IL97612A - N-substituted heterocyclic derivatives their preparation and pharmaceutical compositions containing them - 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

■>νκοηι ΐϊΐ- ίι ,ηΐΊοηΊη-Ν ΠΊ ^p^non union N-Substituted heterocyclic derivatives, their preparation and pharmaceutical compositions containing them SANOFI C. 83020 This invention relates to N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing them.

The compounds in accord with the invention antagonise the action of angiotensin II which is a peptide hormone with the formula: H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH Angiotensine II is a powerful vasopressor agent which is the active biological product of the renin-angiotensine system.

Renin acts on angiotensinogen in plasma- to produce angiotensin I, the latter being converted into angiotensin II by the action of the angiotensin I conversion enzyme.

The compounds in this invention are non-peptide compounds, antagonists of angiotensin II. 3y inhibiting the action of angiotensin II on its receptors, the cojapounds of the invention prevent in particular the increase in blood pressure produced by the hormone-receptor interaction, they also have other physiological effects on the central nervous system.

Thus, the invention compounds are useful in the treatment of cardiovascular diseases like hypertension, heart failure as well as in the treatment of the central nervous system and in the treatment of glaucoma and diabetic retinopathy.

The present invention relates to the compounds of formula which: i and P.2 are alike or different and each independently represents . hydrogen or a group selected from a Ct-C6 alkyl, a C1-C alkoxy, aminof aminomethy1 , carboxy , an alkoxycarbonyl in which the alkoxy is a C-d alkoxy, cyano, tetrazolyl, methyltetrazolyl , methylsulfonylamino , trifluoromethylsulfonylamino , "trifluoromethylsulfonylaminomethyl , N-cyano-acetamide, N- hydroxy-acetamide , N- ( 4-carboxy-l , 3-thiazol-2-yl ) acetamide , ureido , 2-cyano-guanidinocarbonyl , 2-cyano-guanidinomethyl , imidazol -1-yl-carbonyl , 3-cyano-2-methyl-isothioureidomethyl , "with the proviso that at least one of the substituents or R2 is different from hydrogen; — R3 is a hydrogen, a C -C1 alkyi which is unsubstituted or substituted by one or more halogen atoms , a C^-C^ aikenyl, a C3-C_. cycloaikyi, a phenyl, a -phenyialkyi in which the alkyi is C^-C^ , or a phenyl- alkenyl in which the aikenyl is C_.-C3 , said phenyl groups being unsubsti ted or monosubstituted or polysubstituted by a halogen atom, a C1-C. alkyi, a C. -CA halogenoalkyl , a C^-C^ poiyhalogenoalkyi , a hydroxy! or a C^-C^ alkoxy; R4 and R5 each independently represents a Q-Q alkyl, a phenvl or a phenvlaikyi in which the alkyi is - C^-C3 , said alkvl, phenyl and phenyialkyi groups being unsubstituted or substituted by one or more halogen atoms or by a group selected from a C^-CA perfluoro- alkyl , a hydroxy! and a C^-C. alkoxy; or ana together farm a group of the formula =CR-,Ra/ in which Rr . is hydrogen, a C^^-C. alkyl or a phenyl and Ra is a C^-C. alkyi or a phenyl; -Lor else A and .R= together are either a group of the formula (CH=)„ or a group of the .formula (ΟΗ=)ρϊ- (CHa) , in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C -C4 alkyl' group, a phenyl or a phenyialkyi in which the alkyl is C_-C3, or a group N-Re, in which Rs is a hydrogen, a C^-C^ alkyl, a phenyialkyi in which the alkyl is C^C,, a C_,-CA alky!car onyi , a _,-C^ halo- aenoalkvlcarbonyl , a C, -C. 3olvhalocenoalkylcarbon 1 , which pernit appropriate separation or crystallisation of canmaunds cf formula .(I), such as picric acid, c::alic acid or an optically active acid, for example a mandelic acid or a camphesui honic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride , hydrobrcmide, sulfate, hydrogen sulfate, dihydrcgen phosphate, methane sulfonate, methyl sulfate, maieate, fumarate, naph"halene-2-sulfcnate.

The salts of compounds of formula (I) also consist of salts with organic or inorganic bases, for ex mple salts of alkali cr alkaline earth mecals like salts of sodium, potassium, calcium, the salts of sodium and potassium being preferred, or with a tertiary amine, such as trcmetamol, or even salts cf arginine, lysine, or any physiologically acceptable amine.- According to this description and in the claims, which is! lev. a halogen atom is understood to' be a brer-tine, chlorine or fluorine atom. A U-protecting group (also denoted by ?r) is understood to be a group classically used in peptide chemistry for temporary protection of the amine function, for example a 3oc, Z cr Price group cr a benzyl group. An esterified carbo y group is understood to be an ester which is labile under the. approriate conditions, like for eiample a methyl, ethyl, benzyl or tertiary butyi ester. Alkyl means straight-chain, or branched aliphatic hydrocarbon radicals.

Compounds of formula (I) in which Ei is in the ortho position and is a carbcxy group or tetrazoiyl and ?.; is hydrogen are preferred compounds.

Compounds of formula (I) in which R. and Rs linked together with the carbon to which they are bonded constitute a cyclopentane or a cyclohexane are preferred compounds.

Similarly, compounds of formula (I) in which R3 is a straight-chain Ci-Cs alkyl group are preferred compounds.

Compounds of formula (I) in which X is an oxygen atom are likewise preferred compounds.

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

The following abbreviations are used in the description and in the examples: •- v- n-butyl, tert-butyl di ethyl formamide THF tetrahydrofuran DCK dichloramethane SBS -bromo-succini ide CC dicylcohexylcarbodiimide DIPS diisopropylethylami e Fthe ethyl ether TFA trifluoroacetic acid 7 be zyloxycarbonyl 3ac tert-butoxycarbonyl 30P benzotriazolyloxy trisdimethylamino phosphonium hexafluorophosphate Fnoc fluorenylmethylaxycarbonyl- This invention also relates to the method of preparation of compounds (I). The said method comprises the following steps al) a heterocyclic derivative of formula; in which z, t, R3, R. and Rs have the meanings indicated above far I) , is reacted with a derivative of (biphenyl-4-yl)methyl of formula in which Hal is a halogen atom and R' 1 and R' _ are either Ri and R∑ □r a grouping which is a precursor of Ri and R2 respectively; bl) optionally, the compound thus obtained of formula; s treated with Lawesson's reagent j*2, 4-bis (4-methoxyphenyl ) -1,3- ithia-2, -diphosphetan 2, -disulfidej j cl) the compound obtained from al) or bl) of formula 97612/2 in. which I is an oxygen tom ar a sulfur atom, is treated by converting the R' i and/or E' i groups into Hi and/or R_ groups respectively in. order to prepare compound (I).

Amongst compounds 2, the compounds (II) as defined below are novel, and are the subject of a divisional application no. 110820.

The compounds (II) are of the formula: - Rj represents hydrogen, a G-C* alkyl which is unsubstituted or -t substituted with, one or several halogen" atons, a G-G alkenyl, a G-G cyclcalkyi, a phenyl,, a phenylalkyl in which the alkyl is a C,-CK alkyl, a phenylalkenyl in which the alkenyl is a C2-C3 alkenyl, said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C^-C^ alkyl, a C^-C^ .haloalkyl , a C^-C^ polyhaloalkyl, hydroxyl or a C^-C^ alkoxy; - A and Rs each independently represent a G~G alkyl, a phenyl, a phenylalkyl in which the alkyl is a C^-C^ alkyl, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from a Ci-C. perfluoroalkyl, hydroxyl, C1-C4 alkoxy; - or H4 and Rs together form a group of formula in which R7 represents hydrogen, a C1-C4 alkyl or a phenyl and R3 represents a Ci-C. alkyl or a phenyl; - or again R, and Rs linked together represent either a group of formula (CHj)n, or a group of formula (CHs) Y(CH2>q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is a C^-C^ alkyl , or a N-Rg group- in which Rg represents hydrogen, a C^-C4 alkyl, a phenylalkyl in which the alkyl is C^-C^ alkyl, a C^-C^ alkylcarbonyl , a C1-C4 haloalkylcarbonyl , a C1-C4 polyhaioalkylcarbonyl , benzoyl, alpha-aminoacyl or an ΪΓ-protecting group, or R^ and R^ linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p ÷ q = m; - n is an integer from 2 to 11 inclusive; - m is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are zero or one is zero and the other is unity; with the restriction that - when z and t are zero and X is an oxygen atom, R* and R5 are other than; e a Ci-Cs, alkyl, a phenyl, a phenylalkyl in which the alkyl is a C<,-C alkyl, said alkyl, phenyl and phenylalkyl being unsubstituted or substituted with one or several halogen atoms or with a group selected from a C1-C4 perfluoroalkyl , hydroxyl, C1-C4 alkoxy; ?!- or 4 and R5 linked together are other than a H-E6 group in which Re is a hydrogen, a alkyl, a phenylalkyl in which the alkyl is a C-Cs alkyl; s n is different from 6 and, when z=l and S3 is a phenyl, R* and R5 are each different from methyl .

Amongst the derivatives (II), compounds in which z = t = 0 and R4 and Rs together with the carbon to which they are bonded constitute a cyclopentane, are preferred compounds. These compounds correspond to formula; in which X is an oxygen atom or a sulfur atom and R3 is hydrogen, a Ci-Cs alkyl, either unsubstituted or substituted with one or several halogen atoms, a C_-Cs alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a C^- ^ alkyl, a phenylalkenyl in which the alkenyl is a C^-C^ alkenyl, said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C. alkyl, a Ci-C. haloalkyl, a Ci-C_ polyhalaalkyl , hydroxy1 or a Ci-C. ikoxy .

Compounds (II) in which z = 0 and t = 1 of in which R_, R., RE and X have the definitions given above for (II) are preferred compounds.

Finally, compounds (II) in which z = 1 and t = 0 with formula; in which; - R3 represents hydrogen, a Ci-Cs alkyl 'which is unsubstituted or . substituted with cne or several halogen atoms, a C2-C& alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a Cj-CL alkyl, a phenylalkenyl in which the alkenyl is a C^-C^ alkenyl, said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C_ alkyl, a Ci-d haloalkyl, a C1-C4 pclyhaloaikyi , hydroxy 1 or a C1-C4 alkoxy; - Ei and R5 each independently represent a Ci-C3 alkyl, a phenyl, a phenylalkyl in which the alkyl is a C^-C^ alkyl, said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from a Ci-C* perfluoroalkyl , hydroxyl, C1-C4 alkoxy; - or Ei and Rs together farm a group of formula =CR7Rs, in which R-represents hydrogen, a C1-C4 alkyl or a phenyl and Rs represents a C1 alkyl or a phenyl; - or again R and Rs linked together represent either a group of formula ((¾>„, or a group of formula (CH2)PY (CH2)q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a C1-C4 alkyl group, a phenyl or a phenylalkyl in which the alkyl is a alkyl, or a N-Rg group in which Rg represents hydrogen, a alkyl, a phenylalkyl in which the alkyl is a C^-Cg alkyl, a C^-C^ alkylcarbonyl, a Ci-C* halcalkylcarbonyl , a Ci-C* polyhaloalkylcarbonyl , benzoyl, alpha-aminoacyl or a N-protecting group, or R and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - n is an integer from 2 to 11 inclusive; - in is an integer from 2 to 5 inclusive; - X is an oxygen atom or a sulfur atom; with the restriction that R3 is other than a phenyl when RA and Rs each represent methyl; are preferred compounds.

The derivatives 2_ are prepared by known methods. For example, the method described by Jacquier et al. (Bull. Sac. Chim.

France, 1971, 2., 1040-1051) and by Brunken and Bach (Chem. Ber. , 1956, 1363-1373) may be used by reacting an alkyl imidate with an amino acid or its ester according to following reaction scheme : R4^ (CH2)Z- C02R' NH C «5 (CH2)t.-NH2 OR 25 in which R is a Ci-C. alkyl, R' is hydrogen or a C-.-d alkyl and R3, Ή.Λ, Rs, z and t are as defined previously for (I).

This reaction is performed in acid medium, by heating in an inert solvent such as xylene or toluene.

According to another method of working, a compound 2_ may be prepared by reacting in acid .medium an aminoalkylamide ( 5' ' ) on an alkyl ortho-ester (10) according to the following reaction scheme: R (CH2)Z-C0NH2 + R3-C(0R)3 —> 2 R5 (CH2)t-NH2 51 10 where R is a Ci-C« alkyl.

The compound Z. may also be prepared by using a method of working described by H. Takenaka et al.. (Heterocycles, 1989, 2_ (6), 1185-89), by reacting the derivative 5' ' with an acid halide of formula: R3 - CO - Hal 12 in v/hich Hal is a halogen, preferably chlorine.

The reaction is carried out in a basic medium.

More particularly, a compound 2., in accord with another subject of this invention, is prepared by a- method comprising reacting a compound of formula: in which A is an OH group, an NH:- group or an OS' group, R' being hydrogen or a Ci-C. alkyl, with a compound of formula: R3 - B 14 in which 3 is: grouping or - a CQHal grouping, R being a C1-C4 alkyl and Hal representing a halogen atom, preferably chlorine, then optionally the compound thus obtained is treated with Lawesson's reagent (2, 4-bis (4-methoxyphenyl )-l , 3-dithia-2, 4-diphosphetan 2, -disulfide.

The derivative of (biphenyl-4-yl)methyl (3) is prepared in accord 'with a method described in patent application EP 324 377.

The conversion of an- R' 1 and/or R' 2 group into an Ri and/or R group is carried out using methods which are well known ta the specialist in the field. Thus, when the compound (I) to be prepared has an Ri and/or E2 group = carboxy, R' 1 and/or R*2 is an esterified carboxy group. When the compound (I) to be prepared has an R; and/or R. group = tetrazolyl, R' 1 and/or '2 may be either a tetrazolyl protected for example by a trityl group, or a cyano group which will then be replaced by a tetrazolyl optionally protected by a trityl. Conversion of the cyano group into tetrazolyl may be carried out by an azide, for example tributyl tin azide or sodium azide . 8' 1 and/or R'2 groups such as nitro, carboxy, cyano or acid chloride groups may also be used and these may then be converted using reactions which are well-known to the specialist in the field in order to obtain Ri ar.d/or j groups such as those described for compound I.

Thus, when R' 1 and/or R' represent a carboxy, it may be converted into Ri and/or 2 representing an imidazol-'i-yl-carbonyl , or even into N-^4→:arboxy)-l,3-thiazol-2-y^acetaiiide.

The R'i and/or R' representing an acid chloride may be converted into R, and/or R2 representing ίϊ-hydroxyacetamide, N-cyanoacetamiae, ureido or 2-cyanoguanidinocarbonyl .

