NZ237476A

NZ237476A - N-substituted heterocyclic compounds and pharmaceutical compositions.

Info

Publication number: NZ237476A
Application number: NZ237476A
Authority: NZ
Inventors: Claude Bernhart; Jean-Claude Breliere; Jacques Clement; Dino Nisato
Original assignee: Sanofi Sa
Priority date: 1990-03-20
Filing date: 1991-03-19
Publication date: 1994-01-26
Also published as: ES2119764T3; PL165945B1; KR920702349A; RU2099331C1; IE910913A1; EP0454511A1; IL97612A; EP0454511B1; PT97078B; CA2057913A1; DK0454511T3; AU641005B2; IL110820A; HU221188B1; CZ287064B6; CS74591A3; DE69129606D1; HU223141B1; HUT67648A; ATE167475T1

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £37476 237 47 6 P.:or;r/ Z-.K KSpvM'K.IIp; ccrJPv.ilVp; .C9."10u/M1 I.C; . /",or1 O^vlk'Q; (W?vib?r^->, ux pub;::-on : 2 6 JAN 199^ or.,,' I "I <o y$J y*[,j - s* Patents Form No. 5 NEW ZEALAND \ PATENTS ACT 1953 COMPLETE SPECIFICATION N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM WE, SANOFI, a French company of 40 Avenue George V, 75008 Paris, FRANCE hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) n - • / / 7 '• ; • < , / 10 20 This invention, relates to N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions containing then. The .compounds in accord with the invention antagonise the action oi angiatensine II which is a peptide hormone with the formula: H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-QH Angiotensins II is a powerful vasopressor agent which is the active biological product of the renin-angiotensins system. Renin acts on angiotensinogen in plasma to produce angiotensine I, the latter being converted into angiotensine II by the action of the angiotensine I conversion enzyme. The compounds in this invention are non-peptide compounds, antagonists of angiotensine II. By inhibiting the action of angiotensine II on its receptors, the compounds 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 ill 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 25 30 (I) * . S5_J—(CH2)t z(CH2) N E ;v . in which: o Ri and Ri are 3like or different and each independently represents SEP199I"; - <■> /<' V ■v. - iq" hydrogen or a group selected from, a Ci~C» alkyl, a Ci-C* alkoxy, amino, aminomethvl, carboxy, an alkoxycarbonyl in which the alkoxv is a C -C 14 alkoxy,cyano, tetrazolyl, aethyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonyiamino, trifluoroaethylsulfonylaninomethyl, 5-cyano-acetamide, JT-hydroxy-acetamide, N- (4-carboxy-l,3-thiazol-2-yl)acetamide, ureido, 2-cyano-guanidinocarbonyl, 2-cyano-guanidinomethyl, imidazoi-l-yl-carbonyl, 3-cyano-2-methyl-isothioureidomethyl, with the proviso that at least one of the substituents Ri or Rj is different from hydrogen; - & represents hydrogen, a Ci-C« alkyl which is unsubstituted or substituted with one or several halogen atoas, a C2-C4 alkenyl, a C3-C7 cyclaalkyl, a phenyl, a phenylalkyl in which the alkyl is a alkyl, a phenylalkenyl in which the alkenyl is a C2~C3 alkenY1' the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C\-C* alkyl, a Ci-C« haloalkyl, a Ci-C* polyhaloalkyl, hydroxy1 or a C»-C* alkoxy; - Ri and ?.s each independently represent a Ci-Cs alkyl, a phenyl, a phenylalkyl in which the alkyl is a C1~c3 alkyl, the said alkyl, phenyl and phenylalkyl groups 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 R* and Rs together form a group of formula =CR7Ra, in which R7 represents hydrogen, a Ci-C* alkyl or a phenyl and Ra represents a Ci-C* alkyl or a phenyl; - or again R* and Rs linked together represent either a group with formula (CHa)n, or a group of formula (CE2)„Y(CHa),, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Ct-C* alkyl group, a phenyl or a phenylalkyl in which the alkyl is a C^-C^ alkyl, or an S-R* group in which 3s represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is a c1~c4 a Ci-C4 alkylcarbonyl, a Ct-C* haloalkylcarbonyl, a Ci-C* polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or a if-protecting group, or R* and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; ?5.M76 - n is an integer from 2 ta 11 inclusive; - n is an integer iron 2 ta 5 inclusive; - X is an oxygen atom or a sulfur atom; - z and t are sera ar one is zero and the other is one; - and their salts. When a compound of the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound. The salts of compounds of formula (I) of this invention consist of those with organic or inorganic acids which permit appropriate separation or crystalligation of compounds of fornaila <I), such as picric acid, o::alic acid or an optically active acid, for example a mandelic acid or a camphosulphonic acid, and those which form pharmaceutically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, methane sulfonate, methyl sulfate, maleate, fumarate, naphthalene-2-sulfonate. The salts of compounds of formula (I) also consist of salts with organic or inorganic^bases, for example salts of alkali or alialine earth metals like salts of sodium, potassium, calcium, the salts of sodium and potassium being preferred, or with a tertiary amine, such as trometamol, or even salts of arglnine, lysine, or any physiologically acceptable amine. According tc this description and in the claims which follow, a halogen atom is understood to be a bromine, chlorine or fluorine atom. A S-protecting group (also denoted by Pr) is understood to be a group classically used in peptide chemistry for temporary protection of the amine function, for example a 3oc, Z or Fmoc group or a benzyl group. An esterified carboxy group is understood to be an ester which is labile under the approriate conditions, like for example a methyl, ethyl, benzyl or tertiary butyl ester. Alkyl means straight-chain or branched aliphatic hydrocarbon radicals. Compounds of formula (I) in which Ri is in the ortho position and is a carboxy group or tetrazolyl and R2 is hydrogen are 237476 preferred compounds. Compounds of formula (I) in which Si 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 Rs 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: Et : ethyl n3u,t3u : a-butyl, tert-butyl DMF : dimethylforma aide THF : tetrahydrofuran DCX : dichloromethane NBS : J-bromo-succinimide DCC : dicylcohexylcarboditmide DIPEA : diisopropylethylamine Ether : ethyl ether TFA : trifluoroacetic acid Z : benzyloxycarbonyl Boc : tert-butoxycarbonyl BOP : benzotriazolyloxy trisdimethylamino phosphonium hexafluorophosphate Fnoc : fluoreaylmethyloxycarbaayi 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; 10 15 25 23747e I4 R57L(CH2)t Z(CH2) N X„>3 N in which z, t, Ra, R* and Rs have the meanings indicated above for (I), is reacted with a derivative of (biphenyl-4-yl)methyl of formula; ?'2 R'l Hal-CH2 in which Hal is a halogen atom and R' i and R* 2 are either Ri and R2 or a grouping which is a precursor of Rj and R2 respectively; 20 bl) optionally, the compound thus obtained of formula; f4 z(CH2) N kjK3 E'2 is treated with Lawesson's reagent 2,4-bis<4-methoxyphenyl)-l,3-30 dithia-2,4-diphosphetan 2,4-disulfide; cl) the compound obtained from al) or bl) of formula; - 5 - * 1R ^ s / A 7 f- J ~T / in which X is an oxygen atom or a sulfur atoa, is treated by converting the R'1 and/or R'i groups into Ri and/or R: groups 10 respectively in order to prepare compound (I). Amongst compounds Z, the compounds (II) as defined below are novel. Thus, the present invention also relates to compounds (II) of formula; 20 I H R4 R5A-(CH2)t z(dH2) N J\ J-"3 11 X/ M 25 in which; - Rj represents hydrogen, a Ci-C« alkyl which is unsubstituted or substituted with one or several halogen atoms, a Cs-C* alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a c1~cg alkyl, a phenyalkenyl in which the alkenyl is a C2-C3 aHcenY1' tlie said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C* alkyl, a Cj-C« haloalkyl, a Ci-C* polyhalaalkyl, hydroxy1 or a Ci-C* alkoxy; - R* and R* each independently represent a C»-C4 alkyl, a phenyl, a ■■■-r- phenylalkyl in which the alkyl is a C -C alkyl, the said alkyl, phenyl and , fs * c ^ / y/ ^ r; . phenylalkyl groups being unsubstituted or substituted with one or 'V \ ""2 Sfp;?9,n; - 6 - ?37476 several halogen atoms or with a group selected from, a Ci-C* perfluoroalkyl, hydroxyl, Ci-C< alkoxy; - or R« and St together form a group of formula =CR7?.a, in which 37 represents hydrogen, a Ci-C* alkyl or a phenyl and Ra represents a Ci-C* alkyl or a phenyl; - or again ?.* and Re linked together represent either a group of formula (CHj)n, or a group of formula (CH:)PY(CH2>4, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Ci-C-i alkyl group, a phenyl or a phenylalkyl in which the alkyl is Ci-Cj, or an IT-Rs group in which He represents hydrogen, a Ci-Ci alkyl, a phenylalkyl in which the alkyl is C1-C4., a Ci-C* alkylcarbonyl, a Ci-C< haloalkylcarbonyl, a Ci-C* polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or a S-protectinggroup, or 3* and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantane; - p + q = s; - 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 one; with the restriction that - when z and t are zero and X is an oxygen atom, Ra and Rs are other than; * a Ci-Ce alkyl, a phenyl, a phenylalkyl in which the alkyl is a c -c alkyl,the said alkyl, phenyl and phenylalkyl being unsubstituted or substituted with one or several halogen atoms or with a group selected from a Ci-C« perfluoroalkyl, hydroxyl, C1-C1 alkoxy; •* or R* and Rs linked together are other than an H-Re group in which R« is a hydrogen, a Ci-C« alkyl, a phenylalkyl in which the alkyl is a C1-C3 alkyl; 9 n is different from 6 and, when 3=1 and Ra is a phenyl, R* and Re are each different from methyl. Amongst the derivatives (II), compounds in which z = t = 0 , and and R« together with the carbon to which they are bonded 9 7 7 Z 7 f, constitute a cyclopentane, are preferred compounds, compounds correspond to formula; These X^N ,N > R3 I H CII') in which X is an oxygen atom or a sulfur atom and S3 is hydrogen, a Ci-Ce alkyl, either unsubstituted or substituted with one or several halogen atoas, a Ci-C* alkenyl, a C3-C7 cycloalkyl, a phenyl, a 15 phenylalkyl in which the alkyl is a Ci-C3 alkyl' a phenyalkenyl in which the alkenyl is a C2~C3 alkenYl' the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C« alkyl, a C»-C4 haloalkyl, a Ci-C* polyhaloalkyl, hydroxyl or a Ci-C* alkoxy. 20 Compounds (II) in which z = 0 and t = 1 of formula; 25 RS 84 . I H jL-*3 (II") in which Sa, Ri, Rs and X have the definitions given above for (II) are preferred compounds. Finally, compounds (II) in which z = 1 and t = 0 with formula; - 6 - I H in which; - Ha represents hydrogen, a Ci-Ct alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C« alkenyl, a Ca-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a C^-Cg alkyl, phenylalkenyl in which the alkenyl is a C2~C3 alkenyl, the said phenyl groups being unsubstituted or substituted once or several tines with a halogen atom, a Ci-C* alkyl, a Ci-C* haloalkyl, a Ci-C* polyhaloalkyl, hydroxyl or a Ci-C* alkoxy; - Hi and Rs each independently represent a Ci-C* alkyl, a phenyl, a phenylalkyl in which the alkyl is a alkyl, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a Ct-C* perfluoroalkyl, hydroxyl, Ci-C* alkoxy; - or E* and Rs together form a group of formula =CR7Ra, in which R? represents hydrogen, a Ct-C* alkyl or a phenyl and R# represents a C1-C4 alkyl or a phenyl; - or again & and Rs linked together represent either a group of formula (CH2>n, or a group of formula (CHzJpYCCHi)*, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Cj-C* alkyl group, a phenyl or a phenylalkyl in which the alkyl is a C1~C3 alkyl, or an 3-Rs group in which R4 represents hydrogen, a Ct-C* alkyl, a phenylalkyl in which the alkyl is a C ~C4 alkyl, a alkylcarbonyl, a Ci-C* halaalkylcarbonyl, a Ci-C« polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an S-protecting group, or Ri and Rs linked together with the carbon atom to which they are bonded, constitute an indane or an adamantine; ?37476 - 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; with the restriction that R» is other than a phenyl when R4 and Rs 5 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. Cnim. France, 1971, 2., 1040-1051) and by Brunken and Bach (Chem. Ber. , 10 1956, 2£, 1363-1373) may be used by reacting an alkyl imidate with an amino acid or its ester according to the following reaction scheme: 20 25 JCH2)z-C02R' 15 + R3 - r5 (CH2)t.