AU645585B2 - N-sulfonylindoline derivatives, their preparation and the pharmaceutical compositions in which they are present - Google Patents

Abstract

Compounds of formula: <IMAGE> in which - R1 denotes a halogen atom, a C1-C4 alkyl or alkoxy, a hydroxyl or a benzyloxy, cyano, trifluoromethyl, nitro or amino group; - R2 denotes a C1-C6 alkyl, a C3-C7 cycloalkyl, a C5-C7 cycloalkene, a phenyl, unsubstituted or mono- or polysubstituted by a C1-C4 alkyl or alkoxy, a halogen or a trifluoromethyl, nitro or amino group; - R3 denotes a hydrogen atom or a C1-C4 alkyl; - R4 denotes a carboxyl group, a C1-C6 alkoxycarbonyl group, a benzyloxycarbonyl group or a carboxamide group of formula CONR6R7; - R5 denotes a C1-C4 alkyl, 1-naphthyl, 2-naphthyl, 5-dimethylamino-1-naphthyl, phenyl, unsubstituted or substituted by one or more substituents chosen from a halogen, a C1-C4 alkyl, a trifluoromethyl, nitro, amino group free or substituted by one or 2 C1-C4 alkyls, a hydroxyl, a C1-C4 alkoxy, a C1-C4 alkenoxy, a C1-C4 alkylthio or a trifluoromethoxy, benzyloxy, cyano, carboxyl, C1-C4 alkoxycarbonyl, carbamoyl or C1-C4 alkylamido group or, when m = 0, R5 may denote a group: <IMAGE> - each of R6 and R7 independently denotes hydrogen, a C1-C6 alkyl, a phenylalkyl in which the alkyl is C1-C4 or R6 and R7 together form a -(CH2)p- group; - n denotes 0, 1 or 2; - m denotes 0, 1 or 2; - p denotes 4, 5 or 6; and their optional salts. These compounds have an affinity for the vasopressin and ocytocin receptors.

Description

645585

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sanofi ADDRESS FOR SERVICE: DAVIES COLLISON S* Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

S**T

INVENTION TITLE: N-Sulfonylindoline derivatives, their compositions in which they are present preparation and the pharmaceutical a 06 S. The following statement is a full description of this invention, of performing it known to me/us:including the best method 1A- The present invention relates to N-sulfonylindoline derivatives, to their preparation and to the compositions in which they are-present.

US patent 3 838 167 describes some N-sulfonylindole derivatives of the formula

R'

1 I COR'4 1 0

N

I

S02R' 3 s0o 555 15 in which 0 0 is hydrogen, an alkyl or a substituted or unsubstituted phenyl; is a halogen, an alkyl, an alkoxy, a nitro or trifluoromethyl; 20 R' 3 is an alkyl, a phenyl or an alkylphenyl; 4

R'

4 is an alkyl, a substituted or unsubstituted phenyl, an alkoxy or a phenoxy; and n' 0, 1 or 2.

.50 These compounds 1 are synthesis intermediates for the preparation of indole derivatives active on the central nervous system, said derivatives having the formula R'i 2)n

LCOR'

2 in which R' is an alkyl, a subsr.tuted or unsubstituted phenyl or a hydroxyl.

The N-sulfonylindoline derivatives according to the present invention have an affinity for the vasopressin and ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and its effect in the regulation of the arterial pressure. It stimulates several types of receptors V3, Vm, Vb and thus exerts cardiovascular, central, hepatic, antidiuretic and aggregating effects. Vasopressin receptor antagonists can affect the regulation of the central and peripheral circulation, especially the coronary, renal and gastric circulation, as well as the metabolism of water and the 15 release of adrenocorticotrophic hormone (ACTH). The **asopressin receptors, like the ocytocin receptors, are also found on the smooth muscle of the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on the S 20 myoepithelial cells of the mammary gland and in the 0 central nervous system (Presse Mddicale, 1987, 16(10), 481-485, J. Lab. Clin. Med., 1989, 114(6), 617-632, ard Pharmacol. Rev., 1991, 41(1), 73-108).

Thus the compounds according to the invention are useful especially in the treatment of complaints of the central nervous system, the cardiovascular syste S and the gastric sphere in humans and animals.

The present invention relates to compounds of the formula 3 (Ri)n R3 N R4 1

SO

2

(I)

(CH2)m

RS

in which R, is a halogen atom, a alkyl, a hydroxyl, a C -C 4 alkoxy, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; 15 R, is a C 1 alkyl, a C 3 cycloalkyl, a C,-C, cycloalkene or a phenyl which is unsubstituted or a.

monosubstituted or polysubstituted by a C.-C 4 alkyl, a C 1

-C

4 alkoxy, a halogen, a trifluoromethyl group, a nitro group or an amino group; 20 R. is a hydrogen atom or a C-C, alkyl;

R

4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is a benzyloxycarbonyl group or a carboxamide group of the formula CONRR,; Rg is a C 1

-C

4 alkyl; a 1-naphthyl; a 2-naphthyl; a dimethylamino-l-naphthyl or a phenyl which is unsubt stituted or substituted by one or more substituents selected from a halogen atom; a C 1 alkyl; a trifluoromethyl group; a nitro group; an amino group which is free or substituted by one or 2 CX-C 4 alkyls; a hydroxyl; a C.-C 4 alkoxy; a C 1

-C

4 alkenoxy; a C -C 4 alkylthio; a trifluoromethoxy group; a benzyloxy group; a cyano group; a carboxyl group; a C,-

C

4 alkoxycarbonyl group; a carbamoyl group or a C -C 4 alkylamido group, or, when m 0, R 5 can be a group c

M

1p 4

R

6 and R, are each independently hydrogen, a C -C, alkyl or a phenylalkyl in which the alkyl is C 1

-C

4 or R. and R 7 together form a group n is 0, 1 or 2; m is 0, 1 or 2; and p is 4, 5 or 6; *and their salts, where appropriate.

The compounds exhibit cis-trans isomerism around the 2,3 bond of the indoline. The different isomers form an integral part of the invention.

15 By convention, the compounds in which R= and R 4 are on the same side of the ring are called the cis isomers.

By convention, the compounds in which R 2 and R 4 are on opposite sides of the ring are called the 20 trans isomers.

C d .R2

(R

1 )n R4 N "'R3

(I)

S02 C (CH2)m

I

cis isomer 1 I 5 R2 0 (Ri)n R3 N "R

(I)

soz

S

0 (CH2)m trans isomer Moreover, the compounds according to the invention have 2 asymmetric carbon atoms. The optical isoo* mers of the compounds form part of the invention.

C, In the present description and in the claims .t 15 which follow, halogen is understood as meaning a fluorine, chlorine, bromine or iodine atom; alkyl group is understood as meaning linear or branched hydrocarbon groups.

Preferred compounds according to the inven- *t 20 tion are those in which at least one of the following conditions is satisfied: R, is a chlorine or bromine atom or a methoxy group and n 4;

R

2 is a chlorophenyl, a methoxyphenyl or a cyclohexyl; R, is hydrogen; S.t R 4 is an alkoxycarbonyl in which the alkyl group is

C-C

6 or R 4 is a carboxamide group NR 6 R, in which R 6 and R.

7 are C alkyls; R, is a phenyl substituted in the 3 and 4 positions or in the 2 and 4 positions by a methoxy group, or R, is a phenyl substituted in the 4 position by a methyl group; and m is 0.

The compounds which are in the form of the 6 cis isomers are particularly preferred.

The following abbreviations are used in the description and the Examples: DCM dichioromet AcOEt ethrX acetat MeOH methanol EtOH ethanol ether ethyl ether DMF dimethylformamide TF tetrahydrofuran DMSC dimethyl sulfoxide S DIPEA diisoprcopylethylamine DDU 1,8-diazabicyclo[5.4.0 )undec-7-ene TBD l,5,7-triazabicycloC4.4.Oldec-5-ene *fee** SS 15 DBN 1,5-diazabicycloC4.3.0]non-5-ene DMAP 4-dimethylaminopyridine DMPU 1,3-dimethyl-2-oxohoxahydropyrimidinone TMEDA tetramethylethylenediamine LDA lithium diisopropylamide HMPA hexamethyiphosphoramide HMDS 1,1,1,3,3,3-hexamethyldisilazane BOP benzotriazolyloxytris imethylaminophos- **phonium hexafluorophosphate M.p. melting point saline solution water saturated with sodium chloride dry ice solid carbon dioxide TLC thin layer chromatograiphy HPILC high pressure liquid chromatography NMAI nuclear magnetic resolnance s singlet m multiplet sb broad singlet d doublet hydrochloric water: dilute hydrochloric acid, 7 about 1 N NaH dispersion of sodium hydride in mineral oil (Janssen Chemica) Me methyl Et ethyl Ph phenyl RT room temperature The present invention further relates to the method of preparing the compounds This method comprises a) reacting a sulfonyl derivative of the formula Hal-SO-2(H,).m-R. (III) in which Hal is a halogen, preferably chlorine or bromine, and R. is as defined above for with a 2aminophenone derivative of the formula 20

CO-R

2

"(R

NH2 in which R, and n are as defined above for b) treating the resulting compound of the formula CO-R2 (R)n NH I (IV) S02

(CH

2 )m -8 with a halogenated derivative of the formula Hal' CHI R in which HAall is a halogen, preferably bromine, and R, and R 4 are as defined above for c) cyclizing the resulting compound of the formul a 0*0 0 COR 2 /R3 (RI)n N-CU" 0:001

(VI)

.90SO6 2 R4 0:004:(CH2) m 151 in a basic medium in order to prepare the compound (I) *Ogg&:according to the invention; and 20 d) separating the g: and trn isomers of the ,61:4 :compound if appropriate.

The 2-amirnophenone derivatives (II) are kn -wn prepared by known methods such as those described by A.K. Singh et al. Synth. Co~iun. 1986, 1&4) 485, and G.N. Walker, J. Org. Chem., 1962, 1929.

06000 0The halogenosulfony. derivatives (III) arp 0 known or prepared by known methods. Thus, for example, 4-dimethylaminophenylsulfonyl chloride is prepared according to C-ri. SUKENIK et al., J. Axipr. Chem. Soc., 1977, p.2, 851-858; p-benzyloxysulfonyl chloride is prepared according to European patent application 229 566.

An alkoxysulfonyl chloride is prepared from a sodium alkoxysulfonate, which is itself prepared by reacting an alkyl halide with sodium hydroxyphenylsulfonate. The 2-amino-2-trifluoromethylbenzophenones and 9 the other trifluoromethylated derivatives are prepared according to US patent 3 341 592.

2,4-Dimethoxybenzylsulfonyl chloride is prepared according to J. Am. Chem. Soc., 1952, 74, 2008.

The halogenated derivatives are known or prepared by known methods such as those described by A.I. Vogel: A Text Book of Practical Organic Chemistry: Longman, 3rd ed. 1956, p. 383, or G. Kirchner et al., J. Am. Chem. Soc., 1985, 107, 24, 7072.

