pyrrolidine, B isomer form, .is obtained in the form of a white foam. [a]z0365nm = +26.8 +/- 0.8 (c = 0.5%; dichloromethane) [~lH NMR . spectrum (300 MHZ, CDCI3, δ in ppm) : 1.78 - (mt : 4H) ; 2.50 (mt : 4H) ; 2.80 (s : 3H) ; '3.57 (s : 2Ή) ; 3.84 .(mt : 2H) ; 4.34 (mt : 2H) ; 4.50- (s : 1H) ; 6.84 (tt, J = 9 and 2.5 Hz : 1H); .6.98 (mt : 2H) ; from 7.-20 to 7.40 (mt : 8H) ] . 1- { (R*) - [4- (Chloromethyl) phenyl] - (4-chloro- . phenyl) methyl } -3- [ ( 3 , 5-difluorophenyl) (methylsulfonyl ) -methylene] azetidine, B isomer form, may be prepared by carrying out the procedure as described in Example 3, starting with 7.3 g of the mixture of the 2 B diastereoisomer forms l-{ (R*) - [4- ( chloromethyl ). phenyl ] -(4-chlorophenyl)methyl}-3- [ (R) - ( 3 , 5-difluorophenyl ) -(methylsulfonyl) methyl) ] azetidin-3-ol and l-{(R*)-[4-( chloromethyl) phenyl] - (4-chlorophenyl) methyl } -3- [ (S) -(3, 5-difluorophenyl) (methyls.ulfonyl) methyl) ] azetidin-3-ol, 8.2 g of 4-dimethylaminopyridine, 150 cm3 of dichloromethane and 3.2 cm3 of methylsulfonyl chloride. The crude product is chromatographed on a silica gel column (particle size ' 0.04 -0.06. mm, diameter 3 cm,' 89 height 30 cm) under an argon pressure of 0.2 bar, eluting with dichloromethane and collecting 100-cm3 fractions. Fractions 15 to 30 are combined and then-concentrated to dryness under reduced pressure (2.7 kPa) . 2.50 g of 1- {( R* )-[ 4- ( chloromethyl ) phenyl ] - (4-chlorophenyl) methyl.} -3- [ (3, 5-difluorophenylmethyl- · sulfonyl) methylene] azetidine, B isomer form, are obtained in the form of a white foam.
The mixture of the 2 B diastereoisomer .forms 1-{ (R* ) - [ - (chloromethyl) phenyl [4-chlorophenyl) methyl } -3- [ (R) - (3, 5-difluorophenyl) (methylsulfonyl ) methyl ) ] -azetidin-3-ol and 1- { (R* ) - [ - (chloromethyl ) phenyl] - ( 4-chlorophenyl ) methyl } -3- [( S) - (3, 5-difluorophenyl ) - (methylsulfonyl j methyl) ] azetidin-3^ol may be prepared by carrying out the procedure as described in Example 3, starting with 11.0 g of the mixture of the 2 B diastereoisomer forms .1- { (R* ) - -chlorophenyl ) [4-(hydroxymethyl) phenyl] methyl } -3- [ (R) - (3, 5-difluoro-phenyl) (methylsulfonyl ) methyl )] azetidin-3^ol and.1-{ (R*) - (4-chlorophenyl) [4- (hydroxymethyl ) phenyl ] methyl } -3- [ (S) - (3, 5-difluorophenyl ) (methylsulfonyl ) methyl ) ] -azetidin-3-ol, 250 cm3 of dichloromethane and 3.1.cm" of thionyl chloride. The crude product is ' chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3 cm, height 30 cm), under an argon . pressure of 0.2 bar, eluting with a ' cyclohexane and ethyl acetate (70/30 by volume) mixture and collecting 50-cm3 fractions. Fractions 9 to 25 are combined and the concentrated to dryness under reduced pressure 90 (2.7 kPa). 7.3 g. of the mixture of the.2 B diastereoisomer forms 1- { (R* )-[ - (chloromethyl ) phenyl ] (4-chlorophenyl)methyl}-3- [ (R) - (3, 5-difluorophenyl) - (methylsulfonyl ) methyl )] azetidin-3-ol and l-{(R*)-[4- (chloromethyl) phenyl] - ( 4 -chlorophenyl ) methyl } -3- [ (S) - (3, 5-difluorophenyl) (methylsulfonyl ) methyl) ] azetidin-3 ol are obtained in. the form of a. white foam.
The mixture of the 2 B diastereoisomer forms 1 ( (R*) - (4-chlorophenyl),[4- ( hydroxymethyl ) phenyl Imethyl } ' 3- [ (R) - (3, 5-difluorophenyl) (methylsulfonyl) methyl) ] - azetidin-3-ol and 1- { (R* )-[ 4- ( chlorophenyl ) [ 4- (hydroxy methyl) phenyl] methyl } -3- [ (R) -3, 5-difluorophenyl) - (methylsulfonyl) methyl) ] azetidin-3-ol may be prepared by .carrying out the procedure as described in Example. 3, starting with 18.0 g of the mixture of the 2 B diastereoisomer forms 3-acetoxy-l- { (R* ) - ( 4-chloro- phenyl ). [ 4- (methoxycarbonyl ) phenyl] methyl }-3-[(R)-(3,5- difluorophenyl ) (methylsulfonyl ) methyl ] azetidine and 3- acetoxy-l-{ (R*) - ( 4 -chlorophenyl) [4- (methyloxycarbonyl) ■ phenyl]methyl}-3- [ (S) - (3, 5-difluorophenyl) (methylsulfonyl ) methyl ] azetidine , 150 cm3 of anhydrous toluene and 100 cm3 of a 20% solution of diisobutyraluminum hydride in toluene. The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3 cm, height 30 cm), under an argon pressure of 0.1 bar, eluting with a cyclohexane and ethyl acetate (50/50 by volume) mixture' and collecting 50-cm3 fractions. Fractions 15 to 30 are combined and concentrated to dryness under reduced 91 pressure (2.7 kPa) '. 11.0 g of the mixture of the '2 B diastereoisomer forms 1- { (R*) - ( 4-chlorophenyl) [4- (hyd'roxymethyl) phenyl ] methyl } -3- [ (R) - (3, 5-difluoro-phenyl) (methylsulfonyl) methyl] azetidin-3-ol and 1- ( (R*) -[ (4-chlorophenyl) [4- (hydroxymethyl ) phenyl] - . methyl.} -3- [ (S) -3, 5-difluorophenyl ) (methylsulfonyl) -methyl ] azetidin-3-ol are obtained in the form of a white foam.
The mixture of the 2 B diastereoisomer .forms 3-acetoxy-l-{ (R*) - (4-chlorophenyl) [ 4- (methoxycarbonyl ) -phenyl ].methyl } -3- [ (R) - (3, 5-diffluorophenyl ) (methylsulfonyl) methyl] azetidine and 3-acetoxy-l- { (R* ) - ( 4-chlorophenyl ) [4- (methoxycarbonyl ) phenyl ] methyl } -3- [ ( S) - (3, 5-difluorophenyl)methylsulfonyl)methyl] azetidine may be prepared by carrying out the procedure as described in Example 3, starting with .11.2 g of ( 3, 5-difluoro-benzyl) methyl sulfone, 350 cm3 of tetrahydrofuran, 34 cm3 of a 1.6 N solution of n-butyllithium in hexane, 11.2 g of 1- { (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) -phenyl] methyl } azetidin-3-one, B isomer form, and . .5 cm3 of acetyl chloride. The crude product is chromatographed on a 'silica gel column (particle size 0.06-0.200 mm, diameter 4' cm, height 40 cm), eluting with a cyclohexane and ethyl acetate. (70/30 by volume) mixture and ' collecting 100-cm3 fractions. Fractions 10 to 30 are combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 21 g of a still impure cream-colored foam are obtained, which- foam is chromatographed on a silica gel column (particle size 92 0.06-0.200 mm, diameter 4 cm, height 40 cm) , eluting with dichloromethane and collecting 100-cm3 fractions. Fractions 11 to 3.0 are combined and then concentrated to dryness under . reduced pressure (2.7 kPa) . 20.0 g of the mixture of the 2 B diastereoisomer forms 3-acetoxy- . l-{ ( R* ) - ( -chlorophenyl) [4- (methoxycarbonyl) phenyl] - methyl } -3-■[ (R) - (3, 5-difluorophenyl) (methylsulfonyl) - methyl] azetidine and 3-acetoxy-{ (R* ) - ( -chlorophenyl ) - [4 - (-methoxycarbonyl ) phenyl ] methyl }-3-[(S)-(3,5*-- difluorophenyl)' (methylsulfonyl ) methyl] azetidine are - obtained in the form of a white foam. l-{ (R*) - (4-Chlorophenyl) [ 4 -methoxycarbonyl ) - . phenyl]methyl}azetidin-3-one, B isomer form, may be prepared by carrying out the procedure as described in Example 3, starting with 8.7 cm3 of oxalyl chloride, 350 cm3 of dichloromethane, 14.2 cm3 of dimethyl sulfoxide, 29.0 g of l-{ (R*) - (4-chlorophenyl) [4-- (methoxycarbonyl) phenyl] methyl } azeditin-3-ol, B isomer form,' and 43 cm3 of triethylamine . The crude product is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 4 cm, height 40 cm), eluting ■ with dichloromethane and collecting 250-cm3 fractions.. Fractions 7 to 25 are combined and then . concentrated to .dryness under reduced pressure (2.7 kPa) . 15.5 g of 1- {. (R*) - (4-chlorophenyl) [4- (methoxycarbonyl) phenyl] - methyl } azetidin-3-one1, B isomer form, are obtained in the form of. an o.range-colored oil. 1- { (R* ) - ( 4-Chlorophenyl) [ 4 - (methoxycarbonyl ) - phenyl ] methyl } azeditiri-3-ol , B isomer form, may be 93 prepared as described in Example 3, starting with .5 g of methyl (-). -4- [l-(R*) -amino-1- ( - chlorophenyl) methyl] benzoate, 250 cm3 of ethanol, 7.9 g of sodium hydrogen carbonate and 7.7 cm3 of epibromohydrin . 29 g of 1- { (R* ) - '( 4 -chlorophenyl ) [ 4 - (methoxycarbonyl) phenyl] methyl } azeditin-3-ol, B isomer form,, are obtained in the form of a yellow oil.
Methyl (-) -4- [ (R*) -amino- (4-chlorophenyl) - methyl] benzoate may be prepared by carrying out- two successive recrystallizations of the white crystals (3.4 g) named "A crystals" of Example 3, from 68 cm3 of. ethanol- containing 5% of water under reflux. The. crystals obtained are * filtered, drained. and then dried under reduced pressure (2.7 kPa) . 2.2 g of methyl (-)- 4 - [1- (R* ) -amino- (4-chlorophenyl ) methyl ] benzoate D-(-)- tartrate are obtained in' the. form of. whit.e crystals" which are' dissolved in 50. cm3 of ethyl acetate.. The solution obtained is supplemented with 5.0 cm3 of 1 N ' sodium ■ hydroxide, . stirred and then separated after settling. The organic, phase is washed with 50 cm3 of water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) ..1.9 g of methyl (-) -4- [ ( *) -amino- (4- chlorophenyl) methyl] benzoate are obtained in the form of a white solid. [a].20°C, 3.65. nm =:-58.1° +/- 1 (c = 0.5%) Example 5 1- [Bis (thien-2-yl)methyl] -3- [.(RS) -{.3,5- difluorophenyl ) methylsulfonylmethyl ] azetidine may be 94 prepared by carrying out the procedure, as described in Example 3, starting with 0.10 g of 1- [bis ( thien-2- yl) methyl] -3- [ (3, 5-difluorophenyl ) methylsulfonyl- methylene] azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 25 mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm) eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions. Fractions 2 to 5 are combined and concentrated to dryness under reduced pressure (2.7 kEa) . 83 mg of 1- [bis (thien-2-yl) methyl] -• 3- [ (RS) - (3, 5-difluorophenyl) methylsulfonylmethyl ] - ' azetidine are obtained in the form of a white solid [1H NMR spectrum (400 MHz, CDC13, δ in ppm) ·: from 2.60 to 2.70. (mt : 1H) ; 2.66 (s : 3H) ; 3.31 (mt : 2H) ; 3.4.0 . (mt : 1H) ;' 3.73. (broad t, J = 7.5 Hz : 1H) ; 4.27 (d, J = 11 Hz : lH) ; 4.92 (s : 1H) ; 6.83 (tt, J = 9 and 2.5 Hz); from 6.85 to 7.00 (mt : 6H.) ; 1.21 (mt :. 2H) ] . 1- [Bis (thien-2-yl) methyl] -3- [ ( 3 ,.5-difluoro- phenyl.) methylsulfonylmethylene] azetidine may be ■ prepared by carrying out the' operation according to the procedure described in Example 6, starting with- 2.2 g of 1- [bis (thien-2-yl)methyl] -3- [ (3, 5-difluorophenyl ) - methylsulfonylmethyl- (RS) ] azetidin-3-ol , 0.64 cm3 of methylsulfonyl ' chloride, 2.3 g of 4-dimethylamino- pyridine and 75 cm3 of dichloromethane; after purification by chromatography and crystallization from diisopropyl ether, 1.3 g of 1- [bis (thien-2-yl) methyl] - 95 3- [( 3 , 5-difluorophenyl ) methylsulfonylmethylene ] - azetidine are obtained in the form of white crystals melting at 165°C . 1- [Bis (thien-2-yi) methyl] -3- [ (3, 5- difluorophenyl) methylsulfonylmethyl- (RS) ] azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 4 cm3 of 1.6 N n-butyllithium in hexane are added, under argon over 10 minutes, to a solution, cooled to -60°C, of 1.3 g of (-3 , 5-difluoro- benzyl ) methyl sulfone in 20 cm3 of tetrahydrofuran .
After stirring for 45 , minutes . at -70°C, a solution of 1.5 g of 1- [bis (thien-2-yl) methyl] azetidin-3-one in 20 cm3 of tetrahydrofuran is poured in over 10 minutes. After stirring for 3' hours at -70°C, the reaction mixture is allowed to return' to room temperature and . then is supplemented, with 10 cm3.of a saturated aqueous ammonium chloride solution. The mixture is separated after settling, the organic phase is dried over ' magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. (2.7 'kPa) . .The residue is. taken up in 20 cm3 of a mixture of cyclohexane and ethyl acetate (60/40 by volume) the suspension obtained is filtered, the solid is drained and then air-dried. 2.2 g of l-[bis (thien-2-yl)methyl] -3-[ ( 3 , 5-difluoro- phenyl) methylsulfonylmethyl- (RS) ] azetidin-3-ol are obtained in the form of white crystals melting at 145°C. '· 1- [Bis (thien÷2-yl) methyl] azetidin-3-one may be prepared by carrying out the procedure as described in 96 Example 1 (method 2) starting with 4 g of 1- [bis ( thien- 2-yl) methyl] azetidin-3-ol, 2.6 cmJ of dimethyl sulfoxide, 7.7 cm3 of triethylamine , 7.7 cm3, of oxalyl chloride and 100 cm3 of dichloromethane . The residue ·. obtained is. purified by chromatography on a silica gel column (particle size ' 0.04-0.06 mm, diameter 3 cm, height 30 cm) with, as eluent, a cyclohexane and ethyl acetate (1/1 by volume mixture) . The fractions obtained are evaporated to dryness under reduced pressure (2.7 kPa) . 3.2 g of 1- [bis ( thien-2-yl ) methyl ] azetidin- 3-one are obtained in the form of cream-colored crystals melting at 70°C. 1- [Bis (thien-2-yl) methyl] azetidin-3-ol . may be prepared by carrying out the procedure as described in Example 3, starting with 6 g of 1- [bis ( thien-2-yl ) methyl ] amine , 2.5 cm3 of epibromohydrin, 2.6 g of sodium bicarbonate and 50 cm3 of ethanol. 4 g of 1-[bis (thien-2-yl) methyl] azetidin-3-ol are obtained in the form of beige- crystals melting at 115 °C. 1- [Bis (thien-2-yl) methyl] amine may be prepared in the following manner: a solution of 5 cm3 of 2-thiopheninecarbonitrile in 50 cm3 of diethyl ether is poured, dropwise, into- a solution, cooled under. argon-to 10°C, of thien-2-ylmagnesium bromide (prepared from 1.29 g of magnesium and 3.22 cm3 of 2-bromothiophene in 75 cm3 of diethyl ether) . After refluxing for 1 hour and 30 minutes, the reaction medium is cooled to 5°C and then twice 20 cm3 of methanol are poured in dropwise, the suspension is filtered and the solid is 97 washed with methanol. The filtrate obtained [lacuna] a brown solution. 2.45 g of sodium borohydride are added to this solution in several portions, under argon. The mixture is stirred at room temperature for 16 hours and is then diluted with ethyl acetate and slowly supplemented with water. The organic phase is extracted, washed with water, dried. over magnesium' sulfate and evaporated to dryness under ■ reduced pressure (2.5 kPa) at-.55°C. A brown oil is obtained which is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 8 cm, height 23 cm) and eluted with a cyclohexane and ethyl acetate (90/10 and then 85/15' by volume) mixture .. Fractions 21.' to 30 are combined and evaporated to- dryness under reduced pressure (2.7 kPa),. 11 g of 1- [bis ( thien-2- yl) methyl] amine are obtained in the form of a crystallized solid.
Example 6 1- [Bis (p-tolyl) methyl] -3- [ (;RS) methylsulfonyl- · phenylmethyl] azetidine may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g.of 1- [bis (-p-tolyl) methyl] -3- (methylsulfonyl- -phenylmethylene) azetidine, 2 cm3 of .methanol, 2 cm3 of dichloromethane and 25 mg of sodium borohydride. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cmJ fractions.
'Fractions 5 to 10 are combined and concentrated to 98 dryness under reduced pressure (2.7 kPa) . 35 mg of 1- [bis (p-tolyl) methyl] -3- [ (RS) methylsulfonylphenyl-methiyl ] azetidine are obtained in the form of a white solid [XH NMR spectrum (300 MHz , CDC13, δ in ppm) : 2.24 (s : 3H) ; 2.27 (s : 3H);"2.53 (t,J = 7.5 Hz : 1H) ; 2.58 (s : 3H); 3.19 (mt : 2H) ; 3.49 (mt : 1H) ; 3,69 (broad t, J = 7.5 Hz : 1H) ; 4.22 (s : 1H) ; 4.28 (d, J = 11.5 Hz : 1H) ; from 6.95 to 7.45 (mts : 13H) ] . 1- [Bis (p-tolyl) methyl] -3- (methylsulfonylphenyl-methylene) azetidine may be prepared by carrying out the procedure in the following manner: 0.125 cm3 of methylsulfonyl chloride is added to. a solution of 0.48 g of 1- [bis (p-tolyl) methyl] -3- [methylsulfonyl-phenylmethyl- (RS ) ] azetidin-3-ol in 25 cm3 of anhydrous dichloromethane followed in small fractions by 0.465 g of 4 -dimethylaminopyridine . After stirring for 20 hours at 20°C, the reaction' mixture is washed with twice 80 cm3 of water, with 80 cm3 of brine, dried over ■ magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column- (particle size 0.040-0.063 mm, height 17 cm, diameter 3.2 cm), elu-ting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 40-cm3 fractions. Fractions 5 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa)-. The residue is stirred with diisopropyl ether, the solid, is filtered, drained and then dried under reduced pressure (2.7 kPa) . 0.25 g of 99 1- [bis (p-tolyl ) methyl ] -3- (methylsulfonylphenyl-methylene ) azetidine is obtained in the form of a white solid [NMR spectrum in DMS0-d6, T=300K, δ in ppm (250 MHz) : 2.23 (6H, s, .2Ph-CH3), 2.98 (3H, s, SCH3) , 3.76 (2H, s, NCH2), 4.20 (2H, s,'NCH2), 5.55 (1H, s, NCH) , 7.10 (4H, d, J=7Hz, 4 CH arom. ) , 7.32 (4H, d, -J=7Hz, 4CH arom.), 7.43 (5H, s, phenyl)]'. 1- [Bis (p-tolyl) methyl] -3- [ (methylsulfonyl) -phenylmethyl- (RS ) ] azetidin-3-ol may be prepared by carrying out the procedure in the following manner; 0.6 g of 3- [ (methylsulfonyl ) (phenyl) methyl- (RS) ] -azetidin-3-ol hydrochloride is added to a solution of 0.59 g of bromo (bis-p-tolyl ) methane in 20 cm3 of acetonitrile followed by 0.3 g. of potassium carbonate. · After heating for 1 hour and 15 minutes at the reflux temperature, the reaction mixture is. cooled to 20°C and filtered. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is chromatographed on a silica gel column (.particle size 0.04-0.06 mm, diameter 4 cm, height 16 cm), eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) and -collecting 50-cm3 fractions. Fractions 8 to 13 are concentrated to dryness under- reduced pressure (2.7 kPa) . 0.48' g of 1- [bis (p-tolyl) methyl] -3-[ (methyisulfonyl) (phenyl) methyl- (RS) ] azetidin-3-ol is obtained in the form Of a white solid..
Brom (bis-p-tolyl ) methane may be prepared according to the procedure described by BACHMANN W.E., J.Am.Chem.Soc. , 2135, (1933) . 100 3- [ (Methylsulfonyl) phenylmethyl- (RS) ] azeditin- 3-ol hydrochloride may be prepared by carrying out the procedure in the following manner: 12.6 cmJ of a 6.2 N hydrochloric acid solution in dioxane are added to a solution of 2.62 g of 3- [ (methylsulfonyl ) (phenyl)-' methyl- (RS) ] -1- (vinyloxycarbonyl) azetidin-3-ol in 12.6 cm3 of dioxane. After stirring for 20 hours at 20°C, the mixture is concentrated to dryness at 50°C under reduced pressure (2.7 kPa) . The residue is taken up in 25 cm3 of ethanol, heated under reflux for 1 hour and then allowed to return to 20 °C rand filtered. The solid is rinsed with diethyl ether and then drained and dried under reduced pressure (2.7 kPa) . .1.89 g of . 3- [ (methylsulfonyl) phenylmethyl- (RS) ] azeditin-3-ol hydrochloride are obtained in the form of white crystals. 3- [ (Methylsulfonyl ) (phenyl ) me'thyl- ( RS ) ] -1- .( inyloxycarbonyl ) azetidin.-3-ol may be prepared by carrying out the procedure in the following manner: a solution of 0.99 cm3 of vinyl chloroformate in 4 cm3 of anhydrous dichloromethane is poured dropwise into a mixture, cooled to +5°C, of 3.92 g of l-benzhydryl-3-■ [ (methylsulfonyl) (phenyl) methyl- (RS) ] azetidin-3-ol in 500 cm3 of anhydrous dichloromethane. After stirring for 48 hours at 20°C, the reaction mixture is concentrated to dryness, under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter .6 cm, height 15.5 cm), eluting with a. mixture of 101 cyclohexane and ethyl acetate (70/30 by volume) and collecting 50-cm3 fractions. Fractions 17 to 36 are concentrated to dryness under reduced pressure {2.1 kPa) . 0.9 g of 3- [ (methylsulfonyl ) (phenyl) methyl- (RS) ]—1- ( vinyloxycarbonyl ) azetidin-3-o.l is obtained in the form of a white solid. l-Benzhydryl-3- [ (methylsulfonyl)- (phenyl) methyl- (RS) ] azetidin-3-ol may be prepared by carrying out the procedure as described in Example 1 (method Γ) , · starting with 47 cm3 of diisopropylamine , 205.6 cm3 of a 1.6 M solution of n-butyllithium in hexane,.2.2 litres of tetrahydrofuran, "50 g of benzylitiethyl sulfone and 69.6 g of l-benzhydrylazetidin-3-one . 94.3 g of 1-benzhydryl-3- [ (methylsulfonyl ) (phenyl) methyl- , (RS) ] azetidin-3-ol are obtained in the form of white crystals.
Example 7 1- [Bis (3-fluorophenyl) methyl] -3- (RS) -[ (3, 5-di.fLuorophenyl) methylsulfonylmethyl] azetidine may be prepared by carrying out the procedure' as described in Example 3, starting with 0.10 g of l-[.bis(3-fluorophenyl ) methyl] -3- [ (3, 5-difluorophenyl ) methyl-sulfo.nylmethylene] azetidine, 2 cm3 of methanol, 2 · cm3 of dichloromethane and 20 mg of sodium borohydride, with stirring for 48 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm),, eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions. Fractions 3 to 7 are 102 combined and concentrated to dryness under reduced pressure (2.7 kPa) . 95 mg of 1- [bis (3-fluorophenyl) - methyl] -3- (RS) - [ (3, 5-difluorophenyl) methylsulfonyl-' methyl].azetidine are obtained in the form of white crystals [XH NMR spectrum (300 MHz, CDCI3, δ in ppm) : 2.57 (t, J = 7.5 Hz : 1H) ; 2.66 (s : 3H) ; from 3.15 to .3.30 (mt : 2H) ; from 3.30 to 3.50 (mt : 1H) ; 3.66 (broad t, J = 7.5 Hz : 1H) ; 4.27 (d, J = 11.5 Hz :. 1H) ; 4.28 (s : 1H) ; from 6.75 to 7.35 (mt : llH) ] . -■ l-[Bis (3-fluorophenyl) methyl] -3-[ (3, 5- . difluorophenyl) methylsulfonylmethylene] azetidine may be prepared by carrying out the procedure as described in Example 6, starting with 1.15 g of 1- [bis (3-fluorophenyl) methyl ]—3- [ (3, 5-difluorophenyl) (methylsulfonyl) - methyl- (RS) ] azetidin-3-ol, 30 cm3 of dichloromethane, 0.264. cm3 of methylsulfonyl chloride and 0.98 g of 4- dimethylaminopyridine. After chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height 25 cm) , under an: argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (15/85 by volume) as eluent and collecting 60-cm3 fractions, 0.55 g of 1- [bis (3-fluorophenyl) methyl] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) methylene] azetidine is obtained in the form of a' white solid melting at 178 "C. Ί- [Bis (3-fluorophenyl) methyl] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) methyl- (RS) ] azetidin-3-ol may be prepared according to the following procedure: 3.65 cm3 of a 1.6 M solution of n-butyllithium in hexane are poured over 10. minutes into 103 a mixture, cooled to -60°C, of diisopropylamine and 10 cm3 of tetrahydrofuran, the mixture is stirred for 10 minutes at -30°C and then cooled to -70°C. A ■ solution of 1.2 g of (3, 5-difluorobenzyl ) methyl sulfone in.30 cm3 of tetrahydrofuran is then added over minutes. After stirring for 30 minutes at -70°C, the . mixture is supplemented over 30 minutes with a solution of 1.5 g of. 1- [bis ( 3-fluorophenyl ) methyl] azetidin-3-one in 10 cm3 of tetrahydrofuran . After stirring for 2 hours at -70°C,.. the :'reaction mixture is brought to room temperature and then supplemented with 20 cm3 of a saturated . aqueous ammonium chloride solution and' 100 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is washed. with water and then dried over magnesium sulfate, filtered and .' . concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on- a silica gel column (particle size 0.06-0.200. mm, diameter 3.2 cm, height 30 em)., eluting. under an argon pressure of 1 bar with a mixture of ethyl acetate and cyclohexane (20/80 by: volume) and collecting 60-cm3 fractions. Fractions 9 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 1.95 g of 1- [bis ( 3-fluorophenyl ) methyl ] -3- [ (3, 5-difluorophenyl). (methylsulfonyl ) methyl- (RS) ] - azetidin-3-ol are obtained in the form of a white solid melting at 170°C (decomposition) . 1- [Bis ( 3-fluorophenyl) methyl ] azetidin-3-one may be prepared by carrying out the procedure as described 104 in Example 1 (method 2) starting with 0.7 cmJ of oxalyl chloride, 16 cm3 of dichloromethane , 1.12' cm3 of dimethylsulfoxide, 2 .g of 1- [bis ( 3-fluorophenyl ) -methyl] azetidin-3-ol and 3.7 cm3 of triethylamine . 1.55 g of 1- [bis (3-fluorophenyl)methyl] azetidin-3-one are obtained in the form of an oil which crystallizes a.t 20 °C. 1- [Bis (3-fluorophenyl) methyl] azetidin-3-ol may be. prepared by carrying out the procedure as described by KATRITSKY A.R. in J. Heterocycl .. Chem, 31, 271 (1994) starting with 4.9 g of [bis ( 3-fluorophenyl ) -methyl] amine and 1.78 cm3 of epichlorohydrin .
[Bis (3-fluorophenyl) methyl] amine may be prepared in the following manner: a solution of 5.17 g of 3 , 3 ' -difluorobenzophenone oxime in 30 cm3 of tetrahydrofuran is poured, under an argon atmosphere over 30 minutes, into ■ a suspension of 1.27 g of lithi.um aluminum hydride in 80 cm3 of tetrahydrofuran . After stirring for 5 hours under reflux, 1.3 cm3 of water, 1.3 cm3 of 4 N sodium "hydroxide, 2.6 cm3 of water and · then 50.cm3 of ethyl acetate are added successively. After drying over magnesium sulfate and concentrating to dryness under reduced pressure (2.7 kPa), 4.9 g of [bis (.3-fluorophenyl ) methyl] amine are obtained in the form of a yellow oil. 3 , 3 ' -Difluorobenzophenone oxime may be prepared according to the following procedure: a solution of 1.6 g of hydroxylamine hydrochloride in 8 cm3 of water is poured dropwise into a solution of 5.0 g of 105 3.3' -difluorobenzophenone in 10 cm3 of.ethanol and then 1.2 g of sodium hydroxide pellets are added in small fractions. The reaction mixture, heated under reflux for 10 minutes, is cooled to 20°C and then acidified with 7.5 cm3 of 4 N hydrochloric acid. The oily ' precipitate obtained, once it has been triturated, becomes a white .solid which is filtered, washed with water and then dried at 35°C under, reduced pressure (2.7. kPa) . 5.17 g of 3, 3 ' -difluorobenzophenone . oxime are obtained in the form of a white solid.
Exam le 8 1- [Bis (4-chlorophenyl)methyl] -3- (RS) -{ [3- azetidin-l-yl-phenyl] methylsulfonylmethyl } azetidine .may be. prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1- [bis .( 4-chloro- phenyl ) methyl] -3- [ ( azeti'din-l-yl-phenyl ) methylsulfonyl- methylen.e] azetidine, 2 cm3 of methanol, 2 cm3 of dichloromethane and 3,0 mg of sodium borohydride, stirring for 24 hours at 20 °C. The crude product _i.s~ chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with dichloromethane and collecting 4-cm3 fractions. Fractions 5 to- 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 20 mg of 1- [bis ( 4 -chlorophenyl ) - methyl] -3- (RS)'- { [ 3-azetidin-l-yl-phenyl ] methylsulfonylmethyl } azetidine are obtained in' the form- of an off- white lacquer [XH NMR -spectrum (300 MHz, CDC13, δ in ppm) : 2.39 (mt : 2H) ; from 2.50 to 2.65 (mt : 1H) ; 106 2.60 (s : 3H) ; 3.20 (mt : 2H) ; 3.47 (mt : 1H) ; 3.66 (broad t, J = 7 Hz : 1H) ; 3.89 (broad t, J = 7.5 Hz : 4H);\ 4.20 (d, J = .11 Hz : 1H) ; 4.26 (s : 1H) ; from 6.35 to 6.50 (mt : 2H) ; 6.67' (broad d, J = 7.5 Hz : 1H) ; from 7.10 to 7.40 (mt : 9H) ] . 1- [Bis ( -chlorophenyl) methyl] -3-[ (azetidin-1-yl-phenyl) methylsulfonylmethylene] azetidine may be prepared by carrying out the procedure by carrying out the procedure as described- in Example 6, starting with 0.83 g of 1- [bis (4-chlorophenyl)-methyl] -3- [ (azetidin-1-yl-phenyl) methylsulfonylmethyl- (RS) ] azetidin-3-ol , 20 cm3 of dichloromethane, 0.18 cm3 of methylsulfonyl chloride and .0·.75 g of 4 -dimethylaminopyridine . 0.40 g of 1- [bis ( 4-chlorophenyl ) methyl] -3- [ (azetidin-l-yl-phenyl ) methylsulfonylmethylene] azetidine is obtained in the form of a white foam. 1- [Bis ( 4-chlorophenyl) methyl]—3- [( azetidin-1-yl-phenyl) methylsulfonylmethyl- (RS) ] azetidin-3-ol may be prepared by carrying out the procedure. as described in Example 5, starting with 1.55 g of l-(3-methyl- ■ sulfonylmethylphenyl ) azetidine, 5.2 cm3 of a 1.6 M solution of n-butyilithium in hexane, 30 cm3 of tetrahydrofuran and 2.11 g of 1- [bis ( 4-chlorophenyl) -methyl] azetidin-3-one . ^..83 g of 1- [bis ( 4-chloro-phenyl) methyl] -3- [ (azetidin-l-yl-phenyl ) methylsulfonylmethyl- (RS )] azetidin-3-ol is obtained in the form of an. ochre-colored solid melting at 172°C. 1- ( 3-Methylsulfonylmethylphenyl ) azetidine may be prepared by carrying out the procedure in the 107 following manner: a solution of 1.9 g of l-(3-methylsulfanylmethylphenyl ) azetidine in 10 cmJ of ethanol is added to a mixture, cooled to 0°C, of 10 cm3 of water, 5 cm3 of acetic acid, 1.5 cm3 of 36 N sulfuric, acid and 6.15 g of oxone . After stirring for 20 hours at 20°C, the reaction mixture is supplemented with 1.00 cm3 of water, 100.cm3 of ethyl acetate and is then neutralized by stirring with sodium hydrogen carbonate. The mixture obtained is separated after settling, the organic phase is dried over magensium sulfate- and then filtered and concentrated to dryness under reduced pressure (2.7 kPa) . 1.55 g of 1- ( 3-methylsulfonyl-methylphenyl) azetidine are obtained in the form of a light brown gum. 1- [3- (Methylsulfonylmethyl ) phenyl] azetidine may be prepared by carrying out a procedure in the following manner: 2.57 g of potassium tert-butoxide, 0.64 g of 1, 1' -bis (diphenylphosphino) ferrocenyl-palladiunv chloride, 1.49 g of 1, 1' -bis (diphenylphosphino) ferrocene, 0.12 g of copper- iodide and 2.0 g of azetidine are added, under argon, to a solution of 4.6 g of l-iodo-3- (methylsulfanylmethyl ) benzene in 60 cm3 of tetrahydrofuran . After heating for 3 hours at the reflux temperature, the reaction mixture is cooled to room temperature and filtered on celite and then washing the latter with 150 cm3 of ethyl acetate. The combined filtrate and> washings is acidified with 120 cm3 of 1 N hydrochloric acid and then separated after settling. The aqueous phase is supplemented with 108 60 cm3 of ethyl acetate and is then alkalinized with sodium hydrogen carbonate and the mixture is separated after settling. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue is is chromatographed on a silica gel column (particle size 0..06-0.200 mm, diameter 3.5 cm, height 50 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/8Ό by. volume \. and collecting lOO-crn3 fractions. Fractions 1 to 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 1.9 g of 1- [3- (methylsulfonyl-methyl) phenyl] azetidine are obtained in the form of an oil. 1, 1' -Bis (diphenylphosphino) ferrocenylpalladium chloride may be prepared by carrying out the. procedure according to Hayashi T. et al . , in J. Am. Chem. Soc, 106, 15.8 (1984) . . . l-Iodo-3- (methylsulfanylmethyl) benzene may be prepared by carrying out the procedure in the following manner: 6.4 g of sodium methylthiolate are added to a solution of 25 g of .3-iodobenzyl bromide in .80 cm3 of .' N, -dimethylformamide .. After stirring for 20 hours at 20°C,. the reaction mixture is supplemented with 250 cm3 of water, 200 cm3 of ethyl acetate and is stirred and then separated after settling. The organic phase is washed with four times 200 cm3 of water, dried over magnesium sulfate, filtered and then concentrated to dryness at 50°C under · reduced pressure (2.7 kPa) . 22 g 109 of l-iodo-3- (methylsulfanylmethyl ) enzene are obtained in the form of a gum.
Example 9 The mixture of. the 2 A form diastereoisomers 1- (R*)-{4-[ (4-chlorophenyl) -{3- [ ( 3 , 5-difluorophenyl ) - methylsulfonylmethyl- (R) ] -3-imidazolyl-azetidin-l- yl }methyl] benzyl } -IH-imidazole and l-(R*)-{4(4- chlorophenyl) - { 3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethyl- (S) ) } -3-imidazolyl-azetidin-l-yl }methyl] benzyl] - IH-imidazole may be prepared by carrying out the procedure in the following manner: 13.6 mg of imidazole are added to a solution of '50 nig of l-{(R*)-[4-• (chloromethyl) phenyl] - (4-chlorophenyl)methyl}-3-'['(3, 5- difluorophenyl) methylsulfonylmethylene] azetidine, A isomer form, in. 1 cm3 of dichloromethane .. After stirring for 20 hours ■ at 20°C, the reaction mixture is directly chromatographed on a silica gel column: (particle size 0.063-0.200 mm, height 7 cm, diameter 1 cm), eluting under an argon pressure of 0.1 bar with a mixture of dichloromethane and methanol (98/2 by volume) and collecting 4-cm3 fractions. Fractions 4 to . 9 are combined and concentrated to dryness under reduced pressure (2.7 kPa).. 20 mg of the mixture of the 2 A form diastereoisomers 1- (R* )-{ 4- [. ( 4-chlorophenyl) - {3- [ C3, 5-difluorophenyD methylsulfonylmethyl- (R) ] -3- imidazolyl-azetidin-l-yl } methyl] benzyl } -1H-imidazole and 1- (R*) -{.4- [ (4-chlorophenyl )■-{ 3- [3- [ (3,5-difluorophenyl) methylsulfonylmethyl- (S) ] } -3-imidazolyl-azetidin-l-yl }methyl] benzyl] -IH-imidazole are obtained 110 in the form of a white lacquer [XH NMR. spectrum (300 MHz, CDCI3, δ in ppm) : a mixture of diastoero- isomers is observed, * 2.64 (s : 3H) ; 3.42 (d, J = 8 Hz :' 1H) ; .3.50 (d, J = 8 Hz : 1H) ; 3.75 (mt : 1H) ; 4.31 ' (broad d, J = 8 Hz : .1H); 4.40 (s : 1H) / 4.54 and 4.55 (2s : 2H. in total); 4.72. (s : ,1H) ; 6.84 (mt :. 2H) ; 6.87 . is : 1H) ; 6.95 (mt : 1H) ; 7.11 (s : 1H) ; from 7.20' to 7.40 ' (mt 12) ] .
Example 10 ( l-Benzhydrylazetidin-3-yl) phenylmethanone O-methyloxime, a mixture of. the 2 isomers Z and E, may be prepared by. carrying -out the procedure in the following manner: 0.286 g of O-methylhydroxylamine and 0.32 g of sodium acetate are added to a -suspension of 0.80 g of l-benzhydryl-3-benzoylazetidine in 30 cm3 of ethanol. After stirring .for 24 hours at reflux temperature,, the reaction mixture is allowed to cool 'at room temperature and filtered. The filtrate is concentrated to dryness at 50°C under' reduced pressure (2.7 kPa) . The residue is taken up in 100 cm3 of dichloromethane and the solution is supplemented with 20 cm3 of water and 1 N hydrochloric acid, stirring until an acidic pH is obtained. The organic phase is separated after settling, dried over magnesium, sulfate and then filtered and concentrated to dryness under reduced pressure (2.7 kPa).. .