R'i and/or R'2 representing a nitra may be converted into an amino from which Ri and/or such as methylsulfonylamino, trifluoromethylsulfanyland e and trifluoromethylsulfonylaminomethyl may be prepared.

R'i and/or R¾ representing a cyano may be converted into ami omethyl from wiiich can be prepared 3-cyano-2-methylisothioureidomethyl (:according to fc. Gordon et al., J. Org. Chem. , 1970, 35., (6), 2067-2069) or a 2-cyanoguanidomethyl (in accord with R . V, Turner, Synthesis, 1975, 332) Stage al) is performed in an inert solvent such as DMF, DJISO or THF, in a basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate or triethylamine.

Stage bl) is performed by heating under nitrogen in a solvent such as toluene, according to · jthe method described by M. P.

Cava et al., Tetrahedron, 1935, il, 22, 5061.

The method comprising stages al, bl, and cl is called method 1 in the following description.

Alternatively, compounds (I) may be prepared according to another method which is likewise a subject of this invention.

This method comprises: a2) reacting an a inoacid of formula; R (CH2)t-NHPr "C (CH2); COOH in which z, t, R* and Rs have the meanings indicated above for (I) and whose amine function is protected with the Pr group with a (biphenyl-4-yl)methylaTiine derivative of formula: ' in which R ' i and/or R ' 2 represent either Hi and R^ respecti ely, or a precursor of Ri and Ri ; b2) after deprotecting the amine, the compound obtained of formula: is then treated with an alkyl ortho-ester of formula R3C(OR)3 (10) in which Rs has the meaning indicated above for (I) and R is a Ci-C. alkyl; c2) optionally, the compound thus obtained of formula: is treated with Lawesson's reagent 2 , -bis (4-methoxyphenyl ) dithia-2, 4-diphosphetan 2, 4-disulphide; d2) the compound thus obtained in b2 or in c2 of formula: is ther. treated under approprtiate conditions to prepare compound by conversion of the R'2 and/or R' i groups into and/ or Ri groups respectively.

Compounds 7 are known or prepared by known methods (Chemistry of the Amino Acids, Greenstein and Vinitz, John Viley ed. , 1961, vol. 1, p. 697) .

Compounds S_ are prepared according to ^European patent application 324 377. Stage a2) is carried out under the normal conditions for coupling an acid and an amine, for example in the presence of BOP and of DIPEA.

Stage b2> which is the cyclisation of compound 9_ in the presence of 10_ is performed according to Jacquier et ai. (Bull, Soc. Chim. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem. Ber. , 1956, 89_, 1363-1373).

In the following description the method comprising stages a2 to d2 is called method 2.

According to one variant of method 2, in stage b2, an intermediary 9_!_ of formula: may optionally be isolated and then compound 4_ may be prepared by cyciisation in acid medium.

According to another variant of method 2 and in order to prepare a compound I in which R4Rs is one group =C ?R_ an amino acid of formula: = CH2-(CH2 t"NHC0R3 (CH2)z-C00H 71 may be reacted in acid medium with an aldehyde or a ketone of i0 formula: RvCORs in which R7 and Rs have the meanings given above far CI), then a compound of formula: ? 9" is obtained by action with compound Cyclisation of this compound in acid medium leads to compound i.

In this method, to prepare a compound (I) in which Ri and/or R2 is a carboxy group, the substituent R' 1 and/or R' 2 is preferentially a tert-butoxycarbonyl .

Finally, another alternative for the preparation of 30 the compounds (I) according to the invention in which z and t are zero, is the photooxida ion method which is likewise a subject-matter of this invention.

This last method comprises: a3) reacting an imidazole derivative of formula: in which. R3, R_, R_ have the meanings indicated above for (I) with a derivative of biphenyl- -yl methyl of formula: in which Hal is a halogen atom and R" 1 and/or R'2 represents either Ri and R; respectively or a precursor of Ri and R2, in the presence of oxygen and UV irradiation, in a basic medium; b3) optionally, the compound thus obtained of formula: is treated with. Lawesson's reagent 2,4-Ms(4-methoxy)-l,3-clithia-2,4-diphosphetan 2, 4-disulfide; c3) the compound thus obtained from b3 or from c3 of formula: is then treated under appropriate conditions to prepare compound ( I ) by converting the R' i and/or ?, ' 2 groups into Ri and/or R2 groups respectively.

The imidazole derivative 11 is either commercially available, or known, or prepared by known methods as indicated above for the preparation of compunds 2_.

Stags a3) is performed in an inert solvent such as Dffi? for example. To facilitate the reaction, a photosensitizing product such as methylene blue may be added.

In the following description, the method comprising stages a3) to c3) is called method 3.

Compounds ( I ) according to i t e invention in which R. - 13 - and Rs linked together represent a group of formula (CH2)PY(CK2)q in which Y is an H group, may be prepared by catalytic hydragenolysis of a corresponding compound (I) in which Y is an Ζί-Rs group, Re being benzyl.

The affinity of products according to the invention for angiotensine II receptors was studied in a linkage test of angiotensine II labelled with iodine 125 to membrane receptors in rat livers. The method used was that described by S. KEPPENS et al. in Biochem. J., 1982, 208, 809-817.

CIso was measured. This was the concentration which produced 50% displacement of the labelled angiotensine II, linked specifically to the receptor. The CI5 of the compounds according tothe invention is less than 10-6 M.

In addition, the angiotensine II antagonistic effect of the products according to 'ithe invention has been confirmed in various animal species in which the renin-angiotensine system had been activated previously (C. LACOUR et al., J. Hypertension, 1989, 7 (suppl.2), S33-S35).

Compounds according to the invention are active after administration by various routes, particularly the oral route.

No sign of toxicity was observed with these compounds at pharmacologically active doses.

Thus the compounds according to the invention may be used in the treatment of various cardiovascular diseases, particularly hypertension, heart failure, venous insufficiency, as well as in the treatment of glaucoma, diabetic retinopathy, and various diseases of the central nervous system, anxiety, depression, memory disorders or Alzheimer's disease, for example.

This invention also relates to the pharmaceutical compositions containing an efficacious dose of a compound according to the invention or a pharmaceutically acceptable salt and appropriate excipients. The said excipients are chosen according to the pharmaceutical form and the desired method of administration.

In the phaiTTiaceutical compositions of this invention for oral, sublingual, percutaneous, i tramuscular, intravenous, topical, intratracheal, intranasal, transdermic or rectal administration, the active principles of formula I above, or optionally their salts, may be administered in the form of administration units, mixed with classical pharmaceutical supports, to animals and to humans for the prevention or treatment of the illnesses or diseases above. The appropriate forms of administration units include forms for the oral route such as tablets, capsules, powders, granules and oral solutions or suspensions,- sublingual, buccal, intratracheal, intranasal forms of administration, percutaneous, intramuscular or intravenous forms of adminstration and rectal forms of adminstration. For topical application, the compounds according to the invention may be used in creams, ointments or lotions.

In order to obtain the preventive or therapeutic effect desired, the dose of active principle may vary between 0.01 and 50 g per kg body weight and per day.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, active ingredients in combination with a pharmaceutical support. This unit dose may be administered 1 to 5 times per day in such a way as to administer a daily dosage of from 0.5 to 5000 mg, preferably from 1 to 2500 mg.

Vhen a solid composition is prepared in the form of tablets, the principal active ingredient is mixed with a pharmaceutical vehicle such as gelatine, starch, lactose, magnesium stearate, talc, arabic gum and the like. The tablets may be coated with sucrose, a cellulose derivative, or other appropriate material or again they may be treated in such a way that they have a prolonged or retarded activity and they release a predetermined quantity of active principle continuously.

A preparation in capsules is obtained by mixing the active ingredient with a diluant and pouring the mixture obtained into soft or hard capsules.

A preparation in the form of syrup or elixir or for adminstration in the farm of drops may contain the active ingredient together with, a sweetener, preferably with no calorie content, methylparaben and propylparaben as antiseptics, as well as an agent to give a suitable taste and colour.

Powders or granules which can be dispersed in water may contain the active ingredient mixed with dispersion or wetting agents, or suspension agents like polyvinylpyrrolidone, again with sweeteners or taste correctors.

For rectal administration, suppositories which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethyleneglycols, are used.

Far parenteral administration, aqueous solutions, isotonic saline soutions or sterile and injectable solutions which contain pharmacologically compatible dispersion and/or wetting agents, for example propyleneglycol or butyleneglycol , are used.

The active principle may also be formulated in the form of microcapsules, optionally with one or several supports or addit es.

The compositions of this invention may contain, alongside the products of formula I above or one of the pharmaceutically acceptable salts, other active principles such as, far example, tranquillisers or other drugs which may be used in the treatment of the illnesses or diseases indicated above.

Thus, this invention also relates to phaimaceutical compositions containing several active principles in association, one of which is a compound of the invention and the other (s) may be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal anti-inf lammator agent or a tranquilliser.

The fallowing examples illustrate the invention without limiting it in any way. In these examples, the following abbreviations are used; d means density, TA means ambient temperature, KHSQ.- .SQ. means an aqueous solution containing 16.6 g potassium bisulfate and 33.3 g potassium sulfate per The melting points (M.pt.) are given in degrees Celcius unless indicated to the contrary, they were measured without recrystailizing the product.

Purity of the products was checked using thin layer chromatography (TLC) or HPLC. The products are characterised b their iiKR spectra recorded at 200 KHz in deuterated DMSO, the internal reference being tetranethylsilane.

To interpret the HKR spectra, the following were used: s for a singlet s.e. for a broadened singlet d for a doublet t for a triplet q · for a quadruplet quint for a quintuplet sext for a sexxuplet m \for a very broad band or multiplet Moreover, im means imidazole.

In the classic manner, the hydrogen atoms are numbered on the biphenyl as shown in the fallowing formula: n the following compounds, z and t are zero, except when the o pound prepared is a pyrimidinone .

EXAMPLE I 2-n-butyl-4-spirocyclopentane-l-[ (2' - tert-butoxycarbonylbiphenyl-4-yl) methyl] -2-imidazolin-5-one and 2-n-butyl-l-[(2' -carboxybiphenyl-4-yDmethyl] -4-spirocyclopentane-2-imidazolin-5-one tri fluoroacetate. Method 2.

A) 1- QI-Fmac-amino) -cyclopentane carboxylic acid was prepared according to the method described by CHI-ODEU CHANG et al. (Int. J. Peptide Protein Ses. , 1980, 15., 59-66). 14. pt. = 89-91 'O B) N- (2' - iert-butoxycarbcnylbiphenyl-4-yl)methyl-l- QI-Fmoc- mino ) cyclopentanecarboxamide- 1. 700 mg of the product prepared in the precedin . stage were dissolved in 8 ml DMF and 576 mg 4-aminoethyl- (2' -tert-butoxycarbonyDbiphenyl , 970 mg EOF and enough DIPEA to give a pH of 6 were added in succession.

After stirring for 1 hour, the reaction medium was diluted with 100 ml ethyl acetate and 20 ml water. The organic phase was washed successively with a saturated sodium bicarbonate solution, then with a KHSO.-KiSO. solution and finally with a saturated sodium chloride solution. After drying over sodium sulfate, the solution was evaporated to dryness. An oil was obtained with m = 1.2 g.

C) ΪΤ- (2' - tert-butoxycarbonylbiphenyl-4-yl)methyl-l-amino-cyclcpentanecarboxamide-1.

The product obtained in the preceding stage was dissolved in 10 ml DMF, then 1 ml diethyiamine was added and the mixture stirred far 14 hours at TA. The reaction medium was taken up with 100 ml ethyl acetate and 20 ml water and the organic phase was washed once with water, once with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.

The residue was chromatographed on silica gel by eluting with an ethyl acetate/methanol/30% ammonia solution mixture (99/1/0.5 ; v/v/v). 600 mg expected product were obtained.

.IR (CHC^) · 3350 cm-' : H (aniide and amine) 1700 cB-i : C = 0 (COjtBu) 1650 cra-i : C = 0 (CONH) NttR spectrum : 1.25 ppra : s : 9 H .vtBu ) 2.15 - 1,40 ppm- ·. m : 10 H : (C5H8, NH2) 4,40 ppra : d : 2 H : CH^NI. 7,15-7.75 ppm : ra : 8 H : biphenyl 8.60 : t : 1 H : H - CH2 D) 2- -butyl-4-spirocyclopentane-l-[ <2' - tert-butoxycarbonyl-bipheny1-4-y1 ) metb 1] -2-imidazo1in-5-one . 394 mg of product prepared in the preceding stage and 250 mg ethyl orthovalerate were mixed in 2 ml DC¾. 1 drop af acetic acid was added and then the mix was heated to 90"C allowing the DCM to evaporate. After 1 !. hours, the reaction medium was taken up with 50 ml ethyl acetate, 10 ml water and 1 ml saturated sodium bicarbonate solution. The organic phase was then washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chro atographed on silica gel by eluting with an ethyl acetate/toluene mixture (1/2, v/v). 390 mg of the expected product was obtained, which crystallized. M.pt. = 63-65 "C.

IE (CHCl.) : 1710-1720 cm-' : C = 0, C = 0 (ester and imidazoline) 1625 cnH: C = N E spectrum : 0.88 ppm : t : 3 H : CH_3 (nBu) 1.20 ppm : s : 9 H : tBu 1.35 ppm : sext : 2 H : CH3-CH2- 1.58 ppm : quint : 2 H. : CH3-CH2-CH2- 1.95-1,65 ppm : m : 8 H : cyclopentane 2.42 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.78 ppm : s : 2 H : CHj-Ceft 7.20-7.80 ppm : m : 8 H : aromatic H mass spectrum : MH* : 461 E) 2-n-butyl-l-C (2' -carba: MR spectrum : 0.78 ppm : t : 3 H : CH3 (nBu) 1.25 ppm : sext : 2 H : CH3-CH2 1.50 ppm : quint : 2 H : (¾-(]¾-(¾ 1.75-2,00 : m, 8 H : cyclopentane 2.65 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.83 ppm : s : 2 H : CH2-C6H4- 7.20-7.75 ppm : m 8 H : aromatic H mass spectrum : MH* : 405 SXAKPLE 2 2-n-butyl-l-E <2' -carbo:cybiphenyl-4-yl ) methyl] -4-spirocyclopentane-2-imidazolin-5-one trif luoroacetate. Method A) 2-n-b'atyl-4-spirocyclopentane-2-i idazolin-5-one.

The ethyl ester of 1-aminocyclopentane carboxylic acid was prepared according to ADKINS and BILLICA (J. amer. Chem.

Ethyl valerimidate was prepared according to Mac ELVAIN (J. Amer. Chem. Soc, 1942, Si. 1825-1827) and then released from its hydrochloride by the action of potassium carbonate and extraction with DCM.