-NH2 > NH OR 5' I4 R57L(CH2)t Z(CH2) N Js> O N I H in which R is a Ci-C* alkyl, R' is hydrogen or a Ci-C* alkyl and S3, R4, Rs, 2 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. 30 According to another method of working, a compound 2. nay be prepared by reacting in acid medium of an aminoalkylamide (5'') on an alkyl ortho-ester (10.) according to the following reaction scheme: V ^i- ''V /•" /.■••V (/« i -2 SEP 1991 V* N;. v " - 10 - 2 k) t 4 / R4^ ^CCH2)z-C0NH2 /C\ + R3-C(0R)3 — > 2 RS (CH2)t-NH2 £ 12 where R is a Ci-C* alkyl. The compound 2. nay also be prepared by using a method of i0 working described by H. Takenaka et al. (Heterocycles, 1989, 22. <6>, 1185-89), by reacting the derivative 5'' with an acid halide cf formula: R3 " CO - Hal 12 15 in which 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 20 reacting a compound of formula: RA (CH2)zC0A X « Rs (CH2)tNH2 in which A is an NH2 group or an OR1 group, R' being hydrogen or a Ci-C* alkyl, with a compound of formula: 25 R3 - B 14 3° in which B is: - a C (0R)3 grouping Q - a v grouping OR 2 4 NOV J993 - 11 - ?37476 ar - a COHal grouping, R being a Ct-C* alkyl and Hal representing a halogen aton, preferably chlorine, then optionally the compound thus obtained is treated with Lawesson's reagent (2,4-bis(4-2etho;:yphenyl)-l,3-dithia-2,4-diphosphetan 2,4-disulfide. The derivative of (biphenyl-4-yl) methyl (_3) is prepared in accord with a nsthod described in patent application HP 324 377. The conversion of an R* i and/or R' i group into an Ri and/or 82 group is carried out using methods which are well known to the specialist in the field. Thus, when the compound (.1) to be prepared has an. Ri and/or R2 group = carboxy, R'1 and/or His an esterified carboxy group. Vhen the compound (I) to be prepared has an Ri and/or R2 group = tetrazolyl, R'i and/or S*2 nay 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 nay be carried oat by an azide, fcr example tributyl tin azide or sodium aside. R'i and/or 5'2 groups such as nitro, carboxy, cyano or acid chloride groups may also be used and these nay then be converted using reactions which are well-known to the specialist in the field in order to obtain Ri and/or H2 groups such as those described for compound I. Thus, when R'j and/or R* 2 represent a carboxy, it may be converted into Ri and/or R2 representinf an imidazol-l-yl-carbonyl, or even into 5-[(4-carboxy)-l,3-thiazol-2-yl]acetamide. The R'i and/or R'2 representing an acid chloride may be converted intoRi and/or Ri representing 5-hydroxyacetamide, 3-cyanoacetamide, ureido or 2-cyanoguanidinocarbonyl. R' 1 and/or R'2 representing a nitro may be converted into an amino from which Ri and/or Rs such as methylsulfonylamino, trifluoroaethylsulfonylamine and trifluoromethylsulfanylaainomethyl may be prepared. R'i and/or RI2 representing a cyano may be converted into •? 3 7 4 7 6 aainomethyl from which can be prepared 3-cyano-2-methylisothioureidomethyl (according to C. Gordon et al., J. Org. Chem., 1970, 25.. (6), 2067-2069) or a 2-cyar.aguanidanethyl (in accord with R.V. Turner, Synthesis, 1975, 332; Stage al) is performed in an inert solvent such as DHF, DMSO or THF, in a basic mediua, for example in the presence of potassium hydroxide, a aetal alccholate, a aetal hydride, calciua carbonate or triethylaaine. Stage bl) is performed by heating under nitrogen in a solvent such as toluene, according to che method described by X. P. Cava et al., Tetrahedron, 1985, 41, 22, 5061. The method comprising stages al, bl, and cl is called method 1 in the following description. Alternatively, coapounds (I) may be prepared according to another method which is likewise a subject of this invention. This method comprises: a2) reacting an aminoacid of formula; in which z, t, fU and Ks have the aeanings indicated above for (I) and whose amine function is protected with the Pr group with a (biphenyl- 7 4-yl) methylamine derivative of formula: 8 in which R'i and/or S*2 represent either Ri and Ri respectively, or a precursor of Rj and R2; * 20 237 4 7 6 b2> after deprotecting the amine, the compound thus obtained of formula: *\ g yC- (CH2)2-C-NH-CH2 Rs (CH2)t-NH2 R*2 R'i -6-6 is then treated with an alkyl ortho-ester of formula 10 R3C(0R)3 <10) in which Ra has the meaning indicated above for (I) and R is a Ct-C* alkyl; c2> optionally, the compound thus obtained of formula: 15 is treated with Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetan 2,4-disulphide; d2) the compound thus obtained in b2 or in c2 of 30 formula: - 14 - * ■37476 10 Is then treated under approprtlate conditions to prepare compound <I) by conversion of the R'2 and/or R'i groups into R2 and/or Ri groups respectively. Compounds Z are known or prepared by known methods 15 (Chemistry of the Amino Acids, Greenstein and Visits, John Viley ed., 1961, vol. 1, p. 697). Compounds 2. 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 20 presence of BOP and of DIPEA. Stage b2) which is the cyclisation of compound 1 in the presence of !£. is performed according to Jacquier et al. (Bull. Soc. Chim. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem. Ber. , 1956, 22., 1363-1373). 25 In the following description the method comprising stages a2 to <±2 is called method 2. According to one variant of method 2, in stage b2, an intermediary 21 of formula: 30 R4 *5-C-(CH2 ) J5-CO-NH-CH2 (CH2)t-NH-C0-R3 £1 may aptianally be isolated and then compound 4. may be prepared by - 15 - °77^76 cyclisation in acid nedium. According to another variant of method 2 and to prepare a compound I in which R*Rs is one group =CR?R» an amino acid of formula: CH2-(CH2)t-NHC0R3 (CH2)Z-COOH 7* may be reacted in acid medium with an aldehyde or a ketone of 10 formula: RTCOSS in which R7 and Ra have the meanings given above for (I), then a 15 conroound of formula: 20 R'i R«2 0 R7R8C=C-(CH2)Z-C-NH-CH2 (CH2)t-NHC0R3 21 is obtained by action with compound Cyclisation of this compound in acid medium leads to 25 compound i. In this method, to prepare a compound (I) in which Ri and/or Ri is a carboxy group, the substituent R'i and/or R'i is preferentially a tert-butoxycarbonyl. Finally, another alternative for the preparation of 30 compounds (I) according to the invention in which z and t are zero, is the photooxidation method which is likewise a subject-matter of this invention. This last method comprises: a3> reacting an imidazole derivative of formula: - 16 - "2 SEPI99J,';- i\V * ?3Z476 11 10 in which. Ha, H*. Hs have the meanings indicated above for (I) with a derivative of (biphenyl-4-yl)methyl of formula: 15 in which Hal is a halogen atom and R't and/or R'z represents 20 either Hi and Rs respectively or a precursor of Rt and R2, in the presence of oxygen and UV irradiation, in a basic medium; b3) optionally, the compound thus obtained of formula: 25 30 4* if7i'". / -O ■ \ < ' \ -2SfP[J9;- - 17 - D '37 476 5 10 is treated with Lawesson's reagent 2, 4-bis(4-methoxy>-l,3-dithia-2/4- diphosphetaa 2,4-disulfide; c3> the compound thus obtained from b3 or from c3 of formula: 15 20 51 is then treated under appropriate conditions to prepare compound 25 (i) by converting the S* i and/or R'2 groups into Ri and/or Ri groups respectively. The imidazole derivative LL is either commercially available, or known, or prepared by known methods as indicated above for the preparation of compunds Z-30 Stage a3) is performed in an inert solvent such as DMF 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 according to the invention, in which R* - 18 - ? 3 7 4 7 6 and Rs linked together represent a group of formula (CHiVfCCH:)* in which Y is an UH group, may be prepared by catalytic hydragenolysis of a corresponding compound '!> in which Y is an N-Ht group, Ri being benzyl. 5 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, 809-317. 10 Clio was measured. This was the concentration which produced 50% displacement of the labelled angiotensine II, linked specifically to the receptor. The CIso of the compounds according to the invention is less than 10"® X. In addition, the angiotensine II antagonistic effect of 15 the products according to the 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, Z (suppl.2), S33-S35). Compounds according to the invention are active after 20 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, 25 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, zesary disorders or Alzheimer's disease, for example. This invention also relates to the 30 pharmaceutical compositions containing an efficacious dose of a compound according to the invention or a pharmaceutical^ acceptable salt and appropriate excipients. The said excipients are chosen, according to the pharmaceutical form and the desired method of administration. In the pharmaceutical canpositions of this invention for i C 0'5\ " 19 -2SEPI991.S; s. oral, sublingual, percutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transderaic or rectal administration, the active principles of formula I above, or optionally their salts, may be administered in the farm 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 lift ravenous forms of adninstration 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 mg per kg body weight and per day. Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, 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. When 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 adainstration in the form of drops nay 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. 5 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 10 prepared with binders melting at the rectal temperature, far example cacao butter or polyethyleneglycols, are used. For parenteral administration, aqueous solutions, isotonic saline soutions or sterile and injectable solutions which contain pharmacologically compatible dispersion and/or 15 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 additives. 20 The compositions of this invention may contain, alongside the products of formula I above or one of the pharmaceutical^ acceptable salts, other active principles such as, for example, tranquillisers or other drugs which may be used in the treatment of the illnesses or diseases indicated above. 05 Thus, this invention also rleates to the pharmaceutical compositions containing several active principles in association, one of which is a compound according to the invention and the other(s) nay be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal anti-inflammatory 30 agent or a tranquilliser. The following 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, KHSOa-KiSO* means an aqueous solution containing 16.6 g potassium bisulfate and 33.3 g potassium sulfate per - 21 - 30 litre. The melting points (M.pt.> are given in degrees Celcius; unless Indicated to the contrary, they were measured without recrystallizing the product. 5 Purity of the products was checked using thin layer chromatography (TLC) or HPLC. The products are characterised by their BHR spectra recorded at 200 MHz in deuterated DMSO, the internal reference being tetramethylsilane. To interpret the BMR spectra, the following were used: 10 s for a singlet s.e. for a broadened singlet d for a doublet t for a triplet q for a quadruplet 15 quint for a quintuplet sext for a sextuplet m for a very broad band or multiplet Moreover, im means imidazole. In the classic manner, the hydrogen atoms are numbered 20 on the biphenyl as shown in the following formula: R4 RS^CC^t z(CH2) N !>• (I) 5 6 6' 5' In the following compounds, z and t are zero, except when the compound prepared is a pyrimidinone. N.Z. PATENT OFFICE 26 AUG 1993 - 22 - ? 3 7 4 7 6 HYAyPLE 1 2-a-butyl-4-spirocyclopentane-l-C 12' -tert-butoxycarbonylbipheayl-4-yl)aethyl] -2-imida::alin-5-ane and 2-n-butyl-l-[(2, -carboxybipheayl-4-yl)methyl)-4-spirocyGlopentaae-2-iaidazalin.