SK280096B6 - Heterocyclic n-substituted derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

The invention concerns heterocyclic N-substituted derivatives of the formula (I) in which: R1 and R2 denote, for instance, hydrogen or an alkyl group, alkoxy group, amino group, carboxy group, cyano group; R3 is, for instance, hydrogen, an alkyl group, alkenyl group and cycloalkyl group; R4 and R5 are each optionally a substituted alkyl group, phenyl group or phenylalkyl group; or R4 and R5 together form a group of the formula =CR7R8, in which R7 is hydrogen, an alkyl group or a phenyl group and R8 is an alkyl group or phenyl group; or R4 and R5 together are either a group of formula (CH2)n or one of formula (CH2)pY(CH2)q, where Y is, in particular, oxygen or sulphur or a substituted carbon atom; or R4 and R5 together with the carbon atom to which they are bonded constitute an indame or adamantame; p + q = m; n is an integer between 1 and 11; m is an integer between 2 and 5; X is an oxygen or sulphur atom; z and t are zero or one is zero and the other is unity; and their salts; methods of preparation of said derivatives; and pharmaceutical compositions containing said derivatives as its active agent. Application: antagonists to angiotensin II.

Description

Technical field

The invention relates to N-substituted heterocyclic derivatives, processes for their preparation and pharmaceutical compositions containing them as active ingredient.

BACKGROUND OF THE INVENTION

The compounds of the invention agonize the effect of angiotensin II, which is a peptide hormone of the formula

H-Asp-Arg-Val-Tyr-Ile-H-Pro-Phe-OH.

Angiotensin II is a potent vasoconstrictor and is a biologically active product of the renin-angiotensin system: renin acts on angiotensinogenic plasma to produce angiotensin I, which is then converted to angiotensin II by the action of the angiotensin I conversion enzyme.

The compounds of the invention are non-peptide compounds antagonizing the effect of angiotensin II. By antagonizing the effect of angiotensin II on its receptors, the compounds of the invention mainly prevent the increase in blood pressure caused by the hormone-receptor interaction. The compounds of the invention also have other physiological effects at the level of the central nervous system.

Accordingly, the compounds of the invention are useful for the treatment of cardiovascular disorders, such as, in particular, high blood pressure and cardiac insufficiency and in the treatment of the central nervous system, as well as in the treatment of glaucoma and diabetic retinopathy.

SUMMARY OF THE INVENTION

The present invention provides N-substituted heterocyclic derivatives of formula (I)

in which

R 1 and R 3, which are the same or different, each independently of one another represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 4 alkoxy group, an amino group, an aminomethyl group, a carboxy group, an alkoxycarbonyl group, the alkoxy radical of which contains from 1 to 4 carbon atoms, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanocarbamoyl, N-hydroxycarbamoyl (N-hydroxycarbamoyl) - , 3-thiazol-2-yl) carbamoyl, ureido, 2-cyanoguanidinocarbonyl, 1-imidazolylcarbonyl, 3-cyano-2-methylisothioureidomethyl, wherein at least one of R 1 or R 2 is different from hydrogen,

R3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl radical it contains 1 to 3 carbon atoms, a phenylalkenyl group in which the alkenyl radical contains 2 or 3 carbon atoms, said phenyl groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group containing 1 to 4 carbon atoms, a haloalkyl group (C 1 -C 4), (C 1 -C 4) polyhaloalkyl, (C 1 -C 4) hydroxyl and (C 1 -C 4) alkoxy;

R 4 and R 5 independently of one another denote an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl radical contains 1 to 3 carbon atoms, said alkyl, phenyl and phenylalkyl group being optionally substituted by one or more halogen atoms or a group selected from the group consisting of perfluoroalkyl having 1 to 4 carbon atoms, a hydroxyl group and an alkoxy group having 1 to 4 carbon atoms, or

R 4 and R 5 together form a group of the formula = CR 7 R 8, wherein R 7 is hydrogen, C 1 -C 4 alkyl or phenyl, and R 8 is C 1 -C 4 alkyl or phenyl, or else

R 4 and R 5 taken together are either a group of formula (CH 2) n or a group of formula (CH 2) p Y (CH 2) q in which Y represents an oxygen or sulfur atom, or a carbon atom substituted by a C 1 -C 4 alkyl group; or a phenylalkyl group in which the alkyl moiety contains 1 to 3 carbon atoms or a group X-Rg in which R f1 represents a hydrogen atom, an alkyl group containing 1 to 4 carbon atoms, a phenylalkyl group in which the alkyl residue contains 1 to 3 carbon atoms, an alkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a haloalkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a polyhaloalkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a benzoyl group, an alpha-aminoacyl group or An N-protecting group; or

R4 and R5 taken together with the carbon atom to which they are attached form an indane group or an adamantane group, p + q = m, n represents an integer from 2 to 11, m represents an integer from 2 to 5,

X is oxygen or sulfur, z and t are 0 or one of them is 0 and the other is 1, and salts thereof.

Where the compound of the invention contains asymmetric carbon, the invention includes both optically active isomers of the compound.

Salts of the compounds of formula (I) according to the invention include salts of these compounds with mineral or organic acids which allow suitable separation or crystallization of the compounds of formula (I), such as in particular picric acid, oxalic acid or an optically active acid such as mandelic acid or acid. camphorsulfonic acid, or acid-forming pharmaceutically acceptable salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, fumarate or 2-naphthalenesulfonate.

Salts of the compounds of formula (I) also include salts with organic or mineral bases, for example alkali metal or alkaline earth metal salts such as, in particular, sodium, potassium or calcium salts, with preferred salts being sodium, potassium or tertiary amine salts such as is, for example, trometamol, or else arginine, lysine, or salts with any other pharmaceutically acceptable amine.

In the following description and in the definition of the claims, a halogen atom means a bromine atom, a chlorine atom or a fluorine atom; An N-protecting group (also referred to as Pr) is a group that is conventionally used in peptide chemistry to temporarily protect an amino group, such as a Boe, Z, Fmoc, or benzyl group; an esterified carboxyl group is understood to mean an ester which is labile under suitable conditions, for example, methyl ester, ethyl ester, benzyl ester or tert-butyl ester. Alkyl is a straight or branched aliphatic hydrocarbon radical.

Compounds of general formula (I) in which R @ 1 in ortho position and represents a carboxyl or tetrazolyl group and R2 represents hydrogen are preferred compounds.

Compounds of formula (I) in which R 4 and R 5 together with the carbon atom to which they are attached form cyclopentane or cyclohexane are also preferred compounds.

Likewise, compounds of formula (I) wherein R 3 is a straight C 1 -C 6 alkyl group are preferred.

Compounds of formula (I) wherein X is O are also preferred.

Finally, compounds of formula (I) in which z = t = 0 are preferred compounds.

In the description and examples, the following abbreviations have the following meanings:

Ethyl nBu, tBu n-butyl, t-butyl

DMF dimethylformamide

THF tetrahydrofuran

DCM dichloromethane

NBS N-bromosuccinimide

DCC dicyclohexylcarbodiimide

DIPEA diisopropylethylamine ether diethyl ether

TFA trifluoroacetic acid

Z - benzyloxycarbonyl

Boe tert-butoxycarbonyl

BOP benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate

Fmoc fluorenylmethyloxycarbonyl.

The invention also relates to a process for the preparation of N-substituted heterocyclic derivatives of the general formula (I), which is characterized in that a1) is a heterocyclic derivative of the general formula (2):

H wherein z, t, R 3, R 4 and R 5 have the meanings given in claim 1 for the general formula, react with a (biphenyl-4-yl) methyl derivative of the general formula (3)

Hal-CH

wherein Hal represents a halogen atom and R '1 and R' 2 represent R 1 and R 2, respectively. R 2 or a precursor group R 1, respectively. R2, whereby b1) the compound of general formula (4) thus obtained,

reacts with Lawesson's reagent, which is 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphethane-2,4-disulfite, and cl) the compound obtained in step a1) or b1). ) and with the general formula (5)

wherein X is an oxygen or sulfur atom, is converted to a compound of formula (I) by converting the groups R'1 and / or R'2 to the groups R1 and / or R2, and optionally converting the compound to one of their salts.

The derivatives of formula (2) are prepared by known methods. Thus, for example, the procedure described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 3, 1040-1051) and Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373) and react the alkylimidate with the amino acid according to the following reaction line or ester thereof:

P, / CH, / -CO B '\ / / \

R- '

(6) (2), wherein R is C 1 -C 4 alkyl, R 1 is hydrogen or C 1 -C 4 alkyl, and R ₃ , R 4, R 5, while as defined above for formula (I) ).

This reaction is carried out in an acidic medium by heating in an inert solvent such as xylene or toluene.

Alternatively, a compound of formula (2) may be prepared by treating an ortho-alkyl ester of formula (10) with an aminoalkyl amide of formula (5) in an acidic environment according to the following reaction scheme (CH ₂ ) _and -CO NH ₂ + H ₃ -C (OR) ( ₃ '5') (10) wherein R represents an alkyl group having 1 to 4 carbon atoms.

The compound of formula (2) may also be prepared using the procedure described by H. Takenaka et al. (Heterocycles, 1989, 29, 6, 1185-1189). This process comprises treating a derivative of formula (5) with an acid halide of formula (12): R ₃ -CO-Hal (12), wherein Hal is halogen, preferably chlorine. The reaction is carried out in an alkaline medium.

In particular, the compound of formula (2) is prepared by a process according to the invention which comprises the following:

R, / CH, / COA

K (z ^R 5/13), wherein A is OH, NH 2 or OR ', where R' is hydrogen or (C 1 -C 4) -alkyl, is a compound of formula (14):

R3-B wherein B is:

C (OR) ₃ , (14)

NH _C Z or \

OR is COHal, wherein R is C 1 -C 4 alkyl and Hal is halogen, preferably chlorine, optionally treated with Lawesson's reagent.

The (biphenyl-4-yl) methyl derivative of general formula (3) is prepared according to the procedure described in European Patent Application EP 324 377.

The conversion of the group R 1 and / or R 2 into the group R 1 and / or R 2 is carried out by methods known to the person skilled in the art. When the compound of formula (I) to be prepared has a group R 1 and / or R 2 = carboxyl, then R 1 and / or R 2 is an esterified carboxyl group. When the compound of formula (I) to be prepared has a group R 1 and / or R 2 = a tetrazolyl group, then R 1 and / or R 2 may be either a tetrazolyl group, protected for example by a trityl group or cyano, which will then be replaced by a tetrazolyl group optionally protected by a trityl group. Conversion of the cyano group to a tetrazolyl group may be accomplished by an azide, for example, tributyltin azide or sodium azide.

It is also possible to use R 1 and / or R 2 groups, such as nitro, carboxyl, cyano or acid chloride groups, and then convert these groups by reactions well known to those skilled in the art to R 1 and / or R2 which have been described for the compound of formula (I).

When R '1 and / or R' 2 represents a carboxyl group, this group can be converted to R 1 and / or R 2 is imidazol-1-ylcarbonyl or N - [(4-carboxy) -1,3-thiazol-2-yl] carbamoyl.

When R 1 and / or R 2 is an acid chloride group, this group may be converted to R 1 and / or R 2 representing N-hydroxycarbamoyl, N-cyanocarbamoyl, ureide or cyano-2-guanidino-carbonyl.

When R 1 1 and / or R 2 2 is nitro, this group may be converted to an amine group from which R 1 and / or R 2 such as methylsulfonylamino, trifluoromethylsulfonylamino and three fluoromethylsulfonylaminomethyl may be prepared.

When R '1 and / or R' 2 is cyano, this group can be converted to an aminomethyl group from which a 3-cyano-2-methylisothioureidomethyl group is prepared (following the procedure of C. Gordon et al., Described in J. Org. Chem., 1970, 35, 6, 2067-2069) or a 2-cyano-guanidinomethyl group (by the method of RW Turner described in Synthesis, 1975, 332).

Step a1) is carried out in an inert solvent such as DMF, DMSO or THF in an alkaline medium, for example in the presence of potassium hydroxide, metal alcoholate, metal hydride, calcium carbonate or triethylamine.

Step b1) is carried out by heating under a nitrogen atmosphere in a solvent such as toluene according to the procedure described by M. P. Cava et al. in Tetrahedron, 1985, 41, 22, 5061.

In the following description, the process comprising steps a1), b1) and c1) will be called method 1.

Alternatively, the compounds of formula (I) may be prepared by a further process which also forms the subject of the invention. The principle of this method is that: a2) the amino acid of formula (7):

R, / (CH.) NHPr _{R R} / L ⁵ (CH,):

COOH (7), wherein z, t, R4 and R5 are as defined for formula (I), with an amino group protected by Pr, is reacted with a (biphenyl-4-yl) methylamine derivative of formula (8):

(8), wherein R '1 and / or R' 2 are either R 1 and R 2, or precursor groups R 1 and R 2, wherein b2) after deprotection of the amine group to the compound of formula (9) thus obtained :

then treating with an orthoalkyl ester of formula (10): R ₃ C (OR) ₃ (10), wherein R 3 is as defined for formula (I) and R is C 1 -C 4 alkyl, where c2) to the compound of formula (4) thus obtained:

treated with Lawesson's reagent [bis-2,4- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide], and d2) the compound obtained in b2) or c2) of the general formula ( 5):

is then worked up under conditions suitable for the preparation of the compound of formula (I) by converting the groups R ' ₂ and / or R' j into the groups R ₂ and / or R j.

Compounds of formula (7) are known compounds or may be prepared by known methods (Chemistry of the Amino Acids, Greenstein and Winitz, John Wiley ed. 1961, Vol. I, p. 697).

Compounds of formula (8) are prepared according to the procedure described in European patent application 324 377. Step a2) is carried out under conditions customary for coupling of an acid with an amine, for example in the presence of BOP and DIPEA.

Step b2), which is cyclization of a compound of formula (9) in the presence of a compound of formula (10), is carried out according to the procedure of Jacquier et al. (Bull. Soc. Chim. France, 1971, 3, 1040-1051) and the procedure of Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373).

In the following description, the process comprising steps a2) to d2) will be referred to as process (2).