The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 36 cm, diameter 3.8 cm), eluting under an argon pressure of Ill 0.5 bar with a mixture of cyclohexane and ethyl acetate (95/5, 92/8 and then 80/20 by volume) and collecting 30-cm3 fractions. Fractions 8 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.20 g of (l-benzhydrylazetidin-3-yl ) phenyl-methanone O-methyloxime, a mixture- of the.2 isomers Z and E, is obtained in the form of a white solid {lR NMR spectrum (250 MHz, {CD3)2SO d6, d in..ppm) . A 65/35 mixture of isomers is observed, * 2.68-3.02 and. from 3.25 to 3.90 (rots .: 5H in total) ; 3.76 and 3.80 (2s :3H in total); 4.26 and 4.38 (2s : 1H in total); from.7.10 to 7.50 (mt : 15H) ] . ; l-Benzhydryl-3-benzoylazetidine may be prepared by carrying out the procedure in the following manner: .112 cm3 of a 1 M solution of phenylmagnesium bromide in tetrahydrofuran are poured dropwise,. under argon, into a solution, cooled to,0°C, of 11.5 g of (1- -benzhydrylazetidin-3-yl ) carboxylic-N-methoxy-N-methylamide acid in 350. cm3 of te.trahydrofuran, and then the mixture is allowed to return to room temperature. After stirring for 20 hours at 20°C, the . reaction mixture is supplemented with 400 cm3 of a saturated ammonium chloride solution and then with 250 cm3 of ethyl acetate. After stirring, the mixture is separated after settling, the aqueous phase reextracted with 250 cm3 of ethyl acetate and the combined two organic phases are washed with twice 250 cm3 of water, dried over magnesium sulf.ate, filtered and concentrated to dryness at 50°C under 112 reduced pressure (-2.7 kPa) . The residue is stirred with 50 cm3 of diisopropyl ether, the suspension is filtered, the. solid- is drained and then dried under reduced pressure (2.7 kPa) . l-benzhydryl-3-benzoylazetidine are obtained in the form of a cream-colored solid .' (l-Benzhydrylazetidin-3-yl) carboxylic-N- -methoxy-N-methylarnide may be prepared by carrying out the procedure in the following manner: 13.35 g.pf (1-benzhydrylazetidin-3-yl) carboxylic acid and 1.0 g of hydroxybenzotriazole hydrate are added, with stirring, to a suspension of 4.0 g of N, O-dimethylhydroxylamine hydrochloride in 250 cm3 of dichloromethane . 6.92. g of 1- ( 3-dime'thylaminopropyl )-3-ethylcarbodiimide hydrochloride and 8.8 cm3 of N, N-diisopropylethylamine . are added .to this mixture, placed under argon and cooled to +5°C. After stirring for 3 hours at +5°C and then for 20 hours at 20°C, the reaction mixture is. supplemented with 200 cm3 of water and then separated after settling. The organic phase is washed with 300 cm3 of water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) . The residue is stirred with 100 cm3 of diisopropyl ether, the suspension is filtered and the solid is drained and then dried under reduced pressure (2.7 kPa);. 10.76 g of ( l-benzhydrylazetidin-3-yl ) carboxylic-N-methoxy-N-methylamide are obtained, in the form of a cream-colored solid. 113 ( l-Benzhyd'rylazetidin-3-yl ) carboxylic acid may be prepared by carrying out the procedure in the . following manner: a solution of 11 g of potassium hydroxide in 9 cm3 of water is added dropwise to a suspension, cooled to +5°C, of 14 g of ( l-benzhydryl- · ■ azetidin-3-yl) carbonitrile in 140 cm3 of 2-ethoxy- ethanol and then- the mixture is heated to 95°C.. After stirring for 16 hours : at this temperature, the reaction mixture is poured slowly, with stirring, over ice and ■ left at 0°C for 68 hours and then concentrated to dryness to dryness at 50°C under reduced pressure (2.7.kPa). The residue is taken up in 400 cm3 of water, . the solution is acidified to pH 4 with 6 N hydrochloric acid and then supplemented with 400 cm3 of ethyl acetate. The resulting suspension is filtered, the ■' solid is .drained and then dried at 50°C under reduced pressure (2.7 kPa) . 13.55 g of · ( l-benzhydrylazetidin-3- yl ) carboxylic acid are obtained in the form of a- cream- colored solid. ' ( l-Benzhydrylazetidin-3-yl) carbonitrile may be prepared by carrying out the procedure in the following manner: a solution of 18.5.4. g of sodium cyanide in 25 cm3 of water is added dropwise to a- solution of 40 g of l-benzhydrylazetidine-3-yl methylsulfonate in 350, cm3 of N, N-dimethylformamide . After stirring for 24 hours at 65°C, the reaction mixture, allowed to return to room temperature, is then poured, with stirring, . into a mixture of 550 cm3 of water and 300 g of ice. The suspension obtained is filtered, the solid 114 is washed with three times 110 cm3 of water and then dissolved in 350 cm3 of dichloromethane. The solution is dried over magnesium sulfate, filtered. nd concentrated to dryness under reduced pressure (2.7 kPa) . The residue is stirred with 200 cm3 of diisopropyl ether, the suspension filtered, the solid drained and then dried under reduced pressure . (2.7 kPa) . 28.4 g of '( l-benzhydrylazetidin-3-yl ) -carbonitrile are obtained in the form of a pinkish cream-colored, solid. ■ l-Benzhydrylazetidin-3-yl methylsulfonate may be prepared by carrying out the procedure starting with 100 g of l-benzhydrylazetidin-3-ol ,. 800 cm3 of dichloromethane, 31 cm3 of methylsulfonyl chloride and 35 cm3 of pyridine. The crude product obtained is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 50 cm, diameter 11 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate. (80/20, 75/25, and then 70/30 and 60/40 by volume) and collecting.1-litre fractions. Fractions 12 to 31 are. combined and concentrated to dryness under reduced pressure (2.7 kPa) . 66 g of l-benzhydrylazetidine-3-yl methylsulfonate are obtained in the form of a yellowish white solid. l-Benzhydrylazetidin-3-ol may be prepared by carrying out the procedure as described by · Alan R. KATRITZKY et al . , in J. Heterocyclic Chem.; 31, 271 (1994) . 115 Example 11 (RS) -l-[3- ( {1-Bis (4-chlorophenyl)methyl] - azet'idin-3-yl }methylsulfpnylmethyl) phenyl] pyrrolidine may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of l-[3- ( {1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - methylsulfonylmethylene) phenyl] pyrrolidine, "1.5 cm3 of . anhydrous methanol, 1.5 cm3 of anhydrous dichlorometh.ane, and .30 mg of sodium borohydride, stirring for 3 hours at 20°C and then 8 hours at 50°C. The crude product is chromatographed on a silica gel column (particle size 0.04Ό-0.063 mm, height 8 cm, diameter 1 cm),, eluting under an argon pressure of 0.8' bar with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting. 5-cm3 fractions.
Fractions. 22 to 28 are combined and concentrated to dryness under reduced 'pressure (.2.7 kPa) , the residue is stirred with 5 .cm3 of pentane, the solid is filtered, drained and dried. 18. mg of (RS) -1- [3- ( { 1- [bis (4-chlorophenyl)methyl] azetidin-3-yl }methyl- ■ sulfonylmethyl) phenyl] pyrrolidine are obtained' in. the form of white powder [XH NMR spectrum (300 MHz, CDC13, δ in pp.m) : 2.01 (mt : 4ft);. 2.59 (mt : 1H) ; 2.61 (s : ,'3H) ; from 3.10 to 3.25 (mt : 2H) ; 3.27 (mt : 4H) ; from 3.4C to 3.55 (mt : 1H);.'3.66 (mt : 1Ή) ; 4.20 (d, J = 12 Hz : 1H) ; 4.25 (s : 1H) ; from 6.45- to 6.65 (mt r 3H) ; from 7.10 to 7.35 (mt : 9H) ] . 1- [3- ( { 1- [Bis (4-chlorophenyl). methyl] azetidin-3- yl }.methylsulfonylmethylene) phenyl] pyrrolidine may be 116 prepared by carrying out the procedure as described in Example 6, starting with 0.6 g of l-[bis(4- chlorophenyl) methyl] -3- [ (methylsulfonyl ) (3-pyrrolidinylphenyl) methyl- (RS) ] azetidin-3-ol , 0.1 cm3 of methylsulfonyl chloride and 0.5 g of 4-dimethylaminopyridine, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, . height ■ 30 cm) under an' argon pressure of 0,5 bar with. dichloromethane and-ethanol mixture as eluent (98.5/1.5 by volume) and collecting 10-cm3 fractions. Fraction 4 is concentrated to dryness under reduced pressure (2.7 kPa) . After recrystallization from 5 cm3 of diethyl ether, 0.5 g of 1- [3- ({ 1- [bis ( -chlorophenyl) -methyl] azetidin-3-yl }methylsulfonylmethylene) phenyl] -pyrrolidine is obtained in the form of a solid melting at 133°C. ' 1- [Bis (4 -chlorophenyl) methyl] -3- [ (methyl-sulfonyl) ( 3 -pyrrolidinylphenyl ) methyl- (RS) ] azetidin-3-ol may be obtained by carrying out the operation according to the procedure of Example 5, starting with 0.5 g of 1- [3- (methylsulfonylmethyl ) phenyl] pyrrolidine, 0.6 g of 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-one, 15 cm3 of tetrahydrofuran and 1. cm3 of a .1.6 N solution of n-butyllithium in hexane . 0.6 g of 1-[bis ( 4-chlorophenyl ) methyl] -3- [ (methylsulfonyl ) ( 3-pyrrolidinylphenyl) methyl- (RS) ] azetidin-3-ol is. obtained in the form of a cream-colored solid. 117 1- [3- (Methylsulfonylmethyl ) phenyl] pyrrolidine may be prepared by carrying out the procedure described in Example 8, starting with 6.cm3 of water, 6 cm3 of 100% acetic acid, 3.5 cm3 of 36 N sulfuric acid, 3.11 g of oxone, 0..96 g of 1- [3- (methylsulfanylmethyl) phenyl] -pyrrolidine and 6 cm3 of.ethanol. 0.478 g of l-[3- tmethylsulfonylmethyl) phenyl] pyrrolidine is obtained in. the form of a light brown gum. 1- [3- (Methylsulfanylmethyl) phenyl] pyrrolidine ■ may be prepared by carrying out the procedure as described in Example 8', starting with 4.0 g of 1-iodo-3- (methylsulfanylmethyl) benzene, 120 cm3 Of tetrahydrofuran, 2.2 g of sodium tert-butoxide, 0.556 g of 1, l' -b.is (diphenylphosphino) ferrocenylpalladium chloride, 1.26 g of 1, 1' -bis (diphenylphosphino) -ferrocene and 2.6' g of pyrrolidine.' 1.9 g' of l-[3- (methylsulfanylmethyl) phenyl] pyrrolidine are obtained -in. the. form of an oil.
Example 12 . N- (RS)- [3- ({1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } methylsulfonylmethyl ) phenyl] -N-methyl-carbamic acid tert-butyl ester may be prepared- by carrying out the procedure as described in Example 3, starting with 0..10 g bf N- [3- ( {'1- [bis (4-chlorophenyl) -methyl] azetidin-3-yl }methylsulfonylmethylene) phenyl] -N-methylcarbamic acid tert-butyl ester, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 30 mg of sodium borohy-dride , with stirring for 3 hours at 20°C. The crude product is 118- stirred with 10 cm3 of diisopropyl ether, the solid is filtered, drained and then dried under reduced pressure (2.7 kPa>. 94 mg of N- (RS )-[ 3- ({ 1- [bis ( 4 -chlorophenyl ) -methyl ]azetidin-3-yl } methylsulfonylmethyl ) phenyl ] -N-methylcarbamic acid tert-butyl ester are obtained in the form of a white powder [:H NMR spectrum (300 MHz, (CD3)2SO d6, δ· in ppm)' ·: 1.36 (s : 9H); 2.46 (t, J- = 7.5 Hz : 1H) ; 2.75 (s : .3H) ; from 3.00 to 3.55 (mt : 4H) ; 3.17 (s : 3H) ; 4.45 (s : 1H) ; 4.78 (d, J =. 11 Hz' : 1H) ; from 7.20 to 7.50 (mt ,: 12H) ] .
N- [3- ({ 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl } methyl sulfonylmethylene ) henyl ] -N-methylcarbamic acid tert-butyl ester may be prepared by carrying out the procedure as. described in Example 6, starting with 5.6. g of ■ 1- [bis ( 4-chlorophenyl) methyl] -3-{ [3- (N-tert- . butyloxycarbonyl-N-methylamino) phenyl] methylsulfonylmethyl- (RS). } azetidin-3-ol, 100 cm3 of dichloromethane, 1.59 g of methylsulfonyl chloride and 4.5 g of 4-dimethylaminopyridine. The crude product . obtained is purified by chromatography on a . silica . gel ' column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica 250 gj , eluting under a nitrogen pressure of 0.5 bar. with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 100-cm3 fractions.
Fractions 12 to 18 are. combined, concentrated to dryness under reduced pressure (2.7 kPa) . 3.2 g of N- [3- ( { 1- [bis (4-chlorophenyl ) methyl ] azetidin-3-yl }methylsulfonylmethylene) phenyl] -N-methylcarbamic 119 acid tert-butyl ester are obtained in the form of a. white foam. 1- [Bis (4-chlorophenyl) methyl] -3- { [3- (N-tert-, butyloxycarbonyl-N-methylamiho). phenyl ].methyIsulfonyl- methyl-'(RS) } azetidin-3-ol , may be prepared by carrying out the procedure as described in Example 5, starting .with 3.8 g of N- [ 3- (methylsulfonylmethyl ) phenyl ] -N- methylcarbamic acid tert-butyl ester, '50 cm3 of tetrahydrofuran, 9.5 cm3 of a 1.6 N solution of . n- butyllithium in hexane, and 3.82 g of l-[bis(4- chlorophenyl) methyl] azetidin-3-one . The crude product is purified by chromotography on a silica gel column (particle ■ size 0.04-0.06 mm, diameter 4 cm, weight of silica 250 g) , eluting under a nitrogen pressure of 0.5 bar with dichloromethane ' and then with a dichloromethane and ethanol ' (99/1 by volume) mixture and collecting 500-cm3 fractions. Fractions 10 to 16 are combined, concentrated to dryness under reduced pressure (2.7 kPa) . ,5.6 g of 1- [bis ( 4-chlorophenyl) -methyl] -3-{ [3- (N-tert-butyloxycarbonyl-N-methylamino) -phenyl] methylsulfonylmethyl- (RS) } azetidin-3-ol are obtained in. the form of a foam.
N- [3- (Methylsulfonylmethyl) phenyl] -N-methylcarbamic acid tert-butyl ester may be prepared by carrying out the procedure in the following manner:' 3.7 g of di-tert-butyl dicarbonate are added to a solution of 3 g of N- [3- (methylsulfonylmethyl) phenyl] -methylamine in 80 cm3: of dichloromethane. After stirring for 20 hours at 20°C, the reaction mixture is 120 supplemented with 100 cm3 of water and then separated after settling. The organic phase is dried over magnesium sulfate, filtered and then concentrated to" dryness under reduced pressure (2.7 kPa)'. The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm and weight of silica ■ 300 g) , eluting under a nitrogen pressure of 0.5 bar with a mixture ■ of ethyl acetate and cyclohexane (45/55. by volume) and .collecting 100-cm3 fractions. Fractions -11 to 16 are combined and concentrated to dryness under reduced pressure .(2.7 kPa) . 3.8 g of N- [3- (methyl- sulfonylmethyl ) phenyl] -N-methylcarbamic acid tert-butyl ester are obtained in the form of a gum which crystallizes N- [ 3- ( ethylsulfonylmethyl ) phenyl] -methylamine may be obtained by carrying out'the procedure in the following manner: a mixture of 9.65 cm3 of formic acid and. 19.63 cm3 of acetic anhydride is heated at 50 °C for 3 hours under argon, and then the solution- obtained is allowed to return, to room temperature. 40 cm3 of tetrahydrofuran are poured in and the medium is cooled to -20°C. After stirring for 2 hours at -20°C, a 'solution of 14.8 g of 3- (methylsulfonylmethyl ) phenyl-.amine is poured in while the temperature is . maintained . After stirring for 2 hours at -20°C,- and then for 48 hours at 20°C, the mixture is filtered, the solid is drained and then washed with three times 50 cm3 of diisopropyl ether and dried under reduced pressure (2.7 kPa) . A solid A is obtained. The filtrate is 121 concentrated to half the volume, the resulting " suspension is filtered, the solid is drained, washed with diisopropyl ether and dried. A solid B is obtained. The two sol ds A and B are combined and taken up in 375 cm3 of tetrahydrofuran and the mixture, cooled to 0°C, is supplemented, over 20 minutes, with 8.0 cm3 of a 2 M solution of borane-dimethyl sulfide complex in ■ tetrahydrofuran and then heated at reflux temperature for 3 hours. The reaction mixture, _ cooled · to +5°'C, is supplemented over 20· minutes with 60 cm3 of methanol, stirred for 1 hour at room temperature and then supplemented with gaseous hydrochloric . acid to a pH of 1. The mixture is heated under reflux for one hour and then supplemented with 300 cm3 of water and with a 3 N solution of sodium hydroxide to pH 8. The resulting mixture is extracted with 500 cm3 of ethyl acetate, the organic phase is washed successively with a saturated aqueous sodium hydrogen carbonate solution, and with brine, and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . The ■ residue is taken up- in 100 cm3 -of 4 N sulfuric acid, the solution obtained, is washed, with 1.00 cm3 of ethyl acetate, then alkalinized to pH 8 with 3 N sodium hydroxide and with a saturated aqueous sodium carbonate solution and is then extracted with twice 75 cm3 of ethyl acetate. The combined extracts are dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . -8.98 g of N- 122 [3- (methylsulfonylmethyl) phenyl] N-methylairtine are obtained in the form of a pink solid. 3- (Methylsulfonylmethyl) phehylamine may be prepared by carrying out the procedure in" the following manner: a suspension of 23.7 g of 1- (methylsulfonylmethyl ) -3-nitrobenzene in 150 cm3 of methanol and 65 cm3 of 36% hydrochloric acid is heated to reflux temperature and then 18.5 g of .iron are carefully added over 10 minutes, in small fractions. After heating under reflux for 4 hours and then stirring at room temperature for 20 hours, the reaction mixture is supplemented with 5 g of iron and then again heated .under reflux for one hour and then at room , temperature for 20 hours. The mixture is then alkalinized to pH 9 with aqueous ammonia and with sodium hydrogen carbonate, and then extracted with 3 times 250 cm3' of - ethyl acetate, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) . 14.9 g of 3- (methylsulfonylmethyl ) phenyl- amine are obtained in the form of a beige powder. .1- (Methylsulfonylmethyl ) -3-nitrobenzene may be prepared by heating under reflux 23.8 g of 3-nitro- benzyl chloride, 20 g of sodium methyl sulfinate and 250 cm3 of absolute, ethanol . 23.74 g of 1- (methylsulfonylmethyl ) -3-nitrobenzene are obtained in the form of a white powder.
Example 13 (RS) -N- [3- ( {1- [Bis ( 4-chlorophenyl) methyl] -' azetidin-3-yl }methylsulfonylmethyl ) phenyl] -N- 123 methylamine may be' prepared by carrying out the procedure as described in Example 3 starting with 0.10' g of N- [3- ({ 1- [bis ( -chlorophenyl ) methyl] azetidin- 3-yl }methylsulfonylmethylene) phenyl] -N-methylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 45 mg of sodium borohydride, with s.tirring - for 20 hours at- 20°C and then for' 5 hours at 50°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 10 cm, diameter 1 cm) , eluting under an .argon pressure of 0.8 bar with a mixture of cyclohexane and .ethyl acetate (80/20, and then 60/40 by volume) and collecting 5-cm3 fractions. Fractions 20 to 26 are combined and concentrated to dryness under reduced pressure " (2.7 kPa) , the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. mg of (RS) -N- [3- ({ 1- [bis (4-chl.orophenyl) methyl] - azetidin-3^yl }methylsulfonylmethyl ) phenyl] -N- methylamine·. are obtained in the form of a- white powder [l NMR spectrum (300 MHz , CDC13, 8 in ppm) : from 2.50 to 2.65 (mt .: 1H) ; 2.60. (s : 3H) ; 2.82 (d, J = 5 Hz ■: ■ 3H) ; 3.18 (mt : 2H) ;. from 3.35 to 3.50 (mt : 1H) ; 3.64 (broad t, J = 7.5 Hz : 1H). ; 3.80 (mt : 1H) ; 4.18 (d, J = 11.5 Hz : 1H) ; 4.24 (s : 1H) ; from 6.50 to 6.70 (mt : 3H) ; from 7.10 to 7.35 (mt : 9H] .
N- [3- ( { 1- [Bis ( 4 -chlorophenyl ) methyl] azetidin-3- yl }methylsulfonylmethylene) phenyl] -N-methylamine may be prepared by carrying out . the procedure in the following manner: 2.7 g of 1- [bis ( 4-chlorophenyl ) methyl] -3- ( [ 3- 124 ( N-tertbutyloxycarbonyl-N-methylamino).phenyl] methylsulfonylmethylene }.azetidine in 30 cm3 of dioxane and 30 cm3 of a 4.7 N solution of hydrochloric dioxane are stirred for 20 hours. The reaction medium is evaporated to dryness under reduced pressure (2.7 kPa) , taken up in 50 cm3 of water and 50 cm3 of ethyl acetate, stirred and cautiously neutralized with a saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, treated with ." animal charcoal and then concentrated under reduced pressure (2.7 kPa) to a volume of about 25 cm3, then filtered and concentrated to dryness under reduced pressure. 1.3 g of N- [3- ( { 1- [bis ( -chlorophenyl) - . methyl] azetidin-3-yl }methylsulfonylmethylene) phenyl] -N-methylamine are obtained in the form of white crystals, melting at 228°C..
Example 14 (RS)-l-[Bis(4-chlorophenyl)methyl]-3-[ (3, 5-bis-trifluoromethyiphenyl) methylsulfonylmethyl] azetidine may be prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of 1-[bis (4-chlorophenyl)methyl] -3- [ (3, 5-bis-trifluoromethyiphenyl) methylsulfonylmethylene] azetidine, 1.5 'cm3 of anhydrous methanol, 1.5 cm3 of anhydrous dichloromethane and 15 mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is stirred with 5 cm3 of 'pentane, , the solid is filtered, drained and dried. 82 mg of (RS) -1- [bis (4-chlorophenyl) methyl] -3- [ (3, 5-bis-trifluoromethyiphenyl ) - 125 methylsulfonylmethyl] azetidine are obtained in the form of a white powder [XH NMR spectrum (400 MHz,- (CD3)2SO d6, 'δ in ppm) : 2.84 (s : 3H) ; 3.08 (mt : 2H) ; from 3.25 to 3.40 (mt : 1H) ; from 3.45 to 3.65 (mt : 2H) ; 4.45' (s : 1H) ; 5r13 (d, J = 10.5 Hz : 1H) ; from 7.25 to 7.50 (mt : 8H)'; 8.11 (broad s : 2H) ; 8.15 (broad s : 1.H)]. 1- [Bis (4-chlorophenyl) methyl] -3- [ (3, 5-bis-trifluoromethylphenyl) methylsulfonylmethylene] zetidine may be prepared by carrying out the procedure in the following manner: 0.96 g of crushed sodium hydroxide is added in fractions to a solution of 3.16 g of 3-acetoxy-1- [bis (4-chlorophenyl) methyl] -3- { [3, 5-bis ( trifluoromethyl) phenyl] methylsulfonylmethyl- (RS) }-azetidine in '4,0 cm3 of dioxane. After stirring for 1 hour at room temperature, the reaction mixture, is supplemented with 200 cm3 of ethyl acetate, 200 cm3 of water and is then separated after settling. The organic phase is washed with twice 80 cm3 of water, then with 80 cm3 of brine, dried over magnesium sulfate, then filtered and concentrated .to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 14.5 cm, diameter 4.8 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 40-cm3 fractions. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa), 1.49 g of ' 1- [bis- ( 4-chlorophenyl ) methyl ] -3- 126 { [ (3, 5-bis-trifluoromethylphenyl] methylsulfonyl- methylene } azetidine are obtained in the form of a white foam. 3-Acetoxy-l^ [bis ( -chlorophenyl) methyl] -3- { [3, 5-bis ( trifluoromethyl ) phenyl ] methylsulfonylmethyl-. (RS) } -azetidine may be prepared by carrying out the procedure in. the following manner: 4.1 cm3 of a 1.6 N solution of n-butyllithium in hexane are. poured dropwise, under argon, into a solution, cooled; to -78°C, of 2.0 g of [ 3 , 5-bis ( trifluoromethyl ) benzyl ] - methyl sulfone in 35 .cm3 of tetrahydrofuran . After stirring for one hour at -70°C, a solution of 2.0 g of .1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-one in 35 cm3 of tetrahydrofuran is added dropwise. After stirring. for 2 hours at -78°C, a solution of 0.7 cm3 of acetyl chloride in 5 cm3 of anhydrous dietheyl ether is poured . ·. in and then the mixture is. allowed to return to room •.temperature. After stirring for 2 hours and 30 minutes, the reaction mixture is supplemented with 100 cm3 of water and separated after settling. The organic phase is washed with 100 cm3 of water, then with 1.00 cm3"of brine and is then dried over magnesium sulfate and concentrated to dryness . under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter .6 cm, height 16 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (10/90 and then 40/60 by volume.) and collecting 100-cm3 fractions. Fractions 37 to 52 are 127 combined and concentrated to dryness under reduced pressure (2.7 kPa) . 3.56 g of 3-acetoxy- 1- [bis ( 4 - · chlo'rophenyl ) methyl] -3-{ [3, 5-bis (trifluoromethyl ) -phenyl ] methylsulfonylmethyl- (RS) }-azetidine are obtained in the form of a white foam. [3, 5-Bis ( trifluoromethyl ) benzyl] methyl sulfone may be prepared by heating under reflux 1.8 g of 3, 5-bis (trifluoromethyl) benzyl chloride, 50 cm3 of absolute ethanol and 1.22 g of sodium methyl sulfinate. 1.86 g of .[3, 5-bis (trifluoromethyl Jbenzyl] methyl sulfone are obtained in the form of a white solid.
Example 15 Ν·-[4-( (4-Chlorophenyl)-{3-[ (3,5-difluorophenyl) methylsulfonylmethyl- (RS) ] azetidin-1-yl }methyl- (RS) ) benzyl] -N, N-dimethylamine, a mixture of two diastereoisomers ,' may be prepared by carrying out the. procedure as described in Example .3, starting with 0.10 g of N-[4-( (4-chlorophenyl) -{3-[ (3,5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl}methyl- (RS) -benzyl] -N,,N-dimethylamine, 1.5 cm3 of anhydrous methanol, 1.5 cm3 of . anhydrous ' dichloromethane and 45 mg of sodium borohydride, with stirring for 16 hours at 20°C and then for 16 hours at 50°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 22 cm, diameter 1 cm) , eluting under an argon pressure of 0.8 bar with a mixture of ethyl acetate and methanol (97/3 by volume) and collecting 20-cm3 fractions.
Fractions 17 to 25 are combined and concentrated to 128 dryness under reduced pressure (2.7 kPa) , the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 6 mg of N-[4-((.4-chlorophenyl ) -{3- [ (3, 5-difluorophenyl ) methylsulfonyl-methyl- (RS) ] azetidin- 1-yl } methyl- (RS) ) benzyl] -N, N-dimethylamine,' a mixture of two diastereoisomers , are obtained in the form of a white powder [XH NMR spectrum (300 MHz, CDC13,, δ in ppm) : 2.20 (s : 6H) ; 2.53 (t, J = 7 Hz : l'H) ;· 2.65 (s : 3H) ; from 3.10 to.3.25 (mt : 2H) ; from 3.30 to '3.45 (mt : 1H) ; 3.35 (broad s : 2H) ; 3.63 (broad t, J = 7 Hz : 1H) ; 4.24 (s : 1H);" 4.25 (d, J = 11 Hz : 1H) ; 6.82 (tt, J = 9 and 2 Hz .: 1H) ; 6.94 (mt : 2H) ; from 7.15 to 7.35 (mt :' 8H) ] .
N-[4-( (4-Chlorophenyl) -{3- [ ( 3 , 5-difluoro-phenyl) methylsulfonylmethylene] azetidin-1-yl } methyl- (RS) ) benzyl] -N, N-dimethylamine may be prepared by carrying out the procedure in the following manner: 1.0 g of . (RS) -4- ( (4-chlorophenyl) -{3- [ (3, 5-difluorophenyl.) methylsulfonylmethylene] azetidin-l-yl }methyl) benzaldehyde is added, under argon, to a solution of 0.93 cm3 of a 2 M solution of dimethylamine in methanol in 30 cm3 of anhydrous 1 , 2-dichloroethane . After stirring for 30 minutes at room temperature, 0.9 g of sodium triacetoxyborohydride is added in small. fractions. After stirring for 48 hours, the reaction mixture is supplemented with 2.65 cm3 of 1 N sodium hydroxide, 100 cm3 of water and 100 cm3 of dichloromethane and is then separated after settling. The organic phase is washed with twice 80 cm3 of water 129 and with 80 cm3 of 'brine and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7' kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 17.5 cm) , eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (30/70 by volume) and collecting 40-cm3 fractions. Fractions 48 to 53 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.46 g of N- [4- ( (4-chlorophenyl ) -(3- [ (3, 5-difluorophenyl) methylsulfonylmethylene] -azetidin-l-yl }methyl- (RS) ) benzyl] -N, -dimethylamine is obtained in the form. of a white solid.
(RS) -4- ( (4-Chlorophenyl) -{3- [ ( 3 , 5-difluoro-phenyl) methylsulfonylmethylene] azetidin-l-yl}methyl) - ' benzaldehyde may be prepared by carrying out the procedure in the following manner: 75.6 cm3 of 5 N hydrochloric acid are added to a solution of 18.9. g of 1- [ (4-:chlorophenyl) - (4- [1, 3] dioxblan-2-ylphenyl) -methyl] - (RS) -3- [ (3, 5-difluorophenyl ) methylsulfonyl-me-thylene] azetidine in 80 cm3 of tetrahydrofuran . After 3 hours- at room temperature, the mixture is taken up in dichloromethane and distilled water and then brought to pH 14 by addition of 30% sodium hydroxide and separated after settling. The organic phase is washed twice with 100 m3 of water and then 100 cm3 of a saturated. aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under-,, reduced pressure (2.7 kPa) . 16 g of (RS) -4- ( (4-chlorophenyl) - 130 { 3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethylene] - azetidin-l*-yl }methyl) benzaldehyde are obtained in the form of a white foam. 1- [ (4-Chlorophenyl) - ( 4 - [ 1 , 3 ] dioxolan-2- ylphenyl ) methyl] - (RS) -3- [ ( 3 , 5-difluorophenyl ) methy1- sulfonylmethylene ] azetidine may be prepared according to the following method: 13.0 cm3 of 1 , 8 -diazabicyclo- [5-4-0] undec-7-ene are added dropwise to a solution of 34.45 g of the mixture of the two diastereoisomers of 1- [ ( 4-chlor.ophenyl) - ( 4 - [ 1 3 ] dioxolan-2-ylphenyl ) methyl- (RS) ] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl- (RS) ] azetidin-3-yl acetate in 400 cm3 of tetrahydrofuran under argon at 0°C, and after. the usual treatment, the product is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter .2 cm, height 23 cm), eluting under an argon pressure of 0.5 bar . with a mixture of ethyl acetate and cycldhexane (20/80 by volume) and collecting 250^-cm3 fractions; 16.6 g of .1- [ ( 4 -chlorophenyl ) - ( 4-, [l,3]dioxolan-2-ylphenyl)methyl]-(RS)-3-[ (3,5- difluorophenyl ) methylsulfonylmethylene ] azetidine are obtained in the form of a white solid.
The mixture of the two diastereoisomers l-[(4- chlorophenyl) - (4- [1, 3 ].dioxolan-2-ylphenyl ) methyl- (RS) ] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl- (RS) ] azetidin-3-yl acetate diastereoisomers may be obtained in the following manner: by carrying out the procedure according to Example 1 (method 2-)., starting with 11.6 g of ( 3 , 5-difluorobenzyl ) methyl sulfone, 131 .1 cm3 of a 1.6 N solution of n-butyllithium in hexane, 19.3 g of 1- {( -chlorophenyl ) [ 4 -([ 1 , 3 ] dioxolan-2-yl') phenyljmethyl- (RS) } azetidin-3-one and' 8.8 cm3 of acetyl chloride in 500 cm3 of tetrahydrofuran, 37.8 g of the mixture of the two 1- [ (.4-chlorophenyl) -( 4- [1, 3] dioxolan-2-ylphenyl) methyl- (RS) ] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl- (RS) ] azetidin-3-yl acetate diastereoisomers are obtained in the ' form of a white, foam. ' l-{ (4 -Chlorophenyl) [4- ( [1, 3] dioxolan-2-yl ) -phenyl] methyl- (RS) } azetidin-3-one may be prepared in the following manner: 46 cm3 of triethylamine are added, at room temperature, to a solution of 28.32 g of l-{ (4-chlorophenyl) [4- ( [1, 3] dioxolan-2-yl) phenyl] -methyl- (RS) } azetidin-3-ol in 200 cm3 of dimethyl sulfoxide, followed by the dropwise addition of a solution of 34 g of sulfur trioxide-pyridine complex in 100 cm3 of dimethyl sulfoxide. After 0.25 hour at room temperature, . the reaction mixture is poured over ice, extracted with ethyl acetate, washed with 3 times 400 cm3 of water and then with 400 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness- under reduced pressure (2.7 kPa) . The. residue obtained is chromatographed on a silica gel column (particle size 0.04-0.06 -mm, diameter 9.2 cm, height 21 cm) under an argon pressure of 0.5' bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) as eluent and collecting 250-cm3 fractions. Fractions 9 to 18 are 132 combined and then concentrated to dryness under reduced pressure (2.7 kPa) . 20.4 g of 1- { ( 4 -chlorophenyl ). [ 4- ( [1,3] dioxolan-2-yl) phenyl] methyl- (RS ) } azetidin-3-one are obtained in the form of a yellow oil. - l-{ (4-Chlorophenyl) [4- (.[1, 3 ] dioxolan-2- yl-) phenyl] methyl- (RS) } azetidin-3-ol may be prepared as described in Example 3, starting with 35.0 g of {(4- chlorophenyl ) [ 4- ( 1 , 3-dioxolan-2-yl ) phenyl ] methyl } amine , 8.3 g of epibromohydrin, 5.1 g of sodium hydrogen carbonate and 400 cm3 of ethanol. 30.3 g of l-{(4- chlorophenyl) [4- ( [1, 3] dioxolan-2-yl ) phenyl] methyl- (RS ) } azetidin-3-ol , are isolated. { (4-Chlorophenyl) [4- ( [1, 3] -dioxolan-2- yl) phenyl] methyl- (RS) }amine hydrochloride may be prepared according to the method described' by GRISAR M. et al., J. Med Chem. , 885 (1973) starting with 67.2 g of 4- ( [1, 3] -dioxolan-2-yl) benzonitrile, 88.2 g of l-bromo-4-chlorobenzene, 11 g of magnesium and 600 cm3 . of ethyl ether. 42.3 g of { (4-chlorophenyl) [4- ( [1, 3] -dioxolan-2-yl) phenyl] methyl- (RS) }amine are obtained in the form of a yellow oil.
Example 16 l-[ (4-Chlorophenyl) (thien-2-yl) methyl- (RS) ] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl- (RS) ] azetidine, a mixture of two diastereoisomers , may be' prepared by carrying out the procedure as described in Example 3, starting with 0.10 g of l-[(4-chlorophenyl) ( thien-2-yl) methyl- (RS ) ] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethylene] azetidine, 133 1.5 cm3 of anhydrous methanol, 1.5 cm3 of "anhydrous dichloromethane and 45. mg of sodium borohydride, with stirring for 16 hours at 20°C and then for 16 hours. at 50°C. The crude product is chromatographed on a silica 'gel column (particle size 0.040-0.063 mm, height 25 cm, diameter 1 cm) , eluting under an argon pressure of. 1. bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume), and collecting 20-cm3 fractions.
Fractions 37 to 42 are combined and concentrated to dryness under reduced pressure (2.7. kPa) , . the residue is stirred with 5 cm3 of pentane, the solid is filtered, drained and dried. 8 mg of 1- [ ( 4 -chloro- phenyl) ( thien-2-yl ) methyl- (RS )] -3- [( 3 , 5-difluorophenyl ) methylsulfonylmethyl- ( RS ) ] azetidine,' a' mixture of two diastereoisomers, are obtained in the form of a white powder [lH NMR spectrum (300 MHz, CDC13, δ in ppm) . A mixture of diastereoisomers is observed, . from 2.50 to 2.70.(mt : 1H) ; 2.66 and 2.68 (2s : 3H in total); from 3.15 to 3.80 (mt : 4H") ;- from.4..20 to 4.30 (mt : 1H) ; 4.31 and 4.57 (2s : 1H in total) ; from 6.80 to 7.00 and from 7.10 to 7.40 (mts : 10H in total)]. . . l-[ (4-Chlorophenyl) (thien-2-yl) methyl- (RS) ] -3- [ (3, 5-difluorophenyl) methylsulfonylmethylene] azetidine may be prepared by carrying out the procedure as described in Example 6, starting with 0.52 g of a mixture of the two 1- [ (4-chlorophenyl) (thien-2-yl) - methyl- (RS ) ] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl- (RS )] azetidin-3-ol diastereoisomers,. 0.14 cm3 of methylsulfonyl chloride and 0.49 g of 4 -dimethylamino- 134 pyridine. After chromatography on a silica gel column (particle size 0.06-0.200 mm, diameter 2.4 cm, height 20 cm), eluting under 'an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (20/80 by volume) and collecting 30-cm3 fractions, 0.32 g of ( RS ) -1- [ ( 4 -chlorophenyl ( thien-2-yl ) methyl ] -3- [ ( 3 , 5-' difluorophenyl) methylsulfonylmethylene] azetidine is obtained in the form of. a'white solid melting at 176°c .
The' mixture of the two 1- [ (4-chlorophenyl) -. (thien-2-yl)methyl- (RS)] -3-[ ( 3 ,5-difluorophenyl ) methylsulfonylmethyl- ( RS )] azetidin-3-ol diasterebisomers may be prepared by carrying out the . procedure as described in Example 0, starting with 1.60 cm3 of 1.6 N n- butyllithium in solution in hexane, 0.83 g of (3,5- · difluorobe zyl) methyl sulfone and 1.06 g.of ,l-[.(4-. chlorophenyl) (thien-2-yl) methyl- (RS) ] azetidin-3-one . After purification on a silica gel column (particle size 0.06-0.200 mm, diameter 2.8 cm, height -30 cm), ".eluting under, an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (25/75 by volume) and collecting 40-cm3 fractions, 0.55 g of the . mixture of the 1- [( 4 -chlorophenyl )"( thien-2-yl ) methyl- ( RS ) ] -3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethy1- (RS) ] azetidin-3-ol diastereoisomers is obtained in the form of an off-white solid. 1- [ ( 4-Chlorophenyl) .( thien-2-yl).methyl- (RS ) ] azetidin-3-one may. be prepared by carrying out the procedure as described in Example 1 (method 2), starting with 1.83 cm3 of. oxalyl chloride, 20 cm3 of 135 dichloromethane, 3.04 cm3 of dimethyl sulfoxide, 5.2 g of 1- [ ( -chlorophenyl) (thien-2-yl) methyl-(RS) ] azetidin- 3-ol, 80 cm3 of dichloromethane and 9.12 cm3 of • triethylamine . 3.3 g of 1- [ ( 4 -chlorophenyl ) ( thien-2- yl ) methyl- (RS) ] azetidin-3-one are obtained in the form . of a yellow oil which crystallizes at room temperature. 1- [ (4-Chlorophenyl) (thien-2-yl) methyl- , (RS ) ] azetidin-3-o.l may be. prepared by carrying out a procedure, in. the following manner: 4.12 g of sodium bicarbonate are added to ' - solution of 11.0 g of [(4- chlorophenyl) (thien-2-yl) methyl- (RS) ] amine in 80 cm3 of ethanol . The mixture, heated to 65°C, is supplemented with 4.03 cm3 of epibromohydrin . After stirring for 20 hours at 65°C, the crude mixture is filtered and the filtrate concentrated to dryness under reduced- ressure (2.7 kPa) . The residue. is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter .3.6 cm, . height 32. cm) , eluting under an argon. pressure of 0.5 bar with a. mixture -of ethyl acetate and cyclohexane (25/75 by volume) and collecting 60-cm3 fractions. 6.3 g of 1- [( 4-chlorophenyl ) (thien-2-; yl) methyl- (RS) ] azetidin-3-ol are obtained in the form of a pale yellow oil. [ ■( 4 -Chlorophenyl ) ( thien-2-yl ) methyl- ( RS ) ] amine may be prepared in the following manner: 'a solution of 10.92 g of 2-thiophenecarbonitrile in 80 cm3 of diethyl ether is poured slowly into a suspension, cooled to 10°C of 4-chlorophenylmagnesium bromide (prepared from 19.15 g o.f 4-bromochlorobenzene and 2.43 g of 136 magnesium) in 120 cm3 of anhydrous ethyl ether. After . refluxing for one hour, the mixture is cooled to 10°C, supplemented slowly with 40 cm3 of methanol and then filtered on supercel. 4.54 g of sodium borohydride . are added under argon and in small fractions over minutes and then the reaction medium is stirred for 2.0 hours at 20 °C. The mixture obtained is diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 5Q°C under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 5 cm, height ■42 cm), eluting under an argon pressure of 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) and collecting 100-cm3 fractions. Fractions 6 to 12, concentrated to dryness, correspond to 13 g of imine in the form of a yellow oil which is taken up in 100 cm3 of methanol. The solution obtained is supplemented with 2.4 g of sodium bo.rohydride and stirred for one hour at 5°C. The mixture obtained is. diluted with ethyl acetate and then washed with water. The organic phase is dried over magnesium sulfate, concentrated to dryness at 50°C under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.06-0.200 mm, diameter 3.2 cm, height 40 cm), eluting under an argon pressure of. 0.5 bar with a mixture of ethyl acetate and cyclohexane (4/6 by volume) and collecting-:.60-cm3 fractions. 11.0 g of [ ( 4 -chlorophenyl ) (thien-2- 137 yl ) methyl- (RS )] amine are obtained in the form of a yellow oil.
