IL103116A

IL103116A - N-substituted heterocyclic derivatives, pharmaceutical compositions containing certain such compounds and their preparation

Info

Publication number: IL103116A
Application number: IL103116A
Authority: IL
Original assignee: Sanofi Elf
Priority date: 1991-09-10
Filing date: 1992-09-09
Publication date: 1998-04-05
Also published as: PL171524B1; AU661017B2; NO180678B; NZ244258A; FR2681067A1; NO180678C; TW218871B; CZ275992A3; PL295874A1; LT3148B; IL103116A0; FR2681067B1; EP0532410A1; ZA926899B; AU2286892A; LTIP119A; RU2107062C1; JPH05213894A; MX9205155A; LV10255A

Abstract

The invention relates to N-substituted heterocyclic derivatives of formula: <IMAGE> in which: - R1 and R2 are similar or different and each independently represent hydrogen or a group chosen from a C1-C6 alkyl, a C1-C4 alkoxy, an amino, an aminomethyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl, a methylsulphonylamino, a trifluoromethylsulphonylamino, a trifluoromethylsulphonylaminomethyl, an N-cyanoacetamido, an N-hydroxyacetamido, an N-(4-carboxyl-1,3-thiazol-2-yl)acetamido, a ureido, a 2-cyanoguanidinocarbonyl, a 2-cyanoguanidinomethyl, an imidazol-1-ylcarbonyl or a 3-cyano-2-methylisothioureidomethyl, provided that at least one of the substituents R1 or R2 is other than hydrogen; - R3 represents a hydrogen, a C1-C6 alkyl which is unsubstituted or substituted by one or a number of halogen atoms, a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3 or a phenylalkenyl in which the alkenyl is C2-C3, the said phenyl groups being unsubstituted or substituted one or a number of times by a halogen atom, a C1-C4 alkyl, a C1-C4 haloalkyl, a C1-C4 polyhaloalkyl, a hydroxyl or a C1-C4 alkoxy; - R4 represents a C1-C6 alkyl which is unsubstituted or substituted by one or a number of halogen atoms; - R5 represents a cycloalkyl or a cycloalkylmethyl, the said cycloalkyl being C3-C7 unsubstituted or substituted by one or a number of halogen atoms; - or R4 and R5 each represent a cyclopropyl; - X represents an oxygen atom or a sulphur atom; - z and t are zero or one is zero and the other represents one; and its salts. Application: Angiotensin II antagonists. [EP0532410A1]

Description

103116/2 N-Substituted heterocyclic derivatives, pharmaceutical compositions containing certain such compounds and their preparation Elf Sanofi C. 87127 103116/2 - 1 - The present invention relates to N-substituted heterocyclic derivatives, to process and intermediates for their preparation and to pharmaceutical compositions comprising some of these compounds.

The present invention provides compounds of the formula R4 · τ R5^-^H2)t (A) X I Y in which: - R3 is a hydrogen ; a C1-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C5 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is. C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti- tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl , a C1-C4 polyhalogenoalkyl , a hydroxyl or a C1-C4 alkoxy; and - either R,, is a Cx-C6 alkyl which is unsubstituted or substituted by one or more halogen atoms; and - R5 is a cycloalkyl or a cycloalkylmethyl , the cycloalkyl being C3-C7, which is unsubstituted or substituted by one dr. more halogen atoms; - or and R5.are each a cyclopropyl; - Z- and t are each zero or one is zero and the other is one; - X is an oxygen atom or sulfur atom; - la - Y represents hydrogen or a group of the formula n which: RjL and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C5 alkyl, a ^-C^ alkoxy, an amino, an amino- methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl , a methylsulfonylamino , a tri- fluoromethvlsulfonylamino , a trifluoromethyl- sulfonvlaminomethvl, an . N-cyanocarbamoyl. an N- hydroxycarbamoyl, an N- ( 4-carboxy- 1 , 3-thiazol-2- yl) carbamoyl, a ureido, a 2-cyano-guanidino- carbonyl, a 2-cyano-guanidino-methyl , an imida- zol-l-ylcarbonyl and a 3-cyano-2-methylisothiou- reido-meth l , with the provisos that: 1) at least one of the substituents RL or R2 is other than hydrogen; 2) when Y is hydrogen then X is oxygen; 3) when z=t=0, R5 represents a cycloalkyl, and Y is hydrogen, then R3 is other than a phenyl . or a substituted phenyl and its salts. _ Formula (A) above includes the biologically active compounds of the formula in which: - R]_ and R2 are similar or different and are each independently hydrogen or a group selected from a C^- C5 alkyl, a C1-C4 alkoxy, an amino, an aminomethyl , a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl , a methylsulfonylamino, a trifluoromethylsulfonylamino, a trifluoromethylsulfonylaminomethyl , an "' N-cyano- •carbamoyl, an N-hydroxycarbamoyl, an N- ( 4-carboxy- 1 , 3-thiazol-2-yl ) carbamoyl, a ureido, a 2-cyano- guanidinocarbonyl , a .2-cyano-guanidinomethyl , an imidazol-l-ylcarbonyl and a 3-cyano-2-methyliso- thioureidomethyl , with the proviso that at least one of the substituents Ri or R2 is other than hydrogen; - R3 is a hydrogen, a C1-C alkyl ' which is unsubstituted or substituted by one or more halogen atoms ; a C2-C5 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenyl-alkyl in which the ' alkyl is 1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl , a hydroxyl or a C1-C4 alkoxy ; 103116/2 - 3 - \ - R4 is a C1-C5 alkyl which is unsubstituted or substituted by one or more halogen atoms ; - R5 is a cycloalkyl or a cycloalkylmethyl , said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ; - or R4 and R5 are each a cyclopropyl -; - X is an oxygen atom Or sulfur atom; and - z and t are zero or one is zero and the other is one ; and their salts.

The compounds of formula (I) according to the invention antagonize the action of angiotensin II, which is a peptide hormone of the formula H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH Angiotensin II is a potent vasopressor and the biologically active product of the renin-angiotensin system: renin acts on the angiotensinogen of the plasma to produce angiotensin I, which is converted to angiotensin II by the action of the angiotensin I converting enzyme.

The compounds of the formula (I) according to the present invention are non-peptide compounds which antagonize angiotensin II. By inhibiting the action of angiotensin II on its receptors, the compounds according to the invention prevent especially the increase in blood pressure produced by the hormone-receptor interaction; they also have other physiological actions on the central nervous system and on the kidneys, for example.

Thus the compounds of formula (I) according to the invention are useful in the treatment of cardiovascular complaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma and diabetic retinopathy and renal insufficiency. 103116/1 - 3a - If a compound according to the invention has an asymmetric carbon, the invention inclu-des the 2 optical isomers of this compound and their racemic mixture.