-5-ane triflucraacetate. Method 2. A) l-(H-Faoc-amino)-cyclopentane carboxylic acid was prepared according to the nethod described by CHI-0DErJ CHAJJG et al. (Int. J. Peptide Protein Res., 1980, 15, 59-66). X.pt. = 89-91*C) B) 5-(2*-tert-butoxycarbanylbiphenyl-4-yl)methyl-l-(IT-Fmoc-aai no) eye 1 opentanecarboxaMde-1. 700 ag of the product prepared in the preceding stage 15 were dissolved ia 8 ml DMF and 576 ag 4-aair.oethyl-(2' -tert- butoxycarbonyDbiphenyl, 970 ag BOP 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 al water. The organic 20 phase was washed successively with a saturated sodiua bicarbonate solution, then with a KHSO*-£iSO* 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. 25 C) IT-(2'-ter£-butoxycarbonylbipheayl-4-yl)aethyl-l-aaino- cyclopentanecarboxaaide-1. The product obtained in the preceding stage was dissolved ia 10 ml DMF, then 1 al diethylaaiae was added and the mixture stirred for 1L. hours at TA. The reaction aedium was taken up 30 with 100 ml ethyl acetate and 20 al 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/nethanol/30% ammonia solution mixture - 23 - ? 7> 7 4 7 ('. ■■ -> i i < (99/1/0.5 ; v/v/v). 600 ag expected product were obtained. IR (CHC1 • • 3350 cn-i : H (amide and amine) 1700 cm-' : C = 0 (CO^Bii) 5 1650 cm*1 : C = 0 (CONH) NKR spectrua : 1.25 ppo : s : 9 H : tBu 2.15 - 1,40 ppm : m : 10 H : (CjHg, NH2) 4.40 ppm : d : 2 H : CHj-NH 10 7,15-7.75 ppo : n : 8 H : bipheayl 8.60 : t : 1 H : NH - CH2 D) 2-n-butyl-4-spirocyclopeatane-l-[ (2'-tert-butoxycarbanyl-biphenyl-4-yl)sethyl] -2-inidazolin-5-one. 15 394 mg of product prepared in the preceding stage and 250 ag ethyl orthovalerate were aix-ed in 2 ±1 DCM. 1 drop of acetic acid was added and then the niirture was heated to 90°C allowing the DCH to evaporate. After L hours, the reaction medium was taken up with 50 al ethyl acetate, 10 al water and 1 ml saturated 20 sodium bicarbonate solution. The organic phase was then washed with a saturated sodium chloride solution, dried over sodiua sulfate and evaporated to dryness. The residue was chroaatographed on silica gel by eluting with an ethyl acetate/toluene mixture (1/2, v/v). 390 mg of the expected product was 95 obtained, which crystallized. M.pt. = 63-65*C. IR (CHCla) : 1710-1720 cm-' : C = 0, C = 0 (ester and imidazoline) 1625 co*1: C = N MS spectrum : 30 0.88 ppm : t : 3 H : ch3 (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 : CH2-C6m- - 24 - 7.20-7.80 ppm : m : 8 H : aromatic H mass spectrum : HH* : 461 E) 2-a-butyl-l-C (2'-carboxybiphenyl-4-yDmethyl]-4-spirocyclopentane-2-imida::olin-5-one trifluoroacetate. 180 mg of product prepared ia the precediag stage were treated with 3 al DCM and 4 al TFA for 45 minutes. After evaporatioa under vacuum, the residue was taken up with ether, white solid was obtained which was filtered, washed with ether and then dried under vacuum. NKR spectrum : 0.78 ppm : t : 3 H : CH3 (nBu) 1.25 ppa : sext : 2 H : ch3-ch2 1.50 ppo : quint : 2 H : ch3-ch2-ch2 1.75-2,00 : m, 8 H : cyclopentane 2.65 ppn : t : 2 H : CH3-CH2-CH2-CH2-4.83 ppm : s : 2 H : CH2-C6H*- 7.20-7.75 ppm : m 8 H : aromatic H mass spectrum : MH* : 405 SXAHPLS 2 2-n-butyl-l-[ (2' -carboxybiphenyl-4-yl)methyl]-4-spiracyclopentaae-2-iaidazolia-5-one trifluoroacetate. Xethod 1 * » A) 2-n-butyl-4-spirocyclapentane-2-imida2olin-5-one. The ethyl ester of 1-aminocyclopentane carboxylic acid was prepared accoriing to ADKISS and BILLICA (J. amer. Chea. Soc., 1948, Z£■ 3121). 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 - 25 - 237 47 6 10 15 20 25 carbonate and extraction with DCX. The ethyl ester of 1-aminocyclopentane carboxylic acid (1.57 g) and ethyl valerimidate (1.56 g) were dissolved in 12 ml xylene containing 6 drops of acetic acid. After 6'c hours of heating under reflux, the reaction medium was concentrated under vacuum and the residue was then chromatographed an 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. 1.91 g of the product obtained in the form of a thiol: ail. IR (CHCIJ) : 1720 cn-i : C a 0 1635 cnr1 : C *= N Note: the fact that no band is visible between 1500 and 1600 cur' indicates that, in chloroform solution, the product is an imidazolin-5-one. 3MR spectrum : 0.92 ppo : t : 3 H : CH3 (nBu) 1.35 ppm '• sext : 2 H : ch3-ch2" 1,50-1,93 ppm : b : 10 H : Cfy-Cfy-CHj and cyclopentane 2.33 ppo : t : 2 H : CH3-CH2-CH2-CH2-10.7 ppo : a : NH mass spectrum : XH* : 195 The 2-n-butyl~4-spiracyclopentane-2-inidazolin-5-ane prepared in stage A, may also be obtained in accord with another the starting material. a) 1-aminocyclapentanenitrile 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 procedure, described below, by using cyclopentanone as •V - 26 - o -■ i 4 7 A . ^ . -r < - the flask. After T-; hours stirring, the flask was warmed to 60*C for 45 minutes, then the heating was turned off and the stirring continued for 45 ninutes and the flask coaled to 25 *C. The contents were extracted several times with methylene chloride, dried over sodium sulfate, filtered and concentrated under vacuum. 4 g expected product was obtained in an oily form. The 1-aainocyclopentanenitrile obtained was dissolved with 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 SC.pt. = 220 *C This compound is 1-aminocycloper.tanenitrile hemioxalate. b) 1-aminocyclopentaneacetamide. 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 with 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/2.8 ml). The suspension which formed was extracted 6 times in succession with chloroform containing 5% methanol. 3 nl 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. m = 3.79 g K.pt. = 95 *C The analysis results and the IS spectrum confirmed the structure. - 27 - ? 3 7 4 7 c) 2-n-butyl-4-spirccyclopentane-2-imidazolin-5-one This stage was carried out in acccrd with H. Taneia et al., Heterocycles, 1939, 22., 1185-89. 3 g of the compound prepared ia the preceding stage were placed in 70 ml anhydrous THF and 3.3 ml triethylanine 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- (S-valeryDaminocyclapentanecarboxamide. 6 g potassium hydroxide ia 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 mixture was concentrated under vacuum. The residue obtained was absorbed ia 40 ml water and extracted with 10 nl 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 3XR spectrum was similar to that described previously. The hydrochloride of this compound ray be prepared by addition of concentrated hydrochloric acid. The hydrochloride melts at 240 *C while sublimating. B> 2-n-butyl-4-spirocyclopentane-l-[ (2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl]-2-imidazolin-5-one. 970 mg product obtained in stage A) were dissolved ia 10 ml DMF. 270 mg sodium methylate were added and left at TA for 15 minutes with stirring. 2.08 g 4-bromoaethyl-(2'-tert-butoxycarbanyDb&rtienyl were added to the suspension then, after 30 minutes, the mixture was heated at 40°C for 3$ 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 an silica gel by eluting with an ethyl acetate/toluene mixture <1/2 ; v/v). 1.25 expected product which crystallized was ? 7 v r, 7 obtained. M. pt. = 63-66 *C. The 18, SMS and mass spectra as well as the Rf were identical with those obtained ia stage D) of example 1. C) 2-n-butyl-l-C(21-carboxybiphenyl-4-yi)methyl]-4-spiro-cyclopentane-2-imida::alin-5-ane trifluoroacetate. 1.22 g product obtained in the preceding stage were stirred for 40 minutes in a solution containing 6 al DCJC and 3 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 was obtained. X.pt. = 176-178'C. The IS, MR and mass spectra were identical to those obtained in example IE. Koreover, the Rf measured in CCX was identical. EXAMPLE 3 2-n-butyl-l-C <2' -carboxybiphenyl-4-yl)methyl] -4-spiro-cyclapentane-2-imidazolin-5-one trifluroroacetate. Method 3 A) 2-n-butylbenzimidazole was prepared in accord with V.O. PQOL (J. Amer. Chem. Soc., 1937, 5£, 178) and then 2-n-butyl-4,5,6,7-tetrahydrobenzimidazole was prepared in accord with X. HARTXA1T3 and L.PAHIZZOff (Hel. Chim. Acta, 1938, 2i, 1692-1694). 3C.pt. = 145*C. 5XR spectrum : 0.82 ppn : t : 3 H : CHj (nBu) 1.23 ppm : sext : 2 H : CH3-CH2- 1,50 ppn : quint : 2 H : CH3-CH2"CHj- I.65 pps : s : 4 H : h5, H$ (tfctrahydrobenzinidazo 1) 2.35 ppa : s; 4 H : H*, h7 (tetrahydrobenzimidazol) 2.45 pp« : t : 2 H : CH3-CH2-CH2-Cjl2- II.1 ppn : m : NH mass spectrum : X* : 178 3)2-n-butyl-4-spirocyclopentane-l-C(2'tert-butoxycarbonyl- - 29 - biphenyl-4-yi) methyl 3 -2-imidazaI ir.-5-ar.e. 1 g product prepared la the preceding stage was dissolved ia 45 ml DXF with 302 zg sodium aethylate and a few Eg methylene blue. Oxygen was bubbled into the reaction medium 5 which was illuminated with a UV laap. After 15 minutes, 2.14 g 4-bromoniethyl-2'-tert-butoxycarboaylbiphenyi 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. Th-? organic phase was then washed with a 10 saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue was chronatographed on silica gel by eiuting with an ethyl acetate/toluene mixture (1/2 ; v/v). 610 mg expected product which crystallized was obtained. X. pt. = 62-65*C. 15 The IR, 3X5 and mass spectra as well as the Rf were identical to those obtained previously for the sane compound. C) 2-n-butyl-l-C(2'-carboxybiphenyl-4-yl)methylI-4-spiro-cyclopentane-2-imidazolin-5-one trifluoroacetate. This compound was obtained by treatment in acid medium 20 as described in the last stage of example 1 and example 2. The physicochemical data are Identical to those obtained for the sane compound prepared using methods 1 or 2. 25 30 \ -• i >' EXAMPLE 4 2-n-butyl-4,4-dimethyl-l-C(2' -tert-butoxycarbonyl-biphenyl-4-yl)methyl 3-2-imidazolin-5-one. and 2-n-butyl-l-C (2'-carboxybiphenyl-4-yl)methyl]-4,4-dimethyl-2-imidazolin-5-one trifluoroacetate. Method 1. The ethyl ester of alpha-aminoisobutyric acid was prepared according to R. Jacquier et al. (3ull. Soc. Chim. , France, 1971, (3), 1040-1051). 650 mg of this compound and 780 mg ethyl valerimidate were dissolved in 8 al xylene containing 4 drops of acetic acid and heated under reflux for 7 ■ " -2 SEP1991.V -30 \ & '' •<> c P. hcurs. The reaction medium was then concentrated under vacuus and the residue chronatographed on silica gel by eiuting with a chlorofora/methanol/acetic acid fixture (95/3/2 ; v/v/v). After several evaporations of xylene and then of benzene, to remove the acetic acid, 560 ng expected product which crystallized were obtained. X.pt. = 35-38'C. IS (CKCl3> ]j25 cm*1 : C = 0 1635 car1 : C = N Note: the absence of a signal between 1500 and 1600 en"' confiras that the compound present in chloroform solution was a 2-imidazolin-5-one. 3DE spectrum : 0.92 ppm : t : 3 H : CH3 (nBu) 1.20 ppn : s : 6 H : C (CH3)2 1.38 ppn : sext : 2 H : ch3-ch2 1.63 ppn : quint : 2 H : ch3-ch2-ch2-2.38 ppm : t : 2 H : CH3-CH2-CH2-CH2-10.7 ppm : n : 1 H : N-H mass spectrum : MH* : 169 3) 2-n-butyl-4,4-dimethyl-l-[ (2'-tert-butoxycarbcnylbiphenyl-4-yl)aethyl-2-imidazolin-5-one. 520 mg product prepared in the preceding stage were dissolved in 10 ml DMF. 167 mg sodium methylate was added and stirred for 15 minutes under nitrogen. Then 1.25 g 4-branomethyl-2,-tert-butaxycarbonylbiphenyl 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 chronatographed on silica gel by eiuting with an ethyl acetate/toluene mixture (1.2/2 ; v/v). 570 mg expected product which crystallized were obtained. M. pt. = 98-100'C. IS (CHCLs) : 1710-1720 carl ; C = 0, C = 0 (imidazolinone, ester) - 31 - '.■5/476 1625 cm-' : C = N NXR spectrum : 0.78 ppn : t : 3 H : CH3 (nBu) 5 1.08 ppm : s : 9 H, C(CH3)3 1.15 ppm : s : C (CH3)2 and l,20ppm: sext : CH3-CH2- ) 8 H 1.45 ppm : quint : 2 H : ch3-CH2-CH2-2-30 ppm : t : 2 H : CH3-CH2-CH2-rii£-4.65 ppm : s : 2 H : CH2-C6H4-10 7.15-7.65 ppn : m : 3 H : aromatic H A Nuclear Overhauser Effect study confirmed the position of the 5-one and 4,4-dimethyi substitutions an the imidazolinone mass spectrum : MH* : 435 C) 2-a-but7l-l-t(2'-carboxybiphenyl-4-yl)methyl3-4,4-dimethyl-2-15 imidazolin-5-one trifluoroacetate. 460 ag product prepared in the preceding stage were treated with 3 ml DCX and 4 al 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 20 then dried under vacuum. 