Example 17 (RS) - [3- ({ 1- [Bis (4-chlorophenyl) methyl] -a.zetidin-3-yl }methylsulfonylmethyl) phenyl] methanol may be prepared by carrying out the procedure as described in Example 3, starting with 0.050 g of [3- ( { 1- [bis ( 4-chlorophenyl) methyl] a etidin-3-yl Jmethylsulfonyl-methylene) phenyl] methanol, 1.0 cm3 of anhydrous.. methanol, 1.0 cm3 of anhydrous dichloromethane and mg of sodium borohydride, with stirring for 3 hours at 20°C. The crude product is chromatographed on a silica gel column (particle size 0.040-0.063 mm, height 20 cm, diameter 1 em), eluting under an argon pressure of 0.8 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 10-cm3 fractions. Fractions 30 to 38 are combined and concentrated to dryness under reduced pressure (2.7 kPa) , the residue is stirred with 5 cm3 of pentane, the solid is= filtered, drained and dried. 13 mg of ( RS )-[ 3- ({ 1- [bis ( 4-chlorophenyl ) methyl] -azetidin-3-yl Jmethylsulfonylmethyl ) phenyl] methanol are obtained in the form of a white -powder [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 1.75 (t, J = 6 Hz': 1H) '2.52 (t, J = 7.5 Hz : 1H) ; 2.59 (s : 3H) ; 3.17 (broad t, J = 7.5 Hz. : 2H) ; 3.48 (mt : 1H) ; 3.65 (mt : 1H) ; 4.23 (s : .1H); 4.28 (d, J = 11.5 Hz : 1H) ; 4.70 (d, J = 6 Hz : 2H) ; from 7.15 to 7.40 (mt : 12H)].,. 138 [3 - ( { 1- [Bis (4-chlorophenyl) methyl ].azetidin-3- yl Jmethylsulfonylmethylene) phenyl] methanol may be prepared by carrying out the procedure in the following manner: 17 cm3 of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are poured into a solution, cooled to +5°C, of 5.1 g of 1- [bis ( 4-chlorophenyl) - methyl] -3- { [3- ( tertbutyldimethylsilyloxymethyl ) phenyl] -■ methylsulfonyl-methylene } azetidine in 51 cm3 of tetrahydrof ran . After stirring for 20 minutes. at cooled temperature and then for .3 hours at 20 °C, the reaction mixture is . poured into a mixture of 200 cm3 of water and 100 cm3- of ethyl acetate and then separated after settling. The organic phase is washed with water, dried over magnesium sulfate and then filtered and concentrated to. dryness under reduced pressure (2.7 kPa) . The residue obtained is purified by chromatography on a silica gel column . (particle size 0.04-0.06 mm, diameter 2 cm, height 30 cm), eluting under a nitrogen pressure of 0.5 bar with a dichloromethane and ethanol (97/3 by volume) mixture and collecting 100-cm3 fractions. Fractions 10 to 1 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . The yellow solid obtained is taken up in 2 cm3 of dichloromethane and 10 cm3 of ethyl acetate and then filtered on sintered glass and washed with 2 cm3 of ethyl acetate, 1.6 g of [3- ( { 1- [bis ( 4- chlorophenyl) methyl] azetidin-3-yl } methylsulfonyl- methylene) phenyl] methanol are obtained in the form of a white solid melting at 214°C. 139 1- [Bis (4-chlorophenyl) methyl] -3-{ [3- (tert- butyldimethylsilyloxymethyl ) phenyl] methylsulfonyl- meth'ylene } azetidine may be prepared by carrying out the operation according to the procedure of Example 1,. starting with 10.8 g of 1- [bis (4-chlorophenyl) methyl] - .3-{ [3- (tert-butyldimethylsilyloxymethyl) phenyl] - methylsulfonylmethyl- (RS )} azetidin-3-ol , 2 cm3 of methylsulfonyl chloride and 8.5 g of 4-dimethylamino- pyridine, the residue obtained is purified by .. chromotography on a silica gel column . (particle size 0.04-0.06 mm, diameter 4 cm, height 40 cm) under a nitrogen pressure. of 0.5 bar with dichloromethane as eluent and collecting 100-crn3 fractions. Fractions 12 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 5.2 g of 1- [bis ( 4 -chloro- ■ phenyl) methyl] -3- { [3- (tert-butyldimethylsilyloxy- methyl ) phenyl] methylsulfonyl-methylene } azetidine are ■ obtained in the form of a gum. 1- [Bis (4-chlorophenyl) methyl] -3- { [ 3- (tert- butyldimethylsilyloxymethyl) phenyl] methylsulfonylmethyl- (RS )} azetidin-3-ol may be prepared by carrying ■. out the operation according to the procedure of Example ■ 5, starting with 5.8 g of tert-butyl- ( 3-methylsulfonyl- methylbenzyloxy) dimethylsilane and 5.6 g of l-[bis(4- chlorophenyl)methyl]azetidin-3-one, 10.8 g of l-[bis(4- chlorophenyl) methyl ] -3-( [3- ( tert-butyldimethylsilyloxy- methyl) phenyl ] methylsulfonylmethyl- (RS) } azetidin-3-ol are obtained in the form of a gum. 140 tert-Butyl1- ( 3-methylsulfonylme.thylbenzyloxy) -dimethylsilane may be prepared by carrying out the procedure in the following manner: 4.87 g of imidazole are added to a solution of 5.73 g of ( 3-methylsulfonyl-methylphenyl) methanol in 50 cm3 of N, N-dimethylform-amide, followed by.10.3 cm3 of tert-butylchlorodi-methylsilane . After stirring for 20 hours at room temperature, the reaction mixture is concentrated to dryness under ' reduced pressure (2.7 kPa) . The residue is chromatographed on; a silica gel column (particle size 0.06-0.200 mm, diameter 3.5 cm, weight of silica 100 g) , eluting under a nitrogen pressure of 0.5 bar with dichloromethane, and collecting 100-cm3 fractions. Fractions 2 to 7" are combined, concentrated to dryness under reduced pressure (2.7 kPa) . 5.8 g of an oil are obtained, which oil crystallizes at room temperature (m.p. = 75°C.) (3-Methyisulfonylmethylphenyl ) methanol may be prepared by carrying out the procedure in the following .-manner: a. mixture of 26 g of 3- (methylsulfonylmethyl) -. benzoic acid and 4.6 g of lithium aluminum hydride in 600 era3 of tetrahydrofuran is. stirred for 18 hours at a temperature close to 20°C. The solution is cooled to 0°C and then 15 cm3 of ethyl acetate, 30· cm3 of water, 5 cm3, of a 15% aqueous solution of sodium hydroxide and finally 30 cm3 of water are added successively. The mixture is filtered on celite and the filtrate taken up in 600 cm3 of ethyl acetate. The organic phase is taken up in 500 cm3 of water and then 200 cm3' of a saturated 141 aqueous sodium chloride solution, separated after settling, dried over ^anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.-7 kPa) . 10.4 g of ( 3-methylsulfonyl-methylphenyl) methanol; are obtained in the form of a gum. 3- (Methylsulfonylmethyl) benzoic acid may be prepared in the following manner: by carrying out the operation according to the procedure of Example.14, starting with 23.3 g of 3-chloromethylbenzoic acid. 23.3 g of sodium methane sulfinate, 26 ,g of 3- (methylsulfonylmethyl) benzoic acid are obtained in the form of a white solid melting at 210°C.
Example 18 1- [Bis (4-chlorophenyl)methyl] -3- (phenyl'sulfonylmethyl) azetidine may be prepared by carrying out the procedure in the following manner: 13 mg of sodium borohydride are added, under argon, to a solution of 0.15 g of 1- [bis ( -chlorophenyl) me.thyl ) ] -3- (phenylsulfonylmethylene) azetidine in 3 cm3 of anhydrous ethanol and 3.5 cm3 of anhydrous dichloromethane. After stirring for 1 hour and 45 minutes, 1 mg of sodium borohydride are again added and then the mixture is kept stirring, for 20 hours at 20°C. The reaction mixture is then heated to 50°C, supplemented with 9.5 mg of sodium- borohydride and kept stirred for 2 hours .and 30 minutes at 50°C and then cooled to room temperature. 0.5 cm3 of water, 10 cm3 of dichloromethane and then 50 mg of magnesium sulfate are cm3 of water, with 25 cm3 of 1 N sodium hydroxide and extracting the base obtained with 30 cm3 of diethyl ether, then drying and concentrating to dryness under reduced, pressure (2.7 kPa) ] is poured in over minutes. After stirring for 45 minutes at -70°C and then for 2 hours at 20°C, the reaction mixture is supplemented with 12 cm3 of 'a saturated aqueous ammonium chloride . solution, .20 cm3 of water and then extracted with 12 40 cm3 of ethyl acetate. The .combined organic, phases -are [lacuna] with 40 cm3 of water, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure · (2.7 kPa) . The oil obtained, is chromatographed on a silica gel column "(particle size 0.063-0.200 mm, height 40 cm, diameter 5 cm), eluting. under an argon pressure of 0.5 bar, with a mixture of cyclohexane and ethyl acetate (90/10 and then 85/15 by volume) and collecting 100-cm3 fractions. Fractions 10 . to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa)..The oil' obtained is triturated in 10 cm3 of diethyl ether, the suspension filtered and the solid dried. 1.17.g of l-[bis(4-. chlorophenyl ) methyl) ] -3-'(phenylsulfonylmethylene) - ' azetidine are obtained in the form of a white solid [:H NMR spectrum (300 MHz, CDC13 d in ppm) : 3.88 (mt : 2H) ; 4.29 (mt : 2H) ; 4.50. (s : 1H) ; 6.17- . (mt : 1H) ; from 7.20 to 7.40- (mt : 8H) ; 7.56 (broad t, J = 7.5 Hz : 2H) ; 7.64 (tt, J = 7.5 and 1.5 Hz : 1H) ; ' 7.87 ' (broad d,- J = 7.5 Hz : 2H) ] .
( Phenylsulfonylmethyl ) trimethylsilane may be prepared by carrying out the procedure in the following manner: 13 cm3 of a 1.6 M solution of n-butyllithium in hexane are poured, with stirring under argon over 20 minutes, into. a solution, cooled to -70°C, of 3 g of methyl phenyl sulfone in 40 cm3 of anhydrous . tetrahydrofuran . After stirring for - 30 minutes at -70°C, 2.66 cm3 of trimethylchlorosilane are added to the mixture', and the heating is stopped. After. stirring for 4 hours' at room temperature, the reaction mixture is supplemented with 30 cm3 of water and extracted with ■30 cm3 of ethyl acetate. The organic phase is washed with 30 cm3 of water, dried over magnesium sulfate, filtered- and then concentrated to dryness under reduced pressure (2.7· kPa).. 4.34 g of (phenylsulfonylmethyl ) -trimethylsilane are obtained in, the form of a yellow liquid.
Example 20 2-{ 1- [Bis (4-chlorophenyl)methyl] azetidin-3-ylmethylsulfonyl Ipyridine may be prepared by carrying out the procedure in the following manner: 0.125 g of sodium borohydride is added to a solution of 0.25 g of 2- { 1- [bis ( 4-chlorophenyl ) methyl ) ] azetidin-3- . ylidenemethylsulfonyl }pyridine in 20 cm3 of a 50/50 mixture of dichloromethane and ethanol . After stirring for 1 hour at 50 °C, the reaction mixture is cooled to 20°C, supplemented with 20 cm3 of dichloromethane, 1 cm3 of water and 0.1 g of magnesium sulfate. The mixture is filtered and the filtrate is concentrated at 50°C under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.04Ό-0.063 mm, height 15 cm, diameter 1 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by volume) and collecting 10—cm fractions. Fractions 5 to 10 are1 combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.18 g of 2- { 1- [bis ( 4 - chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl.} - pyridine is obtained in the form of a white powder (:H . NMR. spectrum (300 MHz, CDC13, δ.,ίη ppm) : from 2.80 to •3.00 (mt : 3H) ; 3.34 (mt : 2H) ; 3.70 (d, J. = 7 Hz : 2H) ; 4.25 (s : 1H) ; from 7.20 to 7.40 (mt : 8H) ; 7.57 (ddd, J = 8-5 and 1 Hz : 1H) ; 7.97 (split t, J = 8 and 1.5 Hz : 1H) ; 8.07 (broad d, J. = 8 Hz : 1H) ; 8.75' (broad d, J = 5 Hz : 1H) ] . 2-.{ 1- [Bis (4 -chlorophenyl). methyl) ] azetidin-3- ylidenemethylsulfonyl }pyridine may be prepared by. carrying out the procedure in the following manner: 0.25. cm3 of methylsulfonyl chloride is added to a solution of 0.9 g of 1- [bis ( 4-chlorophenyl) methyl) ] -3- (pyrid-2-ylsulfonylmethyl) zetidin-3-ol in 50 cm of dichloromethane, the mixture is stirred for 15 minutes and 0.9 g of 4-dimethylaminopyridine is added. After, stirring for 3 hours at 20°C, 30 cm3 of water and 30 cm3 of dichloromethane are added to the mixture and then, the organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (40/60 by'. volume) and collecting 20-cm3 fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.50 g of 2-{l-[bis(4- chlorophenyl ) methyl ) ] azetidin-3-ylidenemethylsulfonyl } - pyridine is obtained in the form of a yellow powder. 1- [Bis (4-chlorophenyl)methyl) ] -3- (pyrid-2- . ylsulfonylmethyl) azetidin-3-ol may be prepared by' carrying out the procedure in the following manner: 2.13 g of potassium tert-butoxide are added to a " solution, cooled to -78°C under argon, of 2.92 g of 1- ■ [bis (4-chlorophenyl)methyl) ] azetidin-3-one and 3 g of 2-methylsulfonylpyridine. in 50 cm3 of tetrahydrofuran . After stirring for 3 hours at -78°C, the reaction mixture is allowed to return to 0°C and then 50 cm3 of diethyl ether, 10 cm3 of water. and 10 cm3 of a saturated aqueous ammonium chloride solution are added. The organic phase is separated after settling, dried over magnesium sulfate, filtered and concentrated to dryness • under reduced pressure (2.7 kPa) . The residue is chromatographed on a silica gel column (particle size 0.063-0.200 mm, height 30 cm, diameter 3 cm)", eluting under an argon pressure of 0.5 bar, first with dichloromethane and then with a mixture of dichloromethane and methanol (97/3 by. volume) and collecting 20-cm3 fractions. Fractions 8 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) .. A. still impure brown oil is · obtained which is chromatographed on a silica gel column (particle size 0.04-0.063 mm, height 20 cm, diameter 2 cm), eluting under. an argon pressure of 0.5 bar, first with dichloromethane and then' with a mixture of . dichloromethane and methanol (97/3 by volume) and collecting 20-cm3 fractions. Fractions 5 to 25 are combined and concentrated to dryness and. the residue obtained is again chromatographed on. the same column and under the same conditions but eluting with dichloromethane. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.3 g of 1- [bis (4-chlorophenyl) methyl) ] -3- (pyrid-2-ylsulfonylmethyl) azetidin-3-ol is obtained in the form of a white foam. 2-Methylsulfonylpyridine may be prepared by carrying out the procedure in the following manner: 0.25 cm3 of 100% acetic acid is added, with ■ stirring under argon, to a solution of 20 g of. sodium tungstate dihydrate in 10 cm3 of water, followed by 7.0 g of 2-methylsulfanylpyridine . This, mixture is heated to , 65°C, 10 cm3 of 30% hydrogen peroxide are slowly poured in over 15 minutes, then the mixture is stirred at 85°C for 30 minutes and then cooled to +10°C. 1.0 cm3 of 32% aqueous ammonia and 5.0 cm3 of a 37.5% aqueous solution' of sodium hydrogen sulfite are added to the medium, followed by 10 cm3 of water and 50 cm3 of dichloromethane. The mixture is separated after settling, the organic phase is dried o er magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The colorless oil obtained is disintegrated with 50 cm3 of petroleum ether and the ' insoluble gum is filtered and taken up in 30 cm3 of dichloromethane . The solution obtained is concentrated to dryness at 50°C under reduced pressure (2.7 kPa) . 3.5 g of 2-methylsulfonylpyridine are obtained in the form of a colorless oil. 2-Methylsulfanylpyridine may be prepared by carrying out the procedure in the following manner: 6.2 cm3 of methyl iodide are slowly added to a solution of 11.0 g of 2-mercaptopyridine in 105 cm3 of 1 sodium hydroxide. The reaction mixture, whose temperature has risen to 30°C, is cooled to room temperature. After stirring for 2 hours, the mixture is extracted with 100 cm3 of dichloromethane, the organic phase is dried over magnesium sulfate and concentrated-- to dryness at. 50°C under reduced pressure (2.7 kPa) . The oil obtained is purified by distillation under reduced pressure. 9.0 g of 2-methylsulfanylpyridine are obtained in the form of a colorless liquid, b ..p . = 84°C/45 mmKg. ' Example 21 3- { 1- [Bis ( 4-chlorophenyl) methyl] azetidin-3- ylmethylsulfonyl } pyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.15 g of 3- { 1- [bis ( 4-chlorophenyl) methyl) ] - azetidin-3-ylidenemethylsulfonyl } pyridine, 20 cm3 of a 50/50 mixture of d'ichloromethane and ethanol, and 80 mg of sodium borohydride. 0.11 g of 3- { 1- [bis (.4-chloro- phenyl ) methyl] azetidin-3-ylmethylsulfonyl } pyridine is obtained in the form of a white powder NMR spectrum (300 MHz, CDC13, δ in. ppm) : from 2.75 to 2.95 (mt .: 3H) ; 3.35 (mt ' : 2H) ; 3.43 (d, J = 6.5 Hz ; 2H) ; 4.25 (.s : 1H) ; 'from 7.20 to 7.40 (mt : 8H) ; 7.54. (ddd, J = 8-5 and.l Hz : 1H) ; 8.18 (ddd, J = 8-2.5 and 1.5 Hz : 1H) ; 8.90 (dd, J = 5 and 1.5 Hz : 1H) . 9.11 ' (dd, J = 2.5 and 1. Hz . : 1HH . 3- { 1- [Bis ( 4-chlorophenyl) methyl).] azetidin-3- ylidenemethylsulfonyl Jpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 0.8 g of 1- [bis (4-chlorophenyl)methyl) ] - . 3- (pyrid-3-ylsulfonylmethyl ) azetidin-3-ol , 50 cm3 of dichloromethane , .0.22 ■ cm3 of methylsulfonyl chloride and. 0.8 g of 4 -dimethylaminopyridine . 0.50 g of 3-{l- [bis ( 4-chlorophenyl) methyl) ] azetidin-3- ylidenemethylsulfonyl }pyridine is obtained in the. form ; of a cream-colored powder.. 1- [Bis ( 4-chlorophenyl) methyl) ] -3- (pyrid-3- ylsulfonylmethyl) azetidin-3-ol may be prepared by carrying out the procedure as described in Example 20, starting with 3.3.g of 1- [bis (4-chlorophenyl) methyl) ] - azetidin-3-one, 50 cm3 of tetrahydrofuran, 3.5 g of . 3-methylsulfonylpyridine and 2.4 g of potassium tert- butoxide. 1.4 g of 1- [bis ( 4 -chlorophenyl ) methyl ) ] -3- (pyrid-3-ylsulfonylmethyl) azetidin-3-ol are obtained in the form of a white powder. 3-Methylsulfonylpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 33 g of sodium tungstate, 10 cm3 of water, 0.25 cm3 of 100% acetic acid, 9.5 g of 3-methylsulfanylpyridine, 15 cm3 of 30% hydrogen peroxide and then 2 cm3 of 32% ' aqueous ammonia and 2 cm3 of a 3.7.5% aqueous solution of sodium hydrogen sulfite. The crude oil obtained is crystallized with 20 cm3 of diisopropyl ether, the crystals are filtered, drained and dried under reduced pressure (2.7 kPa) . 4.5 g of 3-methylsulfonylpyridine are obtained in the form of white crystals (m.p. =.58°C.) 3-Methylsulfanylpyridine may be prepared by carrying out the procedure in the following manner: cm3 of isoamyl nitrite are added to a mixture, heated to 80°C under argon, of 9.4 g of 3-aminopyridine and 100. cm3 of dimethyl disulfide. After stirring for 2· hours at 90°C, the reaction mixture is cooled to 20°C and .then purified by fractional distillation under reduced pressure. 8.4 g of 3-methylsulfanylpyridine ' are obtained in the form of a pale -yellow- liquid, b.p. = 90°C/30 mm of mercury.
Example 22 4- { 1- [Bis ( -chlorophenyl) methyl] azetidin-3-ylmethylsulfonyl } pyridine may be prepared by carrying out the procedure as described in Example .20, starting with 0.15 g of 4 -{ 1- [bis ( -chlorophenyl ) methyl )] -azetidin-3-ylidenemethylsulfonyl }pyridine, -,.20 cm3 of a 50/50 mixture of dichloromethane and ethanol, and 80 mg of sodium borohydride . 0.13 g of 4 - { l-.[bis ( -chloro-' phenyl) methyl] azetidin-3-ylmethylsulfonyl } yridine is obtained in the form of a white powder [XH NMR spectrum (300 MHz,. CDCI3, δ in ppm) : from 2.75 to 2.90 (mt : 1Η)·; 2.88 (t, J = 7 Hz : 2H) ; 3.36 (t, J = 7 Hz : 2H) ; 3.42 (d, J = 7 Hz : 2H) ; 4.25 (s : 1H) ; from 7.20 to 7..35 (mt : 8H) ; 7.75 Abroad d, J = 6 Hz : 2H) ; 8.93 (broad d, J = 6 Hz : 2H) ].. 4- { 1- [Bis (4 -chlorophenyl) methyl) ] azetidin-3- ylidenemethylsulfonyljpyridine may be prepared by carrying out the procedure as described in . Example 20, starting with 0.8 g of 1- [bis ( 4-chlorophenyl) methyl) ] - 3- (pyrid-4-ylsulfonylmethyl) azetidin-3-ol, 50 cm3 of dichloromethane, 0.22. cm3 of methylsulfonyl chloride and 0.8 g of 4-dimethylaminopyridine . The crude product is purified by chromatography on a silica gel column (particle size 0.04-0..063 mm, height 20 cm, diameter 2 cm) , eluting ■ under an argon pressure of 0.5 bar with a" mixture o.f cyclohexane and . ethyl acetate (40/60 by volume) and collecting 20-cm3 fractions. Fractions .5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa.) . 0.42 g of 4-{l-[bis(4- chlorophenyl ) methyl ) ] azetidin-3-ylidenemethylsulfonyl } -: pyridine is obtained in the form of a white crystalline powde . 1- [Bis (4-chlorophenyl)methyl) ] -3- (pyrid-4- ylsulfonylmethyl) azetidin-3-ol may be prepared by carrying out the procedure as described in-,.Example 20, starting with 2.5 g of 1- [bis ( 4 -chlorophenyl ) methyl )] - azetidin-3-one, 50' cm of tetrahydrofuran, 2.6 g of 4-methylsulfonylpyridine and 1.8 g of potassium tert-butoxide. The crude product obtained is purified by chromatography on a silica gel column (particle, size 0.04-0.063 mm, height j 30 cm, diameter 3 cm)', eluting under an argon pressure of 0.5 bar with dichloromethane and then with a mixture of dichloromethane and methanol (98/2 by volume) and collecting 20-cm3 fractions.
Fractions 8' to 27 are combined and concentrated, to dryness under reduced pressure (2.7 kPa) . A cream-colored powder is obtained which is recrystallized from 5 cm3' of acetonitrile . The crystals are filtered, drained and dried under reduced pressure (2.7 kPa)'. 1.4 g of 1- [bis ( 4 -chlorophenyl ) methyl) ] -3- (pyrid-4- . ylsulfonylmethyl ) azetidin-3-ol are obtained in the form of white crystals, m.p. = 130°C. 4 -Methylsulfonylpyridine may be prepared by carrying out the procedure as described in. Example 20, starting with 14 g of sodium tungstate, 4 cm3, of water, 0.05 cm3 of 100% acetic acid, 3.3 g of 4 -methyl-sulfanylpyridine, 6.5 cm3 of 30% hydrogen peroxide and then 0.25 cm3 of 32% aqueous ammonia and 1 cm3 of 37.5% aqueous solution of sodium hydrogen sulfite. The crude oil obtained is crystallized with 10 cm3 of diisopropyl ether, the crystals are filtered, drained and dried under reduced pressure (.2.7 kPa) . 2.6 g of .4 -methylsulfonylpyridine are obtained in the form of white crystals. 4-Methylsulfanylpyridine may be prepared by carrying out the procedure as described in Example 20, starting with 11.0 g of 4 -mercaptopyridine , 105 cm3 of 1 N sodium hydroxide and 6.2 cm3 of methyl iodide. The crude oil obtained is purified by distillation under reduced pressure. 4.0 g of 4-methylsulfanylpyridine are obtained in the form of a white paste, b.p. = 120°C/45 mm of mercury.
Example 23 1- [Bis (4-chlorophenyl)methyl] -3- [ (3, 5-difluorophenyl) sulfonylmethyl] azetidine may be .prepared by carrying out the procedure- in the following manner: 78 mg of sodium borohydride are added, under argon,, to a solution of 0.50 g of 1- [bis ( 4 -chlorophenyl ) methyl] --3- [ (3, 5-difluorophenyl) sulfonylmethylene ] azetidine dissolved in 25. cm3 of anhydrous methanol and 25 cm3 of anhydrous ' dichloromethane . After stirring for 24 hours, 80 cm3 of water and 50. cm3 of dichloromethane are added, the mixture is separated after settling, washed with 80 cm3 of water and then 80 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and then evaporated to dryness under . reduced; pressure (2.7 kPa) . The residue . is chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 20. cm, diameter 14 cm), eluting under an argon . pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 5-cm3 fractions. Fractions 60 to 82 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 0.'29 g of l-[bis(4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) sulfonyl-methyl] azetidine is obtained in the form of a white solid [^H NMR spectrum (300 MHz, CDC13, δ in ppm) : from 2.75 to 2.95 (mt : 1H);; 2.88. (t, J = 7 Hz : 2H) ; 3.35 (t, J = Hz : 2H) ; 3.41 (d, J = 7 Hz : 2H) ; 4.26 (s : 1H) ; 7.13 (tt, J = 9 and 2.5 Hz : 1H) ; from 7.20 to 7.35 (mt : 8H) ; 7.44 (mt : 2H) ] .
Example 24 1- [Bis (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) sulfonylmethylene] azetidine may be' prepared by carrying out the procedure in the following manner: 4.3 cm3 of methylsulfonyl chloride are added to 18.8 g of 1- [bis (4-chlorophenyl) methyl] -3- [ (3,5-difluorophenyl) sulfonylmethyl ] azetidin-3-ol. dissolved in 800 cm3 of dichloromethane at room temperature, followed, in small portions, by 16 g of 4-dimethylamino pyridine. After 22 hours, the reaction mixture is washed with 3 times 700 cm3 of water, and then 700 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried with magnesium. sulfate, filtered and then evaporated to dryness under, reduced pressure (2.7 kPa) . The residue (25 g) is chromatographed on a silica gel column (particle size 0.02-0.04 mm, height 36 cm, diameter 8.5 cm) eluting under an argon pressure of 0.7. bar with a mixture of cyclohexane and ethyl acetate (90/10 by volume) and collecting 250-cm3 fractions. Fractions 2 to 148 are combined and concentrated to dryness under reduced pressure (2.7 kPa) . 2.79 g of 1- [bis ( 4-chlorophenyl ).meth l ] -3- [ ( 3 , 5- difluorophenyl) sulfonylmethylene] azetidine are obtained in the form of a white solid [lH NMR spectrum (300 MHz, CDC13, δ in ppm) : 3.91 (mt : 2H) ; 4.28 (mt : 2H) ; 4.51 (s : 1H) ; 6.15 (mt : 1H) ; 7.08 (tt, J = 9 and 2.5 Hz' : 1H) ; from 7.25 to 7.40 (mt : 8Ή) ; 7.40 (mt : 2H) ] . 1- [Bis ( 4-chlorophenyl) methyl] -3- [ ( 3 , 5-difluorophenyl) sulfonylmethyl] azetidin-3-ol may be prepared by carrying out the procedure in the following manner: 42.9 cm3 of 1.6 M butyllithium in hexane are added dropwise to a solution of 13.2 g of ( 3 , 5-difluoro-' phenyl) methyl sulfone"~in 800 cm3 of tetrahydrofuran . After 0.5 hour at -7'0oC and 0.5 hour at -30°C, 14 g of-.1- [bis ( 4-chlorophenyl) methyl] azetidin-3-one dissolved in 150 cm3 of tetrahydrofuran are added dropwise at -70°C. After 3 hours at -70°C, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 400 cm3 of water and then 4.00 cm3 of a saturated aqueous sodium chloride . solution, dried with magnesium sulfate, filtered and then evaporated to . dryness under reduced .pressure (2.7 kPa) . The residue (25.14 g) is chromatographed on a silica gel column (particle size 0.06-0.04 mm, height 31 cm, diameter 7.5 cm)-, eluting under an argon pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 200-cm3' fractions . Fractions 13 to 16 are combined and concentrated to dryness under reduced pressure (2.7- kPa)'. After crystallization from ethyl ether, filtration and drying, 4..5 g of l-[bis(4- chlorophenyl) methyl] -3- [ (3, 5- difluorophenyl) sulfonylmethyl] azetidin-3-ol are . obtained in the form of a white solid. ( 3 , 5-Difluorophenyl ) methyl sulfone may be prepared by carrying out the procedure in the · following manner: 225 cm3 of water and, in small quantities at 5°C, 56.3. g of oxoneR are added to a solution of 13.3 g of ( 3 , 5-difluorophenyl) methylsulfide dissolved. in 450 cm3 of methanol .; After : 20 hours at room temperature, the reaction mixture is diluted with dichloromethane and water and separated after settling. The organic phase is washed twice with 700 cm3 of water . and then 700 cm3 of a saturated aqueous sodium chloride · ■ solution, dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa) . 13.2 g of ( 3 , '5-difluorophenyl ) methyl sulfone are obtained in the form of a white solid. ( 3 , 5-Di-fluorophenyl) methylsulfide may be prepared by carrying out the procedure in the following .manner: 64 cm3 of 1.6 M n-butyllith-ium in hexane are added dropwise at -70°C to 11.8 cm3 of l-bromo-3,5-,. difluorobenzene diluted in .200 cm3 , of ethyl e-ther.
After 0.5 hour at -70°C, 14..2 g of S-methyl methylthiosulfonate dissolved in 60 cm3 of tetrahydrofuran are added dropwise at -70 °C. After 3 hours at -70°C and' then 18 hours at room temperature, the reaction mixture is poured into a saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed twice with 200 cm3 of water and then 300 cm3 of a. saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and then evaporated to dryness under reduced pressure (2.7 kPa) . 13.3 g of (3, 5-difluorophenyl) - methylsulfide are obtained in the form of a yellow oil. Example 25 0.25 g of meta-chloroperbenzoic acid is added at room temperature to a solution of 0.40 g of Ί- [bis (4-chlorophenyl) methyl] -3- (phenylsulfanyl) azetidine in 20 cm3 of dichloromethane . After stirring for 3 hours at room temperature, the reaction mixture is washed with 30 cm3 of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . After chromatography on a silica gel column (particle size 0.06-0.200 mm, height 25 cm, diameter 2 cm), eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane 20/80 by volume mixture and collecting 60-cm3 fractions, ■ fractions 9 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPaJ, taken up in heptane in order to isolate 100 mg of 1- [bis (4-chlorophenyl) methyl] -3- [ (RS) -phenylsulfinyl] azetidine in the form of a white solid [lH NMR spectrum (300 MHz, CDC13, δ in ppm) : 3.01 (broad t, J = 7.5 Hz :■ 1H) ; 3.32 (broad t, J = 7.5 Hz : 1H) ; 3.45 (broad t, J = 7.5 Hz : 2H) ; 3.59 (mt : 1H) ; 4.45 (broad s, : 1H) ; from 7.15 to 7.65 (rats : 13H) ] .
Example 26 1.2 g of oxoneR are added in several portions to a solution of 0.80 g of l-[bis(4-chlorophenyl) methyl] -3- (phenylsulfanyl ) azetidine in 3.4 cm3 of water, 3.4 cm3 of acetic acid, 3.4 cm3 of ethanol and 1.7 cm3 of; sulfuric acid. After stirring for 20 hours at room temperature, the reaction mixture is diluted with 100 cm3. of dichloromethane , washed with 3 times 100; cm3 of water, dried over magnesium .sulfate, filtered and concentrated to dryness under' reduced pressure (2.7 kPa). After chromatography on a silica, gel column (particle size 0.06-0.200 mm, height 40 cm, diameter 2 cm) , eluting under an argon pressure of 0.8 bar with an ethyl acetate/cyclohexane (20/80 by volume)' mixture and collecting .60-cm3 fractions, fractions 9 to. 15 are combined and concentrated to ■. dryness under reduced pressure (2.7 kPa) , taken up in heptane, the solid filtered and dried in order to isolate 0.23 g of 1- [bis ( 4-chlorophenyl ) methyl ] -3- (phenylsulfon.yl) azetidine in the form of a white solid [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : from 3.35 to 3.50 (mt : 4H) ; 3.96 (rnt : 1H) ; 4.44 (s : 1H) ; .from 7.20' to 7.35 (mt : 8H) ; 7.57 (broad t, J = 7.5 Hz : 2H) ; 7.68 (tt, J = 7.5 and 1.5 Hz : 1H) ; 7.88 (broad d, J = 7.5 Hz : 2H) ] .
Example 27 ■ 43.5 mg of sodium borohydride are added to a solution, of 0.6 g of methyl 5- ( (1- [bis (4-chlorophenyl) -methyl] azetidin-3-ylidene } methyls-ulfonylmethyl) thien-2- ylcarboxylate in 70 cm3 of methanol cooled to around 0°C. The reaction medium is stirred for 15 minutes at this temperature, and then for 5 hours at 20 °C before again being cooled to around 0°C and supplemented with 8.7 mg of sodium borohydride. After 18 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure. (2.7 kPa) . The residue obtained is supplemented with 100 cm3 of dichloromethane and 20 cm3 of distilled water. The mixture is separated after settling, the- organic phase washed with twice 20 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) . The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)}. 0^.18 g of methyl. (RS) -5- ( { 1- [bis (4-chlorophenyl) -methyl] azetidin-3-yl }methylsulfonylmethyl) thien-2- . ylcarboxylate is obtained in the form of a white powder ilH NMR spectrum (400 MHz, (CD3)2SO d6, δ in ppm) : 2.60 (t, J = 7.5 Hz : 1H) ; 2.86 (s : 3H) ; 3.14 (mt : 2H) ; from 3.20 to 3.35 (mt : 1H) ; 3.45 (broad t, J = 7.5 Hz : 1H) ; 3.82 (s : 3H) ; 4.47 (s :. 1H) ; 5.27 (d, J = 11 Hz : 1H) ; 7.28 ,(d, J = 4 Hz : 1H) ; from 7.30 to 7.50 (mt .: 8H) ; 7.72 (d, J = 4 Hz : 1H) ] .
Methyl 5- ( { 1- [bis ( 4-chlorophenyl ) methyl] -azet.idin-3-ylidene }methylsulfonylmethyl) thien-2-yl-carboxylate may be obtained in the following manner: 5.15 g of methyl 5- (methylsulfonylmethyl ) thien-2-ylcarbo-xylate .are added, at room temperature under an argon atmosphere, to a solution of 6.12 g of l-[bis(4-chlorophenyl) methyl] azetidin-3-one in 200 cm3 of tetrahydrofuran and then the suspension obtained is cooled to -70°C. There are successively added 2.47 g of potassium tert-butoxide , and then after 1 hour 30 min at this temperature a. solution of 1.7 cm3 of methylsulfonylchloride in 8 cm3 of ethyl · ether- over 2 minutes.- The reaction medium is maintained for 1 hour at -70°C and then the temperature is allowed to rise to around 20°C before. pouring in 80 cm3 of distilled water. The tetrahydrofuran is expelled under reduced pressure and the aqueous residue obtained is extracted with 500 cm3 of dichlorome.thane . The mixture : is . separated after settling, the organic phase is washed with 3 times 80 cm3 of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa ) .. The residue obtained is purified by flash chromatography on silica gel [eluent: cyclohexane/ethyl acetate (70/30 by volume)]. 1.6 g of methyl 5- ( {1- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene }methylsulfonylmethyl ) thien-2-ylcarboxylate are obtained in the form of a cream-colored foam.
Methyl 5- (methylsulfonylmethyl ) thien-2-ylca.rboxylate ' may be obtained in the following manner: 31.7 g of sodium methyl sulfinate are added to a solution of 73 g of methyl 5- (bromomethyl) thien-2-ylcarboxylate -in 150 cm3 of ethanol and the suspension obtained is heated under reflux for 7 hours . The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa) . The residue is extracted with four times 500 cm3 of ethyl acetate,, the combined organic phases are washed successively with 250 cm3 of distilled water and 250 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and incompletely concentrated under reduced pressure. The solid which appears is isolated by filtration, rinsed with three times 25 cm3 of ice-cold ethyl acetate and .provides 21.4 g of "methyl 5- (methylsulfonylmethyl) thien-2-ylcarboxylate in the form of a cream-colored powder.
Methyl 5- (bromomethyl ) thien-2-ylcarboxylate may be prepared according to the method described by Wityak J. et al., Bioorg. Med. Chem. Lett. (1995), , 5 (18) , 20-97-100.
Example 28 (RS) -1- [Bis (4-chlorophenyl)methyl] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl ] zetidin-3-ylcyclopropylamine may be prepared in the following manner: 2.52 cm3 of cyclopropylamine are added to a solution of 3 g of 1- [bis (.4 -chlorophenyl ) methyl) ] -3- [ (3, 5-difluorophenyl ) (methylsulfonyl) methylene] - azet.idine in 30 cm3 of dichloromethane, at a temperature in the region of 24 °C, under an inert argon atmosphere.- After 39 hours at a temperature in the region of 24°C, the reaction medium is concentrated under reduced pressure (3 mbar) at a : temperature in the region of 40°C. 3.26 g of a pale yellow foam are thus obtained, which foam is taken up in 30 cm3 of dichloromethane and 2.52 cm3 of cyclopropylamine . The solution obtained is stirred at a temperature in the region of 21°C, under an inert argon atmosphere, for 87 hours and then concentrated under 3 mbar at a temperature in the region of 40°C. 3.64 g of (RS) -1- [bis ( 4-■ chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) - methylsulfonylmethyl] azetidin-3-ylcyclbpropylamine are thus obtained in the form of a pale yellow foam. [1H NMR spectrum (,.300. MHz, CDC13, δ in ppm) : 0.29 (mt : 1H) ; from 0.40 to 0.75 (mt : 3H) ; 2.50 (mt : 1H) ; 2.73 (s : . 3H) ; 2.90 (unresolved complex : lH)v from 3.45" to 3.70 (mt : 3H) ; 4.36 (broad s : 1H) / from 4.60 to 4.80 (broad unresolved complex : 1H) ; 6.87 (tt, J = 9 and 2.5 Hz : 1H) ;. from 7.20 to 7.40 (mt : 10H) ] .
Example 29 (RS) - { 1- [Bis (4 -chlorophenyl) methyl] -3- [ (3, 5- difluorophenyl) methylsulfonylmethyl] azetidin-3-yl } - (2- pyrrolidin-l-ylethyl) amine may be prepared in the following manner: 0.076 cm3 of 1- ( 2-aminoethyl ) - pyrrolidine is added to a solution of 50 mg of 1- [bis .( 4-chlorophenyl) methyl) ] -3- [ (3, 5-difluorophenyl ) - (methylsulfonyl) methylene] azetidine in 0.5 cm3 of dichloromethane, at' a temperature, in the region of 21°C, under an inert argon atmosphere. The solution obtained is stirred at a temperature in the region of 21°C, under an argon atmosphere, for 22 hours, concentrated under an air stream at a temperature in the region of 42 °C and then the crude residue obtained is dried under reduced pressure (about 3 mbar) at a temperature in the region of 40°C. (RS) - { 1- [bis (4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl ] azetidin-3-yl }-( 2-pyrrolidin-l-yl-ethyl) amine is obtained in the form of an ochre-colored foam. [XH NMR spectrum (300 MHz, CDC13, δ in ppm) ; from 1.75 to 1.95 (mt : 4H) ; from 2.55 to 2.85 (mt : 6H) ; 2.79 (s : 3H); 2.91 (t, J = 6.5 Hz : 2H) ; 3.06 (d, J = 8.5 Hz : .1H) ; 3.17 (d, J = 8.5 Hz : 1H)'; 3.32 (d, . J = 8.5 Hz : 1H) ; 3.41 (d, J = 8.5 Hz : 1H) ; 4.31 (s" : 1H) ; 4^.56 (s : Iff); 6.88 (tt, J = 8.5 and 2.5 Hz : 1H)"; 7.22 (s : 4H) ; 7..25 (s : '4H; '7.34 (mt : .2H) ] .