Step a) of the method is carried out in pyridine by heating at a temperature between room temperature and the boiling point of the solvent for a period of time of between a few hours and a few days. If appropriate, the reaction can be carried out in the 15 presence of dimethyliminopyridine, which is used in a catalytic or stoichiometric amount.

Step b) of the method is carried out between the sulfonamide (IV) and an excess of the halogenated derivative in a solvent suchl as dimethylformamide or 20 iimethyl sulfoxide, under an inert atmosphere, at a

S

temperature of between O'C and room temperature, for a time of between a few hours and 24 hours, in the presence of sodium hydride.

Step c) of the method is closely related to an aldolization reaction: The group CH-R. in the a position of the ester or the amide is deprotonated and the carbonyl group of the phenone then acts like an internal electrophile, resulting in cyclization with the appearance of two asymmetric carbons The reaction can be illustrated by the following scheme: 10 0 11 C R2 0 -N C

I

SQ

2 3 (CH2)m base (solvent) 0 00 0 *0 00 00 0 0@ 0 0 15 S02 CH2)m The principles of the aldol addition reaction have been reviewed by C.H. Heathcock in Asymmetric Synthesis, vol. 3: Stereodifferentiating addition reactions, part B, 111-212, Academic Press, 1984, edited by J.D. Morrison.

It is known that the aldol addition of achiral ester anions (or amide anions) on to achiral bases gives rise to the formation of 2 racemic diastereoiso- 25 mers of p-hydroxyesters (or p-hydroxyamides) in a ratio which depends largely on the experimental conditions used. The following may be mentioned among these conditions: the nature of the inouganic or organic base used, the nature of the cations or counterions, the possible presence of additives in the reaction medium, the solvent, the reaction temperature and the structure of the compound undergoi g this reaction.

If R 4 is a carboxamide group CONRR,, in which

R

6 and R, are as defined above for it is possible to use sodium hydroxide in water, in the presence of a 11 cosolvent, with o. without the addition of a phase transfer catalyst.

This reaction can be carried out using organic bases, for example: tertiary organic bases such as triethylamine, guanidines such as 1,5,7-triazabicyclo[4.4.0dec-5ene, or ami4ines such as 1,8- .iazabicyclo[5.4.0]undec-5-ene or 1,5-diazabicyclo[4.3.0]non-5-ene, in a solvent or a mixture of solvents selected for example from benzene, THF, dichloromethane, methanol and dimethylformamide; the reaction is carried out under an inert atmosphere at between 25 and 110°C; the 0** amount of base used is at least stoichiometric; the w« 15 reaction can also be carried out without a solvent, at the temperature of the bath.

It is also possible to use an alcoholate of a primary, secondary or tertiary alcohol with lithium, sodium, potassium, calcium or magnesium.

20 The alcoholate is used in a catalytic or stoichiometric amount in an anhydrous solvent, for example an alcohol (if appropriate in the presence of a cosolvent such as THF), or else in a stoichijmetric amount o*° in THF, DMF or DMSO, if appropriate in ,.he presence of crown ethers, for example dicyclohexyl-18 crown-6; the t reaction is carried out at between 0° and 80°C. It is 0 also possible to use a base such as sodium hydride, lithium hydride or potassium hydride, in a solvent such as, for example, ethyl ether, THF, benzene or DMF, or else alkali metal amides in a solvent such as aqueous ammonia, ether or toluene, at a temperature of between 0 C and 110'C.

The use of ;tn amide of the type RR'NLi or RR'NMgBr, in which R and R' are monovalent radicals, as a deprotonating agent is a method of forming enolates 12 of esters or amides, which are intermediates in the aldolization reaction; this method has recently been reviewed by R.E. Ireland et al., J. Org. Chem., 1991, 56, 650. The reaction solvent can be benzene, hexane or THF used in anhydrous form under an inert atmosphere. Adjuvants such as LiF, LiCl, LiBr, LiI, LiBu, TMEDA, DMPU, HMPA or a crown ether can be added (M.

Murakate et al., J. Chem. Soc. Chem. Commun., 1990, 1657). The influence of the reaction conditions on the proportion of each of the isomers formed has been studied. By way of example, there may be mentioned the use of lithium diisopropylamide at -78°C in anhydrous THF under an inert atmosphere, or in THF in the presence of additives such as, for example, tetramethy- 15 lenediamine, DMPU or HMPA. Examples of other known amides which can be used are lithium cyclohexylamide and lithium 2,2,6,6-tetramethylcyclohexylamide. It is also possible to prepare other amides by reacting the requisite amount of butyllithium in hexane with linear 20 or cyclic secondary amines, the reaction taking place in one of the solvents mentioned above. Finally, various publications describe amides of optically active secondary amines: L. Duhamel et al., Bull. Soc.

*0* Ch!m. France, 1984, II, 421; J.K. Whitesell et al., J.

Org. Chem., 1980, 45, 755; M. Murakata et al., J. Chem.

Soc. Chem. Comm., 1990, 1657; M. Yamaguchi, Tetrahedron Lett., 1986, 22(8), 959; P.J. Cox and N.S. Simpkins, Tetrahedron: Asymmetry, 1991, 1.

The silylamides of lithium, sodium or potassium constitute another group of bases which can be used, among which there may be mentioned (Me 3 Si),NLi, (Me 2 PhSi),NLi, (Et.Li) 2 NLi, (MeSi),NK and (Me 3 Si),NNa.

It is also possible to use mixed amides such as those described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563, for example the lithium salt of N-(trimethyl- 13 silyl)benzylamine or an analog in which the benzylamine is replaced with a chiral primary amine such as or (S)-a-methylbenzylamine.

When chiral amides are used, the 2 diastereoisomers, cis and trans, can together or independently of one another exhibit an optical activity cleated by asymmetric induction and enantiomeric enrichment. The proportion of each of the enantiomers is then determined on a chiral HPLC column.

In step the 2 isomers of the compound (I) formed are extracted by the conventional methods and separated by chromatography or fractional crystallization.

If appropriate, the optical isoners of each of 15 the cis and trans isomers are separated, for example by preparative chromatography on a chiral column.

If the 2 isomers of the compounds are difficult to separate by the customary methods, it is also possible to prepare a compound of the formula R2 0-Si(CH 3 3 (Rl)n I\I, tR3 N 4 (VII) 02 in which R R 2

R

3

R

4

R

5 m and n are as defined above for by reacting hexamethyldisilazane with the corresponding compound The reaction is carried out in the presence of a catalytic amount of imidazole by heating to 60-120"C under an inert atmosphere. The silyl ester is obtained by crystallization from the medium or after chromatography. The 2 isomers 14 of (VII) are separated by chromatography on silica and each isomer of (VII) is then hydrolyzed in an alkaline medium to give each isomer of Several methods can be used to differentiate and characterize the cis isomer and the trans isomer of a compound If R 3 is hydrogen, a comparative analysis is performed by high field NMR (at 250 MHz) coupled for example with a study of the Overhauser effect (NOE) between, for example, the proton of the indoline (R 3 H) and the proton of the hydroxyl.

If R. is a carboxamide group, the IR spectra of the cis isomer and the trans isomer in solution in DCM are different. The cis isomer most commonly has a 15 strong, fine and symmetrical absorption band at around 3550-3520 cm- 1 due to the hydroxyl vibration, whereas the trans isomer has no resolved vibration band in this region.

By means of the data collected, it has been 20 found that the cis isomer is generally the more mobile o in TLC on an aluminum oxide plate (60F254 neutral, type E, Merck), the eluent being DCM containing variable proportions of AcOEt. Similarly, in chromatography on an -lumina column (aluminum oxide 90, particle size 0.063-0.200 mm), the cis isomer is most commonly eluted first, the eluent being DCM containing variable propor-

S

tions of AcOEt or MeOH.

5 If R 4 is an ester group, it is possible to carry out the TLC on a silica plate (Kieselgel 60F250, Merck) using DCM as the eluent; when the TLC is carried out on a mixture of the isomers, the cis isomer is generally the more mobile.

Thus the cis or trans isomerism of a compound according to the invention can most often be determined by an analytical method. It is also pos- 15 sible to utilize the analogy between similar compounds or between compounds prepared from one another.

The compounds in which R 4 is a carboxyl group are prepared by debenzylation of the compounds in which R 4 is a benzyloxycarbonyl group by means of catalytic hydrogenation, for example in the presence of palladium-on-charcoal.

The compounds in which R 4 is a carboxamide group, CONH,, can be prepared from the corresponding compounds in which R 4 is a carboxyl group, for example by a conventional coupling method used in peptide synthesis, for example in the presence of BOP and

DIPEA.

A compound in which R, is an amino group 15 and/or a compound in which R, is a phenyl group which is substituted by .an amino can be prepared by the conversion of a compound obtained in step in which R 1 is a nitro group and/or Rg is a phenyl group substituted by a nitro, the other substi- 20 tuents having the meanings desired for by means of catalytic hydrogenation, for example in the presence of palladium-on-charcoal or rhodium-on-alumina.

The compounds of formula (VI) obtained at the end of step b) are novel and form part of the invcntion.

The affinity of the compounds according to the invention for the vasopressin receptors was determined in vitro using the method described in J. Biol. Chem., S" 1985, 265(5), 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the V, sites of rat liver membranes. The inhibitory concentrations (ICso) of the compounds according to the invention for the binding of tritiated vasopressin are low and range up to nanomolar.

Likewise, the affinity of the compounds (I) according to the invention for the ocytocin receptors 16 was determined in vitro by the displacement of tritiated ocytocin bound to the receptors of a membrane preparation of gestating rat glands. The IC., values of the compounds according to the invention are low and range up to 10-7 M.

Furthermore, the inhibition of the platelet aggregation induced by vasopressin was measured on a human, platelet rich plasma (human PRP) using the method described in Thrombosis Res., 1987, A5, 7-16. The compounds according to the invention inhibit the aggregation induced by 50 to 100 nM vasopressin with low IDS.

values (inhibitory doses) which range up to 10-8 M.

***These results show the antagonistic activity of the comupounds according to the invention towards the V3.

15 receptors.

***The affinity of the compounds according to the invention for the V receptors was measured by a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 529-541.

20 The compounds according to the invention are active after administration by various routes, espe- 4 cially orally No sign of toxicity is observed with these compounds at the pharmaac:;Ligically active doses.

Thus the compounds according to the invention can be used in the treatment or prevention of various vasopressin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency or coronary vasospasm, in particular in smokers; complaints of the central nervous system, for example cerebral edemas, psychotic states or memory disorders; complaints of the renal system, such as renal vasospasm or necrosis of the renal cortex; and complaints of the gastric system, for example ulcers or the syndrome of inappropriate secretion of antidiuretic f 17 hormone (SIADH). In women, the compounds according to the invention can also be used for the treatment of dysmenorrhea or premature labor.