450 mg expected product were obtained in the form of a white solid. X.pt. = 168-171*C. 3TXR spectrum : 0.82 ppn : t : 3 H : ch3 (nBu) 1.30 ppn : sext : CH3-CHj-i 25 1.35 ppn. s : C(CHj)2- J 8 H 1.55 ppn : quint : 2 H : ch3-CH2-CH2-2.62 ppn : t : 2 H : CHj-CH^CH^CHj" 4.82 ppn : s : 2 H : CHj-C^Ha" 30 7.20 - 7.75 ppm : m : 8H aromatic mass spectrum : XH* : 379 EXAMPLE 5 1-C <2'-cyanobiphenyl-4-yl)methyl!-2-n-butyl-4- - 32 - ?3747<; spirocyclopentane-2-imida::olia-5-one and 2-n-butyl-4-spirccycioper.ta:ie-l-[ (2'-(5-tetrazolyl)biphenyl-4-yl)methyl]-2-iaida::::lin-5-ane. Method 1. A) 1-C <2'-cyanobtphenyl-4-yl)iDethyl]-2n-butyl-4-spiro-cyclopentane-2-imidazolin-5-one. A mixture containing 250 ag sodium hydride (an 30% dispersion in mineral oil) and 5 ml DMF was prepared under an atmosphere of nitrogen and a solution containing 0.97 g 2-n-but7l-4-spirocyclopentane-2-imidazalia-5-oi:e (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-bramomethyl-2' -cyano'oiphenyl 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 chronatographed on silica gel by eiuting with a DCH/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-C2'-(5-triphenylmethyl-tetrazolyl)biphenyl-4-yl> methyl3-2-imidazolin-5-one. 1.56 g preceding product, 2.6 g tributyltin azide and 30 al 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 0.8 ml 105 sodium hydroxide and, after 30 minutes stirring, 2.5 g trityl chloride and then the mixture was stirred for 26 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 chronatographed on alumina by eiuting 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-C(2'-(5-tetrazolyl)biphenyl- - 33 - 4-yl)Eethyl]-2-imidazolin-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 421 hydrochloric acid were added and the mixture 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 105 sodium hydroxide- The aqueous phase 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. X. pt. = 180-181*C. NHR spectrum : 0.75 ppo : t : 3 H : CH3 (nBu) 1.10 ppo : sext : 2 H : ch3-CH2-1.20 ppo : quint : 2 H : ch3-ch2-ch2-1,5-2 ppo : o : 8 H : -CsHg 2.2 ppo : t : 2 H : CHj-CHj-CHj-CHj-4.6 ppn : s : 2H : 7 ppn : s : 4 H : CHi-CgHj- 7.35-7.7 ppm : m : 4H : 3*, 41 , 5', 6' H aromatic A Nuclear Overhauser Effect study confirmed the position of the 5-one substitution on the imidazole. D) Potassium salt of 2-n-butyl-4-spirocyclopentane-l-C(2'-C5-tetrazolyl)biphenyl-4-yl)methyl1-2-imidazolin-5-one. 970 ag 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 methanal-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 mixture was decanted, the filtrate evaporated and 5 10 15 20 25 30 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 ng cf the expected potassium salt was obtained. M.pt. 142-144"C. Elenental analysis: C«H27K1UQ. HiO calc: : C : 61.95 H : 6.03 N : 17.34 found: 2 62.02 6,13 17.14 EXAMPLE 6 2-n-butyl-l-C(2*-carboxybiphenyl-4-yl)methyl1-4-(4-spirotetrahydropyran)-2-iaidazolin-5-one trifluoroacetate. and 2-n-butyl-4-<4-spirotetrahydropyran)-l-E <2* -tert-butoxy-carbonyl)biphenyl-4-yl)methyl] -2-inidazolin-5-one. Xethod 2. A) 4-anino-tetrahydropyran-4-carboxyIic acid was prepared starting froa tetrahydropyran-4-one in accord with the method described in the German patent DE - 2 215 721. B) 4-(5-benzyloxycarbonyla2ino)-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 diisopropylethylaaine and then 3.33 g X- (benzyloxycarbonyloxy)succinimide dissolved in 12 ml acetonitrile. After 1^ 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 mnole 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. 110-115'C. - 35 - ~'? c r n •;:> '3/47 C) if—C <2' -tert-butcxycar bo r.y1b i phe ny1-4-y1 /r^thy!] -4-(II-ben2ylaxycarbanylaaina)-tetrahydrapyraa-4-carboxaaide. 350 ag af the compound prepared in stags 3 were dissolved in 15 al DXF and equimalar amounts of 4-aaiacethyl-(2'-tert-butoxycarbonyDbiphenyi, DIPEA and 30? <10% excess) were added. After 40 aiautes, the mediua was taken up with 200 ml ethyl acetate and 200 al water. Tie organic phase was decanted and washed twice with a saturated solution of sodiua bicarbonate and then once with a saturated solution of sodiua chloride. After drying over sodiua sulfate, the organic phase was evaporated off under vacuua. 1.3 g expected product was obtained. D) 3-C <2'-tert-butcxycarbanylbipheayI-4-yi)methyl! -4-amino te-rahydropyran-4-carbcxamide. The product obtained in stage C was dissolved in 30 al methanol. 400 ag 10% palladium on charcoal were added and hydrogen was passed through at atmospheric pressure. After 1 hour, the catalyst was filtered off and -he filtrate was concentrated under vacuua. The residue was chroaatcgraphed on silica by eiuting with an ethyl acetate/aethanol/33% aamonia solution aixture (99/1/0.5 ; v/v/v). 0.93 g expected product was obtained in the fora of a white solid. X.pt. = 125-127*C. S3K spectrua : 8.50 ppm : t : 1 H : H aside 7.60-7.05 ppo : i : S H : H arooatiq 4.25 ppo : d : 2 H : CHj - C6IU- 3.70-3.50 ppo : a : 4 H : CH2 in 2 and 6 of tetrahydropyran 2.00-1.30 ppo : m : 4 H : CH2 in 3 and 5 of tetrahydropyran 1.05 ppo : s : 9 H : t3u E) 2-n-butyl-4-(4-spirotetrahydrapyran)-i-[ (2' -t art-but oxy-carbcnylbipfcieayl-4-yl)methyl!-2-imidazoltn-5-one A aixture containing 0.9 g of the compound obtained in stage D, 327 ag aethyl orthovalerate and 2 drops of acetic acid - 36 - *37<79 were heated for 3 hours at 110*C. The reaction, medium was taken up with 100 ml ethyl acetate and then washed 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 chronatographed on silica by eiuting with an ethyl acetate/toluene mixture <2/1 ; v/v). 550 mg expected product was obtained in the form of a wax. HMR spectrum : 7.05-7.60 ppm : n : 8 H : H aromatic-4.63 ppm : s : 2 H : CH2 - CfiHj- 3,85-3,55 ppm : m : 4 H, CH2 in 2 and 6 of tetrahydropyran 2.30 ppm : t : 2 H : CH2 - c3h7 1.05-1.80 ppm : m : 8 H : CH2-CH2-CH2-CH3. and CH2 in 3 and 5 of tetrahydropyran 1.03 ppm : s : 9 H : tBu 0,75 ppm : t : 3 H : (CH2)3-CH3 IR (CHCla) : 1710-1720 cm-i : C = 0, C = 0 1625 cnr1 : C = N F) 2-n-butyl-4-(4-spirotetrahydropyran)-l-[(2'-tert-butoxy-carbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate 530 ng 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 : : n : 8 H : H aromatic 2 H : Cfy - C6Rr ; n : 4 H, CH2 -in 2 and 6 of.tetrahydropyran 2 H : CH2 - C3H7 : n : 6 H : CH2-CH2-CH2"CH3. fit CH2 • fl L 7-80-7.10 ppn 4.80 ppm : s : 4.00-3.75 ppm 2,60 ppn : t : 1.45-2,00 ppm \:u) inn* 1 in 3 and 5 of tetrahydropyran - 37 - 1.30 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : (Cfy^-CHj EXAMPLE 7 2-n-butyl-l-L (2' -carboxybiph.etiyi-4-yI)methylI -4-[ spire (1-benzyl-4-piperldine)]-2-i2nidazalin-5-one trifluoroacetate. and 2-n-butyl-4 Cspiro(l-beIl^7l-4-piperidine)]-l-[(2,-fcert-butcxycarbonylbiphenyl-4-yl> methyl ]-2-inidazolin-5-one Method 1. A) 4-amina-l-benzyl-piperidine-4-carboxylic acid was prepared from H-beazypiperid-4-one ia accord with the method described in the German patent DE 2 215 721. 3) Ethyl 4-amino-l-benzylpiperidin-4-carboxylate. 3.30 g of the compound prepared in stage A were added to a solution of 13 g hydrochloric acid in 50 ml sthanal at 0*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 aver sodium sulfate and then evaporated to dryness. 3.50 g expected product was obtained in the farm of an oil. 5XR spectrum : 7.20-7.40 ppn : a : 5 H : H aromatic 4,10 ppn : q : 2 H : CH2-CH3 3.45 ppn : s : 2 H : CH2 of benzyl 2.25-2.60 ppo : a : 4 H : CH2 in 2 and 6 of piperidine 1.80-2.05 ppo : a : 2 H : ) CH2 in 3 and 5 of piperidine 1.20-1.40 ppo : a : 2 H : j 1.12 ppm : t : 3 H : CJfe-CH2- - 33 - C) 2-n-butyl-4-Ispiro(l-benzyl-4-piperidine) 1 -2-imidazolia-5-cne Ethyl valerimidate was prepared as in example 2, stage A. 2.06 g ethyl valerimidate, 3.40 g of the compound prepared in stage 3 and 3 drops of acetic acid, in 15 ml xylene, were mixed and heated under reflux for 6 hours. After concentration under vacuum, tie residue was chrocatographed on silica gel by eiuting 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. 170-172*C. IS (CHCla) : 1725 cm*1 C = 0 1640 cm*1 C = N SMR spectrum : 7.10-7.30 ppn : m : 5 H : H aromatic 3,45 ppn : s : 2 H : -CHj-CgHs 1,10-2.75 ppn. : 5 n, 14H : CH2 in 2,3,5,6 of piperidine and (ch2)3-ch3 0.80 ppn : t : 3 H : (CH2)3-CH3 D) 2-n-butyl-4.-[spiro(l-benzyl-4-piperidine)]-1-C(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-one 513 g sodium methylate 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-bromoaethyl(2'-tert-butoxycarbonyl)biphenyl were also added. The mixture was heated at 40°C for 5 hours and then the reaction medium was 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 chronatographed on silica by eiuting with an ethylacetate/methanol mixture (99/5 ; v/v). 0.98 g expected product was obtained. y[,pt. = 103- - 39 - 1 .J 106*C. IR (CHCla) : 1710-1725 cm*1 C = 0, C = 0 (imidazoline, ester) 1630 cm*1 C = N 5 HHR spectrum : 7.70-7.10 ppm : m : 13 H : H aromatic 4.70 ppm : s : 2 H : 3,55 ppm : s : 2 H : CH2-C6H5 1,20-2,75 ppm : 5 n : 14 H : CH2 in 2,3,5,6 of the piperidine 10 et (CH2)3-CH3 1,15 ppm : s : 9 H : tBu 0.85 ppm : t : 3 H : (CH2)3-CH3 E) 2-n~butyl-l-t2'carbaxybiphenyl-4-yl]-4-[spiro(l-benzyl-4-15 piperidine)]-2-imidazolin-5-one trifluoroacetate. 350 mg of the compound obtained in stage D were dissolved in 4 ml 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 20 formed was filtered off, washed with ether and dried under vacuum. 350 mg expected product was obtained. K. pt. 198-200'C. MR spectrum : 7.05-7,75 ppm : a : 13 H : H aromatic-4,75 ppm : s : 2 H : Cfy-CjH*-4.40 ppm : s : 2 H : CHj-C6Hs 3,20-3,60 ppm : n : 4 H : CH2 in 2 and 6, of the piperidine 2.35 ppm : t : 2 H : CHj-CH2-CH2-CH3 2.20-1,40 ppm : 3 unresolved multiplets ^ anc^ 30 0H2-CH,-CH2- CH, piperidine and 1,25 ppm : sext : 2 H : CHj-C^-CHj-Cfy 0r80 ppm : t : 3 H : (CH2)3-CH3 EXAXPLE 8 2-n-butyl-l-[ (2'carboxybiphenyl-4-yl)methyl]-4-<4- - 40 - spiropiperidine)-2-imida::olin-5-ane ditriflucroacetate. and 2-n-butyl-4-(spiropiperidine)-C (2*-tert-butoxycarbonyl-biphenyl-4-yl)methyl] -2-iaiidarcl in-5-cr.s A) 2-n-butyl-4(4-spiropiperidine)-l-[(21-tert-butoxycarbonyl- biphenyl-4-yl)methyl]-2-imidazolin-5-one 300 ng 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 vacuua. 200 mg expected product was obtained. 5HR spectrum : 7,20-7,75 ppo : o : 8 H : H aromatic*. 4.75 ppm : s : 2 H : CH2-C6H4- 3,00-1,70 ppm : 3 unresolved multiplets for the 4 CH^ of the 2*40 ppm : t : 2 H : CHj-CHj-CHj-CHj piperidine 1,60 ppm : quint : 2 H : CH2-CH2-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~CIl3 B) 2-n-butyl-l-C (2'-carboxybiphenyl-4-yl)methyll-4-(4-spiropiperidine )-2-imidazolin-5-one ditrifluoroacetate. 160 mg product obtained in stage A were stirred in 3 al dichloromethane and 4 ml trifluoroacetlc 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). X/pt. 80-85*C. NHR spectrum : 7.15-7,80 ppn : o : 8 H:aromatic H 4.75 ppm : s : 2 H : CH2-C6H4- 3,20-1,60 ppn : 3 unresolved multiplets:4 CH2 of the piperidine 2.40 ppo : t : 2 H : CH2"CH2-CH2-CH3 1.50 ppm : quint : 2 H : CH2"CH2"CH2"CH3 1»30 ppn : sext : 2 H : CH2-CH2-CH2-CH3 0»80 ppm : t : 3 H : (CH2)3-CH3 - 41 - v.. . i/O EXAMPLE 9 2-n-butyl-l-[ <2'carboxybiphenyl-4-yl>zethyl ]-4,4-diphenyl-2-iaidazolin-5-one trifluoroacetate 5 and 2-n-butyl-4,4-diphenyl-l-C (2'-tert-butoxycarbonylbiphenyl-4- yl)methyl1-2-imidazalin-5-one. Method 1. A) Valerinidine hydrochloride 6 g ethyl valeriaidate hydrochloride were added to a 10 solution of 6.75 g ammonia in 80 al methanol at 0*C. After 18 hrs, the reaction aediua was concentrated under vacuua and the expected product was obtained in the fora a of a white solid. 