Example 30 (RS) -{l-[ Bis (4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methanesulfonylme'thyl] azetidin-3-yljmethylamine may be prepared according to Example 29, starting with 50 mg of 1- [bis ( 4-chorophenyl) methyl )] -3-[ ( 3 , 5-difluorophenyl )' (methylsulfonyl ) methylene] -azetidine, 0.5 cm3 of dichloromethane and 0.3 cm3 of a solution of methylamine in tetrahydrofuran (2 M solution) . (RS) - { 1- [bis ( -chlorophenyl ) methyl ] -3- [ (3,5-difluorophenyl ) methylsulfonylmethyl ]azetidin-3-yl }methylamine is obtained in the form of a yellow gum.
[XH NMR spectrum (400 MHz, CDC13 δ in ppm) : from 2.00 to 2.20 (broad unresolved complex : 1H-) ; 2.62 (s : 3H) ; 2.76 (s : 3H) ; 3.04 (d, J = 9 Hz : 1H) ; 3.18 (d, J = 9 Hz : 1H); 3.37 (AB, J = 9 Hz : 2H) ; 4.31 (s : 1H); 4.55 (s .: 1H) ; 6.89 (tt, J = 9 and 2.5 Hz : 1H) ; 7.22 ( s : 4H) ; 7.24 (s : 4H) ; 7.32. (mt : 2H) ] .
Example 31 (RS) - {1- [Bis (4 -chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl] azetidin-3-yl } isobutylamxne may be prepared .according to Example . '29, starting with 50 mg of 1- [bis (4-chlorophenyl) -methyl) ] -3- [ (3, 5-difluorophenyl) (methylsulfonyl) -methylene] azetidine, 0.5 cm3 of dichloromethane and 0.0596. cm3 of isobutylamine . (RS) -{ 1- [bis ( -chlorophenyl).methyl] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonyl-. methyl] azetidin-3-yl } isobutylamine is obtained in the form of a white foam ^H NMR spectrum (300 MHz, CDC13 ;5 in ppm) : 1.01 (2d, J; =.7 Hz : 6 H) ; from' 1.70 to 2.15 (broad unresolved complex : 1H) ; 1.76 (mt : 1H) ; 2.51 (dd, J = 10.5 and 7 Hz : 1H) ; 2.76 (s : 3H) ; 2.80 (dd, J = 10.5 and 6 Hz : 1H) ; 3.01 (d, J = 8.5 Hz : 1H) ; 3.14. (d, J = 8.5 Hz : 1H) ; 3.32 (d, J = 8.5 Hz : 1H) ; 3.44 (d, J = 8.5 Hz : 1H) ; 4.31 (s : 1H) 4.58 (s : 1H) ; 6.88 (tt, J = .8.5 and 2.5 Hz : 1H) from 7.15 to 7.30 (mt : 8H) ; 7.35 (mt : 2H) ] .
Example 32 (RS) -{ 1- [Bis ( -chlorophenyl) methyl] -3- [.(3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-.yl } ethylamine may be prepared according to Example 29 starting with.50 mg of 1- [bis ( 4-chlorophenyl ) methyl) ] -3- [ (.3, 5-difluorophenyl) (methylsulfonyl) methylene] - · azetidine, 0.5 cm3 of dichloromethane and 0.3· cm3 of a solution of ethylamine in tetrahydrofuran (2 M solution) . (RS) -{1- [bis ( -chlorophenyl) methyl] -3- [ (3,5 difluorophenyl) methylsulfonylmethyl ] azetidin-3-yl } ethylamine is obtained in the form of a. yellow gum [LH NMR spectrum(300 MHz, CDC13 5.in ppm) : 1.22 (t, J 7 Hz : 3 H) ; from 2.70 to 2.85 (mt : 2H) ; 2.77 (s : 3H) ; from 2.95 to 3.10 (unresolved complex : 1H) ; 3.05 (d, J = 8.5 Hz : 1H) ; 3.17 (d, J = 8.5 Hz .: 1H) ; 3.33 (d, J = 8.5 Hz : 1H) ; 3.40 (d, J = 8.5 Hz : 1H) ; 4.30 (s : 1H); 4.54 (s : 1H) ; 6.89 (tt, J = 9 and 2,5 Hz : 1H)-; from 7.15 to 7.30 (mt :- 8H) ; 7.34 (mt : 2H) ] .
Example 33 (RS) -N-{l-[Bis ( 4-chlorophenyl ) methyl] -3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl } -N' , N' -dimethylethane-1 , 2-diamine may be prepared according to Example 29, starting with 50 mg of 1- [bis (4-chlorophenyl) methyl) ] -3- [ ( 3 5-difluorophenyl ) - (methylsulfonyl) methylene] azetidine, 0.5 cm3 of dichloromethane and 0.0659 cm3 of N, -dimethylethylene-diamine . (RS) -N- { 1-bis ( 4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3 -yl } - ' , N' -dimethylethane-1, 2-diamine is obtained in the form of a white foam [:H NMR spectrum (300 MHz , CDC13 δ in ppm) : 2.32 (s : 6H) ; 2.53 (t, J = 6 Hz : 2H) ; . 2.79 (s : 3H) ; 2.94 (t, J = 6 Hz : 2H) ; 3.06 (d, J = 8.5 Hz .: 1H); -3.16 (d, J = 8.5 Hz : 1H); 3.30 (d, J = 8.5 Hz : 1H) ; 3.41 (d, J = 8.5 Hz : 1H) ; 4.30 (s : 1H) ; 4.55 (s : 1H) ; 6.88 (tt, J = 9 and 2.5 Hz : .1H) ; 7.21 (s : 4H) ; 7.24 (s : 4H) ; 7.34 (mt : 2H) ] .
Example 34 (RS)-l-[Bis-(4-chlorophenyl)methyl]-3-[ (3,5-difluorophenyl) methanesulfonylmethyl] -3-methylazetidine may be prepared in the following manner: a few drops of pure methyl iodide are added, under .an argon atmosphere at a temperature in the region of 24 °C, to a suspension of 400 mg of magnesium turnings in 2.5 cm3 of anhydrous diethyl ether, followed by 1 cm3 of methyl iodide in solution in 22.5 cm3 of diethyl ether. The suspension . obtained is stirred for 30 minutes at a. temperature in the region of 24 °C and then cooled to a temperature in the region of 0°C with an ice + water mixture. 1.65 g of CuBr.Me2S complex, are added, at. a temperature in the region of 0°C, and then the reaction mixture is stirred for 15 minutes- at a temperature in the region of 0°C. The yellow suspension! obtained is added, at a temperature in the region of 0°C, to a solution of 0.5 g of l-[Bis ( 4 -chlorophenyl ) methyl ) ] -3-[ (3, 5-difluorophenyl) (methylsulfonyl ) methylene] -. azetidine in a mixture of 1 cm3, of tetrahydrofuran and 1 cm3 of diethyl ether. The suspension obtained is stirred for 4 'hours at a temperature in the region of .0°C and then at a temperature in the region of 25 °C for 16 hours. The black suspension obtained is diluted with 100 cm3 of .eth l acetate and 15 cm3 of saturated aqueous ammonium chloride solution. The reaction mixtpre is filtered on sintered glass covered with Celite, the solid residue is rinsed with ethyl acetate and then with water. After decantation of the filtrate, the organic phase is separated, washed with.10 cm3 of water, 10 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure ..(20 mbar) at a temperature in the region of 43°C. 550 mg of an orange-colored foam are thus obtained, which .foam is purified by preparative thin-layer chromatography on silica [14 preparative Merck Kieselgel 60F254' plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane] , eluting with a methanol-dichloromethane mixture. (0.5-99.5 by volume).. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (15-85 by volume) mixture,, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 290 mg of a white foam are obtained, which foam is dissolved in 15 cm3 of anhydrous dichloromethane and reacted with 500 mg of thiophenol resin (supplier Argonaut, 1.45 mMol/g) and 1 g of ethylenediamine resin (0.8 mMol/g) for 38 hours at a. temperature in the region of 20°C. The suspension is filtered on sintered glass,, the resins are rinsed with dichloromethane and the filtrate is concentrated under reduced .pressure (5 mbar) at -a temperature in the region of 43°C. 272.8 mg of a white foam are obtained, which foam is dissolved in 2 cm3 of dichloromethane and reacted with 1 cm3 of ethylenediamine for 72 hours at a temperature in the region of 24°C. The crude residue obtained is taken up in 50 cm3 of ethyl acetate and cm3 of water. After, decantation, the organic phase is washed with 10 cm3 of a 1 N aqueous hydrochloric acid solution, 10 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 10 cm3 of\ water , 10 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (8 mbar) at a temperature in the region of 42°C. 263.4 mg of. a pale yellow foam are obtained, which foam is purified by preparative thin-layer chromatography on silica [7 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane] , eluting with a methanol-' dichloromethane mixture (0.5-99.5'by volume). After elution of the zone corresponding to the desired product with a methanol-dichloromethane (15-85 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 4.0°C, 191.4 mg of (RS)-l- [bis ( 4 -chlorophenyl) methyl] -3- [ ( [3, 5- .difluorophenyl ) methylsulfonylmethyl] -3-methylazetidine are obtained in the form of a white foam [1H NMR spectrum (300.MHz, CDC13, δ in.ppm) : 1.75 (s : 3H) ; 2.67 (s : 3H) ; 2.7.4 (broad d, J = 7.5 Hz : 1H) ; 2.93 (d, J = 7.5 Hz : 1H) ; 3.21 (broad d, J = 7.5 Hz : · 1H) ; 3.46'. (d, J = 7.5 Hz : 1H) ; 4..33 (broad s : 2H) ; 6.87 (tt, J = 9 and 2.5 Hz : 1H) ; 7.12 (mt : 2H) from 7.15 to 7.35 (mt : .8H] .
Example 35 (RS) -1- (2- {1- [Bis (4 -chlorophenyl) methyl] -3- [ (3, 5-d.ifluorophenyl) methylsulfonylmethyl] azetidin-3-yl.sulfanyl }ethyl) -4-methylpiperazine may be prepared in the following manner :' 128 ntg of 1- (ethanethiol-2-yl) -4-methylpiperazine are added to a solution of 99 mg of 1- [bis (4 -chlorophenyl ).methyl) ] -3- [ (3, 5-difluorophenyl) - (methylsulfonyl) methylene] -azetidine in. 2 cm3 of dichloromethane, . at a temperature in . the region of °C. After stirring . overnight at' a temperature in the region of 20°C, 706 mg of Merrifield resin (1.7 rtiMol/g) are added. After stirring overnight at a temperature in. the region of 20°C, the suspension is filtered and the resin is rinsed with twice 1 cm3 of dichloromethane. The' filtrate is concentrated. under reduced pressure. 125 mg of a white oil are thus obtained, which oil is purified by chromatography on silica (13 cm3 of 0.06-0.2 mm silica), eluting with a methanol-dichloromethane (0-100 and then 5-95 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 62 mg of (RS) -1- (2-{l- [bis ( 4 -chlorophenyl ) methyl ] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl ] azetidin-3-ylsulfanyl } ethyl ) -4-methylpiperazine are thus. obtained in the form of white crystals [LH N R spectrum (300 MHz, (CD3)2SO d6, δ in ppm) : 2.15 (s .:. 3H) ; 2.30 and 2.41 (2mfs : 8H) ; 2.55 (mt : 2H) ; 2.85 (s : 3H) ; 3.02 (mt : 2H) ; 3.09 (d,. J = 8.5 Hz : 1H) ; 3.38 (d, J = 8.5 Hz : 1H) ; 3.42 (d, J = 8.5 Hz : 1H) ; 3.79 (d, J '= 8.5 Hz : 1H) ; 4.68 (s : 1H) ; 5.37 (s : 1H) ; from 7.30 to 7.50 (mt : UK) 3 -Example 36 (RS)-(2-{l-[Bis ( 4-chlorophenyl ) methyl] - 3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidin-S-ylsulfanyl } ethyl ) dimethylamine may be prepared by carrying out the. procedure as' in Example .35, starting with 99 mg of 1- [bis ( 4 -chlorophenyl ) methyl )] -3-[( 3 , 5-difluorophenyl) (methylsulfonyl ) methylene] -azetidine, 2 cm3 of dichloromethane , 84 mg of 2- (dimethylamino) ethanethiol and 706 mg of Merrifield resin (1.7 mMol/g) . 36 mg of (RS)-(2-(l-[bis (4-chlorophenyl)methyl] -3- [ (-3, 5-difluorophenyl ) -methylsulfonylmethyl]azetidin-3-ylsulfanyl}ethyl) -dimethylamine are thus obtained in the form of an off-white powder .
Example 37 . (RS)-{1- [ [4- (Chloromethyl)'phenyl] - (4-chloro-phenyl ).methyl] -3- [ (3, 5-difluorophenyl) methylsulfonyl-methyl] azeti.din-3.-yl } ethylamine may be prepared in the following manner: A solution of 40 mg of (RS ) - { 1— [. [ 4 - (chloromethyl) phenyl]- ( 4-chlorophenyl ) methyl] -3- [ (3,5-difluorophenyl) methylsulfonylmethylene] azetidine in 0.1125 cm3 of ethylamine (2 M. solution in tetrahydrofuran) , containing a grain of sodium iodide, is stirred at a temperature in the region of 20°C for 2 hours and then diluted with 20 cm3 of ethyl acetate and 5 cm3 of a saturated aqueous sodium hydrogen carbonate solution. The separated organic phase is washed with 5 cm3 of water, 5 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered on sintered glass and concentrated under reduced pressure (15 mbar) at a temperature in the region of 40°C. The yellow oil obtained is purified by preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm; deposition in solution in dichloromethane] , eluting with a methanol-dichloromethane mixture (3-97-by .volume) . After elution of the zone corresponding to the desired product with a-methanol-dichloromethane (15-85 by. olume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region. of 40°C, 17 mg of (RS)-{l-[[4- (chloromethyl ) phenyl] - ( 4 -chlorophenyl ) methyl ] -3 - [ ( 3 , 5- difluorophenyl) methylsulfonylmethyl]azetidin-3- yl } ethylamine are obtained in the form of a white solid [ΧΗ NMR spectrum (400 MHz , (CD3)2SO d6, 5 in ppm) : 1.11 ( t , J = 7 Hz . :. 3H) ; from 2.10 to 3.55 (mt : 8H) ; 2.95 (s : 3H).; 4.44 (s : 1H) 5.09. (s : 1H) ; from 7.10 to 7.55 (mt : 11H) ] . .
(RS) -{1- [ [4- (Chloromethyl) phenyl] - (4-chloro- phenyl) methyl] -3- ["( 3 , 5-difluorophenyl ) methylsulfonyl- methylene] azetidin. may be prepared in the. following manner: 0.525 cm3 of N, N-diisopropylethylamine'. is added, at a temperature in the region of 21°C, to a solution of 590 mg of (RS) - [4- ( ( 4 -chlorophenyl ) -{3- [ (3, 5- difluorophenyl ) methylsulfonylmethylene],azetidin-1- yljmethyl) phenyl] methanol in 5 cm3 of anhydrous dichloromethane, followed by 0.19 cm3. of methanesulfonyl chloride. After 1 hour at a temperature in the region of 21°C, 2 cm3 of a methanol/dlchloromethane (2.5/97.5 by volume) mixture are added and then after 5 minutes the reaction mixture is concentrated under ■ reduced pressure (20 mbar) at a temperature in the region of 40°C. The^ yellow foam obtained is purified by chromatography on silica (50 g of 0.06-0.2 mm silica contained in a column 3 cm in diameter) , eluting with a methanol/dichloromethane (0/100 and then 1/99 by volume) mixture, collecting 10-cm3 fractions ... The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 421.2 mg of ( RS ) - { 1- [ [ 4 - ( chloromethyl ) -phenyl] - (4 -chlorophenyl) methyl] -3- [ (3, 5-difluoro-phenyl) methylsulfonylmethylene] azetidine are thus obtained in the form of a yellow foam.
( RS )·- [ 4 - ( ( 4 -Chlorophenyl ) - { 3- [ (3, 5-difluorophenyl ) methylsulfonylmethylene] azetidin-l-yl Imethyl) -phenyl] methanol may be prepared in the following manner: 49 mg of sodium tetraborohydride are added portionwise to a solution. of 420 mg of (RS)-[4-( (4-chlorophenyl) -{3- [ (3, 5-difluorophenyl ) methylsulfonylmethylene] azetidin-l-yl }methyl) benzaldehyde in 7 cm3 of "methanol, cooled to a temperature in the region of 0°C (ice + water) . :After 2 hours at a temperature in the region of 0°C, the reaction medium is concentrated under . reduced pressure (15 mbar) at a temperature in the region of 35°C. The residue obtained is purified by chromatography on. silica (40 g of 0.06-0.2 mm silica contained in a column 3 cm in diameter) , eluting with a methanol/dichloromethane (1/99 and then 2.5/97.5 by volume) mixture, collecting 10-cm3 fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 418 mg of (RS) - [ 4- ( ( 4 -chlorophenyl) - { 3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethylene] azetidin-1-yl Jmethyl ) phenyl] methanol are thus obtained in the form of a white foam.
Example 38 . (RS) -{l-[Bis (.4-chlorophenyl)methyl] -3-[ (3,5- bistrifluoromethylphenyl) methylsulfonylmethyl] a etidin- 3-yl } isobutylamine may be prepared according to Example 29 starting with 50 mg of l-[bis(4-. chlorophenyDmethyl) ] -3-.[ (3, 5- bistrifluoromethylphenyl) (methylsulfonyl- methylene] azetidine, 0.5 cm3 of dichloromethane and 0.05 cm3 of isobutylamine. 57 mg of, (RS)-{1- [bis (4-chlorophenyl) methyl] -3-[ (3,5- bistrifluoromethylphenyl ) methylsulfonylmethyl] azetidin- 3-yl } isobutylamine are obtained in the form of a pale yellow foam [ΧΗ NMR spectrum (300 MHz, CDC13, δ ,in ppm) : 1.01 (d, J = 7.5 Hz : 6H) ; 1.76 (mt .: 1H) ; 2.47 (dd, J = 10.5 and 7.5 Hz :.1H) ; from 2.75 to 2.8.5 (mt : 1H) ; 2.79 (s : 3H).; 2.82 (dd, J = 10.5 and 5.5 Hz : 1H) ; '3.00 (d„ J .= 9 Hz : 1H) ; 3.10 (d, J = 9 Ηζ' : 1Η)·; 3.31 (d, J = 9 Hz : .-1H) ; 3^.40 (d, J =.9 Hz .: 1H) ; 4.30 (s : lH.) ; 4.74 (s : 1H);.'7.13 (d, J = 8.5 Hz : 2H) ; from 7.15 to 7.25 (mt : 6H),; 7.96 (broad s' : 1H) ; 8.31 (broad s : 2H) ] .
Example 39 (RS) -1- [Bis( 4-chlorophenyl) methyl] -3-eyano-3- [ (3, 5-difluorophenylmethylsulfonylmethyl] azetidine may be prepared in the following manner: 17 mg of potassium cyanide are added to a solution of 99 mg of l-[bis(4- chlorophenyl) methyl) ] -3- [ (3, 5-difluorophenyl) (methylsulfonyl.) methylene] azetidine in 2.5 cm3 of dimethyl sulfoxide, at a temperature in the region of 20°C. The yellow and then brown solution obtained is heated for 15 minutes at a temperature in the region of 40°C and then cooled to a temperature in the region of 20°C. The reaction medium is concentrated under reduced pressure and then taken up in 10 cm3 of dichloromethane,' washed with three times 5 cm3 of water. The organic phase obtained. is dried over magnesium sulfate, filtered and concentrated under reduced pressure. 100 mg'of a yellow paste are thus obtained, which paste is purified by chromatography on silica (10 cm3 of 0.06-0.2 mm silica, contained in a column 1 cm in diameter), eluting with dichloromethane. The fractions containing only the- desired product are combined and concentrated to dryness under reduced, pressure. .60 mg of '(RS) -1- [bis ( 4- chlorophenyl ) methyl] -3-cyano-3- [ (3, 5-difluorophenyl- methylsulfonylmethyl] azetidine are thus Obtained in the form of a yellow paste ■[1H NMR spectrum (300 MHz, • (CD3)2SO, d6, δ in ppm) : 2.94 (s : 3H) ; 3.07 (d, J = 7.5 Hz : 1H); from 3.20 to 3.40 (mt : 1H) ; 3.61 (broad d, J = 7.5 Hz : .1H); 3'.68 (broad, d, J = 7.5 Hz : 1H) ; 4.64 (s : 1H) ; 5.51 (s : 1H) ; from 7.25 to 7.50 (mt : 11H) ] . " Example 40 (RS) -{ 1- [Bis (4-chlorophenyl) methyl] -3- [ (3, 5- · difluorophenyl ) methylsulfonylmethyl ] azetidin- 3-ylmethyl }-( 1-cyclopropylethyl ) amine may be prepared in the following manner: 0.03 cm3 of cyclopropyl methyl ketone, 0.006 cm3 of acetic acid and then 32 mg of sodium triacetoxyborohydride are successively added to. a solution of 53 mg of (RS) -C- { 1- [bis ( 4-chlorophenyl) -methyl] -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl ] -azetidin-3-yl }.methylamine in 2 cm3 of 1 , 2-dichloroethane at a temperature in the region of 20 °C. The solution obtained is stirred at a temperature in the region of 20°C for 18 hours and then 2 cm3 of a saturated aqueous sodium hydrogen carbonate solution are added. After decantation, the organic phase is concentrated under reduced pressure. 60 mg of a viscous yellow oil are thus obtained, which oil is triturated with isopropyl ·' ether and petroleum ether. After drying under 0.1 mbar, 55 mg of a residue are obtained which is purified by chromatography on silica (4 'cm3 of 0.06-0.2 mm silica contained in a column 1.2 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 5/95 by volume) .mixture . The fractions containing only the desired product are combined, concentrated to dryness under reduced pressure and repurified by chromatography on silica (4 cm3 of 0.04-0.063 mm silica contained in a column 1.2 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 1/99 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness. 20 mg of (RS) -{ 1- [bis (4-chlorophenyl) methyl] -3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl }-( 1-cyclopropylethyl ) amine are thus obtained [XH NMR spectrum (300 MHz, CDCI3, δ in ppm) : a mixture of diastereoisomers is observed, from 0.00 to 0.30 and . from 0.40 to 0.80. (mts : 5H) ; 1.09 and 1.17 (2d, J = 6.5 Hz : 3H in total); 1.87 (mt : 1H) ; from 2.55 to 2.7-5-from 2.75 to 2.95 and from 3.25 to 3.55 (mts : -4H) ;■ 2.68 "(s : 3H); 3.12 (d, J = 8.5 Hz : 1H) ; from 3.80 to 3..90'(mt : 1H) ; 4.42 and 4.43 (2s : 1H . in total); 4.79 and 4.84 (2s : - 1H in total) ; 6.89 (tt, - ,J = 9 and -2.5 Hz : 1Η)·; 7.16 (mt : 2H) ; from 7.15 to 7.35 (mt- : 8H] ) .
(RS) -C- { 1- [Bis ( 4-chlorophenyl) methyl] - 3- [ (3, 5-difluorophenyl)methylsulfonylmethyl] azetidin-3- yl }methylamine may be prepared in the following manner: 1.27 cm3 of a 1.5 M solution of diisobutylaluminum hydride in tetrahydrofuran are added dropwise to a solution of 250 mg of (RS )-l- [bis (4 -chlorophenyl ) - methyl] -3-cyano-3- [ (3, 5-difluorophenyl ) methylsulfonyl- methyl ] azetidine in 10 cm3 of anhydrous tetrahydrofuran, cooled to a temperature in the region of 0°C. Aftex 30. minutes. at a temperature in the region of 0°C and then 4 hours at a temperature in the region of 20°C, the solution is again cooled to a temperature of 0°C. 6.35 cm3 of water and then 1.06 cm3 of aqueous hydrochloric acid (12- N) are added successively. After decantation, the aqueous phase is extracted with three times 10 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 0.42 g of a dark yellow oil is thus obtained which is purified by chromatography on silica (40 cm3 of 0.063-0.2 mm silica contained in a column 2.7 cm in diameter), eluting with a methanol/dichloromethane (0/100 and then 5/95 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 110 mg of (RS)-C-(l- [bis ( 4-chlorophenyl ) methyl] -3- [ (3 , 5-difluoro-phenyl) methylsulfonylmethyl] azetidin-3-yl Jmethylamine are thus obtained.
Example 41 (RS) -N- { 1- [Bis (4-chlorophenyl) methyl] - 3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethyl ] azetidin-3-ylmethyl } isobutyramide may be prepared in. the following manner: 0.0187 cm3 of isobutyric acid, 0.032.cm3 of 1 , 3-diisopropylcarbodiimide and 2.5 mg of- 4-dimethylaminopyridihe are successively added to a .. solution of 53 mg .of (RS.) -C- { 1- [bis ( 4-chlorophenyl) -methyl] -3- [ (3, 5-difluorophenyl Jmethylsulfonylmethyl ] -azetidin^-3-yl Jmethylamine in 2 cm3 of anhydrous dichloromethane at a temperature in the region of 20 °C. After stirring for 72 hours at a temperature in the region of 20°C, 2 cm3 of water are added, the mixture is separated after settling and then the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue obtained is purified by. preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95 by .volume), mixture- After eluti.on of the zone corresponding to the desired product, filtration on sintered glass and then evaporation of the solvent under reduced pressure at a temperature in the region of 40°C, 16 mg of (RS)-N-(l- [bis (4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) -methylsulfonylmethyl] azetidin-3-ylmethyl } isobutyramide are obtained in the form of a pale yellow powder [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 1.22 (d, J = 7 Hz : 6H) ; 2.46 (mt : 1H) ; 2.69 (s : 3H) ; 2.99 (d, J = 8.5 Hz : 1H) ; 3.23 (AB, J = 8.5 Hz : 2H) ; 3.40 (d, J = 8.5 Hz : 1H) ; 3.57 (dd, J = 14 and 4.5 Hz : 1H) ; 4.09 (dd, J = 14 and 7.5 Hz : 1H) ; 4.34 (s : 1H) ; 4.35 (s ■ : 1H) ; 6.71 (dd, J = 7.5 and 4.5 Hz : 1H) ; 6.95 (tt, J = 9 and 2.5 Hz . : 1H) ; from 7.10 to 1.35 (mt : 10H) ] . ' Example 42 . (.RS) -N- { 1- [Bis (4-chlorophenyl) methyl] -3-[ ( 3 , 5-difluorophenyl) methylsulfonylmethyl ] azetidin-3-ylmethyl } cyclopropanecarboxamide may be prepared in a manner similar to Example 39, starting with 53 mg of (RS) -C-{1- [bis (,4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methanesulfonylmethyl ] az.etidin-3-yl }methylamine, 2 cm3 of anhydrous dichloromethane, 0.0167 cm3 of cyclopropanecarboxylic acid, 0.032 cm3 of 1 , 3-diisopropylcarbodiimide and 2.5 mg of 4-dimethylaminopyridine . 28 mg of (RS)-N-(l-[bis ( 4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) - methylsulfonylmethyl ] azetidin-3-ylmethyl } -cyclopropanecarboxamide are obtained in the form of a ■ beige powder [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.81 (mt : 2H) ; 1.01 (mt : 2H) ; from 1.35 to.1.55 (mt : 1H) ; 2.70 (s : 3H) ; 3.02 (d, J = 8.5 Hz .: 1H) ; . 3.21 (limiting AB, J = 8 Hz : 2H) ; 3.45 (d, J = 8.5 Hz :" 1H) ; 3..62 (dd, J = ; 14 and 4.5 Hz : 1H) ; 4.10 (dd, J = 14 and 7.5 Hz) ; 4.31 (s : 1H) ; 4.36 (s :· 1H) ; 6.75 (dd, J = 7.5 and 4.5 Hz : 1H)-; 6.95 (tt,. J =\ 9 and 2 Hz : 1H)-;' 'from 7.15 to 7.35 (mt : 10H) ] .
Example 43 (RS) -{ 1- [Bis (4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-ylmethyl } diethyiamine may be prepared in a manner similar to Example 40, starting with 53 mg of .
(RS) -C- { 1- [bis"(4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3-yl }methylamine, 2 cm3 of 1 , 2-dichloroethane , 0.017 cm3 of acetaldehyde , 0.006 cm3, of acetic acid and .32' mg of. sodium triacetoxyborohydride. 12.mg of (RS )-{ 1- [bis ( 4-chlorophenyl ) methyl ] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidin-3-ylmethyl } diethyiamine are thus obtained in the form of an off-white powder [XH NMR . spectrum (300 MHz, CDCI3, δ in ppm) : ,1.00 (t, J = 7 Hz : 6H-) ; 2.49 (q, J = 7 Hz : 4H) ; 2.54 (d, J- = 13.5 Hz : 1H) ; 2.69 (s : 3H) ; 2.76 (broad d, J = 7.5 Hz : 1H) ; 3.07 (broad d, J = 7.5 Hz : 1H) ; 3.15 (d, J = 13.5 Hz : 1H) ; 3.24 (broad d, J = 7.5 Hz : 1H) ; 4.06 (broad d, J = 7.5 Hz : 1H) : 4.35 (s : 1H) ; 5.02 (s : 1H) ; 6.91 (mt .: 1H) ; from 7.15 to 7.40 (mt : 10H) ] .
Example 44 (RS) -N-{1- [.Bis (4-chlorophenyl) methyl] -3-[ (3, 5-difluorophenyl)methylsulfonylmethyl] azetidin-3-ylmethyl }methanesulfo amide may be prepared in the following manner: 150 mg of anhydrous. IRA-68 resin are added to a solution of 53 mg of (RS) -C- { 1- [bis ( 4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl ) -methylsulfonylmethyl] azetidin-3-yl }methylamine in 2 cm3 of ethyl acetate, at a temperature in the region of 20°C, followed by 0.012 cm3 of methylsulfonyl chloride. After stirring overnight at a temperature in the region of.20°C, 0.001 cm3 of water and then 150 mg of anhydrous IRA-68 resin are added. After stirring for 1 hour at a temperature in the region of 20°C, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. 81 mg of a yellow paste are thus obtained, which paste is purified by preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; ' 20x20 cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone corresponding to the desired product, filtration on sintered glass and evaporation, of the solvents under reduced pressure at a temperature in the region of 40°C, 25 mg of ( RS ) -N- { 1- [bis ( 4 -chlorophenyl ) methyl ] -3- [ (3, 5-difluorophenyDmethylsulfonylmethyl] azetidin-3- ylmethyl }methanesulfonamide are obtained in the form of a pale yellow. powder NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.70 (s : 3H) ; from 2.95 to 3.10 (mt : 2H) ; 3.05 (s : 3H); 3.22 (broad d, J = 8 Hz : 1H) ; 3.52 (d, J = 8 Hz : 1H).; 3.74 (dd, J = 13.5 and 8 Hz .: 1H);. 3.90 (dd, J = 13.5 and 5.5 Hz : 1H) ; 4.23 (s : 1H) ; 4.46 (s : 1H) ; 5.54 (mt : 1H) ; 7.00 (tt, J = 9 and 2 Hz : 1H) ; from 7.05 to 7.35 (mt : 10H) ] .
Example 45 (RS) -l-{l-[Bis (4-chlorophenyl) methyl] -3- [ (3,.5-difluorophenyl)methylsulfonylmethyl] azetidin-3- ylmethyl } -3-isopropylurea may be prepared in the following manner: 0.0197 cm3 of isopropyl isocyanate is added to a solution of 53 mg of · (RS )-C-(l-[bis( 4-chlorophenyl ) methyl] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-3- yl }methylamine in 2 cm3 of dichloromethane , ' at a temperature in the region of 20°C. After stirring • overnight' at a temperature in the region of 20°C, 0..05 cm3 of water' is added and then after .stirring for 15 minutes at a temperature in the region of 20°C, the reaction mixture is dried over magnesium sulfate, filtered. and concentrated under reduced pressure. The. residue obtained (75. mg) is purified by preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; .20x20. cm; thickness 1 mm], eluting with an ethyl acetate-dichloromethane (5-95.by volume) mixture . ' After elution of the zone corresponding to the desired product, filtration on · sintered glass and then evaporation of the solvent' under reduced pressure at a temperature in the region of 40°C, 16 rag of (RS) -1- { 1- [bis ( 4 -chlorophenyl ) -methyl] -3- [ (3,-5-difluorophenyl) methylsulfonylmethyl] -azetidin-3-ylmethyl} -3-isopropylurea are obtained in the form of a pale yellow powder [1H NMR spectrum (300 MHz, CDCI3, δ in ppm). : 1.17 (d, J = 7 Hz : 6H) ; 2.68 (s : 3H) ; 3.00 (broad, d, J = 8.5 Hz : 1H) ; 3.1l' (d, J = 8.5 Hz : 1H) ; 3.17 (d, J = 8.5 Hz : 1H) ; 3.46 (broad- d, J = 8.5 Hz : 1H) ; 3.64 (dd, J = 14 and -5 Hz : 1H).; 3.86 (mt : 1H) ;. 3.96 .(dd, J = 14 and · 7.5 Hz : 1H); 4.15 (d, J = 8 Hz : 1H) ; 4.29 (s : 1H) ; 4.43 (s : 1H) ; 5..11 (mt : 1H) ; 6.94 (tt, J = 9 and 2 Hz : 1H) ; from 7.10: to 7.30 "(mt . : 10H) ] .
Example 46 (RS)-{l-[Bis( 4 -chlorophenyl ) methyl] - -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl.] azetidin-3-ylmethyl } carbamic acid isobutyl ester may be prepared in the following manner: 0.016 cm3 of isobutyl chloroformate is added to a solution of 53 mg. of (RS)-C-( 1- [bis ( 4 -chlorophenyl) methyl] -3- [ (3, 5-difluoro-phenylmethylsulfonylmethyl] azetidin-3-yl }methylamine in 2 cm3 of pyridine, at a temperature in the region of 20°C. After stirring overnight at a temperature in the region of 20°C, the reaction mixture is concentrated under reduced pressure. 68 mg of a yellow paste are obtained, which paste is purified by preparative thin- layer chromatography on silica gel [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm]., eluting with an ethyl acetate-dichloromethane (5-95 by volume) mixture. After elution of the zone corresponding -to the desired product, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 14 mg of (RS )-{ 1- [bis ( -chlorophenyl) methyl] • 3- [ (3, 5-difluorophenyl)methylsulfonylmethyl]azetidin-3- ylmethyl } carbamic acid isobutyl ester are obtained in the form of an off-white powder [ H NMR spectrum (300 MHz, . CDCI3, δ in ppm) : 0.96 (d, J. = 7 Hz : 6H) ; 1.95 (mt : 1H) ; 2.68 (s : 3H) ; 3.04 (d, . J = 8.5 Hz : 1H) ; 3.19 ,(3 : 2H); 3.51 (d, ■ J = 8 Hz : 1H); 3.75 (dd, J = 14 and 5 Hz : lH);'from 3.80 to 4.00 (mt : 3H) ; . 4.30 (s ■: 1H) ; 4.34 (s : lH); 5.63 (unresolved complex: 1H) ; 6.95 '(tt, J = 9 and 2 Hz : 1H) ; from 7.10 to 7.30 ■ (mt : 10H) ] .
Example 47 (RS) -{ 1- [Bis (4-chlorophenyl) methyl] - 3- [( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidin-3- ylmethyl } dimethylamine may be prepared in the following manner: 138 mg of potassium carbonate are added, at a temperature in the region of 20°C, to a solution of 52 mg of (RS ) -C- { 1- [bis ( -chlorophenyl ) methyl] -3- [ (3, 5-difluorophenyl).methylsulfonylmethyl] azetidin- 3-yl }methylamine in 2 cm3 of acetonitrile ,. followed by 0.0075 cm3 of methyl iodide. After stirring overnight at temperature in the region of 20 °C, the reaction medium is. filtered oh sintered glass, the solid is rinsed with dichloromethane and the filtrate is concentrated under reduced pressure. The crude residue obtained (90 mg) is purified by preparative thin-layer chromatography on silica [1 preparative Merck Kieselgel 60F254 plate; 20x20 cm; thickness 1 mm] , eluting with an ethyl acetate-dichloromethane (5-95. by volume) mixture. After ■elution of the zone corresponding to the desired product, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a ■ temperature in the region of -40°C, 11 mg of (RS)-{1- '. . [bis ( 4-chlorophenyl ) methyl] -3- [ (3, 5-difluorophenyl ) - methylsulfonylmethyl] azetidin-3-ylmethyl } dimethylamine are obtained [lH NMR spectrum (300 MHz, CDC13, δ in ppm). : 2.18 (s : 6H); 2.30 (d, J = 13 Hz : 1H) ; from- 4.65 to 4.78 Cmt : 1H) ; 2.70 (s : 3H) ; 2.98 (d, J = 13 -Hz : 1H) ; .3.09 (d, J = 8 Hz : .1H) ;■ 3.32 (d, , j = 7.5 Hz : ΊΗ) ; 4.11 (d, "'J = 8 Hz : 1H) ; 4.'35 (s- : 1H) ; 4.94 (s : 1H) ; 6.92 (mt : 1H.) ; from 7.10 to 7.40 (mt : 10H) ] .
Example 48 (RS) -1- [Bis (4 -chlorophenyl) methyl] - 3- [ ( 4-methox.yphenyl) methylsulfonylmethyl] azetidine may be prepared in the following manner: 25.5 mg of sodium tetraborohydride are added to a solution of 400 mg .of 1- [bis ( 4-chlorophenyl) methyl] -3- [ (4-methoxyphenyl) - methylsulfonylmethylene] azetidine in 4.5 cm3 of ethanol, under an argon atmosphere, at a. temperature in the region of 20°C. After stirring for 16 hours at a temperature in the region of 20°C, 26 mg of sodium tetraborohydride are added. The reaction medium is .stirred at a temperature in the region of 20°C for 4.5 hours and then at a temperature in the region of 50°C for 3 -hours . After cooling- to a temperature in the region of 20°C, the reaction medium is concentrated under reduced pressure. The "white deposit obtained is taken up in 2 cm3 of water and 2 cm3 of dichloromethane . After decantation., the organic phase is concentrated under reduced pressure and the yellow foam obtained is purified by preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel' 60F254 plates, 20x20 cm; thickness 0.5 mm], eluting with. a methanol-dichloromethane (1-99 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90· by volume) mixture, ■filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 14 mg of (RS ) -1- [bis ( 4-chloro-phenyl)methyl] -3- [ (4-methoxyphenyl)methylsulfonyl-methyl ] azetidine are obtained in the form of a white foam [XH NMR; spectrum (300 MHz , CDC13 , δ in ppm) : 2.56 (mt : 1H) ; 2.58 (s : 3H) ; 3.20 (mt : 2H) ; from 3.35 to 3.55 (mt : 1Η); ·3.66 (broad t, J = 7.5 Hz : 1H) ; 3.81 (s : -3H) ; 4.21 (d, J = 4.5 Hz : 1H) ; 4.26 (broad s : 1H) ; 6.90 (d, J = 8.5 Hz : 2H) ; from 7.15 'to 7.40 (mt : 10H)J . 1- [Bis ( 4-chlorophenyl) methyl] -3- [ ( 4-methoxyphenyl) methylsulfonylmethylene] azetidine may be prepared by carrying out . the procedure as described in Example 1, starting . with 1 g of (RS)-1- [bis ( 4 -chlorophenyl) methyl] -3- [methylsulfonyl- ( -methoxyphenyl) methyl] azetidin-3-ol , 20 cm3 of dichloromethane, 0.229 cm3 of methylsulfonyl chloride and 722 mg of 4 -dimethylaminopyridine . After purification by chromatography on silica at atmospheric pressure (100 g of silica, particle size .0.063-0.2 mm contained in a column 3 cm in diameter)-, eluting with dichloromethane), the fractions containing only the desired product .are combined and concentrated to dryness under reduced pressure. 650 mg of l-[bis(4-chlorophenyl ) methyl] -3- [( 4-methoxyphenyl ) methyl-sulfonylmethylene] azetidine are' thus obtained in the form of a yellow, gum.
(RS) -1- [Bis (4-chlorophenyi) methyl] - 3- [methylsulfonyl- ( 4-methoxyphenyl ) methyl ] azetidin-3-ol may be prepared by carrying out the procedure as described in Example 1, starting with 19.6 cm3 of 1.6 N n-butyllithium in solution in hexane, 5.7. g of 4-methoxybenzy.l methyl sulfone and 8.71 g of 1- [bis ( -chlorophenyl) methyl] azetidin-3-one in. 450 cm3 of tetrahydrofuran. 8.3 g of (RS) -1- [bis (4-chloro-phenyl).methyl] -3- [methylsulfonyl- (4-methoxyphenyl) - methyl] azetidin-3-ol are thus obtained in the form of a beige solid. ' 4-Methoxybenzyl methyl sulfone may be prepared by carrying put the procedure as. described in Example 27, . starting with 13.6 cm3 of 4 -methoxybenzyl chloride, 30 mg of sodium iodide, 14.4 g of sodium methyl sulfinate in 125 cm- of ethanol. 5.75 g of 4 -methoxybenzyl methyl sulfone are thus obtained in the form of a white .powder.
