NO301977B1 - Analogous Process for Preparation of N-Substituted Heterocyclic Derivatives, and Intermediates for Their Preparation - Google Patents

Abstract

Heterocyclic N-substituted derivatives of formula (I) and their salts are new. R1, R2 = H, 1-6C alkyl, 1-4C alkoxy, NH2, NH2CH2-, COOH, (1-4C alkoxy)carbonyl, CN, tetrazolyl, methyltetrazolyl, methylsulphonylamino, trifluoromethyl sulphonylamino(methyl), N-cyanoacetamide, N-hydroxy- acetamide, N-((4-carboxy)-1, 3-thiazol-2-yl) acetamido, ureido, 2-cyanoguanidinocarbonyl, 2-cyano-guanidino-methyl, imidazol-1-yl-carbonyl, 3-cyano-2-methyl isothioureidomethyl, with the proviso that R1 and R2 are not both H. R3 = H, 1-6C alkyl (optionally substituted by one or more halogen, 2-6C alkenyl, 3-7C cycloalkyl, Ph, phenyl-(1-3C alkyl) or (2-3C alkenyl)phenyl; the Ph groups are optionally substituted by at least 1 halogen, 1-4C alkyl, halogen-(1-4C alkyl), polyhalogeno-(1-4C alkyl), OH or 1-4C alkoxy. R4, R5 = 1-6C alkyl, Ph, phenyl-(1-3C alkyl), the alkyl, phenyl and phenylalkyl groups being optionally substituted by one or more halogen, perfluoro-(1-4C alkyl), OH or 1-4C alkoxy. Or R4 and R5 together form =CR7R8, (CH2)n or (CH2)pY(CH2)q. R7 = H, 1-4C alkyl or Ph; R8 = 1-4C alkyl or Ph. Y = O, S, C (substituted by 1-4C alkyl, Ph or phenyl-(1-3C alkyl) or NR6. R6 = H, 1-4C alkyl, phenyl-(1-3C alkyl), 1-4C alkylcarbonyl, halogeno-(1-4C(alkyl)carbonyl, polyhalo-(1-4C alkyl)carbonyl, -COPh, alpha-aminoacyl or an N-protecting group. Or R4 and R5 together form indane or adamantane. p + q = m; n = 2-11; m = 2-5; X = O or S. z and t = 0 or one is 0 and the other is 1. Specifically claimed is 2-n-butyl-4- spirocyclopentane -1-((2'-(5-tetrazolyl) biphenyl-4-yl)methyl) -2-imidazolin-5-one.

Description

where the alkyl is C1-C3, C1-C-alkylcarbonyl, C1-C-haloalkyl-

carbonyl, a C1-C6 polyhaloalkylcarbonyl, a benzoyl, an alpha-aminoacyl or an N-protecting group, or R4 and R5

together with the carbon atom to which they are attached, constitute an indane or an adamantane; p + g = m; n is an integer between 2 and 5, X is an oxygen atom or a sulfur atom; z and t are zero or one is zero and the other is 1; and their salts.

Application: antagonists against angiotensin II.

The invention relates to an analogue method for the preparation of a therapeutically active compound, which is an N-substituted heterocyclic derivative.

The compounds produced according to the invention act antagonistically against the action of angiotensin II, which is a peptide hormone with the formula:

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

Angiotensin II is a strong vasopressor which is the biologically active product of the renin-angiotensin system: renin acts on angiotensinogen in plasma so that angiotensin I is produced, which is converted to angiotensin II by the action of the converting enzyme for angiotensin I.

The compounds produced according to the invention are non-peptide compounds, antagonists against angiotensin II. As they inhibit the action of angiotensin II on its receptors, the compounds produced according to the invention prevent in particular the increase in blood pressure produced by hormone-receptor interaction, and they likewise have other physiological effects at the central nervous system level.

Thus, the compounds produced according to the invention are used for the treatment of cardiovascular disorders such as hypertension, heart failure, as well as for the treatment of disorders in the central nervous system and the treatment of glaucoma and diabetic retinopathy.

The invention produces compounds of formula (I):

where:

R1 and R2 are the same or different and represent each,

independently, hydrogen or a group selected from carboxy, alkoxycarbonyl, where alkoxy is C1-C4, cyano, tetrazolyl,

methyltetrazolyl, methyltetrazolyl, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanocarbamoyl, N-hydroxycarbamoyl, N-((4-carboxy)-1, 3-thiazo.l-2-yl)-carbamoyl, ureido, 2-cyanoguanidinecarbonyl, 2-cyano- guanidinemethyl, 1-imidazol-yl-carbonyl, 3-cyano-2-methyl-isothioureidomethyl, provided that at least one of

the substituents R, or R 2 are other than hydrogen;

R3 represents hydrogen, C^-Cg-alkyl, unsubstituted or substituted with one or more halogen atoms, C-C-alkenyl, C3-C7-cycloalkyl, phenyl, phenyl(C2~c3)-alkyl, where

the phenyl group is unsubstituted;

R 4 and R 5 each independently represent C 1 -C 8 alkyl, phenyl,

where the mentioned alkyl and phenyl groups are unsubstituted or substituted with one or more halogen atoms or with

perfluoro(C 1 -C 4 )alkyl; or

R4 and R5 together form a group with formula =CR7Rg, where

R^ represents hydrogen, C^-C4~alkyl or phenyl, and

R 0 represents C 1 -C 6 alkyl or phenyl; or also

R 4 and R 5 taken together may represent a group of formula

(CH_) or a group of formula (CH_) Y(CH„) where Y either

2 n 2 p 2 q

is an oxygen atom or a carbon atom substituted by a C1-C4~alkyl group or phenyl or a group N-Rg where

Rg represents hydrogen, C-^-C^ alkylcarbonyl, polyhalo-C1~C4-alkylcarbonyl, benzoyl, α-aminoacyl or an N-protecting group selected from the groups tert-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl or benzyl, or R4 and R5 taken together with the carbon atom as

they are bound to, constitute indane or adamantane;

p + q = m;

n is an integer from 2 to 11;

m is an integer from 2 to 5; - X is an oxygen or sulfur atom;

z and t are zero or one is zero and the other is 1;

and their salts.

When a compound produced according to the invention exhibits an asymmetric carbon, the invention includes the production of the two optical isomers of this compound.

The salts of the compounds of formula (I) include the salts with the inorganic or organic acids which allow a separation or a suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, e.g. a mandelic acid or a camphosulfonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the methanesulfonate, the methyl sulfate, the maleate, the fumarate, the 2-naphthalene sulfonate.

The salts of the compounds of formula (I) also include the salts with the organic or inorganic bases, e.g. the alkali metal or alkaline earth metal salts such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or also the salts of arginine, lysine, or any acceptable physiological amine.

In the present description and in the patent claims that follow, halogen atom means a bromine atom, chlorine atom or fluorine atom; by N-protecting group (also denoted by Pr) is meant a group classically used in peptide chemistry to enable a temporary protection of the amine function, e.g. a group Boe, Z, Fmoc or a benzyl group; by an esterified carboxy group is meant a labile ester under suitable conditions, such as e.g. a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes the saturated aliphatic hydrocarbon residues, straight or branched.

The compounds of formula I where R 1 is in ortho and represents a carboxy or tetrazolyl group and R 2 is hydrogen are the preferred compounds.

The compounds of formula (I) where R 4 and R 5 bound together, together with the carbon to which they are bound, constitute a cyclopentane or a cyclohexane, are preferred compounds.

Likewise, the compounds of formula (I) where R 3 represents a C 1 -C 6 linear alkyl group are preferred compounds.

The compounds of formula (I) where X represents an oxygen atom are likewise preferred compounds.

Finally, the compounds of formula (I) where z = t = 0 are preferred compounds.

The following abbreviations are used in the description and in the examples:

Et : Ethyl

nBu, tBu : n-butyl, tert-butyl

DMF : dimethylformamide

THF: tetrahydrofuran

DCM : dichloromethane

NBS: N-bromosuccinimide

DCC : dicyclohexylcarbodiimide

DIPEA : diisopropylethylamine

Ether : ethyl ether

TFA: trifluoroacetic acid

Z : benzyloxycarbonyl

Boe : tert-butoxycarbonyl

BOP : benzotriazolyloxytrisdimethylaminophosphonium hexafluorophosphate

Fmoc : fluorenylmethyloxycarbonyl

According to the invention, the method for producing the compounds (I) is characterized by:

al) one leaves a heterocyclic derivative with formula:

where z, t, R3, R4 and R5 have the meanings given above for (I) react with a (4-biphenyl-yl)methyl derivative of formula: where Hal represents: a halogen atom and R<1>, and R'2 represents either R1 and R2 respectively , or a precursor group for R 1 , and R 2 ; bl) optionally, the thus obtained compound of formula: is treated with the Lawesson reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]; cl) the compound obtained in al) or in bl) with formula:

where X represents an oxygen atom or a sulfur atom, is treated to prepare the compound (I) by converting the groups R', and/or R'2 into the groups R1 respectively

and/or R2; or

a2) one leaves an amino acid with formula:

where z, t, R4 and R5 have the meanings given above for (I) and whose amine function is protected by the group Pr, react with a (4-biphenyl-yl)methylamine derivative of formula: where R', and R'2 represent respectively either R1 and R2 or a precursor group for R1 and R2; b2) after deprotection of the amine, the thus obtained compound of formula: is further treated with an alkyl orthoester of formula R3C(OR)3(10) where R3 has the meaning stated above for (I) and R is a C1-C4 alkyl; c2) optionally, the thus obtained compound of formula: is treated with the Lawesson reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]; d2) the thus obtained compound in b2 or in c2 with formula:

is further treated under the appropriate conditions to prepare compound (I) by converting the R1., and/or R'2 groups to R1 and/or R2, respectively; or

a3) reacts with an imidazole derivative of formula:

where R3, R4 and R5 have the designations given above for (I), with a (4-biphenyl-yl)methyl derivative of the formula: where Hal represents a halogen atom and R<1>, and R'2 represents respectively either R, and R2 or a precursor group for R1 and R2, in the presence of oxygen and UV radiation, in a basic environment; b3) optionally, the thus obtained compound of formula: is treated with the Lawesson reagent [2,4-bis[4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]; c3) the thus obtained compound in b3 or in c3 with formula:

is further treated under suitable conditions to prepare the compound (I) by conversion of the R'i~ and/or R'2 groups to the R1 and/or R2 groups, respectively.

Finally, the compound obtained in cl), d2) or c3) is optionally converted into one of its salts with acids or bases.

Furthermore, the present invention relates to the compounds of formula (II):

where:

R 3 is hydrogen, C 1 -C 6 alkyl, unsubstituted or substituted with one or more halogen atoms, C2-C6-alkenyl, C3-C7-cycloalkyl, phenyl, phenyl (C1-C3)-alkyl, wherein

the phenyl group is unsubstituted;

R 4 and R 5 are each, independently, C 1 -C 4 -alkyl, phenyl, the alkyl groups, phenyl groups and phenylalkyl groups being unsubstituted or substituted with one or more halogen atoms or with perfluoro (C 1 -C 1 -alkyl;

or R4 and R5 together form a group of formula =CR7R8,

where R 1 is hydrogen, C 1 -C 4 alkyl or phenyl, and R 8 is C 1 -C 4 alkyl or phenyl;

or R 4 and R 5 taken together are a group of formula (CH 2 ) or a group of formula (CH 2 ) pY (CH 2 ) q, where Y may be an oxygen atom or a carbon atom substituted with C 1 -C 4 alkyl or phenyl, or a group N-Rg where Rg is hydrogen, C1-C4-alkylcarbonyl, polyhalogen (C1-C4)-alkylcarbonyl,

benzoyl, α-aminoacyl or an N-protecting group selected from the groups Boe, Z, Fmoc or benzyl, or R4 and R5, together with the carbon atom to which they are attached, constitute indan

or adamantane;

p + q = rn;

n is an integer from 2 to 11;

m is an integer from 2 to 5;

X is an oxygen or sulfur atom;

z and t are zero or one is zero and the other is 1;

with the limitation that

when z and t are zero and X is oxygen, then R 4 and R 5 are something other than C 1 -C 6 alkyl or phenyl, wherein alkyl and phenyl are unsubstituted or substituted with one or more halogen atoms or with perfluoro(C 1 -C 6 - alkyl;

or R 4 and R 1 , taken together are something other than a group

NR6where Rg is hydrogen,

n is different from 6; or when

z = 1 and R3 is phenyl, then R4 and R5 are different from methyl.

Among the derivatives (II), the compounds where z = t = 0 and R4 and R5, together with the carbon atom to which they are attached, form a cyclopentane, are the preferred compounds. These compounds correspond to the formula:

where X represents an oxygen atom or a sulfur atom and R3 represents a hydrogen, a C1-C6 alkyl, unsubstituted or substituted with one or more halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl, where the alkyl is C1-C3, a phenylalkenyl where the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted one or more times with a halogen atom, a C1-C4 alkyl, a C1- C 4 -haloalkyl, a C 1 -C 4 polyhaloalkyl, a hydroxyl or a C 1 -C 4 alkoxy.

The compounds (II) where z = 0 and t = 1 with formula:

wherein R 3 , R 4 , R 5 and X have the definitions given above for (II), are preferred compounds.

Finally; the compounds (II) where z = 1 and t = 0 with formula:

wherein R 3 , R 5 , p, q, n, m, X, z and t are as defined above for (II), are preferred compounds.

The derivatives 2 are prepared by known methods. E.g. one can use the method described by Jacquier et al. (Bull Soc. Chim. France, 1971, 3, 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 89, 1363-1373) and allowing an alkylimidate to react with an amino acid or its ester according to the following reaction sequence:

where R represents a C 1 -C 4 -alkyl, R < 1> represents hydrogen or an 0 -C 1 -alkyl and R 3 , R A , R 5 , z and t are as defined above for (I).