3)2-n-butyl-4,4-diphenyl-2-iaidazolin-5-one This compound was prepared in accord with the working 15 method described by J. JTYITSAI and K. LEHPEST in Tetrahedron, 1969, 25., 4265-4267, starting with benzil and valeriaidine hydrochloride. X. pt. = 135*C. IR (CHCla) : 1725 car1 C = 0 20 1640 cm-' C = N 2TMR spectrua : 7.20-7,50 ppa : n : 10 H : H arooatic* 2.50 ppo : t : 2 H : CH2-CH2-CJf2-CH3 1.65 ppo : quint : 2 H : CH2-CH2-CH2-CH3 25 1.35 ppn : sext : 2 H : CH2-CH2-CH2-CH3 0,90 ppn : t : 3 H : CH2-CH2-CH2-CH3 11 ppn : s.e. : NH C) 2-n-butyl-4,4-diphenyl-l-C <2'-tert-butoxycarbonylbiphenyl-4-30 yl)methyl I-2-iaidazoiin-5-one This compound was prepared in accord with the usual procedure by the reaction of 4-broaomethyl-2'-tert-butoxy -carbonylbiphenyl on the compound prepared in stage B in DMF in the presence of sodium aethylate. IS (CHCla) : 1715-1725 cn-i C = 0, C = 0 (ester, inidazolinone) - 42 - 1635 cm*1 c = N X2fS spectrum : 7,25-7,80 ppn : n : 18 H : H aromatic 4.85 ppo : s : 2 H : N-CHj-C^Hd-2,60 ppn : t : 2 H : CH2-CH2-CH2-CH3 1#75 ppn : quint : 2 H : CH2-CH2-CH2-CH3 1.40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 1.15 ppn : s : 9 H : tBu 0,90 ppm : t : 3 H ; CHj of n-butyl D) 2-n-butyl-l-C 2'-carbaxybiphenyl-4-yl) methyl]-4,4-diphenyl-2-imidazclin-5-one trifluoroacetate. 500 mg of the product: prepared in stage C were treated with. 2.5 al diciloromethane and 2.5 al trifiuoroacetic acid at 20 *C, far 20 minutes. After concentration under vacuum, the residue was taken up with an ether-hexane mixture, the precipitate which formed was filtered, washed with hexar.e and dried. 440 ag expected product was obtained. X. pt. = 55-60'C. 3TM3 spectrum: 7,15-7,80 ppa : m : 18 H : H aronatir 4,85 ppn : s : 2 H : N-CIk'CglU-2,60 ppn : t : 2 H : CH2-CH2-CH2-CH3 1.70 ppn : quint : 2 H : CH2-CH2-CH2-CH3 1,40 ppm : sext : 2 H : CH2-CH2-CH2-CH3 0,90 ppm : t : 3 H : CH3 of butyl EXAMPLE 10 2-n-butyl-3-C(2'-carboxybiphenyl-4-yl) methyl2-6-spirocyclapentane-5,6-dih.ydro-l-H-pyrimid-4-ane trifluroacetate. A) (l-aminocyclopentyl)acetic acid Cyclopentylidenoacetic acid was prepared in accord with G.A.S. KOS and R. P. LISSTEAD, J. Chen Soc. , 1925, 122., 616. 740 mg of this acid and 5 ail 20% ammonia solution were placed in an autoclave and heated at 150'C for 24 hours. After evaporation of the solvents, the residue was chronatographed on a silica column by eiuting with a mixture of DCM/methanol/20 aqueous ammonia solution <70/30/1 ; v/v/v). 330 ag expected acid was obtained. 3) Ethyl <l-aainocyclopentyl)acetic acetate 330 mg of the acid were dissolved in 10 ml ethanol. This was cooled on an ice bath and saturated with gaseous hydrochloric acid. After 24 hours under reflux, the reaction mediua was evaporated down and the residue taken up with a solution of sodium carbonate and extracted into ethyl acetate, then dried over sodium sulfate, filtered and evaporated. 312 mg expected ester was obtained. C) 2-n-butyl-6-spirocyclopentane-5,6-dihydro-l-H-pyriaidin-4-one. A mixture containing 310 mg of the compound obtained in stage 3, 243 mg ethyl valeriaidate, 10 ml xylene and 5 drops of acetic acid were heated under reflux. After 2 hours and 18 hours, another 348 mg ethyl valerimidate were added, and after 24 hours total under reflux the reaction medium was evaporated down and then chromatographed on silica by eiuting with a DCM/methanol mixture <97/3 ; v/v). 153 ag expected product was obtained. D) 2-n-butyl-3-t (2*-tert-butoxycarbonylbiphenyl-4-yl)nethylJ-5,6-dihydro-l-H-pyrimid-4-one. A mixture of 10 al DMF and 40 mg sodium hydride as an 80% mixture in oil was prepared under an atmosphere of nitrogen 144 mg of the compound prepared in stage C, dissolved in 5 ml DMF, were added slowly, dropwise, at ambient temperature. After 30 minutes with stirring, 288 mg 4-bro^^om^thyl-2, - tert-butoxycarbonylbiphenyl dissolved in 5 ml DMF were added. The mixture was left with stirring for 2 hours and then evaporated down, the residue absorbed in water and extracted into ethyl acetate. This was dried over sodiua sulfate, filtered and evaporated, then purified by column chromatography by eiuting with a hexane/ethyl acetate mixture (85/5 ; v/v). 174 mg expected product was obtained. - 44 - ? j / 4 7 h E) 2-n-butyl-3-[ <2' -carboxybiphenyl-4-yl)methylI-6-spiro- cyciopentane-5,6-dihydra-l-H-pyrizid-4-one trifluoroacetate. 10 ml' trifluoroacetlc acid was cooled on an ice-bath and 161 ag of the compound prepared in stage D were added. This was 5 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. = 108-115"C. 10 MK spectrum : 0.9 ppm : t : 3 H : (CH2)3-CH3 1,1 a 2,1 ppm : m : 12 H : cyclopentane andc^-Cfy-Cfy-Cfy 2,7 ppm : t : 2 H : CH2-ch2-CH2-CH3 3.1 ppm : s : 2 H : -CHj-CO 15 5.1 ppm : s : 2 H : N-CH2-C6HS 7.2 a 7,8 ppm : a : 8 H : H aromatic. . EXAMPLE 11 20 2-n-butyl-4-spirocyclopentane-l-[(2'-tert- butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thione and 2-n-butyl-l-C2' -carboxybiphenyl-4-yl)methyl1-4-spiro-cyclopentane-2-imidazolln-5-thiane 25 A) 2-n-butyl-4-spiracyclapentane-l-C (2*-tert- butoxycarbonylbiphenyl-4-yl)methyl]-2-imidazolin-5-thiane 5.63 g of the compound prepared in example 1, stage D, were dissolved in 40 al anhydrous< toluene and reacted with 3 g of Lawesson's reagent under nitrogen at 80*C. After 5 hours, 30 the reaction medium was filtered and concentrated. The residue was chronatographed on silica by eiuting 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, m = 4.5 g. M.pt. = 77-79*0. JfME spectrum : - 45 - ?3/476 5 0.90 ppn : t : 3 H : ch3 (n-Bu) 1,20 ppm : s : 9 H : tBu 1.35 ppn : sext : 2 H : CH3-ch2- 1.60 ppn : quint : 2 H : CHj-Clfc'Cfy- 1.80-2,10 ppn : n : 8 H : cyclopentane 2,60 ppm : t : 2 H : CH3-CH2-CH2-CH2 5*35 ppn : s : 2 H : 7.25-7,80 ppn : n : 8 H : H aromatic B) 2-n-butyl-l-C(2'carboxybiphenyl-4-yl>methyl]-4-spiro-cyclopentane-2-lmidazolin-5-thione trifluoroacetate 225 mg of the compound obtained in stage A were treated with 5 ml DCX 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. M.pt. = 185-190 *C. 0*78 ppn : t : 3 H : CH3 (n-Bu) 1,20 ppn : sext : 2 H : ch3-ch2 1,50 ppm : quint : 2 H : ch3-ch2-ch2- lj75-2,00 ppm : m : 8 H : cyclopentane 2.40 ppm : t : 2 H : CH3-CH2-CH2-CH2 5.20 ppm : s : 2 H : 7.00-7,65 ppm : a : 8 H : H aromatic 25 EXAXPLE 12 2-n-butyl-4-(2-spiroindane)-l-C(2'-tert-butoxycarbonylbiphenyl-4-yl>methyl]-2-imidazolin-5-one. 30 and 2-n-butyl-l-C (2'-carboxybiphenyl-4-yDaethyl]-4-(2-spiroindane)-2-i3nidazolin-5-one. Method 1. A) 2-amino-2-indane-carboxylic acid was prepared in accord with R.X. Pinder, J. Xed. Chem., 1971, 1£, 9, 8^2 and the corresponding ethyl ester was then prepared in accord with Adkins 3fXR spectrum : Mass spectrum : XH+ : 421 - 46 - 2SEPI99I (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 in the presence of 60 micro-1 acetic acid and heated under reflux for 3 hours. 500 ag ethyl valerimidate were added again and the reflux maintained far 3 additional hours. The reaction medium was concentrated and then chroaatographed on silica by eiuting with a hexane/ethyl acetate/acetic acid aixture <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. fflCR spectrum : 0.90 ppn : t : 3 H : CH3 (n-Bu) 1,2-1,7 ppn : m : 4 H : CH2-CH2-CH3 2.4 ppn : t : 2 H : CH2-(CH2)2-ch3 2,8-3,2 ppn : q : 4 H : 2CH2 (indane) 4.90 ppn : s, 2 H : CHj-C^-7.2 ppn : n : 4 H : H aromatic C) 2-n-butyl-4-(2-spiroindane)-l-C <2'-tert-butoxycarbonyl-biphenyl-4-yl)methyl2-2-imidazolin-5-one. The compound obtained in the preceding stage was dissolved in 20 ml anhydrous DMF and treated with 450 ag sodium aethylate under nitrogen. After 20 minutes at ambient temperature, 3.6 g 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl were added and the mixture 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 chronatographed on silica by eiuting 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). HUE spectrum : - 47 - 23 7476 0,80 ppn : t : 3 H : CH3 n-Bu 1,20 ppn : s : 9 H : tBu 1.20-1.60 ppn : n : 4 H : CH^-CHj-Cfy 2.40 ppn : t : 2 H : CH2-(CH2)2-CH3 2.9-3.3 ppm : q : 4 H : 2CH2 (indane) 4,80 ppn : s : 2 H : N-CH2-C6H4-7.20-7.80 ppn : m : 12 H : H aromatic D) 2-n-butyl-l-C 2' -carboxybiphenyl-4-yl>methyl] -4-spiroindane-2-iaidazolia-5-one trifluoroacetate 1.71 g of the compound obtained in the preceding stage was dissolved in 15 ml DCX and treated with 20 al TFA. After 30 minutes, the reaction medium was concentrated and taken up with ether. After grinding up, the solid obtained was centrifuged, rinsed with ether and dried. 1.42 g expected product was obtained. K.pt. = 217-218*C. SXH spectrum : 0.70 ppn : t : 3 H : ch3 (a-Bu) 1.10-1.50 ppn : m : 4 H : CH2-CH2-CH3 2,30 ppm : t : 2 H : CH2-(ci£)2-CH3 2,8-3.3 ppn : q : 4 H : 2CH2 (indane) 4.70 ppn : s : 2 H : N-Cfe-CtfU-7,1-7.7 ppn : n : 12 H : H aromatic Other compounds in accord with the invention have been prepared ia 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 HTXR spectra. EXAMPLE 13 2-a-butyl-l-C(2 • -(1-imidazolylcarboayl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one - 48 - (I : Ri = -C-N R2 = H, R3 - n-C^, olv' CR4R5 = cyclopentane, X = 0) A aixture containing 404 ag of the compound prepared in example 1, stage E, 15 al THF and 260 ag 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 ng product were obtained which were purified by chromatography on silica by eiuting with a DCX/ethyl acetate mixture (70/30 ; v/v) to obtain the expected coapound. m = 230 ag X.pt. = 120*C EXAMPLE 14 2-a-butyl-l-L (2'-(3-cyano-2-aethyl-isothioureidoaethyl)biphenyl-4-yl)aethyl]-4-spirocyclapentane-2-iaidazolin-5-one. SCH3 (I : Ri = -CH2-NH-C=N-CN, R2 = H, R3 = n-C^Hg, CR4 R5 = cyclopentane, X = 0) A) 1-C(2' -aminomethylbiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-iaidazolin-5-one. This coapound was obtained by hydrogenation of the coapound prepared in example 5. 1 g of the compound prepared in example 5 stage A was placed in 15 al absolute methanol and 2.3 ml ethanol in the presence of (0.5 g) 57, 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. B) A mixture containing 300 ag coapound prepared in the preceding stage and 113 ag 5-cyanimido-S,S-dimethyl- 237 4 7 6 dith-iocarbonate in 3 ml ethanol was refluxed for 24 hours. After the usual treatment, the reaction medium was purified by chromatography on silica by eiuting with a DCM/ethyl acetate mixture (50/50 ; v/v/). The expected product was isolated in 5 the form of a white solid. m = 307 mg M. pt. = 83*C. EXAMPLE 15 10 2-n-butyl-l-C (2l-(2-cyanoguanidinomethyl)biphenyl-4-yl)methyl]-4-spirocyclopentane-2-imidazolin-5-one NH2 (I : Ri = CH2-NH-C=N-CN, R2 = H, R3 = n-C4H9, 15 CR4R5 = cyclopentane, X = 0) This compound was obtained by starting with the compound prepared in the preceding example. 200 mg of the compound were 2q 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 eiuting with a DCM/methanol mixture (95/5 ; v/v). 130 mg expected product was obtained. 25 M.pt. = 100*C. EXAMPLE 16 2-n-butyl-4-spirocyclopentane-l-C (2'-trifluoromethyl-3q sulfonylaminobiphenyl-4-yl)methyl]-2-imidazoli n-5-one trifluoromethylsulfonate (I : Rj = -NHSO2CF3, R2 = H, R3 = n-C^, CR4R5 = cyclopentane, X = 0) A) 4-methyl-2'-nitrobiphenyl - 50 - ? V & 7 / . • t 11.2 g 2-nitrobraaabenzene and 15 g 4-iodotoluene were mixed together, heated to 195*C and left at this tesperature with stirring for 3;: hours. After cooling to ambient temperature, the mixture was taken up with DCM and refluxed. The warm solution was 5 filtered on Celiter; and then the DCM was evaporated off. m = 6.5 g 3. pt. = 80-120*C at 0.2 am Hg, nQ24 = 1.6042 3) 4-broEomethyi-2, nitrobiphenyl. A aixture containing 6.5 g 4-sethyl-2'-nitrobiphenyl, 10 5.42 g 5BS, 118 mg azo-bis-isobutyronitrile and 500 ml tetrachloromethane were refluxed. The mixture was cooled to 0°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-C(2*-nitrobiphenyl-4-yl)methyl!-4-spirocyclo-15 peatane-2-imidazolin-5-one. A mixture containing 260 mg 50% sodium hydride in 5 ml DMF was xade up and 500 mg 2-n-butyl-4-spirccyclopentane-2-iaidazolin-5-one, prepared as in example 2, stage A was added at ambient teaperature and under nitrogen. After 15 minutes with 20 stirring, 901 mg 4-bromommethyl-2' -nitrobiphenyl in 5 ml DMF were added and left for 24 hours with stirring. The reaction medium was concentrated to dryness, and taken up with a water-ethyl acetate aixture. The organic phase was decanted off, dried over sodium sulfate, filtered and then the ethyl acetate evaporated 25 off. The product which was obtained was chromatographed on silica by eiuting with a DCM/ethyl acetate aixture (9/1 ; v/v). 