Example 9 (RS) -2- { 1- [Bis ( 4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3, 5-difluorophenyl)—Nracetyl-morpholine may be prepared in the following manner: 252 mg of supported EDCI (2.3 equivalents, the supported EDCI reagent is commercially available, and . may also be prepared according to the following reference: M. Desai, L. S-tramiello, Tetrahedron Letters, 34, 48', 7685.-768-8 (1993)), 2 cm3 of anhydrous dichloromethane, 0.006 cm3 or morpholine and then 0.010 em5 of triethylamine are successively added, at - a1' temperature in the region of 20°C,. to 37 mg of (RS-{1-.. [bis ( 4-chlorophenyl) methyl] azetidin-3-yl }-( 3, 5-difluorophenyl) acetic . acid hydrochloride. After stirring for 12 hours at a temperature in the- region of 20°C, the reaction mixture is filtered on. sintered glass. The filtrate is washed with 2 cm3 of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced ; pressure (2.7 kPa)- at a temperature in the region of 20°C. 15 mg of (RS)-2-{l- [bis ( 4-chlorophenyl ) methyl] azetidin-3-yl } -2- ( 3 , 5- difluorophenyl) -N-acetylmorpholine are thus obtained in the form of a beige foam [:H NMR spectrum (300 MHz, CDCI3, δ in ppm) : from 2.60 to 3.80 (mt : 13H) ; 3.93 (d, J- = 10 Hz : 1H) ; 4.27 (s.: 1H) from 6,65 to 6.85 (mt : 3H) . from 7.20 to 7.40 (mt : 8H) ] .
Example 50 (RS) -2-{l- [Bis (4-chlorophenyl) methyl] - azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N-cyclohexyl- acetamide may be prepared in the following manner; 0.070 cm3 of cyclohexylamine, 14.4 mg of l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.141 cm3 of triethylamine . and then 4 mg of hydroxybenzotr'iazole hydrate are successively added, to' ■ a., solution of.25.0 mg of (RS) -{1- [bis (4-chlorophenyl) - methyl ] azetidin-3-yl }-( 3 , 5-difluorophenyl) acetic acid hydrochloride in 10 cm3 of. anhydrous dichloromethane-, at a temperature in the region of 20°C. The solution obtained is stirred at ,a tempera'ture in the region of 20°C for about 12 hours. The reaction medium is . deposited on a Varian, cartridge (25 cm3) filled with .12 g of fine silica (0.040-0.063 mm),,, conditioned and then eluted with a dichloromethane-petroleum ether (80-20 by volume) mixture with the aid of a Duramat pump, collecting 1.5-cm3 fractions ...Fractions 11 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 169 mg of (RS) -2-{l- [bis (4- chlorophenyl) methyl] azetidin-3-yl} -2- ( 3, 5-difluoro-phenyl). -N-cyclohexylacetamide are thus obtained in the form of a white foam'^H NMR spectrum (300 MHz, CDC13, δ in ppm) : from.0.90 to 1.45 (mt : 6H) ; from 1.50 to 1.90 (mt : 4H) ; 2.56 (mt : 1H) ; 2.90 (mt : 1H)' from 3.00 to 3.15 (mt : 2H) ; 3.42 !(broad t, J = 7.5 Hz . : : 1H) ; 3.52 (d, J = 10.5' Hz' : 1H) ; from 3.60 to 3.80 (mt : 1H) ; 4.27 (s : 1H) ; 5.25 (broad d, J ='8 Hz .:. 1H) ; 6.90 (tt, . J = 9 and 2.5 Hz : 1H) ; 6.82 (mt : 2H) ; from 7.20 to 7.35 ' (mt : 8H] .
Example 51 (RS) -2- { 1- [Bis ( -chlorophenyl) methyl] -azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-acetyl-piperidine may be prepared in the following manner: 0.012 cm3 of piperidine, 29 mg of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - {1- [bis ( 4 -chlorophenyl).methyl] azetidin-3-yl } -3 , 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of .20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with- 3 'g of fine silica (0.04Ό-0.063 mm), eluting with dichloromethane with the aid of a Duramat pump. The fractions between 8 and 15 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 14. mg of (RS) -2- { 1- [bis ( 4-chloro- phenyl ) methyl] azetidin-3-yl } -2- ( 3 , 5-di fluorophenyl ) -N- acetylpiperidine are thus obtained in the form of a white crystalline powder [ H NMR spectrum (300 MHz, , . CDCI3, δ in ppm) : from 0.95 to 1.15 and from 1.30 to 1.50 (2mts : 6H in total); 2.74 (mt : 2H).; from 3.00 to 3.15 (mt : 2H) from 3.30 to 3.45 .(,mt : 4H) ; from 3.55 to 3.70 .(mt : 1H) ;. 3.95 (d, J = 10 Hz : 1H) ; 4.26 (s .: 1H) ; 6.68 (tt, J = 9 and 2.5 Hz : 1H) ; 6.80 (mt : 2H) ; . from 7.20 to 7.35 (mt : 8H) ] .
Example 52 (RS) -2- { 1- [Bi-s (4-chlorophenyl) methyl] τ ■. azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-acetyl- . pyrrolidine may be prepared in the following manner: 0.010 cm3 of pyrrolidine and 0.023 cm3 of ' diisopropylcarbodiimide, 0.028 cm3 of triethylamine and · 1.5 mg of hydroxybe.nzotriazole hydrate are successively added to a solution of 50 mg of (RS).- { 1- [bis (4-chlorophenyl j.methyl ] azetidin-3-yl }- (3, 5-difluorophenyl) acetic ' acid hydrochloride, in 2 cm3 of . anhydrous dichloromethane at a temperature in the region of 20 °C ..■ The solution obtained is . stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is ■ deposited on a Varian cartridge (6 cm3) filled with 3 g ' of fine silica (0.040-0.063 mm) , eluting with dichloromethane with the aid of a Duramat pump. The fractions between 11 and 19 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 29 mg of (RS) -2- { 1- [bis ( 4-chloro-phenyl) methyl J azetldin-3-yl } -2- ( 3, 5-difluorophenyl) -N-acetylpyrrolidine are thus obtained in the form .of a white foam [XHNMR spectrum (300 MHz , CDC13, δ in ppm) : ■ from 1.75 to 2.00 (mt ' : 4H);.2.74 (mt : 2H) from 3.00 to 3.30 (mt : 3H) ; from 3.35 to 3.60 (mt : 4H) ; 3.80 (d, J = 10.5 Hz : 1H); 4.25 (s : 1H) ; 6.68 (tt, J = 9 and 2.5 Hz : 1H) ; 6.84 (mt : 2H) ; from 7.20 to 7.40 (mt : 8H).] .
Example 53 (RS ) -2- (.1- [Bis (4-chlorophenyl ) methyl ] -azetidin-3-yl } -2- (3, 5 difluorophenyl) -N-cyclopropyl-acetamide may be prepared in the following manner: 0.009 cm3 of cyclopropylamine, 29 mg of 1- ( 3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are .successively added to a solution of 50 mg of (RS) -{ 1- [bis (4-chlorophenyl) -methyl] azetidin-3-yl } - (3,.5-difluorophenyl).acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane at a temperature in the region of 20°C. The solution' obtained is stirred at a. temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on' a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm),, conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 2 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 29 mg of (RS) -2- U- [bis (4- chlorophenyl) methyl] azetidi'n-3-yl } -2- (3, 5-difluorophenyl ) -N-cyclopropylacetamide are thus obtained in the form of a white foam [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.40 (mt : 2H) ; 0.74 (mt : 2H) ; 2.64 (mt : 2H) ; 2.89 (dd, J = 7.5 and 5 Hz : 1H) ; 3.08 (mt : 2H) ; 3.42 (broad t, J = 7.5 Hz : 1H) ; 3.51 (d, J = 10.5 Hz : 1H) ; 4.25' (s : IH) ; 5.50 (unresolved complex : 1H) ; 6.70 (tt, J = 9 and 2.;5 Hz. : IH) 6.81 (mt : 2H) from 7.15 to 7.35 (mt : 8H)]'.
E am le 54 (RS) -2-{l-[Bis (4-chlorophenyl) methyl] - azetidin-3-yl.} -2- (3, 5-difluorophenyl) -N-cyclohexyl-N-• methylacetamide may be prepared in the following manner: 0.016 cm3. of N-methylcyclohe'xylamine, 29 mg of ■ 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotxiazole hydrate are successively added to ■ a solution of 50 mg of ( RS )-{ 1- [bis ( 4-chlorophenyl ) -methyl] azetidin-3-yl }- (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane , at ,a temperature in the region of 20°C. The solution · obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) , conditioned and eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 ' kPa) at 40°C. 17 mg of (RS)-2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N-cyclohexyl-N-methylacetamide are thus obtained in the form of a white foam [lR NMR spectrum (250 MHz, (CD3)2SO d6, at a temperature of 373K, δ in ppm) : from 0.98 to 1.85 (mt : 10H) ; from 2.60 to 3.05 (mt : 8H) ; (broad t, J = 7.5 Hz : 1H) ; 4.25. (broad d, J = 9 Hz : 1H) ; 4.45 (s : 1H).;' 7.00 (mt : 3H) ; from 7.25 to 7.45 (mt : 8H) ] .
Example 55 (RS) -2-{l-[Bis (4-chlorophenyl) methyl ].-azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N- (tetrahydro-furan-2-ylmethyl ) acetamide may be prepared in the following manner: 0.013 cm3 of tetrahydro.furylamine , 29 mg of 1- (3-dimethylaminop'ropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added, to a solution of 50 mg of (RS) -{ 1-bis ( 4-chlorophenyl) -methyl] azetidin-3-yl] - (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The. solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6' cm3), filled with 3 g of fine^ silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3. fractions . Fractions 3 to 8 are combined and concentrated to dryness under reduced pres.sure (2.7'kPa) at 40°C. 27 mg of 2 (RS) -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluoro- ■ phenyl ) -N- ( tetrahydrofuran-2-ylmethyl ) acetamide are thus obtained ·ίη the form of a white solid [XH NMR spectrum (300 MHz, CDCI3, δ in ppm) : from 1.6.5 to 1.95 (mt : 4H) ; 2.64 (mt. : 1H) ; 2.89 (dd, J = 7.5 and 5.5 Hz : 1H) ; from 3.00 to 3.20 (mt : 3H) ; from 3.30 to 3.60 (mt : 2H)'; 3.58 (d, J = 10.5 Hz : 1H) ; from 3.65 to 3.95 (mt : 3H) ; 4.25 (s : 1H) ; 5.81 (mt : 1H) ; 6.68 (tt, J = 9 and 2.5 Hz : 1H) ; 6.82 (mt : 2H) ; . from 7.15 .. to 7.35 (mt : 8H) ] . .
Example 56 (RS) -2- { 1- [Bis (4-chlorophenyl)methyl] -azetidin-3-yl } -2- ( 3, 5-difluorophenyl) .÷N- ( 2-morpholin-4 -ylethyl ) acetamide may be, prepared in the following manner: 0.016 cm3 of aminoethylmorpholine, 29 mg of 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3' of triethylamine "and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution, of 50 'mg of - (RS) -{ 1- [bis ( 4 -chlorophenyl ) -methyl] azetidin-3-yl } - (3, 5-difluorophenyl ) acetic acid hydrochloride" in 2 cm3 of anhydrous dichloromethane , at a temperature in the region of 20 °C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned with dichloromethane with the aid of a Duramat pump, eluted successively with a dichloromethane-ethyl acetate (70-30 by volume) mixture, collecting 2-cm3 fractions, for fractions 1 to 12, and. then with a dichloromethane-methanol (98-2 by volume) mixture, collecting 2-cm3 fractions for fractions 12 to 27. Fractions 13 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 34 mg of (RS ) -2- { 1- [bis ( -chlorophenyl) methyl] azetidin-3-yl] -2- (3, 5-difluoro-phenyl) -N- (2-morpholin-4-ylethyl) acetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.33 (broad t, J = 5 Hz : 4H) ; 2.38 (t, J = 7 Hz : 2H) ; 2.65 (mt : 1H) ; from 2.8-5 to 3.20 (mt : 3H) ;" 3.25 (broad q, J.= 7 Hz : 2H) ; 3.43 · (mt :. 1H) ; 3.57 (t, J = 5 Hz : 4H) ; 3.61 (d, J = .5 Hz : 1H).;. 4.26 (s : 1H) ; 5.98 (unresolved complex: ' 1H) ; 6.70 (tt, J = 9 and 2.5 Hz : 1H) ; .6.83 (mt : 2H) ; from -7.15 to 7.35 (mt. : 8H) ] .
Example 57 (RS ) -2- { 1- [Bis ( 4 -chlorophenyl ) methyl] -azetidin-3-yl } -2 - (.3 , 5-difluorophenyl ) -N- (1-ethyl-pyrrolidin-2-ylmethyl ) acetamide may be prepared in the. following manner: 0.018 cm3 of aminomethylethyl-pyrrolidine, 29 mg. of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide . hydrochloride,. 0..028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) -{ 1- [bis (,4-chlorophenyl) methyl] azetidin-3-yl } - : ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of- anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at. a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of .12 mm in diameter) filled, with 4 cm3 of silica (0.060-0.200 mm), conditioned with dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-methanol (95-5 by volume) mixture. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. The yellow paste thus obtained is taken up in 2 cm3 of ethyl acetate and then with 2 cm3 of distilled water. After, s.tirring, the mixture is f ozen, the organic phase is concentrated to dryness under reduced- pressure (2.7 kPa) at 40°C. The residue obtained is taken up in.2 cm3 of diisopropy.L ether and is then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C..38 mg of (RS) -2- { 1- [bis ( 4-chlorophenyl ) methyl ] azetidin-3-yl } -2 - ( 3 , 5-difluorophenyl ) -N- ( l-ethylpyrr'olidin-2- , ylmethyl ) acetamide are thus obtained in the form of a white foam.[xH NMR spectrum (300 MHz , CDC13 with' addition of a few drops of CD3COOD d4, δ in ppm) : 0..96 and 1.17 (2t, J = 7.5 Hz : 3H in total); from 1.60 to 2.00 (mt : 4H) ; from 2.50 to 2.9.5-from 3.10 to- 3.85 (mts : 11H) ; from 3.95 to 4.10 (mt : 1H) ; 4.10 and 4.14 (2d, J = 10.5 Hz : 1H in total); 5.18 and 5.25 (2 broad s : 1H in total) ; 6.66 (mt : 1H) ; from 6.80 to 7.00 (mt : 2H) ; from 7.15 to 7.45 (mt : 8H) ] . ~ Example 58 (RS).-2-{l-[Bis (4-chlorophenyl)methyl] -a∑etidin-3-yl } -2- (3, 5-difluorophenyl) -N-isobutyl-acetamide may be prepared in the following, manner : 0.012 cm3 of isobutylamine, 29 mg of 1- ( 3-dimethyl-aminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - { 1- [bis ( 4-chloro-phenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the. region of '20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter-) filled with 5 cm3 of silica (0.060-0.200 mm), conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between.0 and 6 cm3 and then with. a. dichloromethane-ethyl acetate (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 40 mg of (RS)-2-{l-[bis( 4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-isobutylacetamide are thus obtained in the form of a white foam [1H NMR spectrum (300 MHz , (CD3)2SO d6 δ in ppm) : 0.75 (d, J = 7.5 Hz : . 6H) ; 1.62 (mf : 1H);"2.61 (mt : 1H) ; from 2.70 to 2.95 (mt : 3H) ; 3.03 (mt : 2H)-; 3.22 (broad t, J = 7 Hz : ' 1H) ; 3.83 (d, J = 10.5 Hz : 1H) ; 4.45 (s : 1H) ; 7.00 (mt : 2H) ; 7.08' (tt, J = 9 and 2.5 Hz : lH) ; from 7.25-to 7.45 (mt : ' 8H) ; 8.11 (t, J = .6 Hz : 1H) ] .
Example 59 (RS) -2-{l- [Bis (4-chlorophenyl) -methyl ] azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) -N, N-dimethylacetamide may be prepared in the following manner: 0.06 cm3 of dimethylamine in 2 M solution in tetrahydrofuran, 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of tr.iethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a- solution of 50· mg of (RS)-{l-[bis( 4-chlorophenyl ) methyl] azetidin-3-yl}- (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3' of anhydrous dichloromethane, at a temperature, in the region of 20°C. The solution ..obtained is stirred at a temperature in the region of 20°C for about 12 hours.. The reaction medium is deposited on a Varian cartridge (of.12 mm in diameter) filled with 4.4 cm3 of silica (0.060-0.200 mm) , conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with . dichloromethane between 0 and 6 cm3 and then with a dichloromethane-ethyl acetate (95-5 by volume) mixture." The fractions containing only the desired product" are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 13 mg of (RS) -2- { 1- [bis ( - chlorophenyl) methyl] azetidin-3-yl } -2- ( 3 , 5-difluorc-phenyl) -N, N-dimethylacetamide are thus obtained in the form of a white powder [XH NMR spectrum (300 MHz, CDCI3, 5 in ppm) : from 2.70 to 2.80 (mt : 2H) ; 2.92 (s : 3H) ; 2.95"' (s ': 3H) ; from 3.00 to 3.15 .(mt : 2H) ; 3.38 (broad t, J = 7.5 Hz : lH); 3.96 (d, J = 10 Hz : 1H) ; 4.26 (s : 1H) ; ■ 6.69 (tt, ' J = 9 and 2.5 Hz : 1H) ; 6.81 (mt : 2H) ; from 7.20 to 7.35. (mt. : 8H) ] .
Example 60 ( RS ) -2- { 1- [Bis ( 4-chlorophenyl) methyl] -azetidin-3-yl } -2- ( 3 , 5-difluorophenyl) -N-benzylacetamide, may be prepared in the following manner :^ 0.013 cm3 of benzylamine, 29. mg of .1- ( 3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5'mg. of hydroxybenzotriazole •hydrate are successively added to a solution of 50 mg of (RS) -{ 1- [bis (4-chlorophenyl) methyl] azet.idin-3-yl } - (3, 5-difluorophenyD-acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction mixture is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4.4 cm3 of 'silica (0.060-0.200 mm) conditioned in dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane between 0 and 6 cm3 and then with a dichloromethane-ethyl acetate (95-5 by volume) mixture.
The fractions containing only the desired product are combined and concentrated to. dryness under reduced pressure (2.7 kPa) at 40°C. 37 mg of (RS) -2- (-1- [bis (.4- chlorophenyl ) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-benzylacetamide are .thus obtained in the form of white . crystals [XH NMR spectrum (300 MHz, . CDC13/ δ in ppm) : 2.67 (mt . :· IH) ;. 2.93 (mt : lH) :. 3.11 (mt : 2H) ; 3.43 (broad t,. J = 7.5 Hz : 1H) ; 3.62 (d, J = 10'.5- Hz ':. 1H) ;' 4.26 (s ': IH) ;■ 4.38 (mt : 2H) ; 5.71 (mt ·: IH)-; 6.71 (broad t, J = 9" Hz : 1H) ; 6.83 (mt :' 2H) ; from 7.10 to 7.40 (mt : 13H).].
Example 61 (RS) -2-{l-.[Bis ( 4-chlorophenyl ) methyl ] - azetid.in-3-yl } -2- (.3, 5-difluorophenyl ) -N-cyclohexyl-- methylacetamide may be prepared in the following. manner :.0.016 cm3 of aminomethylcyclohexane , 29 mg of . 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide . hydrochloride, .0.028, cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole- hydrate are successively added to a solution of 50 mg. of { 1- [bis ( 4-chlorophenyl) methyl] -. azetidin-3-yl }-. (3 , 5-difluorophenyl ) acetic acid ■ hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20 °C. The solution obtained is stirred at a temperature in the region. -of 20°C .for about 12 hours. The- reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cm3 fractions. Fractions 2 to 3 are combined and concentrated to dryness, under reduced pressure (2.7 kPa) at 40°C. 49 mg of (RS) -2-{ 1- [bis (4- chlorophenyl ) methyl] azetidin-3-yl } -2- ( 3 , 5-difluoro- phenyl ) -N-cyclohexylmethylacetamide are thus obtained in the form of a white foam [XH NMR spectrum (300 MHz, CDC13 δ in ppm) : from 0.75 to 1.75 (mt : 11H) ; 2.65 (mt : 1H) ; from 2.85 to 3.15 (mt : 5H) ; 3.42. (broad t, J = 7.5 Hz : 1H) ; 3,57 (d, J = 10.5 Hz : 1H) ; 4.27 (s 1H) ; 5.40 (mt : 1H) ; 6.71 (broad t, J = 9 Hz : 1H) ; 6.83 (mt : 2H) ; from 7.15 to 7.40 (mt : 8H) ] .
Example 62 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] - azetidin-3-yl}-2- ( 3 ,.5-difluorophenyl ) -N- [3- (2- · . oxopyrrolidin-l-yl) propyl] acetamide may be prepared in the following manner: 0.017 cm3 of aminopropyl- pyrrolidinone, 29 mg of 1- ( 3-dimethylaminopropyl ) -3- -e-thylcarbodiimide hydrochloride., · 0.028. cm3 of , triethylamine and 1.5 mg . of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - {■ 1- [bis (4-chlorophenyl) methyl].azetidin-3-yl.} - (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region, of 20°C. The solution obtained is stirred at a ' temperature in the region of 20°C'for about 12 hours. The reaction medium is deposited on a Varian cartridge .(6 cm3) filled with 3' g of fine silica (Ό.040-0.063 mm) conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 2-cmJ fractions. Fractions 4 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 35 mg of (RS) -2-{l-[bis (4-chlorophenyl) methyl] azetidin-3-yl } -2- ( 3 , 5-difluorophenyl) -N- [3- (2-oxopyrrolidin-l-yl) propyl] acetamide are thus obtained in the form of a white foam '^H NMR spectrum (300 MHz, CDC13, δ in ppm) : from.1.50 'to 1.65 (mt : 2H) ; 2.04 (mt : 2H) ; 2.43 (t, J = 8 Hz : 2H); 2.64 (mt ": lH) ; 2.88 (dd, J = 7.5 and 5.5 Hz : 1H) ; from 3.00 to 3.30 (mt : 6H) ; from 3.30 to 3.45 (mt : 3H) ; 3.64 (d, J = 10.5 Hz : 1H) ; .4.27 (s : 1H) ; 6.67 (tt, J = 9 and 2.5 Hz : " 1H) ; 6.9O. (mt : 2H) ; 7.15. (t, J = 6 Hz : 1H) ; from 7.20 to 7.35 (mt : 8H) ] . Example 63 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-acetyl (4-methylpiperazine) may be prepared in the following manner: 0.013 cm3 of N-methylpiperazine, 29 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of ( RS )-{ 1-.[bis ( 4 -chlorophenyl ) -methyl] azetidin-3-yl } - (3, 5-difluorophenyl ) acetic acid hydrochloride in 2. cm3 of anhydrous dichloromethane , at a temperature in the region of 20 °C. The solution obtained is stirred at a temperature in the region of. 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 ,g of fine silica (0.040-0.063 mm), conditioned with dichlorometharie with the aid of a Diramat pump, eluted ■ with a, dichloromethane-ethanol (98-02 by volume)' mixture, collecting 2-cm3 fractions. Fractions 10 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 39 mg of (RS) -2-{ 1- [bis ( 4- chlorophenyl) methyl] azetidin-3-yl } - 2- (3, 5-difluorophenyl ) -N-acetyl ( 4-methylpiperazine) are thus obtained in the form of a white foam [1H NMR ■ spectrum (300 MHz, CDC13, δ in ppm) : 1.83 (mt 1H) from 2.10 to 2.45 (mt : 3H) ; 2.21.' (s : 3-H) ;. 2.74 (mt : 2H) ; from 2.95 to 3.15 (mt : 2H) ; from 3.3.0 to 3.55 (mt : 4H) ; 3.73 (mt : 1H) ; 3.93 (d, J = 10 Hz : 1H) ; 4.25 (s : .1H) ; 6.69 (tt, J = 9 and 2.5 Hz : 1H) ; 6.78 . (mt : 2H) ; from 7.15. to 7.35 (mt ': 8H) ] .
Example 64 (RS)-2-{l-[Bis( 4 -chlorophenyl ) methyl] - ' a.zetidin-3-yl}-2- (3, 5-difluorophenyl) -N- (2, 2-dime-thyl- propyl) acetamide may ; be prepared in the following manner :" 0.014 cm3 of neopentylamine, 29 mg of 1- ( 3-dime.thylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of ' triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of · (RS )-{ 1- [bis ( 4 -chlorophenyl ) - methyl] azetidin-3-yl }- (3, 5-d'ifluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane , at a temperature in the region .of 20 °C. The solution obtained is stirred at a temperature in the region of °C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned with dichloromethane . with the aid of a Duramat pump, eluted with a dichloromethane-petroleum ether (80-20 by ■ volume) mixture, collecting 1.5-cm3 fractions. Fractions 4 to 8 are combined and concentrated to dryness ■ under reduced pressure (2.7 kPa) at 40°C. 40. mg of (RS)-2-{l-' [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - 2- (3, 5-difluorophenyl) -N- (2, 2-dimethylpropyl ) acetamide ' are thus obtained in the form .of a white foam H NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.81 (s : 9H) ; 2.66 (.mt : 1H) ; from 2.90 to 3.20 (mt : 5H) ; 3.44 (broad t, J = .7.5 Hz : 1H)"; 3.61 (d, J = 10.5 Hz : 1H) : 4.28 (s : 1H); 5.40 '{flit : · 1H) ; 6.72 (tt, J = 9 and 2.5 Hz : 1H); 6.85 (mt : 2H) ; from 7:.20 to 7.35 (mt : 8H) ] .
Example 65 (,RS) -2- { 1- [Bis ( 4-chl.orophenyl) methyl] - azetidin-3-yl } -2- ( 3 , 5-difluorophenyl) -N- ( 2-py rolidin- l-ylethyl) acetamide may be prepared in the following manner: 0.015. cm3 of. aminoethylpyrrolidine , 29 mg of .1- (-3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) -{ 1- [bis ( 4 -chlorophenyl )- methyl] azetidin-3-yl } - (3, 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20 °C, for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm)., conditioned, with dichloromethane with the aid of a Duramat pump, eluted with a dichloromethane-ethanol (98-04 by volume) mixture, collecting 1.5-cm3 fractions. Fractions 13 to' 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg of (RS)-2-{l-' [bis ( 4-chlorophenyl) methyl] azetidin-3-yl,} - 2- (3, 5-difluoro.phenyl) -N- ( 2-pyrrolidin-l- ylethyl ) acetamide are thus obtained in the form of a white foam [lR "NMR spectrum (300 MHz, CDC13, δ in ppm) : 1.78 (mt : 4H) ; from .2.50 to 2.70 (mt : 3H) ; 2.54 (mt : 4H) ; 2.91 (dd, J = 7.5 and 5 Hz : 1H) ; 3.10 (mt : .2H) ; from 3.20. to 3.45 (mt : 3H) ; 3.64 (d, J = 10.5 Hz : 1H) ; 4.27 (s : 1H) ; 6.67 (tt, J = 9 and 2.5 Hz : 1H) ; . .6.86 (mt : 2H) ; ■ from 7.15 to 7.35 (mt : 8H) ] .
Example 66 (RS) -2-{l- [Bis ( 4-chlorophenyl ) methyl ] - azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N- cyclopropylmethylacetamide may be prepared in the following manner: 0.011 cm3 of cyclopropanemethylamine , 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide - hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1- [bis ( -chlorophenyl) methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge . (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm), conditioned and then eluted with a dichloromethane-petroleum ether (80-20 by volume) mixture with the aid of- a. Duramat pump, collecting 1.5-cm3 fractions. '· Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 37 mg ,of (RS) -2-{l-[bis (4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-cyclopropylmethylacetamide are thus obtained in the form of a white foam [lH NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.13. (mt :.2H) : 0.45 (mt : 2H) ; 0.86 (mt : 1H);.2.65 (mt :. 1H); 2.91 (dd, J = 7.5 and 5 Hz : 1H)'; from 3.00 to 3.15 (mt : 4H). ; 3.41 (broad. t, J = 7.5 Hz : 1H) ; 3.57 (d, J = 10.5 Hz : 1H) ; 4.25 (s :. 1H) ; 5.50 (mt : 1H) ; 6.70 (tt, J = 9 and 2.5 Hz : 1H) ; 6.84 (mt : 2H) ; from 7.15 to 7.35 (mt : 8H) ] .
Example 67 (RS ) -2- { 1- [Bis ( 4-chlorophenyl ) methyl ] -azetidin-3-yl}-2- (3, 5-difluorophenyl) -N-propylacetamide may be prepared in the following ' manner : 0.015 cm3 of propylamine, 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) -{1- [bis (4-chlorophenyl)methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the 'region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with' 3 g of fine silica (0.040-0.063 mm), conditioned and eluted with dichloromethane with the aid of a Duramat pump. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 21 mg of (RS ) -2- { 1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-yl } -■2-.( 3 , 5-difluorophenyl ) -N-propylacetamide. are thus obtained in the form of a white solid [XH NMR spectrum (300 MHz, CDCI3, δ in ppm) : 0.84 (t, J = 7.5 Hz : 3H) ; 1-45 ' (mt : 2H) ; 2.65 (mt : lH) ; 2.92 (dd, j = 7.5 and 5.5 Hz. : 1H) ; from 3.00 to 3.20 (mt : 2H) ; 3.15 (q, J = 7 Hz : 2H) / ■ 4.43 (broad t, J = 7.5 Hz : 1H); 3.56 (d, J = 10.5 Hz : 1H) ; 4.26 (s : '1H); 5.39 .(mt': 1H) ; 6.70 (tt, J = 9. and 2.5 Hz : 1H) ; 6.83 (mt : 2H) ; from 7.15 to 7.35 (mt : 8H] .
Example 68 (RS ) -2- { 1- [Bis ( 4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3, 5-difluorophenyl) -N-propylacetamide may be prepared in the following manner: 0.050 cm3 of a 2 M solution of methylamine in tetrahydrofuran, 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5- mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) -{1- [bis (4-chlorophenyl) -methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl) acetic acid hydrochloride .in 2 ' cm3 of , anhydrous dichloromethane, at a temperature in the region of 20°C. The solution . obtained is stirred at a temperature in the region of 20°C for about- 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted with dichloromethane with the aid of a Duramat pump. The fractions containing only the desired product are combined and concentrated ' to dryness under · reduced pressure (2.7' kPa) at 40°C. 19 mg of ,(RS)-2-{l- [bis ( -chlorophenyl)methyl] azetidin-3-yl } -2- ( 3 , 5-difluorophenyl) -N-methylacetamide are thus obtained in the form of a white solid [XH NMR spectrum (300 MHz., CDCI3, δ in ppm) : 2.66 (mt : 1H) ; 2.76 (d, J = 5 Hz : 3H); .2.93 (mt : 1H) ; 3.10 (mt : 2H) ; 3.44 (broad t,- J = 7.5 Hz : 1H) ; 3.59 (d, J = 10.5 Hz : 1H) ; 4.28 (s : 1H) ; 5.41 (unresolved complex : 1H) ; 6.71 (tt, J = 9 and 2.5 Hz : 1H) ; 6.83 (mt : 2H) ; from 7.20 to 7.35 (mt : 8 H ) ] .
Example 69 ' (RS)-2-{l-[Bis(4 -chlorophenyl ) methyl ] -azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N-i.sopropylacetamide may. be prepared in the following manner: 0.011.cm3 of isopropylamine , 29 mg of 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride,. 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1- [bis ( -chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of. 20°C for about 12' hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and then eluted with dichloromethane with the aid of a Duramat pump, collecting 1.5-cm3 fractions Fractions 6 to 14 are combined and concentrated to dryness, under reduced pressure (2.7. kPa) at 40°C. 21 mg of (RS) -2- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - 2- ( 3 , 5-difluorophenyl ) -N-isopropylacetamide are thus obtained in the form of a white foam NMR spectrum' (300 MHz, CDCI3 , δ in ppm) : 1.05. (d, J = 7. Hz : 3H) 1.10 (d, J = 7 Hz .: 3H) ; 2.65 (mt : 1H) ; 2.90 (dd, J '= 7.5 and 5.5 Hz : 1H) ; from 3.00 to 3.15 (mt : 2H) ; 3.42 (broad :t, J = 7.5 Hz : 1H) ; 3.51 (d, J = 10.5 Hz ': ,'IH); 4.00 (mt : lH.) ; 4.26 (s : 1H) ; .5.19 (broad, d, J = 7.5 Hz : 1H) ; 6.70 (tt, J = 9 and 2.5 Hz : 1H) ; 6.82 (mt : 2H) : from 7.20 to 7.40 (mt : 8H) ] .
Example 70 (RS) -2-{l-[Bis (4-chlorophenyl) methyl] -azetidin-3-yl}-2-(3, 5-difluorophenyl ) -N-piperidin-1- ylacetamide may be prepared in the following manner: 0.01,3 cm3 'of aminopiperidine, 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide : hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are. successively added to a solution of 50 mg of (RS )-{ 1- [bis ( 4-chlorophenyl ) - methyl ] azetidin-3-yl }-( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution ■ obtained is stirred at a temperature in the region of 20 °C for about 12 hours. The reaction medium is deposited on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned with dichloromethane with the aid of a Duramat pump,' eluted with a dichloromethane-ethanol (98-02 by volume) mixture, collecting 2-cm3 fractions. Fractions' 7 to 12· are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg of . (RS) -2- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - '.' ' 2- ( 3, 5-difluorophenyl )' -N-piperidin-l-ylacetamide are thus obtained in the form of a white solid [ΧΆ NMR- spectrum (300 MHz, CDC13, δ in' ppm) : from 0.95 to 1.85-2.05 and 2.29 ' (mts : lOH) ; from 2.60 to 2.80 (mt ' : 2H) ; from 3.00 to 3.20 (mt : 2H) ; 3.39 (broad t, J = 7.5 Hz' : 1H) ; 4.26 (s : 1H) ; 4.32 (d, J = 10.5 Hz : 1H) ; 6.0.0 (s : 1H) ; 6.65 (tt, J = 9 and 2.5 Hz : 1H) ; 6.85 (mt : 2H) ; from 7.15 to 7.35. (mt : 8H) ] .
Example 71 (RS) -2- {1- [Bis (4-chlorophenyl) methyl] -' azetidin-3-yl } -2- (3, 5-difluorophenyl). -N- cycloheptylacetamide may be prepared in the following manner: 0.015.cm3 of cycloheptylamine , 29 mg of 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS)-{1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20"C. The solution obtained is stirred at a temperature in. the region of 20°C for about 12 ,hours. The reaction medium is deposited, on a Varian cartridge (6 .cm3) filled with. 3 g of fine silica (0.040-0.063 mm) conditioned and then eluted with dichloromethane with the aid of a Duramat pump., collecting 2-cm3 fractions-. Fractions 3 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 24 mg of (RS) -2- {1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - 2- (3, 5-difluorophenyl ). -N-cycloheptylacetamide are thus obtained in- the form of a white foam [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : from 1.20 to 1.9.5 (mt : ' 12H) ; 2.65 (mt : 1H) ; 2.90 (dd, J = 7.5 and 5.5 Hz : 1H) ; from 3.00 to 3.15 (mt : 2H) ; 3.42 (broad t, J = 7.5 Hz :' 1H) ; ■ 3.52 (d, J = 10.5 Hz : 1H) ; 3.86 (mt : 1H) ; 4.26 (s : 1H) ; 5;.31 (broad d, J = 7.5 Hz : 1H) ; 6.70 (tt, J = 9 and 2.5' Hz : 1H) ; 6.82 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H) ] .
Example 72 (RS) -2-{l-[Bis ( 4 -chlorophenyl) methyl] -azetidin-3-yl }.-2- (3, 5-difluorophenyl) acetamide may be prepared in the following manner: 60 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and 3 mg of hydroxybenzotriazol hydrate are successively added to. a solution of 98 mg of (RS)- {1- [bis (4-chlorophenyl)methyl] azetidin-3-yl } - (3, 5-difluorophenyl) acetic acid hydrochloride in 4 cm3 -of anhydrous dichloroethane, at a temperature in the region of 20 °C, ammonia is bubbled through for 2 hours, with stirring at a temperature . in the region of 20°C. The reaction medium is' washed with water' and is then deposited, on a Varian cartridge (6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted with a dichloromethane-ethyl acetate (9-1 by volume) . mixture with the aid of a Duramat pump. The fractions between 36 and.80 ml are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 32 mg of (RS) -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - 2- ( 3 , 5-difluorophenyl) acetamide are thus obtained in the form of an amorphous powder [1H NMR spectrum (300 MHz, CDCI3, δ in ppm) : 2.66 (mt : 1H); 2.95 (dd,.
J = 7 and 5 Hz : 1H) ; from 2.95 to 3.15 (mt : 2H) ; 3.45 (broad t, J = 7 Hz ' : 1H) ; 3.67 (d, J = 10.5 Hz : 1H) ; 4.27 (s : IH) ; from 5.20 to 5.40 (unresolved complex : 2H) ; 6.72 (tt, J = 9 and 2.5 Hz : 1H) ; 6.84 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H) ] .
Example 73 Methyl . (RS) -2- {1- [Bis (4-chlorophenyl) methyl ] -azetidin-3-yi }.-2- ( 3,,5-difluorophenyl) -N-acetylamino acetate may be prepared in the following- manner : 100 mg of glycine methyl ester hydrochloride, 115 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and .6 mg of hydroxybenzotriazol hydrate are successively added to a solution of 200 mg of (RS) -{ 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl) acetic acid hydrochloride in 8 cm3 of dichloroethane, at a temperature in the region of 20°G. The solution obtained is" stirred at a temperature in the region of 20°C for about .12 hours. The reaction medium is washed with water, dried, filtered and then concentrated to dryness under . reduced pressure (2.7 kPa) at 40CC. The residue thus obtained is taken up in 1 cm3 of dichlorqme'thane- and then deposited on an IS;T FlashPack cartridge with^ the reference SIL-020-005 conditioned and eluted with a dichloromethane-ethyl . acetate (95-05 by volume) mixture with the aid of a . Duramat . pump . The fractions between 18 and 42 ml are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 68 mg of methyl (RS)-2-{l-. [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - 2- ( 3 ,.5-difluorophenyl) -N-acetylamino acetate are thus obtained in the form of white cottony crystals [ Η NMR spectrum (300 MHz , CDC13, δ in ppm) : 2.67 (mt :. 1H) ; 2.93. (broad dd, J = 7.5 and 5 Hz : 1H) ; from 3.00 to 3.15 (mt : 2H) ; 3.41 (broad t, J = 7.5 Hz : 1H) ; 3.68 (d, J = 10.5 Hz : 1H) ; 3.74 (s : 3H) ; 3.93 (dd, J = 18 and 5 Hz : 1H).; 4.03 (dd, J = 18 and 5 Hz : 1H) ; 4.27 (s : 1H). ; 5.96 (mt': 1H) ;. 6.71 (tt, J = 9 and 2 Hz : 1H) ; 6.85 (mt : 2H) ; from.7.20 to 7.35 (mt : 8H) ] .