The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt, and suitable excipiants.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the Sa 6active principles of formula above, or their salts 15 if appropriate, can be administered to animals and

C*

humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases.

Appropriate unit forms of administration include forms 20 for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical S" application, the compounds according to the invention S* can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight and per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to 18 administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like.

The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances or they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or 15 hard gelatin capsules.

0 A preparation in the form of a syrup or elixir *or for administration in the form of drops can contain the active ingredient in combination with a sweetener, which is preferably calorie-free, and methylparaben S 20 and propylparaben as antiseptics, as well as with a 0,:3 flavoring and an appropriate color.

Water-dispersible granules or powders can contain the active ingredient mixed with dispersants Qr Swetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

Rectal administration is effected using suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylane glycol or butylene 19 glycol.

The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.

Apart from the products of formula above or one of the pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles which may be useful in th eatment of the disorders or diseases indicated above.

_hu3 thz przaont invntion rclatetophagaceutical compositions con igset active prin- S" ciples in assoc iaaiT, one of which is a compound 4 0 ea 15 EXAMPLES 1 AND 2 Methyl 5-chloro-3-cyclohexyl-3-hydroxy-l- (naphthyl-l-sulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-2-[(naphthyl-l-sulfonyl)amino]cyclohexyl- 20 phenone A mixture containing 3 4 of cyclohexylphenone and 3.2 g of naphthyl-l-sulfonyl chloride is heated in pyridine at 100C for 8 hours.

C*4 The pyridine is evaporated off, water is added, the mixture is extracted with ethyl acetate and the extract is then filtered on silica using dichloromethane as the eluent to give 4.27 g of the expected product.

After recrystallization from a DCM/isopropyl ether mixture, m.p. 140-142'C.

B) 5-Chloro-2-[N-(methoxycarbonylmethyl)-N-(naphthyl-lsulfonyl)amino]cyclohexylphenone 4.27 g of the product obtained in the previous step are dissolved in 20 ml of anhydrous DMF under argon. 320 mg of 80% sodium hydride are added at OC, after 20 minutes 6.1 g of ethyl bromoacetate are then added over 30 minutes and the mixture is stirred for 3 hours at room temperature. After extraction, the crude product obtained is recrystallized from a DCM/isopropyl ether mixture to give 2.45 g of the expected compound.

M.p. 130-132*? C) Methyl 5-chloro-3-cyclohexyl-3-hydroxy-l-(naphthyl- 1-sulfonyl)indoline-2-carboxylate 2.4 g of the compound obtained in the previous step are suspended in 30 ml of methanol under a nitrogen atmosphere, 26 mg of sodium methylate are added at OC, after 10 minutes at room temperature a further 26 mg of sodium methylate are added and, finally, after min, 1 ml of THF is added in order to achieve total *see dissolution. Then, after 1 hour, a precipitate is 15 formed by the addition of dry ice and water. The precipitate is filtered off, taken up with ethyl acetate, washed with water and an aqueous solution of sodium chloride and dried. The oil obtained is chromatographed on silica, the eluents being DCM and then DCM 20 containing up to 10% of AcOEt; the 2 isomers are separated in this way.

The compounds contained in each of the fractions are then recrystallized from a DCM/isopropyl ether mixture.

M.p. 155-157'C: cis isomer M.p. 141-142'C: trans isomer

S

EXAMPLES 3 AND 4 Methyl 5-chloro-3-(2-fluorophenyl)-3-hydroxy-l- (4-nitrophenylsulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-2-fluoro-2-[ (4-nitrophenylsulfonyl)aminobenzophenone A mixture containing 24.9 g of chloro-2'-fluorobenzophenone and 22.1 g of 4-nitro- 21 phenylsulfonyl chloride is refluxed for 10 hours in pyridine. It is evaporated to dryness, water and ethyl acetate are then added and the ethyl acetate phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum. The expected product precipitates on evaporation; it is filtered off and recrystallized from a DCM/isopropyl ether mixture to give 20 g.

M.p. 155°C B) 5-Chloro-2'-fluoro-2- N-(methoxycarbonylmethyl)-N- (4-nitrophenylsulfonyl) amino]benzophenone 5 g of the compound obtained in the previous step are dissolved in 20 ml of DMF at 0°C under argon, 367 mg of 80% sodium hydride are added, 3.5 g of methyl 15 bromoacetate are added after 5 minutes and a further 3.5 g of methyl bromoacetate are added after 1 hour.

After 5 hours at room temperature, the reaction mixture is poured into iced water and then extracted 3 times with ethyl acetate and the extract is washed 3 times 20 with water and an aqueous solution of sodium chloride and thon dried over magnesium sulfate. The product is chromatographed on silica gel using DCM as the eluent to give 6.1 g of the expected compound, which solidifies in metthnol.

C) 3 g of the compound obtained in the previous step are suspended in 50 ml of methanol and cooled in an ice bath. 330 mg (0.1 equivalent) of sodium methylate are 0 added and the mixture is stirred for 60 minutes, the temperature being allowed to rise to 10C. Dry ice and then water are added, the mixture is extracted 3 times with ethyl acetate and the extract is then washed with water and an aqueous solution of sodium chloride, dried and evaporated under vacuum. The crude reaction product (6.1 g) is chromatographed on a silica column prepared in DCM.

22 The 2 isomers are eluted successively with DCM.

The less polar isomer is the cis isomer.

After recrystallization from a DCM/isopropyl ether mixture, m.p. 219-220°C.

The more polar isomer is the trans isomer.

After recrystallization from a DCM/methanol mixture, m.p 203-204 0

C.

EXAMPLES 5 AND 6 Methyl 1-(4-aminophenylsulfonyl)-5-chloro-3-(2- 6* fluorophenyl)-3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer A) 5-Chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N- (4,-aminophenylsulfonyl)amino]benzophenone 15 The e ,chloro-2'-fluoro-2-[N-(methoxycarbonylmethyl)-N- 4-nitrophenylsulfonyl)amino]benzophenone prepared in Example 2, step b, is dissolved in 100 ml of ethyl acetate and 5 ml of methanol and hydrogenated at ordinary pressure for 2 hours in the presence of 620 20 mg ot 10% palladium-on-charcoal; the existence of 3 compounds (starting material, intermediate and expected product) is observed in TLC. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel. The expected compound is eluted with DCM containing 1% of methanol. After recrystallization from DCM/isopropyl ether, m.p. 168- 170oC.

B) Trans isomer 3.4 g of the compound obtained in the previous step are dissolved in 20 ml of methanol and 20 al of THF at O'C under nitrogen and 190 mg of sodium methylate are added. After 60 minutes at 5'C, with stirring, the reaction medium is poured into water and extracted with ethyl acetate. A compound crystallizes and is recrystallized from DCM containing a small 23 amount of methanol.

M.p. 215-216°C.

This is the trans compound according to a study of the NMR spectrum with NOE.

C) Cis isomer 200 mg of the compound prepared in Example 3 are dissolved in 10 ml of ethyl acetate and 2 ml of methanol and hydrogenated at ordinary pressure for 3 hours in the presence of 50 mg of 10% palladium-oncharcoal. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is chromatow, *graphed on silica gel, the eluent being DCM containing 1% of methanol. The product obtained is recrystallized from MeOH/isopropyl ether to give 105 mg.

15 M.p. 186-190°C.

S* 00 EXAMPLES 7 AND 8 Methyl 3-(2-fluorophenyl)-3-hydroxy-5-nitro-ltosylindoline-2-carboxylate, cis ispmer, trans isomer 20 A) 2'-Fluoro-5-nitro-2-tosylaminobenzophenone A mixture containing 10 g of 2'-fluorobenzophenone and 7.5 g of tosyl chloride is refluxed in 50 ml of pyridine for 24 hours. The solvent is evaporated off to dryness, water and ethyl acetate are added, an insoluble material is filtered off and the organic phase is washed with a dilute solution of hydrochloric acid, water and an aqueous solution of sodium chloride and then dried over magnesium sulfate and evaporated, The residue is chroma -graphed on silica and the expected product is eluted wil.h DCM.

B) 2'-Fluoro-2-[N-(methoxycarbonylmethyl)-N-(tosyl)- 4 g of the compound obtained in the previous step are placed in 40 ml of anhydrous DMF and treated at 0°C with 320 mg of 80% sodium hydride and, after 24 minutes, with 6 g of methyl bromoacetate. The mixture is allowed to return to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The residue obtained after evaporat.in of the solvent is purified by chromatography on silica gel.

The oil obtained by elution with DCM and then DCM containing up to 2% of AcOEt solidifies completely.

Elemental aRalysis: IC2HgFN.O S calculated C 56.79 H 3.94 N 5.76 found C 56.54 H 3.88 N 5.54 C) A suspension containing 1.70 g of the product obtained in the previous step in 30 ml of methanol is S' cooled to 10 C under argon and then treated with 100 mg 4 of sodium methylate for 45 minutes. A large volume of 15 water is added, the mixture is extracted with ethyl acetate and the organic phase is washed with water until the washings are neutsal, washed with a saline solution, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica 20 gel. The less polar compound is eluted with pure DCM to give 700 mg: cis isomer.

M.p. 191-192°C after recrystallization (DCM/ isopropyl ether) The more polar compound is eluted with a DCM/ ethyl acetate mixture (95/5, 650 mg are obtained after recrystallization from DCM/isopropyl ether.

M.p. 206-207°C: trans isomer EXAMPLE 9 Methyl 5-amino-3-(2-fluorophenyl)-3-hydroxy-ltosylindoline-2-carboxylate, cis isomer 450 mg of the cis compound obtained in Example 4 are solubilized in 13 ml of an ethyl acetate/methanol mixture (10/3, v/v) and hydrogenated at ordinary temperature and pressure for 2 hours in the presence of 25 100 mg of 10% palladium-on-charcoal. The catalyst is filtered off, the solvent is evaporated off and the residue is chromatographed on silica gel using a DCM/ ethyl acetate mixture v/v) as the eluent.

A white powder is obtained after trituration in a DCM/isopropyl ether mixture.

M.p. 203"C (cis isomer) EXAMPLES 10 AND 11 Methyl 5-chloro-3-cyclohexyl-3-hydroxy-l-(4methoxyphenylsulfonyl)indoline-2-carboxylate, cis isomer, trans isomer A) 5-Chloro-l-[(4-methoxyphenylsulfonyl)amino]cyclohexylphenone 15 A mixture containing 20 g of phenyl cyclohexyl ketone and 18 g of 4-methoxyphenylsulfonyl chloride is heated in pyridine at 100°C overnight, the solvent is concentrated, the residue is taken up with hydLochloric water and extracted with DCM 20 and the extract is dried and concentrated. The residue is recrystallized from an isopropyl ether/cyclohexane mixture to give 27 g of the expected compound, which crystallizes.