According to process variant 2, an intermediate of formula (9 ') can optionally be isolated in step b2):

heaps mean the group = CR7Rg, can react in an acidic environment an amino acid of formula (7 '):

CH3 - (CH3) - NHCOR3

I (to (CH ₂ ), - COOH with aldehyde or ketone of general formula:

R ₇ COR ₈ , wherein R 7 and R 8 have the meanings given for formula (I), whereby a compound of formula (8) is obtained by treatment with a compound of formula (8):

Cyclization of this compound in an acidic medium results in a compound of formula (4). This method for the preparation of a compound of formula (I), wherein R] and / or R ₂ is carboxy, R and R 'i / or R ₂ is preferably tere.-butoxycarbonyl.

Finally, another alternative of the process for the preparation of the compounds of formula (I) according to the invention, in which z and t are equal to zero, comprises photooxidation, and this alternative also forms the subject of the invention.

The latter method consists in that: a3) an imidazole derivative of the general formula (11):

H, in which R 3, R 4 and R 5 have the meanings given for formula (I), reacts with a (biphenyl-4-yl) methyl derivative of formula (3):

in which Hal represents a halogen atom and R '1 and / or R' ₂ represents a cyano group, an esterified carboxyl group or a tetrazolyl group protected, for example, with a trityl group, in the presence of oxygen, ultraviolet light and alkaline; (4 '):

optionally treated with Lawesson's reagent [bis-2,4- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide] and c3) the compound thus obtained in b3) or c3) of the general formula (5 '):

and then to prepare the compound of formula (4) by acidic cyclization.

According to another variant of Method 2, in order to prepare a compound of formula (I) wherein R 4 and R 5 do 5

is then worked up under conditions suitable for the preparation of a compound of formula (I) by converting the groups R1 'and / or R2' into the groups R1 and / or R2.

The imidazole derivative of general formula (11) is either known or commercially available or can be obtained by known methods.

Step c3) is carried out in an inert solvent such as DMF; A photosensitizer such as methylene blue may be added to facilitate the reaction.

In the following description, the process comprising steps a3) to c3) will be called method 3.

Compounds of formula (I) of the invention in which R 4 and R 5 together form a group of formula (CH 2) p - Y (CH 2) q in which Y is NH may be prepared by catalytic hydrogenolysis of the corresponding compound of formula (I) in wherein Y is N-Rg, wherein Rg is benzyl.

The affinity of the products of the invention for angiotensin II receptors was studied using an assay evaluating the binding of angiotensin II radiolabelled with an iodine 125 isotope to rat liver receptors. The method used is described by S. Keppens et al. in Biochem. J., 1982, 208, 809-817.

In this assay, the concentration of CI 50 is measured, the concentration that causes 50% displacement of labeled angiotensin II that is specifically bound to said receptors. The CI50 concentration of the compounds of the invention is less than 10 -6 M.

In addition, the effect of the products of the invention antagonizing the occupation of specific receptors by angiotensin II has also been shown in various animal species in which the renin-angiotensin system has been pre-activated (C. Lacour et al., J. Hypertension, 1989, 7 (Appendix 2), 33 - 35).

The compounds of the invention are effective for various routes of administration, in particular for oral administration.

No signs of toxicity were observed when administering pharmacologically effective doses of the compounds of the invention.

Accordingly, the compounds of the invention may be used for the treatment of various cardiovascular disorders, particularly for the treatment of high blood pressure, cardiac insufficiency and venous insufficiency, as well as for the treatment of glaucoma, diabetic retinopathy and various central nervous system disorders, anxiety, depression and Alzheimer's disease.

The present invention also provides a pharmaceutical composition comprising an effective dose of a compound of the invention, or a pharmaceutically acceptable salt thereof, and suitable pharmacological excipients. These excipients are selected according to the pharmaceutical form of the composition and the desired mode of administration.

In pharmaceutical compositions according to the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active compounds of the formula I or their possible salts can be administered in unit dosage forms in admixture with conventional pharmaceutical by carriers of animals or humans for the prophylaxis or treatment of said disorders or diseases. Said unit dosage forms include forms for oral administration, such as, in particular, tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal and intranasal administration, forms for subcutaneous, intramuscular or intravenous administration, and rectal forms application. For topical application, the compounds of the invention may be used in the form of creams, ointments or lotions.

In order to achieve the desired prophylactic or therapeutic effect, the dose of active ingredient may be between 0.01 and 50 mg per kilogram of body weight per day.

Each unit dose may contain 0.1 to 1000 mg, preferably 1 to 500 mg, of the active ingredients in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times daily to achieve a total daily dose of 0.5 to 5000 mg, preferably 1 to 2500 mg.

In preparing a solid pharmaceutical composition in the form of tablets, the main active ingredient is admixed with a pharmaceutical diluent (in particular), such as, in particular, gelatin, starch, lactose, magnesium stearate, talc and acacia. These tablets may be encapsulated in sucrose, a cellulose derivative or other suitable agent, or may be formulated to have sustained or delayed efficacy and to continuously release a predetermined amount of the active agent.

The pharmaceutical composition in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and incorporating the resulting mixture into soft or solid gelatin capsules.

The pharmaceutical composition in the form of a syrup or elixir, or for administration in the form of drops, may contain the active ingredient together with a sweetening agent, preferably non-caloric, antiseptics, mainly consisting of methylparaben and propylparaben, and an agent providing the composition with a suitable taste and color.

The water-dispersible powders or granules may contain the active ingredient in admixture with dispersing or wetting agents or suspending agents, for example, polyvinylpyrrolidone and sweetening or flavoring agents.

For rectal administration, suppositories are used which are prepared using binders melting at rectal temperature, such as, in particular, cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing pharmaceutically acceptable dispersing agents and / or wetting agents which are compatible with the active ingredient, for example propylene glycol or butylene glycol, are used.

The active ingredient may also be formulated in the form of microcapsules, optionally with one or more carriers or excipients.

The compositions of the invention may contain, in addition to the products of formula (I) or one of the pharmaceutically acceptable salts thereof, other active substances, such as tranquillizers or other medicaments, which may be useful in the treatment of said disorders or diseases.

Accordingly, the present invention also provides a pharmaceutical composition comprising a combination of several active ingredients, one of which is a compound of the invention

And the second or other active agents may be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal anti-inflammatory agent, or a soothing agent.

In the following, the invention will be further elucidated by means of specific exemplary embodiments, which are not to be construed as limiting the scope of the invention in any way. The following abbreviations are used in these examples: d denotes density, TA denotes ambient temperature and KHSO4-K2SO4 denotes an aqueous solution containing 16.6 g of potassium hydrogen sulphate and 33.3 g of potassium sulphate per liter.

Unless otherwise specified, melting points are given in degrees Celsius; these melting points were measured for non-recrystallized products.

The purity of the products was determined by thin layer chromatography (CCM) or high performance pressure column chromatography (HPLC). The products are characterized by their nuclear magnetic resonance (RMN) spectra, determined at 200 MHz in deuterated DMSO using an internal standard which is tetramethylsilane.

The following symbols are used to interpret nuclear magnetic resonance spectra: s singlet

with. e. extended singlet d doublet t triplet q quadruplet quint quintet sext sextet m block or multiplet. The symbol im means imidazole.

The positions of biphenyl are numbered in the classical manner, as can be seen from the following general formula (I) of the compounds of the invention:

In the following compounds z and t, they are zero, except when the compound to be prepared is pyrimidinone.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and 2-n-butyl-1 - [(2-trifluoroacetate) trifluoroacetate 1-Carboxybiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Method 2)

Grade A

N-Fmoc-1-aminocyclopentanecarboxylic acid

This acid is prepared as described by CHIDE, Chang et al. in Int. J. Peptide Protein Res., 1980, 15, 59-66.

Melting point: 89-91 ° C.

Step B N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -1- (N-Fmocamino) -1-cyclopentanecarboxamide

700 mg of the product obtained in the previous step are dissolved in 8 ml of dimethylformamide, followed by the stepwise addition of 576 mg of 4-amino-methyl- (2'-tert-butoxycarbonyl) biphenyl, 970 mg of benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate and sufficient diisopropylethylamine. pH = 6.

After stirring for 1 hour, the reaction mixture is diluted with 100 mL of ethyl acetate and 20 mL of water; the organic phase is washed successively with a saturated aqueous solution of sodium bicarbonate, then with a solution of potassium hydrogen sulphate and potassium sulphate and finally with a saturated aqueous solution of sodium chloride. After drying over sodium sulfate, the solution is evaporated to dryness. An oily product is obtained. Yield: 1.2 g.

Step C N- (2'-tert-Butoxycarbonylbiphen-4-ylmethyl) - (1-amino) -1-cyclopentanecarboxamide

The product obtained in the preceding step is dissolved in 10 ml of dimethylformamide, to which 1 ml of diethylamine is added and the mixture is stirred for one hour and 15 minutes at ambient temperature. The reaction mixture is then taken up in 100 ml of ethyl acetate and 20 ml of water and the organic phase obtained is washed once with water, once with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness.

The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate, methanol and ammonia at a concentration of 30% (99: 1: 0.5 by volume).

Yield of product: 600 mg. Infrared spectrum: (CHCl3) 3350 cm @ -1. H (amide and amm), 1700 cm -1: C = O (CO ₂ tBu), 1650 cm -1: C = O (CONH). Nuclear Magnetic Resonance Spectrum:

1.25 ppm: 9H: tBu;

2.15 - 1.40 ppm: m: 10 H / C ₆ H ₈ NH ₂ /;

4.40 ppm: d: 2H: _CH2 NH;

7.15-7.75 ppm: u: 8H: biphenyl;

8.60: t: 1 H: NH-CH ₂

Grade D

2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

394 mg of the product obtained in the preceding step and 250 mg of ethyl ortovalerate are mixed with 2 ml of dichloromethane. One drop of acetic acid was then added to the mixture, and the mixture was heated to 90 ° C until the dichloromethane was evaporated. After 1 hour and 15 minutes, the reaction mixture is taken up in 50 ml of ethyl acetate, 10 ml of water and 1 ml of saturated aqueous sodium bicarbonate solution. The organic phase is then washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and toluene. The desired product crystallizes from the eluate obtained.

Product yield: 390 mg. Melting point: 63 - 65 ° C. IR (CHCl3) 1710-1720 cm @ -1; C = O, C = O (ester and imidazoline) 1625 cm @ -1: C = N.

Nuclear Magnetic Resonance Spectrum: 0.88 ppm: t: 3H: CH3 (nBu);

1.20 ppm: s: 9H: tBu;

1.35 ppm: sext: 2H: CH3-CH2-;

1.58 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -;

1.95 - 1.65 ppm: u: 8H: cyclopentane; 2.42 ppm: t: 2H: CH3-CH2-CH2-CH2-; 4.78 ppm: s: 2H: _{CH2-C 6} H ₄ -;

7.20-7.80 ppm: u.c.: 8H: H-aromatic; Mass spectrum:

MH +: 461.

Step E 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate

180 mg of the product obtained in the previous step are kept in contact with 3 ml of dichloromethane and 4 ml of tetrahydrofuran for 45 minutes. After evaporation under reduced pressure, the residue is taken up in ether. A white solid is obtained, which is filtered off, washed with ether and dried under reduced pressure.

Yield of product: 155 mg. Melting point: 176-178 ° C.

Nuclear Magnetic Resonance Spectrum: 0.78 ppm: t: 3H: (CtynBu);

1.25 ppm: sec: 2H CH3-CH2;

1.50 ppm: quint: 2H: CH 3 -CH 2 -CH 2;

1.75-2.00: m, 8H: cyclopentane;

2.65 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.83 ppm: s: 2H: CH2-C5H4-;

7.20-7.75 ppm: 8H: aromatic;

Mass Spectrum: MH ⁺ : 405.

Example 2 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazol-5-one trifluoroacetate (method 1)

Step A 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one

1-Aminocyclopentanecarboxylic acid ethyl ester was prepared according to the procedure of Adkins and Billic (J. Amer. Chem. Soc., 1948, 70,3121).

Ethyl valerimidate was prepared according to the procedure of Mac Elvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827) and was liberated from its hydrochloride by treatment with potassium carbonate and extraction with dichloromethane.

1-Aminocyclopentanecarboxylic acid ethyl ester (1.57 g) and ethyl valerimidate (1.56 g) were dissolved in 12 ml of xylene containing 6 drops of acetic acid. After heating at reflux for 6.5 hours, the reaction mixture is concentrated under reduced pressure and the residue is chromatographed on silica gel using a 94: 4: 2 mixture of chloroform, methanol and acetic acid as the eluent. is evaporated several times in the presence of xylene and then benzene to remove acetic acid. The desired product is obtained as a thick oil.

Product yield: 1.91 g. IR (CHCl3) 1720 cm @ ^-1 : CO, 1635 cm @ -1: C = N.

Note: the fact that a band between 1 500 and 1 600 cm cml cannot be observed indicates that the product is 5-imidazolinone in the chloroform solution. Nuclear Magnetic Resonance Spectrum: 0.92 ppm: t: 3H: CH3 (nBu);

1.35 ppm: sec: 2H: CH3-CH2;

1.50-1.93 ppm: u: 10H: CH3-CH2-CH2 and cyclopentane; 2.33 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

10.7 ppm: u.c.: NH; Mass Spectrum: MH ⁺ : 195.

The 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one prepared in Step A may also be obtained by another method described using cyclopentanone as the starting product.

Step a)

-Aminocyklopentánnitril

This step is performed according to A. Strecker (Org. Synth, 1955, 3).

Dissolve 1.97 g of sodium cyanide in 3.9 ml of water in a flask, then add a solution containing 2.33 g of ammonium chloride in 5.9 ml of water and 3.5 ml of 20% ammonia, to the solution thus obtained. flasks add 3 g of cyclopentanone in 3.8 ml of methanol. After stirring for 1.5 hours, the reaction mixture was heated at 60 ° C for 45 minutes, then the heating was stopped, the reaction mixture was stirred for 45 minutes and then cooled to 25 ° C. It is then extracted several times with methylene chloride. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is obtained as an oil. Product yield: 4 g.

The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone and a solution of 2.25 g of oxalic acid dihydrate in 200 ml of acetone is added with stirring. The precipitate formed is centrifuged, washed with acetone and then dried.

Yield: 4.71 g. Melting point: 220 ° C.

This compound is 1-aminocyclopentanenitrile hemioxalate.