The salts of the compounds of -formula (I) according to the present invention include those with mineral or organic acids . which permit separation or suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulfonic acid, and acids which form pharmaceutically acceptable salts such as the hydrochloride,- the hydrobromide, the sulfate, the hydrogensulfate, the dihydrogenphosphate, the methanesulfonate, the methylsulfate, the maleate, the fumarate and the naphthalene-2-sulfonate .

The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with a tertiary amine such as trometamol, or else the salts of arginine, lysine or any physiologically acceptable amine.

According to the present description and in the claims which follow, halogen atom is understood as meaning a bromine, chlorine or fluorine atom; N-protecting group (also designated by Pr) is understood as meaning a group conventionally used in peptide chemistry for affording temporary protection of the amine group, for example a Boc, Z or Fmoc group or a benzyl group; esterified carboxyl group is understood as meaning an ester which is labile under appropriate conditions, such as, for example, a methyl, ethyl, benzyl or tert-butyl ester. "Alkyl" denotes linear or branched saturated aliphatic hydrocarbon radicals.

The compounds of formula ( I ) in which R]_ is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen are preferred compounds.

The compounds of formula ( I ) in which R4 is methyl and R5 is cyclohexyl are also preferred compounds .

Likewise, the compounds of formula (I) in which R3 is a linear Cj-Cs alkyl group are preferred compounds .

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

Finally, the compounds of formula ( I ) in which z = t = 0 are preferred compounds. 2-n-Butyl-4-methyl-4-cyclohexyl-l- [ ( 2 ' - ( tetrazol -5-yl )biphenyl-4-yl ) methyl] -2-imidazolin-5-one or one of its salts with acids or bases are particularly preferred.

The following abbreviations are used in the description and in the Examples: alcohol : ethyl alcohol Et : ethyl nBu, tBu : n-butyl, tert-butyl DMF : dimethylformamide THF : tetrahydrofuran DCM : dichloromethane NBS : N-bromosuccinimide DCC : dicyclohexylcarbodiimide DIPEA diisopropylethylamine ether ethyl ether TFA trifluoroacetic acid Z benzyloxycarbonyl Boc ' tert-butoxycarbonyl BOP : benzotriazolyloxytrisdimethylamino- phosphonium hexafluorophosphate Fmoc : fluorenylmethoxycarbonyl Lawesson's reagent : [2,4-bis(4-methoxyphenyl)-l,3-dithia-2, 4-diphosphetane 2, 4-disulfide] .

The present invention further relates to the method of preparing the compounds ( I ) . In said method : al ) a heterocyclic derivative of the formula in which z, t, R3, R4 and R5 are as defined above for (I), is reacted with a (biphenyl-4-yl )methyl derivative of the formula in which Hal is a halogen atom and R ' and R ' 2 respectively either and R2 or a precursor group Rl and/or R2; bl ) if appropriate, the resulting compound the formula is treated with Lawesson's reagent [2, 4-bis( 4-methoxy-phenyl )-l, 3-dithia-2, 4-diphosphetane 2, 4-disulfide] ; and cl ) the compound obtained in al ) or bl ) , of the formula in which X is an oxygen atom or a sulfur atom, is treated to give the compound ( I ) by conversion of the groups R'i and/or R'2 to the groups and/or R2 respectively ; dl ) the compound so obtained is converted if appropriate, into one of its salts, according to known methods well known by the skilled in the art.

Among the compounds 2, some of them are prior art compounds, the others are new and belong to the scope of the invention.

EP patent application 144 748 discloses herbicides of formula : X in which one of X and Y may represent an alkyl and the other a cycloalkyl ; furthermore the phenyl group may be substituted.

Thus the present invention further relates to the compounds (II) of the formula in which: - z and t are zero or one is zero and the other is one; - R3 is a hydrogen, a C^-C alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C6 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy; - R4 is a C1-C alkyl which is unsubstituted or substituted by one or more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl , the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms ; - or else R4 and R5 are each a cyclopropyl ; - X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl .

Among the derivatives (II), the compounds in which z = t = 0 of the formula : in which X, R3, R4 and R5 are as defined above for (II), with the proviso that R3 is other than a phenyl or a substituted phenyl when R5 represents a cycloalkyl are preferred compounds.

The compounds (II) in which z = 0 and t = 1, of the formula in which R3, R4, R5 and X are as defined above for (II), are preferred compounds.

Finally, the compounds (II) in which z = 1 and t = 0, of the formula in which R3, R4, R5 and X are as defined above for ( II ) , are preferred compounds .

The derivatives 2 are prepared by known methods. For example, it is possible to use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, a, 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 8_9_, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme: H in which R is a C1-C4 alkyl, R' is hydrogen or a C1-C4 alkyl and R3, R4, R5, z and t are as defined above for (I).

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

The compound 5_!_ are known compounds or are prepared by known methods. The compounds 5_1 can be obtained optically pure using methods of asymetric synthesis or methods of resolving the racemic mixture, such as those described in "Synthesis of Optically Active Alpha-aminoacids, R. . Williams, Pergamon Press, 1989".

According to another procedure, the compound 2 can be prepared by reacting an aminoalkylamide ( 5 ' ' ) with an alkyl ortho-ester (1£) in an acid medium in accordance with the following reaction scheme: tt 5 10 in which R is a C1-C4 alkyl.

Using a procedure described by H. Takenaka et al. (Heterocycles, 1989, 29.(6), 1185-89), it is also possible to prepare the compound 2 by reacting an acid halide of the formula R3-CO-Hal 12 in which Hal is a halogen, preferably chlorine, with the derivative 5 ' ' ; the cycl zation of the diamine is then carried out in a basic medium.

If z = t = 0, a derivative 5J can be prepared from a ketone by a procedure described in US patent 4 017 510 or in Swiss patent 540 271 : cyanure H+ ou OH" ttl 5 12 103116/2 The ketone R4R5CO is treated with cyanide (hydrocyanic acid, sodium cyanide or potassium cyanide) and ammonium ions (aqueous ammonia and ammonium chloride) ; the aminonitrile compound 5 " ' is then hydrolyzed to 5" ' , either in a strongly acidic medium or in a basic medium. If appropriate, the aminonitrile " ' can be resolved with an optically active acid by the procedure in European patent 153 000, in which case it is possible to prepare the compound 5_ and then the compound 2 in optically pure form.

More particularly, according to another object of the present invention, the compound 2 is prepared by a method which comprises reacting a compound of the formula R3-B 14 in which B is - a group C(0R)3 NH - a grouo C or * / OR - a group COKal R being a C-j_-C alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula R4 (CH )_COA R5^ (CH2)tNH2 in which A is an OH group, an NH2 group or a group OR', ' being hydrogen or a C^- ^ alkyl.