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

According to another mode of operation, compound 2 can be prepared by the reaction in an acidic environment of an aminoalkylamide (5'') on an alkylortho-ester (10) according to the following reaction core:

where R represents a C 1 -C 4 alkyl.

Using a method described by H. Takenaka et al. (Heterocycles, 1989, 29 (6), 1185-89) one can likewise prepare compound 2, by adding an acid halide of the formula

where Hal represents a halogen, preferably chlorine, react with the 5'<1->derivative.

The reaction is carried out in a basic environment.

More particularly, compound 2 can be prepared by reacting a compound of formula:

where A represents an OH group, an NH2 group or an OR' group, R<1> being hydrogen or a C1-C4 alkyl, with a compound of formula: where B represents: a C (OR) ,-group

or

a COHal group.

where R is a C 1 -C 4 alkyl and Hal denotes a halogen atom, preferably chlorine; and

then optionally the compound thus obtained is treated with the Lawesson reagent 2,4-(bis/4-methoxyphenyl)-1,3-dithia-2,4-diphospho-phetane-disulfide.

The derivative of (4-biphenyl-yl)methyl (3) is prepared according to a method described in EP patent application, publ. no. 324,377.

The conversion of a group R', and/or R'2 into a group R1 and/or R2 is carried out by methods well known to those skilled in the art. Thus, when compound (I) to be prepared has an R. and/or R.sub.2 = carboxy group, represents. R1 and/or R2 an esterified carboxy group. When compound (I) to be prepared has an R1 and/or R2 = tetrazolyl group, R1 and/or R2 can represent either a tetrazolyl protected e.g. with a trityl group, or a cyano group which will further be replaced with a tetrazolyl group, optionally protected with a trityl. The conversion of the cyano group to a tetrazolyl can be carried out using an azide, e.g. tributyltin azide or with sodium azide.

One can likewise use R<1>!- and/or R'2 groups such as the groups, nitro, carboxy, cyano or acid chloride and further convert them by reactions that are well known to the person skilled in the field to obtain R1 and/or R2 -groups as defined for compound (I).

Thus, when R<1.>, and/or R'2 represents a carboxy, it can be converted to R1 and/or R2 representing a 1-imidazol-yl-carbonyl, or also to N-[(4-carboxy)-1, 3-thiazol-yl-2)]-carbamoyl.

R', and/or the R'2 group representing an acid chloride can be converted to R1 and/or R2 representing N-hydroxycarbamoyl, N-cyanocarbamoyl, ureido or 2-cyanoguanidinecarbonyl.