Step b)

-Aminocyklopentánkarboxamid

This step is carried out as described by J. Zabicky in The Chemistry of Amides, Intersciences, New York, 1970, 119.

To the 5.1 g of oxalate obtained in the previous step, 7.65 ml of concentrated sulfuric acid (density: 1.84) are added with stirring, and the mixture is stirred for 45 minutes. Gas evolution is observed and the temperature of the reaction mixture rises to 100 ° C. The mixture was then cooled to 35 ° C and poured into a mixture of ice and concentrated ammonia (10 g / 2.8 mL). The resulting suspension was extracted six times with chloroform containing 5% methanol. 3 ml of ammonia (density: 0.92) are then added to the aqueous phase and this phase is extracted again with 1: 0.5 by volume of chloroform containing methanol. Combined organic phases

Dry over sodium sulphate, filter and concentrate. The desired product is obtained as a white solid. Yield: 3.79 g.

Melting point: 95 ° C.

Analysis and infrared spectroscopy confirmed the structure of the product.

Step c) 2-n-Butyl-4-spirocyclopentan-2-imidazolin-5-one

This step is performed according to H. Takenak et al., Heterocycles, 1989, 29, 6, 1185-1189.

g of the compound obtained in the preceding step are introduced into 70 ml of anhydrous tetrahydrofuran and 3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous tetrahydrofuran are added thereto with stirring. A white suspension is formed. The formed but not isolated intermediate is (N-valeryl) -1-aminocyclopentanecarboxamide. 6 g of stone potassium hydroxide, 7 ml of water and 16 ml of methanol are added. The mixture was then heated at reflux for two hours and 30 minutes, after which 9 g of ammonium chloride were added. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure.

The residue is taken up in 40 ml of water and extracted with 10 ml of ethyl acetate and then twice with 5 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated to dryness to give the desired product.

Yield: 4.85 g.

The nuclear magnetic resonance spectrum is similar to that described in the previous case.

The hydrochloride of this compound can be prepared by adding concentrated hydrochloric acid. The hydrochloride obtained melted at 240 ° C and sublimed.

Step B 2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one

970 mg of the product obtained in Step A are dissolved in 10 ml of dimethylformamide. 270 mg of sodium methylate are added and the mixture is stirred for 15 minutes at ambient temperature. 2.08 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) are added to the suspension, and after 30 minutes the mixture is heated at 40 ° C under nitrogen for 3 hours and 30 minutes. The reaction mixture is then taken up with a mixture containing 100 ml of ethyl acetate, 10 ml of water and 1 ml of saturated sodium bicarbonate solution.

The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and toluene. The desired product is crystallized from the eluate.

Yield of product: 1.25 g. Melting point: 63 - 66 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum, the mass spectrum and the Rf value are the same as the corresponding values of the product of Step D of Example 1.

Grade C

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate

1.22 g of the product obtained in the previous step are stirred for 40 minutes in a solution containing 6 ml of dichloromethane and 8 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ethyl ether; The white precipitate formed is filtered, washed with ether and then dried under reduced pressure to give the desired product.

Yield of product: 1.15 g. Melting point: 176-178 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum and the mass spectrum are identical to those of the product obtained in step E of Example 1. The same applies to the Rf value obtained by thin-layer chromatography.

Example 3 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate (method 3)

Grade A

2-n-butylbenzimidazole

2-n-Butylbenzimidazole was prepared according to the procedure of WO Pool (J. Amer. Chem. Soc., 1937, 59, 178), followed by the preparation of 2-n-butyl-4,5,6,7-tetrahydrobenzimidazole by the procedure of M. Hartmann and L. Panizzone (Hel. Chim. Acta, 1938, 21, 1692-1694).

Melting point: 145 ° C.

Nuclear Magnetic Resonance Spectrum:

0.82 ppm: t: 3H: CH3 (nBu);

1.23 ppm: sec: 2H: CH3-CH2-;

1.50 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -;

1.65 ppm: s: 4H: H5, Hg (terahydrobenzimidazole);

2.35 ppm: s: 4H: H 4, H 7 (tetrahydrobenzimidazole);

2.45 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

II, 1 ppm: u.c.: NH; Mass Spectrum: M +: 178.

Step B 2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one g of the product prepared in the previous step is dissolved in 45 ml of dimethylformamide with 303 mg of sodium methylate and a few milligrams of methylene blue. Oxygen is then bubbled through the mixture and the reaction mixture is illuminated with a UV lamp. After 15 minutes, 2.14 g of 4-bromomethyl- (2'-butoxycarbonyl) biphenyl is added and after one hour the reaction mixture is taken up in 300 ml of ethyl acetate, to which 50 ml of water and 5 ml of saturated aqueous sodium hydrogen carbonate solution are added.

The organic phase is then washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a 1: 2 by volume mixture of ethyl acetate and toluene. The desired product is crystallized from the eluate obtained. Yield of product: 610 mg. M.p .: 62-65 ° C.

The infrared spectrum, the nuclear magnetic resonance spectrum, the mass spectrum and the Rf value are the same as those of the same product obtained by the described process.

Step C 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one trifluoroacetate

This compound is obtained by the acidic reaction described in the last step of Example 1 and Example 2. The physicochemical properties of this compound coincide with similar properties of the same compound prepared by Method 1 or 2.

Example 4

2-n-Butyl-4,4-dimethyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and 2-n-butyl-1 - [(2 1-carboxybiphenyl-4-yl) methyl] -4,4-dimethyl-2-imidazolin-5-one (Method 1)

Step A 2-n-Butyl-4,4-dimethyl-2-imidazolin-5-one

Ethyl alpha-amino isobutyrate was prepared according to the procedure of R. Jacquier et al. (Bull. Soc. Chim., Franc., 1971, 3, 1040-1051). 650 mg of this compound and 780 mg of ethyl valerimidate are dissolved in 8 ml of xylene containing 4 drops of acetic acid and the solution thus obtained is refluxed for 7 hours. The reaction mixture is then concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with a 95: 5: 2 mixture of chloroform, methanol and acetic acid. Evaporation of xylene and benzene several times to remove acetic acid The desired product is obtained which is crystallized. Yield of product: 560 mg. Melting point: 35 - 38 ° C.

Infrared spectrum: (CHCl3): 1725 cm @ -1: C = 0, 1635 cm @ -1; C = N

Note: the absence of a signal between 1500 and 1600 cm -1 confirms that the compound is present as 2-imidazolin-5-one in the chloroform solution.

Nuclear Magnetic Resonance Spectrum: 0.92 ppm: t: 3H: CH3 (nBu);

1.20 ppm: s: 6H: C / CH3 / 2;

1.38 ppm: sext: 2H: CH3-CH2;

1.63 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -;

2.38 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

10.7 ppm: u.c.: 1H: N-H; Mass Spectrum: MH +: 169.

Grade B

2-n-Butyl-4,4-dimethyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

520 mg of the product obtained in the previous step are dissolved in 10 ml of dimethylformamide. 167 mg of sodium methylate are then added to the obtained solution, and the mixture is stirred for 15 minutes under a nitrogen atmosphere. 1.25 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl are then added and the mixture is stirred at 40 ° C for three hours and 30 minutes. The reaction mixture is then taken up in 150 ml of ethyl acetate and then with 20 ml of water and 2 ml of saturated aqueous sodium hydrogen carbonate solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene (1.2 / 2 by volume). The product is crystallized.

Yield of product: 570 mg. Melting point: 98-100 ° C.

Infrared spectrum: (CHCl3):

1710 - 1720 cm -1: C = O, C = O (imidazolinone, ester) 1625 cm -1: C = N

Nuclear Magnetic Resonance Spectrum:

0.78 ppm: t: 3H: CH3 (nBu);

1.08 ppm: s: 9H, C / CH3 / 3;

1.15 ppm: s: C / CH3 / 2 and 1.20 ppm: sext: CH3-CH2- / 8H;

2.30 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.65 ppm: s: 2H: CH2-C6H4-;

7.15-7.65 ppm: u.c.: 8H: H aromatic.

The study of the nuclear Overhauser effect confirms the substitution of 5-one and 4,4-dimethyl on imidazolinone. Mass spectrum:

MH ⁺ : 435.

Grade C

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4,4-dimethyl-2-imidazolin-5-one

460 mg of the product obtained in the previous step are treated for 45 minutes with 3 ml of dichloromethane and 4 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and dried under reduced pressure. The desired product is obtained as a white solid.

Yield of product: 450 mg. Melting point: 168-171 ° C.

Nuclear Magnetic Resonance Spectrum:

0.82 ppm: t: 3H: CH3 (nBu);

1.30 ppm: sext: CH3-CH2-8H and

1.35 ppm: s: C / CH3 / 2;

1.55 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -;

2.62 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.82 ppm: s: 2H: CH2-C6H4-;

7.20-7.75: u.c.: 8H aromatic; Mass Spectrum: MH ⁺ : 379.

Example 5

1 - [(2'-Cyanobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one and

2-n-Butyl-4-spirocyclopentan-1 - [((2 '- (5-tetrazolyl) biphenyl-4-yl) methyl) -2-imidazolin-5-one (Method 1)

Grade A

- [2'-Cyanobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one

A mixture containing 250 mg of sodium hydride (in the form of an 80% dispersion in mineral oil) and 5 ml of dimethylformamide is prepared under a nitrogen atmosphere, and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane- Of 2-imidazolin-5-one (prepared in Step A of Example 2) in 10 ml of dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 1.5 g 4 is added

-bromomethyl-2'-cyanobiphenyl in 10 ml of dimethylformamide. After stirring at ambient temperature for 1 hour, the dimethylformamide was evaporated under reduced pressure and the resulting residue was taken up in ethyl acetate; the organic phase is washed with water, dried over sodium sulphate, filtered and evaporated.

The residue is chromatographed on silica gel, eluting with a 9/1 mixture of dichloromethane and ethyl acetate to give the desired product.

Yield of the product: 1.68 g. Melting point: 92-93 ° C.

Grade B

2-n-Butyl-4-spirocyclopentan-1- [2 '- (5-triphenylmethyl-tetrazolyl) biphenyl-4-ylmethyl] -2-imidazolin-5-one

1.56 g of the preceding product, 2.6 g of tributyltin azide and 30 ml of xylene are heated to reflux for 66 hours. The xylene is then evaporated and the residue is dissolved in 20 ml of dichloromethane and 5 ml of tetrahydrofuran, with 0.8 ml of 10N sodium hydroxide solution added; after stirring for 30 minutes, 2.5 g of trityl chloride are added and the mixture is stirred for 26 hours. After evaporation of the solvents, the residue is taken up in ethyl acetate and washed with water, 3% potassium hydrogen sulphate solution and then with water. After drying and evaporation, the residue is chromatographed on alumina, eluting with hexane / ethyl acetate 9: 1. The desired product is obtained from the eluate obtained. Yield of the product: 1.97 g. Melting point: 150-152 ° C.

Step C 2-n-Butyl-4-spirocyclopentan-1 - [(2 '- (5-tetrazolyl) biphenyl-4-ylmethyl) -2-imidazolin-5-one

1.96 g of the product obtained in the previous step are dissolved in 10 ml of methanol and 10 ml of tetrahydrofuran. After cooling the reaction mixture to 5 ° C, it is added

1.5 ml of 4N hydrochloric acid are added and the mixture is stirred for 3 hours at ambient temperature and then for one hour and 30 minutes at 30 ° C. After evaporation of the solvents, the residue is taken up in water and basified to pH 12 by the addition of 10 N sodium hydroxide solution.

The aqueous phase is extracted with ether, toluene and again with ether. The aqueous phase is then acidified to pH 2 by the addition of 1N hydrochloric acid, extracted with ethyl acetate, dried and evaporated. The white solid obtained is dried at 50 DEG C. under a pressure of 0.05 mm of mercury to give the desired product. Yield: 840 mg.

Melting point: 180-181 ° C.

Nuclear Magnetic Resonance Spectrum:

0.75 ppm: t: 3H: CH3 (nBu);

1.10 ppm: sext: 2H: CH3-CH2-;

1.20 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -;

1.5-2 ppm: u.c.: 8H: -C5H8;

2.2 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.6 ppm: s: 2H: CH2-C6-H4-;

ppm: s: 4H: CH 2 -C 6 -H 4 -;

7.35-7.7 ppm: u: 4H: H3 '4' 5 'g' aromatic.

The study of the nuclear Overhauser effect confirms the position of the 5-one substitution to the imidazole.

Grade D

Potassium salt of 2-n-butyl-4-spirocyclopentan-1 - [(- 2 '- (5-tetrazolyl) biphenyl-4-yl) methyl] -2-imidazolin-5-one

970 mg of the compound obtained in the preceding step are dissolved in 40 ml of a 1: 1 v / v mixture of isopropanol and methanol and the pH of the solution is adjusted to 12 by addition of 85% aqueous and methanolic (1: 1 v / v) potassium hydroxide solution. After evaporation, the residue is taken up with isopropanol and the solvent is evaporated again. The residue was then dissolved in 20 ml of isopropanol with gentle heating, and the solution was allowed to cool to ambient temperature. After decanting and evaporating the filtrate, the residue is taken up in heptane. After trituration the product solidifies; filtered, washed again with heptane and dried under reduced pressure to give the desired product. Product yield: 945 mg.

M.p .: 142-144 ° C.

Elemental analysis: C25H27KN6O, H2O: Calculated (%): C 61.95 H 6.03 N 17.34

Found (%): C, 62.02; H, 6.13; N, 17.14

Example 6 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (4-spirotetrahydropyran) -2-imidazolin-5-one a

2-n-butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one (method 2)

Grade A

4-Amino-4-tetrahydropyranecarboxylic acid

4-Amino-4-tetrahydropyranecarboxylic acid is prepared from 4-tetrahydropyranone by the method described in German patent DE 2 215 721.

Grade B

4- (N-benzyloxycarbonylamino) -4-karboxytetrahydropyrán

1.015 g of the compound from Step A are introduced into 12 ml of water, and 1.22 ml of diisopropylethylamine are added thereto at 10 ° C, followed by 3.33 g of N- (benzyloxycarbonyloxy) succinimide dissolved in 12 ml of acetonitrile. After 15 minutes, the reaction mixture was diluted with 70 mL of ethyl acetate and 10 mL of water and the pH of the mixture was adjusted to 2 with a saturated aqueous solution of potassium hydrogen sulfate.