M.p. 78-80'C B) 5-Chloro-l-[N-(methoxycarbonylmethyl)-N-(4-methoxyphenylsulfonyl)amino]phenyl cyclohexyl ketone The compound obtained in the previous step (27 g) is treated with 2.2 g of sodium hydride in 150 ml of DMF at room temperature under argon for minutes. 50 g of methyl bromoacetate are added and the mixture is left to stand overnight, with stirring. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The residue is chromatographed on silica using DCM as the eluent to give 19.5 g of the 26 expected compound, which crystallizes from methanol.

M.p. 115-116°C C) The product obtained in the previous step (10 g) is solubilized in 350 ml of methanol, and 0.6 g of sodium methylate in 50 ml of methanol is added. After a contact time of 5 minutes, TLC shows that the reaction is complete. The methanol is evaporated off after dry ice has been added to the medium. The residue is taken up with water and extracted with methylene chloride and the extract is chromatographed on silica using methylene chloride as the eluent.

The first fractions contain the less polar isomer, which is recrystallized from isopropyl ether.

M.p. 1 0 (cis isomer) 15 This is followed by the more polar isomer.

M.p. 145°C (trans isomers EXAMPLES 12 AND 13 Methyl 5-chloro-3-hydroxy-3-pentyl-l-tosylindo- 20 line-2-carboxylate, cis isomer, trans isomer A) 4-Chloro-2-hexanoyl-N-tosylaniline A mixture containing 15 g of 4-chloro-2-hexanoylaniline and 10.5 g of tosyl chloride is heated in

O**

100 ml of pyridine at 100°C overnight. The solvent is evaporated off, the residue is taken up with hydrochloric water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product crystallizes from isopropyl ether to give 14.5 g.

M.p. 78-80°C B) 4-Chloro-2-hexanoyl-N-methoxycarbonylmethyl-N-tosylaniline 14 g of the compound obtained in the previous step are treated at O°C under argon with 1 g of sodium hydride in DMF. After stirring for 15 minutes, 22.5 g 27 of methyl bromoacetate are added and the mixture is stirred overnight at room temperature. After evaporation of the solvent and the excess brominated derivative with a vacuum pump, the residue is taken up with water and extracted with methylene chloride, the extract is dried and concentrated and the crude reaction product is then chromatographed on silica using a DCK/pentane mixture (50/50, v/v) as the eluent to give 12.1 g of the expected product.

M.p. 68-70°C C) 5 g of the compound obtained in the previous step are dissolved at 0°C in 100 ml of methanol and treated e* **with 600 mg of sodium methylate. After 10 minutes, TLC shows that the starting material has disappeared. Dry 15 ice is added, the solvent is partially evaporated off, the residue is taken up with water and extracted with methylene chloride and the extract is dried and concentrated. The crude reaction product is chromatographed on silica using DCM as the eluent, which separates the 20 2 isomers. The less polar isomer is recrystallized in the cold from an ether/cyclohexane mixture to give 0.85 g.

M.p. 95-965°C cis isomer The more polar isomer is recrystallized from isopropyl ether to give 2 g of product.

M.p. 102-104 0 C: trans isomer S6 EXAMPLES 14 AND Methyl l-butylsulfonyl-5-chloro-3-(2-chloreophenyl)-3-hydroxyindoline-2-carboxylate, cis isomer, trans isomer A) 2-Butylsulfonamido-2',5-di-hlorobenzophenone 11 g of 5-dichloroaminobenzophenone and 8.2 g of n-butanesulfonyl chloride in 40 ml of pyridine are stirred for 9 days at room temperature. The pyri- 28 dine is evaporated off under vacuum, water is added, the mixture is extracted with 3 volumes of ethyl acetate and the organic phase is washed with hydrochloric water and an aqueous solution of sodium chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue is ,hromatographed on silica gel, the expected product being eluted with a pentane/ethyl acetate mixture (90/10, v/v) to give 4.4 g.

B) 2-[N-(Butylsulfonyl)-N-(methoxycarbonylmethyl)- 4 g of the compound obtained in the previous a" *step are dissolved in 40 ml of anhydrous DMF at 0 C under argon, tVie solution is treated with 320 mg of sodium hydride for 15 minutes, 6.5 g of ethyl bromo- 15 acetate are then added over 2 hours and the mixture is 0 left to stand for 6 hours at room temperature. Water is added, the reaction product is then extracted and the extract is filtered on silica gel using DCM as the eluent to give the expected product in the form of a 20 thick oil.

C) 4.3 g of the compound obtained in the previous step are placed in 50 ml of methanol at 0°C and treated with 54 mg of sodium methylate for 3 hours. After the starting material has disappeared (as shown by TLC), the mixture is poured into a large volume of water and extracted with 3 volumes of ethyl acetate, the organic phase is washed with water and an aqueous solution of Ssodium chloride and dried over magnesium sulfate and the solvent is then evaporated off under vacuum. The residue is chromatographed on silica gel.

The first isomer is eluted with DCM.

M.p. 140-143°C: cis isomer (recrystallization from DCM/isopropyl ether) The second isomer (trans isomer) is eluted with a DCM/isopropyl ether mixture.

29 M.p. 161-163°C: trans isomer (recrystallization from DCM/isopropyl ether) EXAMPLES 16 AND 17 Methyl 5-zhloro-3-(2-chlorophenyl)--(2,5-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate, cis isomer, trans isomer A) 2',5-Dichloro-2-(2,5-dimethoxyphenylsulfonamido)benzophenone This compound is prepared by the procedure described in the previous Examples.

0 0 B) 2',5-Dichloro-2-[N-(2,5-dimethoxyphenylsulfonyl)-Na* (methoxycarbonylmethyl)amino]benzophenone 8.2 g of the compound prepared in the previous 15 step are dissolved in 60 ml of anhydrous DMF at 0 C under argon, 550 mg of 80% sodium hydride are added, after 15 minutes 8 g of methyl bromoacetate are then added and the mixture is stirred for 10 hours at room temperature. The reaction medium is poured into water 20 and the solid formed is filtered off and then dissolved in ethyl acetate. The organic phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum.

The solid is recrystallized from a DCM/isopropyl ether mixture.

M.p. 129-131 0

C

C) Methyl 5-chloro-3-(2-chlorophenyl)-2-(2,5-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate The cyclization step can be carried out in the presence of various reagents.

a) a g of the compound obtained in the previous step is dissolved in 10 ml of DCM at 0°C, 145 mg of DBU are added and the reaction medium is kept for 24 hours at It is poured directly on to a silica column and eluted with DCM.

30 The first compound eluted (231 mg) is recrystallized from DCM/isopropyl ether.

M.p. 168-169°C (cis isomer) The trans isomer is eluted next.

M.p. 193-195°C (recrystallization from DCM/ isopropyl ether) b) 800 mg of the compound obtained in step B are dissolved in 5 ml of anhydrous THF, 0.8 ml of HMPA is added and the mixture is cooled tc -78 0 C under an argon atmosphere, 1 ml of a solution of the complex LDA.TFA (1.5 M) in cyclohexane is added by syringe; after 45 minutes, a further 0.3 ml of LDA is added, o water is then added at -78°C and the mixture is extracted with ethyl acetate.

15 NMR analysis of the product obtained shows the existence of the cis isomer and the trans isomer O0 .t 0 c) 400 mg of the compound obtained in step B are dissolved in 3 ml of anhydrous THF under argon, the solution is cooled to -78'C and 0.9 ml of a molar solution of LiHMDS in THF is then added, followed by 0.4 ml of HMPA in 2 ml of THF. After stirring fce 60 minutes at -78"C, a further 0.3 ml of LiHMDS is added, after minutes water is added at -78'C and the mixture is then extracted with ethyl acetate.

NMR analysis of the product obtained shows the existence of the cis isomer and the trans isomer d) 400 mg of the compound obtained in step B are dissolved in 3 ml of anhydrous THF, the solution is cooled to -78°C under argon and 1.8 ml of a solution of KHMDS (0.5 M) in 1 ml of toluene and 0.4 ml of HMPA in 1 mi of THF are then added. The solution obtained is kept at -78°C for 20 minutes, water is then added and the mixture is extracted with ethyl acetate.

31 NMR analysis *f the product obtained shows the existence of the cis isomer and the trans isomer e) 2 ml of THF and 0.4 ml of HMPA are cooled to -70°C under argon and a molar solution of LiHMDS in 0.9 ml of THF is added; 400 mg of the compound prepared in step B in 3 ml of THF are then added dropwise.

After one hour at -70°C, water is added and the mixture is then extracted with ethyl acetate. NMR analysis of the product obtained shows the existence of the cis isomer and the trans isomer 0* f) 1 g of 1,3-diphenyl-l,l,3,3-tetramethyldisilazane is dissolved in 4 ml of anhydrous THF, and 2.2 ml of a 1.6 M solution of butyllithium in hexane and 15 1.8 ml of THF are added at -10°C under argon.

In a parallel procedure, 400 mg of the compound prepared in step B are dissolved in 3 ml of anhydrous THF at -78 0 C under argon and 2.2 ml of the solution prepared above are added over 5 minutes, followed by 20 0.4 ml of HMPA. After 1 hour, a further 0.5 ml of the solution prepared above is added, the mixture is then *S left to stand for 1 hour at -78°C and, finally, water is added and the mixture is extracted with ether.

NMR analysis of the product obtained shows the existence of the cis isomer and the trans isomer EXAMPLES 18, 19 AND Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-ltosylindoline-2-carboxylate, trans isomer, cis isomer, and isopentyl 5-chloro-3-cyclohexyl-3-trimethylsilyloxy-l-tosylindoline-2-carboxylate, cis isomer A) 5-Chloro-2-tosylavinophenyl cyclohexyl ketone This compound is prepared by the procedure described in the previous Examples.

32 B) chlorophenyl cyclohexyl ketone 5.7 g of the compound prepared in the previous step are dissolved in 50 ml of anhydrous DMF, 420 mg of 80% sodium hydride are added, 12 g of isopentyl bromoacetate are then added after 15 minutes and the mixture is stirred for 8 hours at room temperature. After extraction, the extract is chromatographed on silica gel and an oil is eluted with mixtures from pentane/DCM (20/80, v/v) to pure DCM.

C) Iso;entyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate, trans isomer e 1.6 g of the compound obtained in the previous step are dissolved in 10 ml of anhydrous 3-methyl- 15 butanol. The solution is cooled to 0°C, 7 mg of sodium methylate are added and tile mixture is then brought S. back to ordinary temperature over 150 minutes. Dry ice and water are added, the mixture is extracted by decantation and the extract is washed with water and an 20 aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is eveporated off under vacuum and the residue is then chromatographed on silica gel. A mixture of 2 isomers (1.6 g) is eluted with DCM and recrystallized from a DCM/isopropyl ether mixture: SR 47275 (trans isomer).

D) Isopentyl 5-chloro-3-cyclohexyl-3-trimethylsilyloxy-l-tosylindoline-2-carboxylate, cis isomer The mother liquors from crystallization of the trans isomer (980 mg) are dissolved under argcn in 8 ml of hexamethyldisilazane in the presence of 100 mg of imidazole and the mixture is heat,.' at 120 C. The reaction is followed by TLC on silica gel using DCM as the eluent.