R<1>, and/or the R<*>2 group representing a nitro can be transferred to amino from which R1 and/or R2 such as methylsulfonylamino, trifluoromethylsulfonylamino and trifluoromethylsulfonylaminomethyl are prepared. ;R1., and/or the R'2 group representing a cyano can be converted to aminomethyl from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al., J. Org. Chem., 1970, 35 (6), 2067-2069), and 2-cyano-guanidinemethyl (according to R.W. Turner, Synthesis, 1975, 332). ;Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basic environment, e.g. in the presence of potassium, a metal alcoholate, metal hydride, calcium carbonate or triethylamine. ;Step bl) is carried out by heating under nitrogen in a solvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061. ;In the description below, the method which includes steps al, bl and cl is called method 1. ;The compounds 7 are known or are prepared by known methods (Chemistry of the Amino Acids , Greenstein and Winitz, John Wiley ed., 1061, vol. I, p. 697). ;The compounds 8 are produced according to EP patent application, publ. no. 324 377. Step a2) is carried out under normal conditions for binding an acid to an amine, e.g. in the presence of BOP and DIPEA. ;Step b2) which is ring formation of compound 9 in the presence of 10, is carried out according to Jacquier et al. (Bull. Soc. Chim. France, 1971 (3), 1040-1051) and according to Bach (Chem. Ber., 1956, 89, 1363-1373). ;In the description below, the method comprising steps a2 to d2 is called method 2. ;According to a variant of method 2 in step b2), an intermediate product 9' with formula can possibly be isolated: ; then prepare compound 4 by ring formation in an acidic environment. ;According to another variant of method 2 and to prepare a compound (I) where R4R5 represents a group =CR7R8, one can react in an acidic environment, ;an amino acid with formula: ; with an aldehyde or a ketone of formula: where R7 and R8 have the meanings given above for (I), so by the action of compound 8 a compound of formula: ; The cyclization of this compound in an acidic environment leads to compound 4. In this method, in order to prepare a compound (I) where R1 and/or R2 is a carboxy group, the substituent R1 and/or R2 preferably represents a tert-butoxy-carbonyl group. A final alternative for the preparation of compounds (I) where 2 and t = 0 takes place by means of photooxidation as described as a3), b3) and c3) above. ;The imida2ol derivative 11 is either commercial, or known, or prepared by known methods, indicated above for the preparation of compounds 2. ;Step a3) is carried out in an inert solvent such as e.g. DMF; to simplify the reaction, a photosensitizing product such as methylene blue can be added. ;In the description below, the method comprising steps a3) to c3) is called method 3. ;The compounds (I) which are produced according to the invention where R4 and R5 bound together represent a group of formula (CH2) pY (CH2) where Y is an NH -group, can be prepared by catalytic hydrogenolysis of a corresponding compound (I) where Y is an N-R6 group, R6 being a benzyl. The affinity of the compound produced by the invention for the angiotensin II receptors has been studied in an experiment for the binding of angiotensin II labeled with iodine 125 to membrane receptors from rat liver. The method used is that described by S. Keppens et al., in Biochem. J., 1982, 208, 809-817. CI50 is measured: the concentration that gives 50% displacement of labeled angiotensin II, bound specifically to the receptor. The CI50 for the compounds according to the invention is lower than 10"<6>M. In addition, the antagonist effect to angiotensin II of compounds prepared according to the invention has been ascertained in various animal samples where the renin-angiotensin system has previously been activated (C. Lacour et al., J. Hypertension, 1989, 7 (suppl. 2), S33-S35). ;The compounds prepared according to the invention are active after administration via various routes, especially via the oral route.;No sign of toxicity has been observed with these compounds in pharmacologically active doses. Thus, the compounds can be used in the treatment of various cardiovascular disorders, in particular hypertension, heart failure, venous insufficiency, as well as the treatment of glaucoma, diabetic retinopathies and various disorders of the central nervous system, anxiety, depression, memory loss conditions or Alzheimer's disease eg ;For this purpose, pharmaceutical preparations will contain an effective dose of a compound fre mstilled according to the invention or of a pharmaceutically acceptable salt and suitable additives. The additives mentioned are selected according to the desired pharmaceutical form and method of administration. In such pharmaceutical preparations for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredients with compounds of formula I above or their possible salts can be administered in unit forms for administration , in admixture with classical pharmaceutical carriers, for animals and for humans for the prophylaxis or treatment of the above disorders or diseases. The suitable unit forms for administration include the forms via the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions, the sublingual, buccal, intratracheal, intranasal forms of administration, the subcutaneous, intramuscular or intravenous forms of administration and the rectal forms of administration. For topical application, the compounds prepared according to the invention can be used in creams, pomades or lotions. To obtain the desired prophylactic or therapeutic effect, the dose of active ingredient can vary between 0.01 and 50 mg per kg body weight and per day. Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1-5 times a day to administer a daily dose of 0.5 to 5000 mg, preferably from 1 to 2500 mg. When preparing a solid preparation in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or analogues. The tablets can be encapsulated with sucrose, a cellulose derivative or with other suitable substances or they can also be treated in such a way that they have a prolonged or delayed effect and so that they continuously release a predetermined amount of active ingredient. A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard capsules. A preparation in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably calorie-free, methyl paraben and propyl paraben as antiseptics, as well as a flavoring agent, and a suitable coloring agent . Powders and granules that are dispersible in water may contain the active ingredient in admixture with dispersing agents or humectants or suspending agents, such as polyvinylpyrrolidone, together with sweetening agents or taste-correcting agents. For rectal administration, suppositories are used which are made with binders that melt at rectal temperature, e.g. cocoa butter or polyethylene glycols. For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions containing dispersants and/or pharmacologically compatible humectants are used, e.g. propylene glycol or butylene glycol. The active ingredient can also be designed as micro-capsules, possibly with one or more carriers or additives. ;The compounds produced according to the present invention can, in addition to products with formula I above or one of the pharmaceutically acceptable salts, contain other active ingredients such as e.g. tranquilizers or other drugs that can be used in the treatment of the disorders or diseases listed above. Thus, pharmaceutical preparations can be made which contain several active ingredients in combination, one of which is a compound prepared according to the invention and the other can be a beta-blocking compound, a calcium antagonist, a diuretic, an anti -inflammatory, non-steroidal agent or a sedative. The following examples illustrate the invention. In these examples, the following abbreviations are used: d denotes density, TA denotes room temperature, KHS04-K2S04 denotes an aqueous solution containing 16.6 g of potassium bisulphate and 33.3 g of potassium sulphate in 1 litre. ;The melting points (mp) are given in degrees Celsius; unless otherwise stated, they are measured without recrystallization of the product. The purity of the products is verified by thin-layer chromatography (CCM) or by HPLC. The products are characterized by their NMR spectrum recorded at 200 MHz in deuterated DMSO, the internal reference being tetramethylsilane. ;To interpret the NMR spectra, one uses: ;s for singlet ;s.e. for enlarged singlet ;d for doublet ;t for triplet ;q for quadruplet ;quint for quintuplet ;sext for sextuplet ;m for massive or multiplet ;In addition, im denotes imidazole. ;In the classical way, the hydrogen atoms are numbered on the biphenylyl as represented in the following formula: ; In the following compounds z and t are zero, except when the compound prepared is a pyrimidinone. Example 1 2-n-butyl-4-spirocyclopentane-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. ; and 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4-spiro-cyclopentane-2-imidazolin-5-one-trifluoroacetate - Method 2 ;A) N-Fmoc amino-1-cyclopentanecarboxylic acid is prepared according to the method described by Chi-Deu Chang et al. (Int. J. Peptide protein Res., 1980, 15, 59-66). Sm.p. = 89-91°C. B) N-(2<1->tert-butoxycarbonyl-4-biphenyl-yl-methyl)1-(N-Fmoc-amino)-1-cyclopentanecarboxamide. 700 mg of product prepared in the previous step is dissolved in 8 ml of DMF, and 576 mg of 4-aminomethyl-(2<1->tert-butoxycarbonyl)biphenyl, 970 mg of BOP and a sufficient amount of DIPEA are added successively to bring the to pH = 6. ;After 1 hour of stirring, the reaction medium is diluted with ;100 ml of ethyl acetate and 20 ml of water; the organic phase is washed successively with a saturated solution of sodium bicarbonate, then with a KHSO 4 -K 2 SO 4 ~ solution, finally with a saturated solution of sodium chloride. After drying on sodium sulphate, the solution is evaporated to dryness. An oil m = 1.2 g is obtained. C) N-(2'-tert-butoxycarbonyl-4-biphenyl-yl-methyl)-(1-amino-1)-1-cyclopentanecarboxamide. The product obtained in the previous step is dissolved in 10 ml of DMF, then 1 ml of diethylamine is added, and the mixture is stirred for 1 hour and 15 minutes at room temperature. The reaction medium is taken up again with 100 ml of ethyl acetate and 20 ml of water, then the organic phase is washed once in water, once with a saturated solution of sodium chloride, then dried over sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel by eluting with a mixture of ethyl acetate/methanol/30% ammonia (99/1/0.5; v/v/v). You get 600 mg of the expected product. ;IR (CHC13) ;3350 cm"<1>: H (amide and amine) ;1700 cm"<1>: C = 0 (C02<t>Bu) ;1650cm"1:C = O (CONH) ;RMN -spectrum: ;1.24 ppm: s: 9H: tBu ;2.15-1.40 ppm: m: 10H: (C5H8, NH2) ;4.40 ppm: d: 2H: CH2-NH ;7.15 -7.75 ppm: m: 8H: biphenyl ;8.60 ppm: t: 1H: NH - CH2;D) 2-n-butyl-4-spirocyclopentane-1-(2<1->tert-butoxycarbonyl-4 -biphenyl-yl-methyl)]-2-imidazolin-5-one. 394 mg of the product prepared in the previous step and 250 mg of ethyl orthovalerate are mixed in 2 ml of DCM. One drop of acetic acid is added, then it is heated to 90° C while allowing the DCM to evaporate. After 1 hour and 15 minutes, the reaction medium is taken up again in 50 ml of ethyl acetate, 10 ml of water and 1 ml of saturated sodium bicarbonate solution. The organic phase is further washed with a saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel by eluting with a mixture of ethyl acetate/toluene (1/2, v/v). 390 mg of the expected product is obtained which crystallizes. M.p. = 63-65°C. ;IR (CHC13 ) : ;1710-1 720 cm"<1>: C = O, C = O (ester and imidazoline) ;1625 cm"<1>: C = N ;RMN spectrum: ;0.88 ppm: t: 3H: CH3(nBu) ; 1.2 0 ppm: s: 9H: tBu 1.35 ppm: sext: 2H: CH3-CH2- ;1.58 ppm: quint: 2H: CH3-CH2-CH2- ;1.95-1.65 ppm: m: 8H: cyclopentane ;2.42 ppm: t: 2H: CH3-CH2-CH2-CH2- ;4.78 ppm: s: 2H: CH2-C6<H>4- ;7.20-7.8 0 ppm: m: 8H: H aromatic mass spectrum: ;MH+: 461 E) 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4-spiro-cyclopentane-2-imidazoline- 5-Mon. ;180 mg of the product prepared in the previous step is treated with 3 ml of DCM and 4 ml of TFA for 45 minutes. After evaporation under vacuum, the residue is taken up again in ether. A solid, white substance is obtained which is filtered, washed with ether, then dried under vacuum, m = 155 mg. Sm.p. = 176-178°C. ;RMN spectrum: ;0.7 8 ppm: t: 3H: CH3(nBu) ;1.25 ppm: sext: 2H: CH3-CH2;1.50 ppm: quint: 2H: CH3-CH2-CH2;1 .75-2.00: m, 8H: cyclopentane ;2.65 ppm: t: 2H: CH3-CH2-CH2-CH2- ;4.83 ppm: s: 2H: CH2-C6H4- ;7.20-7 .75 ppm: m: 8H: aromatic mass spectrum: ;MH" : 4 05 ;Example 2 ;2-n-butyl-1[(2'-carboxy-4-biphenyl-yl)methyl]4-spirocyclopentane-2-imidazoline -5-one-trifluoroacetate. Method 1. ;A) 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one. ;The ethyl ester of 1-aminocyclopentanecarboxylic acid is prepared according to Adkins and Billica (J. Amer. Chem. Soc., 1948, 70, 3121). The ethyl valerimidate is prepared according to Mac Elvain (J. Amer. Chem. Soc, 1942, 64, 1825-1827), then liberated from the hydrochloride by the action of potassium carbonate and extraction with DCM. ;The ethyl ester of 1-aminocyclopentanecarboxylic acid (-1.57 g) and ethyl valerimidate (1.56 g) are dissolved in 12 ml of xylene containing 6 drops of acetic acid. After 6.5 hours of heating under reflux, the reaction medium is concentrated under vacuum, then the residue is chromatographed on silica gel by eluting with a mixture of chloroform/methanol/acetic acid (94/4/2; v/v/v). The fraction containing the expected product is evaporated several times in the presence of xylene, then benzene, to eliminate the acetic acid. You get 1.91 g of product in the form of a thick oil. ;IR (CHC13) : ;1720 cm"<1>: C = 0 ;1635 cm"<1>:C = N ;Note: the fact that no band is seen between 1500 and 1600 cm"<1>indicates that in chloroform solution the product is a 5-imidazolinone. ;RMN spectrum: ;0.92 ppm: t: 3H: CH3(nBu) ;1.3 5 ppm: sext: 2H: CH3-CH2- ;1.50-1, 93 ppm: m: 10H: CH3-CH2-CH2and cyclopentane 2.33 ppm: t: 2H: CH3-CH2-CH2-CH2- ;10.7 pm: m: NH ;mass spectrum: MH<+>: 195 ;2 -n-butyl-4-spirocyclopentan-2-imidazolin-5-one prepared in step A, can likewise be obtained according to another method described below, by using cyclopentanone as starting product. ;a) 1-aminocyclopentanenitrile. ;This step carried out according to A. Strecker (Org. Synth., 1955, 3). In a flask, 1.97 g of sodium cyanide is dissolved in 3.9 ml of water, and a solution containing 2.3 3 g of ammonium chloride is added in 5.9 ml of water and 3.5 ml of 20% ammonia, finally 3 g of cyclopentanone in 3.8 ml of methanol are added to the flask After 1.5 hours with stirring, it is kept at 60°C for 4 5 minutes, then you stop the heating, maintaining the stirring for 45 minutes, then cooling to 25°C. It is extracted several times with methylene chloride. It is dried over sodium sulphate, filtered and concentrated under vacuum. You get 4 g of the expected product in oil form. The 1-aminocyclopentanenitrile obtained is dissolved in 300 ml of acetone, and a solution of 2.25 g of dihydrated oxalic acid in 200 ml of acetone is added while stirring. The precipitate formed is dried, washed with acetone, then dried. ;m = 4.71 g ;Sm.p. = 220°C ; This compound is the hemioxalate of 1-aminocyclopentanenitrile. ;b) 1-aminocyclopentanecarboxamide. This step is carried out according to J. Zabicky (The Chemistry of Amides, Intersciences, New York, 1970, 119). ;5.1 g of the oxalate obtained in the previous step is treated for 45 minutes and with stirring with 7.65 ml of concentrated sulfuric acid (d = 1.84). Gas evolution is observed, the temperature increases to 100°C. It is cooled to 35°C and poured onto a mixture of ice-concentrated ammonia (10 g/2.8 ml). The resulting suspension is extracted 6 times in a row with chloroform containing 5% methanol. 