The ( biphenyl-4-yl )methyl derivative (3_) is prepared by a method described in European patent application 324 377, corresponding to IL 88,900. 13 103116/2 The conversion of a group R ' ^ and/or R'2 to a group R_ and/or R2 is effected by methods well known to those skilled in the art. Thus, if the compound (I) to be prepared possesses a group R^ and/or R2 = carboxyl, R'l and/or R'2 are an esterified carboxyl group. if the compound ( I ) to be prepared possesses a group R^ and/or R2 = tetrazolyl, R' _ and/or R'2 can be either a tetrazolyl protected for example by a trityl group, or a cyano group which will subsequently be replaced with a tetrazolyl group protected if necessary by a trityl. The conversion of the cyano group to a tetrazolyl can be effected with an azide, for example tributyltin azide or sodium azide.

It is also possible to use groups 'i and/or R'2 such as nitro, carboxyl, cyano or acid chloride groups and then to convert them by reactions well known to those skilled in the art to give groups- -Κχ and/or 2 as defined for the compound ( I ) .

Thus, if R'2 and/or R'2 are a carboxyl, they can be converted -to R_ and/or R2 in the form of an imidazol-l-ylcarbonyl or else an N- ( 4-carboxy-l , 3- thiazol-2-yl ) carbamoyl, The group R']_ and/or R'2 in the form of an acid chloride can be converted to R]_ and/or 2 in the form of N-hydroxycarbamoyl, N-cyanocarbamoyl, ureido or 2- cyanoguanidinocarbonyl .

The group R']_ and/or R'2 in the form of a nitro can be converted to amino, from which R^ and/or R2 is prepared in the form of methylsulfonylamino, trifluoro- methylsulfonylamino or trifluoromethylsulfonylamino- methyl.

The group R ' ]_ and/or R'2 i the form of a cyano can be converted to aminomethyl , from which a 3-cyano-2-methylisothioureidomethyl is prepared (according to C. Gordon et al . , J. Org. Chem. , 1970, 35.(6), 2067-2069) or a 2-cyanoguanidinomethyl is prepared (according to R.W. Turner, Synthesis, 1975, 332).

Step al ) is carried out in an inert solvent such as DMF, D SO or THF, in a basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate or triethylamine .

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

In the description below, the method comprising steps al, bl and cl is referred to as method 1.

Alternatively, the compounds (I) can be prepared by another method, which is also a subject of the present invention. In this method: a2 ) an amino acid of the formula COOH in which z, t, R4 and R5 are as defined above for (I), and of which the amine group is protected by the Pr group, is reacted with a ( biphenyl-4-yl )methylamine derivative of the formula in which R'i and R'2 are respectively either R^ and or a precursor group of R^ and R2; b2 ) after deprotection of the amine, resulting compound of the formula is then treated with an alkyl ortho-ester of the formula 3C(0R)3 (10), in which R3 is as defined above for (I) and R is a C1-C4 alkyl; c2 ) if appropriate, the resulting compound of the formula is treated with La esson's reagent [2,4-bis(4-methoxyphenyl)-l,3-dithia-2, 4-diphosphetane 2,4-disul-fide] ; and d2 ) the compound thus obtained in b2 or c2, of the formula is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R'l to the groups R2 and/or R^ respectively ; e2 ) the compound so obtained is converted if appropriate, into one of its salts according to known methods well known by the skilled in the art.

The compounds Z are known or are prepared by known methods (Chemistry of the Amino Acids, Greenstein and Winitz, published by John Wiley, 1961, vol. I, p. 697). If appropriate, these compounds can be obtained optically pure using methods of asymetric synthesis or methods of resolving the racemic mixture, such as those described in "Synthesis of Optically Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989".

The compounds £. are prepared according to European patent application 324 377. Step a2 ) is carried out under the usual conditions for the coupling of an acid with an amine, for example in the presence of BOP and DIPEA.

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

In the description below, the method comprising steps a2 to d2 is referred to as method 2.

In one variant of method 2, in step b2, it is possible, if appropriate, to isolate an intermediate 9_!_ of the formula and then to prepare the compound 4 by cyclxzation in an acid or alkaline medium.

The affinity of the products according to the invention for angiotensin II receptors was studied in a test for the binding of angiotensin II, labeled with iodine 125, to rat liver membrane receptors. The method used is the one described by S. KEPPENS et al. in Biochem. J., 1982, 20_8_, 809-817.

The IC50, namely the concentration which gives a 50% displacement of the labeled angiotensin II bound specifically to the receptor, is measured. The IC50 of the compounds according to the invention is less than 10"6 M.

Also, the effect of the products according to the invention as angiotensin II antagonists was observed on different animal species in which the renin-angiotensin system had been activated beforehand (C. LACOUR et al., J. Hypertension, 1989, 2 (suppl. 2), S33-S35) .

The compounds according to the invention are active after administration by different routes, especially after oral administration.

No signs of toxicity are observed with these compounds at the pharmacologically active doses.

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

The present invention further relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, or of a pharmaceutically acceptable salt, and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration .

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula I above, or their salts if appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

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

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

When a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances, or else they can be treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.

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

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

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

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

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

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

In addition to the products of formula I above or one of their pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles such as, for example, tranquilizers or other drugs which can be useful in the treatment of the disorders or diseases indicated above.

Thus the present invention relates to pharmaceutical compositions containing several active principles in association, one being a compound according to the invention and it being possible for the other or others to be a beta-blocking compound, a calcium antagonist, a diuretic, a non-steroidal antiinflammatory or a tranquilizer.

The following Examples illustrate the invention without however implying a limitation. The following abbreviations are used in these Examples: d denotes density, RT denotes room temperature, KHSO4-K2SO4 denotes an aqueous solution containing 16 . 6 g of potassium bisulfate and 33 . 3 g of potassium sulfate per liter.

The melting points (m.p.) are given in degrees Celsius; unless indicated otherwise, they were measured without recrystallization of the product.

The purity of the products is checked by thin layer chromatography (TLC) or HPLC. The products are characterized by their NMR spectra run at 200 MHz in deuterated DMSO with tetramethylsilane as the internal reference.

The specific optical rotation [a]D are measured at 22 *C ; path length : 10 cm, concentration 1 g per 100 ml.

The following abbreviations are used in the interpretation of the NMR spectra: s ; singlet sb : broad singlet d : doublet t : triplet q : quadruplet quint quintuplet sext : sextuplet m : unresolved signals or multiplet In addition, im denotes imidazole.

EXAMPLE 1 ( , S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4-cyclohexyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate A) 5-Cyclohexyl-5-methylhydantoin This compound is prepared according to J. Org. Chem., 1960, 25_, 1920-1924.

A solution of 50 g of cyclohexyl methyl ketone in 400 ml of 95* alcohol is added over 30 minutes to 29.4 g of sodium cyanide and 192 g of ammonium carbonate in 400 ml of water. The mixture is heated at 55-60* C for 4 hours and then evaporated to half its volume under vacuum and left to stand overnight at +4* C. The precipitate formed is filtered off, washed with water and then dried under vacuum over phosphorus pentoxide to give 65.5 g of the expected hydantoin, which is identified by its IR and MR spectra.

M.p. = 220* C.

B) ( R, S ) -2-Amino-2-cyclohexylpropionic acid This compound is prepared according to J. Org.