The ethyl ester of l-aminacyclopentane carboxylic acid (1.57 g) and ethyl valerimidate (1.56 g) were dissolved in 12 ml xylene containing 6 drops of acetic acid. After 6¾ hours of heating under reflux, the reaction medium was concentrated under vacuum and the residue was then chromatographed on silica gel by eluting with a chloroform/methanol/acetic acid mixture (94/4/2 ; v/v/v). The fraction containing the expected product was evaporated several times in the presence of xylene and then of benzene to remove acetic acid. 1.91g of the product was obtained in the form of a thick ail. 1720 cm-' : C = 0 1635 cra-I : C = N ITote: the fact that no band is visible between 1500 and 1600 cm"1 indicates that, in chloroform solution, the product is an imidazolin-5-one.

MR spectrum : 0.92 ppm : t : 3 H : CH3 (nBu) 1.35 ppm : sext : 2 H : CH3-CH2- 1.50-1,93 ppm : m : 10 H : CH3-CH2-CH2 and cyclopentane 2.33 ppm : t : 2 H : CH3-CH2-CH2-CH2- 10.7 ppm : m : NH mass spectrum : JtH* : 195 The 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one prepared in stage A, may also be obtained in accord with another procedure, described below, by using cyclopentanone as the starting material. a) 1-aminocyclopentanenitrile This stage is carried out in accord with A. Strecker (Org. Synth. , 1955. 3.) . 1.97 g sodium cyanide was dissolved in 3.9 ml water in a round-bottomed flask and a solution containing 2.33 g ammonium chloride in 5.9 ml water and 3.5 ml 20% ammonia solution was added, then 3 g cyclopentanone in 3.8 ml methanol were added to the flask. After 1"¾ hours stirring, the flask was warmed to 60 'C for 45 minutes, then the' heating was turned off and the stirring continued for 45 minutes and the flask cooled to 25"C. The contents were extracted several tines with methylene chloride, dried over sodium sulfate, filtered and concentrated under vacuum. 4 g expected product was obtained in an oily form.

The 1-aminocyclopentanenitri le obtained was dissolved j ith 300 ml acetone and a solution of 2.25 g oxalic acid dihydrate in 200 ml acetone was added with stirring. The precipitate which formed was centrifuged, washed with acetone and then dried. m = 4.71 g Ii.pt. = 220 "C This compound is 1-aminocyclopentanenitrile hemioxalate. b) 1-ami ocy iopentaneacetamide.

This stage was carried out in accord with J. Zabicky, (The Chemistry of Amides, Intersciences, New York, 1970, 119). 5.1 g of the oxalate obtained in the preceding stage were treated with 7.65 ml concentrated sulfuric acid (d = 1.84) for 45 minutes v/ith stirring. A gas was evolved and the temperature increased to 100 *C. The mixture was cooled to 35°C and poured into a mixture of ice and concentrated ammonia solution (10 g/2.3 ml). The suspension which formed was extracted 6 times in succession with chloroform containing 5% methanol. 3 ml ammonia solution (d = 0.92) were added to the aqueous phase and this was then extracted again with chloroform containing methanol (1/0.5 ; v/v). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The expected product was obtained in the form of a white solid. a = 3. 9 g M.pt. = 95'C The analysis results and the IR spectrum confirmed the structure. c) 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one This stage was carried ^out in accord with H. Taneka et al., Heterocycles, 1989, 29., 1185-89. 3 g of the compound prepared in the preceding stage were placed in 70 ml anhydrous THF and 3.3 ml triethylamine and 3 ml valeryl chloride in 10 ml anhydrous THF were added with stirring.

A white suspension was produced. The intermediate compound which was formed, but not isolated, was 1- (Il-valeryl >aminacyclopentanecarboxamide. 6 g potassium hydroxide in pellet form, 7 ml water and 16 ml methanol were added. Heating under reflux was performed for two and a half hours and then 9 g ammonium chloride were added. After 15 minutes stirring, the mix was concentrated under vacuum. The residue obtained was absorbed in 40 ml water and extracted with 10 ml ethyl acetate and then twice with 5 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. The filtrate was concentrated to dryness. 4.85 g expected product were obtained. The MR spectrum was*-similar to that described previously. The hydrochloride of this compound may be prepared by addition of concentrated hydrochloric acid. The hydrochloride melts at 240*C while subli/nati g.

B) 2-n-butyl-4-spirocyclopentane-l-[ (2' - tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-imidazolin-5-one. 970 rag product obtained in stage A) were dissolved in 10 ml DKF. 270 mg sodium methylate were added and left at TA for 15 minutes with stirring. 2.08 g 4-bromomethyl- (2' - tert-butoxycarbonyl) biphenyl were added to the suspension then, after 30 minutes, the mixture was heated at 40°C for 3 ½ hours under nitrogen. The reaction medium was taken up with 'a mixture of 100 ml ethyl acetate, 10 ml water and 1 ml saturated sodium bicarbonate solution. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1/2 ; v/v) . 1.25 expected product which crystallized was obtained. Jt.pt. = 63-66*C.

The IS, MR and mass spectra as well as the Rf were identical with those obtained in stage D) of example 1.

C) 2-n-butyl-l-[ (2' -carboxybiphenyl-4-yl ) methyl] -4-spiro-cyclapentane-2-imidazolin-5-one trifluaroacetate. 1.22 g product obtained in the preceding stage were stirred for 40 minutes in a solution containing 6 ml DCM and 8 ml TFA. After concentration under vacuum, the residue was absorbed in ethyl ether, the white precipitate which formed was filtered, washed with ether and then dried under vacuum. 1.15 g expected product fas obtained. Jt.pt. = 176-178 °C.

The IR, iR and mass spectra were identical to those obtained in example IE. Moreover, the Kf measured in CC was identical .

EXAMPLE 3 2-n-butyl-l-[ (2' -carboxybiphenyl-4-yl)methyl] -4-spiro-cyclopsntane-2-imidazolin-5-one trifluroroacetate. Method 3 A) 2-n-butylbenzimidazole was prepared in accord with W.O. POOL (J. Amer. Chem. Sac, 1937, 52., 173) and then 2-n-butyl-4, 5,6,7-tetrahydrobenzimidazole was prepared in accord with ¾. HARTMAiiN and L. PANIZZGK" (Hel. Chim. Acta, 193S, 21, 1692-1694). M. pt. = 145'C.

MR spectrum : 0.82 ppm : t : 3 H : C¾ (nBu) 1.23 ppm : sext : 2 H : CH3-C¾- 1,50 ppm : quint : 2 H : (¾-(¾-(¾- I.65 ppm : s : 4 H : H5, ¾ (tetrahydrobenzimidazol). 2.35 ppm : s; 4 H : ¾, H7 (tetrahydrobenzimidazol). 2.45 ppm : t : 2 H : CH3-CH2-CH2-CH2- II.1 ppm : m : NH mass spectrum : M* : 178 B) 2-n-butyl-4-spirocyclopentane-l-[ (2* iert-butoxycarbonyl- biphenyl-4-yl ) methyl] -2-imidazolin-5-ane. 1 g product prepared in the preceding stage was dissolved in 45 ml DKF with 303 mg sodium methylate and a few mg methylene blue. Oxygen was bubbled into the reaction medium which was illuminated with a UV lamp. After 15 minutes, 2.14 g 4-bromamsthyl-2' -teri-butoxycarbanylbiphenyl was added and then, after 1 hour, the reaction medium was taken up with 300 ml ethyl acetate containing 50 ml water and 5 ml saturated sodium bicarbonate solution. The organic phase was then washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel. by eluting with an ethyl acetate/toluene mixture (1/2 ; v/v) . 610 mg expected product which crystallized was obtained. M. pt. = 62-65'C.

The IR, MR and mass spectra as well as the Rf were identical to those obtained previously for the same compound. C) 2-n-butyl-l-C (2' -carboxybiphenyl -4-yl ) methyl] -4-spiro-cyclopentane-2-imidazol in-5-one trif luoroacetate .

This compound was obtained by treatment in acid medium as described in the last stage of example 1 and example 2. The physicochemical data are identical to those obtained for the same compound prepared using methods i or 2.

EXAMPLE 4 2-n-butyl-4 , 4-dimethyl-l-[ (2' - teri-butoxycarbonyl-biphenyl-4-yl ) methyl] -2-imidazol i -5-one .' and 2-n-butyl-l-t (2 ' -carboxybiphenyl-4-yl ) methyl] - , 4-dimethyl-2-imidazolin-5-one trifluoroacetate. Method 1.

The ethyl ester of alpha-aminoisobutyric acid was prepared according to R. Jacquier et al. (Bull. Sac. Chim. , France, 1971, (3), 1040-1051). 650 mg of this compound and 780 mg ethyl valerimidate were dissolved in 8 ml xylene containing 4 drops of acetic acid and heated under reflux for 7 hours. The reaction medium was then concentrated under vacuum and the residue chromatographed on silica gel by eluting with a chloroform/methanol/acetic acid mixture (95/5/2 ; v/v/v). After several evaporations of xylene and then of benzene, to remove the acetic acid, 560 mg expected product which crystallized were obtained. M. pt . = 35-38 'C.

IS (CHC13) 1725 cm-1 . c = 0 1635 cm-1 : C = N ITote: the absence of a signal between 1500 and 1600 cm-' confirms that the compound present in chloroform solution was a 2-imidazolin-5-one.

MR spectrum : 0.92 ppm : t : 3 H : CH3 (nBu) 1.20 ppm : s : 6 H : C (CH3)2 1.38 ppm : sext : 2 H : CH3-CH2 1,63 ppm : quint : 2 H : CH3-CH2-CH2- 2.38 ppm : t : 2 H : CH -CH2-CH2-CH2- 10,7 ppm : m : 1 H : N-H mass spectrum : MH" : .169 3) 2-n-butyl-4, 4-dimethyl-l-C (2' - teri-butoxycarbanylbiphenyl-4- yl ) methyl-2-imidazolin-5-cne. 520 mg product prepared in the preceding stage were dissolved in 10 ml DKF. 167 mg sodium methylate was added and stirred for 15 minutes under nitrogen. Then 1.25 g 4-bromomethyl-2' -tert-butoxycarbonylbiphenyl was added and the mix was stirred for 3·; hours at 40"C. The reaction medium was taken up with 150 ml ethyl acetate and then 20 ml water and 2 ml saturated sodium bicarbonate solution. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1.2/2 ; v/v). 570 mg expected product which crystallized were obtained. M.pt. = 98-100 .

IE (CHCLs) : 1710-1720 cm-l : C = 0, C = 0 (imidazolinone, ester) 1625 cra-i : C = N N R spectrum : 0.78 ppm : t : 3 H : CH3 (nBu) 1.08 ppm : s : 9 H, C(CH3)3 1,15 ppm : s : C (CH3)2 and !l ,20 ppm : sext : CH3-CH2- ) 8 H 1.45 ppm : quint : 2 H : CH3-CH2-CH2- 2.30 ppm : t : 2 H : CH3-CH2-CH2-CH~2- 4.65 ppm : s : 2 H : CH2-C6H4- 7,15-7.65 ppm : m : 5 H : aromatic H A Nuclear Overhauser Effect study confirmed the position of the 5-one and 4,4-dimethyl substitutions on the imdazolinone mass spectrum : MH* : 435 C) 2-n-butyi-l-t (2 ' -carboxybiphenyl-4-yl )methyl3 -4 ^~o¾nethyl-2-imidazalin-5-one trifluoroacetate. 460 mg product ' repared in the preceding stage were treated with 3 ml DCK and 4 ml TFA for 45 minutes. After concentration under vacuum, the residue was taken up with ether and the precipitate which formed was filtered, washed with ether and then dried under vacuum. 450 mg expected product were obtained in the form of a white solid. H.pt. = 163-171 'C.

NMR spectrum : 0.82 ppm : t : 3 H : CH3 (nBu) 1.55 ppm : quint : 2 H : CH3-CH2-CH2- 2.62 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.82 ppm : s : 2 H : CHj-CeH*- 7.20 - 7.75 ppm : m : 3H aromatic mass spectrum : HH* : 379 EXAMPLE 5 1-t (21 -cyanobiphenyl-4-yl) methyl] -2-n-butyl-4- spiracyclopentane-2-imidazolin-5-one and 2-n-butyl-4-spirocyclopentane-l-- (2'-(5-tetrazolyl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Method 1.

A) 1-C (2' -cyanobiphenyl-4-yl )methyl] -2n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one.

A mixture containing 250 mg 1 sodium hydride (an 30% dispersion in mineral oil) and 5 ml D F was prepared under an atmosphere of nitrogen and a solution containing 0.97 g 2-n-butyl-4—spiracyclopentane-2-imidazol in-5-one (prepared as in example 2, stage A) in 10 ml DMF was added dropwise. This was stirred for 30 minutes at TA and then a solution of 1.5 g 4-bro omethyl-2 ' -cyanobiphenyl in 10 ml DMF was added. After stirring for 1 hour at TA, the DMF was evaporated off under reduced pressure and the residue was absorbed in ethyl acetate. The organic phase was washed with water and then dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel by eluting with a DCM/ethyl acetate mixture (9/1 ; v/v). 1.68 g expected product was recovered. M.pt. = 92-93 "C B) 2-n-butyl-4-spirocyclopentane-l-C 2' - (5-t i henylmethyl-tetrazolyl ) biphenyl-4-yl ) methyl] -2-iaidazolin-5-one. 1.56 g preceding product, 2.5 g tributyltin azide and 30 ml xylene were heated under reflux for 66 hours. The xylene was then evaporated off and the residue was dissolved in 20 ml DCM and 5 ml THF, while adding 0.3 ml 1Oil sodium hydroxide and, after 30 minutes stirring, 2.5 g trityl chloride and then the mix was stirred for 25 hours. After evaporating off the solvents, the residue was taken up with ethyl acetate and washed well with a 3% solution of potassium hydrogen sulfate and water. This was dried and evaporated. The residue was chromatographed on alumina by eluting with a hexane/ethyl acetate mixture (9/1 ; v/v). 1.97 g expected product was obtained. M.pt. = 150-152 'C.

C) 2-n-butyl-4-spirocyclopentane-l-[ (2' - (5-tetrazolyl)biphenyl- 4-yl) methyl] -2-iinidazolin-5-one. 1.96 g product prepared in the preceding stage were dissolved in 10 ml methanol and 10 ml THF. After cooling the reaction medium to 5°C, 1.5 ml 4N hydrochloric acid were added and the mix was stirred for 3 hours at TA and 30 *C. After evaporation of the solvents, the residue was taken up with water and adjusted to pH 12 by adding 101 sodium hydroxide. The aqueous phase was extracted with ether, toluene and then ether again. The aqueous phase was acidified to pH 2 by the addition of IN hydrochloric acid and then extracted into ethyl acetate, dried and evaporated.