3 ml of ammonia (d = 0.92) are added to the aqueous phase and extracted again with chloroform containing methanol (1/0.5; v/v). The combined organic phases are dried over sodium sulphate, filtered and concentrated. The expected product is obtained in the form of a white solid. ;m = 3.79 g ;Sm.p. = 95°C. ;The results from the analysis and the IR spectrum enable confirmation of the structure. ;c) 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one ;This step is carried out according to H. Takenaka et al., ;Heterocycles, 1989, 29 (6), 1185-89. 3 g of the compound prepared in the previous step are placed in 70 ml of anhydrous THF and 3.3 ml of triethylamine, and 3 ml of valeryl chloride in 10 ml of anhydrous THF are added while stirring. A white suspension is formed. The intermediate compound formed but not isolated is (N-valeryl)-1-aminocyclopentanecarboxamide. 6 g of potassium in tablet form, 7 ml of water and 16 ml of methanol are added. Heat under reflux for 2.5 hours, then add 9 g of ammonium chloride. After stirring for 15 minutes, concentrate under vacuum. The obtained residue is taken up again with 40 ml of water and extracted with 10 ml of ethyl acetate, then 2 times with 5 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and filtered. The filtrate is concentrated to dryness.-You get 4.85 g of the expected product. The NMR spectrum is similar to that described above. The hydrochloride of this compound can be prepared by adding concentrated hydrochloric acid. The hydrochloride melts at 240°C as it sublimes. B) n-butyl-4-spirocyclopentane-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. ; 970 mg of the product obtained in step A) are dissolved in 10 ml of DMF. 270 mg of sodium methylate are added and left to stand with stirring for 15 minutes at room temperature. 2.08 g of 4-bromomethyl-(2'-tert-butoxycarbonyl)biphenyl is added to the suspension, then, after 30 minutes, it is heated at 40°C under nitrogen for 3.5 hours. The reaction medium is taken up again 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 a saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel by eluting with a mixture of ethyl acetate/toluene (1/2; v/v). 1.25 g of the expected product is obtained which crystallizes. Sm.p. = 63-66°C. The IR spectrum, the NMR spectrum and the mass spectrum as well as Rf are identical to those obtained in step D) in example 1. C) 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl )methyl]-4-spiro-cyclopentane-2-imidazolin-5-one-trifluoroacetate. ;1.22 g of the product from the previous step is stirred for 40 minutes in a solution containing 6 ml of DCM and 8 ml of TFA. After concentration under vacuum, the residue is taken up again in ethyl ether; the white precipitate formed is filtered, washed with ether, then dried under vacuum. You get 1.15 g of the expected product. Sm.p. = 176-178°C. ;IR spectrum, NMR spectrum and mass spectrum are identical to those obtained in Example 1E, likewise the observed Rf in CCM is identical. ;Example 3 ;2-n-butyl-1-[(2<1 ->carboxy-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one-trifluoroacetate Method 3. A) 2-n-butylbenzimidazole is prepared according to W.O. Pool (J. Amer. Chem . Soc, 1937, 59, 178), then 2-n-butyl-4,5,6,7-tetrahydrobenzimidazole is prepared according to M. Hartmann and L. Panizzon (Hel. Chim. Acta, 1938, 21, 1692 -1694). ;M.p. = 145°C. ;RMN spectrum: ;0.8 2 ppm: t: 3H: CH3(nBu) ;1.2 3 ppm: sext: 2H: CH3-CH2- ;1, 5 0 ppm: quint: 2H: CH3-CH2-CH2- ;I, 65 ppm: s: 4H: H5, H6(tetrahydrobenzimidazole) ;2.3 5 ppm: s: 4H: H4, H7(tetrahydrobenzimidazole) ;2.4 5 ppm: t: 2H: CH3-CH2-CH2-CH2- ;II, 1 ppm: m: NH ;- mass spectrum: M<+>: 17 8 ;B) 2-n-butyl-4-spirocyclopentane-1-[(2 '-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one 1 g of the product prepared in the previous step is dissolved in 45 ml of DMF m ed 3 03 mg of sodium methylate and a few mg of methylene blue. Oxygen is allowed to bubble in the reaction environment, which is illuminated with a UV lamp. After 15 minutes, 2.14 g of 4-bromomethyl-(2'tert.-butoxycarbonyl)biphenyl are added, then, after one hour, the reaction medium is taken up in 300 ml of ethyl acetate to which 50 ml of water and 5 ml of saturated sodium bicarbonate solution have been added. The organic phase is further washed with a saturated sodium chloride solution, then dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel by eluting with a mixture of ethyl acetate/toluene (1/2, v/v). 610 mg of the expected product which crystallizes is obtained. ;Sm.p. = 62-65°C. The IR spectrum, the RMN spectrum, the mass spectrum, as well as the Rf, are identical to those obtained before for the same compound. C) 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4-spiro-cyclopentane-2-imidazolin-5-one-trifluoroacetate. ;This compound is obtained by treatment in an acidic environment as described in the last step in example 1 and in example 2. The physiochemical data are identical to those obtained for the same compound prepared by methods 1 or 2. ;Example 4 ; 2-n-Butyl-4,4-dimethyl-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. ;2-n-butyl-1-[(2<1->carboxy-4-biphenyl-yl)methyl]-4,4-dimethyl-2-imidazolin-5-one-trifluoroacetate - Method 1. ;A) 2 -n-butyl-4,4-dimethyl-2-imidazolin-5-one. The ethyl ester of alpha-aminoisobutyric acid is prepared according to R. Jacquier et al. (Bull. Soc. Chim., France, 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 heated under reflux for 7 hours. The reaction medium is then concentrated under vacuum, and the residue is chromatographed on silica gel by eluting with a mixture of chloroform/methanol/acetic acid (95/5/2, v/v/v). After several evaporations with xylene, then with benzene to eliminate the acetic acid, 560 mg of the expected product is obtained which is crystallized. Sm.p. = 35-38°C. ;IR (CHC13) ;1725cm"<1>:C = O ;1635 cm"1:C = N ;Note: the absence of signal between 1500 and 1600 cm"<1>confirms that the compound present in the chloroform solution is a 2-imidazoline- 5-one. ;RMN spectrum: ;0.92 ppm: t: 3H: CH3(nBu) ;1.2 0 ppm: s: 6H: C (CH3)2 ;1.38 ppm: sext: 2H: CH3 -CH2;1.63 ppm: quint: 2H: CH3-CH2-CH2- ;2.38 ppm: t: 2H: CH3-CH2-CH2-CH2- ;10,"7 ppm: m: 1H: N-H ;mass spectrum : MH+: 169 ;B) 2-n-butyl-4,4-dimethyl-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl) methyl]-2-imidazolin-5-one. 520 mg of the product prepared in the previous step are dissolved in 10 ml of DMF. 167 mg of sodium methylate are added, and the mixture is stirred under nitrogen for 15 minutes. 1.25 g of 4-bromomethyl-(2'-tert-butoxycarbonyl)biphenyl is then added and it is allowed to stand with stirring at 40°C for 3.5 hours. The reaction medium is again taken up in 150 ml of ethyl acetate, then in 20 ml of water and 2 ml of saturated sodium bicarbonate solution. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel by eluting with a mixture of ethyl acetate/toluene (1.2/2; v/v). 570 mg of the expected product which crystallizes is obtained. Sm.p. = 98-100°C. ;IR (CHC13) : ;1710-1720 cm"<1>: C = 0, C = 0 (imidazolinone, ester) ;1625 cm"<1>:C = N ;RMN spectrum: ;0.78 ppm: t: 3H: CH3(nBu) ;1.08 ppm: s: 9H: C(CH3)3;1.15 ppm: s: C (CH3) and 1.2 0 ppm: sext: CH3-CH2~) 8H ;1.4 5 ppm: quint: 2H: CH3-CH2-CH2- ;2.3 0 ppm: t: 2H: CH3-CH2-CH2-CH2- ;4.65 ppm: s: 2H: CHj-C^ - ;7.15-7.65 ppm: m: 8H: H aromatic ;N.O.E. study (Nuclear Overhauser Effeet) confirms the position of the substitutions 5-one and 4,4-dimethyl on imidazolinone. mass spectrum: MH.: 435 C) 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4,4-dimethyl-2-imidazolin-5-one-trifluoroacetate. 4 60 mg of the product prepared in the previous step is treated with 3 ml of DCM and 4 ml of TFA for 45 minutes. After concentration under vacuum, the residue is taken up again in ether, and the precipitate formed is filtered, washed in ether, then dried under vacuum. You get 450 mg of the expected product in the form of a white, solid substance. Sm.p. = 168-171°C. ;RMN spectrum: ;0.82 ppm: t: 3H: CH3(nBu) ;1.30 ppm: sext: CH3-CH2-) ;1.3 5 ppm: s: C(CH3)2<->) 8H ;1.55 ppm: quint: 2H: CH3-CH2-CH2- ;2.62 ppm: t: 2H: CH3-CH2-CH2-CH2- ;4.82 ppm: s: 2H: CH2-C64- ;7, 20-7.75: m: 8H aromatic ;mass spectrum: MH+: 3 79 ;Example 5 ;1-[(2<1->cyano-4-biphenyl-yl)methyl]-2-n-butyl-4-spirocyclopentane -2-imidazolin-5-one, ;and 2-n-butyl-4-spirocyclopentane-1-[(2<1>(5<1>tetrazolyl)-4-biphenyl-yl ) methyl ] -2-imidazolin- 5-on. Method 1. A) 1-[(2<1->cyano-4-biphenyl-yl)methyl]-2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one. A mixture containing 250 mg of sodium hydride (dispersed to 80% in mineral oil) and 5 ml of DMF is prepared under a nitrogen atmosphere and a solution containing 0.97 g of 2-n-butyl-4-spirocyclopentane-2- is added drop by drop imidazolin-5-one (prepared in Example 2, step A) in 10 ml DMF. The mixture is stirred for 30 minutes at room temperature, then a solution of 1.5 g of 4-bromomethyl-2'-cyanobiphenyl in 10 ml of DMF is added. After stirring for 1 hour at room temperature, the DMF is evaporated under reduced pressure, the residue is taken up again with ethyl acetate, the organic phase is washed with water, then dried over sodium sulfate, filtered and evaporated. The residue is chromatographed on silica gel by eluting with a mixture of DCM/ethyl acetate (9/1, v/v). 1.68 g of the expected product is recovered. Sm.p. = 92-93°C. B) 2-n-butyl-4-spirocyclopentane-1-[21-(5-triphenylmethyltetrazolyl)-4-biphenyl-yl-methyl]-2-imidazolin-5-one. ;1.56 g of the preceding product, 2.6 g of tributyl tin azide and 30 ml of xylene are heated under reflux for 66 hours. The xylene is further evaporated, and the residue is dissolved in 20 ml of DCM and 5 ml of THF, adding 0.8 ml of 10N sodium hydroxide and, after stirring for 30 minutes, 2.5 g of trityl chloride, and allowing it to stand under stirring for 26 hours. After evaporation of the solvents, the residue is taken up again with ethyl acetate and washed in water, then with a 3% solution of acidic potassium sulphate and water. It is dried and evaporated. The residue is chromatographed on aluminum dioxide by eluting with a mixture of hexane/ethyl acetate (9/1; v/v). You get 1.97 g of the expected product. ;Sm.p. = 150-152°C. C) 2-n-butyl-4-spirocyclopentane-1-[2'-(5-tetrazolyl)-4-biphenyl-yl)methyl]-2-imidazolin-5-one. ;1.96 g of the product prepared in the previous step is dissolved in 10 ml of methanol and 10 ml of THF. After cooling the reaction environment to 5°C, 1.5 ml of 4N hydrochloric acid is added and it is stirred for 3 hours at room temperature and 1 hour at 30°C. After evaporation of the solvents, the residue is taken up again with water, and it is brought to pH 12 by adding ION sodium hydroxide. The aqueous phase is extracted with ether, toluene and again with ether. The aqueous phase is acidified to pH 2 by adding 1N hydrochloric acid, then extracted into ethyl acetate, dried and evaporated. The white solid obtained is dried at 50°C under 0.05 mm of mercury. You get 850 mg of the expected product. Sm.p. = 180-181°C. ;RMN spectrum: ;0.75 ppm: t: 3H: CH3(nBu) ;1.10 ppm: sext: 2H: CH3-CH2- ;1.2 0 ppm: quint: 2H: CH3-CH2-CH2- ;1.5-2 ppm: m: 8H: -C5H8;2.2 ppm: t: 2H: CH3-CH2-CH2-CH2- ;4.6 ppm: s: 2H: CH2-C6H4<->;7 ppm: s: 4H: CH^C^- ;7.35-7.7 ppm: m: 4H: H3, 4, 5, 6, aromatic ; The N.O.E. study confirms the position of the 5-one substitution on the imidazole. D) The potassium salt of 2-n-butyl-4-spirocyclopentane-1-[(2<1>(5-tetrazolyl)-4-biphenyl-yl)methyl]-2-imidazolin-5-one. ;One dissolves 970 mg of the compound obtained in the previous step in 40 ml of a mixture of isopropanol-methanol (1/1, v/v), adjusts to pH 12 by adding an 85% potassium solution in a mixture of methanol-water (20/1, w/w). Evaporate, take up the remainder with isopropanol and evaporate again. The residue is dissolved in 20 ml of isopropanol by gentle heating, then allowed to return to room temperature. It is allowed to decant, the filtrate is evaporated, then the residue is recovered with heptane. After trituration, the product becomes solid; it is filtered, then washed again with heptane and dried under vacuum. You get 945 g of the expected potassium salt. Sm.p. = 142-144°C. ;Elementary analysis: C25<H>27KN60, H20 ;Calculated: C: 61.95 H: 6.03 N: 17.34 ;Found % 62.02 6.13 17.14 ;Example 6 ;2-n-butyl- 1-[(2<1->carboxy-4-biphenyl-yl)methyl]-4-(4-spirotetra-hydropyran)-2-imidazolin-5-one-trifluoroacetate, ;and 2-n-butyl-4- (4-spirotetrahydropyran)-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. Method 2. A) 4-amino-4-tetrahydropyrancarboxylic acid is produced from 4-tetrahydropyranone according to the method described in German patent DE-2 215 721. B) 4-(N-benzyloxycarbonylamino)-4-carboxytetrahydropyran. ;1.015 g of the compound in step A is placed in 12 ml of water and treated at 10°C with 1.22 ml of diisopropylethylamine, then 3.33 g of N-(benzyloxycarbonyloxy)succinimide dissolved in 12 ml of acetonitrile. After 1 hour and 15 minutes, the reaction medium is diluted with 70 ml of ethyl acetate and 10 ml of water, and it is brought to pH 2 with a saturated potassium bisulphate solution. After decantation, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate, then evaporated under vacuum. The residue is diluted in 60 ml of ether, then 7 mmol of dicyclohexylamine is added. The precipitate formed is filtered and washed with ether; it is further dissolved in a mixture of ethyl acetate and water, and it is brought to pH 1.5 using a saturated potassium bisulphate solution. The organic phase is decanted, washed with a saturated sodium chloride solution, evaporated under vacuum, and 1.9 g of a white solid is obtained. Sm.p. = 110-115°C. ;C) N-(2'-tert-butoxycarbonyl-4-biphenyl-yl-methyl)-4-(N-benzyloxycarbonylamino)-4-tetrahydropyrancarboxamide. 850 mg of the compound prepared in step B is dissolved in 15 ml of DMF, and equimolar amounts of 4-aminomethyl-(2'-tert-butoxycarbonyl)bisphenyl, DIPEA, then BOP (10% excess) are added. After 40 minutes, the environment is taken up again with 200 ml of ethyl acetate and 200 ml of water. The organic phase is decanted, then washed twice with a saturated sodium bicarbonate solution, twice with a 5% solution of sodium bisulfate, then once with a saturated sodium chloride solution. After drying on sodium sulphate, the organic phase is evaporated under vacuum. You get 1.8 g of the expected product. D) N-(2<1->tert-butoxycarbonyl-4-biphenyl-yl-methyl)-4-amino-4-tetrahydropyrancarboxamide. ;The product obtained in step C is dissolved in 30 ml of methanol. 400 mg of 10% palladium on carbon and hydrogen are added at atmospheric pressure. After 1 hour, the catalyst is filtered, then the filtrate is concentrated under vacuum. The residue is chromatographed on silica by eluting with a mixture of ethyl acetate-methanol-3% ammonia (99/1/0.5, v/v/v). 0.93 g of the expected product is obtained in the form of a white solid. Sm.p. = 125-127°C. ;RMN spectrum: ;7.05-7.60 ppm: m: 8H: H aromatic ;7.60-7.05 ppm: m: 8H: H aromatic ;4.25 ppm: d: 2H: CH2-C6H4 - ;3.70-3.50 ppm: m: 4H: CH2i 2 and 6 in tetrahydropyran 2.00-1.80 ppm: m: 4H: CH2i 3 and 5 in tetrahydropyran 1.05 ppm: s: 9H: tBu E) 2-n-butyl-4-(4-spirotetrahydropyran)-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-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 is heated for 3 hours at 110°C. The reaction medium is taken up again with 100 ml of ethyl acetate, then it is washed with a saturated sodium bicarbonate solution, a saturated sodium chloride solution, then dried over sodium sulfate and the ethyl acetate is evaporated. The obtained residue is chromatographed on silicon dioxide by eluting with a mixture of ethyl acetate/toluene (2/1, v/v). You get 550 mg of the expected product in the form of wax. ;RMN spectrum: ;7.05-7.60 ppm: m: 8H: H aromatic ;4.63 ppm: s: 2H: CH2-C6H4- ;3.85-3.55 ppm: m: 4H, CH2i 2 and 6 in tetrahydropyran 2.3 0 ppm: t: 2H: CH2-C3H7; 1.05-1.80 ppm: m: 8H: CH2-CH2-CH2-CH3 and CH2; in 3 and 5 in tetrahydropyran ; 1.03 ppm : s: 9H: tBu ;0.75 ppm: t: 3H: (CH2)3-CH3;IR (CHC13) ;1710-1720 CH2: C = O, C = O ;1625 cm"<1>:C = N F) 2-n-butyl-4-(4-spirotetrahydropyran)-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one-trifluoroacetate. 