After decantation, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and then evaporated under reduced pressure. The residue is dissolved in 60 ml of ether and 7 millimoles of dicyclohexylamine are added. The precipitate formed is filtered off and washed with ether. The washed precipitate is then dissolved in a mixture of ethyl acetate and water, and the pH of the solution is adjusted to 1.5 with a saturated solution of potassium hydrogen sulfate. The organic phase is decanted, washed with saturated sodium chloride solution and evaporated under reduced pressure to give a white solid.

Product yield: 1.9 g. Melting point: 110-115 ° C.

Step C N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -4- (N-benzyloxycarbonylamino) -4-tetrahydropyranecarboxamide

850 mg of the compound prepared in Step B are dissolved in 15 ml of dimethylformamide and treated with equimolar amounts of 4-aminomethyl- (2'-tert-butoxycarbonyl) biphenyl and diisopropylethylamine, followed by benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate (10F). After 40 minutes, the reaction mixture is taken up in 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted and then washed twice with saturated aqueous sodium hydrogen carbonate solution, twice with 5% sodium hydrogen sulphate solution and once with saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic phase is evaporated under reduced pressure to give the desired product.

Yield of product: 1.8 g.

Step D N- (2'-tert-Butoxycarbonylbiphenyl-4-ylmethyl) -4-amino-4-tetrahydropyranecarboxamide

The product obtained in Step C is dissolved in 30 ml of methanol. To this solution is then added 400 mg of 10% palladium on charcoal and the product is hydrogenated at atmospheric pressure. After one hour, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate, methanol and 33% ammonia (99: 1: 0.5 by volume). The desired product is then obtained from the eluate as a white solid. Yield of product: 0.93 g.

Melting point: 125-127 ° C.

Nuclear Magnetic Resonance Spectrum:

8.50 ppm: t: 1H: H amide,

7.60 - 7.05 ppm: m: 8H: H aromatic,

4.25 ppm: d 2H: CH2-C6H4-,

3.70 to 3.50 ppm: m: 4H: _CH2 at position 2 and 6 tetrahydropyran,

2.00-1.80 ppm: m: 4H: CH2 in position 3 and 5 of tetrahydropyran,

1.05 ppm: s: 9H: tBu.

Step E 2-n-Butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

A mixture containing 0.9 g of the compound obtained in Step D, 327 mg of methyl orthovalerate and 2 drops of acetic acid was heated at 110 ° C for 3 hours. The reaction mixture is then taken up in 100 ml of ethyl acetate and then washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated with ethyl acetate.

The residue is chromatographed on silica gel, eluting with a 2: 1 by volume mixture of ethyl acetate and toluene. The desired product is obtained from the eluate as a wax.

Yield of product: 550 mg.

Nuclear Magnetic Resonance Spectrum: 7.05 - 7.60 ppm: m: 8H: H aromatic,

4.63 ppm: s: 2H: _CH2-C (J H ₄ -,

3.85-3.55 ppm: m: 4H, CH2 in position 2 and 6 of tetrahydropyran,

2.30 ppm: t: 2H: CH2-C3H7,

1.05 - 1.80 ppm: m: 8H: CH ₂ -CH ₂ -CH ₂ -CH ₃ and CH ₂ in position 3 and 5 of tetrahydropyran

1.03 ppm: s: 9H: tBu,

0.75 ppm: t: 3H: (CH 2) 3 -CH 3,

Infrared spectrum:

(CHCl3)

1710-1720 cm ¹ : C = O, C = 0, 1625 enr ¹ : ON.

Step F 2-n-Butyl-4- (4-spirotetrahydropyran) -1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

530 mg of the product obtained in the preceding step are treated with 4 ml of dichloromethane and 5 ml of trifluoroacetic acid for 45 minutes. After evaporation under reduced pressure, the residue is taken up in ether and the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product.

Yield of product: 510 mg. Melting point: 159-162 ° C. Nuclear Magnetic Resonance Spectrum:

7.80 - 7.10 ppm: m: 8H: aromatic,

4.80 ppm: s: 2H: CH2Cl2Cy-,

4.00-3.75 ppm: m: 4H, CH2 at the 2- and 6-position of tetrahydropyran,

2.60 ppm: t: 2H: CH2 - C3H7,

1:45 - 2.00 ppm: m: 6 H: _{CH2 CH2 CH2 CH3} and _CH2 in the 3 and 5 of the tetrahydropyran

1.30 ppm: sext: 2H: CH ₂ CH ₂ CH ₂ CH _3, 0.80 ppm: t: 3 H: _(CH2) 3-CH _third

Example 7

2-n-Butyl 1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [spiro- (1-benzyl-4-piperidin)] - 2-imidazolin-5-one trifluoroacetate and

2-n-butyl-4- [spiro (1-benzyl-4-piperidin)] - 1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one (method 1)

Grade A

4-Amino-1-benzyl-4-piperidinecarboxylic acid

4-Amino-1-benzyl-4-piperidinecarboxylic acid is prepared from N-benzyl-4-piperidone according to the procedure described in German patent DE 2 215 721.

Grade B

Ethyl 4-amino-1-benzyl-4-piperidinecarboxylate

3.80 g of the compound prepared in Step A are introduced into a solution of 13 g of hydrochloric acid in 50 ml of ethanol at 0 ° C, and the reaction mixture is heated to reflux for 5 hours. After concentration under reduced pressure, the residue is washed with ether, then dissolved in a mixture of ether and water, to which a saturated aqueous potassium carbonate solution is added to reach a pH of 9. The ether phase is decanted, washed with saturated sodium chloride solution and dried over sulphate. sodium hydroxide and evaporated to dryness. The desired product is obtained as an oil. Product yield: 3.50 g.

Nuclear Magnetic Resonance Spectrum:

7.20 - 7.40 ppm: m: 5H: aromatic H,

4.10 ppm: q: 2H, CH ₂ CH _3,

3:45 ppm: s: 2H: _CH2 of benzyl,

2.25 to 2.60 ppm: m: 4 H: _CH2 in the 2 and 6 of the piperidine,

1.80 - 2.05 ppm: m: 2H:

and

1.20 - 1.40 ppm: m: 2 H: _CH2 in the 3 and 5 piperidine 1.12 ppm: t: 3 H: CH ₃ CH ₂ -,

Step C 2-n-Butyl-4- [spiro- (1-benzyl-4-piperidin)] - 2-imidazolin-5-one

Ethyl valerimidate was prepared according to the procedure of Step A of Example 2. A mixture of 2.06 g of ethyl valerimidate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid in 15 ml of xylene was heated to reflux for 6 hours. After concentration under reduced pressure, the residue is chromatographed on silica gel, eluting with a 82: 15: 3 mixture of chloroform, methanol and acetic acid. Extraction with chloroform at pH 9 to remove acetic acid gives the desired product.

Yield of product: 2.80 g. Melting point: 170-172 ° C. Infrared spectrum: (chloroform) 1725 cm ^-1 C = O, 1640 cm ^-1 C = N.

Nuclear Magnetic Resonance Spectrum:

7.10 - 7.30 ppm: m: 5H: aromatic H,

3.45 ppm: s: 2H: _{CH2-C 6} H ₅ -,

1.10 - 2.75 ppm: 5 m: 14 H, _CH2 of the 2, 3, 5 and 6 of the piperidine and _(CH2) 3-CH 3,

0.80 ppm: t: 3H: (CH 3) ₃ CH ₃ .

Grade D

2-n-Butyl-4- [spiro- (1-benzyl-4-piperidin)] - 1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

To 2.78 g of the compound obtained in Step C dissolved in 25 ml of dimethylformamide was added 513 mg of sodium methylate and after 15 minutes 4.16 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl was heated. The reaction mixture is taken up in 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution and the organic phase is decanted, washed once with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to dryness. on silica gel, eluting with a 95: 5 mixture of ethyl acetate and methanol. The desired product is then obtained from the eluate.

Product yield: 0.98 g. Melting point 103-106 ° C. Infrared spectrum (CHCl3)

1710 - 1725 cm ¹ C = O, C = O (imidazoline, ester) 1630 cm * ¹ C = N.

Nuclear Magnetic Resonance Spectrum:

7.70 - 7.10 ppm: m: 13H: H aromatic,

4.70 ppm: s: 2H: _CH2-C (5H4-, 3.55 ppm: s: 2H: CH2-C5H5

1.20 to 2.75 ppm: 5 m: 14 H, CH ₂ at position 2, 3, 5, 6, and piperidine _(CH2) 3-CH3

1.15 ppm: s: 9H: tBu, 0.85 ppm: t: 3H: (CH 2) 3 -CH 3.

Step E 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [spiro- (1-benzyl-4-piperidin)] - 2-imidazolin-5-one

350 mg of the compound obtained in Step D are dissolved in 4 ml of dichloromethane and 5 ml of trifluoroacetic acid. After 45 minutes, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ether / hexane, the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product.

Product yield: 350 mg. Melting point: 198-200 ° C.

Nuclear Magnetic Resonance Spectrum: 7.05-7.75 ppm: m: 13H: H aromatic;

4.75 ppm: s: 2H: C1-C8Hq-:

4.40 ppm: s: 2H: CH2-C6H5;

3.20- 3.60 ppm: m: 4Η: _CH2 in the 2 and 6 of the piperidine;

2.35: t: 2H: CH2 --CH2 --CH2 --CH3;

2.20- 1.40 ppm: 3 multiplets: _CH2 in the 3 and 5 of the piperidine and CH ₂ -CH ₂ -CH ₂ -CH 3;

1.25 ppm: sext: 2 H: _{CH2-CH2-CH2-CH3;}

0.80 ppm: t: 3H: (CH2 ₎ 3-CH3.

Example 8

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [4-spiropiperidine]] - 2-imidazolin-5-one difluoroacetate and

2-n-butyl-4- [4-spiropiperidin] -1 - [(2'-tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one

Step A 2-n-Butyl-4- (4-spiropiperidine)] - l - ^[(2 -tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one

300 mg of the compound of Example 7, Step D are dissolved in 10 ml of methanol. To this solution was added 180 mg of 10% palladium on charcoal, and the mixture was hydrogenated with hydrogen for 3 hours. The catalyst is then filtered off and the filtrate is concentrated to dryness to give the desired product.

Product yield: 200 mg.

Nuclear Magnetic Resonance Spectrum:

7.20-7.75 ppm: u.c.: 8H: H aromatic;

4.75 ppm: s: 2H: CH2-C6H4-;

3.00 to 1.70 ppm: 3 to 4 multiplets _CH2 piperidine;

2.40 ppm: t: 2H: CH2 --CH2 --CH2 --CH3;

1.60 ppm: quint: 2H: CH2-CH2-CH2-CH3;

1:35 ppm: sext: 2 H: _{CH2-CH2-CH2-CH3;}

1.20 ppm: s: 9H: tBu;

0.90 ppm: t: 3H: (CH2) 3-CH3.

Step B 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- [4-spiropiperidine] -2-imidazolin-5-one

160 mg of the product obtained in Step A are stirred in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid for 45 minutes. The reaction mixture was then concentrated under reduced pressure and the resulting residue was taken up in ether. After drying under reduced pressure, a gummy product is obtained and then a foamed product.

Product yield: 150 mg. Melting point: 80 - 85 ° C.

Nuclear Magnetic Resonance Spectrum:

7.15-7.80 ppm: u.c.: 8H: H aromatic;

4.75 ppm: s: 2H; CH2-C6H4-;

3.20- 1.60 ppm: multiplets, 3: 4 _CH2 of piperidine;

2.40 ppm: t: 2H; CH ₂ -CH 2 -CH ₂ -CH _3;

1.50 ppm: quint: 2 H: _{CH2-CH2-CH2-CH3;}

1.30 ppm: sext: 2 H: _{CH2-CH2-CH2-CH3;}

0.80 ppm: t: 3H: (CH2) 3-CH3.

Example 9

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4,4-diphenyl-2-imidazolin-5-one trifluoroacetate; and

2-n-Butyl-4,4-diphenyl-1 - [(2-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one (Method 1)

Grade A

In aleramidine hydrochloride g ethylvalerimidate hydrochloride is added to the solution

6.75 ammonia in 80 ml methanol at 0 ° C. After 18 hours, the reaction mixture is concentrated under reduced pressure to give the desired product as a white solid.

Step B 2-n-Butyl-4,4-diphenyl-2-imidazolin-5-one

This compound was prepared according to the method of J. Nyitrai et al

K. Lemperta, described in Tetrahedron, 1969, 25, 4265-4275, from benzyl and valeramidine hydrochloride. Melting point: 135 ° C.

Infrared spectrum:

(CHCl3):

1725 cm -1 C = O 1640 cm -1 C = N.

Nuclear Magnetic Resonance Spectrum:

7.20-7.50 ppm: m: 10H: H aromatic;

2.50 ppm: t: 2H: CH2-CH2-CH2-CH3;

1.65 ppm: quint: 2H: CH2-CH2-CH2-CH3;

1.35 ppm: t: 3H: CH2 --CH2 --CH2 --CH3;

0.90 ppm: t: 3H: CH2-CH2-CH2-CH3;

ppm: s.e. : NH.

Step C 2-n-Butyl-4,4-diphenyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

This compound is prepared in a conventional manner by treatment of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl in Step B in the presence of sodium methylate in dimethylformamide.

Infrared spectrum: (CHCl3):

1715 - 1725 cm @ -1 C = O, C = O (ester, imidazolinone) 1635 cm @ -1 · c = N.

Nuclear Magnetic Resonance Spectrum: 7.25-7.80 ppm: m: 18 H: H aromatic;

4.85 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -;

2.60 ppm: t: 2H: CH2-CH2-CH2-CH3-;

1.75 ppm: quint: 2H: CH2-CH2-CH2-CH3-;

1.40 ppm: sext: 2H: CH2-CH2-CH2-CH3-;

1.15 ppm: s: 9H: tBu;

0.90 ppm: t: 3H: CH3 of n-butyl.