The white solid which was obtained was dried at 50*C under a reduced pressure of 0.05 mm mercury. 840 mg expected product was obtained. 3i.pt. = 180-151 *C.

ME spectrum : 0.75 ppm : t : 3 H : CH3 (nBu) 1.10 ppm : sext : 2 H : CH3-C¾- 1,20 ppm : quint : 2 H : CH3-CH2-CH2- .1,5-2 ppm : m : 8 H : -C5Hg 2,2 ppm : t : 2 H : CH3-CH2-CH2-CH2- 4.6 ppm : s : 2H : CH2-C6H4- 7 ppm : s : 4 H : CH2-C6H4" 7.35-7.7 ppm : m : 4H : 3' , 4' , 5' , 6' H aromatic A Nuclear Overhauser Effect study confirmed the position of the 5-one substitution an the imidazole.

D) Potassium salt of 2-n-butyl-4-spirocyclopentane-l-C <2' - (5-tetrazol l )biphenyl-4-yl ) methyl] -2-imidazoli -5-one. 970 mg of the compound obtained in the preceding stage were dissolved in 40 ml of an isopropanol-methanol mixture (1/1 ; v/v) and the pH was adjusted to pH 12 by adding an 85% potassium hydroxide solution in a ethanol-water mixture (20/1 ; v/v). This was evaporated, the residue was taken up with isopropanol and evaporated again. The residue was dissolved in 20 ml isopropanol by heating gently and then left to return to ambient temperature. The mix was decanted, the filtrate evaporated and then the residue taken up with heptane. After grinding up, the product solidified. It was filtered off, washed again with heptane and dried under vacuum. 945 mg of the expected potassium salt was obtained. M.pt. 142-144 .

Elemental analysis: 'C25H27K.isO.H2O calc: : C : 61.95 H : 6,03 N : 17.34 found: X 62.02 6,13 17.14 EXAMPLE 6 2-n-butyl-l-C (2' -carboxybiphenyl-4-yl)methyl] -4-(4-spirotetrahydropyran)-2-imida2olin-5-one trifluoroacetate. and 2-n-butyl-4- (4-spirotetrahydropyran)-l-[ (2' - tert-butoxy-carbonyI)biphenyl-4-yl)methyl]-2-imidazolin-5-one. Method 2.

A) 4-amino-tetrahydropyran-4-carboxylic acid was prepared starting from tetrahydropyran-4-one in accord with the method described in the German patent DE - 2 215 721.

B) 4- (N-ben2ylo:cycarbonylamino)-4-carboxy-tetrahydropyran. 1.015 g compound from stage A was placed in 12 ml water and treated at 10°C with 1.22 ml diisopropylethylamine and then 3.33 g LT- (ben2yloxycarbonyloxy)succinimide dissolved in 12 ml acetonitrile. After 1¼ hours, the reaction medium was diluted with 70 ml ethyl acetate and 10 ml water and adjusted to pH 2 using a saturated solution of potassium bisulfate.

After decanting, the organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated under vacuum. The residue was diluted in 60 ml ether and then 7 mmole dicycohexylamine was added. The precipitate which formed was filtered and washed with ether. It was then dissolved in a mixture of ethyl acetate and water and adjusted to pH 1.5 with a saturated solution of potassium bisulfate. The organic phase was decanted off, washed with a saturated solution of sodium chloride, evaporated under vacuum and 1.9 g of a white solid was obtained. M.pt. 110-115Τ.

C) ϋ-C (2'-tert-butaxycarbonylbiphenyl-4-yl)methyl]-4-(lI-benzyloxycarbonylamino)-tetrahydropyran-4-carboxamide. 850 mg of the compound prepared in stage B were dissolved in 15 ml DMF and equimolar amounts of 4-aminoethyl-(2' - tert-butoxycarbonyDbiphenyl, DIPEA and BOP (10% excess) were added. After 40 minutes, the medium was taken up with !200 ml ethyl acetate and 200 ml water. The organic phase was decanted and washed twice with a saturated solution of sodium bicarbonate and then once with a saturated solution of sodium chloride.

After drying over sodium sulfate, the organic phase was evaporated off under vacuum. 1.8 g expected product was obtained.

I)) 4-N-E (2' - tert-butoxycarbonylbiphenyl-4-yl ) methyl] -4-amino-tet ahydropyran-4-carboxamide.

The product obtained in stage C was dissolved in 30 ml methanol. 400 mg 10% palladium on charcoal were added and hydrogen was passed through at atmospheric pressure. After 1 hour, the catalyst was filtered off and the filtrate was concentrated under vacuum. The residue was chromatographed on silica by eluting with an ethyl acetate/methanol/33% ammonia solution mixture (99/1/0.5 ; v/v/v). 0.93 g expected product was obtained in the form of a white solid. X.pt. = 125-127°C.

MR spectrum : 8.50 ppra : t : 1 H : H amide 7.60-7.05 ppm : in : 8 H : H aromatic 4.25 ppm : d : 2 H : CH2 - (¼¾- 3.70-3.50 ppm : m : 4 H : CH2 in 2 and 6 of ^etrahydropyran 2.00-1.80 ppm : m : 4 H : CH2 in 3 and 5 of tetrahydropyran. 1.05 p m : s : 9 H : tBu E) 2-n-butyl-4- (4-spirotetrahydropyran)-l-[ (2' - terr-butoxy-carbonylbiphenyl-4-yl ) methyl! -2-imida2olin-5-one A mixture containing 0.9 g of the compound obtained in stage D, 327 mg methyl orthovalerate and 2 drops of acetic acid were heated for 3 hours at llO'C. The reaction medium was taken up withlOO ml ethyl acetate and then v/ashed with a saturated solution of sodium bicarbonate and a saturated solution of sodium chloride and then dried over sodium sulfate and the ethyl acetate evaporated off. the residue which was obtained was chro atographed on silica by eluting with an ethyl acetate/toluene mixture (2/1 ; v/v). 550 mg expected product was obtained in the form of a wax.

MR spectrum : 7.05-7.60 ppm : m : 8 H : H aromatic 4.63 ppm : s : 2 H : CH2 - C6¾r 3,85-3.55 ppm : m : 4 H, CH2 in 2 and 6 of tetrahydropyran: 2.30 ppm : t : 2 H : CH2 - C3HV 1.05-1.80 ppm : B : 8 H : CH2-CH2-CH2-CH3. and CH2 in 3 and5 of tetrahydropyran. 1.03 ppm : s : 9 H : tBu 0,75 ppm : t : 3 H : (CH2)3-CH3 IB (CHCls) : 1710-1720 cm-l : C = 0, C = 0 1625 cm-i : C = N F) 2-n-butyl-4- (4-spirotetrahydropyran)-l-C <2' - tert-butoxy- carbonylbi henyl-4-yl) ethyl] -2- midazolin-5-one 530 mg of the product obtained in the preceding stage were treated with 4 ml dichloromethane and 5 ml TFA for 45 minutes. After evaporation under vacuum, the residue was taken up with ether, the precipitate which was formed was filtered, washed with ether and then dried under vacuum. 510 mg expected product was obtained. M. pt. 159-162 *C.

MR spectrum : 7.80-7.10 ppm : m : 8 H : H aromatic 4.80 ppm : s : 2 H : C¾ - C6H4- 4.00-3.75 ppm : m : 4 H, CH2 in 2 and6 of tetrahydropyran, 2.60 ppm : t : 2 H : CH2 - C3H7 1.45-2,00 ppm : m : 6 H : CHJ-CHJ-CHJ-CIW. and CH2. in 3 and 5 of tetrahydropyran.. 1.30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 EXAMPLE 7 2-n-butyl-l-[ (2' -car'boxybiphenyl-4-yl ) methyl ] -4-C spiro (1-benzyl-4-piperidine) ] -2-imidazolin-5-one trifluaroacetate. and 2-n-butyl-4-[ spira ( l-benzyl-4-piperidine)7-l-2'-tert-butaxycarbonylbiphenyl-4-yl) methyl1 -2-imidazoli -5-one Method 1.

A) 4-amina-l-benzyl-piperidine -4-carboxylic acid was prepared from -benzypiperid-4-one in accord with the method described in the German patent DE 2 215 721.

E) Ethyl 4-amino-l-benzylpiperidin-4-carboxyiate. 3.80 g of the compound prepared in stage A were added to a solution of 13 g hydrochloric acid in 50 ml ethanol at O'C and then heated under reflux for 5 hours. After concentration under vacuum, the residue was washed with ether and then dissolved in am ether-water mixture to which was added a saturated solution of potassium carbonate until pH 9 was reached. The ethereal phase was decanted, washed with, a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. 3.50 g expected product was obtained in the form of an oil.

MR spectrum : 7.20-7.40 ppm : m : 5 H : H aromatio_.- . 4,10 ppm : q : 2 H : CH2-CH3 3.45 ppm : s : 2 H : CH2 of benzyl. 2.25-2.60 ppm : m : 4 H : CH2 in 2 and6 of piperidine 1.80-2.05 ppm : m : 2 H : ) CH2 in.3 and 5 of piperidine 1.20-1.40 ppm : m : 2 H : j 1,12 ppm : t : 3 H : CH3-CH2- C) 2-n-butyl-4-[ spiro (l-benzyl-4-piperidine) ] -2-imidazolin-5-one Ethyl valerimidate was prepared as in example 2, stage A. 2.06 g ethyl valerimidate, 3.40 g of the compound prepared in stage B and 8 drops of acetic acid, in 15 ml xylene, were mixed and heated under reflux for 6 hours. After concentration under vacuum, the residue was chromatographed on silica gel by eluting with a chloroform/methanol /acetic acid mixture (82/15/3 ; v/v/v). 2.80 g expected product was obtained after extraction with chloroform at pH 9 to remove acetic acid. M. pt. 17Q-172°C.

IE (CHCls) : 1725 cm-1 C = 0 1640 cm-» C = N !T S spectrum : 7.10-7.30 ppm : m : 5 H : H aromatic 3,45 ppm : s : 2 H : -CH2-C6H5 1.10-2.75 ppm : 5 m, 14 H : CH2 dr. 2,3,5,6 of piperidine aid (C¾)3-CH3 0.80 ppm : t : 3 H : (CH2)3-CH3 D) 2-n-butyl-4-Cspiro(l-benzyl-4-piperidine)]-l-[ (2*-tert-butoxycarbonylbiphenyl-4-yl ) methyl] -2-imidazalin-5-one 513 g sodium ethylate were added to 2.78 g of the compound prepared in stage C dissolved in 25 ml DMF, and after 15 minutes, 4.16 g 4-bromomethyl (2* - tert-butoxycarbonyl ) biphenyl were also added. The mixture was heated at 40°C for 5 hours and then the reaction medium war. taken up with 300 ml ethyl acetate, 50 ml water and 5 ml saturated solution of sodium bicarbonate. The organic phase was decanted off washed once with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated under vacuum. The residue was chromatographed on silica by eluting with an ethylacetate/methanol mixture (995/5 ; v/v), 0.98 g expected product was obtained · M.pt. = 103- ioe*c. 1710-1725 cm-i C = 0, C = 0 (imidazoline, ester) 1630 cm-l C = N KMR spectrum : 7.70-7.10 ppm : m : 13 H : H aromatic- 4470 ppm : s : .2 H : (¾-<¼¾- 3,55 ppm : s : 2 H : CH2-C6H5 1,20-2,75 ppm : 5 m : 14 H : CH2 in 2,3,5,6, of the piperidine and (CH2)3-CH3 1.15 ppm : s : 9 H : tBu 0.85 ppm : t : 3 H : (CH2)3-CH3 E> 2-n-butyl-i-C2' carba:cybiphenyl-4-yll -4-[ spira (l-benzyl-4-piperidine) ] -2-imidazolin-o-one trifiuoraacetate. 350 rag of the compound obtained in stage D were dissolved in 4 mi dichloromethane and 5 ml TFA. After 45 minutes, the medium was concentrated under vacuum and the residue taken up with an ether-hexane mixture. The precipitate which was formed was filtered off, washed with ether and dried under vacuum. 350 mg expected product was obtained. M.pt. 198- 200°C.

NMR spectrum : 7.05-7,75 ppm : m : 13 H : H aromati 4.75 ppm : s : 2 H : CH2-C6H4- 4.40 ppm : s : 2 H : 3,20-3,60 ppm : tn : 4 H : CH2 in 2 and 6, of the piperidine 2.35 ppm : t : 2 H : CH2-CH2-CH2-CH3 2.20-1,40 ppm ; 3 unresolved multiplets: CH2 in 3 and 5 of the piperirii.nR and CH2-CH2-CH2- CH3 1.25 ppm : se t : 2 H : CH2-CH2-CH2-CH3 0,80 ppm : t : 3 H : (CH2)3-CH3 EXAMPLE 8 2-n-butyl- 1-i (2 ' carboxybiphenyl-4-yl ) methyl] -4- (4- spiropiperidine)-2-imidazolin-5-ane ditrif luoroacetate. and 2-n-butyl-4-(spiropiperidine)-C (2' - tert-butoxycarbonyl-bipheny 1-4-yl) methyl] -2- imidazol in-5-one A) 2-n-butyl-4 (4-spiropiperidirie) -1-E{2 ' -tert )utoxycarbonyl-biphenyl-4-yl) methyl/ 2-imdazoline-5-one . 300 mg of the compound from example 7, stage D, were dissolved in 10 ml methanol. 180 mg 10% palladium on charcoal were added and hydrogen was passed through for 3 hours at atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under vacuum. 200 mg expected product was obtained.

M spectrum : 7,20-7,75 ppm : m : 8 H : H aromati 4.75 ppm : s : 2 H : (¾-<¼¾- 3,00-1,70 ppm: 3 unresolved multiplets far the 4 CH-, of the piperidine 2,40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.60 ppm : quint : 2 H : CH2-CH_2-CH2-CH3 1,35 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1,20 ppm : s : 9 H : tBu 0,90 ppm : t : 3 H : (CH2)3-CU3 B) 2-n-butyl-l-[ (2' -carbaxybiphenyl-4-yl ) methyj¾_( -.SpirO-' pi eridi e ) -2-imidazal in-5-one ditrif luoroacetate. • 160 mg product obtained in stage A were stirred in 3 ml dichloromethane and 4 ml trif luoroacetic acid for 45 minutes.

This was concentrated under vacuum and the residue was taken up with /ether. A gum was obtained which turned into a foam after drying under vacuum (150 mg). M/pt. 80-85°C.