500 ng expected product was obtained. D) 1- [ ('2' - aminobiphenyl-4-yl)aethyll -2-n-butyl-4-spirocyclo-pentane-2-imidazolin-5-one. 30 450 mg of product obtained in the preceding stage were placed in 10 al 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-C(2*-trifluoromethyl- C r r, u ; - 51 - ? 3 / 4 7 6 sulfonylaainobiphenyl-4-yl) metiiyl 3 -2-iaidazolin-5-one trifluoroaethylsulfonate 225 ng product obtained in tie preceding stage and 0.1 mi triethylaaine were mixed in 4 al OCX and to this was added 5 0.2 al trifluoromethylsulfonic acid anhydride, under argon, at -78'C and then left to return, to ambient temperature. The reaction aediua was washed with water and a solution of sodium bicarbonate and then dried and concentrated. 150 mg of an amorphous white solid was obtained. 10 SXR spectrum : 0,4-1,3 ppn : n, 7 H : CH3-CH2-CH2- l#4-2,3 ppn : m, 10 H : CH3-CH2-CH2-CH2 and cyclopentane 4-4.8 ppn : systen AB, 2H : N-CH2-C6H4-7-7,6 ppn : m, 8 H : aromatic 15 8.3 ppn : s, 1 H : -NH 10 ppn : s.e., 1 H : CFjSOjH^ EXAXPLS 17 20 2-a-butyl-4-spirocyclopentane-l-C(2'- trifluoromethylsulfcnylaainonethyl-bipheayl-4-yl)methyl]-2-imidazolin-5-one trifluoroaethylsulfonate (I : Rj = CH2NHSO2CF3, R2 s H, R3 = n-C^, CR4R5 = cyclopentane, X = O) The preparation took place starting with 1—C(2'— 25 aninomethylbiphenyl-4-yl)methyl]-2-n-butyi-4-spirocyclopentane-2-imidazolin-5-ane, 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 al trifluoroaethylsulfonic acid anhydride. This was allowed to 30 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 eiuting with DCM/ethyl acetate (95/5 ; v/v, then 99.5/0.5 ; v/v). m = 90 mg was obtained. - 52 - ? 3 7 4 X.?t. = 90"C. 3XR spectrum : 0,4-1,2 ppm : m, 7 H : -CHj-Cfy-Cfy I*3-2,45 ppm : m, 10 H : CH2-CH2-CH2-CH3 and cyclopentane 5 4,1-5 ppm : m 4 H : N-CHz-C^-and NH-CH2-C6H4- 7,1-7,7 ppm : m, 8 H : H aromatic 8.4 ppn : s, 1 H : NH 2-n-bui:yl-l-£ (2' -(!I-hydrox7acetanide)biphenyl-4-yl>nethyl2-4- spirocyclapeataae-2-imidazolin-5-one (I : R, = -C0-NH0H, R2 = H, R3 = n-QH*, cr4r5 = cyclopentane, X = 0) The compound prepared in example 2 was released from its trifluoroacetlc acid salt by taking up this compound with an acetate-water mixture and by adjusting the pH of the solution to pH 6 by adding a saturated solution of 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 mg of this compound were dissolved in chloroform, 860 ml thionyl chloride was added at 0*C and the mixture 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 DMF solution containing 200 mg hydroxylamine hydrochloride and 700 aicro-1 DIPEA in 10 ml DMF. After 2 hours at 0*C, the reaction medium was concentrated and taken up with 100 ml DCM 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 M. pt. = 35*C. \ I. 1J >• t:'\ 2 SEP 199iy C n ^ 1; ^ - 53 - EXAMPLE 19 2-n-butyl-4-spirocycl3pantane-l-!I (2'-'jreidafcipher.yl-4-yl)methyl]-2-imidazalin-5-ane (I : R, = NHCONH2, R2 = H, R3 = 11-C4H9, CR4R5 = cyclopentane, X = 0) This compound was prepared by using the method described by 3.3. Xobu et al. in Org. Synth., 1957, 21, 52 starting with l-[(2*-aain.abiphenyl-4-yl )methyl]-2-n-buty1-4-spiracyclopentane-2-iaidazolin-5-one, prepared in example 14 stage A. 1 g of the latter was dissolved in 50 ml 65 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 cf sodium chlcride. After drying over sodium sulfate and filtration, the solution was concentrated and the oil obtained was purified by chromatography on silica by eiuting with a DCX/methancl mixture (9/1 ; v/v). m = 600 mg 5MR spectrum : 0,85 ppo : t, 3 H : CH2-CH3 1,35 ppm : sext, 2 H : 1,6 ppm : quint, 2 H : CH2-CH2-CH3 1.7-2 ppn : m, 8 H : cyclopentane 2,45 ppm : t, 2 H : CH2-CH2-CH2-CH3 4.8 ppm : s, 2 H : -CH2-CjH4-6,05 ppm : s, 2 H : NH2 7-8 ppm : m, 9 H : 8 H aromatic . + NHCO EXAMPLES 20 and 21 l-[ (2'-carboxybiphenyl-4-yl)methyl3-2-n-propyl-4-spirocyclo-hexane-2-iaidazolin-5-one and 1-t(2'-(5-cyanacarboxyamide)biphenyl) methyl]-2-n-propyl-4-spirocyclohezane-2-imidazolin-5-one - 54 - 2 / "r-1""? / L 1 H : A) ethyl butyrimidate hydrochloride CH3 - CH2 - CH2 - » »C1 OC2H5 This coapound was prepared in accord with XcElvain (J. Aner. Chen. Soc., 1942, fi±, 1825-1827). 23 nl butyronitrile were added to a solution of 10.6 g gaseous hydrogen chloride in 20 al anhydrous ethanol and left for 4 days at 0*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 vacuua. 25.8 g 15 expected product was obtained. 3) Ethyl butyriaidate 16 g i si date obtained in stage A were dissolved in 100 al dichloroaethane and 50 nl water and 15 3 potassiua carbonate were added. After decanting, the dichloroaethane was 20 dried over potassiua carbonate and then evaporated to dryness without being heated. C) The ethyl ester of 1-aminocyclohexane carboxylic acid 1-aninocylohexanoic acid is available commercially. 15 g of this aainoacid 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 nediua 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 nl ether and 100 nl water. A 30 solution of potassiua 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-imidazolin-5-one - 55 - ?3 14 g of the product obtained ia stage C were dissolved in 200 nl xylene containing 0.6 al acetic acid. Half the imidate obtained in stage 3 was added and the aixture was heated under reflux. After 1': hours, half of the remaining iaidate 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 imidazolinone was obtained. X.pt. = 124-125*C. IR (CHCls) : 1715 cm*1 : C = 0 1635 cm-' : C - N Kate : The compound present in solution is actually an imidazolin-5-one, from the positions of the IS bands. E) 2-n-propyl-4-spirocyclohexaae-l-C (2'-tert-butoxycarbonyl-biphenyl-4-yl)aethyl]-2-iaidazalin-5-one 970 ag imidazolinone obtained in stage D was added to 0.24 q of 80% sodium hydride in oil in suspension in 10 ml dimethylforaamide. After stirring for 20 minutes, 1.91 g 4-braaomethyl-2,-teri-butoxycarbonylbiphenyl, prepared according 1 European patent 324 377, was added over 5 minutes. After 1 hour's stirring, the aedium was concetrated under vaccum and half taken up with 100 ml ethyl acetate and then in 20 ml water. The organic phase was decanted off, washed with a saturated solution of sodiua chloride, dried over sodium sulfate and then concentrated under vacuum. The residue was chramatagraphed on silica by eiuting with an. ethyl acetate/toluene mixture. 2.10 g expected product was obtained in the fora of a wax. IR (CHCls) : 1705-1715 cm-' : C = 0, C = 0 Caster, imidazolinone) 1635 co-1 : C = N Analysis of the SXR spectrum confiraed the structure. F) 1-C <2'-carboxybiphenyl-4-yl)methyl3-l-n-propyl-4-spirocyclohexane-2-imidazolin-5-one (Exaaple 20). - 56 - Al 1.25 g tertiarybutyl ester obtained in stage S were stirred for 45 minutes ir. a aixture of 11 al dichloroaethane and 15 nl trifluoroacetic acid. After concentration under vacuua, the residue was taken up with ether- The solid which formed was filtered, washed with ether and then dried. 1.04 g of white soid was obtained. X.pt. = 170-172*C. 5MR spectrua : 7,10-7,80 ppn : m, 8 H : aromatic 4,90 ppn : s, 2 H : N-CH2"C6H<i-2,45 ppm : t, 2 H : CH3-CH2-CH2- 1,40-1,80 ppm : m, 12 H : spirocyclohexane + CH3-CH2-CH2-0,90 ppm : t, 3 H : CH3-CH2"CH2- 1.60 g trifluoroacetate obtained as above were dissolved in 150 al ethyl acetate plus 20 al water. IN" sodium hydroxide solution w added to obtain pH 5. The organic phase was decanted off, washed with a saturated solution of sodiua chloride, dried over sodiua sulfate and then evaporated to dryness. The residue obtained was absorbed in ethyl ether, filtered and dried. a = 1.14 g X.pt. = 208-210 *C G) 1~[ (2' - (H- cyanocarboxamide) biphenyl-4-yl)methylI-2-propyl-4-spirocyclohexane-2-iaidazolin-5-ane. (Szaaple 21) To 300 ag of compound prepared in the preceding stage, in suspension in 5 al DCX, were added 0.54 ml thionyl chloride. After 1"; hours, the reaction aedium was concentrated under vacuum, then evaporated twice from bencene. The acid chloride thus obtained was dissolved in 2 ml dioxan and added to 42 ag cyanaaide in solution in 1 ml dioxan containing 0.2 al 105 sodium hydroxide solution. After 1^ hours, the reaction aedium was diluted with 150 al 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 sodiua chloride, dried over sodium sulfate and then evaporated to dryness. The residue was chroaatographed - 57 - on silica by elutiag with a chlorofora/oethaaoi/acetic acid mixture (90/Q/2 ; v/v/v). 160 ng expected product was obtained as a solid. IR(KBr) : 2150 cnr1 : C = N mass spectrum : MH* : 429 ITMR spectrum : 7,20-7,70 ppn : n, 8 H : aromatic 4.75 ppm : s, 2 H : N-CH2-C$IU-2.40 ppn : 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 1-C (2* - {5- (4-carboxy-l, 3-thiazol-2-yl >acetamids> biphenyl-4-yl)methyl]-2-a-propyl-4-spirocyclohexane-2-iaidazolin-5-one. N 1—COOH (I : Hi s -C0NH-|j^ J) , R2 » H, R3 » n-C3H7, CR4R5 = cyclohexana, X = 0 This compound was prepared from the compound obtained in example 20. The 2-amino-4-ethaxycarbonyl-l, 3-thiazale was prepared in accord with B. Plouvier et al., J. Heteracycl. Chem., 1989, 2S. (6), 1646. A) 1-C(2'-(N-(carbethoxy-1,3-thiazol-2-yl) acetamido)-bipheayl-4-yl) methylJ-2-n-propyl-4-spirocyclohexane-2-imidazolin-5-one. To a solution of 404 mg of compound prepared in example - 58 - 20 and 190 mg of tie thiazole derivative in 4 ml DCM and 1 ml DMF, were added 500 ag BO? and 0.14 al 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 5 acetate and washed twice with a KHSO*-£iSO« 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 eiuting with an 10 ethyl acetate/toluene mixture. 120 mg expected product was obtained. M. pt. = 96-98*C. B) 1-t <2'-{IT-(4-carboxy-l,3-thiazol-2-yl)acetamide)biphenyl-4-yl> methyl]-2-n-propyl-4-spiracyclohexane-2-imidazolin-5-one. 15 To 110 ng of product obtained in the preceding stage, dissolved in 1 ml methanol and 1 al dioxan, was added 0.5 ml 2N sodium 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 20 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. a = 100 mg M.pt. = 145-148*C 25 NMR spectrum : 8.0 ppn : s, 1 H : H in 5 of thiazole 7.1-7,7 ppn : i, 8 H : aromatic ri 4,7 ppn : s, 2 H : N-CH2-C6H4-2.25 ppn : t, 2 H : CH2-CH2-CH3 30 1,2-1,8 ppn : n, 12 H : cyclohexaneand CH2-CH2-CH3 0.85 ppn : t, 3 H : CH2-CH2-CH3 EXAMPLE 23 / 2-n-butyl-l-C <2'-(2-cyanoguanidinacarbonyl>biphenyl-4- c:.a - 59 - SEP 1991 • yl) methyl ]-4-spirocyc lope r.tane-2-inida::olir.-5-ane. NH2 (I : Ri = CONH-C=N-CNf, R2 = H, R3 = IJ-C4H9, CR4R5 = cyclopentane, X = 0). The acid chloride of coapound A obtained in example 2 was prepared. 1 g cf 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 ng dicyanodiamide, 0.5 ml 105 sodium hydroxide solution, 0.5 ml water and 10 ml dioxan 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 eiuting with a DCM/methanol mixture (95/5 ; v/v). 100 mg expected product was isolated. EXAMPLE 24 4-benzylidene-2-n-butyl-l-£(2'carboxybiphenyl-4-yl)methyl]-2-imidazolin-5-one trifluoroacetate. (I : R, = COjH, Rj = H, R3 = n-C^, r4r5 = =CH-C6H5, X = 0). A) 4-(l-benzylidene-l-valeryiamino-methylamidoaethyl)-2,biphenyl-tertbutyl-carboxylate M. pt. = 105*C. C02tBu Starting from 5-Bac-alpha-dehydro-<L)-phenylalanine, the - 60 - ? 7,14 7 H-carboxyanhydride of alpha-dehydro-(L)-phenylalanine was prepared in accord with S. 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-5 tertbutyl-carboxylate. 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 100'C, concentrated under vacuum and then chronatographed on silica by eiuting with a 10 hexane/ethyl acetate mixture (4/1 ; v/v>. 580 ng of a white solid was obtained. H.pt. = 154*C IMR spectrum : I,3 ppm : s, 9 H : t-Bu -5 0,65 ppn : t, 3 H : CH3 (n-Bu) 2 ppm : t, 2 H : CI^-C^'CHj-CHj-CQ 4.4 ppm : d, 1 H : CHj-NH 6.8 ppn : s, 1 H : CH (=CH-C$H5) 20 3) 4-benzylidene-2-n-butyl-l-[(2'- tert-butoxycarbonylblphenyl-4-yl) methyll-2-imidarolin-5-one 440 mg of compound obtained in stage A were dissolved in 1 ml acetic acid and heated for 30 minutes at 100*C. The mixture was evaporated to dryness under vacuum and the 25 residue was chronatographed on silica by eiuting with a hexane/ethyl acetate mixture (4/1 ; v/v). 130 ng of expected product was obtained in an oily form. SMS spectrum : 4.9 ppn : s, 2 H : CH2 ( N-CHj-CfiiU-) 30 C) 4-benzylidene-2-n-butyl-l-E(2'carboxybiphenyl-4-yl)methyl3-2-imidazali n-5-one tr i f1uoroacetate. 