Example 74 (RS) -2-{l-[Bis (4-chlorophenyl)methyl] -azetidin-3-yl } -2- (3 , 5-difluorophenyl ) -N- ( 3-dimethyl-aminopropyl ) acetamide may be prepared in the following manner: 0.015 cm3 of N, N-dimethylpropane-1 , 3-diamine ,. 29 mg of 1- ( 3-dimethylaminopropyl ) -3-ethylcarbodiimide hydrochloride, 0.028 cm3 of triethylamine and 1.5 mg of hydroxybenzotriazole hydrate are successively added to a solution of 50 mg of (RS) - { 1- [bis (4-chlorophe.nyl) -methyl ] zetidin-3-yl } - (3, 5-difluorophenyl) acetic acid hydrochloride in 2. cm3 of anhydrous . dichloromethane, at a temperature in the region of 20 °C. The solution-obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is deposited on a Varian cartridge (of 12 mm in diameter) filled with 4 cm3 of silica (0.060-0.200 mm) conditioned with dichloromethane with the aid of a vacuum apparatus, eluting with dichloromethane' between 0 and 6 cm3 and then with a dichloromethane-methanol (95-5 by volume) mixture. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 33 mg [lacuna] (RS) -2- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl }.-2- ( 3 , 5-difluorophenyl ) -N- ( 3-dimethylamino- · propyl ) acetamide are thus . obtained in the form of white crystals [1H NMR spectrum (300 MHz , CDC13, with addition of a few drops of CD3COOD d4, 8 in ppm): : 1.91 (mt : 2H) ; 2.71 (s : -6H); 2.95 (mt : 2H) ; from 3.15 to 3.40 (mt : 2H) ; from 3.40 to 3.60 (mt : 1H) ; from 3.60 to 3.80 (mt : 2H) ; 4.00 (mt : 2H) ; 4.28 (d, J = 10.5 Hz : 1H) ; 5.22 (s : ' 1H) ; 6.68 (tt, J = 9 and' 2.5 Hz : 1H) ; 6.90 (mt : 2H) ; 7.33 (mt : 4H) ;' 7.46 (d, J = 8 Hz : 4H) ] . Example 75 (RS) -2- { 1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } -2- (3, 5-difluorophenyl )-N-'( 2-hydroxyethyl ) acetamide may be, prepared in the following manner:- 0.024 cm3 of ethanolamine , 29 mg of 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide ■hydrochloride, 0.028 cm3 of . triethylamine and'l.,5 ,mg of hydroxybenzotriazole hydrate are successively added to a. solution of 50 mg of (RS ) - { 1- [bis ( 4 -chlorophenyl) -methyl] azetidin-3-yl } - (3, 5-difluorophenyl ) acetic acid hydrochloride in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20 °C. The reaction medium is washed with 2 cm3 of a saturated sodium bicarbonate solution, dried over magnesium sulfate and is then deposited on an 1ST FlashPack cartridge with the reference SIL-016-002. conditioned with dichloromethane and eluted with a. dichloromethane-ethyl acetate (95-05 by volume) mixture with the aid of a- Duramat pump. The fractions between 25 and 60 cm3 are combined and concentrated to dryness under reduced .pressure (2.7 kPa) at 40°C. The residue obtained is again chromatographed on an 1ST FlashPack cartridge with the reference SIL-016-002 conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (95-05 by volume) mixture with the- aid of a Duramat pump . The fractions between.25 and 35 cm3 are combined and concentrated to dryness under reduced ' pressure (2.7 kPa) at 40°C. 14 mg of (RS)-2-{l- [bis ( 4 -chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl ) -N- ( 2-hydroxyethyl ) acetamide are thus obtained in the form of a white solid [lH NMR spectrum. (300 MHz, CDC13, δ in ppm) : 2.65 (mt : 1H) ; 2.91 (mt : 1H) ; from 3.00 to 3.15 (mt : 2H) ; from 3.30 to 3.50 (mt : 3H) ; .3.60 (d, J = 10.5. Hz : 1H) ; 3.66; (t, J = 5.5 Hz : 2H) ; 4.26 (s : 1H) ; 5.88 (mt : 1H) ;. 6.71. (tt, J = 9 and 2 Hz : 1H) ; 6.84 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H) ] . -Example 76 (RS) -1- [ {1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } - (3, 5-difluorophenyl ) methyl ] -3-propylurea may be prepared in the following manner: 0.056 cm3 of triethylamine and 0.064 cm3 of diphenylphosphonoazide are successively added to a solution of 50 mg of (RS)-{ 1- [bis (4-chlorophenyl ) methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 3 cm3 ■ of anhydrous toluene, under an inert argon atmosphere, at a temperature' in the region of 20°C. The solution obtained is stirred at a temperature in the. region of 50°C for about 1 hour. 0.016 cm3 of propylamine is added, the stirring is- maintained at a temperature in the region of 20°C for about 12 hours. The reaction medium is concentrated to. dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue is taken up in 1 cm3 of . .dichloromethane and then deposited on a Varian cartridge (.6 cm3) filled with 3 g of fine silica (0.040-0.063 mm) conditioned and eluted'with a dichloromethane-ethyl acetate. (95-5 by. olume) mixture with the aid of a Duramat. pump. The fractions between. 12 and 16 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 13 mg of . (RS) -1- [ { 1- [b.i.s ( 4 -chlorophenyl) methyl] azetidin-3-yl }.-- 2 ( 3 , 5-difluorophenyl) methyl] -3-propylurea are .thus obtained in the form of .a beige solid NMR spectrum (400 MHz, CDCI3,. δ in p.pm) : 0.92 (t, J = 7.5 Hz : 3H) ; 1.53 (mt. : 2H) ; from 2.55 to 2.75 (mt : 1H) ; from 2.80 to 3.25 (mt : 6H) ; 4.26 (t, J = 5.5 Hz :. 1H) ; 4.29 (s 1H) ; 4.92 (t, J = 7 Hz : 1H) ; 5.31 ' (d, J = 5.5. Hz : 1H) ; 6.66 (tt, J = 9 and 2.5 Hz : 1H) ; 6.79 (mt : 2H) ; from 7.15 to 7.40 (mt : 8H) ] .
Example 77 (RS) -{ 1- [Bis (4-chlorophenyl) methyl] azetidin-. 3-yl }- (3, 5-difluorophenyl) acetic acid hydrochloride may be prepared in the following manner: 3 cm3 of 6 N hydrochloric acid are added to a solution of 0.44 g of (RS) - { 1- [bis (4-chlordphenyl) methyl] azetidin-3-yl }'- (3 , 5-difluorophenyl ) acetic acid ethyl ester in.7 cm3 of dioxane. The solution obtained is stirred under reflux for about 2 hours and . then left at a temperature in the region of 20°C for about 12 hours. The precipitate formed is filtered on No, 3 sintered glass, washed with 10 cm3 of diisopropyl ether and then dried under reduced pressure (0.27 kPa) at a temperature in the region of 40°C. 0.185 g of (RS) -{ 1- [bis (4-chlorophenyl) methyl] -azetidin-3-yl }-( 3 , 5-difluorophenyl) acetic acid hydrochloride is thus obtained in the form of a white powder [XH NMR spectrum ,( 400 MHz , (CD3)2SO d6, at a temperature of 363K, δ in ppm) : 2.87 (dd, J = 14 and-4. Hz .: lH);- 2.95 (mt : 1H) ; 3.18 (mf : 1H) ; 3.96 (d, J- = "10.5 Hz : 1H) ; 4.18 (t,- J = 9 Hz .': 1H) ; 4.72 (t, J = 9 Hz :.1H) ; 5.26 (unresolved complex : 1H) ; 7.00 (mt : 2H) ; 7.06 (tt, J = 9.5 and 2.5 Hz : 1H) ; from 7.30 to. 7.60 (mt : 8H) ] .
Example 78 (RS) { 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl }-( 3 , 5-difluorophenyl) acetic acid ethyl ester may be prepared in the following manner: 121 mg of sodium borohydride are added,, at a temperature in the region of 0°C, to a suspension of 0.78 g of (RS)- { 1- [bis ( 4 -chlorophenyl) methyl] azetidin-3-ylidene] - (.3 , 5-difluoropheny.l) acetic acid ethyl ester in 20 cm3 of ethanol. The suspension obtained is stirred at a- temperature in the region of 20°C for about 12. hours. The reaction medium is poured. into 200 cm3 of distilled water and then extracted with three times 40 cm3 of - ethyl acetate. The organic phase is successively washed with 3 times 40 cm3 of distilled water and then with 40 cm3 of a saturated sodium chloride solution. After decantation, the organic phase is dried over magnesium sulfate, filtered and 'concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue obtained is chromatographed on a column filled with 75 cm3 of fine silica (0.040-0.063 mm) under a pressure of 0.7 bar with a dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from 0 to 10%), collecting 15-cm3 fractions. Fractions 4 to 11 are combined and . concentrated to dryness under reduced pressure (2.7 kPa) at 40'°C. 0.4;6 g of (RS)-{1- [bis (4-chlorophenyl)methyl].azetidin-3-yl}- (3, 5-· ' difluorophenyl ) acetic acid ethyl ester is thus obtained in the form of a yellow lacquer [1H N R spectrum ( 300 MHz, CDCl'3, δ in ppm) : 1..19 ( t , J = 7 Hz : 3H) ; 2.62 (broad t, J = 6 Hz : .1H); 2.87 (dd, J = 7.5 and . 6 Hz : 1H) ; from 2.95 to 3-15 (mt : -2H); 3.39 (broad t, J = 7.5 Hz : 1H)'; 3.78 (d, J = 10.5 Hz : 1H) ; 4.10 (mt : 2H) ; 4.25 (s : 1H); .6.69 (tt, J = 9 and 2.5 Hz : 1H),\ 6.80 (mt:: 2H) ; from 7.20 to 7.35 (mt : 8H) ] .
Fractions. 16 to- 26 from the preceding chromatography are combined and concentrated to dryness under reduced .pressure (2.7 kPa) at 40°C. 0.24 g of (RS) -2- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) ethanol is thus obtained in the . . form of a yellow foam [lH NMR spectrum (300 MHz , CDC13, δ in ppm) :' 1.98 (unresolved complex : 1H) ; 2.69 (mt : 1H) ; from 2.70 to 2.85 (mt : 1H) ; from 2.90 to 3.10 (mt .: 2H) ; 3.18 (mt : 1H) ; 3.44 (mt : 1H) ; from 3.65 to 3.85 (mt : 2H) ; .4.28 ' (s : lH) ; from 6.60 to 6.80 (mt .: , 3H) ; from 7.20 to 7.35" (mt : 8H) ] . ' { 1- [Bis ( 4 -chlorophenyl ) methyl ] azetidin- 3-ylidene}- (3, 5-difluorophenyl) acetic acid ethyl ester may be prepared in the following manner: 6.6 g of 4-dimethylaminopyridine and 2.1 cm-3' of methylsulfonyl chloride are added to a solution of 9.1 g of {1- [bis-4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl } - (3, 5-difluorophenyl) acetic, acid ethyl ester in -200 cm3 of dichloromethane . The solution obtained is stirred .at a temperature in the region of 20°C for. about 12 hours. The reaction mixture is washed three times with 250 cm3 of distilled water and then dried with magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa)- at a temperature in the region of 40°C..The residue obtained. is taken up hot with 50 cm3 of i.sopropyl ether and then left at a temperature in the region of 20°C for about 12 hours. The white suspension obtained is filtered on sintered glass, washed with, 20 cm3 of petroleum ether and then dried under vacuum under ' reduced pressure (0.27 kPa) at a temperature .in the region of 40°C for 2 hours. 7.9 g of {1- [bis (4-chlorophenyl)methyl] azetidin-3-ylidene } - (3, 5-difluorophenyl) acetic acid ethyl ester are thus obtained in the form of a cream-colored powder [1H NMR spectrum (300 MHz, CDC13, δ in ppm) : 1.25 (t, J = 7 Hz : 3H) ; 3.85 (mt : 2H) ; 4.12 (AB, J = 7.5 Hz : 2H) ; 4.23 (mt :. 2H) ; 4.51 (s : 1H) ; from 6.65 to 6.80 (mt : 3H) ; from 7..20 to 7.40 (mt : 8H)]. { 1- [Bis ( 4 -chlorophenyl) methyl]- - 3-hydroxyazetidin-3-yl }-( 3 , 5-difluorophenyl ) acetic acid ethyl ester may be prepared in the following manner: 34.54 ,cm3 of a 1.6 M butyllithium solution in hexane are added dropwise over 15 minutes to a solution of 7.73 cm3 of diisopropylamixie in 125 cm3 of anhydrous tetrahydrofuran under an inert nitrogen atmosphere at a temperature in the region of -70 °C,. the stirring, is maintained at this temperature for 45 minutes, a •solution of 11.01. g of ethyl 3 ,.5-di.fluorophenylacetate in 85 cm3 o.f anhydrous tetrahydrofuran are added over 15 minutes, the stirring is continued for 1 hour at -78°C, 16.84 g of 1- [bis ( 4 -chlorophenyl ) methyl ] - azetidin-3-one in 90 cm3 of anhydrous tetrahydrofuran are added, the stirring is continued for 1 hour at -70°C,' 300 cm3 of a saturated ammonium chloride . solution are added over 30 minutes at 0°C with vigorous stirring, the' reaction mixture is separated after ' settling after 12 hours,, the organic phase is washed 3 times with a saturated sodium bicarbonate, solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) . The. esidue obtained is chromatographed on a column 70 mn in diameter filled, with 2000 cm3 of fine silica. (0.040-0.063 mm) under a pressure of 0.7 bar with a dichloromethane-ethyl acetate (99-01 by volume) . mixture. The ' fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C for 2 hours. '9.1 g of { 1- [bis (4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl }-( 3 ,.5-difluorophenyl ) acetic acid ethyl ester are thus obtained in the form of a cream-colored solid [XH-NMR spectrum . (3,00 MHz', CDC13, δ in ppm) : 1.'25 (t, J -7 Hz : 3H) ; 2.87 (d, J = 8 Hz' : 1H) ; 3.07 (d, J = 8 Hz : 1H) ; (broad d, J = 8 Hz : 1H) ; 3.28 (broad d, J = 8 Hz : 1H);.4.12 (s : 2H) ; 4.2.1 (mt : 2H)'; 4.36 (s : 1H) ; 6.78 (tt, J = 9 and 2.5 Hz : IK); 6.98 (mt : 2H.) ; from 7.20 to 7.40 (mt. : 8H) ] .
Ethyl 3 , 5-difluorophenylacetate . may be prepared in the following- manner : 20.4 cm3 of triethylamine and then 27.6 g of 3 , 5-difluorophenylacetic acid chloride in solution in 60 cm3 of dichloromethane are successively added to a solution of 12 cm3 of ethanol in 300 cm3 of anhydrous .dichloromethane at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction mixture is successively washed with twice 150 cm3 of a decinormal solution of hydrochloric acid and then with • twice 150 cm3 of a saturated sodium bicarbonate solution The organic phase is dried with magnesium sulfate, filtered and concentrated to dryness .under reduced pressure (2.7 kPa) at a · temperature in the region of 40°C. 29 g of ethyl 3 , 5-difluorophenyl acetate are thus obtained in the form of a yellow oil. 3 , 5-Difluorophenylacetic acid chloride may be .prepared in the following manner: 19.3 cm3 of oxalyl chloride and then a few drops of dimethylformamide are successively added to a solution of 25 g of . . . 3 , 5-difluorophenylacetic acid in 350 cm3 of 1 , 2-dichloro.ethane at a temperature in the region of 20°C,. after stirring for 3 hours at a temperature in the region of 20°C, 30 cm3 of oxalyl chloride and a then few drops of dimethylformamide are again successively added. The reaction medium is concentrated to dryness, under reduced pressure (2.7 kPa) at a temperature in ■ the region of.40°C. 27.6 g of 3 , 5-difluorophenylacetic . acid chloride are thus obtained in . the form of a yellow . oil.
Example 79 (RS) -1- [Bis (4-chlorophenyl) methyl] -3- [1- (3, 5- difluorophenyl) -1-methylsulfonylethyl] azetidine is obtained in the following manner: 0..5 cm3 of a 2 M ■ solution of lithium diisopropylamide is added' to a solution of 0.5 g of (RS) -1- [bis ( -chlorophenyl ) - methyl) ] -3-.[ (3, 5-difluorophenyl ) (methylsulfonyl ) - methyl] azetidine in 10 cm3 of tetrahydrofuran cooled to -78 °C and maintained under an inert atmosphere. The temperature is allowed to. rise to -20°C and then 0.06 cm3 of iodomethane is added. The temperature is allowed to rise to. 0°'C oyer a period of 2 hours and then.20 cm3 of a saturated aqueous ammonium chloride solution are added. The reaction medium is separated after settling and .the aqueous phases are extracted with twice 20 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate and evaporated to dryness at 40°C under 2.7 kPa, providing 550 mg of cream-colored residue. The residue is chromatographed on a silica column (Dynamax, reference 83-121-C, size 21.4 mm x 250 mm, precolumn 21.4' mm x . 50 mm, reference R00083121G, .8 μ silica, porosity 60 Angstroem; Rainin Instrument Co. Inc., Mac Road, ..Woburn, - MA 01801, USA) , eluting with a heptane: •isopropanol (99:1 by volume) mixture at 15 cm3 per-. minute (detection 254' nm, 10-cm3 fractions).' The. fractions containing the compound with an Rf=32/77 (cyclohexane : ethyl acetate 70:30, 254 nm, silica plates reference 1.05719, Merck KGaA, 64271 Darmstadt, Germany) are combined and evaporated at 40 °C under 2.7 kPa, providing 80 mg of 1- [bis ( 4 -chlorophenyl ) - methyl] -3- [1- (3, 5-difluorophenyl ) -l-methylsulfonyl- ethyl ] azetidine in the form of a white amorphous powder [1H NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.05 (s : 3H) ; 2.5 (s : 3H) ; 2.63· (t, J = 7.5 Hz' .: 1H) ; 3.17 ' (broad t, J = .8 Hz : : 1H) ; 3.32 (mt : 1H) ; 3.44 (broad t, J 8,Hz : 1H);.3:71 (mt : 1H).; 4.27 (s : 1H); 6.83 . (tt, J = 9 and 2.5. Hz : 1H) ; 7.15 (mt : 2H) ; from 7.20 to 7.40. (mt : 8H) ] .
Example 80 (RS)'-l- [Bis (4-fluorophenyl) methyl] - 3- [ ( 3 , 5-difluorophenyl) methylsulfonylmethyl ] azetidine may be prepared in the following manner: a few granules of potassium iodide are added to a suspension of 0..191 cm3 of bis ( 4-fluorophenyl ) chloromethane, .300 mg of (RS) -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl ]'- azetidine and 167 mg of potassium carbonate in 5 cm3 of acetonitrile, at a temperature in the region of 20°C... After 48 hours at a temperature in the region of 20°C, the reaction medium is -filtered on sintered glass, the solid is rinsed with acetonitrile and the filtrate is purified by preparative thin-layer chromatography on silica [3 preparative Merck Kieselgel 60F254 plates, - 20x20 cm; thickness 1 mm] , eluting with a methanol- dichloromethane (1-99 by volume) mixture. After elution of the zone corresponding to the desired product with a ' methanol-dichloromethane. (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, 39 mg of (RS) -1- [bis (4-fluorophenyl) methyl ]-3- [ (3, 5-difluorophenyl ) methylsulfonyl- methyl] azetidine are obtained in the form of a yellow foam [XH N R spectrum' (300 MHz, CDC13, .5 in ppm) : 2.5 ' (broad t, J = .7 Hz : 1H) ; 2.66 (s : 3H) ; 3.18 (mt : • 2H) ; from 3.20 to 3.45 .(mt : 1H) ; 3.63 (broad t, J = 7 Hz : 1H) ; 4.27 (s : 1H) ; 4.28 (d, ■ J. = 11 Hz : 1H) ; 6.83 (tt, J = 9 and 2 Hz : 1H) ; from 6.90 to 7.05 (mt : 6H) ; from 7.25 :to 7.40 (mt : 4H) ] .
. (RS ) -3- [ ( 3 , 5-Difluorophenyl ) methylsulfonyl- methyl] azetidine hydrochloride may be. prepared may be . prepared in the following . manner : a suspension of 8.5- g of l-benzhydryl-3- [ (3, 5-difluorophenyl) (methylsulfonyl methylene] azetidine and 1.3 g of palladium hydroxide (20% by weight of palladium), in 600 cm3, of methanol, 20 cm3 of 1 N hydrochloric acid and 4 cm3 of acetic acid, is stirred at a temperature in the region of 20°C under a hydrogen atmosphere (1.5 bar) until complete absorption of a. volume of 2.1 liters of hydrogen is ' obtained. The reaction medium is then filtered oh ..sintered glass covered with charcoal. The filtrate is concentrated to dryness .under reduced pressure and then the residue obtained is taken up in ethanol'. The crystallized white product is filtered, and dried. 5.4 g of (RS ) -3- [( 3, 5-difluorophenyl ) methylsulfonyl- methyl ] azetidine hydrochloride are thus obtained in the form of white crystals. l-Benzhydryl-3» [ ( 3 , 5-difluorophenyl ) (methylsulfonyl) methylene] azetidine may be prepared may be prepared in the following manner: a mixture of 18.8 g of 3-acetoxy-l-benzhydryl-3- [ (3, 5-difluorophenyl) - (methylsulfonyl) methyl] azetidine and 3.9 g of lithium ' hydroxide monohydrate in 120 cm3 of acetonitri.le is heated at a temperature in the region of 70°C for 3 hours. After cooling to a temperature in the region of 2°C, 120 cm3 of . tert-but 1 and methyl ether and 80 cm3 of distilled water are successively added followed, slowly, by 5 cm3 of acetic acid. After decantation, the organic phase is washed with 80 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 80 cm3 of distilled water, 80 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced ■ pressure. The residue obtained is taken up in ethanol . . After leaving overnight at a temperature in the region of 20°C,. the mixture obtained is filtered on sintered glass, the white crystals obtained are rinsed with ethanol, diisopropyl ether. ;and dried under reduced pressure at a temperature in the region of 45°C. 14.6 g of l-benzhydryl-3- [( 3 , 5-difluorophenyl ) (methylsulfonyl) methylene] azetidine are thus obtained in the. form of white crystals. 3-Acetoxy-l-benzhydryl-3- [ ( 3 , 5-difluorophenyl ) methylsulfonyl ) methyl ] azetidine may be prepared may be prepared in the following manner: 47.1 cm3 of Γ.6 Ν n-butyllithium in solution in hexane are added dropwise over · approximately 25 minutes to a suspension of 12.37·$ of 3 , 5-difluorobenzyl methyl sulfone in ■ 200 yt3 of tetrahydrofuran, under an inert nitrogen atmosphere at .a temperature in the region of -30 °C. The cloudy yellow solution is stirred at a temperature in the region1 of -30°C for 2 hours and then a solution of 11.87 g of l-benzhydrylazetidin-3-one in 75 cm3 of · dichloromothane is added dropwise. The reaction mixture is stirred for 1.5 hours at a temperature in the region ■ of -30°C. and then 6.07 cm3 of acetyl chloride are added and' the temperature of the medium is allowed to return to a temperature in- the region of -10°C over about minutes. 200 cm3 of water and 100 cm3 of dichloromethane are added. After stirring vigorously for 30 minutes and decantation, the organic phase is washed with 3 times 150 cm3 of a saturated aqueous sodium hydrogen carbonate solution, 150· cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crystalline residue obtained is taken up i 50 cm3 of boiling ethanol. The white suspension obtained is allowed to stand overnight at a^ temperature in the region of 20 °C and then the solid obtained is drained over sintered glass, rinsed with diisopropyl ether and dried under reduced pressure at a temperature in the region of 50°C. 19.5 g of 3-acetoxy-l-benzhydryl-3- [ ( 3 , 5-difluorophenyl) (methyl- sulfonyl) methyl] azetidine are thus obtained in the form of white crystals. l-Benzhydrylazetidin-3-one may be prepared according to the procedure described by KATRITZKY A.R. . 5 et al.' in J. Heterocycl. Chem., 271 (1994). 3 , 5-Difluorobenzyl methyl sulfone may be prepared may be prepared in the following manner: a mixture of 66.69 cm3 of 3 , 5-difluorobenzyl bromide, .'71.97 g of the sodium salt of methanesulfinic acid and 10 150 mg of sodium iodide in 625 cm3 of ethanol is .heated under- reflux, under an argon atmosphere, for about •16 hours. After cooling to a temperature in the region of 20°C, the reaction medium is diluted with 3 liters . of . ethyl acetate , washed with 500 cm3 of water, 500 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure (50 rnbar) at a temperature in the region of 40°C. The residue obtained .is..taken . up in . 300 cm3 of ethyl ether, and the solid is filtered on · '20. sintered glass, rinsed with 200 cm3 of ethyl ether, dried under reduced pressure at a temperature in the region of 20°C. 86 g of 3 , 5-difluorobenzyl methyl sulfone are thus obtained in the form of a white powder.
Example 81 (RS) - { 1- [ (3-pyridyl) - ( 4 -chlorophenyl ) methyl ] - 3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethy1] azetidine may be prepared in the following manner: a mixture of 47 mg of 3- (pyridyl ) - ( 4 -chlorophenyl ) bromomethane , 50 rr.g of (RS ) -3- [( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidine hydrochloride and 58 mg of potassium carbonate in 2 cm3 of acetonitrile, is stirred for about 3 hours at a temperature in the region of 20°C, for 2 hours at the reflux" temperature of the solvent, for about 16 hours at a temperature in the region of 20°C and then for 1.5 hours at the reflux temperature of the solvent. A few granules of potassium iodide are then added and the reaction mixture is maintained for about 2 hours at the reflux temperature of the solvent. After cooling to a temperature in the region of 20°C, the reaction medium is purified by preparative thin-layer ' chromatography on silica [2 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration- on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C,. 11 mg of (RS) - { 1- [ (3-pyridyl) - ( 4 -chlorophenyl) methyl] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidine are obtained in the form of a colorless lacquer [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.59 (mt : 1H) ; 2.66 (s : 3H) ; 3.21 (mt : 2H) ; from 3.30 to 3.50 (mt : 1H) ; 3.67 (mt : 1H) ; 4.28 (broad d, J = 11 Hz : 1H) ; 4.32 (broad s : 1H) ; 6.84 (tt, J = 9 and 2 Hz : 1H) ; 6.95 (mt : 2H) ; 7.19 (broad dd, J = 8 and 5 Hz : 1H) ; from 7.20 to 7.40 (mt : 4H) ; 7.64 (broad d, J = 8 Hz : 1H) ; 8.45 (mt : 1H) ; 8.59 (very broad s : 1H] . (3-Pyridyl) - (4-chlorophenyl) bromomethane may be prepared in the following manner: a mixture of 150 mg of ( 3-pyridyl )-( 4 -chlorophenyl ) methanol in 0.356 cm3 of hydrobromic acid (at 33% in acetic acid) and 0.101 cm3 of acetyl bromide is heated under reflux for 1 hour and then left at a temperature in the region of 20°C for 2 hours, before being concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 234 mg of ( 3-pyridyl )-( 4-chlorophenyl ) -bromomethane are thus obtained in the form of a gummy beige solid. - ( 3-Pyridyl )-( 4 -chlorophenyl ) methanol may be prepared in the following manner: 0.5 cm3 of 3-pyridinecarboxaldehyde is slowly added to a solution of 5.83 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 5 cm3 of tetrahydrofuran, under an inert argon atmosphere. After about 3 hours, 3 .cm3 of a saturated aqueous ammonium chloride solution and 10 cm3 of water are added to the reaction medium. After stirring for 5 minutes at a temperature in the region of 20 °C, the reaction medium is acidified to a pH of about 2 with a 1 N aqueous hydrochloric acid solution. The aqueous phase is extracted with 3 times 15 cm3 of dichloromethane . The remaining aqueous phase is treated with 10 cm3 of a 1 N aqueous sodium hydroxide solution and reextracted with 3 times 15 cm3 of ethyl acetate. The organic phases containing the ethyl acetate are combined, dried over magnesium sulfate, ■filtered and concentrated under reduced pressure. 466 mg of ( 3-pyridyl )-( 4-chlorophenyl ) methanol are thus obtained in the form of a bright yellow solid.
Example 82 .(RS) -{ 1- [ (4-Pyridyl) - ( 4-chlorophenyl ) methyl] - 3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine may be prepared in the following manner: a mixture of 160 mg of ( 4- (pyridyl)- ( 4-chlorophenyl) bromomethane, 169 mg of (RS) -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl ] azetidine hydrochloride and 94 mg of potassium carbonate in 5 cm3 of acetonitrile , is stirred for about 17 hours at a temperature in the region of 20°C. A few granules of sodium iodide are then added and after stirring , for 2 hours at a temperature in the region of 20°C, the reaction mixture is maintained for about 1.5 hours at the reflux temperature of the solvent.
After cooling to a temperature in the region of 20°C, the reaction medium is purified by preparative thin- layer chromatography on silica [4 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired products with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 4.0°C, there are obtained a first mixture of diastereoisomers, that is to say 24 mg of ' ( RS ) - { 1- [( 4-pyridyl) - ( -chlorophenyl ) methyl] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidine in the form .of a yellow lacquer, and a second mixture of diastereoisomers, that is to say 31 mg of (RS) - { 1- [ (4-pyridyl) - ( -chlorophenyl) methyl] -3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl] azetidine in the form of a yellow 'foam. The first mixture of diastereoisomers has the characteristics are the following [XH NMR spectrum (300 MHz,"CDCl3, δ in ppm)': 2.62 (t, J = 7 Hz : 1H) ; 2.67 (s : 3H) ; 3.21 (broad t, J = 7 Hz : 2H) ; 3.42 (mt : 1H) ; 3.70 (broad t, J = 7 Hz : 1H) ; 4.28 (s : 1H) ; 4.28 (d, J = 11 Hz : 1H) ; 6.85 (tt, J = 9 and 2.5 Hz ,: 1H) ; 6.97 (mt ■': 2H) ; from 7.20 to 7.35 (mt' : 6H) ; 8.52 (dd, J = ' 4.5 and · -1.5 Hz : 2H) . ' The second mixture of diastereoisomers .has the characteristics are. the following [lH NMR spectrum (300 MHz, CDC13, S in ppm) : 2.59 "(t, J = .7 Hz : 1H) ; ' 2.67 (s : 3H) ; 3.26 (mt : 2H) ; from 3.35 to 3.50 (mt : 1H) ; 3.63 (broad t, J = 7 Hz : 1H) ; 4.28 (s : 1H) ; 4.28 (d, J = 11 Hz : 1H) ; 6.85' (tt, J = 9 and 2 Hz : 1H) ; 6.97 (mt : 2H) ; from 7.20 to 7.40 (mt :. 6H) ; 8.50 (dd, . J = 4.5 and. 1.5 Hz : 2H) . ( 4 -Pyridyl ) - ( 4 -chlorophenyl ) bromomethane may be prepared in the following, manner : a solution of 100 mg of ( 4 -pyridyl )-( 4 -chlorophenyl ) methanol in 0.24. cm3 of hydrobromic acid (at 33% in acetic acid) is heated, under reflux for 1 hour and then allowed to return to a temperature in the region of 20°C. 0.675 cm3 of acetyl bromide is then added and the reaction mixture is heated under reflux for 1.5 hours and then allowed to return to a temperature in the region of 20°C before being concentrated under reduced pressure. 163 mg of (4 -pyridyl )-( 4-chlorophenyl ) bromomethane " are thus •obtained in the form of a beige ' foam-gum. ( 4 -Pyridyl )-( 4-chlorophenyl) methanol may be prepared in the following manner: 348 mg of sodium tetraborohydride are added, at a temperature in the region of 20°C, to a solution of 2 g of 4- (4-chlorobenzoyl) pyridine in 160 cm3 of ethanol. After stirring for 2 hours at a temperature in the region of 20°C, 90 mg of sodium tetraborohydride are added. After about .1.5 hours at the same temperature, the reaction medium is diluted with 200 cm3 of dichloromethane and 200 cm3 of water. The pH of the aqueous phase is adjusted to a value of about 5 by addition of about 13 cm3 of an aqueous 1 N hydrochloric acid solution.
After decantation, the aqueous phase is extracted with 3 times 100 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 2 g of ( 4 -pyridyl )-( 4 -chlorophenyl ) methanol are thus obtained in the form of a white powder.
Example 83 (RS) -{ 1- [ (2-Chloropyrid-5-yl) - (4-chloro-phenyl) methyl]—3- [ ( 3,· 5-difluorophenyl) methylsulfonyl-methyl] azetidine may be prepared in the following manner: a mixture of.300 mg of (2-chloropyrid-5-yl) - ( 4 -chlorophenyl ) bromomethane, 225 mg of (RS) -3- [ (3, 5-difluorophenyl ) methylsulfonylmethyl ] -azetidine hydrochloride, 125 mg of potassium iodide and 521 mg of potassium carbonate in 5 cm3 of acetonitrile, is heated for about 2 hours at the reflux temperature of the solvent. After cooling to a temperature in the ' region of 20°C, the reaction medium is filtered on sintered glass. The solid residue is rinsed with dichloromethane and the filtrates are evaporated under reduced pressure. 402 mg of a chocolate foam are thus obtained, which foam is purified by preparative thin-layer chromatography on silica [4 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], . eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40°C, there are obtained a first mixture of diastereoisomers , that is to say 14 mg of (RS)-{l-[(2-chloropyrid-5-yl) - (4-chlorophenyl) methyl] - 3- [ (3, 5-difluorophenyl.) methylsulfonylmethyl ] azetidine in the form of a brown foam, and a second mixture of -diastereoisomers, that is to say 10 mg of (RS) - { 1- [ (2-chior.opyrid-5-yl) - ('4-ch orophenyl ).methyl ] -3- [ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidine in the form of. a beige foam.
The first mixture of diastereoisomers has the characteristics are the following: [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.57 (t, J = 7.5 Hz : 1H) ; 2.65 (s : 3H) ; from 3.15 to' 3.30 (mt : 2H) ; 3.40 (mt ■ :. 1H) ; 3.63 (broad t, J = 7.5 Hz : 1H) ; 4.27 (d, J = 11 Hz : 1H) ; 4.31 (s : 1H) ; 6.84 (tt, J = 9 and 2 Hz : 1H) ; 6.95 (mt : 2H) ; from '7.20 to 7.35 (mt : 5H) ; 7.63 (dd, J = 8 and 2.5 Hz : 1H) ; 8.38 (d, J = 2.5 Hz : 1H) .
The second mixture of diastereoisomers has the characteristics are the following: [1H NMR spectrum (300 MHz, CDC13, δ in ppm): 2.57 (t,' J = 7.5 Hz : 1H) ; 2.64 (s : 3H) ; 3.18 (broad t, J = 7.5. Hz : '2H) ; 3.38 (mt : 1H) ; 3.63 (broad t, J = 7.5 Hz : 1H) ; 4.24 (d, J = 11.5 Hz : .1H) .29 (s : 1H) ; 6.83 (tt, J = 9 and 2 Hz : 1H) ; 6.94 (mt : 2H) ; 7.20 (d, J = 8 Hz : 1H) ; from 7.20 to 7.35 (mt : 4H) ; 7.59 (dd, J = 8 and 2.5 Hz : 1H)'; 8.34 (d, J = 2.5 Hz : 1H) . 2- (Chloropyrid-5-yl) - ( 4-chlorophenyl) bromo-methane may be prepared in the following manner: 0.153 cm3 of thionyl bromide is added to a solution of 100 mg of ( 2-chloropyr'id-5-yl) -( 4-chlorophenyl) methanol in 2 cm3 of carbontetrachloride , under an inert .argon atmosphere, at a temperature in the region of 0°C.
After' 3.5 hours at a temperature in the region of 0°C, the .reaction medium is concentrated under reduced pressure and coevaporated with a few cm3 of toluene. 1.3 g .of a brown liquid are thus obtained, which liquid is taken up in dichloromethane and supplemented with water and sodium dithionite.' After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.33 g of 2- (chloropyrid-5-yl) - (4-chlorophenyl) bromo-methane is thus obtained in the form of a brown oil.' 2- (Chloropyrid-5-yl ) - (4-chlorophenyl) bromo-methane may be prepared by carrying out the procedure in a manner similar to Example 84, starting with 22.5 cm3 of 4-chlorophenylmagnesium bromide (1 M solution in ethyl ether) in 30 cm3 of tetrahydrofuran, under an inert argon atmosphere, and 2.9 g of 2-chloropyridine-5-carboxaldehyde in 30 cm3 of tetrahydrofuran . 3.42 g of 2- (,chloropyrid-5-yl ) - ( -chiorophenyl) methanol are thus obtained, in the form of a pale green powder. 2-Chloropyridine-5-carboxaldehyde may be prepared according to the following reference: G. Pandey, T.D. Bagul, A.K. Sahoo, J. Org. Chem., 1998, 63, 760-768.
Example 84 (RS) -5- ((4-chlorophenyl) -{3- [ ( 3 , 5-difluoro-phenyl) methylsulfonylmethyl] azetidin-1-yl } methyl) pyrimidine may be prepared in the following manner: a mixture of 50 mg of 5-[bromo- (4-chlorophenyl)methyl]pyrimidine, 52.6 mg of (RS ) -3- [ ('3 , 5-difluorophenyl ) methylsulfonylmethyl ] -azetidine ' hydrochloride, 44 mg of potassium iodide and 73 mg of potassium carbonate in 2 cm3 of acetonitrile , is heated for about 5 hours at the reflux temperature of the solvent. After cooling to a temperature in the region of 20°C, the reaction medium is purified by direct deposition on preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel 60F254 plates; 20x20 cm; thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced · pressure at a temperature in the' region- of 40°C, 'there are obtained a first mixture- .of diastereoisomers , that is to say 8 mg of ( RS ) -5- ( ( 4 -chlorophenyl ) - { 3-[ (3, 5-difluorophenyl) methylsulfonylmethyl] azetidin-1-yl }methyl ) pyrimidine in the form of a yellow foam, and a second mixture of diastereoisomers, that is to say 6 mg of (RS ) -5- ( (4 -chlorophenyl ) - { 3- [ ( 3 , 5-difluorophenyl ) methylsulfonylmethyl ] azetidin-l-yl }methyl ) -pyrimidine in the form of a yellow foam.
The first mixture of diastereoisomers has the characteristics are the following: [lH NMR spectrum (300 MHz, CDCI3, δ in ppm) : 2.60 (broad t, J = 7 Hz : 1H) ; 2.66 (s : 3H) ; 3.24 (broad t, J = 7 Hz : 2H) ; 3.41 (mt ,: 1H) ; 3.66 (broad t, J = 7 Hz : 1H). / 4.28 (d, J = 11.5 Hz : 1H) ; 4.33 (broad s : 1H) 6.84 (broad t, J = 9 Hz : 1H) ; 6.95 (mt : 2H) ; from 7.25 to 7.35 (mt : 4H)-; 8.71 (broad s : 2H) ; 9.08 (broad s : 1H) .
The second mixture of diastereoisomers has the characteristics are the following: [XH NMR spectrum (300 MHz, CDCI3, δ in ppm) : 2.61 (t, J = 7 Hz : 1H) ; 2.66 (s : ';3H);' 3.24 ' (broad t, J = 7 Hz : 2H) ; 3.43 (mt : 1H) / 3.65 (broad t, J = 7 Hz : 1H) ; 4.28 (d, J = 11.5 Hz : ,1H); 4.33 (s : lH) ; 6.85 (tt, J = 9 and 2 Hz : 1H)'; 6.96 (mt : 2H) ; from 7.25 to 7.35 (mt : 4H) ; 8.69 (s : 2H) ; 9.06 (s : 1H) .
- [Bromo- ( -chlorophenyl ) methyl] yrimidine may be prepared in the following manner: 0.36 cm3 of thionyl bromide is added to a solution of 205 mg of (4-chlorophenyl ) pyrimidin-5-ylmethanol in 1 cm3 , of carbontetrachlori.de, and 1 cm3 of dichloromethane , - under an inert argon atmosphere, at a temperature in the region of 0°C. After 2.5 hours at a temperature in the region of 0°C, the reaction medium is brought to a temperature in the region of 20 °C, concentrated under reduced. pressure and coevaporated with a few cm3 of toluene. The brown liquid obtained is taken up in 10 cm3 of dichloromethane, washed with .5 cm3 of a saturated aqueous sodium dithionite solution and then with water. After decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 227 mg of a beige viscous liquid are thus obtained, which liquid is taken up in a minimum quantity of dichloromethane and purified by preparative thin-layer chromatography on silica [2 preparative Merck Kieselgel 60F254 plates; 20x20 cm, thickness 0.5 mm], eluting with a methanol-dichloromethane (2.5-97.5 by volume) mixture. After elution of the zone corresponding to the desired product with a methanol-dichloromethane (10-90 by volume) mixture, filtration on sintered glass and then evaporation of the solvents under reduced pressure at a temperature in the region of 40 °C, 51 mg of 5-[bromo- (4-chlorophenyl) methyl] yrimidine are obtained in the form of a yellow foam. 4- (Chlorophenyl) pyrimidin-5-ylmethanol may be prepared by carrying out the procedure in a manner similar to Example 83, 2.5 cm3 of n-butyllithium (1.6 M solution in hexane) are added dropwise to a solution of 636 mg of 5-bromopyrimidine in 10 cm3 of tetrahydrofuran, under an inert argon atmosphere, at a temperature in the region of -78 °C. After 10 minutes at a temperature in the region of -78 °C, a solution of 562 mg of 4-chlorobenzaldehyde in 1 cm3 of tetrahydrofuran is added dropwise. After stirring for 30 minutes at a temperature in the region of -78°C, the temperature of the reaction medium is allowed to rise slowly to a temperature in the region of 20°C, and 15 cm3 of a saturated aqueous ammonium chloride solution, 60 cm3 of ethyl acetate and 10 cm3 of water are .added successively. The aqueous ' phase is extracted with 15 cm3 of ethyl acetate, the organic phases are ' combined, dried over magnesium sulfate, filtered on-sintered glass and concentrated under reduced pressure (20 mbar) at a temperature in the region of 44°C. The bulk of the orange-colored oil obtained (1.09 g) is purified by chromatography on a column 30 mn in diameter filled with 60 g of medium silica (0.063-0.200 mm) at atmospheric pressure, eluting with a methanol/dichloromethane (0/100 to 7/93 by volume) gradient. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure. 293 mg of 4- (chlorophenyl).pyrimidin-5-yl ) methanol are thus obtained in the form of a yellow oil.