MR spectrum : 7.15-7,80 ppm : m : 8 H : aromati'C H 3.20-1,60 ppm : 3 unresolved multiplets for the 4 ΰή^ of the p4^dirie 2.40 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.50 ppm : quint : 2 H : CH2-CH2-CH2-CH3 "1*30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0*80 ppm : t : 3 H : (CH2)3-CH3 . 2-n-butyl-l-[ (2 ' carboxybiphenyl-4-yl ) methyl J -4 , 4-diphenyl-2-imidazclin-5-one trifluoroacetate and 2-n-butyl-4, 4-diphenyl-l-t (2' - tert-butoxycarbanylbiphenyl-4-yUmethyll -2-imidazalin-5-ane. Method 1.

A) Valerimidine hydrochloride 6 g ethyl valerimidate hydrochloride were added to a solution of 6.75 g ammonia in 80 ml methanol at O'C. After 18 hrs, the reaction medium was concentrated under vacuum and the expected product was obtained in the form a of a white solid.

B) 2-n-but l-4, 4-diphenyl-2-imidazolin-5-one This compound was prepared in accord with the working method described by J. NYITSAI and K. LEKPEET in Tetrahedron, 1969, 25., 4265-4267, starting with benzil and valerimidine hydrochloride. M. pt. = 135 .

IE (CHCls) : 1725 cm-' C = 0 1640 cm-' C = N R spectrum : 7.20-7,50 ppm : m : 10 H : H aromati 2,50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1,65 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1,35 ppm : sext : 2 H : 0,90 ppm : t : 3 H : CH2-CH2-CH2-CH3 11 ppm : s.e. : NH C) 2-n-butyl-4, 4-diphenyl-l-[ (2' - tert-butoxycarbonylbiphenyl-4-yl ) methyl ] -2-imidazoli -5-one This compound was prepared in accord with the usual procedure by the reaction of 4-bromomethyl-2' - tert-butoxy -carbonylbiphenyl on the compound prepared in stage B in DMF in the presence of sodium methylate.

IE (CHCla) : 1715-1725 cm-1 C = 0, C = 0 (ester, iraidazolinone) 1635 cm-1 C = OR spectrum : 7.25-7,80 ppm : m : 18 H : H aromatic 4.85 ppm : s : 2 H : N-CH2-C6H4- 2,60 ppm : t : 2 H : CH2-CH2-CH2-CH3 1,75 ppm : quint : 2 H : CH2-CH2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1.15 ppm : s : 9 H : tBu 0.90 ppm : t : 3 H : CH3 of' n-butyl D) 2-n-butyl-l-[ 2' -carbaxybiphenyl-4-yl)methyl]-4, 4~diphenyl-2-imidazoli -5-ane trifluaroacetate. 500 Eg of the product prepared in stage C were treated with 2.5 HI dichlaromethane and 2.5 ml triflucroacetic acid at 20 *C, for 20 minutes. After concentration under vacuum, the residue was taken up v/ith an ether-hexane mixture, the precipitate which formed was filtered, washed with hexane and dried. 440 mg expected product was obtained. H.pt. = 55-60 °C.

JittR spectrum: 7.15-7,80 ppm : m : 18 H : H aromatic 4,85 ppm : s : 2 H : N-CH2-C6H4- 2,60 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.70 ppm : quint : 2 H : (¾-(¾-(-¾-(¾ 1,40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0,90 ppm : t : 3 H : CH30f ¾ utyl EXAMPLE 10 2-n-butyl-3-[ (2 ' -carbaxybiphenyl-4-yl ) methyl ] -6-spirocyclapentane-5,6-dihydro-l-H-pyrimid-4-one trifluroacetate. A) C) 2-n-cut i-6-spirocyciapantans-5, 6-dihydro-i-H-pyrimidin-4-ons.

A mixture containing 310 mg of the compound obtained in stage Ξ, 243 mg ethyl valerimidats, 10 ml xylene and 6 drops of acetic acid were heated under reflux. After 2 hours and 13 hours, another 343 mg ethyl vaierimidate were added, and after.24 hours total under reflux the reaction medium was evaporated down and then chrcmatagraphed an silica by eiuting with a DC}!/ ethanol mixture (97/3 ; v/v). 153 mg expected product was obtained.

D) 2-n-butyl-6-spirocyclopentane-3- [ (21 -tert-butoxy- carbonylbiphenyl-4-yl) -methyl] -4 (1H) -5 , 6-dihydro-pyrimidin-4-one .

A mixture of 10 ml D¾F and 40 mg sodium hydride as an 30% mix in oil was prepared under an atmosphere of nitrogen. 144 mg of the compound prepared in stags C, dissolved in 5 ml DKF, were added slowly, dropwisa, at ambient temperature. After 30 minutes with stirring, 288 mg 4-broma sthyi-2' - iert- butaxycarbonyibiphenyl dissolved in 5 ml D¾F were added. The nix was left with stirring far 2 hours and then evaporated down, the residue absorbed in water and extracted into ethyl acetate. This was dried over sodium sulfate, filtered and evaporated, then purified by column chromatography by eiuting with a hexane/ethyl acetate mixture (35/5 ; v/v) . 174 mg expected product was obtainsd.

E) 2-n-butyl-3-[ (2' -carboxybiphenyl-4-yl ) methyl ] -6-spiro-cyclopentane-5, 6-dihydro-l-H-pyrimid-4-one trifluoroacetate. 10 ml trifiuoraacetic acid was cooled on an ice-bath and 161 rag of the compound prepared in stage D were added. This was left for 30 minutes with stirring and then evaporated down. The residue was taken up with ethyl ether and then evaporated down again. This operation was repeated | and then the residue was dried under vacuum. 140 mg expected compound was obtined in the form of an amorphous powder. M/.pt. = 10S~115*C. 1MB spectrum : 0.9 ppm : t : 3 H : (CH2)3-CH3 1.1 a 2,1 ppm : m : 12 H : cyclopentaneand^CH2-CH2-CH2-CH3 2,7 ppm : t : 2 H : CH2-CH2-CH2-CH3 3.1 ppm : s : 2 H : -CHj-CO 5.1 ppm : s : 2 H : N-CH2-C6HS 7.2 a 7,8 ppm : m : 8 H : H aromatic. .

EXAMPLE 11 2-n-butyl-4-spirocyclopentane-l-E (2'-tert-butoxycarbonylbiphenyl-4-yl > methyl] -2-imidazolin-5-thione and 2-n-butyl-l-C 2' -carboxybiphenyl-4-yl) methyl] -4-spiro-cyclopentane-2-imida2olin-5-thione A.) 2-n-butyl-4-spirocyclopentane-l-[ <2'-tert-butoxycarbanylbiphenyl-4-yl )methyl3 -2-imidazolin-5-thione 5.63 g of the compound prepared in example 1, stage D, were dissolved in 40 ml anhydrous< toluene and reacted with 3 g of Lawesson's reagent under nitrogen at 80°C. After 6 hours, the reaction medium was filtered and concentrated. The residue was chromatographed on silica by eluting with a DCM/ethylacetate mixture (95/5 ; v/v). The expected product was obtained in the form of an oil which crystallized in the cold, ra = 4.5 g. M. pt. = 77-79'C. 5KR spectrum : 0.90 ppm : t : 3 H : CH3 (n-Bu) 1,20 ppm : s : 9 H : tBu 1.35 ppm : sext : 2 H : CH^-CH2- 1.60 ppm : quint : 2 H : CHj-CH2-CH2- 1,80-2,10 ppm : in : 8 H : cyclopentane 2,60 ppm : t : 2 H : (¾-(¾-(;¾-(¾ 5% 35 ppm : s : 2 H : CHj-Cgft,- 7,25-7,80 ppm : m : 8 H : H aromatic B) 2-n-butyl-l-C (2 ' carboxybiphenyl-4-yl ) methyl] -4-spiro-cyclopentane-2-imidazoli -5-thione trifluoraacetate 225 mg of the compound obtained in stage A were treated with 5 ml DCM and 5 ml TFA for 30 minutes. After concentration, the residue was taken up with ether. The expected compound was obtained in the form of a yellow powder which was centrifuged and then rinsed with hexane. m = 160 mg. K.pt. = 185-190'C.

ME spectrum : Mass spectrum : MH+ : 421 0478 ppm : t : 3 H : CH3 (n-Bu) 1,20 ppm : sext : 2 H : CH3-CH2 1,50 ppm : quint : 2 H : CH3-CH2-CH2- 1^75-2,00 ppm : m : 8 H : cyclopentane 2,40 ppm : t : 2 H : CH3-CH -CH2-CH2 5.20 ppm : s : 2 H : CH2-C6H4- 7.00-7,65 ppm : m : 8 H : H aromatic EXAMPLE 12 2-n-butyl-4- (2-spiroindane)-l-[ (2' - tert-butoxycarbonylbiphenyl-4-yl > methyl] -2-imidazolin-5-one. and 2-n-butyl- 1-[ (2' -carboxybiphenyl-4-yi ) methyl] -4- (2-spiroindane)-2-imidazolin-5-one. Method 1.

A) 2-amino-2-i dane—r—carboxylic acid was prepared in accord with R.M. Pinder, J. Med. Chem. , 1971, 14, 9, 892 and the corresponding ethyl ester was then prepared in accord with Adkins (ref. cited in example 2A).

B) 2-n-butyl-4- (2-spiroindane)-2-imidazolin-5-one 2.78 g of the ethyl ester prepared in stage A and 2.5 g ethyl valerimidate were dissolved in 20 ml xylene ^i the presence of 60 micro-1 acetic acid and heated under reflux for 3 hours. 500 mg ethyl valerimidate were added again and the reflux maintained for 3 additional hours. The reaction medium was concentrated and then chromatographed on silica by eluting with a hexane/ethyl acetate/acetic acid mixture (3/8/0.3 ; v/v/v). The pure fractions were combined and evaporated from toluene. 3.07 g expected product was obtained in the form of a white solid. M. pt. = 148-150'C.

HKR spectrum : 0.90 ppm : t : 3 H : CH3 (n-Bu) 1.2-1,7 ppm : m : 4 H : (¾-(¾-(¾ 2.4 ppm : t : 2 H : CH2-(CH2)2-CH3 2,8-3,2 ppm : q : 4 H : 2CH2 (indane) 4,90 ppm : s, 2 H : CH2-C6H4- 7.2 ppm : m : 4 H : H aromatic.

C) 2-n-butyl-4- <2-spiroindane)-l-C (2' - tert-butoxycarbonyl-biphenyl-4-yl ) ethyl ] -2-imidazolin-5-one .

The compound obtained in the preceding stage was dissolved in 20 ml anhydrous DMF and treated with 450 mg sodium methylate under nitrogen. After 20 minutes at ambient temperature, 3.6 g 4-bromomethyl-2'-tert-bLrtxixycarbonylbiphenyl were added and the mix was left with stirring at 40"C for 6 hours. The reaction medium was concentrated and then the normal washings were carried out and the product was chromatographed on silica by eluting with a dichloromethane/ethyl acetate mixture (95/5 ; v/v). The expected compound was obtained in the form of a foam, (m = 1.84 g) .

NMB spectrum : 0,80 pm : t : 3 H : CH3 n-Bu 1.20 ppm : s : 9 H : tBu 1.20-1.60 ppm : m : 4 H : CH^-CH^-C 2.40 ppm : t : 2 H : CH2-(CH2)2-CH3 2,9-3.3 ppm : q : 4 H : 2CH2 (indane) 4,80 ppm : s : 2 H : N-CH2-C6H4- 7.20-7,80 ppm : m : 12 H : H aromatic D) 2-n-butyl-l-C 2' -carboxybiphenyl-4-yl >methyl] -4-spiroindane-2-imidazolin-5-one trifluoroacetate 1.71 g of the compound obtained in the preceding stage was dissolved in 15 ml DC¾ and treated with 20 ml TFA. After 30 minutes, the reaction medium was concentrated and absorbed in ether. After grinding up, the solid obtained was centrifuged, rinsed with ether and dried. 1.42 g expected product was obtained. ¾. t. = 217-218*C.

M5 spectrum : 0.70 ppm : t : 3 H : C¾ (n-Bu) 1,10-1,50 ppm : m : 4 H : CH2-CH2-CH3 2.30 ppm : t : 2 H : CH2- (CH2)2-CH3 2,8-3.3 ppm : q : 4 H : 2CH2 (indane) 4,70 ppm : s : 2 H : N-CH2-C6H- 7,1-7,7 ppm : m : 12 H : H aromatic Other compounds in accord with the invention have been prepared in accord with one of the methods described above.

They are summarised in table I. The structure of each of these compounds is in accordance with their IIKR spectra.

EXAMPLE 13 2-n-butyl-l-E (2' - (i-imidazolylcarbonyl ) biphenyl-4-yl ) methyl] -4-spir'ccyclopentane-2-imidazoli -5-one CR4R5 = cyclopentane, X = 0) A mixture containing 404 mg of the compound prepared in example 1, stage E, 15 ml THF and 260 mg carbonyldiimidazole was stirred for 72 hours at ambient temperature. The reaction medium was evaporated, taken up with '. ethyl acetate and washed with water and then a solution of sodium chloride. 420 mg product were obtained which were purified by chromatography on silica by eluting with a DCM/ethyl acetate mixture (70/30 ; v/v) to obtain the expected compound. m = 230 mg tt.pt. = 120 *C EXAMPLE 14 2-n-butyl-l-C <2' - (3-cyano-2-methyl-isothioureidomethyl ) bip enyl-4-yl ) methyl 3 -4-spirocyclopentane-2-imidazolin-5-one.

SCH3 (I : Rl = -CH2-NH-C=N-CN, R2 = H, R3 = n-Cz^Hg, CR R5 = cyclopentane, X = 0) A) l-[ (2' -aminomethylbiphenyl-4-yl)methyl3 -2-n-butyl-4-spirocyclopentane-2-imidazalin-5-one.

This compound was obtained by hydrogenation of the compound prepared in example 5. 1 g of the compound prepared in example 5 stage A was placed in 15 ml absolute methanol and 2.3 ml ethanol in the presence of (0.5 g) 5% palladium on charcoal and hydrogen was passed through at ambient temperature for 24 hours. After treatment, 730 mg expected product was obtained in an oily form.

A mixture containing 300 mg compound prepared in the preceding stage and 113 mg .U-cyanimido-S, S-dimethyl- dithiocarbonate in 3 ml ethanol was refluxed for 24 hours.

After the usual treatment, the reaction medium was purified by chromatography on silica by eluting with a DCM/ethyl acetate mixture (50/50 ; v/v/). The expected product was isolated in the form of a white solid. = 307 mg M.pt. = 83°C.