Step D 2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-, 4-diphenyl-2-imidazolin-5-one trifluoroacetate

500 mg of the product of Step C was treated with 2.5 mL of dichloromethane and 2.5 mL of trifluoroacetic acid at 20 ° C for 40 minutes. After concentration under reduced pressure, the resulting residue is taken up in ether / hexane, the precipitate formed is filtered off, washed with hexane and dried to give the desired product. Yield of product: 449 mg.

Melting point: 55-60 ° C.

Nuclear Magnetic Resonance Spectrum:

7.15-7.80 ppm: u.c.: 18H: H aromatic;

4.85 ppm: s: 2H: N-CH 2 -C 6 H 4 -;

2.60 ppm: t: 2H: CH2-CH2-CH2-CH3-;

1.70 ppm: quint: 2H: CH2-CH2-CH2-CH3-;

1.40 ppm: sext: 2H: CH2-CH2-CH2-CH3-; 0.90 ppm: t: 3H: CH3 butyl.

Example 10

2-n-Butyl-3 - [(2'-carboxybiphenyl-4-yl) methyl] -6-spirocyclopentane-5,6-dihydro-4-1H-pyrimidinone trifluoroacetate

Grade A

(1-Aminocyclopentyl) acetic acid

Cyclopentylideneacetic acid was prepared as described by G. A. R. Horse and R. P. Linstead in J. Chem. Soc., 1925, 127, 616. 740 mg of this acid and 5 ml of 20% ammonia are introduced into the autoclave and the mixture is heated at 150 ° C for 24 hours. After evaporation of the solvents, the resulting residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol / 20% ammonia solution (70/30/1, v / v) mixture.

Step B Ethyl ethyl 1-aminocyclopentyl acetate

330 mg of the acid is dissolved in 10 ml of ethanol. The solution was then cooled in an ice bath and saturated with hydrogen chloride gas. After refluxing for 24 hours, the reaction mixture is evaporated, the residue taken up in sodium carbonate solution and extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to give the desired ester. Product yield: 312 mg.

Step C 2-n-Butyl-6-spirocyclopentane-5,6-dihydro-4-1H-pyrimidinone

A mixture containing 310 mg of the compound obtained in Step B, 348 mg of ethyl valerimidate, 10 ml of xylene and 6 drops of acetic acid was heated to reflux. After 2 hours and 18 hours, 348 mg of ethyl valerimidate are again added and after 24 hours of total reflux, the reaction mixture is evaporated and the residue is chromatographed on a column of silica gel, eluting with a dichloromethane / methanol (97: v / v) mixture. 3. The desired product is then obtained from the eluate. Product yield: 153 mg.

Step D 2-n-Butyl-6-spirocyclopentan-3 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -5,6-dihydro-4-1H-pyrimidinone

A mixture of 10 ml of dimethylformamide and 40 mg of 80% (in oil) sodium hydride is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in Step C, dissolved in 5 ml of dimethylformamide, are then added dropwise at ambient temperature. After stirring for 30 minutes, 288 mg of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl dissolved in 5 ml of dimethylformamide is added. After stirring for two hours, the reaction mixture is evaporated, the resulting residue is taken up in water and extracted with ethyl acetate. After drying over sodium sulphate, filtering and evaporating, the residue is chromatographed on a silica gel column, eluting with a hexane / ethyl acetate mixture (85/5; v / v).

Grade E

To 10 ml of trifluoroacetic acid cooled in an ice-water bath was added 161 mg of the compound prepared in Step D. The mixture was stirred for 30 minutes and then evaporated. The residue was taken up in ethyl ether and then evaporated again. This operation is repeated once more and the residue is dried under reduced pressure. The desired compound is thus obtained in the form of an amorphous powder.

Yield: 140 mg. M.p .: 108-115 ° C.

Nuclear Magnetic Resonance Spectrum:

0.9 ppm: t: 3H: (CH 2) 3-CH 3;

1.1 to 2.1 ppm: m: 12 H: cyclopentane and _CH2-CH3 CH2'CH2;

2.7 ppm: t: 2H: CH2-CH2-CH2-CH3-;

3.1 ppm: s: 2H: CH2 --CO;

5.1 ppm: s: 2H: N-CH 2 -C 6 H 5;

7.2 to 7.8 ppm: m: 8H: H aromatic.

Example 11 2-n-Butyl-4-spirocyclopentan-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazoline-5-thione and

2-n-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazoline-5-thione

Step A 2-n-Butyl-4-spirocyclopentane-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazoline-5-thione

5.63 g of the compound prepared in Step D of Example 1 are dissolved in 40 ml of anhydrous toluene and 3 g of Lawesson's reagent are added to this solution at 80 ° C. After 6 hours, the reaction mixture was filtered and the filtrate was concentrated. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate. The desired product is obtained as an oil which crystallizes on cooling. Product yield: 4.5 g.

Melting point: 77-79 ° C.

Nuclear Magnetic Resonance Spectrum: 0.90 ppm: t: 3H: CH3 (n-Bu);

1.20 ppm: s: 9H: tBu;

1.35 ppm: sext: 2H: CH3 --CH2 -;

1.60 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -; 1.80-2.10 ppm: M: 8H: cyclopentane;

2.60 ppm: t: 2H: CH3-CH2-CH2-CH2;

5.35 ppm: s: 2H: CH2-C6H4-; 7.25-7.80 ppm: m: 8H: H aromatic.

Grade B

2-n-Butyl-1 - [(2-carboxybiphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazoline-5-thione trifluoroacetate

225 mg of the compound obtained in Step A is treated with 5 ml of dichloromethane and 5 ml of trifluoroacetic acid for 30 minutes. After concentration, the resulting residue is taken up in ether. The title compound is obtained as a yellow powder, which is centrifuged and washed with hexane. Yield of product: 160 mg.

Melting point: 185-190 ° C.

Mass Spectrum: MH ⁺ : 421.

0.78 ppm: t: 3H: CH3 (n-Bu);

1.20 ppm: sec: 2H: CH3-CH2;

1.50 ppm: quint: 2H: CH 3 -CH 2 -CH 2 -; 1.75-2.00 ppm: u.c.: 8H: cyclopentane;

2.40 ppm: t: 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

5.20 ppm: s: 2H: CH2-C6H4-; 7.00-7.65 ppm: m: 8H: H aromatic.

Example 12 2-n-Butyl-4- (2-spiroindan) -1 - [(2'-tert-carbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one a

2-n-butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (2-spiroindan) -2-imidazolin-5-one (method 1)

Grade A

2-Amino-2-indanecarboxylic acid was prepared as described by R. M. Pinder in J. Med. Chem., 1971, 14, 9, 892 and the corresponding ethyl ester is then prepared according to the procedure of Adkins (see Example A Step A).

Step B 2-n-Butyl-4- (2-spiroindan) -2-imidazolin-5-one

2.78 g of the ethyl ester prepared in step A and 2.5 g of ethyl valerimidate are dissolved in 20 ml of xylene in the presence of 60 μΐ of acetic acid and the solution is then heated to reflux for three hours. 500 mg of ethyl valerimidate are then added and heating is continued at reflux for a further 3 hours. The reaction mixture is then concentrated and the residue is chromatographed on silica gel, eluting with a 3: 8: 0.3 hexane / ethyl acetate / acetic acid mixture. The pure fractions were combined and evaporated with toluene. The desired product is obtained as a white solid. Product yield: 3.07 g. M.p .: 148-150 ° C.

Nuclear Magnetic Resonance Spectrum: 0.90 ppm: t: 3H: CH3 (n-Bu);

1.2-1.7 ppm: u.c.: 4H: CH2-CH2-CH3; 2.4 ppm: t: 2H: CH 2 - / CH 2/2-CH 3;

2.8-3.2 ppm: q: 4 H: CH2 ₂ / indan /; 4.90 ppm: s: 2H: CH2-C6H4-;

7.2 ppm: m: 4H: H aromatic.

Step C 2-n-Butyl-4- (2-spiroindan) -1 - ((2´-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

The compound obtained in the preceding step is dissolved in 20 ml of anhydrous dimethylformamide and 450 mg of sodium methylate are added to this solution under a nitrogen atmosphere. After 20 minutes at ambient temperature, 3.6 g of 4-bromomethyl- (2'-tert-butoxycarbonyl) biphenyl is added and the mixture is allowed to stir at 40 ° C for 6 hours. The reaction mixture is concentrated, followed by conventional washing, and the residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate. The desired product is obtained as a foamed product.

Yield of product: 1.84 g.

SK 280096-6

Nuclear Magnetic Resonance Spectrum: 0.80 ppm: t: 3H: CH3;

1.20 ppm: s: 9H: tBu;

1.20-1.60 ppm: u.c.: 4H: CH2-CH2-CH3;

2.40 ppm: t: 2H: CH2 - / CH2 / 2-CH3;

2.9-3.3 ppm: q: 4H: 2CH2 (indane);

4.80 ppm: s: 2H: N-CH 2 -C 6 H 4 -;

7.20- 7.80 ppm: m: 12H: H aromatic;

Grade D

2-n-Butyl-1 - [(2'-carboxybiphenyl-4-yl) methyl] -4- (2-spiroindan) -2-imidazolin-5-one

1.71 g of the compound obtained in the preceding step are dissolved in 15 ml of dichloromethane, and 20 ml of trifluoroacetic acid are added thereto. After 30 minutes, the reaction mixture is concentrated and the residue is taken up in ether. After trituration, the solid obtained is centrifuged, washed with ether and dried to give the desired product. Yield of product: 1.42 g. Melting point: 217-218 ° C.

Nuclear Magnetic Resonance Spectrum:

0.70 ppm: t: 3H: CH3 (n-Bu);

1.10-1.50 ppm: u.c.: 4H: CH2-CH2-CH3;

2.30 ppm: t: 2H: CH 2 - / CH 2/2-CH 3; 2.8-3.3 ppm: q: 4H: 2CH 2 (indane);

4.70 ppm: s: 2H: N-CH 2 -C 6 H 4 -;

7.1-7.7 ppm: m: 12H: H aromatic.

Other compounds of the invention were prepared according to any of the procedures described. These compounds are shown in Table 1. The structure of each of these compounds was confirmed by analysis of their nuclear magnetic resonance spectra.

Example 13

2-n-Butyl-1 - [(2 '- (1-imidazolylcarbonyl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one General Formula (I):

^ 2 ”

R ₃ = nC ₄ H ₉ , CR 3 R ³ cyclopentane ₍ X = O).

A mixture of 404 mg of the compound prepared in Step E of Example 1, 15 ml of tetrahydrofuran and 260 mg of carbonyldiimidazole is stirred at ambient temperature for 72 hours. The reaction mixture is then evaporated, taken up in ethyl acetate, washed with water and then brine, to give 420 mg of product which is purified by chromatography on silica gel, eluting with a dichloromethane / ethyl acetate mixture (70/30; v / v). The desired product is then isolated.

Yield: 230 mg. Melting point: 120 ° C.

Example 14

2-n-Butyl-1 - [(2 '- (3-cyano-2-methylisothioureidomethyl) -biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one General Formula (I):

SCHj

I

R 1 = -CH 2 NH-C = N-CN

R2 = H,

R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

Grade A

1 - [(2'-Aminomethylbiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one

This compound is obtained by hydrogenation of the compound prepared in Example 5.

g of the compound prepared in Step A of Example 5 is introduced into 15 ml of absolute methanol and 2.3 ml of ethanol containing 0.5 g of 5% palladium on charcoal and the compound is hydrogenated at ambient temperature for 24 hours. After the usual treatment of the hydrogenation mixture, the desired product is obtained in the form of an oily product. Yield of product: 730 mg.

Grade B

A mixture containing 300 mg of the compound prepared in the preceding step and 113 mg of N-cyanimido-S, S-dimethyldithiocarbonate in 3 ml of ethanol was heated to reflux for 24 hours. After usual work-up, the reaction mixture is purified by chromatography on silica gel, eluting with a 50:50 mixture of dichloromethane and ethyl acetate. The desired product is isolated as a white solid. Yield of product: 307 mg.

Melting point: 83 ° C.

Example 15

2-n-Butyl-1 - [(2 '- (2-cyanoguanidinomethyl) biphenyl-4-yl) methyl] -spirocyclopentan-2-imidazolin-5-one

General formula (I):

NH2

I

R 1 = -CH, NH-O.N-CN

R2 = H,

R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

This compound is obtained from the compound prepared in the previous example. 200 mg of this compound are introduced into 10 ml of absolute alcohol, the alcohol is saturated with ammonia at 10 ° C and heated at 80 ° C in an autoclave for one hour. After concentrating the reaction mixture to dryness, the residue is chromatographed on silica gel, eluting with a dichloromethane / methanol (95/5; v / v) mixture. The desired product is then isolated from the eluate. Product yield: 130 mg. Melting point: 100 ° C.

Example 16 2-n-Butyl 4-spirocyclopentane-1 - [(2'-trifluoromethylsulfonylaminobiphenyl-4-yl) methyl] -2-imidazolin-5-one trifluoromethylsulfonate

General formula (I):

R | = -NHSO2CF3

R2 = H,

R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

SK 280096-6

Grade A

4-Methyl-2'-nitrobiphenyl

A mixture of 2-nitrobromobenzene (11.2 g) and 4-iodotoluene (15 g) was heated to 195 ° C and stirred at this temperature for three hours and 30 minutes. After cooling to ambient temperature, the reaction mixture was taken up in dichloromethane, heated to reflux and the warm solution was filtered through celite, and the dichloromethane was evaporated from the filtrate. Yield: 6.5 g.

Boiling point: 80-120 ° C at 26.6 Pa. n _D 24 = 1.6042.

Grade B

4-Bromomethyl-2'-nitrobiphenyl

A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl, 5.42 g of N-bromosuccinimide, 118 mg of azo-bisisobutyronitrile and 500 ml of carbon tetrachloride was heated to reflux for 5 hours. The reaction mixture was then cooled to 0 ° C and centrifuged. The liquid fraction obtained is concentrated to give an oily product which is used in the next step.