53 0 mg of the product obtained in the previous step is treated with 4 ml of dichloromethane and 5 ml of TFA for 45 minutes. After evaporation under vacuum, the residue is taken up again in ether, the precipitate formed is filtered, washed in ether, then dried under vacuum. This gives 510 mg of the expected product. M.p. = 159-162°C. ;RMN spectrum: ;7.80-7.10 ppm: m: 8H: H aromatic ;4.8 0 ppm: s: 2H: CH2- C6H4- ;4.00-3.75 ppm: m: 4H, CH2i 2 and 6 in tetrahydropyran 2.60 ppm: t: 2H: CH2-C3H7;1.4 5-2.00 ppm: m: 6H: CH2-CH2 -CH2-CH3 and CH2; in 3 and 5 in tetrahydropyran; 1,3 0 ppm: sext: 2H: CH2-CH2-CH2-CH3;0.8 0 ppm: t: 3H: (CH2)3-CH3; Example 7 ;2-n-butyl-1-[(2'-carboxy- 4-biphenyl-yl)methyl]-4-[spiro-(1-benzyl-4-piperidine)]-2-imidazolin-5-one-trifluoroacetate, and 2-n-butyl-4-[spiro(l- benzyl-4-piperidine)]-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. Method 1. A) 4-amino-1-benzyl-4-piperidinecarboxylic acid is prepared from N-benzyl-4-piperidone according to the method described in German patent DE-2 215 721. ;B) 4-ethyl-4- amino-1-benzyl-piperidine carboxylate. ;3.80 g of the compound prepared in step A is added to a solution of 13 g of hydrochloric acid in 50 ml of ethanol at 0°C, then it is kept under reflux for 5 hours. After concentration under vacuum, the residue is washed with ether, then dissolved in an ether-water mixture to which a saturated potassium carbonate solution is added to reach pH 9. The ether phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulfate, then evaporated to dryness . You get 3.50 g of the expected product in the form of oil. ;RMN spectrum: ;7.20-7.40 ppm: m: 5H: H aromatic ;4.10 ppm: q: 2H: CH2-CH3;3.45 ppm: s: 2H: CH2i benzyl ;2.25 -2.60 ppm: m: 4H: CH2i 2 and 6 in piperidine 1.80-2.05 ppm: m: 2H: CH2i 3 and 5 in piperidine 1.20-1.40 ppm: m 2H: ;1, 12 ppm: t: 3H: CH3-CH2-;C) 2-n-butyl-4-[spiro(1-benzyl-4-piperidin)]-2-imidazolin-5-one. ;Ethyl valerimidate is prepared as in example 2, step A. 2.06 g of ethyl valerimidate, 3.40 g of the compound prepared in step B and 8 drops of acetic acid are mixed in 15 ml of xylene, and heated under reflux for 6 hours. After concentration under vacuum, the residue is chromatographed on silica gel by eluting with a mixture of chloroform/methanol/acetic acid (82/15/3, v/v/v). 2.80 g of the expected product is obtained after extraction with chloroform at pH 9 to eliminate the acetic acid. Sm.p. = 170-172°C. ;IR (chloroform) ;1725cm"<1>:C = O ;1640cm"<1>:C = N ;RMN spectrum: ;7.10-7.30 ppm: m: 5H: H aromatic ;3.4 5 ppm: s: 2H: -CH2-C6H5;1.10-2.75 ppm: 5m, 14H: CH2i 2,3,5,6 in piperidine and ;(CH2)3-CH3;0.80 ppm: t : 3H: (CH2)3-CH3;D) 2-n-butyl-4-[spiro(1-benzyl-4-piperidine)]-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl) methyl]-2-imidazolin-5-one. ;To 2.78 g of the compound obtained in step C, dissolved in 25 ml of DMF, 513 mg of sodium methylate are added and after 15 minutes 4.16 g of 4-bromomethyl-(2'-tert-butoxycarbonyl)biphenyl. It is heated at 40°C for 5 hours, then the reaction medium is taken up again with 300 ml of ethyl acetate, 50 ml of water and 5 ml of saturated sodium bicarbonate solution. The organic phase is decanted, washed once more with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica by eluting with a mixture of ethyl acetate/methanol (95/5, v/v). You get 0.98 g of the expected product. Sm.p. = 103-106°C. ;IR (CHC13) ;1710-1725 cm"<1>: C = O, C = O (imidazoline, ester) ;1630cm"<1>:C = N ;RMN spectrum: ;7.70-7.10 ppm: m: 13H: H aromatic ;4.70 ppm: s: 2H: CH2-C6H4- ;3.55 ppm: s: 2H: CH2-C6<H>5;1.20-2.75 ppm: 5m : 14H: CH2i 2,3,5,6 in piperidine and (CH2)3-CH3;1.15 ppm: s: 9H: tBu ;0.85 ppm: t: 3H: (CH23-CH3;E) 2- n-butyl-1-[(2<1->carboxy-4-biphenyl-yl)methyl]-4-[spiro(1-benzyl-4-piperidine)]-2-imidazolin-5-one-trifluoroacetate. ;350 mg of the compound obtained in step D is dissolved in 4 ml of dichloromethane and 5 ml of TFA. After 45 minutes, the environment is concentrated under vacuum, then the residue is taken up again in a mixture of ether-hexane, the formed precipitate is filtered, washed with ether and dried under vacuum. "You get 350 mg of the expected product. ;Sm.p. = 198-200°C. ;RMN spectrum: ;7.05-7.75 ppm: m: 13H: H aromatic ;4.7 5 ppm: s: 2H: CH2-<C>6<H>4- ;4.4 0 ppm: s: 2H: CH2-C6-H5;3.2 0-3.60 ppm: m: 4H: CH2i 2 and 6, from piperidine 2.3 5 ppm: t: 2H: CH2-CH2-CH2-CH3;2.20-1.40 ppm: 3 massives: CH2i 3 and 5 from piperidine and ch2—ch2—CHq—ch3 ;1.25 ppm: sext : 2H: CH2-CH2-CH2-CH3;0.8 0 ppm: t: 3H: (CH2)3;Example 8 ;2-n-butyl-1-[(2<1->carboxy-4-biphenyl- yl)methyl]-4-(4-spiropiperidine)-2-imidazolin-5-one-ditrifluoroacetate, and 2-n-butyl-4-[4-spiropiperidine]-1-[(2'-tert- butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one A) 2-n-butyl-4-(4-spiropiperidin)-1-[(2<1->tert-butoxycarbonyl-4- biphenyl-yl)methyl]-2-imidazolin-5-one. 300 mg of the compound from example 7, step D, is dissolved in 10 ml of methanol. 180 mg of 10% palladium on carbon is added, and it is hydrogenated for 3 hours at atmospheric pressure. The catalyst is filtered, and the filtrate is concentrated under vacuum. 200 mg of the expected product is obtained Oct. ;RMN spectrum: ;7.20-7.75 ppm: m: 8H: H aromatic ;4.75 ppm: s: 2H: CH2-C6<H>4- ;3.00-1.70 ppm: 3 massives for the 4 CH2i piperidine 2.4 0 ppm: t: 2H: CH2-CH2-CH2-CH3;1.60 ppm: quint: 2H: CH2-CH2-CH2-CH3;1.3 5 ppm: sext: 2H: CH2 -CH2-CH2-CH3;1.2 0 ppm: s: 9H: tBu ;0.90 ppm: t: 3H: (CH2)3-CH3;B) 2-n-butyl-l-[(2<1 ->carboxy-4-biphenyl-yl)methyl]-4-(4-spiro-piperidine)-2-imidazolin-5-one-difluoroacetate. 160 mg of the product obtained in step A is stirred in 3 ml of dichloromethane and 4 ml of trifluoroacetic acid for 45 minutes. It is concentrated under vacuum, the residue is taken up again in ether. A gum is obtained, then a foam after drying under vacuum (150 mg). Sm.p. = 80-85°C. ;RMN spectrum: ;7.15-7.80 ppm: m: 8H: H aromatic ;4.75 ppm: s: 2H: CH2-C6H4- ;3.20-1.60 ppm: 3 massive: 4 CH2from piperidine 2.4 0 ppm: t: 2H: CH2-CH2-CH2-CH3;1.50 ppm: quint: 2H: CH2-CH2-CH2-CH3;1.3 0 ppm: sext: 2H: CH2-CH2- CH3;0.80 ppm: t: 3H: (CH2)3-CH3;Example 9 ;2-n-butyl-1-[(2<1->carboxy-4-biphenyl-yl)methyl]-4,4 -diphenyl-2-imidazolin-5-one-trifluoroacetate, ;and 2-n-butyl-4,4-diphenyl-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl) methyl ] -2 -imidazolin-5-one. Procedure 1. ;A) Valeramidine chlorohydrate. ; 6 g of ethyl valerimidate chlorohydrate is added to a solution of 6.75 g of ammonia in 80 ml of methanol at 0°C. After 18 hours, the reaction medium is concentrated under vacuum, and the expected product is obtained in the form of a white solid. ;B) 2-n-butyl-4,4-diphenyl-2-imidazolin-5-one. This compound is prepared according to the method described by J. Nyitrai and K. Lempert in Tetrahedron, 1969, 25, 4265-4275, starting from benzyl and valeramidine chlorohydrate. Sm.p. = 135°C. ;IR (CHClj) ;1725 cm"<1>: C = O ;1640 cm"<1>:C=N ;RMN spectrum: ;7.20-7.50 ppm: m: 10H: H aromatic ;2 .50 ppm: t: 2H: CH2-CH2CH2CH3;1.65 ppm: quint: 2H: CH2-CH2-CH2-CH3;1.3 5 ppm: sext: 2H: CH2-CH2-CH2-CH3;0.90 ppm: t: 3H: CH2-CH2-CH2-CH3;11 ppm: s.e.: NH ;C) 2-n-butyl-4,4-diphenyl-1-[(2'-tert-butoxycarbonyl-4-biphenyl- yl)methyl]-2-imidazolin-5-one. This compound is prepared according to the usual procedure by reacting the compound prepared in step B and 4-bromomethyl-(2'-tert-butoxycarbonyl)biphenyl, in the presence of sodium methylate in DMF. ;IR (CHCl3) ;1715-1725 cm"<1>:C =0, C = 0 (ester, imidazolinone) ;1635cm"<1>:C = N ;RMN spectrum: ;7.25-7.80 ppm: m: 18H: H aromatic ;4.85 ppm: s: 2H: N-CH2-C64- ;2.60 ppm: t: 2H: CH2-CH2-CH2-CH3;1.7 5 ppm: quint: 2H: CH2-CH2-CH2-CH3;1.40 ppm: sext: 2H: CH2-CH2-CH2-CH3;1.15 ppm: s: 9H: tBu ;0.9 0 ppm: t: 3H: CH3from n -butyl ;D) 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4,4-diphenyl-2-imidazolin-5-one-trifluoroacetate. ;500 mg of the product prepared in step C is treated with 2.5 ml of dichloromethane and 2.5 ml of trifluoroacetic acid at 20°C for 40 minutes. After concentration under vacuum, the residue is taken up again with a mixture of ether-hexane, the precipitate formed is filtered, washed in hexane and dried. You get 440 mg of the expected product. Sm.p. = 55-60°C. ;RMN spectrum: ;7.15-7.80 ppm: m: 18H: H aromatic ;4.85 ppm: s: 2H: N-CH2-C6H4- ;2.60 ppm: t: 2H: CH2-CH2 -CH2-CH3;1.7 0 ppm: quint: 2H: CH2-CH2-CH2-CH3;1.4 0 ppm: sext: 2H: CH2-CH2-CH2-CH3;0.90 ppm: t: 3H: CH3i butyl. Example 10 2-n-butyl-3-[(2'-carboxy-4-biphenyl-yl)methyl]-6-spirocyclopentane-5,6-dihydro-1H-4-pyrimidinone-trifluoroacetate. ;A) (1-aminocyclopentyl)acetic acid. ;Cyclopentylideneacetic acid is prepared according to G.A.R. Kon and R.P. Linstead, J. Chem. Soc., 1925, 127, 616. 740 mg of this acid and 5 ml of 20% ammonia are placed in an autoclave and heated at 150°C for 24 hours. After evaporation of the solvents, the residue is chromatographed on a silica column by eluting with a mixture of DCM-methanol-20% aqueous ammonia solution (70/30/1, v/v/v). You get 330 mg of the expected acid. ;B) (1-aminocyclopentyl) ethyl acetate. ;One dissolves 330 mg of acid in 10 ml of ethanol. It is cooled in an ice bath and saturated with hydrochloric acid in gaseous form. After refluxing for 24 hours, the reaction medium is evaporated, the residue is taken up again with a sodium carbonate solution, and extracted with ethyl acetate, then dried over sodium sulfate, filtered and evaporated. 312 mg of the expected ester is obtained. C) 2-n-butyl-6-spirocyclopentane-5,6-dihydro-1H-4-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 is kept under reflux. After 2 hours and 18 hours, 348 mg of ethyl valerimidate is added again, and after 24 hours of reflux in total, the reaction medium is evaporated, then chromatographed on silica by eluting with a DCM-methanol mixture (97/3, v/v). You get 153 mg of the expected product. D) 2-n-butyl-6-spirocyclopentane-3-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl)methyl]-5,6-dihydro-1H-4-pyrimidinone. A mixture of 10 ml of DMF and 40 mg of 80% sodium hydride in oil is prepared under a nitrogen atmosphere. 144 mg of the compound prepared in step C, dissolved in 5 ml of DMF, is added drop by drop at room temperature. After 30 minutes with stirring, 288 mg of 4-bromomethyl-2<1->tert-butoxycarbonyl-biphenyl dissolved in 5 ml of DMF are added. You let it stand for 2 hours while stirring, then you evaporate, take up the rest with water and extract it in ethyl acetate. It is dried over sodium sulphate, filtered and evaporated, then purified by column chromatography, eluting with a mixture of hexane-ethyl acetate (85/5, v/v). You get 174 mg of the expected product. E) 10 ml of trifluoroacetic acid is cooled using an ice water bath and 161 mg of the compound prepared in step D is added. It is allowed to stand with stirring for 30 minutes, then evaporated. The rest is taken up with ethyl ether, then evaporated again. This operation is repeated, then the residue is dried under vacuum. 140 mg of the expected compound is obtained in the form of an amorphous powder. Melting point = 108-115°C. ;RMN spectrum: ;0.9 ppm: t: 3H: (CH2)3-CH3;1.1- 2.1 ppm: m: 12H: cyclopentane and CH2-CH2-CH2-CH3;2.7 ppm: t: 2H: CH2-CH2-CH2-CH3;3.1 ppm: s: 2H: CH2-C0 ;5.1 ppm: s: 2H: N-CH2-C6<H>5;7.2- 7.8 ppm: m : 8H: H aromatic ; Example 11 ; 2-n-butyl-4-spirocyclopentane-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-thione ; and 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazoline-5-thione trifluoroacetate. A) 2-n-butyl-4-spirocyclopentane-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-thione. ;5.63 g of the compound prepared in Example 1, step D, is brought into solution in 40 ml of anhydrous toluene and treated at 80°C under nitrogen with 3 g of Lawesson's reagent. After 6 hours, the reaction medium is filtered and concentrated. Chromatography is carried out on silica by eluting with a mixture of DCM-ethyl acetate (95/5, v/v). The expected product is obtained in the form of an oil which crystallizes when cold, m = 4.5 g. M.p. = 77-79"C. ;RMN spectrum: ;0.90 ppm: t: 3H: CH3(n-Bu) ;1.20 ppm: s: 9H: tBu ;1.3 5 ppm: sext: 2H: CH3-CH2- ;1.60 ppm: quint: 2H: CH3-CH2-CH2- ;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 ;B) 2-n-butyl-1-[(2'-carboxy- 4-biphenyl-yl)methyl]-4-spiro-cyclopentane-2-imidazolin-5-thione-trifluoroacetate. ; 225 mg of the compound obtained in step A is treated with 5 ml of DCM and 5 ml of TFA for 30 minutes. After concentration the residue is taken up again in ether. The expected compound is obtained in the form of a yellow powder which is dried, then purified with hexane. m = 160 mg. M.p. = 185-190°C. ;Mass spectrum: MH<+>: 421 ; NMR spectrum: ;0.78 ppm: t: 3H: CH3(n-Bu) ;1.2 0 ppm: sext: 2H: CH3-CH2;1.50 ppm: quint: 2H: CH3-CH2-CH2- ;1.75-2.00 ppm: m: 8H: cyclopentane ;2.4 0 ppm: t: 2H: CH3-CH2-CH2-CH2;5.2 0 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-butoxycarbonyl-4-biphenyl-yl) methyl ] -2 -imidazolin-5-one, ; and 2-n-butyl-1-[(2'-carboxy-4-biphenyl-yl)methyl]-4-(2-spiroindan)-2-imidazolin-5-one. Method 1. A) 2-amino-2-indane carboxylic acid is prepared according to R.M. Pinder, J. Med. Chem., 1971, 14, 9, 892 and the corresponding ethyl ester is further prepared according to Adkins (reference mentioned in Example 2A). ;B) 2-n-butyl-4-(2-spiroindan)-2-imidazolin-5-one. ;2.78 g of ethyl ester, prepared in step A and 2.5 g of ethyl valerimidate are brought into solution in 20 ml of xylene in the presence of 60/L acetic acid and kept under reflux for 3 hours. 500 mg of ethyl valerimidate is added again and kept under reflux for a further 3 hours. The reaction medium is concentrated, then chromatographed on silica by eluting with a mixture of hexane-ethyl acetate-acetic acid (3/8/0.3; v/v/v). The pure fractions are combined and evaporated with toluene. 3.07 g of the expected product is obtained in the form of a white solid. Sm.p. = 148-150°C. ;RMN spectrum: ;0.90 ppm: t: 3H: CH3(n-Bu) ;1.2-1.7 ppm: m: 4H: CH2-CH2-CH3;2.4 ppm: t: 2H: CH2-(CH2) 2-CH3 ;2.8- 3.2 ppm: q: 4H: 2CH2(indane) ;4.9 0 ppm: s, 2H: CH2-C6H4- ;7.2 ppm: m: 4H: H aromatics; C) 2-n-butyl-4-(2-spirondane)-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. The compound obtained in the previous step is brought into solution in 20 ml of anhydrous DMF and treated with 450 mg of sodium methylate under nitrogen. After 20 minutes at room temperature, 3.6 g of 4-bromomethyl-(21-tert-butoxycarbonyl) biphenyl is added and it is left to stand with stirring at 40 °C for 6 hours. The reaction medium is concentrated, then the usual washings are carried out, and chromatograph on silica eluting with dichloromethane-ethyl acetate (95/5, v/v) to give the expected compound as a foam (m = 1.84 g). ;NMR spectrum ;0.8 0 ppm: t: 3H: CH3n-Bu ;1.2 0 ppm: s: 9H: tBu ;1.2 0-1.60 ppm: m: 4H: CH2-CH2-CH3;2.4 0 ppm: t: 2H: CH2-(CH2) 2-CH3 ;2.9- 3.3 ppm: q: 4H: 2CH2(indane) ;4.8 0 ppm: s: 2H: N-CH2-C6<H>4- ;7.20- 7.80 ppm: m: 12H: H aromatic ;D) 2-n-butyl-1-[(2<1->carboxy-4-biphenyl-yl)methyl)-4-(2-spiro-indan) - 2-imidazolin-5-one.; 1.7<*>1 g of the compound obtained in the previous step is brought into solution in 15 mg of DCM and treated with 20 ml of TFA. After 30 minutes