EXAMPLE 15 2-n-butyl-l-[ (2' - (2-cyanoguanidinomethyl )biphenyl-4-yl >methyl] -4-spirocyclopentane-2-imidazolin-5-one NH2 (I : Ri = CH2-NH-C=N-CN, I?2 = H, R3 = n-C^g, CR4R5 = cyclopentane, X = 0) This compound was obtained by starting with the compound prepared in the preceding example. 200 mg of the compound were placed in 10 ml absolute ethanol, saturated with ammonia at about 10°C and then heated in an autoclave at 80°C for 1 night. After concentration of the reaction medium to dryness, chromatography was performed on silica by eluting with a DCM/methanol mixture (95/5 ; v/v>. 130 mg expected product was obtained.

M.pt. = 100°C.

EXAMPLE 16 2-n-butyl-4-spirocyclopentane-l-[ (2* -trif luoromethyl-sulfonylaminobiphenyl-4-yl ) methyl] -2-imidazolin-5-one trifluoro ethylsulfonate (I : l = -NHS02CF3, R2 = H, R3 = n-C4H9, CR4RS = cyclopentane, X = 0) A) 4-methyl-2' -nitrobiphenyl 11.2 g 2-nitrobromobenzene and 15 g 4-iodotoluene were mixed together, heated to 195 *C and left at this temperature with stirring for 3¾ hours. After cooling to ambient temperature, the mix was taken up withDCM and refluxed. The warm solution was filtered on Celite© and then the DCM was evaporated off. m = 6.5 g B.pt. = 80-120°C at 0.2 mm Kg, Πρ24 =1.6042 B) 4-bromomethyl-2' nitrobiphenyl .

A mixture containing 6.5 g 4-methyl-21 -nitrobiphenyl , 5,42 g UBS, 118 mg azo-bis-isobutyronitrile and 500 ml tetrachloro ethane were refluxed. The mix was cooled to O'C, centrifuged, and the filtrate concentrated to obtain 9 g of an oily product which was used as such in the next stage.

C) 2-n-butyl-l-[ (2' -ni trobi hen l- -yl ) ethyl ] -4-spirocyclo-pentane-2-imidazol in-5-one .

A mixture containing 260 mg 80% sodium hydride in 5 ml DMF was made up and 500 mg 2-n-butyl-4-spirocyclcpentane-2-imidazolin-5-cne, prepared as in example 2, stage A was added at ambient temperature and under nitrogen. After 15 minutes with stirring, 901 mg 4-bromommethyl-2' -nitrobiphenyl in 5 ml DKF were added and left for 24 hours with stirring. The reaction medium was concentrated to dryness, and taken up with a water-ethyl acetate mixture. The organic phase was decanted off, dried over sodium sulfate, filtered and then the ethyl acetate evaporated off. The product which was obtained was chromatagraphed o silica by eluting with a DCM/ethyl acetate mixture (9/1 ; v/v). 500 mg expected product was obtained.

D) 1-i (2' aminobiphenyl ~4-yl ) methyl] -2-n-butyl-4-spirocyclo-pentane-2-imidazolin-5-one. 450 mg of product obtained in the preceding stage were placed in 10 ml methanol, in the presence of 5% palladium on charcoal, at ambient temperature, to be hydrogenated. After filtration of the catalyst and evaporation, 240 mg expected product was obtained.

E) 2-n-butyl-4-spirocyclopentane-l-[ <2' -trifluoromethyl- sulfonyla inobi phenyl-4-yl) methyl -2-imidazoli -5-one trif luoromethylsulfonate 225 rag product obtained in the preceding stage and 0.1 ml triethylamine were mixed in 4 ml DCM and to this was added 0.2 ml trif luoromethylsulfonic acid anhydride, under argon, at -78 *C and then left to return to ambient temperature. The reaction medium was washed with water and a solution of sodium bicarbonate and then dried and concentrated. 150 mg of an amorphous white solid was obtained.

EMS spectrum : 0.4-1,3 ppm : m, 7 H : CH3-CH2-CH2- 1,4-2.3 ppm : m, 10 H : Cf^-CI^-CI^-CHj and cyclopentane 4-4.8 ppm : system AB, 2H : N-CH2-C6H4- 7-7.6 ppm : m, 8 H : aromatic. 8.3 ppm : s, 1 H : -NH 10 ppm : s.e. , 1 H : CF3S03H EXAMPLE 17 2-n-b'jtyl-4-spirocyciopentane-l-[ (2' -trifluoromethylsulfan 1ami nomethyl-bi phenyl-4- l ) methyl 3 -2-imidazol in-5-one t if luoromethylsulfonate : R, = CH2NHS02CF3, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0) The preparation took place starting with l-/[(2'-a inc et ylbi phenyl-4-yl ) ethyl 3 -2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, prepared in example 14, stage A. 322 mg of this compound and 0.122 ml triethylamine were placed in 3.4 ml DCM at -70'C and to this was added 0.294 ml trif luoromethylsulfonic acid anhydride. This was allowed to return to ambient temperature, poured into dilute acetic acid and extracted with DCM. The solution was dried over sodium sulfate, filtered and the DCM evaporated off. The residue was chromatographed twice on silica by eluting with DCM/ethyl acetate (95/5 ; v/v, then 99.5/0.5 ; v/v). m = 90 mg was obtained.

M.pt. = 90'C.

ITMR spectrum : 0,4-1,2 ppra : m, 7 H : -CH2-CH2-CH3 1,3-2,45 ppm : m, 10 HZ: and cyclopentane 4,1-5 ppra : m 4 H : Ν-ΓΗ^Η*- and NH-CH2-C6H4- 7.1-7,7 ppm : m, 8 H : H aromatic- 8.4 ppm : s, 1 H : NH EXAMPLE 18 2-n-butyl-l- [ (2 ' - (N-hydroxycarbamoyl) biphenyl-4-yl) methyl] 4-spirocyclopentane-2-imidazolin-5-one (1 : 1?! = -C0-NH0H, R2 = H, R3 = n-C4H9, C¾a5 = cyclopentane, X = 0) The compound prepared in. example 2 was released from its trifiuoroacetic acid salt by taking up this compound with an ethyl acetate-water mixture and by adjusting the pti oi the solution to pH 6 by adding a saturated solution cf sodium bicarbonate. The organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to give the free base in the form of a white solid. 450 ng of this compound were dissolved in chloroform, 860 ml thionyl chloride was added at 0*C and the mix left with stirring at ambient temperature for 2 hours. The solution was concentrated and traces of thionyl chloride removed by azeotropic distillation with toluene. The acid chloride thus obtained was added dropwise to a D F solution containing 200 mg hydroxylamine hydrochloride and 700 micro-i IPEA in 10 ml DKF. After 2 hours at 0*C, the reaction medium was cancentrated and taken up with 100 ml DCtt and 50 ml water. The pH was adjusted to 7 and the organic phase extracted and dried over sodium sulfate. After filtration, the solution was concentrated. . The product obtained was recrystallized from an ethyl acetate/ethyl ether/hexane mixture. m = 360 mg Jt.pt. = 85*C.

EXAMPLE 19 2-n-butyl-4-spirocyclopentane-l-[ (2' -ureidobiphenyl-4-yl ) methyl] -2-imidazolin-5-one (I : R, = NHCONH2, R2 = H, R3 = n-C4H9, CR4R5 = cyclopentane, X = 0) This compound was prepared by using the method described by B.B. Kobu et al. in Org. Synth., 1957, 21, 52 starting with l-[ (2'-aminobiphenyl-4-yl ) methyl] -2-n-butyl-4-spirocyclcpentane-2-imidazolin-5-one , prepared in example 14 stage A. 1 g of the latter was dissolved in 50 ml 6N hydrochloric acid and treated with potassium isocyanate for 1 hour at 5'C.

The reaction medium was concentrated,. -';taken up with ethyl acetate, washed with sodium bicarbonate and then with a saturated solution of sodium chloride. After drying over sodium sulfate and filtration, the solution was concentrated and the oil obtained was purified by chromatography on silica by eluting with a DCM/methancl mixture (9/1 ; v/v). ni = 600 mg MR spectrum : 0,85 ppm : t, 3 H : CH2-CH3 1,35 ppm : sext, 2 H : CH2-CH3 1,6 ppm : quint, 2 H : CH2-CH2-CH3 1,7-2 ppm : m, 8 H : cyclopentane 2,45 ppm : t, 2 H : CH2-CH2-CH2-CH3 4,8 ppm : s, 2 H : -CH2-C6H - 6,05 ppm : s, 2 H : NH2 7-8 ppm : m, 9 H : 8 H aromatic + NHC0 EXAMPLES 20 and 21 l-[ (2' -carboxybiphenyl-4-yl)methyl] -2-n-propyl-4-spirocyclo-hexane-2-i idazolin-5-one and l-[ (2' - (N-cyanocarboxyamide)biphenyl ) methyl] -2-n-propyl-4-spiracyclohexane-2-imidazolin-5-one A) ethyl butyrimidate hydrochloride NH , HC1 CH3 - CH2 - CH2 - C OC2H5 This compound was prepared in accord with McElvain (J. Amer. Chem. Soc. , 1942, SI, 1825-1827). 23 ml ■ butyronitrile were added -to a solution of 10.6 g gaseous hydrogen chloride in 20 ml anhydrous ethanol and left for 4 days at O'C. Then the mixture was poured, with stirring, into 200 ml anhydrous ether at O'C. The precipitate which formed was filtered, washed with ether and then dried under vacuum. 25.8 g expected product was obtained.

B) Ethyl butyrimidate 16 g imidate obtained in stage A were dissolved in 100 ml dichloromethane and 50 ml water and 15 g potassium carbonate were added. After decanting, the dichloromethane was dried over potassium carbonate and then evaporated to dryness without being heated.

C) The eth l ester of l-arrdnocyclohexane carboxylic 1- aminocyclohexane carboxylic acid is available ccnniercially. 15 g of this aminoacid were added to a solution of 23 g gaseous hydrogen chloride in 150 ml anhydrous ethanol at O'C. This was heated under reflux for 5 hours, then the reaction medium was concentrated to dryness and absorbed in ether. The white solid which was obtained was filtered, washed with ether and then dissolved in a mixture of 300 ml ether and 100 ml water. A solution of potassium carbonate was added to adjust the pH to 9.

The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. 14 g expected product was obtained in the form of an oil.

D) 2-n-propyl-4-spirocyclohexane-2-i idazolin-5-one 14 g of the product obtained in stage C were dissolved in 200 ml xylene containing 0.6 ml acetic acid. Half the imidate obtained in stage B was added and the mix was heated under reflux. After 1¾ hours, half of the remaining imidate was added and then the last quarter was added after 4 hours. After a total of 7 hours refluxing, the medium was evaporated to. dryness. The solid which was obtained was taken up with /hexane , filtered, washed in ether and then dried. 10.3 g expected iniidazolirione was obtained.

M.pt. .= 124-125°C.

IE (CKC13> : 1715 cm-i : C = 0 1635 cm-i : C = N ffote : The compound present in solution is actually an imidazolin-5-one, from the positions of the IE bands.

E) 2-n-propyl-4-spiracyclohexane-l-[ (2* - tert-butoxycarbonyl-biphenyl-4-yl) methyl] -2-i idazQlin-5-one 970 mg i dazolinone obtained in stage D was added to .24 g of 80% sodium hydride in oil in suspension in 10 ml dimethylformamide. After stirring for 20 minutes, 1.91 g 4-bromomethyl-2' - tert-butoxycarbonylbiphenyl , prepared ac cnrding to European patent 324 377, was added over 5 minutes. After 1 hour's stirring, the medium was concetrated under vaccum and half was taken up with 100 mi ethyl acetate and then in 20 ml water. The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue was chromatographed on silica by eluting with an ethyl acetate/toluene mixture. 2.10 g expected product was obtained in the form of a wax.

IB (CHCls) : 1705-1715 cm-i : C = 0, C = 0 (ester, imidazolinone) 1635 cm-l : C = N Analysis of the MR spectrum confirmed the structure.

F) l-[ (2' -carboxybiphenyl-4-yl) methyl] -l-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Example 20). 1.25 g tertiarybutyl ester obtained in stage E were stirred for 45 minutes in a mixture of 11 ml dichloromethane and 15 ml trifluoroacetic acid. After concentration under vacuum, the residue was taken up with ether. The solid which farmed was filtered, washed with ether and then dried. 1.04 g of white soid was obtained.

M.pt. = 170-i72"C.

ME spectrum : 7,10-7,80 ppm : m, 8 H : aromat^ 4,90 ppm : s, 2 H : N-CH2-C6H4- 2,45 ppm : t, 2 H : CH3-CH2-CH2- 1,40-1,80 ppm : m, 12 H : spirocyclohexane + C¾-CH2-CH2- 0,90 ppm : t, 3 H : CH3-CH2-CH2- 1.60 g trifluoroacetate obtained as above were dissolved in 150 ml ethyl acetate plus 20 ml water. IN sodium hydroxide solution was added to obtain pH 5. The organic phase was decanted off, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The residue obtained was absorbed in ethyl ether, filtered and dried. m = 1.14 g M.pt. = 20S-210'C spiracyclohexane-2-imidazolin-5-ane. (Example 21) To 300 mg of compound prepared in the preceding stage, in suspension in 5 ml DCM, were added 0.54 ml thionyl chloride.

After 1¾ hours, the reaction medium was concentrated under vacuum, then evaporated twice from benzene. The acid chloride thus obtained was dissolved in 2 ml dioxan and added to 42 rasr cyanamide in solution in 1 ml dioxan containing 0.2 ml 10N sodium hydroxide solution. After 1¾ hours, the reaction medium was diluted with 150 ml ethyl acetate and 20 ml water and adjusted to pH 5 with acetic acid. The organic phase was decanted, washed with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The residue was chromatographed on silica by eluting with a chloroform/methanol/acetic acid mixture (90/8/2 ; v/v/v). 160 mg expected product was obtained as a solid.

IR(KBr) : 2150 cm-1 : C = N ^ mass spectrum : MH* : 429 MR spectrum : 7,20-7,70 ppm : m, 8 H : aromati 4.75 ppm : s, 2 H : N-CH2-C6H4- 2.40 ppm : t, 2 H : CH3-CH2-CH2- 1,30-1,80 ppm : m, 12 H : CH3-CH2-CH2- and spirocyclohexane 0.85 ppm : t, 3 H : CH3-CH2-CH2 EXAMPLE 22 l-[ (2' - {N- (4-carboxy-l, 3-thiazol-2-yl)acetamide>biphenyl-4-yl ) ethyl] -2-n-propyl-4-spirocyclohexane-2- midazolin-5-one.

N COOH -CONH-ll jj , R2 = H, R3 = n-C3H7, CR4R5 = cyclohexane, X = 0 This compound was prepared from the compound obtained in example 20.

The 2-amina-4-ethoxycarbonyl-l, 3-thiazole was prepared in accord with B. Plouvier et al., J. Heterocycl. Chem. , 1989, 2Ji (6),' 1646.