Grade C

2-n-Butyl-1 - [(2'-nitrobiphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one

A mixture containing 260 mg of sodium hydride (80%) in 5 ml of dimethylformamide is prepared, and 500 mg of 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared under nitrogen atmosphere, is added to this mixture under nitrogen. in Example 2, Step A. After stirring for 15 minutes, 901 mg of 4-bromomethyl-2'-nitrobiphenyl in 5 ml of dimethylformamide was added thereto, followed by stirring for 24 hours. The reaction mixture is then concentrated to dryness, the residue is taken up in a mixture of water and ethyl acetate. The organic phase is decanted, dried over sodium sulphate and filtered. Ethyl acetate was then evaporated from the filtrate. The product is chromatographed on silica gel, eluting with a 9/1 mixture of dichloromethane and ethyl acetate. The desired product is then isolated from the eluate.

Yield of product: 500 mg

Step D 1 - [(2'-Aminobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one

450 mg of the product obtained in the preceding step are introduced into 10 ml of methanol and the mixture is hydrogenated in the presence of 5% palladium on charcoal at ambient temperature. Filtration of the catalyst and evaporation of the solvent gave the desired product. Yield of product: 240 mg

Grade E

225 ml of the product obtained in the previous step and 0.1 ml of triethylamine are mixed in 4 ml of dichloromethane, 0.2 ml of trifluoromethylsulphonic anhydride are added to the mixture under argon at -78 ° C and the mixture is allowed to cool to room temperature. ambient temperature. The reaction mixture was washed with water and then with sodium bicarbonate solution, then dried and concentrated to give a white solid amorphous product. Product yield: 150 mg.

NMR: 0.4-1.3 ppm: m: 7 H: _CH3-CH2-CH2 -;

1.4-2.3 ppm: m: 10H: _{CH3-CH2-CH2-CH2} and cyclopentane;

4-4.8 ppm: system AB, 2H: N-CH ₂ -CqH 4 -;

7-7.6 ppm: u.c.: 8H: aromatic;

8.3 ppm: s: 1H: -NH;

ppm: s.e., 1H: CF3SO3H.

Example 17

2-n-Butyl-4-spirocyclopentane-1 - ((2'-trifluoromethylsulfonylaminomethylbiphenyl-4-yl) methyl] -2-imidazolin-5-one trifluoromethylsulfonate

General formula (I):

R 1 = CH ₂ NHSO ₂ CF 3, r ₂ = h,

R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

Starting from 1 - [(2'-aminomethylbiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one prepared in step A of Example 14. 322 mg of this compound and 0.122 ml The triethylamine is introduced into 3.4 ml of dichloromethane at -70 ° C and 0.294 ml of trifluoromethylsulfonic anhydride is added. The mixture was then allowed to warm to ambient temperature, poured into dilute acetic acid, extracted with dichloromethane, dried over sodium sulfate, filtered and evaporated. The residue is chromatographed twice on silica gel, eluting with a 95/5 mixture of dichloromethane and ethyl acetate and then 99.5: 0.5.

Product yield: 90 mg Melting point: 90 ° C.

Nuclear Magnetic Resonance Spectrum: 0.4-1.2 ppm: m 7H: -CH ₂ -CH ₂ -CH 3;

1.3 to 2.45 ppm: m: 10 H: CH ₂ CH ₂ CH ₂ CH _3, and cyclopentane;

4.1- 5 ppm 4H of _N-CH2 and NH--CgH4- _CH2 -CgH4-;

7.1-7.7 ppm: m, 8H: H aromatic;

8.4 ppm: s 1H: NH.

Example 18 2-n-Butyl-1 - [(2 '- (N-hydroxycarbamoyl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one

General formula (I):

R1 = -CO-NHOH,

R2 = H,

R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

The compound prepared in Example 2 is released from its salt (trifluoroacetic acid salt) by removing this compound with a mixture of ethyl acetate and water and adjusting the pH of the solution to 6 by adding a saturated aqueous solution of sodium bicarbonate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give the free base as a white solid.

450 mg of this compound is then dissolved in chloroform, 860 ml of thionyl chloride are added thereto at 0 ° C, and the mixture is then stirred for two hours at ambient temperature. The solution is then concentrated and traces of thionyl chloride are removed by azeotropic des

By filtration with toluene. The acid chloride thus obtained is then added dropwise as a solution in dimethylformamide to a solution containing 200 mg of hydroxylamine hydrochloride. After 2 hours at 0 ° C, the reaction mixture is concentrated, taken up in 100 ml of dichloromethane and 50 ml of water. The pH of the mixture is then adjusted to 7, the organic phase is extracted and dried over sodium sulfate. After filtration, the filtrate is concentrated. The product obtained is crystallized from a mixture of ethyl acetate, ethyl ether and hexane.

Product yield: 360 mg, mp 85 ° C.

Example 19 2-n-Butyl-4-spirocyclopentan-1 - [(2'-ureidobiphenyl-4-yl) methyl] -2-imidazolin-5-one

General formula (I):

R1 = NHCONH2, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0.

This compound was prepared using the method described by B. B. Kobu et al. in Org. Synth., 1957, 37, 52, from 1 - [(2'-aminobiphenyl-4-yl) methyl] -2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared in Step A of Example 14 .

g of the above product is dissolved in 50 ml of 6N hydrochloric acid, potassium isocyanate is added and the mixture is left at 5 DEG C. for 1 hour. The reaction mixture is then concentrated, taken up in ethyl acetate, washed with sodium bicarbonate solution and then with saturated sodium chloride solution. After drying over sodium sulfate, the solution is concentrated and the oil obtained is purified by chromatography on silica gel, eluting with a 9/1 mixture of dichloromethane and methanol.

Product yield: 600 mg Nuclear Magnetic Resonance Spectrum: 0.85 ppm: t, 3H: CH 2 -CH 3;

1.35 ppm: sext, 2H: CH2 --CH3;

1.6 ppm: quint, 2H: CH2-CH2-CH3;

1.7-2 ppm: m, 8H: cyclopentane; 2.45 ppm: t: 2H: CH2-CH2-CH2-CH3;

4.8 ppm: s, 2H: -CH 2 -C 6 H 4 -;

6.05 ppm: s: 2H: NH2;

7-8 ppm, m, 9H: 8H aromatic + NHCO.

Examples 20 and 21 1 - [(2'-Carboxybiphenyl-4-yl) methyl] -2-n-propyl-4-spirocyclopentan-2-imidazolin-5-one and

- [(2'-N-cyanocarbamoylbiphenyl-4-yl) methyl] -2-n-propyl-4-spirocyclopentan-2-imidazolin-5-one

General formula (I):

R1 = CO-NH-CN

_R2 = H, R3 = n-C 3 H _7, CR4R5 = cyclohexane, X is = 0.

Grade A

Ethylbutyrimidate hydrochloride .NH

CH ₃ -CH ₂ -CH ₂ -C HCl.

OC ₂ H ₅

This compound was prepared as described by McElvain in J. Amer. Chem. Soc., 1942, 64, 1825-1827.

To a solution of hydrogen chloride gas (10.6 g) in ethanol (20 ml) was added butyronitrile (23 ml) at 0 ° C and after stirring at 0 ° C for 4 days, the reaction mixture was poured into 200 ml of anhydrous ether at 0 ° C with stirring. ; the precipitate formed is filtered off, washed with ether and dried under reduced pressure to give the desired product.

Yield: 25.8 g.

Step B The ethylbutyrimidate g of the imidate obtained in Step A was dissolved in 100 ml of dichloromethane and 50 ml of water, followed by the addition of 15 g of potassium carbonate. After decantation, the dichloromethane phase is dried over potassium carbonate and evaporated without heating.

Grade C

1-Aminocyclohexanecarboxylic acid ethyl ester

1-Aminocyclohexanecarboxylic acid is commercially available. 15 g of this amino acid is added at 0 ° C to a solution of 23 g of hydrogen chloride gas in 150 ml of anhydrous ethanol. The mixture was then heated to reflux for 5 hours, then concentrated to dryness and taken up in ether. The white solid obtained is filtered off, washed with ether and dissolved in a mixture of 300 ml of ether and 100 ml of water. The pH is adjusted to 9 by addition of potassium carbonate solution. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then evaporated to dryness. The desired product is thus obtained in the form of an oil.

Product yield: 14 g.

Step D 2-n-Propyl-4-spirocyclohexane-2-imidazolin-5-one g of the product obtained in Step C are dissolved in 200 ml of xylene containing 0.6 ml of acetic acid. Half of the imidate obtained in step B is then added and the mixture is heated to reflux. After one hour and 30 minutes, the remaining imidate is added, with the last quarter of the imidate added after 4 hours. After heating to reflux for 7 hours, the reaction mixture is evaporated to dryness. The solid residue is taken up in hexane, filtered, washed with ether and dried to give the desired imidazolinone.

Yield: 10.3 g. Melting point: 124-125 ° C. Infrared spectrum: (CCHI3):

1715cm- ^! : C = 0.1635 cm @ ^-1 : C = N.

Note: according to the infrared band values, the compound present in the solution is indeed 5-imidazolinone.

Step E 2-n-Propyl-4-spirocyclohexane-1 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one

To 0.24 g of sodium hydride (80% in oil) suspended in 10 ml of dimethylformamide is added 970 mg of the imidazolinone obtained in step D. After stirring for 20 minutes under a nitrogen atmosphere, 1.91 g of 4-bromomethyl-2 is added over five minutes. tert-Butoxycarbonylbiphenyl prepared according to European Patent Application 324 377. After stirring for one hour, the reaction mixture is concentrated to half its original volume under reduced pressure, then 100 ml of ethyl acetate and then 20 ml of water are taken out. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then concentrated to dryness.

The residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene. The desired product is obtained as a waxy substance. Yield of product: 2.10 g.

IR (CHC1 _3):

1705 - 1715 cm @ -1 C = O, C = O (ester, imidazolinone), 1635 cm @ -1 · C = N.

Analysis of the nuclear magnetic resonance spectrum confirms this structure.

Step F 1 - [(2'-Carboxybiphenyl-yl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20)

1.25 g of the tert-butyl ester obtained in step E are stirred for 45 minutes in a mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid. After concentration under reduced pressure, the residue is taken up in ether. The solid residue is filtered off, washed with ether and then dried. The desired product is obtained as a white solid.

Product yield: 1.04 g. Melting point: 170-172 ° C.

Nuclear Magnetic Resonance Spectrum:

7.10-7.80 ppm: m, 8H: aromatic;

4.90 ppm: s, 2H: N-CH 2 -C 6 H 4 -; 2.45 ppm: t, 2H: CH 3 -CH 2 -CH 2 -;

1.40-1.80 ppm: m, 12H: spirocyclohexane + CH3-CH2-CH2-;

0.90 ppm: t: 3H: CH3-CH2-CH2-;

1.60 g of the trifluoroacetate obtained above were dissolved in 150 ml of ethyl acetate and then 1N sodium hydroxide solution was added to adjust the pH to 5.0. The organic phase is then decanted, washed with saturated sodium chloride solution and then evaporated to dryness. The solid residue was taken up in ethyl ether, filtered and dried. Yield of product: 1.14 g. Mp .: 208-210 ° C.

Step G 1 - [(2'-N-Cyanocarbamoylbiphenyl-4-yl) methyl] -2-propyl-4-spirocyclopentan-2-imidazolin-5-one (Example 21)

To a suspension of 300 mg of the compound obtained in the preceding step in 5 ml of dichloromethane was added 0.54 ml of thionyl chloride. After one hour and 30 minutes, the reaction mixture was concentrated under reduced pressure, then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and 42 mg of cyanamide dissolved in 1 ml of dioxane containing 0.2 ml of 10N sodium hydroxide solution are added to the solution thus obtained. After one hour and 30 minutes, the reaction mixture is diluted with 150 ml of ethyl acetate, 20 ml of water, and the pH of the solution is adjusted to 5 by addition of acetic acid, the organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated.

The residue is chromatographed on silica gel, eluting with a 90: 8: 2 mixture of chloroform, methanol and acetic acid. The desired product is then isolated from the eluate.

Yield of product: 160 mg. Infrared spectrum:

(KBr): 2150 cm -1; C = N, Mass spectrum: MH ⁺ : 429.

Nuclear Magnetic Resonance Spectrum:

7.20-7.70 ppm: m, 8H: aromatic;

4.75 ppm: s, 2H: N-CH 2 -C 6 H 4 -;

2.40 ppm: t: 2H: CH3-CH2-CH2-;

1.30-1.80 ppm: m, 12H: CH3-CH2-CH2- and spirocyclohexane;

0.85 ppm: t: 3H: CH3-CH2-CH2;

Example 22

- [N-2 '- (4-carboxy-1,3-thiazol-2-ylcarbamoylbiphenyl-4-yl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one

General formula (I):

R3 = n-C3H7,

CR 4 R 5 = cyclohexane, X = O.

This compound is obtained from the compound obtained in Example 20. 2-Amino-4-ethoxycarbonyl-1,3-thiazole is prepared according to the procedure described by B. Plouvier et al. in J. Heterocycl. Chem., 26, 6, 1646 (1989).

Grade A

- [(N- (4-carbethoxy) -1,3-thiazol-2-ylcarbamoyl) methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one

To a solution of 404 mg of the compound prepared in Example 20 and 190 mg of the thiazole derivative in 4 ml of dichloromethane and 1 ml of dimethylformamide were added 500 mg of benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate and 0.14 ml of triethylamine. The mixture was then stirred for 40 hours at ambient temperature and then for 7 hours at 50 ° C. The reaction mixture is then taken up in 50 ml of ethyl acetate and washed twice with potassium hydrogen sulphate solution and potassium sulphate solution, washed twice with saturated sodium bicarbonate solution and once with saturated sodium chloride solution. After drying over sodium sulfate, the organic phase is concentrated under reduced pressure and the residue is chromatographed on silica gel, eluting with a mixture of ethyl acetate and toluene. The desired product is then obtained from the eluate.

Yield of product: 120 mg. Melting point: 96 - 98 ° C.

Grade B

To 110 mg of the product obtained in the previous step, dissolved in 1 ml of methanol and 1 ml of dioxane, was added 0.5 ml of 2N sodium hydroxide solution. After stirring for 35 minutes, the reaction mixture was diluted with 10 mL of water and 60 mL of ethyl acetate, and then the pH of the reaction mixture was adjusted to 5 by the addition of 1N hydrochloric acid. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulphate and then concentrated. The residue was taken up in ether, filtered and dried. Yield of product: 100 mg.

M.p .: 145-148 ° C.