Chem., 1960, 25_, 1920-1924.

A mixture containing 7 g of the hydantoin prepared in the previous step and 28 g of barium hydroxide octahydrate in 150 ml of water is heated at 160* C for 5 hours in a steel tube. The reaction medium is saturated with dry ice, the insoluble material formed is filtered off and the filtrate is then concentrated under vacuum. The solid residue is taken up in acetone, filtered off and dried to give 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350* C with decomposition.

C) Ethyl ester of ( R, S ) -2-amino-2-cyclohexylpropionic acid 3 g of the acid prepared in the previous step are added to 40 ml of absolute alcohol saturated with gaseous hydrochloric acid and the mixture is then refluxed for 20 hours, with stirring. The reaction medium is evaporated under vacuum and the residue is taken up in an ether/water mixture, which is brought to pH 9 by the addition of a saturated solution of sodium bicarbonate. The organic phase is decanted, washed with a saturated solution of sodium chloride and then evaporated under vacuum to give 2 . 1 g of the expected ester in the form of an oil. Identification by IR and NMR spectra.

D) Ethyl valerimidate This compound is prepared in the form of the hydrochloride according to Mac Elvain (J. Amer. Chem. Soc, 1942 , £4 , 1825- 1827 ) . It is freed from its hydrochloride by reaction with potassium carbonate and then extracted with DCM.

E ) ( R, S ) -2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin- 5-one 2 g of the ester prepared in step C and 2 . 35 g of ethyl valerimidate are mixed in 6 ml of xylene, to which 6 drops of acetic acid are added; the reaction medium is refluxed for 6 hours. It is then concentrated under vacuum and the residue is chromatographed on fine silica gel using a chloroform/methanol/acetic acid mixture ( 95/9/3 ; v/v/v) as the eluent. The fractions containing the desired product are combined and then evaporated under vacuum; the residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of a solution of sodium hydroxide. The organic phase is decanted, washed with water and then with a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. The expected product is obtained in the form of a thick oil, which solidifies to give an amorphous solid, m = 1.56 mg.

- IR (chloroform): 1720 cm"1 : C=0 1640 cm-1 : C=N - NMR consistent.

F) 4-Bromomethyl-2 ' -tert-butoxycarbonylbiphenyl This compound is prepared by the method described in European patent application 324 377.

G ) ( R, S ) -2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' -tert- butoxycarbonylbiphenyl-4-yl )methyl] -2-imidazolin-5- one 1.5 g of the imidazolinone prepared in the previous step are dissolved in 20 ml of D F. 250 mg of sodium hydride as an 80% dispersion in oil are added. After stirring for 20 minutes, 2.48 g of the compound prepared in step F) are added and the reaction medium is left to stand for 2 hours at RT. It is taken up in an ethyl acetate/water mixture; the organic phase is decanted, washed with water and with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue is chromatographed on silica using an ethyl acetate/toluene mixture (1/4; v/v) as the eluent to give 1.8 g of the expected product in the form of a white wax.

- IR (chloroform): 1710-1730 cm-1 : ester and imidazolinone C=0 1630 cm-1 : C=N H ) ( R, S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl )methyl] - 4-cyclohexyl-4-methyl-2-imidazolin-5-one trifluoro- acetate 1.5 g of the compound obtained in the previous step are stirred for 40 minutes in 7 ml of TFA and 7 ml of DCM. The reaction medium is concentrated under vacuum and taken up in ether to give a white solid, which is filtered off, washed with ether and dried under vacuum. m = 1.40 g.

M.p. = 171* C.

MH+ : 447.

- NMR: 7.10-7.70 ppm : m : 8 aromatic H 4.45 ppm : s : 2 H : -CH2-C6H4- 1.25 ppm : s : CH3 in the 4 position EXAMPLE 2 ( R, S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4-cyclohexy1-methyl-4-methyl-2-imidazolin-5-one trifluoroacetate The following compounds are prepared from cyclohexyl methyl ketone according to the procedures described in Example 1 : A ) 5-Cyclohexylmethyl-5-methylhydantoin M.p. = 205-206* C.

B) (R,S)-2-Amino-3-cyclohexyl-2-methylpropionic acid Characterized by its IR and NMR spectra.

C) Ethyl ester of (R, S ) -2-amino-3-cyclohexyl-2-methyl- propionic acid Characterized by its IR and NMR spectra.

D) (R, S ) -2-n-Butyl-4-cyclohexylmethyl-4-methyl-2- imidazolin-5-one This product is obtained in the form of an oil, which solidifies. Identification by IR and NMR.

- IR (chloroform): 1720 cm-1 : imidazolinone C=0 1630 cm"1 : C=N E ) ( R, S ) -2-n-Butyl-4-cyclohexylmethyl-4-methyl-l- [ ( 2 ' - tert-butoxycarbonylbi-phenyl-4-yl )methyl] -2-imida- zolin-5-one This product is obtained by treating the compound of step D with 4-bromomethyl-2 ' -tert-butoxycarbonylbiphenyl in the presence of sodium hydride. After purification by chromatography, the product is in the form of an oil, which crystallizes in the refrigerator.

Yield : 51% .

M.p. « 73-75 * C.

- IR (KBr): 1700-1730 cm-1 : imidazolinone and ester C=0 1630 cm-1 : C=N F) (R,S) -2-n-Butyl-l- [ ( 2'-carboxybiphenyl-4-yl)methyl]- 4-cyclohexylmethyl-4-methyl-2-imidazolin-5-one trifluoroacetate Yield : 90% .

M.p. = 143- 146 * C.

- NMR: 7 . 20-7 . 80 ppm : 8 H : aromatic protons 4. 85 ppm : m : 2 H : N-CH2-C6H4- 2.70 ppm : t : 3 H : -CH2-CH2-CH2-CH3 1.80-0.85 ppm : m : 20 H : 4-methyl 4-cyclohexylmethyl -CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : CH2-CH2-CH2-CH3 EXAMPLE 3 (R, S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4-cyclohexyl-4-ethyl-2-imidazolin-5-one trifluoro- acetate A) (R, S )-2-Amino-2-cyclohexylbutyronitrile hemioxalate 1.18 g of ammonium chloride and 1.5 ml of a 32% aqueous solution of ammonia are added successively to a solution of 1.03 g of sodium cyanide in 6 ml of water, followed, over 15 minutes, by 2.8 g of cyclohexyl ethyl ketone in 5 ml of methanol, and the reaction medium is heated at 60* C for 6 hours. It is cooled and extracted 4 times with DCM and the extracts are then evaporated under vacuum. The residue is treated again with the same amounts of cyanide, ammonium chloride, aqueous ammonia, water and methanol at 60* C for 6 hours. The reaction medium is then cooled and extracted 4 times with DCM and the extracts are dried and then evaporated under vacuum. The residue is taken up . in 30 ml of acetone, and a solution of 1.1 g of oxalic acid dihydrate in 10 ml of acetone is added dropwise. After 15 minutes, the precipitate formed is filtered off, washed with acetone and then with ether and dried under vacuum to give 2.87 g of product, which becomes pasty at 120* C. Identification by IR and NMR.