A product of low polarity appears after 1 hour and a second compound, which is slightly more polar 33 than the previous one, appears after one night. The solvent is evaporated off to dryness under vacuum and the residue is chromatographed on silica gel. The less polar compound is eluted with a DCM/pentane mixture (50/50, v/v) to give 304 mg, which are recrystallized from a DCM/isopropyl ether mixture.

M.p. 118-121°C E) Isopentyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate, cis isomer 2.4 mg of solid sodium hydroxide are added to a suspension of the mother liquors of the cis isomer isolated above (220 mg) in 1 ml of water and 3 al of THF. After 3 hours, water is added, the THF is partially evaporated off and the mixture is extracted 15 under vacuum at room temperature by the custonary methods. The residue is chromatographed on silica using a DCM/pentane mixture (95/5, v/v) as the eluent.

According to the NMR spectrum, 87% of the compound obtained is in the cis form.

EXAMPLE 21 Butyl 5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxylate This compound is prepared by the reaction of butyl bromoacetate with 5-chloro-2-tosylaminophenyl cyclohexyl ketone, followed by cyclization in the presence of sodium methylate in butanol.

o* The compound formed is the trans isomer.

M.p. 115 0

C

EXAMPLES 22 AND 23 Methyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-2methy3-l-tosylindoline-2-carboxylate, cis isomer, trans isomer A mixture containing 0.5 g of 34 2-[N-(1-methoxycarbonylethyl)-N-(tosyl)amino]benzophenone, 0.1 g of sodium methylate and 2 ml of DMF is stirred for 20 hours at room temperature under nitrogen. It is concentrated under vacuum, the residue is taken up with water and the precipitate is filtered off and washed with water. The residue is chromatographed on silica using DCM as the eluent to give 60 mg of the cis isomer and 250 mg of the trans isomer.

EXAMPLE 24 Methyl 5-chloro-3-(2-chlorophenyl)-l-(4-cyanophenylsul, nyl)-3-hydroxyindoliine-2-carboxylate, cis 4e isomer A) 2-(N-(4-cyanophenylsulfonyl)amino]-2',5-dichloro- 15 benzophenOne 10 g of 2-amino-2',5-dichlorobenzophenone and 7.7 g of 4-cyanophenylsulfonyl chloride are heated in pyridine at 100"C for 48 hours in the presence of 4.6 g of DMAP, the mixture is evaporated to dryness, water 20 and ethyl acetate are added, the organic phase is washed with dilute hydrochloric water, water and an aqueous solution of sodium chloride and dried over magnesium sulfate and the solvent is evaporated off S* under vacuum. The precipitate formed is filtered off and then recrystallized twice from a DCM/isopropyl ether mixture to give the expected product.

S, M.p. 172-173'C B) 2-[N-(4-Cyanophenylsulfonyl)-N-(methoxycarbonylmethyl) 10 g of the compound obtained in the previous step are dissolved in 70 ml of DMF at O'C under argon, 740 mg of 80% todium hydride are then added and 14 g of methyl bromoacetate are added after 15 minutes. After 24 hours, water is added, the aqueous phase is decanted, the solid obtained is extracted with AcOEt and the 35 organic phase is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under vacuum to give the expected product, which is recrystallized from DCM/isopropyl ether.

M.p. 186-188°C C) 2 g of the previous compound are suspended at O'C in ml of an MeOH/THF mixture v/v) and treated with 100 mg of sodium methylate. After 3 hours at ordinary temperature, total dissolution is observed.

The solvents are partially evaporated off under vacuum, a large amount of water is added and the mixture is extracted with ethyl acetate. The extract is washed S with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under 15 vacuum. The residue is chromatographed on siLica gel.

The 2 isomers are successively eluted with methylene chloride.

The less polar isomer is recrystallized from DCM/isopropyl ether.

20 M.p. 222-223°C (cis isomer) S" EXAMPLES 25 AND 26 Methyl 5-chloro-3- (-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline-2-carboxylate, trans isomer, cis isomer A) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)berzophenone S' 5.6 g of 2-amino-2',5-dichlorobenzophenone and g of 3,4-dimethoxyphenylsulfonyl chloride are heated in pyridine overnight at 100'C. The pyridine is evaporated off to dryness, water and ethyl acetate containing a small amount of DCM are added and the mixture is extracted.After washing several times with water and drying over sodium sulfate, the extract is evaporated under vacuum and 7.7 g of the expected product are 36 recrystallized from a DCM/AcOEt mixture.

M.p. 164°C B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- (methoxycarbonylmethyl)amino]beenophenone 7.2 g of the compound obtained in the previous step are dissolved in anhydrous DMF at 0°C under nitrogen. 500 mg of sodium hydride are added, followed after 10 minutes by 9.5 g of ethyl bromoacetate. After 1 night, excess water is added and the precipitate obtained is filtered off. It is dissolved in DCM, the n solution is dried over magnesium sulfate and the solvent is evaporated off. 7.7 g of the expected product are recrystallized from a DCM/isopropyl ether mixture.

M.p. 164"C 15 C) Trans isomer A suspension of 7 g of the product obtained in the previous step in 90 nl of methanol containing 2 ml GC THF is coiled to O'C under nitrogen and treated with 720 mg of sodium methylate. Afi e 2 hours at ordinary 20 temperature, the unreacted starting material is filtered off, a large volume of water and dry ice are added and the mixture is extracted with ethyl acetate.

"i 4 products appear in TLC. The most abundant product is **e recrystallized twice from a DCM/isopropyl ether mixture.

M.p. 184-185° 0 trans isomer D) Cis isomer 1.3 g of the compound obtained in step B are dissolved at O'C in 13 ml of DCM in the presence of 180 mg of DBU. After stirring overnight, the reaction medium is poured directly on to a silica column prepared in DCM and the mixture of compounds resulting from cyclization is thus separated by elution with DCM.

Chromatography is the/n carried out on alumina using a DCM/isopropyl ether mixture (70/30, v/v) as the eluent 37 sees 00 *06 00SO 09 0 0.

400 The cis isomer is thus ksolated.

N14R spectrum at .2-00 MHz inl DMSO at T 370*K: Delta Appearance integration kssign-ment ailso DMSO 3e15 s 3 H C 2

CH

3 3. b9 s 3 H OCH:, 3.85 s) H OCH 3 5.10 s Hi CH 6.50 1 H OH 7.00 to 7.80 m 10 H aromatic protons EXAMPLES 27, 28, 29 AND Benzyl 5-chloro-3- (2-chilorophenyl ,-3-hydroxy-,.p,.tosylindoline-2-car-boxyl ate, trans isomer, cis isomer, and 5-chl (2-chlorophenyl )-3-hydroxy-l-p.tosylindoli~ne-2-carboxYlic acid, trans isomer, i isomer A) 2' ,5-Dichloro-2-[N-(tosyl)-N-(benzyloxycArbonyl- 20 methyl )amino) benzophenone g of one (prepared by the customary method" and 1.6, g of sodiuin hydride reacted in 100 ml of DMF. Af ter atirring, f or 15 minut,,, 34 q of benzy. bromoacetate are added and thte 'mixture is left to stand overnight at room te~peratn%;T. The DMF is evaporated off, the residue, is, taken up with watet~ and extracted with methy1'. n cr1 oride and thev) dried a nd, concentrated. The crude product obtained is chromatogaphed on silica gel using DCI4 as the eluent. The 14.39 g of product obtained are rezrystallized from isopropyl ether.

M.P. 99-1014C, 38 B) Benzyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l-ptosylindoline-2-carboxylate, trans isomer 1 g of the compound obtained in the p.avious step is treated at -78°C with 1.2 ml of concentrated LI (1.5 M) in cyclohexane. After 3 hours, the wixture j taken up with water and extracted with DCM and the extract iF, ried and concentrated. The crude reaction product is chromatographed on silica gel using DCM as the eluent and the mixture of 2 isomers is separated.

The more polar isomer is recrystallized twice from a DCM/isopropyl ether mixture to give 600 mg of trans isomer.

M.p. 168-1G9 C (recrystallization from DCM/ isopropyl ether) 15 C) Benzyl 5-chloro-3-(2-chlorophenyl)-3-hydroxy-l-p- 0 tosylindoline-2-carboxylate, cis isomer 2 g of the compound prepared in step A are dissolved in DCM at 0 C and 54.0 mg of DBU are added.

After 20 minutes at O'C, a potassium sulfate solution and water are added, the mixture is then extracted and the extract is dried and concentrated. Chromatography on silica using DCM as the eluent gives 450 mg of the less polar product (cis isomer) and 700 mg of the more polar product (trans isomer).

The cis isomer is obtained in the form of a foam.

Elemental analysis: calculated C 63.27 H 4.05 N 2.46 found 61.29 4.20 2.48 D) 5-Chloro-3-(2-chlorophenyl)-3-hydroxy-l-p-tosylindoline-2-carboxylic acid, trans isomer 500 mg of the trans isomer of the compound prepared in step B are dissolved in 300 ml of ethyl acetate in the presence of 100 mg of palladium-oncharcoal. The product crystallizes after 10 min of 39 bydrogenolysis. The palladium is filtered off and the crystals are t!1ln solubilized with h~ot DMF. The DMF is concentrated and the residue is taken up with a large volume of THF. The mixture is concentrated, methanol is added and the product crystallizes to give 175 mg of the expected product (trans isomer).

NMR:

*0 a

SS

0e

U

S

U

C.

U..

*eU S..

15 Delt a Appearance Int~egration Assignne'at 2.44 s 3 H Gil 3 (tosyl) 4.87 s 1 H H6 (2-chiorophenyl) 6.74 d 1 H H4 (indole) 6.98 s I H OH 7.28-7.53 in 7 H aromatic protons 7.88 d OH (J 8.6 Hz) 2 H H2, H6 (tosyl) In the same way, the cis isomer of the acid is prepared by hydrogenolysis of the benzyl ester obtained in step C.

20 M.p. 209-212*C EXAMPLE 31 5-Chlorco-3- C 21-hlorophenyl 4-dimethoxyphenylsulfonyl )-3-hydroxyindolirie-2-carboxylic acid, cis isomer This aicid is prepared by the procedure described in the previous Example via the benzyl ester of said acid.

M.p. 130-132*C Methyl esters of formula were prepared by analogous procedures. They are described in Table 1 below.

40 TABLE 1 1' OH RI 0 2 CH3 N H

ISO

2 For each compound of formula having the substituents R, R2 and R. in the Table below, the cis isomer is indicated and then the ns isomer, unless stated otherwise.

E xample I RI R 2 [5 Solvent *0 0* 0** 0eeS o *5 S 5*

S

0 *5*S S S *5 V

S.

5 0*S 5-01 5-01 phenyl cyclopentyl cyclohexyl p- tolyl p- tolyl p- toly.