if the reaction medium is concentrated, then taken up again with ether. After trituration, the solid obtained is dried, rinsed with ether and dried. You get 1.42 g of the expected product. Sm.p. = 217-218°C.

NMR spectrum:

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

1.10-1.50 ppm: m: 4H: CH2-CH2-CH3

2.30 ppm: t: 2H: CH 2 -(CH 2 ) 2 -CH 3

2.8-3.3 ppm: q: 4H: 2 CH2(indane)

4.70 ppm: s: 2H: N-CH2-C6<H>4-

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

Other compounds have been prepared according to one of the methods according to the invention described above. They are collected in Table 1. The structure of each of these compounds has been confirmed by analysis of their NMR spectrum.

Example 13

2-n-butyl-1-[21-(1-imidazolylcarbonyl)-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one.

CR4R5= cyclopentane, X =O)

A mixture containing 404 mg of the compound prepared in example 2, step E, 15 ml of THF and 260 mg of carbonyldiimidazole is stirred at room temperature for 72 hours. The reaction medium is evaporated, taken up again with ethyl acetate, washed with water, then with a sodium chloride solution, to obtain 420 mg of product which is purified by chromatography on silica by eluting with a mixture of DCM-ethyl acetate (70/30, v/v) for to get the expected connection.

m = 230 mg

Sm.p. = 120°

Example 14

2-h-butyl-1-[21-(3-cyano-2-methyl-isothioureidomethyl)-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one~.

A) 1-[(2'-aminomethyl-4-biphenyl-yl)methyl]-2-n-butyl-4-spiro-cyclopentan-2-imidazolin-5-one.

This compound is obtained by hydrogenation of the compound prepared in Example 5. 1 g of the compound prepared in Example 5, step A, is placed in 15 ml of absolute methanol and 2.3 ml of ethanol in the presence of (0.5 g) 5% palladium on carbon , and hydrogenation is carried out at room temperature for 2 4 hours. After treatment, you get 730 mg of the expected product in oil form. B) A mixture containing 300 mg of the compound prepared in the previous step and 113 mg of N-cyanimido-S,S-dimethyldithiocarbonate in 3 ml of ethanol is kept under reflux for 24 hours. After the usual treatment, the reaction medium is purified by chromatography on silica by eluting with a mixture of DCM-ethyl acetate (50/50, v/v). The expected product is isolated in the form of a white solid.

m = 307 mg

Sm.p. = 83°C

Example 15

2-n-butyl-1-[2'-(2-cyanoguanidinemethyl)-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one.

This compound is obtained from the compound prepared in the previous example. 200 mg of the compound is taken in 10 ml of absolute ethanol, saturated with ammonia at 10°C, then heated at 80°C in an autoclave for one night. After concentration to dryness of the reaction environment, chromatography is performed on silica by eluting with a DCM-methanol mixture (95/5, v/v). You get 130 mg of the expected product.

Sm.p. = 100°C.

Example 16

2-n-Butyl-4-spirocyclopentane-1-[(2'-trifluoromethylsulfonylamino-4-biphenyl-yl)methyl]-2-imidazolin-5-one trifluoromethylsulfonate.

(In: R, = -NHS02C<F>3, R2= H, R3= n-C4H9, CR4R5= cyclopentane,

X = O)

A) 4-methyl-2'-nitrobiphenyl.

11.2 g of 2-nitrobromobenzene and 15 g of 4-iodotoluene are mixed, heated to 195°C and left to stand with stirring at this temperature for 3.5 hours. After it has returned to room temperature, it is taken up again in DCM, kept under reflux and the hot solution is filtered on Celite<®>, then the DCM is evaporated.

m = 6.5 g

Eb = 80-120°C under 0.2 mm Hg, nD24 = 1.6042.

B) 4-bromomethyl-2<1->nitrobiphenyl.

A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl, 5.42 g of NBS, 118 mg of azo-bis-isobutyronitrile and 500 ml of carbon tetrachloride is maintained under reflux for 5 hours. The filtrate is cooled to 0°C, dried and concentrated to obtain 9 g of an oil product, used as in the following step. C) 2-n-butyl-1-[(2'-nitro-4-biphenyl-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one.

A mixture containing 260 mg of 80% sodium hydride in 5 ml of DMF is prepared, and 500 mg of 2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared in example 2 step A, is added at room temperature under nitrogen. After 15 minutes with stirring, 901 mg of 4-bromomethyl-2'-nitrobiphenyl is added in 5 ml of DMF, and it is kept with stirring for 24 hours. The reaction medium is concentrated to dryness, taken up again with a mixture of water-ethyl acetate. The organic phase is decanted, dried over sodium sulphate and filtered, then the ethyl acetate is evaporated. The product obtained is chromatographed on silica by eluting with a mixture of DCM/ethyl acetate (9/1, v/v). You get 500 mg of the expected product. D) 1-[(2<1->amino-4-biphenyl-yl)methyl]-2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one. 450 mg of the product obtained in the previous step is placed in 10 ml of methanol, in the presence of 5% palladium on carbon, at room temperature to be hydrogenated. After filtering the catalyst and evaporation, 240 mg of the expected product is obtained. E) In 4 ml of DCM, 225 mg of the product obtained in the previous step, 0.1 ml of triethylamine are mixed and 0.2 ml of trifluoromethylsulfonic anhydride is added under argon at -78°C, then it is allowed to return to room temperature. The reaction medium is washed with water, a solution of acidic sodium carbonate, then dried and concentrated. You get 150 mg of a white, amorphous, solid substance.

NMR spectrum:

0.4-1.3 ppm: m, 7H: CH3-CH2-CH2-

1.4-2.3 ppm: m, 10H: CH3-CH2-CH2-CH2and cyclopentane 4-4.8 ppm: system AB, 2H: N-CH2-C6H4-

7-7.6 ppm: m: 8H: aromatic

8.3 ppm: s, 1H: -NH

10 ppm: s.e. , 1H: CF 3 SO 3 H

Example 17

2-n-Butyl-4-spirocyclopentane-1-[(2'-trifluoromethylsulfonylaminomethyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one-trifluoromethyl-sulfonate.

(I:<R>1<=>CH2NHS02CF3,R2= H, R3<=>n-C4H9, CR4R5<=>cyclopentane, "X = O)

The preparation is carried out from l-[(2<1->aminomethyl-4-biphenyl-yl)methyl]-2-n-butyl-4-spirocyclopentan-2-imidazolin-5-one, prepared in example 14 step A. 322 mg of this compound and 0.122 ml of ethylamine are placed in 3.4 ml of DCM at -70°C, and 0.294 ml of trifluoromethylsulfonic anhydride is added. It is allowed to return to room temperature, poured into dilute acetic acid, extracted with DCM, dried over sodium sulfate, filtered and the DCM evaporated. The residue is chromatographed twice on silica eluting with DCM-ethyl acetate (95/5, v/v), so 99.5/0.5; v/v).

You get m = 90 mg

Sm.p. = 90°C.

NMR spectrum:

0.4-1.2 ppm: m, 7H: CH2-CH2-CH3

1.3-2.45 ppm: m, 10H: CH2-CH2-CH2-CH3and cyclopentane 4.1-5 ppm: m 4H: N-CH2-C6H4- and NH-CH2-C6H4-

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

8.4 ppm: s, 1H: NH

Example 18

2-n-butyl-1-[((2•-N-hydroxycarbamoyl)-4-biphenyl-yl)methyl]-4-spirocyclopentan-2-imidazolin-5-one.

(I: R1= -CO-NHOH, R2= H, R3= n-<C>4H9, CRAR4= cyclopentane,

X = O).

The compound prepared in example 2 is released from its salt of trifluoroacetic acid by taking this compound again in a mixture of ethyl acetate-water and by bringing the solution to pH 6 by adding a saturated solution of acidic sodium carbonate. The organic phase is washed with a 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 brought into solution in chloroform, 860 ml of thionyl chloride is added at 0°C, and it is allowed to stand with stirring at room temperature for 2 hours. The solution is concentrated, and the traces of thionyl chloride are eliminated by azeotropic distillation with toluene. The thus obtained acid chloride is added drop by drop in solution in DMF to a solution containing 200 mg hydroxylamine hydrochloride and 700 µl DIPEA in 10 ml DMF. After 2 hours

at 0°C the reaction medium is concentrated, taken up again with 100 ml DCM and 50 ml water. It is brought to pH 7, the organic phase is extracted, then it is dried over sodium sulphate. After filtration, the solution is concentrated. The product obtained is recrystallized in a mixture of ethyl acetate-ethyl ether-hexane.

m = 3 60 mg

Sm.p. = 85°C.

Example 19

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

(In: R1= NHC0N<H>2, R2= H, R3= n-C4H9, CR4R5= cyclopentane,

X = 0).

This compound is prepared by using the method described by B.B. Kobu et al. in Org. Synth., 1957, 37, 52 from [(2'-amino-4-biphenyl-yl)methyl]-2-n-butyl-4-spiro-cyclopentan-2-imidazolin-5-one, prepared in Example 14 step A. 1 g of the latter is brought into solution in 50 ml of 6N hydrochloric acid and treated with potassium isocyanate for 1 hour at 5°C. The reaction medium is concentrated, taken up again with ethyl acetate, washed with acidic sodium carbonate, then with a saturated sodium chloride solution. After drying on sodium sulfate and filtration, the solution is concentrated and the oil obtained is purified by chromatography on silica by eluting with a DCM-methanol mixture (9/1, v/v).

m = 600 mg

NMR spectrum:

0.85 ppm: t, 3H: CH2-CH3

1.3 5 ppm: sext, 2H: CH2-CH3

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

1.7-2 ppm: m, 8H: cyclopentane

2.4 5 ppm: t, 2H: CH2-CH2-CH2-CH3

4.8 ppm: s, 2H: -CH2-C6<H>4-

6.05 ppm: s, 2H: NH2

7-8 ppm: m, 9H: 8 H aromatics + NHCO

Example 2 0 and 21

1-[(21-carboxy-4-biphenyl-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one,

°g 1_[(2'-N-cyanocarbamoyl-4-biphenyl-yl)methyl]-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one.

(In: R^= CO-NH-CN, R2= H, R3<=>n-C3H7, CR4R5= cyclohexane,

X = 0).

A) Chlorohydrate of ethyl butyrimidate.

This compound is prepared according to McElvain (J. Amer. Chem. Soc., 1942, 64, 1825-1827).

To a solution of 10.6 g of hydrochloric acid in gaseous form in 20 ml of anhydrous ethanol, 23 ml of butyrnitrile is added at 0°C, then, after leaving the reaction environment for 4 days at 0°C, it is poured under stirring at 2 00 ml of anhydrous ether at 0°C; the precipitate formed is filtered, washed with ether, then dried under vacuum. You get 25.8 g of the expected product.

B) Ethyl butyrimidate.

16 g of imidate obtained in step A are dissolved in 100 ml of dichloromethane and 50 ml of water, and 15 g of potassium carbonate are added. After decanting, the dichloromethane is dried over potassium carbonate, the sauce is evaporated to dryness without heating it. C) Ethyl ester of 1-aminocyclohexanecarboxylic acid.

The 1-aminocyclohexanecarboxylic acid is commercial. 15 g of this amino acid is added at 0°C to a solution of 23 g of hydrochloric acid in gaseous form in 150 ml of anhydrous ethanol. Heat under reflux for 5 hours, then concentrate the reaction medium to dryness, and take it up again with ether. The white solid obtained is filtered, washed in ether, then dissolved in a mixture of 300 ml of ether and 100 ml of water. It is brought to pH 9 by adding a potassium carbonate solution. The organic phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulfate, then evaporated to dryness. You get 14 g of the expected product in the form of an oil.

D) 2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one.

14 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 added, and it is heated under reflux. After 1.5 hours, half of the remaining imidate is added, then the last quarter after 4 hours. After a total of 7 hours under reflux, the environment is evaporated to dryness. The solid obtained is taken up again in hexane, filtered, washed in ether, then dried.

10.3 g of the expected imidazolinone is obtained.

Sm.p. = 124-125°C

IR (CHClj)

1715 cm"<1>:C = O

1635 cm'<1>: C = N

Note: The compound present in the solution is usually a 5-imidazolinone, according to the values of the IR bands. E) 2-n-propyl-4-spirocyclohexane-1-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-2-imidazolin-5-one. To 0.24 g of 80% sodium hydride in oil in suspension in 10 ml of dimethylformamide, 970 mg of the imidazolinone obtained in step D is added. After 20 minutes of stirring under nitrogen, 1.91 g of 4-bromomethyl-2<1-> tert-butoxycarbonyl-biphenyl, prepared according to European patent application 324 377. After 1 hour of stirring, the medium is concentrated under vacuum half a time and taken up again with 100 ml of ethyl acetate, then with 20 ml of water. The organic phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulfate, then concentrated under vacuum. The residue is chromatographed on silica by eluting with an ethyl acetate-toluene mixture. You get 2.10 g of the expected product in the form of wax.

IR (CHC13)

1705-1715 cm"<1>: C = 0, C = 0 (ester, imidazolinone)

1635cm"1:C = N

Analysis of the NMR spectrum confirms the structure.

F) 1-[(2'-carboxy-4-biphenyl-yl)methyl]-2-n-propyl-4-spiro-cyclohexane-2-imidazolin-5-one. (Example 20).