- IR of the free base: 2220 cm-1 : C≡N B ) ( R, S ) -2-Amino-2-cyclohexylbutyramide 2 . 84 g of the nitrile obtained in step A are added over 30 minutes to 6 ml of pure sulfuric acid. The mixture is heated for 1 hour at 85 * C and then 30 minutes at 100 * C. After cooling, the reaction medium is added dropwise to 20 ml of iced 32% aqueous ammonia. The mixture is extracted with chloroform and the extract is then dried over sodium sulfate and evaporated under vacuum to give 2 . 5 g of the expected product in the form of a wax. Identification by IR and NMR.

C) (R, S ) -2-n-Butyl-4-cyclohexyl-4-ethyl-2-imidazolin-5-one 2 . 45 g of the product obtained in the previous step are dissolved in 30 ml of THF; 1 . 84 ml of triethylamine are added, followed, over 25 minutes, by a solution of 1 . 73 ml of valeroyl chloride in 10 ml of THF. After stirring for 2 hours, 3 . 57 g of potassium hydroxide pellets, then 4 ml of water and then 10 ml of methanol are added and the mixture is refluxed for 3 hours. After cooling, 6 g of ammonium chloride are added and the reaction medium is concentrated to half its volume and then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum. The residue is taken up in 10 ml of hexane and left to stand for 4 hours at 0 * C. The solid formed is filtered off and dried. m = 2 . 62 g.

M.p. = 80-85 * C.

Identification by NMR and IR (chloroform and KBr).

D) ( R, S )-2-n-Butyl-l-[ ( 21 -tert-butoxycarbonylbiphenyl- 4-yl )methyl] -4-cyclohexyl-4-ethyl-2-imidazolin-5-one The procedure described in Example 1, step G), is followed; 1.50 g of the expected product are obtained, after chromatography, by treating 1 g of the product of step C) with 4-bromomethyl-2 ' -tert-butoxycarbonylbiphenyl .

- IR (chloroform): 1700-1720 cm~l : imidazolinone and ester C=0 1635 cm-1 : C=N E ) ( R, S )-2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl )methyl] - 4-cyclohexyl-4-ethyl-2-imidazolin-5-one trifluoroacetate The expected product is obtained by treating the compound obtained in the previous step by the method described in Example 1, step H).

Yield : 85%. .p. = 159-161* C.

- NMR: 7.10-7.70 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : - -CH2-C6H4- 2.60 ppm : t : 2 H : -CH2-CH2-CH2-CH3 0.90-1.90 ppm : m : 17 H : cyclohexyl + -CH2-CH3 + -CH2-CH2-CH2-CH3 0.80 ppm : t : 3 H : -CH3 0.60 ppm : t : 3 H : -CH3 EXAMPLE 4 ( R, S )-2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' -( tetra- zol-5-yl )biphenyl-4-yl )methyl] -2-imidazolin-5-one A) 4-Methyl-2 ' - ( tetrazol-5-yl )biphenyl 2 ' -Cyano-4-methylbiphenyl is prepared according to European patent application 324 377. 2 g of this compound are placed in a round-bottomed flask in the presence of 4 g of tributyltin azide and 20 ml of xylene and the mixture is refluxed for 110 hours. After it has returned to RT, the reaction medium is diluted with toluene and the organic phase is then extracted 3 times with 50 ml of 1 N sodium hydroxide solution. The aqueous phases are combined, washed with ether and then cooled in a bath of iced water and acidified to pH 1-2 by the addition of concentrated hydrochloric acid. The precipitate formed is filtered off, washed with water and dried under vacuum over phosphorus pentoxide to give 2.18 g of the expected product .

M.p. = 146-148* C after recrystallization from ethyl acetate.

B) 4-Methyl-2 ' - ( triphenylmethyltetrazol-5-yl )biphenyl 5.46 g of the compound obtained in step A, 6.9 g of trityl chloride, 100 ml of DCM and 4 ml of triethylamine are mixed in a round-bottomed flask. The medium is refluxed for 4 hours and then evaporated. The residue is taken up in ethyl acetate and washed with water, a 3% solution of potassium hydrogensulfate, 1 N sodium hydroxide solution, water and then a saturated solution of sodium chloride. It is dried over sodium sulfate, filtered and evaporated to give 11 g of the expected product.

M.p. = 161-164· C.

C) 4-Bromomethyl-2 ' - ( triphenylmethyltetrazol-5-yl ) biphenyl A mixture containing 11 g of the compound prepared in step B, 140 ml of carbon tetrachloride, 4 . 12 g of NBS and 0 . 4 g of benzoyl peroxide is refluxed for 3 hours. After it has returned to RT, it is filtered and the filtrate is then evaporated. The residue is taken up in 30 ml of isopropyl ether. The precipitate formed is filtered off and then dried under vacuum.

The product obtained is used as such in the next step.

D ) ( R, S ) -2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' - ( tri- phenyl-methyltetrazol-5-yl )biphenyl-4-yl )methyl] -2- imidazolin-5-one 394 mg of sodium hydride as an 80% dispersion in oil are suspended in 100 ml of anhydrous DMF under nitrogen, 1 . 71 g of 2-n-butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one in 10 ml of anhydrous DMF, prepared in Example 1 , step E), are added gradually, with stirring, and the mixture is stirred for 30 minutes. 4. 86 g of the compound prepared in step C) are added and the mixture is stirred for 3 hours at RT. It is evaporated to dryness, the residue is then taken up in 60 ml of ethyl acetate and the medium is filtered and evaporated to dryness. The oil obtained is chromato-graphed on silica using an ethyl acetate/hexane mixture ( 1/3 ; v/v) as the eluent. After evaporation of the solvents, 3 . 45 g of the expected product are obtained in the form of a solid foam.

- MR (CDCI3): 0 . 9 ppm : m : 3 H : -CH2-CH2-CH2-CH3 1-1 . 8 ppm : m : 18 H : 4-methyl + 4-cyclohexyl + CH2-CH2-CH2-CH3 2 .35 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 4. 5 ppm : s : 2 H : N-CH2-C6H4- 6 . 70-8 ppm : m : 23 H : aromatic protons E ) ( R, S ) -2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' - ( tetra- zol- 5-yl )biphenyl-4-yl )methyl] -2-imidazolin-5-one 3 . 38 g of the compound prepared in step D) are dissolved in a mixture of 40 ml of methanol and 20 ml of THF. 3 . 5 ml of 4 N hydrochloric acid are added and the mixture is stirred for 3 hours at RT. After evaporation to dryness, the residue is taken up in 10 ml of 2 N sodium hydroxide solution and 10 ml of ether and the mixture is then stirred until a solution is formed. The aqueous phase is extracted twice with ether. The aqueous phase is acidified to pH 6 with dilute hydrochloric acid and then extracted 3 times with ethyl acetate and the extracts are dried over sodium sulfate and evaporated to dryness to give 1 . 72 g of the expected product in the form of a white solid foam.