Example 85 The phenolic ester of 4- ( { 1- [bis ( 4--chloro-phenyl) methyl] azetidin-3-ylidene }methylsulfonylmethyl ) -3 , 6-dihydro-2H-pyridine-l-carbothioic acid may be -prepared in the following manner: 0.140 g of ,4-dimethylaminopyridine and then 0.042 cm3 of methanesulfonyl chloride are added to a solution of 0.23 g of the phenolic ester of 4- ( { 1-bis ( 4-chloro-phenyl) methyl].-3-hydroxyazetidin-3-yl }methylsulfonylmethyl ) -3 , 6-dihydro-2H-pyridine-l-carbothioic acid in ■5 cm3 of dichloromethane . The reaction mixture is stirred for 20 hours at 20°C and then diluted with cm3 of water. After decantation, the organic- phase is successively washed with 100 cm3 of water and 100 cm3 of a saturated NaCl solution, dried over magnesium sulfate and then concentrated to dryness at 40°C under 2.7 kPa. The oil obtained is triturated for 45 minutes in 50 cm3 of diisopropyl ether. ,· The solid formed is filtered, providing 120 mg of the phenolic ester of 4- ( { 1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-ylidene }methylsulfonylmethyl ) -3, 6-dihydro-2H-pyridine-1-carbothioic acid in the form of a beige solid melting at 184°C [ 1H NMR spectrum (400 MHz, CDC13, δ in ppm) : 2.53 (unresolved complex: 2H) ; 2.95 (s : 3H) ; 3.90 (unresolved complex: 2H) ; 4.04 (t, J = 5.5 Hz : 1H) ; 4.24 (mt : 3H) ; 4.49 '(unresolved complex: 2H) ; 4,.60 (mt : 1H) ; 5.90 (unresolved complex: 1H) ; from 7.05 to 7.50 (mt :- 13H) ] .
The phenolic ester of 4- ({ 1- [bis ( 4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl }methyl-sulfonylmethyl).-3 , 6-dihydro-2H-pyridine-l-carbothioic acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester; of -methylsulfonylmethyl- . 3 , 6-dihydro-2H-pyridine-l-carbothioic acid and 0.708 g of 1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-one in 15 cm3 of dry tetrahydrofuran cooled under an inert atmosphere to -78 °C. The reaction mixture is stirred at -78 °C for 4 hours and then 0.354 g of 1- [bis (4-chlorophenyl) -methyl] azetidin-3-one are added. After two hours at -78°C, the temperature is allowed to return to 20°C. The reaction mixture is diluted in 100 cm3 of water and then the . tetrahydrofuran is evaporated off under 2.7 kPa at 40°C. The aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40°C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 urn, porosity 60Angstroem, column 5 cm in diameter), eluting with a cyclohexane : ethyl acetate (6:4 by volume) mixture. The fractions with an Rf=11/64. ( cyclohexane : ethyl acetate 6:4, silica plate, Merck reference 1.05719,·' Merck KGaA, 64721 Darmstatd, Germany) .are combined and concentrated under 2.7 kPa at 40°C. to give 240 mg of the phenolic ester of 4- ( { 1- [bis (4-chlorophenyl) methyl] -3-hydroxyazetidin-3-yl }methylsulfonylmethyl) -3, 6-dihydro-2H-pyridine-l-caxbothioic acid.
The "phenolic ester of 4 -methylsulfonylmethyl-3 , 6-dihydro-2H-pyridine-l-carbothioie acid may be prepared in the following manner: 0.778 cm3 of. phenyl thiochloroformate is added to a solution of 1 g of l-benzyl-4-methylsulfonylmethyl-1 , 2, 3, 6-tetrahydropyridine in 10 cm3 of dichloromethane under an argon atmosphere.. The solution instantly acquires a very dark amber color. The reaction mixture is stirred for 4 hours at 21°C and then diluted in 100 cm3 of dichloromethane. The organic medium is washed with twice 50 cm3 of water, dried over magnesium sulfate and · evaporated to dryness at 40°C under 2.7 kPa .. The residue obtained is purified by chromatography on a silica cartridge (reference SIL-020-005, FlashPack, Jones Chromatography Limited, New Road, Hengoed, Mid Glamorgan, CF82 8AU, Great Britain), eluting with a cyclohexane : ethyl acetate 6:4 mixture (10 cmVmin, 5-cm3 fractions) . The fractions with an Rf=12/74 (cyclohexane : ethyl acetate 1:1,. silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) are combined and. concentrated' under 2.7 kPa at 40°C to give 700 mg of. the phenolic ester of 4-methylsulfonylmethyl-3 , 6-dihydro-2H-pyridine.-l-carbothioic acid-. ' l-Benzyl-4-methylsulfonylmethyl-1 , 2 , 3 , 6-tetrahydrbpyridine may be prepared in the following manner: a solution of 5.14 g.of sodium borohydride and 25 g of sodium, carbonate in 700 cm3 of water is added dropwise over one hour, without exceeding a temperature of 5°C in- the reaction medium, to a solution of 17.6 g of l-benzyl-4-methylsulfonylmethylpyridinium bromide in 700 cm3 of water cooled to 5°C. The reaction medium is stirred for four hours at 0°C and then the temperature is allowed to return, to room temperature overnight. The yellow solid formed is isolated by filtration and dried under 2.7 kPa, giving 9.6 g of l-benzyl-4-methylsulfonylmethyl-1 ,-2 , 3, 6-tetrahydropyridine having an Rf of 44/81 ( dichloromethane : methanol , 95:5 by volume, silica plate, Merck reference 1.05719, Merck KGaA, 64271 Darmstatd, Germany) . 1-Benzyl-4-methylsulfonylmethylpyridinium bromide may be prepared in the following manner: 14 cm3 of benzyl bromide are added to a solution of 10 g of 4-methylsulfonylmethylpyridine in 200 cm3 of acetonitrile and then the mixture is heated under reflux for 3 hours and is then, allowed to · return to room temperature overnight. The solid formed is ■ filtered, dried under vacuum at 2.7 kPa, giving 17.6 g of l-benzyl-4-methylsulfonylmethylpyridinium bromide. 4-Methylsulfonylmethylpyridine may be ' prepared in thej following manner: 14 g of sodium hydroxide pellets and then 35.7 g of sodium methanesulfinate are slowly added to a solution of 57.4 g of 4-chloromethylpyridine hydrochloride in 700 cm3 of ethanol .. After addition, the temperature is 2.8 °C. The reaction mixture is heated under reflux for two hours and then allowed to return to room temperature overnight. The reaction medium is heated to .50°C and then filtered hot on paper.. The filtrate is evaporated to dryness at 40°C under 2.7 kPa . The residue is recrystallized from 300 cm3 of isopropanol, giving '29.6 g' of 4-methylsulfonylmethylpyridine .
Example 86 (RS)-l-[2-{l-[Bis ( 4 -chlorophenyl) methyl] - azetidin-3-yl } -2- (3-, 5-difluorophenyl ) ethyl] - 3-propylurea may be prepared by carrying out the procedure in the following manner: 0.052 cm3 of n-propyl isocyanate is added to a solution of 90 mg of (RS)-2- { 1- [bis ( -chlorophenyl) methyl] azetidin-3-yl } - 2- (3, 5-difluorophenyl) ethylamine in 5 cm3 of .tetrahydroduran . After stirring for about 72 hours at' a temperature in the region of 20 °C,' the reaction mixture is filtered, concentrated to dryness under reduced pressure, and taken up in diisopropyl ether. The mixture obtained is filtered and concentrated to dryness under reduced pressure. 80 mg of a pale yellow ■ solid are thus obtained, which solid is dissolved in 5 cm3 of tetrahydrofuran, and to which 80 mg of · scavenger resin are added. After stirring for about 18 hours at a temperature in the region of 20°C, the reaction mixture is filtered and then concentrated to dryness under reduced pressure. 36 mg of a pasty solid are thus obtained, which solid is purified by chromatography under pressure on a "silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate (50/50 by volume). Fractions 16 to 20 are combined and concentrated to dryness under reduced pressure. 6 mg of (RS) -1- [2-{l- [bis (4-chlorophenyl) methyl] azetidin-3-yl }- 2- (3, 5-difluorophenyl) ethyl ] -3-propylurea are obtained in the form of an oil [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.88 (t, J = 7.5 Hz : 3H) ;' from 1.35 to 1.60 (mt : 2H) ; from 2.25 to 2.55 and from 2.65 to 3.05 (2 series of mts : 6H in total); 3.04 (mt : 2H-).; 3.22 (mt. : 1H) ; 3.38 (mt : 1H) ; 4.07. (mt: ΊΗ) ; from 4.10 to 4.20 (mt : 1H) ; 4.17 (s : 1H) ; 6.62 (tt, J = 9 and 2.5 .Hz : 1H); '6.82 (mt : 2H) ; from 7.20 to 7.45 (mt : 8K] .
(RS) -2- { 1- [Bis (4-chlorophenyl) methyl] - azetidin-3-yl}.-2- (3, 5-difluorophenyl) ethylamine may be prepared by carrying out the procedure in the following manner: 1.2 g of (RS ) -2- { 1- [bis ( 4-chlorophenyl) methyl] - azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) methanesuifonic acid ethyl ester in solution in 10 cm3 of methanol and then a solution of 30 cm3 of ammonia in 30 cm3 of methanol are introduced into an autoclave cooled by a bath of acetone and dry ice. The closed autoclave is - shaken and heated to a temperature in the region of 60°C for 24 hours. -After cooling to a temperature in the region of 20°C, the ammonia is allowed to evaporate * in the air, at a tempeat-ure in the region of 20°C, and then the remaining solution is concentrated to dryness under ' reduced" pressure". A gum is thus obtained which is triturated with -ethyl ether, at a temperature in the region/of 20°C for about 16 hours'. The insoluble matter obtained is filtered and dried in a desiccator for.. 3 hours. 830 mg of (RS) -2- { 1- [bis ( 4-chlorophenyl) - methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) ethylamine are thus obtained in the form of a whitish solid..
(RS)-2-{l-[Bis( 4-chlorophenyl ) methyl] - azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) methanesulfonic acid ethyl ester may be prepared by carrying out the procedure in the following manner: 0.34 cm3 of methanesulfonyl chloride is added to a solution of 1.9 g of (RS) -2- { 1- [bis ( 4-chloropheriyl) methyl] aze.tddin-3-yl } -2- ( 3 , 5-difluorophenyl ) ethanol in 20 cm3 of dichloromethane , at a temperature in the region of 20°C. After cooling of the reaction mixture to a temperature in the region of 10°C, 0.89 cm3 of triethylamine is added. After stirring the solution for 20 hours at a temperature in the region of 20°C, 100 cm3 of water are added dropwise followed by 150 cm3 of ■ dichloromethane. The organic phase separated after settling but is washed with twice 50 cm3 of water, 50 cm3 of a saturated aqueous sodium' chloride solution, 50 cm3 of water, and then dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure .. The yellow foam thus obtained. (2 g) is purified on a silica column (particle size 0.020 -0.045 mm), at a pressure of 0.4. bar, eluting with a mixture of ■ cyclohexane and ethyl acetate (80/20 by volume) . Fractions 49 ,to 111 are combined and concentrated to dryness under reduced pressure. 1.2 g of (RS) -2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) methanesulfonic acid ethyl ester are obtained in the form of a white foam.
Example 87 (RS) -N-[2-{l-[Bis ( 4-chlorophenyl ) methyl ] -azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) ethyl 1 cyclo-propanecarboxamide may be prepared by carrying out the procedure in the following manner: 0.018 cm3 of diisopropylcarbodiimide , 10 mg of cycl.opropanecarboxylic acid, 16 mg of hydroxybenzotriazole hydrate and then 0.4 g of morpholine supported on polystyrene are added ' successively to a solution of 90 mg of (RS ) -2- { 1- [bis- ( 4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) ethylamine in 5 cm-3 of tetrahydrofuran, at a temperature in the region of 20 °C. The suspension obtained is stirred at a temperature in the region of 20°C for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. 80 mg of a pasty product are thus obtained, which product is purified by passage over an SPE cartridge (SCX phase, 1 g of phase) . 76 mg of a residue are thus obtained, which residue is purified by chromatography under pressure on a silica cartridge, eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) . Fractions 9 to 19 are combined and- •concentrated . to . dryness under reduced pressure. 12 mg of (RS ) -N- [2- { 1- [bis ( 4-chlorophenyl ) -methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl).ethyl] -cyclopropanecarboxamide are obtained in the form of a colorless oil [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.70 (mt : 1H) ; from 0.80 to 1.00 (mt : 2H) ; from 1.15 to 1.35 (mt : 1H) ; from 2.35 to 2.55 and from 2.70 to 3.10 (2 series of mts : 7H in total); 3.26 (mt : 1H) ; 3.47 (mt : 1H) ; 4..19 (s : 1H) ; 5.63 (mt : 1H) ; 6.62 (tt, J = 9 and 2.5 Hz : 1H) ; 6.81 (mt : 2H) ; from 7.20. to .7.45 (mt : 8H) ] .
Example 88 (RS) -N-[2-{l- [Bis (4-chlorophenyl ) methyl ] -azetidin-3-yl }·-2- (3, 5-difluorophenyl ) ethyl] - 3-methylbutyramide may be prepared by carrying out the procedure in the following manner: 114 mg of HATU, 30.6 mg of isovaleric acid and then 0.2 g of morpholine supported, on polystyrene are added to a solution of 45 mg of (RS ) -2- { 1- [bis ( 4-chlorophenyl ) methyl] azetidin-3-yl}-2- (3, 5-difluorophenyl) ethylamine in 5 cm3 of tetrahydrofuran, at a temperature in the region of 20°C. The suspension obtained is stirred at a temperature in the region of 20°C for 20 hours. The reaction medium is filtered and concentrated to dryness under reduced pressure. 46 ,mg of an orange-colored oil are thus obtained, which oil is purified by chromatography under pressure on a cartridge of' .5 g of silica, eluting with a mixture of cyclohexane and ethyl acetate (70/30 by volume) . The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure.. 6 mg of (RS)-N-[2-( 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -2-(3, 5-difluorophenyl) ethyl] -3-methylbutyramide are. obtained in the form of a colorless oil [XH N R. spectrum (400 MHz, CDCI3 , δ in ppm) : 0.88 (d,. J = 6.5 Hz : 3H) ; 0.91 (d, J = 6.5 Hz : 3H) ; from 1.85 to 2.10 (mt : 3H) ; from 2.30 to 2.55 and from 2.70 to 3.10 (2 series of . mts : 6H in total); 3.37 (mt : 2H) ; 4.19 (s : 1H) ; 5.45 (mt .: 1H) ; 6.65 ( tt , J = 9 and 2.5 Hz : 1H) ; 6.82 (mt :. 2H) ; from 7.20 to 7.45 (mt : 8H) ] .
Example 89 (RS)--N-[2-{l-[Bis ( -chlorophenyl ) methyl- azetidin-3-yl } -2- (3, 5-difluorophenyl ) ethyl] iso- butyramide may be prepared by carrying out the • procedure in the manner . similar to Example 3 above: starting with 45 mg of (RS ) -2- { 1- [bis ( 4-chlorophenyl ) - methyl] azetidin-3-yl } -2- ( 3 , 5-difluorophenyl ) ethylamine, 5 cm3 of tetrahydrofuran, 114 mg of HATU, 26 mg of isobutyric -acid and 0.2 g of morpholine supported on polystyrene, 10 mg of (RS) -N- [2- { 1- [bis ( 4-chlorophenyl) methyl] azetidin-3-yl } -2- (3, 5-difluorophenyl) ethyl] isobutyramide' are obtained in the form of an opaque oil [1H NMR spectrum (400 MHz, (CD3) 2SO d6, δ in ppm) : 0.87 (d, J = 7. Hz : 3H) ; 0.93 ■ ( d, J = 7 Hz : 3H) ; from 2.15 to 2.85 (mt : 7H) ; ■ from 3.00 to 3.25" (mt : 2H) ; 4.40 (s : 1H) ; from 7.00 to 7.20 (mt : 3H) ; 7.38 (mt : 4H) ; 7.52. (mt : 4H) ; 7.77 (mt : IK) J .
Example 90 { 1- [Bis ( 4-chlorophenyl) methyl] azetidin-3-yl } - ( 3 , -difluorophenyl ) methanone may be prepared by carrying out the procedure in the following manner: 3 cm3 of a 0.5 N solution of .3, 4-difluorophenylmagnesium bromide in tetrahydrofuran are added to a solution of 128 mg of 1- [bis ( 4-chlorophenyl ) methyl ] azetidine- 3-carboxylic acid N-methoxy-N-methylamide in 3 cm3 of tetrahydrofuran, cooled in a bath of acetone and dry ice. After stirring for 20 hours at a temperature in the region of O'C.lp cm3 of water .are added and then the reaction medium is stirred for 1 hour at a temperature in the region of 20 °C. The aqueous phase separated by settling is extracted with 20 cm3 of ethyl acetate. The combined organic phases are washed with twice 15 cm3 of water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. 123 mg of a residue are thus obtained, which residue is purified by chromatography under pressure on a cartridge of 20 g of silica, eluting with dichloromethane (stabilized on amylene) . 47 mg of { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - 3, -difluorophenyl) methanone are thus obtained in the form of a white powder [ΧΆ NMR spectrum (300 MHz, CDC13, δ in ppm) : 3.34 (t, J = 7.5 Hz 2H) ; 3.56 (t, J = 8 Hz : 2H) ; 4.05.(.rat : 1H) ; 4.35 (s : 1H) ; from 7.15 to 7.40 (mt : 9H) ; 7.58 (dmt, J = 9 Hz : 1H) ; 7.70 (ddd, J = 9/7.5 and 2.5 Hz :.' 1H] . 1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide may be prepared by carrying out the procedure .in the following manner: 2.65. cm3 of 1-methylpiperidine are added to a suspension of 2.03 g of N, O-dimethylhydroxylamine hydrochloride in 40 cm3 of dichloromethane, cooled to a temperature in the region of 0°C by an ice- cold water bath. The yellow solution obtained (solution A) is stored at a temperature in the region of 0°C. 2.65 cm3 of 1-methyipiperidine and then 1.6 cm3 of methyl chloroformate are added successively to a suspension of 7 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid in 300 cm3 of dichloromethane and 40 cm3 of tetrahydrofuran, cooled to a temperature in the region of -8°C by an ice and isopropanol bath.
After stirring for. about 5 minutes at a temperature in the region of -8°C, solution A prepared above is added dropwise. After stirring for 10 minutes at a temperature in the region of -8°C, the cooling bath is removed, and the reaction mixture is stirred at a temperature in the region of 20 °G for about 20, hours, and then washed with 3: times 150 cm3 of water, and concentrated to dryness under reduced pressure . 8.19 g of a residue are thus obtained, which residue is purified under pressure on 500 g of Amicon silica, (diameter of the particles: 20 - 45 ?m) , eluting with an ethyl acetate/dichloromethane (8 - 92 by volume) mixture.. 6.6 g of Ί- [bis (4-chlorophenyl) methyl ] -azetidine-3-carboxylic acid N-methoxy-N-methylamide are thus obtained in the form of a pale yellow oil. 1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid may.- be prepared in a manner similar to that described by ANDERSON A.G. and LOK R. J. Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin- 3-ol, using,- as raw material, 1- [bis (4-chlorophenyl) -methyl] azetidin-3-ol .
Example 91 { 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone may be prepared by carrying out the procedure as for {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, -difluorophenyl) methanone, starting with 1.1 g of 1- [bis (4-chloropheriyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide, 1.5 cm3 of 1-bromo- 3, 5-difluorobenzene, and 316 mg of magnesium turnings. 880 mg of { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone are thus obtained in the form of a pale yellow viscous oil [XH NMR spectrum (300 MHz, CDCi3, δ in ppm) : 3.34 (t, J = -7.5 Hz : 2H) ; 3.55 (t, J = 8 Hz : 2H) ; 4.03 (mt : 1H) ; 4.44 (s : 1H) ; 7.01 (tt, J = 9 and 2.5 Hz : 1H) ; from 7.20 to 7.40 ' (mt : 10H) ] .
Example 92 {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl }-cyclohexylmethanone may be prepared by carrying out the procedure as for ( 1- [bis (4-chlorophenyl) methyl] -azetidin-3-yl } - (3, 4-difluorophenyl) methanone, starting with 284 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid N-methoxy-N-methylamide and 1.68 cm3 of 2 N cyclohexylmagnesium chloride in THF. 116 mg of {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl-}.-cyclohexylmethanone are thus obtained in the form of a ■yellow viscous oil [XH NMR spectrum (400 MHz, CDC13 δ in ppm) : from 1.10 to 1.35 and from 1.55 to 1.85 (2 series of mt : 10H in total) / 2.30 (mt : 1H) ; 3.14 (t, J = 8 Hz : 2H); 3.36 (t, J = 8 Hz : 2H) ; 3.56 (mt : 1H) ; 4.31 (s :' 1H) ; from 7.20 to 7.35 (mt : 8H) ] .
Example 93 {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl } -phenylmethanone may be prepared by carrying out the . procedure as for {1- [bis (4-chlorophenyl) methyl] -azetidin-3-yl } - (3, 4-difluorophenyl) methanone, starting with 258 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic N-methoxy-N-methylamide and 1.02 cm3 of 3 N phenylmagnesium bromide in THF. 208 mg of { 1- [bis (4-chlorophenyl) methyl ] azetidin-3-yl } -phenylmethanone are thus obtained in the form of a yellow viscous oil [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 3.35 (t, J = 8 Hz : 2H) ; 3.57 (t, J = 8 Hz : ' 2H) ; 4.13 (mt : 1Ή) ; 4.35 (s : 1H) ; 7.25 (dmt, J = 8 Hz : 4H); 7.34 (dmt, J = 8 Hz : 4H); 7.45 (broad t, J = 8 Hz : 2H) ; 7.56 (tt, J = 8 and 1.5 Hz : 1H); 7.84 (dmt, J = 8 Hz : 2H) ] . .
Example 94 (RS) -1- { 1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } -1- (3, 5-difluorophenyl) ethanol may be prepared by carrying out the procedure in the following manner: 0.1.67 cm3 of a 3 N methylmagnesium bromide solution is added to a solution of 100 mg o€ { 1- [bis (4-chlorophenyl) methyl ] azetidin-3-yl } - ( 3 , 5-difluorophenyl) methanone in 4 cm3 of tetrahydrofuran, cooled to a temperature of less than -40°C. After stirring for 20 hours at a temperature in the region of 0°C, '5 cm3 of water are added and then the aqueous phase separated by settling is extracted with 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure. 91 mg of a residue are thus obtained, which residue is purified by chromatography under pressure on a cartridge of 10 g of silica, eluting with an ethyl acetate/cyclohexane (1/9 by volume) mixture. 74 mg of (RS)-l-(l- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -1- (3, 5-difluorophenyl) ethanol are thus obtained in the form of a colorless oil [:H NMR spectrum (300 MHz, CDCI3, δ in ppra) : 1.46 (s : 3H) ; 2.71 (mt : 1H) ; 2.82 (mt : 1H) ; 2.98 (t, J = 7.5 Hz : 1H) ; 3.24 (t, J = 7.5 Hz : 1H) ; 3.34 (mt : 1H) ; 4.31 (s : 1H) ; 4.33 (mf : 1H); 6.67 (tt, J = 9 and 2.5 Hz : 1H) ; 6.98 (mt : 2H) ; from 7.25 to 7.35 (mt : 8H) ] .
Example 95 { 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone O-allyloxime may be prepared by carrying out the procedure in the following manner: a solution of 100 mg of { 1- [bis (4-chloro-phenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) -methanone and 101 mg of O-allylhydroxylamine hydrochloride in 5 cm3 of pyridine is stirred at a temperature in the region of 20 °C for 20 hours. 5 cm3 of water are then added and the reaction mixture is extracted with twice 5 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure. Ill mg of a yellow oil are thus obtained, which oil is purified by chromatography under pressure . on a cartridge of 20 g of silica (diameter of the' particles from 0.04 to 0.063 mm), eluting with an ethyl acetate/cyclohexane (2/98 by volume) mixture. 68 mg of { 1- [bis (4-chlorophenyl) methyl ] azetidin-3-yl } - (3 , 5-difluorophenyl) methanone O-allyloxime are thus obtained in the form of a colorless viscous oil [ H NMR spectrum (300 MHz, CDCI3, δ in ppm) . A mixture of the 2 Z and E isomers is observed in the approximate proportions 65/35 or conversely; 2.84 and 3.11 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz : 2H in total); 3.4-4 and 3.66 (2 broad t, respectively J. = 7.5 Hz and J = 8 Hz : 2H in total); 3.58 and 3.81 (2 mts : 1H total); 4.16 and 4.30 (2 s : 1H in total); 4.59 (mt : 2H); 5.22 (dmt, J = 11 Hz : 1H) ; 5.27 (dmt, J = 18 Hz : 1H) ; 5.96 (mt : 1H) ; 6.80 (tt,. J = 9 and 2.5 Hz.: 1H) ; 6.91 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H] .
Example 96 { 1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone O-ethyloxime may be prepared by carrying out the procedure as described for the preparation of { l-[bis (4-chlorophenyl) methyl] - 253 azetidin-3-yl } - (3, 5-difluorophenyl ) methanone O-allyloxime :' starting with 100 rng of { 1- [bis ( 4 -chloro- phenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl ) - methanone' and 90 mg of O-ethylhydroxylamine hydrochloride,- 83 mg of { 1- [bis ( 4-chlorophenyl) methyl] - azetidin-3-yl }-( 3 , 5-difluorophenyl ) methanone .
O-ethyloxime are thus obtained in the form of a colorless viscous oil [lH NMR spectrum (300 MHz , CDC13/. δ in ppm) . A mixture of the 2 Z and E isomers is observed in the. approximate proportions 65/35 or conversely; 1.25' and 1.27 ( 2 t , J = 7 Hz : 3H in total); 2.82 and 3.12 (2 broad t, respectively J = 8 Hz and J = 7.5 Hz : 2H in total); .3. 5 and 3.66 (2 broad t, respectively J = 7.5 Hz and J = 8 Hz : 2H in total); 3.58 and 3.78 (2 mts : ΙΗ'- total); from 4.05 to 4.20 (mt : 2H) ; 4.16 and 4.30 (2 s : 1H in total); 6.80 (tt, J = ■9 and 2.5 Hz : 1H) ; 6.91. (mt : 2H) ; from 7.20 to 7.35 (mt :. 8H) ] .
Example 97 (RS).-l-[{l-[Bis(4-chlorophenyl)methyl]-azetidin-3-yl } - ( 3 , 5-difluorophenyl) methyl] -3-methylurea may be prepared in the following manner: 0.336 cm3 of triethylamine and 0.384 cm3 of diphenylphosphonoazide are added successively to a solution of 300 mg of { 1- [bis (4-chlorophenyl ) methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 15 cm3 anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 60°C for about 90 minutes. 2.6 cm3 of a 2 M methylamine solution in tetrahydrofuran are added, the stirring is maintained at a temperature in the region of 20 °C for about 12 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 °C. The residue is taken up in 1 cm3 of methanol and then deposited on a_ BOND- ELUT SCX VARIAN 5 g cartridge with the reference 1225-6027 conditioned with methanol. The cartridge is washed with methanol and eluted with 2 N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 °C. 250 mg of a light oil are thus obtained, which oil is taken up in 1 cm3 of dichloromethane and then deposited on a cartridge 16 mn in diameter, filled with 5 g of silica of particle size 0.015-0.035 mm, conditioned .and eluted with dichloromethane between 0 and 40 cm3 and then eluted with a dichloromethane-ethyl acetate (80-20 by volume) mixture with the aid of a pumping system. ■ The- fractions between 50 and 80 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 140 mg of (RS)-1-[{1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - ( 3 , 5-difluorophenyl ) methyl ] -3-methylurea are thus obtained in the form of a foam [XH NMR spectrum (400 MHz, CDC13, δ in ppm) : 2.66 (mt : 1H) ; 2.82 (d,. J = 5 Hz : 3H) ; 2.95 (mt : 1H) ; 3.03 (mt : 1H) ; 3.18 (mt : 2H) ; 4.2 (mt.: 1H)'; 4.30 (s : 1H) ; 4.92 (t, J = 7 Hz : 1H) ; 5.36 (broad d, J = 7 Hz : 1H) ; 6.67 (tt, J ='9 and 2.5 Hz : 1H) ; 6.80 (mt : 2H) ; from 7.20 to 7.30 (mt : 8H) ] .
The preparation of { 1- [bis (4-chlorophenyl) -methyl] azetidin-3-yl}- (3, 5-difluorophenyl) acetic acid hydrochloride has been described in the patent "carbon-containing derivatives", example 77.
Example 98 (RS) -1- [ { 1- [Bis (4-chlorophenyl) methyl] -azetidin-3-yl } - (3, 5-difluorophenyl) methyl] -3-isopropylurea may be prepared in the following manner: 3 cm3, that is 0.1 mM of a freshly prepared solution of (RS) -1- [bis (4-chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) isocyanatomethyl] azetidine are added to a solution of 17 μΐ of isopropylamine in 1 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20 °C. The solution obtained is stirred at a temperature in the region of 20°C for about 12 hours. The reaction medium is concentrated to dryness under reduced pressure (2..7 kPa) at a temperature in the region of 40 °C. The solid residue is taken up in 1 cm3 of methanol and then deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge with the reference 1210-2040, conditioned with methanol. The cartridge is washed with methanol and then eluted with 2 N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness under reduced pressure (2.7 kPa} at a temperature in the region of 40°C. The solid residue thus obtained is taken up in 1 cm3 of dichloromethane and then deposited on an 1ST FlashPack cartridge with the reference SIL 016-002, filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a dichloromethane-e.thyl acetate (90-10 by volume) mixture with the aid of a pumping system. The fractions between 20 and 38 cm3 are combined and concentrated to dryness under reduced pressure * (2.7 kPa) at 40°C. 14 mg of (RS) -1- [ { 1- [bis (4-chloro-phenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) -methyl] -3-isopropylurea are thus obtained in the form of a white foam [XH NMR spectrum (400 MHz, CDC13, δ in ppm) : 1.14 (d, J = 6.5 Hz : 3H) ; 1.15 (d, J = 6.5 Hz : 3H) ; 2.66 (mt : 1H) ; 2.92 (broad dd, J = 8 and 5.5 Hz : 1H) 3.01 (broad dd, J = 8 and 5.5 Hz : 1H) ; 3.16 (t, J = 8 Hz :■ 1H)7 3.20 (t, J = 8 Hz ■ :..lH.) ; 3.85 (mt : 1H) ; 4.06 (d, J = 8 Hz : 1H) ; 4.29 (s : 1H) ; 4.91 (t, J = 7 Hz : 1H) ; 5.17 (d, J - 6..5 Hz : 1H) ; 6.66 (tt, J = 9 and 2 Hz : 1H) ; 6.78 (mt : 2H) ; from 7.20 to 7. '35 (mt : 8H) ] .
(RS) -1- [bis (4-chlorophenyl) methyl] -3-[ (3, 5-difluorophenyl) isocyanatomethyl] azetidine may be prepared in the following manner: 0.126 cm3 of triethylamine and 0.195 cm3 of diphenylphosphonoazide are added successively to a solution of 150-.mg of {l-[bis (4-chlorophenyl)methyl]azetidin-3-yl}- ( 3 , 5-difluorophenyl ) acetic acid hydrochloride in 9 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 50 °C for about 1 hour. The mixture is allowed to cool and (RS ) -1- [bis ( 4-chlorophenyl ) methyl ] - 3- [ ( 3 , 5-difluorophenyl ) isocyanatomethyl] azetidine is thus obtained , in solution in toluene and will be subsequently used in this- form.
Example 99 (RS) -1- [ {1- [Bis (4-chlorophenyl ) methyl ] - azetidin-3-yl } - ( 3 , 5-difluorophenyl) methyl] - 3-isobutylurea may be prepared in the following manner: 3 cm3, that is 0.1 mM of a freshly prepared solution of (RS) -1- [bis ( -chlorophenyl) methyl] -3- [ (3, 5-difluorophenyl) isocyanatomethyl] azetidine are added to a solution of 20 μΐ of isobutylamine in 1 cm3 of anhydrous toluene, under an inert nitrogen atmosphere, at a temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20 °C for about 12 hours. The reaction medium is •concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The solid residue is taken up in 1 cm3 of methanol and then ■ deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge . with the reference 1210-2040 conditioned with methanol. The cartridge is washed with methanol and then eluted with 2 N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness . under reduced pressure (2.7 kPa) at a temperature in the region of 40°C. The residue thus obtained is taken up in 1 cm3 of dichloromethane and then deposited on an 1ST FlashPack cartridge with' the reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a dichloromethane-ethyl acetate (90-10 by volume) mixture with the aid of a jpumping system. The fractions between 0 and 15 cm3 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 14 mg of (RS) -1- [ { 1- [bis (4-chlorophenyl)methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methyl] -3-isobutylurea are thus obtained in the form of a white foam NMR spectrum (400 MHz, CDCI3, δ in ppm) : 0.89 (d, J = 6.5 Hz : 3H) ; 0.90 (d, J = 6.5 Hz : 3H) ; 1.74 (mt : 1H) ; 2.66 (mt : 1H) ; from 2.90 to 3.25 (mt : 6H) ; 4.29 (s and mt : 2H in total); 4.90 (t, J-= 7 Hz. : 1H).; 5.34 (broad d, J = 6.5 Hz : 1H) ; 6.66 (tt, J = 9 and 2 Hz : 1H); 6.80 (mt ' : 2H) ; from 7.20 to 7.35 (mt : 8H)]'.
Example 100 N-Methyl-N-phenyl-1- [bis (4-chlorophenyl) - methyl] azetidine-3-carboxamide may be prepared in the following manner: 0.039 cm3 of N-methylaniline, 87 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 0.063 cm3 of triethylamine and then 4 mg of hydroxvbenzotriazol hydrate are added successively to a solution of 100 mg of 1- [bis ( -chlorophenyl ) - methyl ] azetidine-3-carboxylic acid in 2 cm3 of anhydrous dichloromethane, at a . temperature in the region of 20°C. The solution obtained is stirred at a temperature in the region of 20 °C for about 12 hours. The reaction medium is deposited on an 1ST FlashPack cartridge with the reference SIL 016-005 filled with 5 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a gradient bf ' dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from Ό to 5 by volume) with the aid of a pumping system, collecting 1.5 cm3 fractions. Fractions 3 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at :50°C. 95 mg of 1- [bis (4-chloro-phenyl ) methyl ] azetidine-N-methyl-N-phenyl-3-carboxamide are thus obtained in the form of a cream-colored foam [XH NMR spectrum (400 MHz , CDC13, δ in ppm) : 3.08 (mt : . 2H); 3.21 (mt : 3H) ; 3.27 (s : 3H) ; 4.35 (s : 1H) ; 7.06 (d, J = 7.5 Hz : 2H) ; from 7.1-5 to 7.45 (mt : 11H) ] . Example 101 1- [Bis (4-chlorophenyl) methyl] azetidine- N-benzyl-N-methyl-3-carboxamide may be prepared in the following manner: 0.0213 cm3 of N-benzylmethylamine is added to a suspension of 1.50 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid activated on . TFP resin I 65 μΜ) in 2 cm3 of dichloromethane. The suspension is stirred at a temperature in the region of 20°C for 22 hours and then filtered on sintered glass. The solid residue is washed a.gain with twice 1 cm3 of dichloromethane . The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 °C. 38 mg of 1- [bis (4-chlorophenyl) methyl] azetidine-N-benzyl-N-methyl-3-carboxamide are thus obtained in the form of a colorless gum [XH NMR spectrum (300 MHz, CDC13, δ in ppm) : 2.78 (s : 3H) ; from 3.25 to 3.55 (mt : 5H); 4.38 (mt : 2H) ; 4.57 (s : 1H) ; from 7.15 to 7.40 (mt . : 13H] .. 1- [Bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid activated on TFP resin may be prepared in the following manner: 2 g of 1- [bis (4-chlorophenyl) methyl] azetidine-3-carboxylic acid, 73 mg of 4-dimethylaminopyridine, 0.927 cm3 of 1, 3-diisopropylcarbodiimide are added to a suspension of 2.7 g of TFP resin (free phenol functional group, ■ 1.1 mmol/g, that is 2.975 mM) in 40 cm3 of anhydrous dimethylformamide . After stirring for 19 hours at a temperature in the region of 20\C, the suspension is. filtered, the resin is washed with 40 cm3 of dimethylformamide, 40 cm3 of tetrahydrofuran, 40 cm3 of dichloromethane and then dried under vacuum to a constant weight. 3.6 g of 1- [bis (4-chlorophenyl) -methyl] azetidine-3-carboxylic acid activated on TFP resin are thus obtained. ' · . 1- [Bis (4-chlorophenyl) methyl] azetidine- . . 3-carboxylic acid may be prepared in a manner similar to that described by ANDERSON A.G. and LOK -R. , J. Org. Chem., 37, 3953-3955 (1972) from 1-benzhydrylazetidin- 3-ol, using, as raw material, 1- [bis (4-chlorophenyl) -methyl] azetidin-3-ol .
The TFP resin (free phenol functional group) may be prepared according to the procedure described in patent W09967228.
Example 102 (RS) - [ { 1- [Bis (4-chlorophenyl) methyl] azetidin- 3-yl}- (3, 5-difluorophenyl) methyl] methylamine may be prepared in the following manner: 0.099 cm3 of methylamine is added to a solution of 108 mg of { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone in 2 .cm3 of anhydrous 1 , 2-dichloroethane, followed successively by 84 mg of sodium triacetoxyborohydride and 0.014 cm3 of acetic acid. After stirring for 12 hours at a temperature in the region of 20°C, 0.992 cm3 of methylamine, .85 mg of sodium triacetoxyborohydride and then 0.143 cm3 of acetic acid are- again added successively. "The solution obtained is stirred at. a temperature in the region of 20°C for about 24 hours and then washed with 4 cm3 of a saturated sodium bicarbonate solu'tion. The organic phase is separated by settling and then dried over magnesium sulfate, filtered and then concentrated under ■reduced pressure (.2.7 kPa) . The residue thus obtained is purified on an 1ST FlashPack cartridge with the reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm) conditioned with dichloromethane and eluted with a gradient of dichloromethane-methanol mixture (the ' percentage of methanol varying from 0 to 6 by volume) with the aid of a pumping . system, collecting 1 cm3 fractions. Fractions 8 to 18 are combined and. concentrated to dryness under reduced pressure (2.7 kPa) at 50°C. 66 mg of [{ 1- [bis (4-chlorophenyl) -methyl] azetidin-3-yi }- (3, 5-difluorophenyl ) methyl] -methylamine are thus obtained in the form of a colorless honey [XH NMR spectrum (300 MHz , CDC13, δ in ppm) : 2.25 (s : 3H); 2.60 (mt : 1H) / 2.68 (t, J = 7 Hz : 1H) ; 2.94 (t, J = 7 Hz : 1H) ; 3.02 (broad t, J = 7 Hz : 1H) ; 3.34 (broad t, J = 7 Hz : 1H) ; 3.58 (d, J = 9 Hz : 1H) ; 4.25 (s : 1H) ; 6.67 (tt, J = 9 and 2.5 Hz : 1H) ; 6.80 (mt : 2H) ;. from 7.20 to 7.35 (mt : 8H) ] .
Example 103 , (RS) - [ { 1- [Bis (4-chlorophenyl) methyl] azetidin- 3-yl }- (3, 5-difluorophenyl) methyl] isobutylamine may be prepared in the following manner: 0.028 cm3 of isobuthylamine is added to a solution of 109 mg of { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3,.5-difluorophen'yl) methanone in 2 cm3 of anhydrous 1, 2-dichloroethane, followed successively by 85 mg of sodium triacetoxyborohydride and 0.015 cm3 of acetic acid. The solution obtained is stirred at a temperature in the region of 20 °C for about 12 hours. The reaction medium is deposited on a cartridge filled with 5 g of silica, conditioned with dichloromethane and eluted with a gradient of dichloromethane-ethyl acetate mixture (the percentage of ethyl acetate varying from 0 to 10 by volume) with the aid of a pumping system. The fractions containing the desired product are combined and concentrated, to dryness under reduced pressure (2.7 kPa) at 40 °C. 8 mg of (RS) - [ { 1- [bis (4-chloro-phenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) -methyl] isobutylamine are thus obtained [lH NMR spectrum (300 MHz,.CDCl3, δ in p'pm) : 0.85 (d, J = 7 Hz : 3H) ; 0.87 (d, J = 7 Hz : 3H) ; 1.63. (mt :. 1H); 2.15 (dd, J = 11 and 7.5 Hz : 1H) ; 2.25 (dd, J = 11 and 7 Hz : 1H) ; ' 2.57 (mt : 1H) ; 2.70 (t, J = 7 Hz : 1H) ; 2.92 (t, J = 7 Hz : 1H) ; 3.01 (broad t, J = 7.5 Hz : 1H) ; 3.33 (broad t, J = 7.5 Hz :« 1H) ; 3.66 (d, J. = 9 Hz : 1Ή) /. 4.25 (s : 1H); 6.66 (tt, J = 9 and 2.5 Hz : 1H) ; 6.81 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H) ] .