A) 1-E2'- — (carbethoxy)-l, 3-thiazol-2-yl )3cetamido) biphenyl-4-yl) methyl] -2-n-prapyl-4-spirocyclohexane-2-imidazolin-5-one.

To a solution of 404 mg of compound prepared in example 20 and 190 mg of the thiazole derivative in 4 ml DCM and 1 ml DMF, were added 500 mg BOP and 0.14 ml triethylamine . This was stirred for 40 hours at ambient temperature and then for 7 hours at 50*C. The reaction medium was taken up with 50 ml ethyl acetate and washed twice with a KHSO.-KzSO. solution, then twice with a saturated solution of sodium bicarbonate and then once with a saturated solution of sodium chloride. After drying over sodium sulfate, the organic phase was concentrated under vacuum and the residue was chromatographed on silica by eluting with an ethyl acetate/toluene mixture. 120 mg expected product was obtained, Jt.pt. = 96-98'C.

B) l-[ (2' -{if- (4-carbo:y-l, 3-thiazol-2-yl )acetamide) biphenyl-4-yl > methyl] -2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one.

To 110 mg of product obtained in the preceding stage, dissolved in 1 ml methanol and 1 ml dioxan, was added 0.5 ml 2Έsodium hydroxide solution. \ After 35 minutes stirring, the reaction medium was diluted with 10 ml water and 60 ml ethyl acetate and adjusted to pH 5 by the addition of IN hydrochloric acid. The organic phase was decanted, washed with a saturatedd solution of sodium chloride, dried over sodium sulfate and then concentrated. The residue was taken up with ether, filtered and dried, = 100 ng It. pt. = 145-148'C MS spectrum : 8.0 ppm : s, 1 H : H m 5 of thiazole 7,1-7,7 ppm : m, 8 H : aromatic H ,7 ppm : s, 2 H : N-CH2-C6IV 2.25 ppm : t, 2 H : CH2-CH2-CH3 lt-2-1,8 ppm : m, 12 H : cyclohexane and CH2-CH2-CH3 0„85 ppm : t, 3 H : CH2-CH2-CH3 EXAItPLE 23 2-n-butyl-l-[ <2' - (2-cyanoguanidinocarbonyl )biphenyl-4- yl > ethyl ] -4-spirocyclopentane-2-imidazolin-5-one.

H2 I (I : Rl = CONH-C=N-CN, R2 = H, R3 = n-C/^Hg, CR4R5 = cyclopentane, X = 0) .

The acid chloride of compound A obtained in example 2 was prepared. 1 g of this compound was placed in 20 ml DCM in the presence of 1.8 ml thionyl chloride and stirred at ambient temperature for 2 hours. After concentration of the medium, it was absorbed in benzene and then concentrated again. The crude product which was isolated was then used. It was mixed with 417 mg dicyanodiamide, 0.5 mi ION sodium hydroxide solution, 0.5 ml water and 10 ml dicxan and left with stirring for 5 hours. The reaction medium was taken up with water and ethyl acetate, potassium carbonate was added and then it was concentrated. The residue obtained was chromatographed on silica by eluting with a DCM/ methanol mixture (95/5 ; v/v). 100 g expected product was isolated. ii.pt. = 105'C.

EXAMPLE 24 4-benzyiidene-2-n-butyl-l-[ (2' carboxybi henyl-4-yl ) methyl 3 -2-imidazoli -5-one trif luoroacetate .

(I : Rl = C02H, R2 = H, R3 = n-C4H9, R4R5 = =CH-C6H5, X = 0).

A) 4- (i-benzylidene-l-valeryl mi o-methylamidomethyl ) -2'- biphenyl-terttiutylcarboxylate. n-C4H9-C0-NH- Starting from N-Boc-alpha-dehydro- (L) -phenylalanine, the - 50 - N-carboxyanhydride of alpha-dehydro- (L) -phenylalanine was prepared in accord with R. Jacquier et al. , Tetrahedron Lett., 1984, 25. (26), 2775. To 430 mg of this compound in solution in 5 ml THF, were added 644 mg 4-aminomethyl-2' -biphenyl tertbutylcarboxylate. This was stirred for 2 hours at ambient temperature and then 1 ml methyl orthovalerate was added and the mixture evaporated to ^dryness under vacuum without external heat. The residue was heated for 3 hours at lOO'C, concentrated under vacuum and then chromatographed on silica by eluting with a hexane/ethyl acetate mixture (4/1 ; ν/ν).·· 580 mg of a white solid was obtained.

H. pt. = 154'C MR spectrum : I, 3 ppm : s, 9 H : t-Bu 0,65 ppm : t, 3 H : CH3 (n-Bu) 2 ppm : t, 2 H : CH3-CH2-CH2-CH2-CO 4.4 ppm : d, 1 H : CH2-NH 6,8 ppm : s, 1 H : CH (=CH-C6H5) B) 4-benzylidene-2-n-butyl-l-[ (2' - tert-butoxycarbonylbiphenyl-4- yl ) methyl] -2-imidazolin-5-one 440 mg of compound obtained in stage A were dissolved in 1 ml acetic acid and heated for 30 minutes at lOO'C.

The mix was evaporated to dryness under vacuum and the residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (4/1 ; v/v). 130 mg of expected product was obtained in an oily form.

MS spectrum : 4.9 ppm : s, 2 H : CH2 ( N-CH2-C6H4-) C) 4-benzylidene-2-n-butyl-l-[ (2' carboxybiphenyl-4-yl ) methyl ] -2- imidazolin-5-one trifluoroacetate. 100 mg compound obtained in the preceding stage were dissolved in 1 ml DCM and 1 ml trifluoroacetic acid was added and then left with stirring for 40 minutes at ambient temperature and evaporated under vacuum. The residue was taken up with DCM and then evaporated several times. On the addition of ethyl ether,' a white solid precipitated. m = 101 mg It. pt. = 85*C Mass spectrum : MH* : 439 MR spectrum : 0,82 ppm : t, 3 H : CH3 (n-Bu) 1.3 ppm : sext, 2 H : CH3-CH2- 1.6 ppm : m, 2 H : CH3-CH2-CH2- 2,6 ppm : t, 2 H : CH3-CH2-CH2-CH2- 4.82 ppm : s, 2 H : CH2-C6H4- 7.05 ppm : s, 1 H, =CH-C6H5 7.2-8,2 ppm : m, 13 H : aromatic EXAMPLE 25 4-benzyl idene-l-[ (2' -carboxybiphenyl-4-yl)methyl] -2-phenyl-2-isidazoli -5-one (I : Ri = C02H, R2 = H, R3 = C6H5, 4R5 = =CH-C6H5, X = 0) .

A> 4-benzylidene-2-phenyl-oxazol-5-one. 1.8 g hippuric acid and 0.4 g potassium bicarbonate were dissolved in 4 ml acetic anhydride and heated for a few minutes at 50 *C, than cooled to ambient temperature and 1.49 % benzaldehyde added. After i hour at ambient terperature, 20 mi distilled water at 8Q°C were added. The solid which precipitaed was centrifuged, washed with water and then with ethanol and dried. 1.24 g expected product in the form of a yellow solid was formed.

M.pt. = 215'C.

MR spectrum : 7.4 ppm : s, 1 H : =CH-C6H5 8.1-8-4 ppm : m, 10 H : aromatic B> 4- (l-benzoylainino-l-benzylidene-fflethylamidomethyl)-2,-biphenyl-tert-butylcarboxylate A mixture containing 500 mg of the compound obtained in the preceding stage, 570 mg 4-aminomethyl-2'-biphenyl-tert-butylcarboxiylate and 10 ml pyridine was heated at 110°C for 3 hours. It was then evaporated under vacuum, taken up with chloroform and then evaporated again. The residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (3/1 and then 2/1 ·, v/v). 106 mg expected product was obtained in the form of a yellow solid.

NMR spectrum : 1.1 ppm : s, 9 H : t-Bu 4,35 ppm : t, 2 H : -CH2-NH 7.05-7,06 ppm : m, 19 H : H aromatic + C6HS-CH= 8,65 ppm : t, 1 H : NH-CH2 9.9 ppm : s, 1 H : NH-CH= C) 4-benzylidene-l-[ (2' -carboxybiphenyl-4-yl ) methyl 3 -2-phenyl-2-imidazolin-5-one A mixture of 1.2 g compound obtained in the preceding stage and 1.1 g freshly melted sodium acetate in 5 ml acetic acid were heated under reflux for 6 hours. This was allowed to cool and then an insoluble material was precipitated by the addition of chloroform. The filtrate was evaporated and the residue was chromatographed on silica by eluting with a chloroform/methanol mixture (98/2 ; v/v). The solid which v/as obtained was recrystallized from ethyl ether. m = 692 mg K.pt. = 120 ;::C MR spectrum : 4.95 ppm : s, 2 H : (¾-(¼¾- 7,1-8.3 ppm : m, 19 H : H aromatic + =CH-C6H5 EXAMPLES 26 and 27 2-n-butyl-l-[ (2' -(2-methyltetrazol-5-yl)biphenyl-4-yl) methyl] -4-spirocyclopentane-2-imidazolin-5-one (Example 26) and 2-n-butyl-l-[ (2' - (l-methyltetrazol-5-yl ) biphenyl-4-yl) methyl] -4-spiracyclopentane-2-imida2olin-5-ane (Example 27). 500 mg of the compound prepared in example 5 and 58 mg sodium hydride were mixed in 10 ml DMF and stirred far 30 minutes before adding 179 mg methyl iodide and 2 ml DMF and leaving with stirring at ambient temperature for 4 hours. The reaction medium was concentrated, taken up with^ water- and then extracted with ethyl acetate. This was dried over sodium sulfate, filtered and the solvent evaporated off. The residue was chromatographed on silica by eluting with a hexane/ethyl acetate mixture (6/4 ; v v). 2 fractions were isolated: 90 mg compound in example 26 and 184 mg compound in example 27 MR spectra Example 26 0.7 ppm : t, 3 H : CH3- (n-Bu) 1,2 ppm : sext, 2 H : CH3-CH2- 1,4 ppm : quint, 2 H : CH3-CH2-CH2- 1.5-1,9 ppm : m, 8 H : cyclopentane 2.25 ppm : t, 2 H : CH3-CH2-CH2-CH2- 4,15 ppm : s, 3 H : N-CH3 4.6 ppm : s, 2 H : -N-CH2-C6H4- 7 ppm : system AA', BB*, 4 H : CH2-C6H4- 7.3-7.75 ppm : m, 4 H : CH2-C6H4-C6H4- Example 27 0.7 ppm : t, 3 H : CH3 (n-Bu) 1.15 ppm : sext, 2 H : CH3-CH2- 1,38 ppm : quint, 2 H : CH3-CH2-CH2- 1,5-1,9 ppm : m, 8 H : cyclopentane 2.2 ppm : t, 2 H : CH3-CH2-CH2-CH2- 3.35 ppm : s, 3 H : N-CH3 4.6 ppm : s, 2 H : N-CjfrC^ 7 ppm : systeme AA\ BB\ 4 H : N-CH2-C6H4- 7,4-7.8 ppm : m, 4 H : CH2-C6H -C6H - EXAMPLE 28 2-n-butyl-6-spirocyclopentane-3-[ (2* - (terazcl—-5-yl)biphenyl-4-yl ) methyl] -4 (1Η)-5, 6-dihydropyrimidin-4-one.

A) ethyl cyclopentylidenacetate 6 g of 80% sodium hydride was placed in 40 ml benzene and 57.1 ml ethyl triethylphosphonoacetate were added dropwise at a temperature below 35 °C. After 1 hour at ambient temperature, 24.3 ml cyclopentanone were added dropwise. The mixture was thenheated to 65'C for 15 minutes and then cooled to ambient temperature and the supernatant liquid decanted off. 25 ml benzene were added, heated to 65 *C far 15 minutes, coaled dawn and then the supernatant liquid was recovered. The operation was repeated once more. By evaporation of the liquors, 42 g expected product was obtained and this was distilled. ■ B.pt. = 102°C at 11 mm Hg m = 22.8 g B) (l-aiainccyclopentyl)acetai-ide. 150 ml gaseous ammonia was added to 20 g ethyl cyclopentylideneacetate prepared in the preceding stage and heated to 150'C for 72 hours. The product obtained after evaporation was purified by chromatography on silica by eluting with a DCM/methanol/20% ammonia mixture (90/10/1 ; v/v/v/). The product obtained was dissolved in DC¾ and dried over sodium sulfate. It was then filtered and the DCM evaporated to obtain 7.2 g expected product.

C) 2-n-butyl-6-spirocyclopentane-4 (1Η)-5, 6-di ydropyriinidiri-4--one A mixture containing 4.57 g (1-aminocyclopentyl ) acetamide prepared previously, 25 ml methyl orthovalerate and a few drops of acetic acid was heated for 18 hours at 100 'C.

After evaporation of excess orthovalerate, the residue was taken up with an ethyl acetate/sodium bicarbonate mixture and then- washed with an aqueous solution of sodium chloride, dried aver sodium sulfate and then purified by chromatography an silica by eluting with a DCK/methanol mixture OS/2 ; v/v). a = 5 g iTMR spectrum : 0,75 ppm : t, 3 H : CH3 (nBu) 1.2 ppra : sext, 2 H : CH3-CH2- 1.3-1,8 ppm : ra, 10 H : CH3-CH2-CH2 andcyclopentane 2 ppm.: t, 2 H : CH3-(¾-(:¾-(¾÷ ■ 2.15 ppm : s, 2 H : CH2-C0 9.95 ppm : s.e. , 1 H : NH ...... ■ This compound is that obtained in example 10, stage C.

D) 2-n-butyl-6-spirocyclopentane-3- [ ( 2 ' -triphenylmethyl- tetrazol-5-yl) biphenyl-4-yl-methyl] -4 (1H) -5 , 6-dihydro- pyrimidin-4-one . 327 mg 80% sodium hydride were mixed under nitrogen for 30 minutes in 30 ml DI£F with 1.5 g of the preceding pyrimidinone and 5.27 g 4-bromomsthyl-2' - (triphenylmethyltetrazol-5- yDbiphenyl were added. After 4 hours with stirring at ambient temperature, the solvents were evaporated, the residue was taken up with ethyl acetate and water, dried over sodium sulfate and concentrated. The product obtained was purified by chromatography on silica by eluting with an ethyl acetate/hexane mixture (3/7 ; v/v). m = 3.2 g E) 2-n-butyl-6-spirccyclopentane-3-C (2 ' - (tetr azol-5-yl )biphenyl- 4-yl ) ethyll - (lH)-5, 6-dihydropyrimidin-4-one. 3 g of the compound obtained in the preceding stage were placed in methanol and cooled on a water-ice bath, 2.2 ml 41T HC1 were added and left for 5 hours at ambient temperature. After evaporation the residue was taken up with ethyl acetate and water and sodiim hydroxide solution was added until the pH reached 11. The mixture was decanted and the aqueous phase washed with ethyl ether and toluene and then again with ether. This phase was adjusted to pH 5 by the addition of dilute hydrochloric acid and then extracted with ethyl acetate, dried and concentrated. The product obtained was purified on silica by eluting with a DCM/methanol mixture (95/5 ; v/v). 800 mg expected product was obtained.