- MR (CDCI3): 0. 9 ppm : t : 3 H : CH2-CH2-CH2-CH3 0. 95-2 . 7 ppm : m : 18 H : 4-cyclohexyl + 4-methyl + -CH2-CH2-CH2-CH3 2. 1 ppm : t : 2 H : -CH2-CH2-CH2-CH3 4. 4-4. 7 ppm : AB system : 2 H : N-CH2-C6H4- 6. 95-7. 1 ppm : q : 4 H : aromatic protons 7 . 3-7 . 6 ppm : m : 3 H : aromatic protons 7 . 8 : d : 1 H : aromatic protons EXAMPLE 5 2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 21 -( tetra zol-5-yl )biphenyl-4-yl )methyl] -2-imidazolin-5-one, levorotatory A) 5-Methyl-5-phenylhydantoin 30 g of acetophenone diluted in 250 ml of 95* alcohol are added over 30 minutes to a mixture of 18.35 g of sodium cyanide and 125 g of ammonium bicarbonate in 250 ml of water and the reaction medium is heated at 60-65* C for 22 hours, with stirring. It is concentrated to half its volume under vacuum and the solid which has precipitated is filtered off, washed with water and ether and then dried under vacuum to give 38 g of a white solid, which is identified by IR.

M.p. = 190-192* C.

B) (R,S)-2-Amino-2-phenylpropionic acid 20 g of the compound prepared in the previous step are added to a mixture of 75 g of barium hydroxide octahydrate and 500 ml of water and the reaction medium is then heated at 160* C for 5 hours in a steel tube. It is saturated with dry ice and the precipitate is then filtered off. The filtrate is concentrated under vacuum and the white solid formed is taken up in acetone, filtered off, washed with acetone and ether and then dried to give 15.3 g of the expected acid.

M.p. = 260-265* C (with decomposition).

C) Ethyl ester of (R, S)-2-amino-2-phenylpropionic acid Using a spatula, 24 g of the acid prepared in the previous step are added to a solution of 80 g of gaseous hydrochloric acid in 210 ml of absolute ethanol, with stirring, and the mixture is refluxed for 6 and a half hours. It is concentrated under vacuum, the residue is taken up in 600 ml of ethyl acetate and 100 ml of water, and 2 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 25.5 g of the expected product in the form of an oil. Identification by IR.

D) Dextrorotatory ethyl ester of 2-amino-2-phenylpro- pionic acid The enantiomers of the ester prepared in the previous step are separated by the method described by Y. Sugi and S. Mitsui in Bull. Chem. Soc. Japan, 1969, 42. 2984-2988. 19.8 g of ( L )( + ) -tartaric acid are added to the 25.5 g of ester obtained in step C, diluted in 210 ml of absolute ethanol. The mixture is heated to 60* C to give a total solution, which is then left to stand at RT for 4 hours. The precipitate formed is filtered off, then rinsed with twice 70 ml of absolute alcohol and then redissolved in 200 ml of alcohol at the boil and the solution is then left to stand at RT for 72 hours. The acicular crystals formed are filtered off, rinsed twice with 30 ml of alcohol and then dried under vacuum to give 11.9 g of the tartaric acid salt of the expected dextrorotatory ester.

M.p. = 172-173* C. [a]D = +44.5* (C = 1, water).

The remaining alcoholic solution is enriched in the tartaric acid salt of the levorotatory ester. 6.1 g of the tartaric acid salt of the dextrorotatory ester are taken up in 30 ml of water and then 200 ml of ethyl acetate, and 5 N sodium hydroxide solution is added until the pH is 9. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 3 . 33 g of the expected product in the form of an oil . [a]D = +24 * (C = 2 , ethanol ) . Identification by NMR.

E) Dextrorotatory ethyl ester of 2-amino-2-cyclohexyl- propionic acid 3 . 30 g of the dextrorotatory ester obtained in the previous step are diluted in 120 ml of acetic acid; 1 . 5 g of platinum oxide are added and the mixture is then hydrogenated at atmospheric pressure. After hydrogenation for 40 hours, the reaction medium is filtered and then concentrated under vacuum. The residue is taken up in an ether/water mixture and 6 N hydrochloric acid is added until the pH is 2 . The organic phase is separated from the aqueous phase. Ethyl acetate is added, followed by 5 N sodium hydroxide solution until the pH is 9 . 5 . The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 3 . 10 g of the expected product. [a]D = +18 * (C = 2 , ethanol). Literature : W.A. Bonner et al., J. Amer. Chem. Soc, 1956 , 78 , 3218-3221 .

Identification by NMR.

F ) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, levorotatory A mixture containing 3 g of the dextrorotatory ester obtained in the previous step, 4 . 7 g of ethyl valerimidate and 8 drops of acetic acid in 15 ml of xylene is brought to the reflux point, with stirring.

After refluxing for 7 hours, the reaction medium is concentrated under vacuum. The residue is chromatographed on silica using a chloroform/methanol/ acetic acid mixture (95/9/3) as the eluent; the fractions containing the product are combined and concentrated under vacuum. The residue is taken up in an ethyl acetate/water mixture and the pH is brought to 9 by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum to give an oil, which changes to an amorphous solid, m = 2.36 g. [a]D = -57.2* (C = 1, chloroform).

- IR (chloroform): 1720 cm-1 : C=0 1640 cm-1 : C=N The IR spectrum confirms the 5-one form of the imidazolinone in solution.

G) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[(2'-(triphenyl- methyl-tetrazol-5-yl )biphenyl-4-yl ) methyl] -2-imida- zoline-5-one, levorotatory This compound is prepared from the product prepared in step F by following the procedure described in Example 4, step D.

Yield : 73%. [a]D = -22.8* (C = 1, chloroform).

- NMR: superimposable on that of the compound of Example 4, step D.

H) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[(2' - ( tetrazol-5- yl ) biphenyl-4-yl )methyl] -2-imidazolin-5-one, levorotatory This compound is prepared from the product prepared in step G by following the procedure described in Example 4 , step E.

Yield : 85% . [a]D = -25 . 9 ' (C = 1 , methanol).

- NMR: superimposable on that of the compound of Example 4 , step E.