2 -naphthyl p-tolyl p- tolyl Icyclohexyl.

154 170 187-190 DCI4/MeOH 153-157 D014/isopropyl ether 11B0 ether/cyci ohexane 144 ether/cycl ohexane 177 MeOH 150 ether/cyclohexane 158 DCM/isopropyl ether 172 DCM/isopropyl ether 165-166 DCM/isopropyl ether 212-213 DCI4/isopropyl ether

S

a a. a.

S. V 0 5-01 isopropyl 12-F-phenyl 41 p* a..

Oeee a 4 a a.

a .Oa* a.

a 0* a. a.

a *00 a a a. oil a 44

M*

46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-01 5.-Cl 5-Cl 5-Cl phe-ayl cycloheptyl IP-tolyl 2-Cl -pheniyl cyclahexyl cyclohexyl cyq~lohexyl 2-Cl .phenyl 2-Cl -phenyl 2-Cl- phenyl p-tolyl 4-dime thyl aminophenyl 2, 4, 6-trimethyiphenyl n-butyl 2-r 3 -Ph-enY1 2-CF,-pbenyl 4-benzyloxyphenyl 4-Gi-phenyl p-tolyl 206 DCM/isopropyl ether/i MeOH 19a~-194 Ac0Et/MeOH 170-172 isopropyl ether 154-155 174 255 184-185 198-200 DGI4/isopropyl ether 139 -142 DCM/isopropyl ether 200 -203 DCM/isopropyl ether 150-153 MeOH/isopropyl ether 216 242 166 DCM/isopropyl ether 195 DCM, 'sopropyl ether 174 230 224 186 EtOH 1,68 4-Ci-phenyll p-tolyl 2-Ci 3 phenyl p-tolyl 42

S*

C

we

C.

C

we.

C. *9 be..

C

4* *e

C

*e*b CC

C

CCC.

9

C.

61t 66 67 68 69 71 72 73 74 76 77 cis 78 79 80 81 82 83 84 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Br 2-Cl-phenyl 'e-Cl -phenyl 2-methoxyphenyl 3-Cl -phenyl 2-methyl phenyl 2-Cl-phenyl 2-Cl-phenyl 5-Cl 12-Cl-phenyl 4-OH-phenyl 3-Cl-phenyl M-tolyl p- tolyl p- tolyl 3 ,4-diClphenyl 3 -methoxyphenyl- 2,3,4-trimethoxyphenyl 4-butoxyphenyl 4-trifluoror,,ethoxyphenyl 3, 4-d-A methoxcyphanyl 238 AcOEt

NR(*

163 MeOH/isopropyl ether 175 186 173 229 165 240 137 210 196 175 132 207 183 124-125 hexane 190-192 Me0H/isopropyl ether 170 166 162-164 *Cwwg C 4 C CC CC 9 9 9 2 -Cl -phenylI 2-Cl-phenirl 2-F-phenyl 43 00 0 0 *0 00 @0 o .*o 0S 00 0 0000 0 000...

0 0e 0 00 0 000000 0 0000 *0 00 0 00 0 000 20 86 87 88 89 90 91 92 93 94 trans 96 97 98 99 100 101, trans 102 5-Cl 5-Br 5-Cl 2-Cl -phenyl 2-Cl -phenyl 2-Cl-pheflyl 5-Cl 12-Cl-phenyll phenyl.

2-CH 3 01 2-Cl 4-methoxyphenyl 3,4-dimethoxyphenyl 4-ethoxyphenyl p-tolyl p-tolyl p-tolyl p- tolyl 3 -m~ithoxy pbenyl 4-CF,-phenyl 162 -165 DCM./isopropyl ether 148 isopropyl ether 230 DCHi/isopropyl ether 173 hexane/isopropyl ether 217 hexane/isopropyl ether 160-162 199 174 hexane/isopropyl ether 186 hexane/isopropyl ether 215 165 216 EtOH 189 202 166 205 206.5 191 0 See.. 0 00 90 0 0 5- CH 3 5-CF 3 5-Cl 5-Cl 5-Cl 2-Ci-phenyl 2- CF 3 phenyl 2-CF 3 phenyl 2-Cl -phenyl 2-Cl-phenyl

L

I i 44 For this compound, the silylated derivative (VII) was prepared: cis isomer, m.p. 176-178°C.

Example 65: NMR spectrum at 200 MHz in DMSO at T 380 0

K:

Delta Appearance Integration Assignment 2.45 DMSO 3.10 s 3 H C0 2

CH

3 5.00 s 1 H CH 6.30 s 1 H OH 6.80-7.80 m 11 H aromatic protons a.

a *0 a a..

a a a a a a.

3* a EXAMPLES 104 AND 105 N,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-ltosylindoline-2-carboxamide, trans isomer, cis isomer A) 5-Chloro-2-tosylaminophenyl cyclohexyl ketone This compound is the one prepared in Example 18, step A.

B) Dimethylbromoacetamide A solution containing 56 g of bromoacetyl bromide in 100 ml of DCM is cooled to 0°C and gaseous 20 dimethylamine is bubbled into the medium until it becomes basic. The mixture is filtered and dried and the crude amide is concentrated to give an oil (22 g).

C) chlorophenyl cyclohexyl ketone 4.3 g of 5-chloro-2-tosylaminophenyl cyclohexyl ketone are placed in 20 ml of DMF in the presence of 360 mg of 80% sodium hydride, after 15 minutes at RT 5.4 g of the compound prepared in step B are added and the mixture is stirred overnight at RT. The reaction medium is poured into water and the precipitate is filtered off and then taken up with DCM, dried and concentrated. The expected product crystallizes from isopropyl ether.

m 3.9 g M.p. 184-187'C 45 D) N, N-Dimethyl-5-chloro-3-cycohexy-3-hydroxy-'ltosyli-doline-2-c!-i..toxamide, trans isomer g of the compound obtained in the previous step are cooled to -78 0 C in 20 ml of anhydrous THF, 2.3 ml of a 1.5 M solution of LDA in cyclohexane are added and the mixture is stirred for 2 hours at -78 0 C. It is poured into water and extracted with D014 and the extract is dried and concentrated. The crude product obtained is chromatographed on silica; an AcOEt/DCM mixture (10/90, v/v) elutes a compound which is shown .by NNR to be the trans isomer. It is r~tcrystallized from an isopropyl ether/DCM mixture.

00- M.p. 179-182 0

C

6:69E) N ,N-Dimethyl-5-chloro-3-cyclohexyl-3-hydroxy-1- 15 tosylindoline-2-carboxamide, cis isomer 1. 5 g of the product obtained in step C are treated with 950 mg of DBU in 10 ml of DOM for 24 hours at RT. The reaction medium is then chromatographed on silica using a DCMv/AcOEt mixture (95/5, v/v) as the eluent to give the other isomjer (cis isomer) It is recrystallized from isopropyl ether.

m 120 mg M.P. =152-155*C EXAMPLES 106 AND 107 N,N-Dimethyl-5-chloro-3-( 2-chlorophenyl)-3- **hydroxy-1-tosylindoline-2-carboxamide, trans isomer, cis isomer.

A) 5, 2'-Dichloro-2-tosylaminobenzophenone This compound is prepared by the customary method.

B) 2- (Tosyl (dimethylcarbamoylmethyl )amino]-5,2'dichlor obenzophenone 8.4 g of 5,2'-dichloro-2-tosylaminobenzophenone are dissolved in 40 ml of DMF and treated with 0.7 g of 46 sodium hydride; after 15 minutes, 10 g of dimethylbromoacetamide, prepared in Example 1, are added and the mixture is stirred overnight at RT. The reaction medium is poured into water, the precipitate formed is filtered off and taken up with DCM and the solution is dried and concentrated. 9.2 g of the expected product are obtained after crystallization from isopropyl ether.

M.p. 154-157°C C) N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy- 1-tosylindoline-2-carboxamide, trans isomer 1.5 g of the compound obtained in the previous step are treated at -78°C, in 100 ml of anhydrous THF, with 2.6 ml of a 1.5 M solution of LDA in cyclohexane 15 for 3 hours. The mixture is poured into water and extracted with DCM and the extract is dried and con- S"centrated. The residue is chromatographed on silica using a DCM/AcOEt mixture (94/6, v/v) as the eluent. A small amount of the less polar compound is collected 20 and the more polar compound is then eluted: trans Sisomer.

It is recrystallized from a DCM/isopropyl ether mixture.

M.p. 232-233°C D) N,N-Dimethyl-5-chloro-3-(2-chlorophenyl)-3-hydroxy- 1-tosylindoline-2-carboxamide, cis isomer 1.5 g of the compound prepared in step B are refluxed in DCM for 24 hours in the presence of 900 mg of DBU. The mixture is chromatographed on a silica column using a DCM/AcOEt mixture (95/5, v/v) as the eluent. 190 mg of the expected product are obtained after recrystallization from isopropyl ether.

M.p. 220-221°C E) The compound of step B (1.0 g) is dissolved in acetonitrile (25 ml), and 109 mg of sodium hydroxide in 47 2 ml of water are added. The medium is heterogeneous; it is stirred violently at 45 0 C for 1 hour, using a turbine and compressed air, either in the presence of 110 mg of benzyltriethylammonium chloride or without the addition of this reagent, After extraction, the product obtained in the form of a mixture of the 2 isomers, cis and trans, is determined. The ratio of the 2 isomers observed by NMR at 360K in DMSO is 1/1.

EXAMPLE 108 chloro-3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide, cis isomer 15 A) Sodium 4-allyloxyphenylsulfonate 30 g of sodium phenylsulfonate are dissolved in 60 ml of ethanol and 50 ml of 15% sodium hydroxide, g of allyl bromide are added and the mixture is refluxed for 48 hours. The ethanol is concentrated and S 20 the precipitate obtained is filtered off and then dried under vacuum in the presence of phosphorus pentoxide to give 23.3 g of the expected product.

S. B) 4-Allyloxyphenylsulfonyl chloride The product obtained in the previous step (23.3 g) is treated overnight with 24 g of phosphorus pentachloride under reflux in 300 ml of DCM. The medium is filtered and concentrated to give an oil (16.5 g).

C) 2- [N-(4-Allyloxyphenylsulfonyl)amino]-2',5-dichlorobenzophenone The sulfonyl chloride obtained in the previous step is added to 19 g of 2',5-dichloro-2-aminobenzophenone in 200 ml of pyridine. After one night at room temperature, the pyridine is concentrated, the residue is taken up with hydrochloric water and extracted with 48 DCM and the extract is dried and concentrated. The crude product is chromatographed on silica and a DCM/ pentane mixture (50/50, v/v) elutes the expected product, which is crystallized from a DCM/isopropyl ether mixture to give 8.5 g of the expected product.