100 mg compound obtained in the preceding stage were dissolved la 1 ml OCX and 1 ml trifluoroacetlc acid was added and then left with stirring for 40 minutes at ambient temperature and - 61 - 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 H.pt. = 85*C Xass spectrum : KH* : 439 SHE spectrum : 0.82 ppm : t, 3 H : CH3 (n-Bu) I.3 ppm : sext, 2 H : CH3-CH2-10 1.6 ppn : o, 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 ppo : o, 13 H : aronatic 15 EXAMPLE 25 4-benzylidene-l-t(2'-carboxybiphenyl-4-yl)methyl]-2-phenyl-2-imidazolin-5-one (I : R, = COjH, R2 = H, R3 = QHs, r4r5 = ^CH-C^Hj, 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, then cooled to ambient temperature and 1.49 g benzaldehyde added. After 1 hour at ambient temperature, 20 ml distilled water at 80*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. SMR spectrum : 7.4 ppm : s, 1 H : sCH-C^Hs 8.1-8.4 ppo : a, 10 H : aromatic C *\ 2 SEP 1991 - 62 - ? 7, "7 £ 7 /; B> 4- (l-benzoylamino-l-benzylidene-aethyiaaidoaethyD^'-biphenyltert bu tylcarboxy1ate • A mixture containing 500 ag of the compound obtained in the preceding stage, 570 mg 4-aminomethyl-2'-biphenyl-tert 5 butylcarboxuylate and 10 ml pyridine was heated at 110 *C for 3 hours. It was then evaporated under vacuum, taken up with chloroform aad then evaporated again. The residue was chromatographed an silica by eiuting with a hexane/ethyl acetate mixture (3/1 and then 2/1 ; v/v). 106 mg expected product was 10 obtained in the form of a yellow solid. IMS spectrum : 1.1 ppm : s, 9 H : t-Bu 4.35 ppo : t, 2 H : -CH2-NH 7.05-7,06 ppm : o, 19 H : H aromatic + C6Hs-CH= 15 8'65 PP" : t, 1 H : NH-CH2 9.9 ppa : s, 1H : NH-CH= C) 4-benzylidene-l-C (2'-carboxybiphenyl-4-ylJaethylJ-2-phenyl-2-iaidazolin-5-one A mixture of 1.2 g compound obtained in the preceding 20 stage aad 1.1 g freshly melted sodium acetate ia 5 ml acetic acid were heated under reflux far 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 eiuting with a chloroform/methanol 25 mixture (98/2 ; v/v). The solid which was obtained was recrystallized from ethyl ether. m = 692 mg M. pt. = 120 zC NMR spectrum : 3q 4.95 ppn : s, 2 H : Clfc-CaiU- 7.1-8.3 ppo : a, 19 H : H aromatic" + =CH-C$Hs EXAMPLES 26 and 27 2-n-butyl-l-C(2'-(2-methyltetrazol-5-yl)biphenyl-4-yl)methyl 1-4-spirocyclopentane-2-imidazolin-5-one (Example 26) "2 5EP!9?: - 63 - and 2-n-butyl-l-C (2'-(l-methyltetrazcl-o-yl) biphenyl-4-yl)methyl] -4-spirocycIopenta::e-2-i3idazalin-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 ng 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 eiuting 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 SMR spectra Example 26 0.7 ppm : t, 3 H : CH3- (n-Bu) 1,2 ppm : sext, 2 H : ch3-ch2- 1.4 ppa : quint, 2 H : CH3-CH2-CH2- 1,5-1,9 ppn : n, 8 H : cyclopentane 2.25 ppm : t, 2 H : CH3-ch2-CH2-CH2- 4,15 ppo : s, 3 H : N-ch3 4,6 ppn : s, 2 H : -N-CIfc-Ce^- 7 ppa : system AA*, BB*, 4 H : C^-Cggt- 7.3-7.75 ppo : a, 4 H : Example 27 0,7 ppa : t, 3 H : ch3 (n-Bu) 1,15 ppo : sext, 2 H : CH-t-CH?-1,38 ppo : quint, 2 H : CH3-CH2-CH2-1,5-1,9 ppo : m, 8 H : cyclopentane 2.2 ppo : t, 2 H : CH3-CH2-CH2-CH2- \ -v. » - 64 - 9 5 7 4 7 6 3,35 ppn : s, 3 H : N-ch3 4.6 ppm : s, 2 H : N-CHj-CfcHa 7 ppm : systeme AA1, BB'j 4 H : N-CHi'Cgjk" 7,4-7,8 ppm : m, 4 H : CHj'CgEi-CjHi" EXAMPLE 28 5 2-n-butyl-6-spirocyclopentane-3-E(2'-(tetrazol-5-yl)biphenyl-4-yl) methyl!-4 <1H> -5,5-dihydropyrimidin-4-one. A) ethyl cyclopentylidenacetate 10 6 g of 80% sodium hydride was placed in 40 ml benzene aad 57.1 ml ethyl triethylphosphonoacetate were added dropwise at a temperature below 35 *C. After 1 hour at ambient temperature, 24.3 ml cyclopentaaoae were added dropwise. The mixture was then heated to 65°C for 15 minutes and then colled to 15 ambient temperature aad the supernatant liquid decanted off. 25 ml benzene were added, heated to 65 *C for 15 minutes, cooled down and then the supernatant liquid was recovered. The operation was repeated once more. Sy evaporation of the liquors, 42 g expected product was obtained aad this was distilled. 20 B.pt. = 102*C at 11 ma Hg m = 22.8 g 3) (l-aainocyclopentyl)acetamide. 150 ml gaseous ammonia was added to 20 g ethyl cyclopentylideneacetate prepared in the preceding stage and 25 heated to 150*C for 72 hours. The product obtained after evaporation was purified by chromatography on silica by eiuting with a DCM/methanol/20% ammonia mixture (90/10/1 ; v/v/v/). The product obtained was dissolved in DCM and dried over sodium sulfate. It was then filtered and the DCM evaporated to obtain 30 7.2 g expected product. C) 2-n-butyl-6-spirocyclopentane-4(1H)-5,6-dihydropyrimidin-4-one A mixture containing 4.57 g (1-aininocyclopentyl) acetamide prepared previously, 25 nl 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 1 ,v/ '• '/ <■ V "2 SEP 1991 ^0...... J I H / O taken up with an ethyl acetate/sodium bicarbonate mixture and then washed with an aqueous solution of sodium chloride, dried over sodium sulfate and then purified by chromatography on silica by eiuting with a DCM/methanol mixture (98/2 ; v/v). 5 a = 5 g 1TMR spectrum : 0,75 ppm : t, 3 H : CHj (nBu) 1.2 ppo : sext, 2 H : CH3-CH2- 1.3-1,8 ppm : m, 10 H : CH3-CH2-CH2 and cyclopentane 10 2 ppm : t, 2 H : CH3-CH2-CH2-CH2- 2.15 ppn : s, 2 H : CH2-C0 9.95 ppn : s.e., 1 H : NH This compound is that obtained in example 10, stage C. D) 2-n-butyl-6-spirocyclopentane-3-C(2'- 15 (triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl]-pyrimidin-4- one. 327 mg 80% sodium hydride were mixed under nitrogen for 30 minutes in 30 ml DMF with 1.5 g of the preceding pyrimidinone and 5.27 g 4-bramonethyl-2'-(triphenylmethyltetrazol-5-20 yl)biphenyl 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 eiuting with an ethyl acetate/hexane 25 mixture (3/7 ; v/v). m = 3.2 g E) 2-n-butyl-6-spirocyclopentane-3-C(2'-(tetrazol-5-yl)biphenyl-4-yl)methyl]-4(1H)-5,6-dihydropyrimidi n-4-ane. 3 g of the compound obtained in the preceding stage were 30 placed in methanol and cooled on a water-ice bath, 2.2 ml 45 HC1 were added and left for 5 hours at ambient temperature. After evaporation the residue was taken up with ethyl acetate and water and sodium 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 2 5 j~ p-, • - 66 - pH 5 by the addition of dilute hydrochloric acid and then extracted with ethyl acetate, dried and concentrated. The product obtained was purified an silica by eiuting with a DCM/methanol mixture (95/5 ; v/v). 800 mg expected product was obtained. NttR spectrum : 0,85 ppm : t, 3 H : CH3 (nBu) 1*30 ppn : 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 ppn : 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 : n, 4 H : CHj-C^-C^- EXAXPLE 29 2-n-butyl-3-[(2'-carboxybiphenyl-4-yl)methyl] -5-spirccyclopentane-5(lH)-5,6-dihydropyrimidin-4-one trifluoroacetate A) ethyl l-cyanccyclopentanecarboxylate This compound was prepared according to Helv. Chim. Acta, 1952, 25. (?>, 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. Ta 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 1,4-dibromobutane were added simultaneously and dropwise to the reaction medium. Vhen the addition had finished, reflux was maintained for 2 hours. Then it was evaporated, absorbed in an ethyl ether -water mixture, washed with a saturated solution of sodium chloride and then dried. The product obtained distilled at - 67 - 115-120'C at 11 mm Hg. m = 24 g. B) ethyl l-aminomethylcyclopentanecarboxylate This compound was prepared by catalytic hydrogenation of the ethyl 1-cyanocyclopentanecarboxylate. ae 20 g of the ethyl 1-cyanocyclopentanecarboxylate were placed in 200 al ethanol with 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 Cellitev:.1, and evaporation, the residue was chromatographed an silica by eiuting with a DCM/methanol/20% ammonia mixture (98/2/0.5 ; v/v/v). m = 12.8 g C) 2-n-butyl-5-spirocyclopentane-4(lH>-5,6-dihydropyrimidin-4-one. A mixture containing 13.12 g of the compound obtained in the preceding stage and 13.5 g ethyl valerimidate 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 aad then dried and concentrated. m = 14 g. M. pt. = 89-91'C 3FMR spectrum : 0,80 ppm : t, 3 H : CH3 (nBu) 1.10-1,80 ppm : m, 12 H : CH3-CH2-CH2- et 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-spirocyclopentane-3-C (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 ail DMF, in the presence of 115 agof 30% sodium hydride in oil, under argon, and stirred at ambient temperature for half an hour. 1.08 g 4-bromomethyl-2'-tert-butoxy - 68 - QQ1 ' carbonylbiphenyl were added aad the aizcture was stirred for another 2 hours. After evaporation, the residue was absorbed ia an ethyl acetate - water mixture, washed with a saturated solutioa of sodiua chloride, cancentrated aad chromatographed on silica by eiuting with an ethyl acetate/hexane aixture (3/7 ; v/v). a = 280 ag E) 2-n-butyl-3-C (21 -carbo:cybiphenyl-4-yl)methyl] -5-spirocyclopentane-5(lH>-5,6-dihydropryriaidin-4-one trifluoroacetate 250 ml of the tertiarybutyl ester prepared ia the preceding stage were dissolved in 10 ml DCM. This was cooled in an iced water bath and then 5 al cold trifluoroacetic acid wereadded and left for one hour with stirring in the cold, then for 1 hour at ambient temperature. The mixture was evaporated under reduced pressure. The residue was taken up with ethyl ether and then evaporated. The operation was repeated 3 times and then the residue from evaporation was taken up with hexane, ground up and the hexane decanted. The product was taken up with ethyl ether and the precipitate was filtered. a = 190 ag M.pt. = 153-155*C ITMR spectrua : 0.3S ppm : t, 3 H : CH3 (nBu) 1.35 ppm : sext, 2 H : CH3-CH2- 1*^5-2,20 ppn : a, 10 H : CHs-Cf^-CI^-and cyclopentane 2.80 ppm : t, 23 : CH3-CH2«CH2-CH2- 3.80 ppm : s, 2 H : CH2 (pyrimidinone) 5,15 ppa : s, 2 H : N-CH2- 7,25 ppa : a, 8 H : aromatic Table 1 (ex.) Ri : R3 CR4R5 Salt X. • ' £* * « (30) CO2H n-C4Hg cyclohexane TFA 172-174 (31) CO2CH3 11-C4H9 cyclopentane —- 86-87 (32) #- CO2H n-C4H9 C(CH3)C6H5 TFA 55-60 (33) CO2H n-C4Hg C(C2H5)2 TFA 82-84 (34) CO2H 11-C3H7 cyclopentane TFA 164 (35) (**) n-C4Hg cyclopentane — 163-164 (36) CO2H C6H5 cyclopentane TFA 178 (37) CO2H n-C4Hg cycloheptane TTA 160-162 (38) CO2H ch3 cyclopentane TFA 140 (39) CO2H 11-C4H9 cyclopropane — 204-205 (40) tetrazolyl-5 -CH2-CH2- ch=ch2 cyclopentane — 110 |37 4 7 » W r (41) tetrazolyl-5 n-C4H9 cyclohexane - 130 (42) tetrazolyl-5 1J-C3H7 cyclohexane — 141 05 (43) CO2H cyclopen cyclopentane TFA 82-88 -tyl (44) co2h n-CsHu cyclopentane TFA 151 (45) CO2H CH2-C6H5 cyclopentane TFA 88 10 (46) CO2H H cyclopentane — 230 (47) CO2H 11-C4H9 cyclobutane TFA 178 15 (48) CO2H n-C4H9 cyclododecane TFA 130-135 (49) CO2H 11-C4H9 adamantane-2 TFA 164-166 (50) co2h □-C4H9 (phenyl-4) TFA 155-157 20 cyclohexane (51) CO2H n-C4H9 (methyl-4) TFA 198-200 cyclohexane <*0 25 (52) CO2H n-C4Hg (N-acetyl) TFA piperidine-4 (53) CO2H C3F7 cyclopentane — 141-143 30 (54)*- CO2H 11-C4H9 CV.CF3 ch3\=/ — 207-209 • </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 2 3 7 4 7 (T (55) ^fr (56) (57) (58) CO2H CO2H CO2H C02H n-C4H9 11-C4H9 n-C4H9 Q-C4H9 <N-CO / CF5 CI _/ N-C0-^H-NH2 V-/ CH-C2H5 CH3 o C6H5 TFA TFA TFA 105 qv-vOfc ** : Rt « H et R2 « CO2H * These compounds have an asymsstric carbon atoa and were isolated 1 in the form of a mixture of optical isomers 72 15 Vi/HAT^WE CLAIM IS: - 1. A compound of formula : 4 7§ 10 (i) R5-J_CCH2)t CCH2L N 20 25 30 in which: - Ri and Ri are alike or different and each independently represents hydrogen or a group selected from, a Ci-Cs alkyl, a Ci-Ci alkoxy, amino, aminomethyl, carboxy, an alkoxycarbonyl in which the alkoxy is a C1~C4 alkoxy, cyano, tetrazolyl, methyltetrazolyl, methylsulfonylamino, trifluoromethylsulfonylamino, trifluoromethylsulfonylaminonethyl, N-cyano-acetamide, N-hydroxy-acetamide, N-(4-carboxy-l,3-thiazol-2-yl)acetajiide, ureido, 2-cyano-guanidinocarbonyl, 2-cyano-guanidinomethyl, imidazol-1-yl-carbonyl and 3-cyano-2-methyl-isothioureidomethyl, with the proviso that at least one of the substituents Ri or S2 is