EXAMPLE 6 2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' - ( tetra-zol-5-yl )biphenyl-4-yl )methyl] -2-imidazolin-5-one, dextrorotatory A) Levorotatory ethyl ester of 2-amino-2-phenylpropio- nic acid The alcoholic solution obtained in Example 5 , step D), is concentrated after separation of the crystals of the tartaric acid salt of the dextrorotatory ethyl ester of 2-amino-2-phenylpropionic acid. The solid residue is taken up in 150 ml of water and 600 ml of ethyl acetate and the pH is brought to 9 by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride, dried over sodium sulfate and then concentrated under vacuum to give 20. 6 g of the ester enriched in the levorotatory form. 15 . 9 g of ( D ) ( - ) -tartaric acid are added to 20. 5 g of this ester diluted in 200 ml of absolute ethanol, and a solution is formed at the boiling point of the alcohol. After 5 hours at RT, the acicular crystals formed are filtered off, washed twice with 50 ml of absolute alcohol and then dried under vacuum to give 16.3 g of the tartaric acid salt of the expected product . .p. = 172-173* C. [a]D = -45.2* (C = 1, water). 6 g of the salt obtained are taken up in 50 ml of water and 200 ml of ethyl acetate and the pH is brought to 9.5 by the addition of 5 N sodium hydroxide solution. The organic phase is decanted, washed with water and a saturated solution of sodium chloride and then dried over sodium sulfate and concentrated under vacuum to give 3.31 g of the expected product in the form of an oil, which is identified by NMR. [a]D = -25.5* (C = 2, ethanol ) .

B) Levorotatory ethyl ester of 2-amino-2-cyclohexyl- propionic acid The procedure of Example 5, step E), is followed to give 3.20 g of the expected product from 3.30 g of the compound of step A. [a]D = -19.2* (C = 1, ethanol).

C) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, dextrorotatory The procedure of Example 5, step F), is followed. [a]D = +56.9' (C = 1, chloroform).

The NMR and IR spectra are superimposable on those of the levorotatory isomer prepared in Example 5, step F).

D) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[ ( 2 ' -( triphenyl- methyl-tetrazol-5-yl )biphenyl-4-yl )methyl] -2-imida- zolin-5-one, dextrorotatory The procedure described in Example 5, step G), is followed to give 2.3 g of the expected product in the form of a white solid from 1.1 g of the compound prepared in step C. [a]D = -23.8* (C = 1, methanol) and NMR spectrum superimposable on that of the compound prepared in Example 4, step D.

E) 2-n-Butyl-4-cyclohexyl-4-methyl-l- [ ( 2 ' - ( tetrazol-5- yl ) biphenyl-4-yl )methyl] -2-imidazolin-5-one, dextrorotatory The procedure described in Example 5, step H, is followed to give 1.1 g of the expected product in the form of a white solid from 2.15 g of the compound prepared in step D. [a]D = +27.1* (C = 1, methanol).

The NMR spectrum is superimposable on that of the compound prepared in Example 4.

Likewise, the following compounds according to the invention were prepared according to the procedure described in Example 3: EXAMPLE 7 ( R, S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4-cyclopropyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate M.p. = 149-150* C.

- NMR: 7.05-7.80 ppm : m : 8 H : aromatic protons 4.70 ppm : s : 2 H : N-CH2-C6H4- 2.45 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.05-1.45 ppm : m + s : 8 H : -CH2-CH2-CH2-CH3 + CH3 in the 4 position + cyclopropane CH 0.70 ppm : t : 3 H : CH3-(CH2)3- 0.05-0.45 ppm : m : 4 H : 2 cyclopropane CH2 EXAMPLE 8 ( R, S ) -2-n-Butyl-l- [ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4, 4-dicyclopropyl-2-imidazolin-5-one trifluoro acetate M.p. = 132-134· C.

- Mass spectrum: MH+ : 431 - NMR: 7.15-7.80 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : N-CH2-C6H4- 2.50 ppm : t : 2 H : CH2-CH2-CH2-CH3 1.1-1.60 ppm : m : 6 H : CH2-CH2-CH2-CH3 + 2 cyclopropane CH 0.80 ppm : t : 3 H : (CH2)3-CH3 0.10-0.80 ppm : m : 8 H : 4 cyclopropane CH2 EXAMPLE 9 (R, S )-2-n-Butyl-l-[ ( 2 ' -carboxybiphenyl-4-yl ) -methyl] -4-cyclopentyl-4-methyl-2-imidazolin-5-one trifluoroacetate M.p. = 104-107* C.

- NMR: 7.20-7.80 ppm : m : 8 H : aromatic protons 4.85 ppm : AB system : 2 H : N-CH2-C6H4- 2.75 ppm : distorted t : 2 H : CH2-CH2-CH2-CH3 2.20-1.00 ppm : m + s : 16 H : cyclopentane + CH3 in the 4 position + -CH2" CH2-CH3 0.80 ppm : t : 3 H : CH3-(CH2)3- EXAMPLE 10 ( R, S ) -2-n-Butyl-4-cyclopentyl-4-methyl-l- [ ( 2 ' -tetrazol-5-yl )-biphenyl-4-yl ) methyl] -2-imidazolin-5-one.

This compound is prepared by following the procedure described in Example 4.

M.p. = 78-80 C - NMR : (CDC13) 7.05-7.8 ppm : m : 8H : aromatic protons 4.70 ppm : s : 2 H : -N-CH2-C6H4- 2.40 ppm : t : 2 H : -CH2-CH2-CH2-CH3 2.15-1.20 ppm : m : 13 H : -CH2-CH2-CH2-CH3 + 4-cyclopentyl 1.20 ppm : s : 3 H : CH3-4 0.95 ppm : t : 3 H : -CH2-CH2-CH2-CH3-

Claims

1. 42 103116/3 WHAT IS CLAIMED IS :

2. 1. A compound of the formula in which: - R3 is a hydrogen ; a C1-C5 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-C5 alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C-1-C3, or a phenylalkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti- tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl , a polyhalogenoalkyl , a hydroxyl or a C1-C4 alkoxy; and - either R4 is a C1-C6 alkyl which is unsubstituted or substituted by one or more halog.en atoms; and - R5 is a cycloalkyl or a cycloalkylmethyl , the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms; - or R4 and R- are each a cyclopropyl; - Z snd t are each zero or one is zero and the other is one; - X is an oxygen atom or sulfur atom; 103116/3 4 3 Y represents hydrogen or a group of the formula n which: R_ and R2 are similar or different and are each independently hydrogen or a group selected from a C}_-C5 alkyl, a C1-C4 alkoxy, an amino, an amino- methyl, a carboxyl, an alkoxycarbonyl in which 'the alkoxy is C-L-C4, a cyano, a tetrazolyl, a methyltetrazolyl , a methylsulfonylamino, a tri- fluoromethylsulfonylamino , a trifluoromethyl- sulfonylaminomethyl , an N-cyanocarbamoyl, an N- hydroxy;carbamoyl, an N- ( 4-carboxy- 1 , 3-thiazol-2- yl ) carbamoyl, a ureido, a 2-cyano-guanidino- carbonyl, a 2-cyano-guanidino-methyl , an imida- zol-l-ylcarbonyl and a 3-cyano-2-methylisothiou- reido-methyl , with the provisos that: 1) at least one of the substituents R-L or R2 is other than hydrogen; 2) when Y is hydrogen then X is oxygen; 3) when z=t=0, R5 represents a cycloalkyl, and Y is hydrogen, then R3 is other than a phenyl or a substituted phenyl and its salts. 103116/3 44 compound according to claim 1 of the formula n which: Rj_ and R2 are similar or different and are each independently hydrogen or a group selected from a C]_-C alkyl, a C1-C4 alkoxy, an amino, an amino'- methyl, a carboxyl, an alkoxycarbonyl in which the alkoxy is C1-C4, a cyano, a tetrazolyl, a methyltetrazolyl , a methylsulfonylamino , a tri- fluoromethylsulfonylamino , a trifluoromethyl- sulfonylaminomethyl , an N-cyanocarbamoyl, , an N- hydroxy carbamoyl, an N- ( 4-carboxy- 1 , 3-thiazol-2- yl ) carbamoyl, a ureido, a 2-cyano-guanidino- carbonyl, a 2-cyano-guanidino-rnethyl , an imida- zol-l-ylcarbonyl and a 3-cyano-2-methylisothiou- reido-methyl, with the proviso that at least one of the substituents R_ or R2 is other than hydrogen; - R3 is a hydrogen ; a alkyl which is unsubstituted or substituted by one or more halogen atoms ; a 2-C alkenyl, a C3-C7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C-1-C3, or a phenylalkenyl in which the 103116/2 45 alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti- tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a Cl-C4 polyhalogenoalkyl , a hydroxy! or a ^-C^ alkoxy; and - R4 is a C1-C5 alkyl which is unsubstituted or substituted by one or more' halogen atoms; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms; - or R4 and R5 are each a cyclopropyl; - X is an oxygen atom or sulfur atom; and - z and t are zero or one is zero and the other is one; and its salts.