M.p. 96-97°C D) 2-(N-(4-Ally3,oxyphenylsulfonyl)-N-(N',N'-dimethylcarbamoylmethyl)amino 4 g of the product obtained in the previous step are dissolved in 20 ml of DMF under nitrogen, 310 mg of 80% sodium hydride are added, the mixture is stirred for 15 minutes at RT and 3.1 g of bromo-N,Ndimethylacetamide are then added. After one night at RT, the medium is poured into water, the product is 15 filtered off and takn up with DCM, the solution is dried and concentrated and the residue is then crystallized from a DCM/isopropyl ether mixture to give 4 g of the expected product, which is finally recrystallized from the same solvent mixture.

M.p. 133-135'C E) 3-(2-chlorophenyl)-3-hydroxyindoline-2-carboxamide, cis isomer 3.8 g of the product obtained in the previous step are treated at 30"C with 1.8 g of DBU in 20 ml of DCM for 3 days. The medium is chromatographed on Salumina and DCM elutes the less polar compound, which is recrystallized from a DCM/isopropyl ether mixture to give m 840 mg.

M.p. 181-182'C 49 EXAMPLE 109 N-Benzyl-N-methyl-5-chloro-3-(2-chlorophenyl)- 3-hydroxy-l-(3,4-dimethoxyphenylsulfonyl)indoline-2carboxamide, cis isomer A) N-Methyl-N-benzylbromoacetaiide At 0°C, a solution of 10 g of bromoacetyl bromide in 20 ml of DCM is added to a solution of 6 g of methy.lberzylamine and 5g of triethylamine in 50 ml of DCM.

After one night at RT, ether is added, the precipitate formed is filtered off and the filtrate is concentrated to give 12 g of the expected product in crude form.

B) 2',5-Dichloro-2-(3,4-dimethoxyphenylsulfonamido)benzophenone This compound was prepared in Example 25, step 15 A.

e C) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-N- *O (N'-methyl-N'-benzylcarbamoylmethyl)amino]benzophenone g of the compound described in step B are S 20 dissolved in 30 ml of DMF and treated with 400 mg of S sodium hydride. After 15 minutes, 12 g of the brominated derivative prepared step A are added and the mixture is stirred at RT for 24 hours. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is chromatographed on silica and the expected product is eluted with DCM.

S* m 2.1 g M.p. 148-150*C D) N-Benzyl-N-methyl-5--coro-3-(2-chlorophenyl)-3hydroxy-1-(3,4-dimethoxyphenylsulfonyl)indoline-2carboxamide, cis isomer The 2.1 g of product obtained in the previous step are treated with 1 g of DBU in 20 ml of DCM for 3 days. The reaction medium is poured on to an alumina 50 column and DCK elutes the less polar isomer (870 mg) in the form of an oil. After drying, a foam is obtained which is characterized by NMR: 2.81 ppma s 3H N-CH3 3.60 ppm m 8H 20CH 3

N-CH

2

-C,H

5.35 ppm s IH CH (2-indoline) 7.80 ppm m 16H aromatic protons

OH

EXA&MPLES 110 AND ill 5-Chloro-3-(2-chorophenyl) 4-dimethoxyphenylsulfonyl) -3-hydroxy-2-pyrrolidinocarbonylindoline, cis isomer, trans isomer This compound is preparzd by the customary pro- 15 cedure by the reaction of pyrrolidine bromoacetamide o ecee with 2- 4-dimethoxypheny1sulfonamidb) 2'-dichlorobenzophenone and then cyclization of the resulting product with DBU in chloroform. A product is eluted on an alumina column with DCM/AcOEt (90/10, it is the cis isomer.

M.p. 237*C

SOO:

AcOEt elutes the trans isomer, which is then es, recrystallized from AcOEt.

0 00* M.p. 230*C EXAMPLE 112 5-Chloro-3-(2-chlorophenyl)-l-(3,4-dimethc xyphenylsulfonyl)-3-hydroxyindoline-2-carboxamlde, trans isomer A) 2' 5-Dichloro-2- 4-dimethoxyphenylsulfonamido) benzophenone 114 g of 2-amino-5,2'-dichlorobenzophenone and 100 g of 3,4-dimethoxyphenylsulfony. chloride are mixed in 300 ml of pyridine. After 4 days at RT, the excess pyridine is evaporated off, the residue is taken up 51 with hydrochloric water and extracted with DCM and the extract is dried and concentrated. The expected product then crystallizes from a DCM/isopropyl ether mixture.

m 181 g M.p. 159-161°C B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenylsulfonyl)- N-(benzyloxycarbonylmethyl)amino]benzophenone 172 g of the *roduct prepared above are dissolved in 800 ml of DCM and cooled to 0°C. 11.7 g of 80% sodium hydride are added gradually under nitroen, 255 g of benzyl bromoacetate are then added after SS**minutes and the mixture is stirred for 24 hours at RT.

The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried Sand concentrated. The expected product crystallizes from isopropyl ether and is then recrystallized from a DCM/isopropyl ether mixture.

m 136.5 g M.p. 102-104'C C) Benzyl 5-chloro-3-(2-chlorophenyl)-l-(3,4-dimethoxy- •yphenylsulfonyl)-3-hydroxyindoline-2-carboxylate, trans isomer 3 g of the product obtained in the previous step ire treated with 740 mg of TBD in 20 ml of DCM at RT for 1 hour. The reaction medium is chromatographed Son silica and DCM elutes the expected compound in the form of the trans isomer, which is the only isomer formed by the cyclization reaction.

The compound obtained is rcrystallized from a DCM/isopropyl ether mixture.

m 2 g M.p. 190-192°C 52 D) 5-Chloro-3- (2-c~ihlcrophenyl) 3, 4-dimethoxyph~nylsulfonyl )-3-hydroxyindoline-2-carboxylic acid, trans isomer The benzyl ester obtained in the previous step, in 50 ml of AcOEt, is treated with hydrogen forc minutes in the presence of 100 mg of 10% Pd/c. The reaction medium is filtered on C61ite, the m~aterial on the filtei: is washed with hot methanol and the filtrat6 is conceNtrated. The expected product crystaI4i1zes, from a DCM/isopropyi ether mixture.

m. 1.5 g 218-221 0

C

E) 5-Chloro-3-(C2-chiorophenyl ,4-dimethoxyphenylsulfonyl )-3--hydroxyindoline-2- r= ,,.-amide, trans 15 isomer 0* 0 0 6 op 0 4 000 0040 0 *OhO 000000

I

00 4 9 03 180 mg of the compound obtained in the previous Step, in 15 ml of DC!4, are treated With 140 mg of BOP in the presence of a suf f icient amount of DIPEA to solubilize the acid. After 15 minutes, gaseous ammonia is introduced f or 10 minutes. The medium is poured into a saturated solution of sodium hydrogencarbonate and extracted and the extract is dried and then concentrated. The crude product is chroinatographed on silica using a DCI4/AcOEt mixture (80/20, V/v) as the eluent to give the expected compound, whfrtch is then recrystallized from a DCM/isopropyl ether mixture.

m 63 mg M.p. 183-1850C EXAMPLES 113 AND 3114 3-cyclohexyl-3-hydroxy-1tosylindoline-2-carboxamide, cis isomer, trans isomer A) 2- (N-tosylamino) -S-chJlorophenyl cyclohexyl ketone is prepared by the customary method.

53 B) 2-[N-(N'-Isopentylcarbamoylmethyl)-N-(tosyl)amino]cyclohexyl ketone 7.2 g of the compound obtained above in 130 ml of DMF are cooled to O'C and placed under argon, 1.1 equivalents of sodium hydride are added and the mixture is allowed to return to RT. 15.2 g of N-isopentyl-2bromoacetamide are then added and the mixture is stirred overnight at RT. The DMF is evaporated off, the residue is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is chromatographed on silica using an ether/ pentane mixture (70/30, v/v) as the eluent.

C) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxamide, mixture of isomers S 15 2.1 equivalents of LDA are added to 3 g of the above product in 50 ml of anhydrous THF at -20 0 C and the temperature is then kept at +4 0 C for 30 minutes.

The medium is poured into a saturated solution of ammonium chloride and extracted and the extract is dried and concentrated. Chromatography on silica using methylene chloride as the eluent gives the expected product in the form of a mixture of 2 isomers.

m 2 g D) N-Isopentyl-5-chloro-3-cyclohexyl-3-trimethylsilyloxy-l-tosylindoline-2-carboxamide 1 g of the product obtained above is heated at 100l C in 5 g of HMDS for 12 hours under argon in the presence of 0.1 g of imidazole. The medium is evaporated, the residue is taken up with DCM and the solution is chromatographed on silica. DCM successively elutes the less polar isomer, which is recrystallized from isopropyl ether: m 345 mg M.p. 137-138 0

C

and then the more polar isomer, which is recrystallized 54 from isopropyl ether: m 165 mg M.p. 175-176°C E) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosylindoline-2-carboxamide, cis isomer 150 mg of the less polar isomer obtained above are treated with 10 mg of sodium hydroxide at 0OC in ml of THF and 2 ml of water for 3 hours. The mixture is taken up with water and extracted with DCM and the extract is dried and concentrated. The crude product is recrystallized from a DCM/isopropyl ether mixture.

m 120 mg M.p. 189-191°C rg F) N-Isopentyl-5-chloro-3-cyclohexyl-3-hydroxy-l-tosyl- 15 indoline-2-carboxamide, trans isomer S" 150 mg of the more polar isomer obtained in step D are treated with 10 mg of sodium hydroxide in ml of THF and 2 ml of water for 2 hours at RT. The mixture is taken up with water and extracted with DCM and the extract is dried and concentrated. The expec- 0 ted product is recrystallized from a DCM/isopropyl 0 ether mixture.

m 65 -ig a M.p. 195-196'C The compounds according to the invention which 1Spete are described in Table 2 below were prepared by fol- S* lowing the procedure given in the Examples described above: 5F TABLE 2 Rl OH I H ,16 N CON S02 R7 For each compound of formula having the substituents RI, R 2

(R'

5

)P.

and NR 6

R

7 in the Table below, the ci isomer is indicated and then the trans isomer, unless stated otherwise.

00 0 0 b0 0* 0 .00 0000 009000

S

0*

S

S.