1.25 g of the tert-butyl ester obtained in step E is stirred for 45 minutes in a mixture of 11 ml of dichloromethane and 15 ml of trifluoroacetic acid. After concentration under vacuum, the residue is taken up again in ether. The solid formed is filtered, washed in ether, then dried. 1.04 g of a white, solid substance is obtained.

Sm.p. = 170-172°C

NMR spectrum:

7.10-7.80 ppm: m, 8H: aromatic

4.90 ppm: s, 2H: N-CH2-C6<H>4-

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

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

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

1.60 g of trifluoroacetate obtained above is dissolved in 150 ml of ethyl acetate plus 20 ml of water. 1N sodium hydroxide is added to obtain a pH of 5.0. The organic phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulfate, then evaporated to dryness. The solid residue is taken up again in ethyl ether, filtered and dried.

m = 1.14 g

Sm.p. = 208-210°C

G) [1-(2<1->N-cyanocarbamoyl-4-biphenyl-yl)methyl]-2-propyl-4-spirocyclohexane-2-imidazolin-5-one. (Example 21)

To 300 mg of the compound prepared in the previous step in suspension in 5 ml of DCM, 0.54 ml of thionyl chloride is added. After 1.5 hours, the reaction medium is concentrated under vacuum, then evaporated twice with benzene. The acid chloride thus obtained is dissolved in 2 ml of dioxane and added to 42 mg of cyanamide in solution in 1 ml of dioxane containing 0.2 ml of ION sodium hydroxide. After 1.5 hours, the reaction medium is diluted with 150 ml of ethyl acetate, 20 ml of water, and it is brought to pH 5 using acetic acid, the organic phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulphate, then evaporated to dryness. The residue is chromatographed on silica by eluting with a mixture of chloroform/methanol/acetic acid (90/8/2, v/v). You get 160 mg of the expected product in solid form.

IR (KBr)

2150 cm"<1>:C = N

Mass spectrum:

MH<+>: 429

NMR spectrum:

7.20-7.70 ppm: m, 8H: aromatic

4.75 ppm: s, 2H: N-CH2-C6H4-

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

1.3 0-1.80 ppm: m, 12H: CH3-CH2-CH2- and spirocyclohexane 0.85 ppm: t, 3H: CH3-CH2-CH2

Example 22

1-[(N-2'-(4-carboxy-1,3-thiazol-2-yl-carbamoyl)-4-biphenyl-yl-methyl]-2-n-propyl-4-spirocyclohexane-2-imdiazolin- 5-on.

CR 4 R 5 = cyclohexane, X =0

This compound is prepared from the compound obtained in example 20.

2-amino-4-ethoxycarbonyl-1,3-thiazole is prepared according to B. Plouvier et al., J. Heterocycl. Chem., 1989, 26 (6), 1646. A) 1-[2'-(N-(4-carbethoxy)2-1,3-thiazol-yl)-carbamoyl-4-biphenyl-4-yl)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 DCM and 1 ml of DMF, 500 mg of BOP and 0.14 ml of triethylamine are added. It is stirred for 40 hours at room temperature, then 7 hours at 50°C. The reaction medium is again taken up in 50 ml of ethyl acetate, and it is washed twice with a solution of KHSO 4 -K 2 SO 4 , then twice with a saturated sodium bicarbonate solution, then once with a saturated sodium chloride solution. After drying over sodium sulfate, the organic phase is concentrated under vacuum, and the residue is chromatographed on silica by eluting with a mixture chromatographed on silica by eluting with a mixture of ethyl acetate-toluene. You get 120 mg of the expected product.

Melting point = 96-98°C.

B) To 110 mg of the product obtained in the previous step, dissolved in 1 ml of methanol and 1 ml of dioxane, 0.5 ml of 2N sodium hydroxide is added. After stirring for 35 minutes, the reaction medium is diluted with 10 ml of water and 60 ml of ethyl acetate, and it is brought to pH 5 by the addition of 1N hydrochloric acid. The organic phase is decanted, washed with a saturated sodium chloride solution, dried over sodium sulfate, then concentrated. The residue is taken up again in ether, filtered and dried.

m = 100 mg

Sm.p. = 145-148°C

NMR spectrum:

8.0 ppm: s, 1H: H in 5 of thiazole

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

4.7 ppm: s, 2H: N-CH2-C6H4-

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-CH_3

Example 23

2-n-butyl-1-[2•-(2-cyanoguanidinecarbonyl)-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one.

The acid chloride of the compound obtained in example 2 is prepared: 1 g of this compound is placed in 20 ml of DCM in the presence of 1.8 ml of thionyl chloride and stirred at room temperature for 2 hours. After concentration of the environment, it is taken up again with benzene, then concentrated again. The isolated crude product is then used. It is mixed with 417 mg of dicyandiamide, 0.5 ml of 10N sodium hydroxide, 0.5 ml of water and 10 ml of dioxane, then it is left under stirring for 5 hours. The reaction medium is taken up again with water and ethyl acetate, potassium carbonate is added, then concentrated. The obtained residue is chromatographed on silica by eluting with a DCM-methanol mixture (95/5, v/v). 100 mg of the expected product is isolated.

Sm.p. = 105°C.

Example 24

4-Benzylidene-2-n-butyl-1-[(2'-carboxy)-4-biphenyl-yl-methyl]-2-imidazolin-5-one trifluoroacetate.

(In: R 1 = CO 2 H, R 2 = H, R 3 = n-C 4 H 9 , R 4<R> 5 , <=><=>CH-C 6 H 5 , X = 0).

A) 4-(1-benzylidene-1-valerylamino-methylamidomethyl)-2'-biphenyl-tert-butylcarboxylate.

Starting from N-Boc α-dehydro (L) phenylalanine, the N-carboxylic anhydride of α-dehydro (L) phenylalanine is prepared according to

R. Jacguier et al., Tetrahedron Lett., 1984, 25 (26), 2775. p.

To 430 mg of this compound in solution in 5 ml of THF, 644 mg of 4-aminomethyl-2<1->biphenyl-tert-butylcarboxylate is added, it is stirred for 2 hours at room temperature, then 1 ml of methyl orthovalerate is added and it is evaporated to dryness, under vacuum without heating it. The residue is heated for 3 hours at 100°C, concentrated under vacuum, then chromatographed on silica by eluting with a mixture of hexane-ethyl acetate (4/1, v/v). You get 580 mg of a white, solid substance.

Sm.p. = 154°C

NMR spectrum:

1.3 ppm: s, 9H: t-Bu

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

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

4.4 ppm: d, 1H: CH2-NH

6.8 ppm: s, 1H: CH (=CH-C6H5)

B) 4-benzylidene-2-n-butyl-1-[(2<1->tert-butoxycarbonyl-4-biphenyl-yl) methyl]-2-imidazole in-5-one.

440 mg of the compound obtained in step A is dissolved in 1 ml of acetic acid and heated for 30 minutes at 100°C.

It is evaporated to dryness under vacuum and the residue is chromatographed on silica by eluting with a mixture of hexane-ethyl acetate (4/1, v/v). You get 130 mg of the expected product in oil form.

NMR spectrum:

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

C) 100 mg of the compound obtained in the previous step is dissolved in 1 ml of DCM, and 1 ml of trifluoroacetic acid is added, then left to stand with stirring for 40 minutes at room temperature and evaporated under vacuum. It is repeated several times with DCM, then evaporated. When ethyl ether is added, a white solid is precipitated.

m = 101 mg

Sm.p. = 85°C

Mass spectrum:

MH<+>: 439

NMR spectrum:

0.8 2 ppm: t, 3H: CH3(n-Bu)

1.3 ppm: sext, 2H: CH3-CH2-

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

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

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

7.05 ppm: s, 1H: =CH-C6H5

7.2-8.2 ppm: m, 13H: aromatic

Example 25

4-Benzylidene-1-[(2'-carboxy)-4-biphenyl-yl-methyl]-2-phenyl-2-imidazolin-5-one.

(In: Rt = CO 2 H, R 2 = H, R 3 = C 6 H 5 , R 4<R> 5<=><=>CH-C 6 H 5 , X = 0).

A) 4-benzylidene-2-phenyl-5-oxazolone-5.

1.8 g of hippuric acid and 0.4 g of potassium bicarbonate are dissolved in 4 ml of acetic anhydride, heated for a few minutes at 50°C, then cooled to room temperature, and 1.49 g of benzaldehyde is added. After 1 hour at room temperature, 20 ml of distilled water at 80°C is added. The solid that is precipitated is dried, washed in water, in ethanol, then dried. You get 1.24 g of the expected product in the form of a yellow solid."

Melting point = 215°C.

NMR spectrum:

7.4 ppm: s, 1H: =CH-C6H5

8.1-8.4 ppm: m, 10H: aromatic

B) 4-(1-benzoylamino-1-benzylidene-methylamidomethyl)-2'-biphenyl-tert-butylcarboxylate.

A mixture containing 500 mg of the compound obtained in the previous step, 570 mg of 4-aminomethyl-2<1->biphenyl-tert-butylcarboxylate and 10 ml of pyridine is heated at 110°C for 3 hours. One evaporates under vacuum, takes it up again with chloroform, then evaporates again. The residue is chromatographed on silica by eluting with a mixture of hexane-ethyl acetate (3/1, then 2/1, v/v). 106 mg of the expected product is obtained in the form of a yellow solid.

NMR spectrum:

1.1 ppm: s, 9H: t-Bu

4.35 ppm: t, 2H: -CH 2 -NH

7.05-7.06 ppm: m, 19H: H aromatic + C6H5-CH=

8.65 ppm: t, 1H: NH-CH 2

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

C) A mixture of 1.2 g of the compound obtained in the previous step and 1.1 g of freshly melted sodium acetate is heated for 6 hours under reflux in 5 ml of acetic acid. It is allowed to cool, then an insoluble substance is precipitated by adding chloroform. The filtrate is evaporated, and the residue is chromatographed on silica by eluting with a mixture of chloroform-methanol (98/2, v/v). The solid obtained is recrystallized in ethyl ether.

m = 692 mg

Sm.p. = 120°C

NMR spectrum:

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

7.1-8.3 ppm: m, 19H: H aromatic + =CH-C6H5

Examples 26 and 27

2-n-butyl-1-[(2<1>(2-methyl-5-tetrazol-yl)-4-biphenyl-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one, (Example 26 ),

and 2-n-butyl-1-[2'(1-methyl-5-tetrazol-yl)-4-biphenyl-yl)methyl]-4-spir<q>cyclopentane-2-imidazolin-5-one (example 27).

In 10 ml of DMF, you mix 500 mg of the compound prepared in example 5 and 58 mg of sodium hydride, you stir it for 30 minutes, then you add 179 mg of methyl iodide and 2 ml of DMF, and you leave it under stirring at room temperature for 4 hours. The reaction medium is concentrated, taken up again in water, then extracted with ethyl acetate. It is dried over sodium sulphate, filtered and the solvent evaporated. The residue is chromatographed on silica by eluting with a mixture of hexane-ethyl acetate (6/4, v/v). Two fractions are isolated:

90 mg of the compound from Example 26 and

184 mg of the compound from Example 27.

The NMR spectrum:

Example 2 6

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

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

1.4 ppm: quint, 2H: CH3-CH2-CH2-

1.5-1.9 ppm: m, 8H: cyclopentane

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

4.15 ppm: s, 3H: N-CH 3

4.6 ppm: s, 2H: -N-CH2-C6H4-

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

7.3- 7.75 ppm: m, 4H: C^-C^-C^-

Example 2 7

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

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

1.38 ppm: quint, 2H: CH3-CH2-CH2-

1.5-1.9 ppm: m, 8H: cyclopentane

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

3.35 ppm: s, 3H: N-CH 3

4.6 ppm: s, 2H: N-CH2-<C>6H4

7 ppm: system AA1 , BB', 4H: N-CH2-C6<H>4-

7.4-7.8 ppm: m, 4H: CH^-C^-C^

Example 28

2-n-butyl-6-spirocyclopentane-3-[2'-(5-tetrazolyl)-4-biphenyl-yl)methyl]-4(1H)-5,6-dihydro-4-pyrimidinone.

A) Cyclopentylidene ethyl acetate.

In 40 ml of benzene there are 6 g of 80% sodium hydride, and 57.1 ml of triethylethylphosphonoacetate are added drop by drop at a temperature lower than 35°C. After 1 hour at room temperature, 24.3 ml of cyclopentanone are added drop by drop. It is heated at 65°C for 15 minutes, then cooled to room temperature and the overlying liquid layer is decanted. 25 ml of benzene are added, heated at 65°C for 15 minutes, cooled, decanted, then the liquid on top is extracted. The operation is repeated once. Evaporating the liquids gives 42 g of the expected product which is distilled.

Boiling point = 102°C under 11 mm of mercury

m = 22.8 g

B) (1-aminocyclopentyl)acetamide.

150 ml of ammonia in gaseous form is added to 20 g of ethyl cyclopentylidene acetate prepared above and it is heated at 150°C for 72 hours. The product obtained after evaporation is purified by chromatography on silica eluting with a mixture of DCM-methanol-20% ammonia (90/10/1, v/v/v). The product obtained is dissolved in DCM, dried over sodium sulfate. The DCM is filtered and evaporated to obtain 7.2 g of the expected product. C) 2-n-butyl-6-spirocyclopentane-4(1H)-5,6-dihydro-4-pyrimidinone.

A mixture containing 4.57 g of (1-aminocyclopentyl)acetamide prepared above, 25 ml of methyl orthovalerate and a few drops of acetic acid is heated at 100° C. for 18 hours. After evaporation of the excess ortho-valerate, the residue is taken up again with a mixture of ethyl acetate-sodium bicarbonate, then washed with an aqueous solution of sodium chloride, dried over sodium sulfate, then purified by chromatography on silica eluting with a mixture of DCM-methanol (98 /2, v/v),

m = 5 g

NMR spectrum:

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

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

1, _3-1.8 ppm: m, 10H: CH3-CH2-CH2and cyclopentane 2 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 one obtained in Example 10, step C.