3. A compound according to claim 2 wherein R^ is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen.

4. A compound according to claim 2 or claim 3 wherein R4 is methyl and R5 is cyclohexyl .

5. A compound according to any one of claims 2 to 4 wherein R3 is a linear C1-C5 alkyl group.

6. A compound according to any one of claims 2 to 5 wherein X is oxygen.

7. A compound according to any one of claims 2 to 6 wherein z = t = 0.

8. A compound according to claim 2 which is 2-n-butyl-4 -methyl-4-cyclohexyl-l- [ ( 2 ' - ( tetrazol-5-yl )biphenyl-4 yl )methyl] -2-imidazolin-5-one or one of its salts with acids or bases .

9. A method of preparing a compound ( I ) according to 103116/2 46 any one of claims 2 to 8, wherein: al ) a heterocyclic derivative of the formula H in which X, z, t, R3, R4 and R5 are as defined for (I) in claim 2, is reacted with a ( biphenyl-4-yl ) methyl derivative of the formula in which Hal is a halogen atom and ' 1 and R'2 are respectively either R^ and R2 or a precursor group of R^ and R2; bl ) if appropriate, the resulting compound of the formula 4 103116/2 47 is treated with Lawesson's reagent [2, 4-bis( 4-methoxy-phenyl )-l, 3-dithia-2, 4-diphosphetane 2, 4-disulfide] ; and cl ) the compound obtained in al ) or bl ) , of the formula in which X is an oxygen atom or a sulfur atom, is treated to give the compound ( I ) by conversion of the groups R'i and/or R'2 to the groups R^ and/or R2 respectively dl) the compounds so obtained is converted, if appropriate, into one of its salts.

10. A method of preparing a compound ( I ) according to any one of claims 2 to 8, wherein: a2 ) an amino acid of the formula COOH in which z, t, R4 and R5 are as defined for (I) in claim 2 and of which the amine group is protected 103116/2 48 by the Pr group, is reacted with a ( biphenyl-4-yl ) methylamine derivative of the formula in which R'^ and R'2 are respectively either R^ and R2 or a precursor group of R^ and R2 b2 ) after deprotection of the amine, the resulting compound of the formula is then treated with an alkyl ortho-ester of the formula 3C(OR)3 (10), in which R3 is as defined for (I) in claim 2 and R is a C1-C4 alkyl; c2 ) if appropriate, the resulting compound of the formula 4 103116/2 49 is treated with Lawesson's reagent [2, 4-bis( 4-methoxy-phenyl )-l, 3-dithia-2, 4-diphosphetane 2, 4-disulfide] ; and d2 ) the compound thus obtained in b2 or c2, of the formula is then treated under suitable conditions for preparing the compound ( I ) by conversion of the groups R'2 and/or R' ± to the groups R2 and/or R^ respectively e2) the compounds so obtained is converted, if appropriate, into one of its salts.

11. A compound according to claim 1 of the formula in which: - R3 is a hydrogen, a CI^-CQ alkyl which is unsubstituted or substituted by one or more halogen atoms, a c2~c6 alkenyl, a C3-C7 103116/2 50 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenyl alkenyl in which the alkenyl is C2-C3, said phenyl groups being unsubstituted or monosubstituted or polysubsti- tuted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl , a hydroxyl or a"Ci-C4 alkoxy; either - R4 is a ¾-Οβ alkyl which is unsubstituted or substituted by one or more halogen atoms; and R5 is a cycloalkyl or a cycloalkylmethyl , said cycloalkyl being C3-C7, which is unsubstituted or substituted by one or more halogen atoms; - or R4 and R5 are each a cyclopropyl; - z and t are zero or one is zero and the other is one, - X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z = t = 0, R5 represents a cycloalkyl.

12. A compound according to claim 11 of the formula in which R3, R4, R5 and X are as defined for II in claim I/) and R3 is a C1-C alkyl.

13. A compound according to claim 11 of the formula 103116/2 51 in which X is an oxygen atom and R3 is a alkyl. .

14. A compound according to claim H of the formula in which 1*3, R^, R5 and X are as defined above for ( II ) in claim ljZ) .

15. A compound according to claim 11 of the formula in which X^ R3, R4 and R5 are as defined for (II) in claim 1Q .

16. A method of preparing a compound according to any one of claims 11. to 15, which comprises reacting a compound of the formula R3-B 14 in which R3 is as defined above for (II) in claim 103116/2 52 11 and B is i - a group C(OR)3 NH - a group C or OR - a group COHal R being a C1-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula in which R4 and R5 are as defined above for (II) in claim 11 and A is an OH group, an NH2 group or a group OR', R' being hydrogen or a C1-C4 alkyl.

17. A pharmaceutical composition in which a compound according to any one of claims 2 to 8 is present as the active principle.

18. A pharmaceutical composition in which a compound according to any one of claims 2 to 8 is present in association with a beta-blocking compound.

19. A pharmaceutical composition in which a compound according to any one of claims 2 to 8 is present in association with a diuretic.

20. A pharmaceutical composition in which a compound according to any one of claims 2 to .8 is present in association with a non-steroidal antiinflammatory. ~

21. A pharmaceutical composition in which a compound according to any one of claims 2. to 8 is present in 103116/2 53 association with a calcium antagonist.

22. A pharmaceutical composition in which a compound according to any one of claims 2 to 8 is present in association with a tranquilizer. icants OHN AND PARTNERS