Example 104 (RS) -[ {1- [Bis (4-chlorophenyl) methyl] azetidin-3-yl}- (3, 5-difluorophenyl) methyl] butylamine may be prepared in the following manner: 0.0265 cm3 of n-butylamine is added to a solution of 108 mg of { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methanone in 2 cm3 of anhydrous 1, 2-dichloroethane, . followed successively by 95 mg of sodium triacetoxyborohydride and 0.0143 cm3 of acetic acid. After stirring for about 16 hours at a temperature in -the region of 20°C, 0.0265 cm3 of n-butylamine, 85 mg of sodium triacetoxyborohydride and then 0.143 cm3 of acetic acid are again successively added. The solution obtained is stirred at a temperature in the, region of 20°C for about 24 hours and then washed with 4 cm3 of a saturated sodium bicarbonate solution. The organic phase is separated by settling and then dried over magnesium sulfate, filtered and then concentrated under reduced pressure (2.7 kPa) . The residue thus .obtained is purified on an : 1ST FlashPack cartridge . with the . reference SIL 016-002 filled with 2 g of silica (0.065-0.090 mm), conditioned with dichloromethane and eluted with a gradient of dichloromethane-methanol mixture (the percentage of methanol varying from 0 to 6 by volume) with the aid of a pumping system, collecting 1 cm3 fractions. Fractions 25 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 50 °C. 37 mg of RS) -[ {1- [bis (4-chlorophenyl) methyl] azetidin-3-yl }- (3, 5-difluorophenyl) methyl] butylamine are thus obtained in the form of a colorless honey [:H NMR spectrum (300 MHz, CDCI3, δ in ppm) -: 0.85 (t, J = 7.5 Hz : 3H) ; from 1.20 to 1.50 (mt : 4H) ; 2.37 (broad t, J = 7 Hz : 2H); 2.56 (mt : l'H) ; 2.67 (t, J = 7 Hz : 1H) ; 2.89. (t, J = 7 Hz : 1H) ; 2.99 (broad t, J = 7 Hz : 1H) ; 3.32 (broad t, J = 7 Hz : 1H) ; 3.67 (d, J = 9 Hz : 1H) ; 4.24 (s.: 1H) ; 6.65 (tt, J = 9 and 2.5 Hz : 1H) ; 6.80 (mt : 2H) ; from 7.20 to 7.35 (mt : 8H] .
Example 105 (RS) -N- [ {1- [Bis (4-chlorophenyl) methyl] - azetidin-3-yl } - (3, 5-difluorophenyl) methyl ] -■- 3-methylbutyramide may be prepared in the following manner: 0.025 cm3 of Ν,Ν'-diisopropylcarbodiimide, 10 mg of hydroxybenzotriazole. hydrate, 30 mg of (RS) -C- { 1- [bis (4-chlorophenyl) methyl] azetidin-3-yl } -C- (3, 5-difluorophenyl) methylamine are added successively to a solution of 0.017 cm3 of isovaleric acid in 2 cm3 of anhydrous dichloromethane, at a temperature in the region of 20 °C. The solution obtained is -stirred at a temperature in the region of 20 °C for about 12 hours. The reaction medium- is deposited on a BOND-ELUT SCX VARIAN 500 mg cartridge with the reference 1210-2040, conditioned with methanol. The cartridge is washed with methanol and then eluted with 2N ammoniacal methanol. The ammoniacal fractions are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 °C. 35 mg of (RS) -N- [ {1- [bis (4-chlorophenyl)methyl] azetidin-3-yl } - (3, 5-difluorophenyl) methyl] -3-methylbutyramide are thus obtained in the form of a yellow honey ' [lE NMR spectrum (300 MHz, CDC13, δ in ppm) : 0.98 (d, J = 5 Hz : 6H) ; from 2.05 to 2.25 (mt : 3H) ; 2.71 (mt : 1H):; 2.90 (mt : lH) ; 3.00 (mt : lfl) ; 3.20 (mt :'2H); 4.30 (s : lH) ; . 5.14 (t, J = 7.5 Hz. : 1H);.6.48 (broad d, J = 7.5 Hz : 1H) ; 6.67 (tt, J = 9 and 2.5 Hz : 1H) ; 6.75 (mt : 2H) ; from 7.20 to 7.40 (mt : 8H) ] .
(RS) -C-{1- [Bis (4-chlorophenyl) -methyl] azetidin-3-yl } -C- (3, 5-difluorophenyl) methylamine may be prepared in the- following manner: to a solution of 216 jng of (RS )-{ 1- [bis ( 4 -chlorophenyl ) methyl ] -azetidin-3-ylj - ( 3 , 5-difluorophenyl) methanone in 10 cm3 of methanol, followed successively by 385 mg of ammonium acetate and 29 mg of sodium cyanoborohydride . The solution obtained is stirred at a temperature in the region of 20 °G for about 12 hours' and then made lukewarm at 45°C for 6 h. 29 mg of sodium cyanoborohydride are added to this solution. The stirring is continued 'at a. temperature in the region of 20°C for 72 hours. The reaction medium is poured into a' mixture of 30 cm3 of ice-cold water with 5 'cm3 of a 4 N aqueous sodium hydroxide solution, and then extracted, with twice 30 .cm3 of ethyl acetate, the organic phase is extracted with twice 30 cm3 of N hydrochloric acid, the aqueous phase thus obtained is alkalinized with' a . normal aqueous sodium, hydroxide solution and then extracted with three times 20 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 40°C. 35 mg of (RS ) -C- { 1- [bis (4-chlorophenyl ) methyl] azetidin-3-yl } -C- (3, 5-difluorophenyl) methylamine are thus obtained in the form of a yellow honey.
The medicaments according to the invention consist of a compound of formula (I) or an isomer or a salt of such a compound, in the pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product which may be inert or physiologically active. The medicaments acco.rding to the invention may be used orally, parenterally, rectallyi or topically.
As solid compositions for oral administration, tablets, pills, powders (gelatine capsules, sachets) or granules may be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under an argon stream. These compositions may also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablets) or a glaze .
. ' . As liquid compositions for oral administration, there .may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil.
These compositions may comprise substances 'other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
Sterile compositions for parenteral administration may be preferably solutions which are aqueous or nonaqueous, suspensions or emulsions. As solvent or vehicle, there may be used water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions may also contain ' adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
Sterilization may be carried out in several ways, for example by asepticizing filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be prepared in the .form of sterile solid compositions which may be dissolved at' - the time of use in sterile water or any other injectable sterile medium.
Compositions for rectal administration are suppositories or. rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic, glycerides or polyethylene glycols . . .
Compositions for topical administration may be, for example, creams, lo.ti.ons, collyria, collutoria, nasal drops . or aerosols.
"-.In human therapy, the' compounds according to the invention are particularly useful for. the treatment and/or prevention' of psychoses including schizophrenia, anxiety disorders, depression, epilepsy, neurodegeneration, cerebellar and spinocerebellar disorders,, cognitive disorders, cranial trauma, panic • attacks, peripheral neuropathies, glaucomas, migraine, Parkinson's disease, Alzheimer's disease, Huntington's chorea, Raynaud's syndrome, tremor, ■ obsessive- compulsive disorder, senile dementia, thymic disorders, Tourette's syndrome, tardive dyskinesia, ι bipolar disorders, cancers, movement disorders induced by medicaments, dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, immunological diseases, multiple sclerosis, vomiting, asthma, appetite disorders, (bulimia, anorexia), obesity, memory disorders, intestinal transit disorders, in weaning from chronic treatments and alcohol or drug abuse (opioids, barbiturates, cannabis, cocaine, amphetamine, phencyclide, hallucinogens, benzodiazepines for example) , as analgesics or potentiators of the analgesic activity of the narcotic and nonnarcotic drugs.
The doses depend on the desired effect, the duration of . the treatment and the route of administration used; they are generally between 5 mg and.1000 mg per day orally for an adult with unit doses ranging from 1 mg to 250 mg of active substance.
In general, the doctor will determine the appropriate dosage depending on the age, weight and any other factors specific to the subject to. be treated.
The following examples illustrate the compositions according to the invention: EXAMPLE A Gelatin capsules containing a dose of 50 mg of active product and having the following composition are prepared according to the usual technique: - Compound of formula (I) .....· 50 mg - Cellulose ■. 18 mg - Lactose 55 mg - Colloidal silica .' 1 mg - Sodium carboxymethylstarch 10 mg - Talc 10 mg - Magnesium stearate 1 mg EXAMPLE B , .
Tablets containing a dose of 50 mg of active product and having the following composition are' prepared according to the usual technique: Compound of formula (I) 50 mg ' Lactose .". 104 mg Cellulose ... 40 mg Polyvidone 10 mg Sodium carboxymethylstarch . 22 mg Talc 10 mg Magnesium stearate 2 mg Colloidal silica ... 2 mg Mixture of hydroxymethylcellulose , glycerin titanium oxide (72-3.5-24.5) qs 1 finished coated tablet containing 245 mg 151428/2 277 EXAMPLE C An injectable solution containing 10 mg of active product having the following composition is prepared: - Compound of formula (I) 10 mg - Benzoic acid 80 mg - Benzyl alcohol....,' 0.06 ml — Sodium benzoate...; 80 mg - Ethanol, 95% 0.4 ml - Sodium hydroxide 24 mg - Propylene glycol.; 1.6 ml - Water qs 4 ml Material which is outside the scope of the claims does not constitute a part of the claimed invention.

Claims (58)

151428/4 - 278 - What is claimed is:
1. A compound of formula in which • R represents a radical selected from CRi R2, C=C(R5)S02 R6 and C=C(R7) S02 alk, • either R-i represents a hydrogen atom and R2 represents a radical selected from -C(RB)(RII) (R12), -CO-NR13R14, -CH2-CO-NR13 R14, -CH2 -CO-R6, -CO-R6, -CO-cycloalkyI, -SO-R6, -S02 -Re, -C(OH)(R12)(R6), -C(OH)(R6)(alkyl), -C(=NOalk)R6, -C^NO-CHr- CH=CH2)R6, -CHz-CH(R6)NR3iR32l -CH2-C(=NOalk)R6, -CH(R6)NR31R32, -CH(R6)NHS02 alk, - CH(R6)NHCONHalk and -CH(R6)NHCOalk, • or RT represents an alkyl, NH-R15, cyano, -S-alk-NR16 Ri7, -CH2 -NR1B R19, or -NR20 R2i radical and R2 represents a -C(R8) (Rn) (Ri2) radical, • R3 and R4, which may be identical or different, phenyl or indenyl, these aromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, formyl, hydroxyl, trifluoromethyl, trifluoromethoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22 R23, -CO-NH-NR2 R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl and -alk-NR24 R25 radicals; or a heteroaromatic radical selected from the benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, imidazolyl, isochromanyl, isoquinolyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1 ,2,3,4-tetrahydroisoquinolyl, thiazolyl and thienyl rings, these heteroaromatic radicals being unsubstituted or substituted with one or more radicals selected from halogen, alkyl, alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -COOH, -COOalk, -CO-NH-NR24 R25, -CONR^ R23, -alk-NR24R25, • 151428/3 - 279 - alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalky!, alkylsulfinylalkyl, alkylsulfonylalkyl and hydroxyalkyl radicals, • R5 represents a hydrogen or alkyl radical, • R6 represents an Ar or Het radical, • R7 represents a cycloalkyi, heterocycloalkyi or heterocyclenyl radical, optionally substituted by a -CSO-phenyl radical, • R8 represents a hydrogen or alkyl radical, • R9 represents a radical selected from -CO-NR26 R27, -COOH, -COOalk, -CH2 OH, -NH-CO-NH-alk, -CH2 -NHR2B and -NHCOOalk, • R10 represents an Ar or Het radical, • Rn represents a radical selected from -S02 -alk, -S02 -Ar and -S02 -Het, • Ri2 represents a hydrogen, Ar or Het radical, • 13 represents a hydrogen or alkyl radical, • Ri represents an Ar, Het, -alk-Ar or -alk-Het radical, • R15 represents an alkyl, cycloalkyi or -alk-NR29 R30 radical, • R16 and Ri7, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, Ri6 and R17, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, • R 8 represents a hydrogen or alkyl radical, • R19 represents a hydrogen, alkyl, cycloalkyi, cycloalkylalkyl, cycloalkylcarbonyl, -S02 alk, -CO-NHalk or -CO-alk radicals • Or, alternatively, R18 and R1B, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle ring, optionally containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl radicals, -NR20 21 represents a 3- to 8-membered saturated or unsaturated monocyclic heterocycle ring, optionally containing another heteroatom selected from oxygen, nitrogen and sulfur, R22 and R23, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, R22 and R23, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl radicals, R24 and R2s, which may be identical or different, represent a hydrogen, alkyl, -COOalk, cycloalkyl, alkylcycloalkyl, -alk-O-alk or hydroxyalkyl radical or, alternatively, R24 and R25, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen and being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo, hydroxyalkyl, -alk-O-alk or -CO-NH2 radicals, R26 and R27, which may be identical or different, represent a hydrogen, alkyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, -alk-COOalk, -alk-Ar, -alk-Het, Het or -alk-N(alk)2 radical, or, alternatively, R26 and R27, taken together with the nitrogen atom to which they are attached, may form a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle, optionally containing one or more other heteroatoms selected from oxygen, sulfur and nitrogen, and optionally substituted with one or more halogen, alkyl or alkoxy radicals, R28 represents a -CH2 -alk, benzyl, -S02 alk, -CONHalk, -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO-(CH2)nOH radical, n is equal to 1 , 2 or 3, R29 and R30, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, R29 and R30, taken together with the nitrogen atom to which they are attached, form a 3- to 10-membered saturated mono- or bicyclic heterocycle, optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, and being optionally substituted with one or more alkyl radicals, • R31 and R32, which may be identical or different, represent a hydrogen, alkyl, Ar or -alk-Ar radical or, alternatively, R31 and R32, taken together with the nitrogen atom to which they are attached, form a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and pipendinyl, • alk represents an alkyl or alkylene radical, • Ar represents a phenyl or naphthyl radical optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, -CO-alk, cyano, -COOH, -COOalk, -CONR22 R23, -CO-NH-NR2 R25, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, hydroxyalkyl, -alk-NR24 R25, -NR24 R25, alkylthioalkyl, formyl, hydroxyl, CF3, OCF3, Het, -O-alk-NH-cycloalkyl and S02 NH2 radicals, • Het represents a 3- to 10-membered unsaturated or saturated mono- or bicyclic heterocycle containing one or more heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more halogen, alkyl, alkoxy, alkoxycarbonyl, -CONR22 R23, hydroxyl, hydroxyalkyl, oxo or S02 NH2 radicals, • the alkyl, alkylene and alkoxy radicals are in the form of a straight or branched chain and contain 1 to 6 carbon atoms, the cycloalkyl radicals contain 3 to 10 carbon atoms and the heterocycloalkyl and heterocyclenyl radicals contain 3 to 10 carbon atoms, • their optical isomers and their salts with an inorganic or organic acid.
2. A compound according to claim 1 , wherein Het is selected from benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, 2,3-dihydrobenzofuryl, 2,3-dihydrobenzothienyl, furyl, indolinyl, indolyl, isochromanyl, isoquinolyl, piperidyl, pyrrolyl, pyridyl, pyrimidinyl, quinolyl, 1 ,2,3,4-tetrahydroisoquinolyl, 1 ,2,3,4-tetrahydroquinolyl, thiazolyl and thienyl.
3. A compound of formula (I) according to claim 1 , wherein R16 and R17 together with the nitrogen atom to which they are attached form a heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl and piperazinyl rings.
4. A compound of formula (I) according to claim 1 , wherein R18 and Ri9 together with the nitrogen atoms to which they are attached form a heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl and piperazinyl rings.
5. A compound of formula (I) according to claim 1 , wherein the heterocycle formed by NR2o R21 is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl, piperazinyl and imidazolyl rings.
6. A compound of formula (I) according to claim 1 , wherein f½ and R23 together with the nitrogen atom to which they are attached form a heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl and piperazinyl rings.
7. A compound of formula (I) according to claim 1 , wherein R2 and R25 together with the nitrogen atom to which they are attached form a heterocycle selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl rings.
8. A compound of formula (I) according to claim 1 , wherein R26 and R27 together with the nitrogen atom to which they are attached form a heterocyle selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl rings.
9. A compound of formula (I) according to claim 1 , wherein R2B and R30 together with the nitrogen atom to which they are attached form a heterocycleselected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiamorpholinyl or piperazinyl rings.
10. A compound of formula (I) according to claim 1 , wherein: • R represents a CR-i R2 radical, either Ri represents a hydrogen atom and R2 represents a -C(R8)(Rii)(Ri2) or C(R8)(R9)(Rio) radical, or represents an alkyl radical and R2 represents a -C(R8)(Ru)(R12) radical, • R3 and R4, which may be identical or different, represent either a phenyl or indenyl which is unsubstituted or substituted with one or more halogen, alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, -CONR22 R23, hydroxyalkyl or -alk-NR24 R25 radicals; or a heteroaromatic ring selected from the pyridyl, pyrimidinyl, thiazolyl and thienyl rings, said heteroaromatic ring being unsubstituted or substituted with one or more halogen, alkyl, 151428/2 - 283 - alkoxy, hydroxyl, trifluoromethyl, trifluoromethoxy, cyano, -CONR22 R33, -alk-NR2 R25 or hydroxyalkyl radicals, • R8 represents a hydrogen atom, • R9 represents a -CO-NR26 R27, -COOalk, -CH2 OH, -NH-CO-NH-alk, -CH2 -NHR28 or -NHCOOalk radical, • R 0 represents an Ar or Het radical, • R represents a -S02 -alk, -S02 -Ar or -S02 -Het radical, • R12 represents a hydrogen, Ar or Het radical, • R22 and R23, which may be identical or different, represent a hydrogen or alkyl radical or, alternatively, R22 and R23, together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated mono- or bicyclic heterocycle, said heterocycle optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, said heterocycle further being optionally substituted with one or more alkyl radicals, • R2 and R25, which are identical or different, represent a hydrogen, alkyl, cycloalkyl, alkylcycloalkyl or hydroxyalkyl radical or, alternatively, R24 and R25 together with the nitrogen atom to which they are attached form a 3- to 10-membered saturated or unsaturated mono- or bicyclic heterocycle, said heterocycle optionally containing another heteroatom selected from oxygen, sulfur and nitrogen, said heterocycle further being optionally substituted with one or more alkyl, -COalk, -COOalk, -CO-NHalk, -CS-NHalk, oxo or -CO-NH2 radicals, • Ar represents a phenyl or naphthyl radical optionally substituted with 1 or 2 subtituents selected from a halogen, alkyl, alkoxy, -CO-alk, cyano, -COOalk, -CONR22 R23, alkysulfonyl, hydroxyalkyl, -alk-NR24 R25, -NR24 R25, hydroxyl, CF3, -O-alk-NH-cycloalkyl and S02 NH2 radicals, • Het represents a benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, isoquinolyl, pyrrolyl, pyridyl, quinolyl, 1 ,2,3,4-tetrahydroisoquinolyl, 1 ,2,3,4-tetrahydroquinolyl, thiazolyl or thienyl ring, their optical isomers and their salts with an inorganic or organic acid.
11. A compound of claim 1 selected from the group consisting of: 151428/2 - 284 - • (RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azetid • (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(m^ • (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(3,5-difluorophenyl)(methylsulfonyl)methyl]azeti^ • (RS)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]azetidine, • (R)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]azetidine, • (S)-1-[bis(4-chlorophenyl)methyl)]-3-[(pyrid-3-yl)(methylsulfonyl)methyl]azetidine, • (RS)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-diflourophenyl)methylsulfonylmethyl]azetidi • (R)-1-[bis(3-fluorophenyl)methyl]-3-[(3,5-diflourophenyl)methylsulfonylmethyl]azetidine • (S)-1 -[bis(3-fluorophenyl)methyl]-3-[(3,5-diflourophenyl)methylsulfonylmethyl]azetidin • 1 -[bis(4-chlorophenyl)methyl]-3-(RS)-{[3-azetidin-1-yl-phenyl]methylsulfonylmethyl^ • 1-[bis(4-chlorophenyl)methyl]-3-(R)-{[3-azetidin-1-yl-phenyl]methylsulfonylm • 1 -[bis(4-chlorophenyl)methyl]-3-(S)-{[3-azetidin-1-yl-phenyl]m^ • (RS)-1-[3({1 -[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidine, • (R)-1-[3({1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidine, • (S)-1-[3({1-[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]pyrrolidin • (RS)-N-[3({1 -[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N- methylamine, • (R)-N-[3({1 -[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N- methylamine.and • (S)-N-[3({1 -[bis (4-chlorophenyl)methyl]azetidin-3-yl}methylsulfonylmethyl)phenyl]-N- methylamine, as well as their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
12. A compound of claim 1 selected from the group consisting of: • (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5- bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine, • (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5- bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine, 151428/2 - 285 - (S)- 1 -[bis(4-chlorophenyl)methyl]-3-[(3, 5-bistrifluoromethylphenyl)methylsulfonylmethyl]azetidine, 1-[bis(4-chlorophenyl)methyl]-3-(phenylsulfonylmethyl)azetidine, (RS)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluoro-phenyl) methylsulfonylmethyl]-3-methylazetidine, (R)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-3-methylazetidine, (S)-1-[bis(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]-3-methylazetidine, (RS)-2-{1 -[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (R)-2-{1-[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (S)-2-{1 -[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-cyclohexylacetamide, (RS)-2-{1-[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (R)-2-{1 -[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamide, (S)-2-{1-[bis(4-chlorophenyl)methyl]azeditin-3-yl}-2-(3,5-difluorophenyl)-N-isobutylacetamid (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (R)-2-{1 -[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-cyclopropylmethylacetamide, (S)-2-{1-bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difiuorophenyl)-N-cyclopropylmethylacetamide, (RS)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N-isopropylacetamide, and 151428/2 - 286 - • (R)-2-{1 -[bis(4 hlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N- isopropylacetamide, as well as their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
13. A compound of claim 1 selected from the group consisting of: • (S)-2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-2-(3,5-difluorophenyl)-N- isopropylacetamide, • (RS)-1-[bis(4-chlorophenyl)methyl]-3-[1 -(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine, • (R)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine, • (S)-1-[bis(4-chlorophenyl)methyl]-3-[1-(3,5-difluorophenyl)-1-methylsulfonylethyl]azetidine, • (RS)-1 -[bis(4-fluorophenyl)methyl]-3-(3,5-difluorophenyl)methylsulfonylethyl]azetidine, • (R)-1 -[bis(4-fluorophenyl)methyl]-3-(3,5-difluorophenyl)methylsulfonylethyl]azetidine, • (S)-1-[bis(4-fluorophenyl)methyl]-3-(3,5-difluorophenyl)methylsulfonylethyl]azetidine, • (RS)-{1 -[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]- azetidine, • (SS)-{1 -[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]- azetidine, • (RR)-{1-t(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5-difluorophenyl)methylsulfonylmethyl]- azetidine, • (SR)-{1 -[(3-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, • (RS)-{1 -[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, • (SS)-{1 -[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, • (RR)-{1 -[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, 151428/2 - 287 - • (SR)-{1-[(4-pyridyl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, • (RS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1- yl}methyl)pyrimidine, • (SR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1- yl}methyl)pyrimidine, • (RR)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1- yl}methyl)pyrimidine, • (SS)-5-((4-chlorophenyl)-{3-[(3,5-difluorophenyl)-methylsulfonylmethyl]azetidin-1- yl}methyl)pyrimidine, • (SS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5- diflourophenyl)methylsulfonylmethyl]azetidine, • (RR)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5- diflourophenyl)methylsulfonylmethyl]azetidine, • (RS)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5- diflourophenyl)methylsulfonylmethyl]azetidine, and • (SR)-{1-[(2-chloropyrid-5-yl)-(4-chlorophenyl)methyl]-3-[(3,5- difluorophenyl)methylsulfonylmethyl]azetidine, as well as their optical isomers and their pharmaceutically acceptable salts with an inorganic or organic acid.
14. A pharmaceutical composition containing, as an active ingredient, at least one compound of claim 1.
15. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical, in which represents hydrogen and R2 represents a C(R8) (Rn) (R12) radical in which R8 represents hydrogen, R represents a -S02 -Ar, -S02 -Het or -S02 alk radical and R 2 represents a hydrogen, Ar or Het radical, this process comprising reducing a derivative of formula: 151428/2 - 288 - in which Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen, Ar, Het or alkyl radical, Ar and Het having the same meanings as in claim 1 , isolating the product and, optionally, converting it to a salt with an inorganic or organic acid.
16. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR^ R2 radical, in which R, represents hydrogen and R2 represents a C(R8) (R ) (R12) radical in which R8 represents hydrogen, R^ represents an -S02 -Ar, -S02 -Het or -S02 alk radical, and R 2 represents a hydrogen, Ar or Het radical, wherein a compound of formula R3 CH(Br)R is reacted with a compound of formula: in which Ra represents an alkyl, Het or Ar radical and Rb represents a hydrogen, Ar, Het or alkyl radical, Ar and Het having the same meanings as in claim 1 , the product is isolated and is optionally converted to a salt with an inorganic or organic acid.
17. Process for preparing a compound of formula (I) according to claim 1 wherein R represents a C=C(R5)S02 R6 or C=C(R7)S02 alk radical, this process comprising dehydrating a compound of formula: 151428/4 - 289 - in which either Ra represents a Ar or Het radical and Rb represents a hydrogen or alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted with a -CSO-phenyl, Rc represents a hydrogen atom or an acetyl radical, R3, R*, Ar and Het have the same meanings as in claim 1, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
18. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a C=C(R5)S02 R6 or C=C(R7)S02 alk radical, this process comprising reacting R3 CH(Br)R with a compound of formula: in which either Ra represents a Ar or Het radical and Rb represents a hydrogen or alkyl radical, or Ra represents an alkyl radical and Rb represents a cycloalkyl, heterocycloalkyl or heterocyclenyl radical optionally substituted with a -CSO-phenyl radical, Rc represents a hydrogen or acetyl radial, R3, R4, Ar and Het have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
19. A process for preparing compound bf formula (I) according to claim 1 wherein R is a CRi R2 radical in which R, represents a hydrogen atom and R2 represents a C(RB) (R9) (R10) radical in which R8 represents a hydrogen atom, R9 represents a -CO- NR26R27 radical and Ri0 represents an Ar or Het radical, this process comprising reacting an amine HNR26 R27 in which R26 and R2 have the same meanings as in claim 1 , with an acid of formula: 151428/5 - 290 - in which R3, R4 and R 0 have the same meanings as in claim 1 , isolating the product and optionally converting it to a salt with an inorganic or organic acid.
20. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi 2 radical in which Ri represents a hydrogen atom and R2 represents a C(R8) (Rg) (R-io) radical in which R8 represents a hydrogen atom, R9 represents a -COOH radical and R 0 represents an Ar or Het radical, this process comprising hydrolyzing the corresponding ester of formula: in which R3, R4 and R10 have the same meanings as in claim 1 and alk represents an alkyl radical (1-6 C in the form of a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
21. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which Ri represents a hydrogen atom and R2 represents a C(RB) (R9) (R10) radical in which R8 represents a hydrogen atom, R9 represents a -COOalk or -CH2 OH radical and R10 represents an Ar or Het radical, this process comprising reducing a compound of formula: in which R3, R and R10 have the same meanings as in claim 1 and alk represents a straight or branched chain alkyl radical having 1 -6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
22. A process for preparing compound of formula (I) according to claim 1 wherein R represents a 151428/2 - 291 - CRt R2 radical in which R, represents a hydrogen atom and R2 represents a C(R8) (R9) (R10) radical in which R8 represents a hydrogen atom, R9 represents a -NHCOOalk radical and R10 represents an Ar or Het radical, this process comprising reacting an alcohol alkOH, wherein alk represents a straight or branched chain alkyl radical having 1-6 carbon atoms, with a compound of formula: in which R3, R and Ri, have the same meanings as in claim 1 , isolating the product and optionally converting it to a salt with an inorganic or organic acid.
23. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR, R2 radical in which Ri represents a hydrogen atom and R2 represents a C(R8) (Rg) (Rio) radical in which R8 represents a hydrogen atom, R9 represents a -NH-CO-NH-alk radical and R10 represents an Ar or Het radical, this process comprising reacting an amine, alkNH2, wherein alk represents a straight or branched chained alkyl radical having 1-6 carbon atoms with a compound of formula: in which R3, R and Rio have the same meanings as in formula (I), isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
24. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -C(R8) (Rg) (Rio) radical, R8 is a 151428/3 - 292 - hydrogen atom, R9 is a -CH2 -NHR2e radical, R2e represents a -CH2 -alk or benzyl radical and R10 represents an Ar or Het radical, this process comprising reacting a derivative of formula: in which R3, R4 and R10 have the same meanings as in claim 1 , with an aldehyde, RdCHO, wherein Rd represents a -CH2 -alk or benzyl radical and alk represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
25. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which Ri is a hydrogen atom and R2 represents a -C(R8) (R9) (R10) radical, R8 is a hydrogen atom, R9 is a -CH2 -NHR2B radical, R28 represents a -S02 alk radical and R10 represents an Ar or Het radical, this process comprising reacting an amine of formula: in which R3, R and Rm have the same meanings as in claim 1 , with a compound, CIS02 Re, wherein Re represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
26. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR! R2 radical in which R, is a hydrogen atom and R2 represents a -C(R8) (Rg) (R10) radical, R8 is a hydrogen atom, R9 is a -CH2 -NHR28 radical, R28 represents a -CO-NHalk radical and R10 represents an Ar or Het radical, this process comprising reacting a compound of formula: 151428/3 - 293 - in which R3, R and R10 have the same meanings as in claim 1 , with a compound, RfNCO, wherein Rf represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
27. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR R2 radical in which is a hydrogen atom and R2 represents a -C(R8) (R9) (R10) radical, R8 is a hydrogen atom, R9 is a -CHZ -NHR2B radical, R2e represents a -COalk, cycloalkylalkylcarbonyl, cycloalkylcarbonyl or -CO-(CH2)nOH radical and R10 represents an Ar or Het radical, this process comprising reacting a compound of formula: in which R3, R4 and R10 have the same meanings as in claim 1 , with an acid, HOOCRg, wherein Rg represents a straight or branched chain alkyl radical having 1-6 carbon atoms, a cycloalkyialkyi radical wherein the cycloalkyl portion has 3-10 carbon atoms and the alkyl portion is a straight or branched chain having 1-6 carbon atoms, a cycloalkyl radical having 3-10 carbon atoms, or -(CH2)n OH radical and n is equal to 1 , 2 or 3, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
28. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which Ri is a hydrogen atom and R2 is a -CONR13 R14 radical, this process 151428/2 294 comprising reacting an amine, HNR13 R14, in which R-|3 and R-|4 have the same meanings as in claim 1 , with a compound of formula: R3 R4 in which R3 and R4 have the same meanings as in formula (I), isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
29. A process for preparing a compound of formula (I) according to claim 1 for which R represents a CRi R2 radical in which R- is a hydrogen atom and R2 is a -CH2 -CONR13 R14 radical, this process comprising reacting an amine, HNR-|3 R 4, in which R13 and R have the same meanings as in claim 1 , with a compound of formula: in which R3 and R4 have the same meanings as in claim 1 , isolating the product and optionally converting it to a salt with an inorganic or organic acid.
30. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical, in which Ri is a hydrogen atom and R2 is a -CH2 -CONR13 R14 radical, this process comprising reducing a compound of formula: R4- 151428/3 295 in which R3, R4, R13 and RM have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
31. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which Ri is a hydrogen atom and R2 represents a radical -SOR6, this process comprising oxidizing a compound of formula: R3 in which R3, R and R6 have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
32. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -S02 R6 radical, this process comprising oxidizing a compound of formula: R3 in which R3, R4 and R6 have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
33. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR R2 radical in which Rv is a hydrogen atom and R2 represents a -COR6 or -CO-cycloalkyl radical, this process comprising reacting a compound of formula: CON(C¾)OCH3 151428/3 - 296 - in which R3 and R* have the same meanings as in claim 1 , with a compound, RhMgBr, wherein Rh has the same meanings as R6 in claim 1 or, alternatively, represents a cycloalkyl radical having 3-10 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
34. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -C(OH)(Re)(R12) radical, this process comprising reacting a compound of formula: in which R3, R and R6 have the same meanings as in claim 1 , with a compound, RiMgBr, wherein Ri has the same meanings as R12 in claim 1 or, alternatively, represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
35. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R is a hydrogen atom and R2 represents a -C(=NOalk)R6 or -C(=NO-CH2 -CH=CH2)R6 radical, this process comprising reacting a compound of formula: in which R3 and R4 have the same meanings as in claim 1 , with a compound RjONH2 wherein Rj represents a straight or branched chain alkyl radical having 1-6 carbon atoms or -CH2-CH=CH2, 151428/2 - 297 - isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
36. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRT R2 radical in which R, is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical wherein R3i and R32 represent hydrogen atoms, this process comprising reacting aqueous ammonia with a compound of formula: in which R3, R4 and R6 have the same meanings as in claim 1 and Ms represents a methylsulfonyloxy radical, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
37. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR† R2 radical in which R^ is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical, R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical, this process comprising reacting a halide, HalR3i , with a corresponding compound of formula (I) wherein R represents a CR^ R2 radical in which R, is a hydrogen atom and R2 represents a -CH(R6)NR3 R32, radical, R3i and R32 are hydrogen atoms, isolating the product and, optionally converting it to a salt with an inorganic or organic acid.
38. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R, is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical, R3 and R32 are alkyl, Ar or -alk-Ar radicals, this process comprising reacting a halide, HalR32, with a corresponding compound of formula (I) wherein R represents a CRi R2 radical in which R^ is a hydrogen atom and R2 represents a -CH(R6)NR3 R32 radical, R3 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
39. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R^ is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical wherein R31 is a hydrogen atom and R32 is an alkyl or alkyl-Ar radical wherein the alkyl portion is a straight or 151428/2 - 298 - branced chain of 1 -6 carbon atoms, this process comprising reacting an aldehyde, RaCHO, wherein Ra is an alkyl or -alk-Ar radical, with a corresponding compound of formula (I) wherein R represents a CR R2 radical in which R^ is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical, R3 and R32 being hydrogen atoms, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
40. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R-i is a hydrogen atom and R2 represents a -CH(R6)NR3i R32 radical, R31 is an alkyl, Ar or -alk-Ar radical and R32 is a (2-6 C) alkyl or -(2-6 C)alk-Ar radical, this process comprising reacting an aldehyde, RaCHO, wherein Ra is an alkyl or -alk-Ar radical with a corresponding compound of formula (I) wherein R represents a CR! R2 radical in which R, is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical, wherein R31 is a hydrogen atom and R32 is an alkyl, Ar or -alk-Ar radical, isolating the product isolated and optionally converting it to a salt with an inorganic or organic acid.
41. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRT R2 radical in which Ri is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical, R3 and R32, together with the nitrogen atom to which they are attached, form a heterocycle selected from aziridinyl, azetidinyl, pyrrolidinyl and piperidinyl, this process comprising reacting a dihalide, Hal-(2-5C)alk-Hal, with a corresponding compound of formula (I) wherein R represents a CRi R2 radical in which Ri is a hydrogen atom and R2 represents a -CH(R6)NR31 R32 radical wherein R31 and R32 are hydrogen atoms, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
42. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R-i is a hydrogen atom and R2 represents a -CH(R6)NHS02 alk radical, this process comprising reacting a compound of formula: 151428/2 - 299 - in which R3, R4 and R6 have the same meanings as in claim 1 , with a compound, CIS02 alk, wherein alk represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product and optionally converting it to a salt with an inorganic or organic acid.
43. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -CH(R6)NHCONHalk radical, this process comprising reacting a compound of formula: in which R3, R4 and R6 have the same meanings as in claim 1 , with a compound, alkNCO, wherein alk represents an alkyl radical (1-6 C in the form of a straight or branched chain), the product isolated and optionally converted to a salt with an inorganic or organic acid.
44. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -CH(R6)NHCOR3i radical, this process comprising reacting a compound of formula: in which R3, R4 and R6 have the same meanings as in claim 1 , with a compound, R31 COOH, wherein R3i has the same meaning as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid. 151428/3 - 300 -
45. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which is a hydrogen atom and R2 represents a -CH2 -CORe radical, this process comprising reacting a compound of formula: in which R3 and R4 have the same meanings as in claim 1 , with a compound of formula R6 MgBr wherein R6 has the same meaning as in claim 1 , isolating the product and optionally converting it to a salt with an inorganic or organic acid.
46. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R, is a hydrogen atom and R2 represents a -CH2 -CH(R6)-NR31 R32 radical, this process comprising reacting a compound of formula: in which R3 and R4 have the same meanings as in claim 1 , with a compound of formula HNR3 R32 wherein R31 and R32 have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
47. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a radical CR, R2 in which R^ is a hydrogen atom and R2 represents a -CH2 -C(=NOalk)R6 radical, this process comprising reacting a compound of formula: 151428/3 - 301 - in which R3 and R4 have the same meanings as in claim 1 , with a compound of formula alkONH2 wherein alk represents a straight or branched chain alkyi radical having 1-6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
48. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R^ represents a cyano radical and R2 represents a -C(RB) (RH) (RI2) radical in which RB is a hydrogen atom, this process comprising reacting a compound of formula: in which R3l R , Rn and R-|2 have the same meanings as in claim 1 , with sodium cyanide, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
49. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR, R2 radical in which Ri represents a -S-alk-NR16 R17 radical and R2 represents a -C(RB) (Rn) (R12) radical in which R8 is a hydrogen atom, this process comprising reacting a compound of formula: in which R3, R , R and Ri2 have the same meanings as in claim 1 , with a compound, HS-alk-NR16 R17, wherein alk represents a straight or branched chain alkyi radical having 1-6 carbon atoms and R 6 and Rn have the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid. 151428/2 - 302 -
50. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R, represents a -NHR15 radical and R2 represents a -C(R8) (Rn) (Ri2) radical in which R8 is a hydrogen atom, this process comprising reacting a compound of formula: in which R3, R , Rn and R12 have the same meanings as in claim 1 , with a compound, H2 NR15, wherein R15 has the same meanings as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
51. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR-i R2 radical in which represents an alkyl radical and R2 represents a -C(R8) (Rn) (Ri2) radical in which R8 is a hydrogen atom, this process comprising reacting a compound of formula: in which R3, R4, Rn and R12 have the same meanings as in claim 1 , with a compound, alkMHal, wherein alk represents a straight or branched chain alkyl radical having 1-6 carbon atoms and M represents a metal, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
52. A process for preparing a compound of formula (I) according to claim 1 , wherein R represents a CRi R2 radical in which represents a -NR20 R2i radical and R2 represents a -C(R8) (Rn) (R12) radical in which R8 is a hydrogen atom, this process comprising reacting a compound of formula: 151428/3 - 303 - in which R3, R , RH and R¾2 have the same meanings as in claim 1 , with a compound, HNR2o R∑i, wherein NR20 21 has the same meaning as in claim 1 , isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
53. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which Ri represents an -CH2-NR18 R19 radical, wherein R18 and R19 represent hydrogen atoms, this process comprising reducing a corresponding compound of formula (I) wherein Ri represents a cyano radical, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
54. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R represents an -CH2-NR18 R19 radical, R18 represents a hydrogen atom and Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02 alk, -CO-NHalk or -COOaik radical, this process comprising reacting a halide, HalRi9 , wherein Hal represents a halogen, with a corresponding compound of formula (I) wherein R represents a CRi R2 radical in which Ri represents an -CH2-NR18 R19 radical, R1B and R19 each represent a hydrogen atom, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
55. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which R, represents an -ΟΗΣ-ΝΡΊ 8 Ri9 radical, Ri8 represents an alkyl radical and Rig represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02 alk, -CO-NHalk or -COOaik radical, this process comprising reacting an alkylhaiide with a corresponding compound of formula (I) wherein R represents a CR R2 radical in which Ri represents an -CH2-NR18 R19 radical, RIB represents a hydrogen atom, and RiB represents an alkyl, cycloalkyl, cycloalkylalkyl, cycloalkylcarbonyl, -S02 alk, -CO-NHalk or -COOaik radical, isolating the product, and optionally converting it to a salt with an inorganic or organic acid. 151428/3 - 304 -
56. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CRi R2 radical in which either (A) Ri represents a hydrogen atom and R2 represents a -C(R8) (Rg) (R10) radical or (B)-C(R8) (Rnj (Ri2>, or represents an alkyl, NH-R15, cyano, -S-alk-NR16 R17, -CH2-NRi8 Ri9 or -NR20 R2i radical and R2 represents a -C(R8) (Rn) (Ri2) radical and R8 represents an alkyl radical, this process comprising alkylating a corresponding compound of formula (I) wherein R8 is a hydrogen atom, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
57. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a radical C=C(R7)S02 alk, this process comprising oxidizing a derivative of formula: in which R3 * and R have the same meanings as in claim 1 and alk represents a straight or branched chain alkyl radical having 1-6 carbon atoms, isolating the product, and optionally converting it to a salt with an inorganic or organic acid.
58. A process for preparing a compound of formula (I) according to claim 1 wherein R represents a CR-i R2 radical in which R-\ is a hydrogen atom and R2 represents a -CH(R6)NR3i R32 radical, R31 is a hydrogen atom and R32 is an alkyl radical, this process comprising reacting a corresponding compound of formula (I) wherein R represents a CR^ R2 radical in which R, is a hydrogen atom and R2 represents a -CO-R6 radical with an amine, HNR3 R32, wherein R3 is a hydrogen atom and R32 is an alkyl radical, isolating the product, and optionally converting it to a salt with an inorganic or organic acid. It*** six WN*lb LUZZATTO & LUZZATTO
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