MR spectrum : 0,85 ppm : t, 3 H : C¾ (nBu) 1»30 ppm : sext, 2 H : CH3-CH2 1.40-1,95 ppm : m, 10 H : cyclopentane and CH2-CH2-CH2-CH3 2.30 ppm : t, 2 H : CH2-CH2-CH2-CH3 2,55 ppm : s, 2 H : CH2-C0 4,95 ppm : s, 2 H : N-CH2-C6H4- 7,05 ppm : m, 4 H : CH2-C6H4- 7,55-7,82 ppm : m, 4 H : CH2-C6H4-C6H4- EXAttPLE 29 2-n-butyl-3-[ (2' -carboxybiphenyl-4-yl ) methyl] -5-spiracyclopentane-5 (lH)-5, 6-dihydrop yrimidine -4-one trifluoroacetate A) ethyl 1-cyanocyclopentanecarboxylate This compound was prepared in accord with Helv. Chi . Acta, 1952, 35. <7>, 2561. 9.2 g sodium were dissolved in 200 ml absolute ethanol. Half of the solution of sodium ethylate formed was poured into an ampoule. To the remainder were added 24.88 g ethyl cyanoacetate and the mixture was refluxed.

Into another ampoule were poured 43.19 g 1,4-dibromobutane and then the sodium ethylate and 1, -dibromobutane were added simultaneously and dropwise to the reaction medium. When the addition had finished, reflux was maintained for 2 hours. Then it was evaporated, taken up with a ethyl ether -water mixture, washed with a saturated solution of sodium chloride and then dried. The product obtained distilled at 115-12CTC at 11 mm Hg. m = 24 g.

B) ethyl 1-aminomethylcyclopentanecarboxylate This compound was prepared by catalytic hydrogenation of the ethyl 1-cyanocyclapentanecarboxylate. s 20 g of t e ethyl 1- cyamcyclopentenecarboxylate were placed in 200 ml ethanol v/ith 10% ammonia and hydrogenated for 72 hours at 60 'C under a pressure of 100 bars in the presence of rhodium on alumina. After filtration on Cellite®, and evaporation, the residue was chromatographed on silica by eluting with a DCM/ ethanol/20% ammonia mixture (98/2/0.5 ; v/v/v). m = 12.8 g C) 2-n-butyl-5-spirocyclopentane-4 (1Η)-5, 6-dihydropyrimidin-4-one .

A mixture containing 13.12 g of the compound obtained in the preceding stage and 13.5 g ethyl valeri idate in 100 ml xylene containing a few drops of acetic acid was refluxed for 13 hours. The reaction medium was evaporated, taken up with ethyl acetate and a 10% sodium carbonate solution and then dried and concentrated. m = 14 g.

K. pt . = 89-91 NMH spectrum : 0,80 ppm : t, 3 H : CH3 (nBu) 1.10-1,80 ppm : m, 12 H : CH3-CH2-CH - and cyclopentane 2,05 ppm : t, 2 H : CH3-CH2-CH2-CH2- 3,20 ppm : s, 2 H : CH2 (pyrimidinone) 10 ppm : 1 H, s : NH-CO D) 2-n-butyl-5-spirocyclapentane-3-[ (2' - tert-butoxycarbonyl biphenyl-4-yl ) methyl] -5, 6-dihydropyrimidin-4-one. 500 mg of product obtained in the preceding stage were placed in 40 ml DMF, in the presence of 115 mg of 80% sodium hydride in oil, under argon, and stirred at ambient temperature for half an hour. 1.08 g 4-bromomethyl-2' - tert-butoxy carbonylbiphenyl were added and the mix was stirred for another 2 hours. After evaporation, the residue was absorbed in an ethyl acetate - water mixture, washed with a saturated solution of sodium chloride, concentrated and chromatographed on silica by eluting with an ethyl acetate/hexane mixture (3/7 ; v/v) . m = 280 mg E) 2-n-butyl-3-C (2 ' -carboxybiphenyl-4-yl ) methyl] -5-spirocyclopentane-5 (lH)-5, 6-dihydropryrimidin-4-one trifluoroacetate 250 ml of the tertiarybutyi ester prepared in the preceding stage were dissolved in 10 ml DCM. This was cooled in an iced water bath and then 5 ml cold trifluoroacetic acid wereadded and left for one hour with stirring in the cold, then for 1 hour at ambient temperature. The mix was evaporated under reduced pressure. The residue was taken up with ethyl ether and then evaporated. The operation was repeated 3 times and then 1 the residue from evaporation was taken up with j e ane, ground up and the hexane decanted. The product was taken up with ethyl ether and the precipitate was filtered, m = 190 mg H. pt. = 153-155 °C MR spectrum : 0.85 ppm : t, 3 H : CH3 (nBu) I.35 ppm : sext, 2 H : CH3-CH2- 1,45-2,20 ppm : m, 10 H : CH3-CH2-CH2- and cyclopentane 2,80 ppm : t, 2 H : CH3-CH2-CH2-CH2- 3.80 ppm : s, 2 H : CH2 (pyrimidinone) 5.15 ppm : s, 2 H : N-CH2- 7,25 ppm : m, 8 H : aromatic Table 1 R4 : (41) : tetrazolyl-5 : n-C Hg : cyclohexane - : 130 : : (42) : tetrazolyl-5 : n-C3H7 : cyclohexane : — : 141 : : (43) : C02H : cyclopen : cyclopentane : TFA : 82-88 : : -tyl : (44) : CO2H : n-C5Hn : cyclopentane : TFA : 151 : : (45) CO2H : CH2-C6H5 : cyclopentane : TFA : 88 : : (46) : CO2H : H : cyclopentane : 230 : : (47) : CO2H : n-C_ H9 : cyclobutane : TFA : 178 : (48) C02H : n-C H9 : cyclododecane : TFA : 130-135 : (49) CO2H n-C4H9 adamantane-2 TFA 164-166 : (50) CO2H n-C Hg (phenyl-4) TFA 155-157 : cyclohexane (51) : CO2H n-C4Hg : (methyl-4) TFA . 198-200 : cyclohexane : q0 -q¾ : : (52) : CO2H : n-C4Hg : (N-acetyl) : TFA : piperidine-4 : (53) : C02H : C3F7 : cyclopentane : — : 141-143 : : — : 207-209 : : 105 These compounds have an asymmetric carbon atom and were isolate the form of a mixture of optical isomers

Claims (1)

1. 97612/2 CLAIMS : 1- A compound of formula: in which: R1 and R2 are alike or different and each independently represents hydrogen or a group selected from a C^-Cg alkyl, 20. III.91 a C1-C^ alkoxy, amino, aminomethy1 , carboxy, an alkoxycarbonyl in which the alkoxy is a C^C^ alkoxy, cyano, tetrazolyl, methyltetrazolyl , methylsulfonylamino , 20. III.91 trifluoromethylsulfonylamino, trifluoromethylsulfonylaminomethyl , N-cyano-acetamide, N- 20. III.91 hydroxy-acetamide , N- ( 4-carboxy-l , 3-thiazol-2-yl ) acetamide , ureido , 2-cyano-guanidinocarbonyl , 2-cyano-guanidinomethyl , imidazol-l-yl-carbonyl , 3-cyano-2-methyl-isothioureidomethyl , "with the proviso that at least one of the substituents R-L or R2 is different from hydrogen; - R3 is a hydrogen, a C'__-Ce alkyl which is unsubsti- 20. III.91 tuted or substituted by one or more halogen atoms, a C2-C≤ aikenyi, a C3-C_. cycloalkyl, a phenyl, a -phenylalkyl in which the alkyl is ^-C^ , or a phenyl- alkenyl in which the alkenyl is z-C , said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C -CA alkyl, a 20. III.91 " C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl , a hydroxy1 or a C1-C4 alkoxy; R and R5 each independently represents a Q-Q alkyl, a phenyl or a phenylalkyl in which the alkyl is C1-C3, said alkyl, phenyl and phenylalkyl groups being un substituted or substituted by one or more halogen 20. III.91 atoms or by a group selected from a C^-CA perfluoro- alkyl , a hydroxyl and a alXoxy; or RA and Rs together form a group of the formula in which R is hydrogen, a C1-C1 alkyl or a 20. III.91 phenyl and Re is a C^C^ alkyl or a phenyl; Lor else 4 and .Rs together are either a group of the formula in which Y is either an oxygen atom, or a sulfur atom, or a carbon atom substituted by a C1-C4 20. III.91 alkyl' group, a phenyl or a phenylalkyl in which the alkyl is C._-C3, or a group N-Re / in which Rs is a hydrogen, a C^-C^ alkyl, a phenylalkyl in which the alkyl is C^-C., a C^-C^ alkylcarbonyl , a C,_-C4 halo- 20. III.91 genoalkylcarbonyl, a C,-C4 polyhalogenoalkylcarbonyl , 20. III.91 a benzoyl, an alpha-aminoacyl or an N-protecting group, or RA and Rs., together with the carbon atom to which they are bonded, form an indane or an adaman- tane; — p ÷ q = m ; 0. III.91 — n is an integer between 2 and 11 ; or n = 7 to 11 — Ki is an integer between 2 and 5 ; — X is an oxygen atom or sulfur atom; and 20. III.91 — 2 and _t are zero or one is zero and the other is one ; for t=1, z=0 and its salts. A compound as claimed in claim 1 in which. S, is in the artho position and represents a carboxy or tetrazolyl group and R2 is hydrogen. A compound as claimed in any one of claims 1 or 2 in which and Rs linked together constitute with the carbon to which they are banded a cyclopentane or a cylcohexane. A compound as claimed in any one of claims 1 to 3 in which is a straight-chain C-.-Ce alkyl group. A compound as claimed in any one of claims 1 to 4 in which X is oxygen. A compound as claimed in any one of claims 1 to 5 in which z = t = 0.· A compound as claimed in claim 1 in which it is 2-n-butyl-4-spirocyclcpe tane-l-E (2' - (5-tetrazolyl )biphenyl-4-vl ) methyl ] ~2-inidazal in-5-one A method for the preparation of a compound (I) as claimed in any one of claims 1 to 7 -comprising : al) reacting a heterocyclic derivative of formula : in which z , t, RS) R_ and Rs have the meanings indicated for (I) in claim 1, with a (biphenyl-4-yl) methyl derivative of formula : which Hal represents a halogen atom and R' and represent either Ri and Ri, or a precursor grouping for Ri and R2, respectively ; bl) optionally, the compound thus obtained with formula : is treated with Lawesson's reagent 2, 4-bis (4-methoxyphenyl ) - 1 , 3-dit ia-2, 4-dip asphetan 2 , 4-disulfide ; cl) the compound obtained in al) or bl), of formula in whic X represents an oxygen atom or a sulfur atom, is treated to prepare compound (I) by converting the R' i and/or '¾ groups into and/or R2 groups respectively . 9. A method for the preparation of a compound (I) in accord with any one of the claims 1 to 7 comprising : a2> reacting an a inoacid of formula : ^(CH2)t-NHPr C COOH in which 2 , t, R. and 5 have the meanings indicated for in claim 1 and whose amine function is protected by the group, with a (biphenyl-4-yl)methylamine derivative of formula : R'2 R*i in which R' 1 and R'_ represent either Rt and R_ or precursors of Ei and R_ respectively ; b2) after deprotection of the amine, the compound thus obtained of formula : is then treated with an alkyl ortho-ester of formula R_C(0R)a (10) in which R3 has the meaning indicated for (I) in claim 1 and R. is a C1-C. alkyl : c2) optionally, the compound thus obtained of formula ; is treated with La esson's reagent 2, 4-bis(4-methoxyphenyD-1, 3-dithia-2, -diphasphetan 2, 4-disulfide ; d2) the compound thus obtained in Ό2) or c2) of formula : is then treated under appropriate conditions to prepare compound (I) by converting the R' i and/or 5' 2 groups into R2 and/or Ri groups respectively. A method for the preparation of a compound in accord with claim 6 (comprising : a3) reacting an imidazole derivative of formula : i,n which S3, R. and Rs have the meanings indicated for (I) in claim 1, with (biphenyl-4-yl ) methyl derivative of formula: in which Hal represents a halogen atom and R' and R'∑ represent either Ri and Si or precursors of Ri and R2 respectively, in the presence of oxygen and UV irradiation, in a basic medium ; b3)optionally, the compound thus obtained of formula is treated with Lawesson's reagent 2, -bis (4-i.ethO yphenyl ) -l,3-dithia-2, 4-diphosphetan 2, -disulf ide ; c3) the compound thus obtained in b3) or c ) of formula : 97612/2 is then treated under appropriate conditions to prepare compound (I) by converting the R and/or R'2 groups into Rt and/or R2 groups respectively. 11. A process according to any one of claims 8 to 10, in which the group R is a cyano group and R'2 is hydrogen, and in which the cyano group is converted into the tetrazolyl group Rj by means of an azide. 12. A process according to claim 11, in which the azide is tributyltin azide or sodium azide. 13. A process according to claim 8, in which the compound of formula 2 in which z=t=o, R3 is the n-butyl group, and R4 and R5 are a cyclopentane group, is reacted with a compound of formula 3 in which R'2 is hydrogen and R is a cyano group to form a compound of formula 4 in which the substituents are as above defined and in which this compound of formula 4 is treated with an azide to obtain the compound 2-n-butyl-4-spirocyclopentane-l-[(2'-tetrazol-5- yl)biphenyl-4-yl)-methyl]-2-imidazolin-5-one. 14. A pharmaceutical preparation which comprises as the active principle a compound in accordance with any one of the claims 1 to 7. 15. A pharmaceutical preparation containing a compound in accordance with any one of the claims 1 to 7 in association with a beta-blocking compound. 16. A pharmaceutical preparation containing a compound in accordance with any one of the claims 1 to 7 in association with a diuretic. 97612/2 17. A pharmaceutical composition containing a compound in accordance with any one of the claims 1 to 7 in association with a non-steroid anti-inflammatory agent. 18. A pharmaceutical composition containing a compound in accordance with any one of the claims 1 to 7 in association with a calcium antagonist. 19. A pharmaceutical composition containing a compound in accordance with any one of the claims 1 to 7 in association with a tranquillizer. For the Applicants,