different from hydrogen; - R3 represents hydrogen, a C1-C6 alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a Cs-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a C2-<"6 or a phenylalkenyl in which the alkenyl is a alkenyl, the said phenyl groups being unsubstituted or substituted once or several times with a :G AUG 13S3 - 73 - 4 7$ halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, hydroxyl or a Ci-C* alkoxy; - R* and Rs each independently represent a Ci-Cs alkyl, a phenyl or a phenylalkyl in which the alkyl is a C^-Cg alkyl, the 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 and C^-C^ alkoxy; - or Pu and Rs together form a group with the formula =CR7Rb, in which R7 represents hydrogen, a Ci-C* alkyl or a phenyl and Rs represents a Ci-C* alkyl or a phenyl; - or R^ and linked together represent either a group with formula (CH2>n, or a group with formula (CH2>&Y(CH2)4, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Ci-C.i alkyl group, a phenyl or a phenylalkyl in which the alkyl is a C1~C3 alkyl, or an N-Eg group in which R« represents hydrogen, a Ci-C* alkyl, a phenylalkyl in which the alkyl is a c1~c4 alkyl, a c1~c4 alkylcarbonyl, a C1~C4 haloalkylcarbonyl, a C1-C1 polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an If-protecting group, or R* and Rs 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 one; - and its salts. A compound as claimed in claim 1 in which Ri is in the ortho position and represents a carboxy or tetrazolyl group and R2 is hydrogen. A compound as claimed in claim 1 or claim 2 in which and Rj. linked together constitute with the carbon ;to which 2S747g they are bonded a cyclopentane or a cyclohexane. A compound as claimed in any one of claims 1 to 3 in which R3 is a straight-chain C\-C& 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 2 = t = 0. A compound as claimed in claim 1 in which it is 2-n-butyl-4-spirocyclopentane-l-[ <2'-<5-tetrazolyl)biphenyl-4-yl)methyl]-2-imidazolin-5-one. A method far the preparation of a compound of formula (I) as claimed in any one of claims 1 to 7 comprising : al) reacting a heterocyclic derivative of formula : in which z, t, Rs, Hi and Rs have the meanings indicated for formula in claim 1, with a <biphenyl-4-yl)methyl derivative of formula.: 84 R5J-.(CH2)t \ (CH2)7 N 1 H In which Hal represents a halogen atom and R' i and R*2 - 75 - 25 30 23 7 a 7 6 represent either and Rj/ as defined for formula (I) in claim 1, or a precursor grouping for and R2; respectively; bl) optionally, the coapound thus obtained with formula : R4 R5 t (CH2)t (CH2)_ N z II. 10 in which all variables are as defined in formulae 2 and 3, is treated with Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetan 2,4-disulfide ; 15 cl) the compound obtained in al) or bl), of formula: R4 K5^L(CH2)t (CH2)2 20 in which X represents an oxygen atom or a sulfur atom and all other variables are as defined in formulae 2 and 3, is treated to prepare a compound of formula (I) by converting the R'^ and/or R'2 groups into R^ and/or R2 groups, as defined for formula (I) in claim 1, respectively. 9. A method for the preparation of a compound of formula (I) as claimed in any one of the claims 1 to 7 comprising: a2) reacting an aminoacid of formula: - 76 - 11 oct 1993 237476 R4^ ^/,(CH2)t"NHPr C 7 coop in which z, t, R4 and R5 have the meanings indicated for formula (I) in claim 1 and whose amine function is protected by the Pr group, with a (biphenyl-4-yl)methylamine derivative of formula: R'2 R'i H2N-CH2 ^ ^ \\ ^ ^ / in which R'^ and R^ represent either R^ and Rj as defined for formula (I) in claim 1 or precursors of and R2 respectively? 15 - b2) after deprotection of the amine, the compound thus obtained of formula : RA R'i \ 20 (ch2)2-c-nh-ch ZJ{ \ v\. R5 (CH2)t-NH2 in which all variables are as defined in formulae 7 and 8, 25 is then treated with an alkyl ortho-ester of formula R^C(OR)g (10) in which R3 has the meaning indicated for formula (I) in claim 1 and R is a C1-C4 alkyl: c2) optionally, the compound thus obtained of formula: o : o'- 1 * OCT 1993 - 77 - 237476 10 15 20 in which Rj is as defined for formula (I) in claim 1 and all other variables are as defined in formulae 7 and 8, is treated with Lawesson's reagent 2,4-bis (4-nethoxyphenyl) -1,3-dithia-2,4-diphosphetan 2,4-disulfide; d2) the compound thus obtained in b2) or c2) of formula: I"4 Xs/-(CH2h (ch2)z n in which X represents an oxygen atom or a sulphur atom and all other variables are as defined in formula 4 is then treated under appropriate conditions to prepare a compound of formula (I) by converting the R1 ^ and/or R'2 groups into and/or R^ groups respectively, as defined for formula (I) in claim 1. 30 10. A method for the preparation of a compound as claimed in claim 6 comprising: a3) reacting an imidazole derivative of formula : M N 11 R5 \3 in which R3, r^ anrf R^ have the meanings indicated for formula (I) in claim 1, with (biphenyl-4-yl)methyl derivative of formula: - 78 - - f ^ I O V- i \ 't /\i 23 7 4 R'2 Hal-CH2 -Q-C 10 15 in which Hal represents a halogen atom and R* i and R'2 represent either Ri and Ra or precursors of Ri and Ra respectively, in the presence of oxygen and UV irradiation, in a basic medium ; b3)optionally, the compound thus obtained of formula 20 in which all variables are as defined for formulae 11 and 3, is treated with Lawesson's reagent 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetan 2,4-disulfide ; c3> the compound thus obtained in b3) or c3) of formula : 25 30 R4 '°—Q 51 in which X represents an oxygen atom or a sulfur atom and all other variables are as defined in formulae 11 and 3, 5 I - 79 - % 15 20 25 is then treated under appropriate conditions to prepare a compound of formula (I) by converting the R'^ and/or R'j groups into and/or R2 groups respectively. 11. A compound of formula : in which : - Ra represents hydrogen, a Ci-Cs alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C* alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a Ci~C6 alkyl or a phenylalkenyl in which the alkenyl is a C^~C^ alkenyl, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C4 alkyl, a Ci-C* haloalkyl, a Ci-C* polyhaloalkyl, hydroxyl or a Ci-C* alkoxy; - Rt and Rs each independently represent a Cj-Cs alkyl, a phenyl or a phenylalkyl in which the alkyl is a Cj-C^ alkyl, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a Ci-Cx perfluoroalkyl, hydroxyl and alkoxy; - or R* and Rs together form a group with the formula =CR7Ra, in which R7 represents hydrogen, a C1-C1 alkyl or a phenyl II - 80 - 23 74 76 and Ra represents a C1-C4 alkyl or a phenyl; - or and R- linked together represent either a group with formula (CHi)n, or a group with formula (CHi)PY(CHi)q, in which Y is either an oxygen atoa, a sulfur atom, or a carbon atom substituted with a Ci-C* alkyl group, a phenyl or a phenylalkyl in which the alkyl is a c1~cg alkyl, or an N-Rg group in which Rs represents hydrogen, a Ci-C* alkyl, a phenylalkyl in which the alkyl is a C1~C4 alkyl, a alkylcarbonyl, a haloalkylcarbonyl, a C -C4 polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an N-protecting group, or ft and Ss linked together with the carbon atom to which they are bonded, constitute an indane or an adanantane; - 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 one; with the restriction that, -when s and t are zero and X is an oxygen atom, R* and Rs are other than a C^-Cg alkyl, a phenyl or a phenyl alkyl in which the alkyl is a C^-C^ alkyl, the said alkyl, phenyl and phenyl alkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group chosen from a perfluoroalkyl, hydroxyl and a C^-C^ alkoxy; ' or and R^ linked together are other than (CI^) Y (Cf^) where p+q must equal 2 to 5 and Y is an N-Rg group in which Rg is hydrogen, a alkyl or a phenylalkyl in which the alkyl is a alkyl, and 9 n is different from 6 ; or 0 when R^ represents a substituted phenyl group, R^ and R^ together are other than a (CI^) grouP in which n is between 3 and 5; and, when z = 1 and R^ is a phenyl, R^ and R,- are each different from methyl. '.v A compound as claimed in claim 11 of formula: .! 11 OCT 1993 23 74 di') in which X is an oxygen atom or a sulfur atom and R3 is hydrogen, a Ci-Cs alkyl, unsubstituted or substituted with one or several halogen atoms, a Ci-Cs alkenyl, a cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a C^-C alkyl or a phenylalkenyl in which the alkenyl is C2-C21 the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a C1-C1 alkyl, a C-.-Cx haloalkyl, a Ci-C* polyhaloalkyl, hydroxyl or a Ci-Ci alkoxy, with the proviso that is other than a substituted phenyl group when X is oxygen. 13. A compound as claimed in claim 11, of formula: R4 R5-Y N y \»/ R3 en") I H in which S3, R», Rs and X have the definitions given above for formula (II) in claim 11. 14. A compound as claimed in claim 11, of formula: R4 R5 <*• J l|_*3 di"') A / I . H , ■' £. j\ , -V" ^ J - 82 - 11 on 1593 ill which ; - R3 represents hydrogen, a Ci-C« alkyl which is unsubstituted or substituted with one or several halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is a c^-cg alkyl or a phenylalkenyl in which the alkenyl is a C -C3 alkenyl, the said phenyl groups being unsubstituted or substituted once or several times with a halogen atom, a Ci-C« alkyl, a C1-C4 haloalkyl, a Ci-C* polyhaloalkyl, hydroxyl or a Ci-C* alkoxy; - Rt and Rs each independently represent a Ci-Ce alkyl, a phenyl or a phenylalkyl in which the alkyl is a C^-C3 alkyl, the said alkyl, phenyl and phenylalkyl groups being unsubstituted or substituted with one or several halogen atoms or with a group selected from, a C1-C4 perfluoroalkyl, hydroxyl and alkoxy; - or L and Rs together form a group with the formula =CR?R8, in which R7 represents hydrogen, a Ci-C< alkyl or a phenyl and Ra represents a C1-C4 alkyl or a phenyl; ~ or R^ and linked together represent either a group with formula (CH2>n, or a group with formula (CH2)PY(CH2)q, in which Y is either an oxygen atom, a sulfur atom, or a carbon atom substituted with a Ci-C* alkyl group, a phenyl or a phenylalkyl in which the alkyl is a Ci-C3 alkyl> an N-Rg group in which Rs represents hydrogen, a C1-C4 alkyl, a phenylalkyl in which the alkyl is a C^-C^ alkyl, a C^-Cj alkylcarbonyl, a C^-C haloalkylcarbonyl, a C»-Ci polyhaloalkylcarbonyl, benzoyl, alpha-aminoacyl or an N-protecting group, or Ri and Rs 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; 23 74 7 6 - X is an oxygen atom or a sulfur atoas; with the restriction that Rs is other than a phenyl when R4 and Rs are each methyl. 5 15. A method for the preparation of a compound as claimed in any one of claims 11 to 14 comprising reacting a compound of formula: *4 (CH2)zC0A iO ><( 11 R5 (CH2)tNH2 in which z, t, and R,. have the definitions indicated 15 above for formula (II) in claim 11, A is an NH2 group or an OR' group, R' being hydrogen or a C1-C4 alkyl, with a compound of formula : Rj - B 14. 20 in which Ri has the definition indicated in any one of claims 11 to 14 and B is: - a C(0R>s group ' 0\ 25 - a C group 7 \ OK ^ ^ ' 24 f;0V|J93 --or a COHal group, v 30 S being a Ci-C1 aliyl and Hal being a halogen atom; then optioanlly, the compound thus obtained is treated with Lawesson's reagent, 2, 4-bis(4-methoxyphenyl)-l,3-dithia-2, 4-diphosphetan 2,4-disulfide. 16. The method according to claim 15 wherein Hal is chlorine. 17. A pharmaceutical preparation which comprises as the active - 84 - principle a compound as claimed in any one of claims 1 to 7. A pharmaceutical preparation containing a compound as claimed in any one of claims 1 to 7 in association with a beta-blocking compound. A pharmaceutical preparation containing a compound as claimed in any one of claims 1 to 7 in association with a diuretic. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 7 in association with a non-steroid anti-inflammatory agent. A pharmaceutical composition containing a compound as claimed in any one of claims 1 to 7 in association with a calcium antagonist. A pharmaceutical composition containing a compound as claimed in any one of the claims 1 to 7 in association with a tranguillizer. SANOFI </div>