D) 2-n-butyl-4-spirocyclopentane-1-[2'-(triphenylmethyl-5-tetrazolyl)-4-biphenyl-yl-methyl]-6-pyrimidinone.

327 mg of 80% sodium hydride in 30 ml of DMF and 1.5 g of the pyrimidinone prepared above are mixed for 30 minutes under nitrogen, and 5.27 g of 4-bromomethyl-2'-(5-triphenylmethyltetrazolyl)-biphenyl are added. After 4 hours with stirring at room temperature, the solvents are evaporated, taken up again with ethyl acetate and water, dried over sodium sulfate and concentrated. The product obtained is purified by chromatography on silica by eluting with a mixture of ethyl acetate-hexane (3/7, v/v).

m = 3.2 g

E) 3 g of the compound obtained in the previous step is placed in 15 ml of methanol, and it is cooled with a water-ice bath, 2.2 ml of 4N HC1 is added, and it is left to stand for 5 hours with stirring at room temperature. After evaporation, it is taken up again with ethyl acetate and with water, then sodium hydroxide is added to reach a basic pH (pH 11). It is allowed to decant, the aqueous phase is washed with ethyl ether and toluene, then again with ether. This aqueous phase is brought to pH 5 by adding dilute hydrochloric acid, then extracted with ethyl acetate, dried and concentrated. The product obtained is purified on silica by eluting with a mixture of DCM-methanol (95/5, v/v). You get 800 mg of the expected product.

NMR spectrum:

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

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, 2H: N-CH2-C6HA-

7.05 ppm: m, 4H: CH2-C6H4-

7.55-7.82 ppm: m, 4H: CH2-C6H4-C6HA-

Example 29

2-n-butyl-3-[(2'-carboxy-4-biphenyl-yl)methyl]-5-spirocyclopentane-5(1H)-5,6-dihydro-4-pyrimidinone-trifluoroacetate.

A) 1-cyanocyclopentaneethyl carboxylate.

This compound is produced according to Heiv. Chim. Acta, 1952, 35 (7), 2561.

9.2 g of sodium are dissolved in 200 cm<3> of absolute ethanol. Half of the formed sodium ethylate solution is poured into a flask. To the remaining half, 24.88 g of ethyl cyanoacetate are added, and it is kept under reflux.

4 3.19 g of 1,4-dibromobutane are poured into another ampoule, the sodium ethylate solution and 1,4-dibromobutane are added drop by drop at the same time in the reaction environment. After the end of the addition, it is kept under reflux for 2 hours. It is evaporated, taken up again with a mixture of ethyl ether-water, washed with a saturated sodium chloride solution, then dried. The product obtained is distilled at 115-120°C under 11 mm of mercury.

m = 24 g.

B) 1-aminomethylcyclopentaneethyl carboxylate.

This compound is produced by catalytic hydrogenation of 1-cyanocyclopentaneethyl carboxylate. 20 g of 1-cyanocyclopentaneethyl carboxylate are placed in 200 ml of ethanol with 10% ammonia and hydrogenated at 60°C under a pressure of 100 bar in the presence of rhodium on aluminum dioxide for 72 hours. After filtration on Celite<®> and evaporation, the residue is chromatographed on silica by eluting with a mixture of DCM-methanol-20% ammonia (98/2/0.5; v/v/v). m = 12.8 g C) 2-n-butyl-5-spirocyclopentane-4(1H)-5,6-dihydro-4-pyrimidinone.

A mixture containing 13.12 g of the compound obtained in the previous step and 13.5 g of ethyl valerimidate in 100 ml of xylene containing a few drops of acetic acid is refluxed for 13 hours. The reaction medium is evaporated, taken up again with ethyl acetate and a 10% sodium carbonate solution, then dried and concentrated.

m = 14 g

Sm.p. = 89-91°C.

NMR spectrum:

0.80 ppm: t, 3H: CH3(nBu)

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

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

10 ppm: 1H, s: NH-CO

D) 2-n-butyl-5-spirocyclopentane-3-[(2'-tert-butoxycarbonyl-4-biphenyl-yl)methyl]-4(1H)-5,6-dihydro-4-pyrimidinone.

500 mg of the product obtained in the previous step is placed in 40 ml of DMF, in the presence of 115 mg of 80% sodium hydride in oil, under argon and stirred at room temperature for half an hour. 1.08 g of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl is added and it is kept for 2 hours with stirring. After evaporation, the residue is taken up again with a mixture of ethyl acetate-water, washed with a saturated sodium chloride solution, then dried, concentrated and chromatographed on silica by eluting with a mixture of ethyl acetate-hexane (3/7, v/v).

m = 280 mg

E) Dissolve 250 ml of the tert-butyl ester prepared in the previous step in 10 ml of DCM. It is cooled in an ice water bath, then 5 ml of cold trifluoroacetic acid is added and left to stand for 1 hour while stirring in the cold, then 1 hour at room temperature. One evaporates under reduced pressure. The residue is taken up again with ethyl ether, then evaporated. The operation is repeated three times, then the residue from evaporation with hexane is recovered, triturated, then the hexane is decanted. It is taken up again with ethyl ether and the precipitate is filtered.

nine = 190 mg

Sm.p. = 153-155°C

NMR spectrum:

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

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

1.4 5-2.2 0 ppm: m, 10H: CH3-CH2-CH2- and cyclopentane 2.8 0 ppm: t, 2H: CH3-CH2-CH2-CH2-

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

5.15 ppm: s, 2H: N-CH2-

7.2 5 ppm: m, 8H: aromatic

Claims (7)

1. Analogous process for the preparation of a therapeutically active compound (I) where: R± and R2 are the same or different and each represents, independently, hydrogen or a group selected from carboxy, C₁-C₁- alkoxycarbonyl, cyano, tetrazolyl, methyltetrazolyl, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl, N-cyanocarbamoyl, N-hydroxycarbamoyl, N-((4-carboxy)-1,3-thiazole -2-yl)carbamoyl, ureido, 2-cyano-guanidinecarbonyl, 2-cyanoguanidinemethyl, 1-imidazol-yl-carbonyl, 3-cyano-2-methylisothioureidomethyl, on the condition that at least one of the substituents R 1 or R 2 is different from hydrogen; R 3 represents hydrogen, C 1 -C 8 alkyl, unsubstituted or substituted with one or more halogen atoms, C1-C3-alkenyl, C3-C7-cycloalkyl, phenyl, phenyl(C3-C3)-alkyl, where the phenyl group is unsubstituted; R 4 and R 5 each independently represent C 1 -C 8 alkyl, phenyl, where the said alkyl and phenyl groups are unsubstituted or substituted with one or more halogen atoms or with perfluoro(C1~C4)-alkyl; or R4 and Rj. together form a group with formula =CR7Rg, where R 7 represents hydrogen, C 1 -C 4 alkyl or phenyl, and R 8 represents C 1 -C 4 alkyl or phenyl; or also R 4 and R 1 , taken together may represent a group of formula (CH2)n or a group of formula (CH2)pY(CH2) where Y is either an oxygen atom or a carbon atom substituted by a C1-C4 alkyl group or phenyl or a group N-Rg where Rg" represents hydrogen, C1-C4 alkylcarbonyl . or adamantane; p + q = rn; n is an integer from 2 to 11; m is an integer from 2 to 5; X is an oxygen or sulfur atom; z and t are zero or one is zero and the other is 1; and their salts, characterized by: al) reacting a heterocyclic derivative with formula: where z, t, R^, R4 and R^ have the previously stated meanings for formula (I), with a (4-biphenyl-yl)methyl derivative of formula: where Hal represents a halogen atom and R'^ and R' 2 represent R 1 and R 2 respectively, or a precursor group for R and R 2 ; bl) optionally to treat the compound thus obtained with with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disphosphetane-2,4-disulfide]; cl) treating the compound obtained in al) or in bl) where X represents an oxygen or sulfur atom, to prepare compound (I) by converting the groups and/or R'2 to the groups R1 and/or R2, respectively; or a2) to convert an amino acid of formula: where z, t, R4 and R5 have the meanings given above for formula (I), and whose amine function is protected with the group Pr, with a (4-biphenyl-yl)methylamine derivative of formula: where R 1 and R 2 represent R and R 2 , respectively, or a precursor group for R 1 and R 2 ; b2) after deprotection of the amine to treat the thus obtained connection with formula: with an alkyl orthoester of formula R3C(OR)3(10) where R3 has the meaning given for formula (I), and R is a c-i_"c4~ alkyl; c2) possibly treating the thus obtained compound with formula: with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]; d2) then treating the compound thus obtained in b2 or in c2 with formula: under suitable conditions to prepare compound (I) by converting the groups R' 2 and/or R'^ to the groups R 2 and/or R 1 , respectively; or a3) to react an imidazole derivative with formula: where R3, R4, R5 have the meanings given for formula (I) above, with a (4-biphenyl-yl)methyl derivative of formula: where Hal represents a halogen atom and R'^ and R' 2 represent R 1 and R 2 , respectively, or a precursor group for R 1 and R 2 , in the presence of oxygen and UV irradiation, in a basic environment; b3) possibly treating the compound thus obtained with formula: with Lawesson's reagent [2,4-bis[4-methoxyphenyl)-1,3-dithia-2,4 diphosphetane-2,4-disulfide]; c3) treating the compound thus obtained in b3 or in c3 with formula: under suitable conditions to prepare compound (I) by converting the groups R'^ and/or R' 2 to the groups R 1 and/or R 2 , respectively; whereby the compound obtained in cl), d2) or c3) is then optionally converted into one of its salts with acids or bases. 2. Method as set forth in claim 1, characterized in that a compound of formula 2, (10) or 11 is used, where R is a straight-chain C.sub.-C.sub.1 alkyl group, and in that a compound is used, with formula 3 or 8. where R'^ is in the ortho position and represents a carboxy group or tetrazolyl group, and R' 2 is hydrogen. 3. Method as stated in any of claims 1 and 2, characterized in that a compound of formula 2, 7 or .11 is used where R4 and R5 together with the carbon atom to which they are attached form a cyclopentane or a cyclohexane. 4. Process as set forth in any one of claims 1 to 3, characterized by reacting a compound of formula 2. where R4 and R5 taken together form a group -(CH2)4-, z = t=0 and R3 is the group n-butyl, with a compound of formula 3. where R2 'is hydrogen and R^' is a tetrazolyl precursor group, the group R-j_' is converted to the tetrazolyl group, and the compound obtained is optionally converted to one of its salts with acids or bases to form 2-n-butyl-4-spirocyclopentane-1-[(2'-(5-tetrazolyl)-4-biphenyl-yl)methyl]-2-imidazolin-5- on or one of its salts with acids or bases. 5. Compound, characterized in that it has the following formula: where: R 3 is hydrogen, C 1 -C 6 alkyl, unsubstituted or substituted with one or more halogen atoms, C2-C6-alkenyl, C3-C7-cycloalkyl, phenyl, phenyl (C1-C3)-alkyl, the phenyl group being unsubstituted; R 4 and R 5 are each independently C 1 -C 8 -alkyl, phenyl, wherein alkyl- the groups, phenyl groups and phenylalkyl groups are unsubstituted or substituted by one or more halogen atoms or by perfluoro(C±-C4)-alkyl; or R^ and R^ together form a group of formula =CR7R8, where R7 is hydrogen, C±-C4 alkyl or phenyl, and RQ is C1-C4 alkyl or phenyl; or R 4 and R 1 taken together are a group of formula (CH 2 )n or a group of formula (CH2) pY (CH2) q, where Y can be an oxygen atom or a carbon atom substituted by Cx-C^-alkyl or phenyl, or a group N-Rg where Rg is hydrogen, C1-C4 -alkylcarbonyl, polyhalogen (C1-C4) -alkylcarbonyl, benzoyl, α-aminoacyl or an N-protecting group selected from the groups Boe, Z, Fmoc or benzyl, or R4 and R5, together with the carbon atom to which they are attached, constitute indan or adamantane; p + q = m; n is an integer from 2 to 11; m is an integer from 2 to 5; X is an oxygen or sulfur atom; z and t are zero or one is zero and the other is 1; with the restrictions that: A when z and t are zero, and X is oxygen, then 1) R4 and Rj. anything other than C-L-C 8 alkyl; phenyl, phenyl {C±-C3)alkyl, where the said alkyl, phenyl and phenylalkyl are unsubstituted or substituted with one or more halogen atoms or with a group selected from perfluoro-(Ci~C4)-alkyl, hydroxyl, C^ -C 1 -C 4 -Alkoxy; or 2) R 4 and R 1 - taken together are other than a group NR 6 wherein R 8 is hydrogen, C 1 -C 4 alkyl, phenyl (C 1 -C 2 ) alkyl; or 3) R4 and R5, taken together, are different from the group = CR7R8when R3 is hydrogen, phenyl, methylphenyl. or benzyl; 4_) n is different from 6 ; 5) R 4 and R 5 taken together are other than a group (CH 2 ) where n is between 3 and 5, when R 3 is a substituted phenyl group; B when z = 1 and R3 is phenyl, then R4 and R5 are different from methyl; C when z and t are 0, and X is sulphur, then 1) R 4 and R 5 are something other than phenyl when R 3 is methyl, phenyl, chlorophenyl, methoxyphenyl or methylphenyl; or 2) R4 and R5 something other than <C>1-C3-alkyl when R3 is methyl or phenyl; or 3) R4 and R5 something other than methoxyphenyl or chlorophenyl when R3 is phenyl; or 4) R4 and R6 something other than chlorophenyl when R3 is methyl. 6. Connection as stated in claim 5, characterized by z = t = 0; R 3 is n-butyl; R4 and R5 taken together form the group -(CI^^-; X is oxygen. 7. Compound as stated in claim 6, characterized in that it is in the form of its chlorohydrate.