Nuclear Magnetic Resonance Spectrum: 8.0 ppm: s, 1H: H at position 5 of the thiazole

7.1-7.7 ppm: m, 8H,: aromatic H,

4.7 ppm: s, 2H: N-CH 2 -C 6 H 4 -,

2.25 ppm: t, 2H: CH2 --CH2 --CH3,

1.2-1.8 ppm: m, 12H: cyclohexane and CH2-CH2-CH3, 0.85 ppm: t, 3H: CH2-CH2-CH3.

Example 23

2-n-Butyl-1 - [(2 '- (2-cyanoguanidinocarbonyl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one Formula (I) nh ₂ I

R1 = CONH-C = N-CN

R2 = H,

R3 = n-C4Hc), CR4R5 = cyclopentane, X = O.

The acid chloride of the product obtained in Example 2 is prepared. 1 g of this compound is introduced into 20 ml of dichloromethane and the mixture is stirred in the presence of 1.8 ml of thionyl chloride at ambient temperature for 2 hours. After concentrating the reaction mixture, the residue is taken up with benzene and then concentrated again. The isolated crude product is then used further. 417 mg of dicyanodiamide, 0.5 ml of 10N sodium hydroxide solution, 0.5 ml of water and 10 ml of dioxane are added and the mixture is stirred for 5 hours. The reaction mixture was taken up in water and ethyl acetate, potassium carbonate was added and the mixture was concentrated. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. The desired product is then isolated from the eluate. Yield of product: 100 mg. Melting point: 105 ° C.

Example 24

4-benzylidene-2-n-butyl-l - [(2'-carboxy) biphenyl-4-ylmethyl] -2-imidazolin-5-one

General formula (I):

R] = CO 2 H, R 2 = H, R ₃ = n-C4H9, R4R5-CH-C6H5, X = O

Grade A

4- (1-Benzylidene-1-valerylaminomethylamidomethyl) -2-biphenyltert-butyl carboxylate

From N-Boc-alpha-dehydro- (L) -phenylalanine, alpha-dehydro- (L) -phenylalanine-N-carboxyanhydride is prepared as described by R. Jacquier et al. Tetrahedron Lett., 1984, 25, 26, 2775. To 430 mg of this compound dissolved in 5 ml of tetrahydrofuran is added 644 mg of 4-aminomethyl-2'-biphenyl tert-butyl carboxylate and the mixture is stirred at ambient temperature for two hours. 1 ml of methyl orthovalerate is added and the mixture is evaporated to dryness under reduced pressure without heating. The residue is heated at 100 ° C for 3 hours, concentrated under reduced pressure and chromatographed on silica gel, eluting with hexane / ethyl acetate (4: 1). The white solid is then isolated from the eluate.

Yield: 580 mg. Melting point: 154 ° C.

Nuclear Magnetic Resonance Spectrum:

1.3 ppm: s, 9H: t-Bu

0.85 ppm: t: 3H: CH3 (nBu);

1.35 ppm: sext, 2H: CH3-CH2-;

1.45-2.20 ppm: m, 10H: CH3-CH2-CH2- and cyclopentane;

2.80 ppm: t, 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

3.80 ppm: s, 2H: CH2 (pyrimidinone);

5.15 ppm: s, 2H: N-CH 2 -;

7.25 ppm: m, 8H: aromatic.

Step B 4-Benzylidene-2-n-butyl-1 - [(2'-tert-butoxycarbonylbiphenyl-4-ylmethyl) -2-imidazolin-5-one

440 mg of the compound obtained in Step A are dissolved in 1 ml of acetic acid and the solution thus obtained is heated at 100 ° C for 30 minutes. The reaction mixture is then evaporated to dryness and the residue is chromatographed on silica gel, eluting with a 4: 1 by volume mixture of hexane and ethyl acetate. The desired product is then obtained as an oil.

Product yield: 130 mg.

Nuclear Magnetic Resonance Spectrum:

4.9 ppm: s: 2 H: _CH2 (N-CH2-C6H4-).

Grade C

100 mg of the compound obtained in the preceding step are dissolved in 1000 μΐ of dichloromethane, and then 1 ml of trifluoroacetic acid is added, the mixture is stirred for 40 minutes at ambient temperature and then evaporated under reduced pressure. The residue was taken up several times with dichloromethane and then evaporated. Addition of ethyl ether precipitates a white precipitate.

Yield of product: 101 mg. 85 °.

Mass spectrum:

MH ⁺ : 439.

Nuclear Magnetic Resonance Spectrum.

0.82 ppm: t, 3H: CH3 (n-Bu);

1.3 ppm: sext, 2H: CH ₃ CH ₂ -;

1.6 ppm: m, 2H: CH3-CH2-CH2-;

2.6 ppm: t, 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.82 ppm: s, 2H: CH2-C6H4-; 7.05 ppm: s, 1H, .dbd.CH - CH2 (H5);

7.2-8.2 ppm: m, 13H: aromatic.

Example 25 4-Benzylidene-1 - [(2'-carboxy) biphenyl-4-ylmethyl] -2-phenyl-2-imidazolin-5-one

General formula (I):

R | = CO 2 H, R 2 = H, R 3 = C ₆ H ₅ , R ₄ R ₅ = CH-C ₅ H ₅ , x = o.

Step A 4-Benzylene-2-phenyl-5-oxazolone

1.8 g of hippuric acid and 0.4 g of potassium bicarbonate were dissolved in 4 ml of acetic anhydride and the solution thus obtained was heated at 50 ° C for several minutes, after which the solution was cooled to ambient temperature. Then 1.49 g of benzaldehyde is added. After one hour at ambient temperature, 20 ml of distilled water at 80 ° C are added. The precipitated solid is centrifuged, washed with water and ethanol and then dried. The desired product is obtained as a yellow solid.

Melting point: 215 ° C.

NMR: 7.4ppm: s, 1 H, = CH-C 6 H _5,

8.1-8.4 ppm: m, 10H: aromatic

Grade B

4- (1-Benzoylamino-1-benzylidenemethylamidomethyl) -2'-biphenyl tert-butyl carboxylate

A mixture containing 500 mg of the compound obtained in the preceding step, 570 mg of 4-aminomethyl-2'-biphenyl-tert-butyl carboxylate and 10 ml of pyridine was heated at 110 ° C for 3 hours. The mixture was then evaporated under reduced pressure, the residue taken up in chloroform and then evaporated again. The residue is chromatographed on silica gel, eluting with hexane / ethyl acetate 3: 1 (v / v) and then 2: 1 (v / v). The desired product is obtained as a yellow solid.

Yield of product: 106 mg.

Nuclear Magnetic Resonance Spectrum:

1.1 ppm: s, 9H: t-Bu;

4.35 ppm: t, 2H: --CH2 --NH; 7.05-7.06 ppm: m, 19H: aromatic H + C8 H5-CH =; 8.65 ppm: t: 1 H: _NH-CH2;

9.9 ppm: s: 1H: NH-CH =.

Grade C

A mixture of 1.2 g of the compound obtained in the preceding step and 1.1 g of freshly melted sodium acetate in 5 ml of acetic acid is heated to reflux for 6 hours. The reaction mixture was then allowed to cool, whereupon an insoluble portion precipitated by the addition of chloroform. The filtrate is evaporated and the residue is chromatographed on silica gel, eluting with a 98/2 mixture of chloroform and methanol. The solid obtained is recrystallized from ethyl ether.

Yield of product: 692 mg. Melting point: 120 ° C.

Nuclear Magnetic Resonance Spectrum:

4.95 ppm: s, 2H: CH2-C6H4-

7.1 - 8.3 ppm: m, 19H, H aromatic + = CH-CqH5 ·

Examples 26 and 27

2-n-Butyl-1 - [(2 '- (2-methyltetrazol-5-yl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Example 26) and 2-n -Butyl-1 - [(2 '- (1-methyltetrazol-5-yl) biphenyl-4-yl) methyl] -4-spirocyclopentan-2-imidazolin-5-one (Example 27)

500 mg of the compound prepared in Example 5 and 58 mg of sodium hydride are introduced into 10 ml of dimethylformamide and the mixture is stirred for 30 minutes, 179 mg of methyl iodide and 2 ml of dimethylformamide are added and the mixture is stirred at ambient temperature for 4 hours. hours. The reaction mixture is then concentrated, the residue is taken up with water and extracted with ethyl acetate; The extract was dried over sodium sulfate, filtered, and the solvent was evaporated. The residue is chromatographed on silica gel, eluting with hexane / ethyl acetate (6: 4). Two fractions are collected:

mg of the compound of Example 26 and 184 mg of the compound of Example 27.

Example 26

0.7 ppm: t: 3H. CH 3 - (n-Bu);

1.2 ppm: sext, 2H: CH3-CH2-;

1.4 ppm: quint, 2H: CH 3 -CH 2 -CH 2 -;

1.5-1.9 ppm: m, 8H: cyclopentane;

2.25 ppm: t, 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

4.15 ppm: s: 3H: N-CH3;

4.6 ppm: s, 2H: -N-CH 2 -C 6 H 4 -;

ppm: system AA 'BB', 4H: CH2-C6H4-;

7.3- 7.75 ppm: m, 4H: CH2-C6H4-C6H4-.

Example 27

0.7 ppm: t: 3H: CH3 (n-Bu);

1.15 ppm: sext, 2H: CH3-CH2-;

1.38 ppm: quint, 2H: CH 3 -CH 2 -CH 2 -;

1.5-1.9 ppm: m, 8H: cyclopentane;

2.2 ppm: t, 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

3.35 ppm: s, 3H: N-CH3;

4.6 ppm: s: 2H: N-CH2-Q5H4;

ppm: system AA ', BB', 4H: N-CH 2 -C 6 H 4 -;

7.4- 7.8 ppm: m: 4 H: CH2-C ₆ H ₄ -C6H4-.

Example 28 2-n-Butyl-6-spirocyclopentan-3 - [(2 '- (5-tetrazoyl) biphenyl-4-yl) methyl] -5,6-4 (1H) -dihydro-4-pyrimidinone

Grade A

Ethyl cyklopentylidénacetát

6 g of sodium hydride (80%) are introduced into 40 ml of benzene, and 57.1 ml of ethyl triethylphosphonoacetate are added dropwise thereto at a temperature below 35 ° C. After one hour at ambient temperature, 24.3 ml of cyclopentanone are added dropwise. The mixture was heated to 65 ° C for 15 minutes, then cooled to ambient temperature and the supernatant was decanted. 25 ml of benzene are added and after 15 minutes of heating to 65 ° C, the mixture is cooled and the supernatant is decanted again. This procedure is repeated once more. Evaporation of the supernatants gave 42 g of the desired product which was distilled.

Boiling point: 102 DEG C. at a pressure of 1.243 kPa. Product yield: 22.8 g.

Step B (1-Aminocyclopentyl) acetamide

To 20 g of ethyl cyclopentylideneacetate prepared in the previous step is added 150 ml of ammonia gas and the mixture is then heated at 150 ° C for 72 hours. After evaporation, the product is purified by chromatography on silica gel, eluting with a dichloromethane / methanol / 20% ammonia (90/10/1) mixture. The product is dissolved in dichloromethane and dried over sodium sulfate. Filtration and evaporation of the dichloromethane from the filtrate gave the desired product.

Yield: 7.2 g.

Grade C

2-n-Butyl-6-spirocyclopentane-5,6-4 (1H) -dihydro-4-pyrimidinone

The mixture containing 4.57 g of (1-aminocyclopentyl) acetamide prepared in the previous step, 25 ml of methyl orthovalerate and a few drops of acetic acid was heated at 100 ° C for 18 hours. After evaporating the excess orthovalerate, the residue is taken up in a mixture of ethyl acetate and sodium bicarbonate, washed with brine, dried over sodium sulfate and purified by chromatography on silica gel, eluting with a dichloromethane / methanol (98/2; v / v) mixture.

Product yield: 5 g.

Nuclear Magnetic Resonance Spectrum: 0.75 ppm: t, 3H: CH3 (nBu);

1.2 ppm: sext, 2H: CH3-CH2-;

1.3-1.8 ppm: m, 10H: CH3-CH2-CH2 and cyclopentane;

ppm: t, 2H: CH3-CH2-CH2-CH2-;

2.15 ppm: s: 2H: _CH2-CO;

9.95 ppm: s.e., 1H: NH.

This compound is the compound obtained in Step C of Example 10.

Step D 2-n-Butyl-4-spirocyclopentane-1- [2 '- (triphenylmethyl-5-tetrazolyl) biphenyl-4-ylmethyl] -6-pyrimidinone

327 mg of sodium hydride (80%) in 30 ml of dimethylformamide and 1.5 g of the pyrimidinone prepared in the previous step are mixed under nitrogen atmosphere for 30 minutes, and 5.27 g of 4-bromomethyl-2 '- (triphenylmethyltetrazolyl) are added to the mixture. -5) biphenyl. After stirring at ambient temperature for 4 hours, the solvent is evaporated, the residue is taken up in ethyl acetate and water, dried over sodium sulphate and concentrated. The product obtained is purified by chromatography on silica gel, eluting with a 3: 7 mixture of ethyl acetate and hexane. Yield: 3.2 g.

Step E g of the compound obtained in the preceding step is introduced into 15 ml of methanol and the mixture is cooled in an ice-water bath, 4N hydrochloric acid (2.2 ml) is added and the mixture is stirred for 5 hours at ambient temperature. After evaporation, the residue is taken up in ethyl acetate and water, then sodium hydroxide is added to reach pH 11. Decantation is carried out, the aqueous phase is washed with ethyl ether and toluene and then again with ether. The aqueous phase is adjusted to pH 5 by addition of dilute hydrochloric acid, the aqueous phase is then extracted with ethyl acetate, dried and concentrated. The product obtained is purified on silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. The desired product is then isolated from the eluate. Yield of product: 800 mg.

NMR spectrum: 0.85 ppm: t: 3H: _CH3 / NSA /;

1.30 ppm: sext, 2H: CH3-CH2;

1.40-1.95 ppm: m, 10H: cyclopentane and CH2-CH2-CH2-CH3;

2.30 ppm: t, 2H: CH2 --CH2 --CH2 --CH3;

2.55 ppm: s, 2H: CH2 --CO;

4.95 ppm: s: 2 H: N-CH ₂ -C ₆ H ₄ -; 7.05 ppm: m: 4 H: CH2-CGH ₄ -; 7.55 to 7.82 ppm m 4 H: CH2-C ₆ H ₄ -C ₆ H 4.