15 IT R

,-R

6 M. p. 00C Ex. RI R 2

(R

5 P, -N crystallization -"R7 solvent

S

a

SOSO

a *0 0 0e 0 900 0 00505*

S

@0 05 0 115 116 117 118 119 trans 120 121 5-Cl 5-Cl 5-Cl 5-Br 2-Cl -phenyl cyclohexyl 2-Cl-phenyl 2-F-phenyl 3 ,4-dimethoxy 4-CH 3 3 ,4-dimethoxy 3,4-dimethoxy N 2

NHCH,

NHCH

3

N(CH

3 2 201 DCM/isopropyl ether 222 DCM/isopropyl ether 224- 225 DCM/isopropyl ether 141-148 DCM/isopropyl ethc-, 148 DCM/isopropyl ether 165 DCM/isopropyl ether 214 DOM/isopropyl ether 56

SO

9 9 99 .9 9 909 *0S* 9 9 9 9 9 .9 122 cis 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 5-Cl 2-Ci-phenyl 2 -Cl -phenyl 2-Cl -phenyl -phenyl 2 Cl-pherlyl 2 -methoxyphenyl 2,5 -dime thoxy 4-methoxy 3 ,4-dixmethoxy 3,4-dime thoxy 2 ,4-dimethoxy 3 ,4-dimethoxy N( CH 3 2 1N(CH 3 2

N~(CH

2

CH

3 2

N(CH

3

-CH.-

CH

2

C

6

HS

N(CH

3 2

N(CH

3 2

N(CHCH

3 2

N(CH

2

CH-

3 2 N~(CH2CH 3 2 140-142 DCM/isopropyl ether 240 DCM/hexane 187 DCM/hexane 213 hexane/iso propyl ether 200 hexane/iso propyl ether 125-130 hexane/iso propyl ether 140-142 DOM/isopropyl ether 213 206 205 hexane/isopropyl ether 206 hexane/isopropyl ether 1.89 isopropyl ether 191 isopropyl ether 208- 209 isopropyl ether 214- 215 isopropyl. ether 225

S

9999.9 9 9 .994 99 9* 9 9.

0 999 9 999999 9 99 99 99 9 9 5-GH 3 2-Ci-phenyl 13,4-dimethoxy 5-CH 3 2-Cl-phenyl S2-Cl-phenyl 2,4-dime thoxy 2,4-dime thoxy 5-Cl 57 138 200 139 5-Cl 2-Ci-phenyl 4-cyano N(CH 3 )2 242-243 THF/EtOH 140 228-231 DCM/isopropyl ether 141 5-G1 2-Ci-phenyl 3,4-dimethoxy bl(C 4

H

9 2 203 c is DCM/isopropyl ether 142 5-Cl cyclohexyl 3,4-diinethoxy

N(CH

2

CH

3 2 117-120 143 NMR 144 5-Cl 2-F-phenyl 4-nitro N(CH 3 2 230 ci s 15 NMR spectrum 6:00 Example 143: trans isomer 1.8 ppm mn 17H 2CH, (ethyl), 11H cyclohexyl 2.8 3.5 ppm :m 4H -H22 3.7 ppm :s 3H1 00113 **3.75 ppm s :3H 00H 3 4.7 ppm :s :1H1 H (indoline) 5.65 ppm :s 1H :OH (indoline) 6.8 7.6 ppm mn 6H1 aromatic protons EXAMPLES 145 AND 146 0 Methyl 5-chloro-3- (2-chlorophenyl )-3-hydroxy-ltosylindoline-2-carboxylate, dextrorotatory cis isomer, levorotatory cis isomer The optical isomers of methyl 5-chloro-3-(2chiorophenyl )-3-hydroxy-1-tosylindoline-2-carboxylateI ego**:described in Example 48 of Table 1, were separated by preparative chromatography on a chiral column.

30 Supercritical phase analytical chromatography is first carried out on the product of Example 48.

The column used is a Chiralcel 0DO column marketed by DAICEL. This column consists of silica gel coated with cellulose carbamate.

The eluent is a carbon dioxide/propan-2-ol/di- 58 ethylamine mixture (75/25/0.3, v/v/v) used at a flow rate of 2 ml/minute. The exit pressure is 160 atmospheres, the temperature is 32°C and UV detection is carried out at 226 nm.

The chromatogram shows 2 peaks of equal areas and with retention times of about 4 minutes and 5.4 minutes.

A Chiralcel® column is also used for preparative chromatography.

The sample of product to be chromatographed is dissolved in methanol (30 mg/ml) and 1 ml is injected into the column. The eluent is a hexane/propan-2-ol mixture (80/20, v/v) used at a flow rate of 1.5 ml/ S* minute. UV detection is carried out at 226 nm. The 15 analysis time is 45 minutes. Twelve fractions were collected and analyzed in the supercritical phase.

Under the same conditions, 13 injections of

S

mg are then carried out. The fractions corresponding to the first peak, collected between 16 and 24 minutes, are pooled; the fractions corresponding to the second peak, collected between 29 and 42 minutes, are pooled.

After passage under a stream of nitrogen, each batch is recrystallized from a DCM/isopropyl ether/hexane mixture.

S 25 The first peak gives a product with a chromatoyraphic purity of more than 99.9%; this is the dextrorotatory cis isomer.

a= 3 +236 (chloroform) M.p. 174-177'C (after recrystallization from 30 DCM/hexane/isopropyl ether) m 130 mg The second peak gives a product with a chromatographic purity of more than 99.5%; this is the levorotatory cis isomer.

a0, 25 -238 (chloroform) -59- M.p. 174-177*C (after recrystallization from DCM/hexane/isopropyl ether) in 83 mng 5 a 0 0 0 3

Claims (10)

1. A compound of the formula N R4 I S02 in which -RX is a halogen, atom, a alkyl, a hydroxyl, a C, -C 4 alkoxy,, a benzyloxy group, a cyano group, a trifluoromethyl group, a nitro group or an amino group; R is a C.,-C 6 alkyl, a cycloalkyl, a C,-C. cycloalkene or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a alkyl, a C.-C 4 alkoxy, a halogen, a trifluoromethyl group, a nitro group or an amino group; R 3 is a hydrogen atom or a alkyl; -R 4 is a carboxyl group, an alkoxycarbonyl group in which the alkyl group is 6 a benzyloxycarbonyl group or a carboxamide group of the formula CONRR.; -R 5 is a C,-C 4 alkyl; a l-naphthyl; a 2-naphthyl; a dimethylamino-l-naphthyl or a phenyl which is unsub- .:*stituted or substituted by one or more substituents selected from a halogen atom; a alkyl; a tri- fluoromethyl group; a nitro group; an amino group which is f ree or substituted by one or 2 C ,-C 4 alkyls; a hydroxyl;~ a alkoxy; a alkencory; a alkylthio; a trifluoromethoxy group, a ben- zyloxy group; a cyano, group; a carbonyl group, a C.- 61 C 4 alkoxycarbonyl group; a carbamoyl group or a C -C, alkylamido group, or, when m 0, R, can be a group 0\ CH2 R and R 7 are each independently hydrogen, a C,-C, alkyl or a phenylalkyl in which the alkyl is C 1 -C 4 or RG and R, together form a group -(CH 2 n is 0, 1 or 2; m is 0, 1 or 2; and p is 4, 5 or 6; and its salts, where appropriate.

2. A compound according to claim 1 in which R, is a o chlorine or bromine atom or a methoxy group, n and the other substituents are as defined for in claim 1.

3. A compound according to claim 1 in which R, is a vethoxyphenyl, a chlorophenyl or a cyclohexyl and the other substituents are as defined for in claim 1.

4. A compound according to claim 1 in which R, is hydrogen and the other substituents are as defined for in claim 1. A compound according to claim 1 in which R 4 is an alkoxycarbonyl in which the alkyl group is C 1 -C 6 and the other substituents are as defined for in claim 1.

6. A compound according to claim 1 in wh aI R 4 is a carboxamide group CONR 6 R, in which R 6 and i 7 are C.-C, alkyls, and the other substituents are as defined for in claim 1.

7. A compound according to claim 1 in which R, is a phenyl substituted in the 3 and 4 positions or in the 2 62 and 4 positions by a methoxy group, or else R, .s a phenyl substituted in the 4 position by a methyl qcoup, and the other substituents are as defined for in claim 1.

8. A compound accecding to claim 1 in which m is 0 and the other substituents are as defined for in claim 1.

9. A compound according to claim 1 in the form of the cis isomer in which R 2 and R 4 are on the same side of the indoline ring. A method of preparing a compound according to claim 1, which comprises a) reacting a sulfonyl derivative of the foc'- mula o eog Hal-SO- (CH (III) C in which Hal is a halogen, preferably chlorine or c" bromine, and R, is as defined for in claim 1, with a 2-aminophenone derivative of the formula CO-R 2 to 0. (R *I C*ln s A(II) to INH 2 in which R R, and n are as defined above for b) treating the resulting compound of the for- mula C 63 (Ri n IJNH s0 2 (IV) (CH2)m with a halogenated derivative of the formula '040 Hal' C -R3(V) in which Hall is a halogen, preferably bromine, and R, and R 4 are as defined for in claim 1; c) cyclizing the resulting compound of the for- mula COR2 0 0* (RI)n N-CH (VI) :i 02 \R4 CH2)M in a basic medium in order to prepare the compound (I) according to claim 1; and d) separating the gj and trans isomers of the compound if appropriate. -64-

11. A pharmaceutical composition in which a compound according to any one of claims 1 to 9 i present as the active principle, together with a pharmaceutically acceptable carrier.

12. A compound according to claim 1, a method for the preparation or use thereof, or a pharmaceutical composition comprising a said compound, substantially as hereinbefore described with reference to the Examples. *DAVIES COLLISON CAVE DATED this 5th day of November, 1993 $ianofi Ey Its Patent Attorneys .DAVIES COLLISON CAVE oi 931105,q: operkdab,8147&spe.64 N-Sulfanylindoline derivatives of the formula II (CH2)m age.., in w~hich a 0 RI. is a halogen atom, a alkyl, a hydroxyl, a alkoxy, a benzyloxy group, a cyano group, a triflupromethyl group., a nitro group or an amino group; -R 2 is a C alkyl, a C 3 cycloalkyl, a C,-C, 9: 4 cycloalkene or a phenyl which is unsubstituted or so 0 monosubstituted or polysubstitutc- by a al~kyl, :4Q a C.-C 4 alkoxy, a halogen, a trifluoromethyl group, a 0 nitro group or Nna amino group; is a hydrogen atom or a CL-C 4 alkyl; -R 4 is a carboxyl. group,, an alkoxycarbon~yl group in which the alkyl group is a benzyloxycarbonyl group or a carboxamide group of the formula COI4RR,,V -RS is a C.-C 4 alkyl, a I-naphthyl, a 2-naphthyl, a diinethylamino-l-naphthyl or a phenyl. Which is unsub-_ stituted or substituted by one or more substituents selected from a halogen atom, a C,-C 4 alkyl, a tri- fluoromethyl group, a nitro group, an amino group which is free or substituted by one or 2 C,-C 4 alkyls, a hydroxyl, a alkoxy, a alkenoxy, a C.-C 4 alkylthio, a trifluoroinethoxy group, a ben- zyloxy group, a cyano group, a carboxyl group, a Ca lkoxycarbonyl group, a carbainoyl group or a C, -C 4 alkylaniido group, or, when m 0, R. can be a group 0 ~0/ and R are each independently hydrogen, a C 1 alkyl or a phenylalkyl in which the alkyl is CX- 4 £9d or and R 7 together form a group -n is 0, 1 or 2; -mi is 0, 1 or 2; and -p is 4, 5 or 6; and their salts, where appropriate.