Example 29 2-n-Butyl-3 - [(2 '-carboxybiphenyl-4-yl) methyl] -5-spirocyclopentane-5,6-5 (1H) -dihydro-4-pyrimidinone trifluoroacetate

Grade A

Ethyl 1-cyanocyclopentanecarboxylate

This compound was prepared as described in Helv. Chim. Acta, 1952, 35, 7, 2561. 9.2 g of sodium are dissolved in 200 ml of absolute ethanol. Half of the sodium ethylate solution thus obtained is poured into a flask. To the remaining half was added 24.88 g of ethyl cyanoacetate and the mixture was brought to reflux.

43.19 g of 1,4-dibromobutane was poured into another flask, and then sodium ethylate and 1,4-dibromobutane were added dropwise to the flask. After completion of the addition, the contents were maintained at reflux for 2 hours. After evaporation, the residue is taken up in a mixture of ethyl ether and water, washed with saturated sodium chloride solution and then dried. The product obtained is distilled at a temperature in the range of 115-120 ° C at a pressure of 1 mm Hg. Product yield: 24 g.

Grade B

Ethyl 1-aminomethyl cyclopentanecarboxylate

This compound is prepared by catalytic hydrogenation of ethyl 1-cyanocyclopentanecarboxylate.

g of ethyl 1-kaynocyclopentanecarboxylate was introduced into 200 ml of ethanol containing 10% ammonia, and the resulting mixture was hydrogenated at 60 ° C at 10 MPa in the presence of alumina for 72 hours. After filtration through celite and evaporation of the filtrate, the residue is chromatographed on silica gel, eluting with a dichloromethane / 20% ammonia (98: 2: 0.5 by volume) mixture. Yield: 12.8 g.

Step C 2-n-Butyl-5-spirocyclopentane-5,6-4 (1H) -dihydro-4-pyrimidinone

A mixture of 13.12 g of the compound obtained in the preceding step and 13.5 g of ethylvalerimidate in 100 ml of xylene containing a few drops of acetic acid is heated to reflux for 13 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and 10% sodium carbonate solution, dried and concentrated. Product yield: 14 g. M.p .: 89-91 ° C.

Nuclear Magnetic Resonance Spectrum: 0.80 ppm: t, 3H: CH3 (nBu);

1.10-1.80 ppm: m, 12H: CH3-CH2-CH2 and cyclopentane; 2.05 ppm: t: 2 H: _{CH3 CH2 CH2} CH2;

3.20 ppm: s, 2H: CH2 (pyrimidinone);

ppm: 1H, s: NH-CO.

Step D 2-n-Butyl-5-spirocyclopentan-3 - [(2'-tert-butoxycarbonylbiphenyl-4-yl) methyl] -5,6-4 (1H) -dihydro-4-pyrimidinone

500 mg of the product obtained in the preceding step are introduced into 40 ml of dimethylformamide under a nitrogen atmosphere and in the presence of 115 mg of sodium hydride (80% in oil), and the mixture is stirred at ambient temperature for 30 minutes. 1.08 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl is then added and the resulting mixture is stirred for 2 hours. After evaporation, the residue is taken up in ethyl acetate, washed with saturated sodium chloride solution, dried and concentrated, and the residue is chromatographed on silica gel, eluting with a 3: 7 mixture of ethyl acetate and hexane. Yield: 280 mg .

Grade E

250 ml of the tert-butyl ester prepared in the previous step are dissolved in 10 ml of dichloromethane. The solution is cooled in an ice-water bath, 5 ml of cold trifluoroacetic acid are added and the mixture is stirred in the cold for one hour and then at ambient temperature for one hour. The reaction mixture was then evaporated under reduced pressure. The residue was taken up in ethyl ether and then evaporated. This operation is repeated three times, after which the evaporation residue is taken up in hexane, stirred and the hexane is decanted. After addition of ether, the precipitate formed is filtered off. Product yield: 190 mg.

Mp: 153-155 ° C.

Nuclear Magnetic Resonance Spectrum: 0.85 ppm: t, 3H: CH3 (nBu);

1.35 ppm: sext, 2H: CH3-CH2-;

1.45 to 2.20 ppm: m: 10H: _{CH3-CH2-CH2-and} cyclopentane;

2.80 ppm: t, 2H: CH 3 -CH 2 -CH 2 -CH 2 -;

3.80 ppm: s, 2H: CH2 (pyrimidinone);

5.15 ppm: s: 2 H: _N-CH2 -;

7.25 ppm: m, 8H: aromatic.

Table 1

Pr. ^least 1 3 Tepl.top. à C / 30 co ₂ h ^{n C} 49 cyklchexén I? A 172-174 31 CO-C.T. cyclopentane - 56-37 32 ⁺ COgH c / ch ₃ / c ₆ h ₅ TFA 55-60 33 co ₂ a --A ° C / C ₂ H _5/2 TFA 82-34 34 cc ₂ x ⁿ '' 3 ^r '7 cyclopentane T? A Ι64 35 cyclopentane 163-164 36 CO-.T ^C 6 ^H 5 cyclopentane TFA 178 37 CO-H R-Cp, cyclopentane TFA 160-162 38 CC 3 ^Cl: 3 cyclopentane TFA 140 39 U.S. Pat n-C. WITH, 4 7 cyclopropene - 204-205 40 5-tetra zolvl -c: - ' ₂ -ch-- cyklcpentsr. - 110 41 5-tetrezclyl and-C ^ cyklonexan 130 42 5-tetT8zelyl cyklehexén - 141 43 CC ¹ -H oyxlopentyl cyclopentane TFA S2-88 44 co ₂ e cyclopentane TFA 151 45 co ₂ .h CH ₂ -C ₅ H _g cyclopentane TFA 88 CC-H s cyclopentane - 230 47 CO-3 ⁿ -C _t E _Q cyklosutén TFA 178 48 co ₂ s N-C ^ cyclododecane TFA 130-135 49 CC, H ^{n c} 4 ^: 9 2-ADCs: entan TFA 164-166 50 CO ₂ E nC ₄ H, / 4-phenyl / cyclohexanol TFA 155-157 51 what. ₂ h nC _A / 4-ajethyl / cyklotiexén TFA 198-200 52 co ₂ h aC _A / N scetyl / - 4-piperidine TFA 90-95 73 c = ₂ H _V , cyklcpenten. - 141-143 5 / C0 ₂ 3 = -C, ₃₉ ^ch 3 - 207-209 55 CCpH CH m 10 =

++ R 1 = H and R ₂ = CO ₂ H + these compounds have asymmetric carbon and are isolated in the form of a mixture of their optically active isomers

Claims (16)

PATENT CLAIMS 1. N-substituted heterocyclic derivatives of general formula (I) R 1 and R ₂ , which are the same or different, each independently represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 4 alkoxy group, an amino group, an aminomethyl group, a carboxy group, an alkoxycarbonyl group, wherein the alkoxy radical contains from 1 to 4 carbon atoms, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanocarbamoyl, N-hydroxycarbamoyl (N-hydroxycarbamoyl) - 1,3-thiazol-2-yl) carbamoyl, ureido, 2-cyanoguanidinocarbonyl, 1-imidazolylcarbonyl, 3-cyano-2-methylisothioureidomethyl, wherein at least one of R 1 or R ₂ is different from hydrogen . R3 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms and optionally substituted by one or more halogen atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl radical it contains 1 to 3 carbon atoms, a phenylalkenyl group in which the alkenyl radical contains 2 or 3 carbon atoms, said phenyl groups being optionally substituted by one or more substituents selected from the group consisting of halogen atoms, an alkyl group containing 1 to 4 carbon atoms, a haloalkyl group (C 1 -C 4), (C 1 -C 4) polyhaloalkyl, (C 1 -C 4) hydroxyl and (C 1 -C 4) alkoxy; R 4 and R 5 independently of one another represent an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenylalkyl group in which the alkyl radical contains 1 to 3 carbon atoms, said alkyl, phenyl and phenylalkyl group being optionally substituted by one or more halogen atoms or a group selected from the group consisting of perfluoroalkyl having 1 to 4 carbon atoms, a hydroxyl group and an alkoxy group having 1 to 4 carbon atoms, or R 4 and R 5 together form a group of the formula = CR 7 R 8, wherein R 7 is hydrogen, C 1 -C 4 alkyl or phenyl, and R 8 is C 1 -C 4 alkyl or phenyl, or else R 4 and R 5 taken together are either a group of formula (CH ₂ ) _n or a group of formula (CH ₂ ) p Y (CH ₂ ) q in which Y represents an oxygen or sulfur atom or a carbon atom substituted by an alkyl group containing 1 to 4 carbon atoms , a phenyl group or a phenylalkyl group wherein the alkyl moiety contains 1 to 3 carbon atoms or an N-Rg group wherein Rg is hydrogen, an alkyl moiety having 1 to 4 carbon atoms, a phenylalkyl group in which the alkyl moiety contains 1 to 3 carbon atoms carbon atoms, an alkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a haloalkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, a polyhaloalkylcarbonyl group in which the alkyl moiety contains 1 to 4 carbon atoms, benzoyl, alpha- an aminoacyl group or an N-protecting group, or R4 and R5 taken together with the carbon atom to which they are attached form an indane group or an adamantane group, P + q = m, n is an integer from 2 to 11, m is an integer from 2 to 5, X is oxygen or sulfur, z and t are 0 or one of them is 0 and the other is 1, and salts thereof. N-substituted heterocyclic derivatives according to claim 1, in which R 1 is in the ortho position and represents a carboxy or tetrazolyl group and R ₂ represents a hydrogen atom. N-substituted heterocyclic derivatives according to claims 1 and 2, in which R 4 and R 5 together with the carbon atom to which they are attached form a cyclopentane or cyclohexane group. N-substituted heterocyclic derivatives according to claims 1 to 3, in which R 3 represents a straight alkyl group having 1 to 6 carbon atoms. N-substituted heterocyclic derivatives according to claims 1 to 4, in which X represents an oxygen atom. N-substituted heterocyclic derivatives according to claims 1 to 5 of the general formula (I), in which z = t = 0. A compound according to claim 1, which is 2-n-butyl-4-spirocyclopentan-1 - [(2 '- (tetrazol-5-yl) -biphenyl-4-yl) methyl -2-Imidazolin-5-one or one of its salts with acids or bases. A process for the preparation of an N-substituted heterocyclic derivative according to any one of claims 1 to 7, characterized in that a1) the heterocyclic derivative of the general formula (2) is wherein z, t, R 3, R 4 and R 5 are as defined in claim 1 for formula (I), reacted with a (biphenyl-4-yl) methyl derivative of formula (3) H 1 -CH 2 - in which Hal represents a halogen atom and R 1 ' and R'2 denote Rj, respectively. R 2 or a precursor group R 1, respectively. R2, wherein b1) optionally reacting the compound of formula (4) thus obtained with Lawesson's reagent, which is 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide, and c1) the compound obtained in step a1) or b1) and having the general formula (5) ( S), in which X represents an oxygen atom or a sulfur atom, is converted to a compound of formula (I) by converting the groups R'1 and / or R'2 into the groups R 1 | and / or R 2 and the compound obtained is optionally converted into one of its salts. A process for the preparation of an N-substituted heterocyclic derivative of general formula (I) according to any one of claims 1 to 7, characterized in that a2) is an amino acid of general formula (7): R. (CH ₂ ), - NHPr _R / ¹⁵ (0¾ COOH ⁽⁷⁾ wherein z, t, R4 and R5 are as defined in claim 1 for formula (I), and wherein the amine function is protected with a Pr group, reacts with a (biphenyl-4-yl) methylamine derivative of the general formula formula (8): wherein R 1 and R 2 are either R 1 and R 2, respectively. R2, or a precursor group R1, respectively. R2, whereby b2) the compound thus obtained, which, after deprotection of the amine function, has the general formula (9) (CH3-NH), is reacted with an alkyl ortho-ester of the general formula (10) R ₃ C (OR) ₃ (10), wherein R 3 is as defined in claim 1 for formula (I) and R is C 1 -C 4 alkyl, and c2) optionally a compound of formula (4) so obtained. ) reacts with Lawesson's reagent, which is 2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide, and d2) the compound thus obtained in b2) or c2) of the general formula (5): is then worked up under appropriate conditions to give the compound of formula (I) by converting the groups R'2 and / or R'j into the groups R2 and / or R1; and optionally converting the compound to one of its salts. A process for the preparation of an N-substituted heterocyclic derivative of general formula (I) according to claim 6, characterized in that a3) reacts an imidazole derivative of general formula (11): wherein R 3, R 4 and R 5 are as defined in claim 1 for formula (I), with a (biphenyl-4-yl) methyl derivative of formula (3): wherein Hal represents a halogen atom and R 1 and R '2 represent either R 1 and R 2, respectively. R 2 or a precursor group R 1, respectively. R2, in the presence of oxygen and irradiated with ultraviolet light in a basic medium, and b3) optionally, the compound of formula (4 ') thus obtained: Q reacts with Lawesson's reagent, which is 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide, whereby c3) the compound thus obtained in a3) or b3) of the general formula (5 '): is worked up under appropriate conditions to a compound of formula (I) by converting the groups R '1 and / or R' 2 into the groups R 1 and / or R 2 and the compound thus obtained is then optionally converted into one of its salts. Pharmaceutical composition, characterized in that it comprises, as active ingredient, an N-substituted heterocyclic derivative according to any one of claims 1 to 7. A pharmaceutical composition comprising the N-substituted heterocyclic derivative according to any one of claims 1 to 7 in combination with a beta-blocking compound. A pharmaceutical composition comprising the N-substituted heterocyclic derivative according to any one of claims 1 to 7 in combination with a diuretic. A pharmaceutical composition comprising the N-substituted heterocyclic derivative according to any one of claims 1 to 7 in combination with a non-steroidal anti-inflammatory agent. A pharmaceutical composition comprising the N-substituted heterocyclic derivative according to any one of claims 1 to 7 in combination with a calcium antagonist. A pharmaceutical composition comprising the N-substituted heterocyclic derivative according to any one of claims 1 to 7 in combination with a soothing agent.