NZ244258A

NZ244258A - 1-(biphenylmethyl)-imidazoline and -pyrimidine derivatives

Info

Publication number: NZ244258A
Application number: NZ244258A
Authority: NZ
Inventors: Pierre Perreaut; Claude Muneaux; Yvette Muneaux
Original assignee: Sanofi Formerly Elf Sanofi
Priority date: 1991-09-10
Filing date: 1992-09-08
Publication date: 1996-10-28
Also published as: NO180678C; NO923509D0; EP0532410A1; IL103116A; HU9202889D0; KR930006008A; MX9205155A; RU2107062C1; AU2286892A; MY108089A; LV10255B; LTIP119A; TW218871B; FR2681067A1; HUT63616A; IL103116A0; LV10255A; JPH05213894A; ZA926899B; CA2077967A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £44258 24 4 2 5 8 Priority Date{s): Aft-UUV Compteta Specification Filed: ,$\3.\.33. class-. ....«Ol2>feH>3..|AS>.V....0lteA.K..3lX.)..<±.!.S Pubftfcation Data: P.O. Journal No: .... ..J«fcoai HO DRAWINQS Patents Form No. 5 WE, NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, [THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT ELF SANOFI, a French company of 32-34 rue Marbeuf, 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) let t 244258 N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present The present invention relates to N-substituted heterocyclic derivatives, to their preparation and to the pharmaceutical compositions in which they are present. 10 The compounds 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 15 bioloc tcally 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. 20 The compounds of 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 25 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 according to the invention are useful in the treatment of cardiovascular 30 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. (followed by page 2) 2 2 4 4 2 5 8 The present invention relates to compounds of the formula 5^-^h2), (CH2>z jf x i (I) ch2 in which: - Ri and R2 are similar or different and are each independently hydrogen or a group selected from a C^-Cg 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-acetamide, an N-hydroxyacetamide, an N-(4-carboxy-l,3-thiazol-2-yl)acetamide, a ureido, a 2-cyano-guanidinocarbonyl, a 2-cyano-guanidinorcethyl, an imidazol-l-ylcarbonyl and a 3-cyano-2-roethyliso-thioureidomethyl, with the proviso that at least one of the substituents Rj or R2 is other than hydrogen; - r3 is a hydrogen, a C^-Cg 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 polysubstituted by a halogen atom, a C1-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy ; 3 244258 - R4 is a C^-Cg 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 5 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 ; 10 and their salts. If a compound according to the invention has an asymmetric carbon, the invention includes the 2 optical isomers of this compound and their racemic mixture. The salts of the compounds of formula (I) 15 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 20 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 25 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 30 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 4 244258 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-5 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 10 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 15 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. 20 Likewise, the compounds of formula (I) in which R3 is a linear C^-Cg alkyl group are preferred compounds. The compounds of formula (I) in which X is an oxygen atom are also preferred compounds. 25 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 30 preferred. The following abbreviations are used in the description and in the Examples: 2 4 4 2 5 10 15 alcohol Et nBu, tBu DMF THF DCM NBS DCC DIPEA ether TFA Z BOC BOP Fmoc ethyl alcohol ethyl : n-butyl, tert-butyl dimethylformamide tetrahydrofuran dichloromethane N-bromosuccinimide dicyclohexylcarbodiimide dlisopropylethy1amine ethyl ether trifluoroacetic acid benzyloxycarbonyl tert-butoxycarbonyl benzotriazolyloxytrisdimethylamino-phosphonium hexafluorophosphate fluorenylmethoxycarbonyl 20 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 R, (CH2>z ^ N O | H (CH2)t N J— R, 25 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 6 244258 Hal-CH2 3 in which Hal is a halogen atom and R'^ and R'2 are respectively either R^ and R2 or a precursor group of Rl and/or R2; bl) if appropriate, the resulting compound of the formula is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide]; and cl) the compound obtained in al) or bl), of the formula (CH2)t 7 15 244258 R4 R5 (ch2> z (CvH2>t n J- r3 in which X is an oxygen atom or a sulfur atom, is treated to give the compound (I) by conversion of the 5 groups R'i and/or R'2 to the groups Ri 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. 10 Among the compounds 2., some of them are prior art compounds, the others are new and are the subject of New Zealand Patent Specification Ho. 272256. EP patent application 144 748 discloses herbicides of formula : x Y O ■n n h in which one of X and Y may represent an alkyl and the other a cycloalkyl ; furthermore the phenyl group may 20 be substituted. New Zealand Patent Specification No. 272256 relates to the compounds (II) of the formula n.7. ; v , . - r 1 , r-* \ 8 244258 r4 r5^ (qH2)t (CH2) N II Z^—R3 X N 3 i H in which: - z and t are zero or one is zero and the other is one; 5 - R3 is a hydrogen, a C1-C5 alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-Cg 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 10 phenyl groups being unsubstituted or monosubstituted or polysubstituted by a halogen atom, a C^-C4 alkyl, a C1-C4 halogenoalkyl, a C1-C4 polyhalogenoalkyl, a hydroxyl or a C1-C4 alkoxy; - R4 is a C^-Cg alkyl which is unsubstituted or 15 substituted by one or more halogen atoms ; and - R5 is a cycloalkyl or a cycloalkylmethyl, the cycloalkyl being 03-07, which is unsubstituted or substituted by one or more halogen atoms ; - or else R4 and R5 are each a cyclopropyl ; 20 - X represents an oxygen atom, with the proviso that R3 is other than a phenyl or a substituted phenyl when z » t = 0 and represents a cycloalkyl. Among the derivatives (II), the compounds in 25 which z = t = 0 of the formula : Vfiii-JT OFFICE 10 APfi 1905 2 A 4 2 5 8 R< ■N N I H JU, (ir) 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 10 (II") I H 15 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 (II ') in which R3, R4, R5 and X are as defined above for 20 (II), are preferred compounds. The derivatives 2. are prepared by known 10 2 4 4 2 5 8 methods. For example, It Is possible to use the method described by Jacquier et al. (Bull. Soc. Chim. France, 1971, 1040-1051) and by Brunken and Bach (Chem. Ber., 1956, 1363-1373) and to react an alkyl imidate with an amino acid or its ester in accordance with the following reaction scheme: R4 (ch2)z-co2R' \ / c + r3 - c (ch2),-nh2 "or r 4 R5 -^h2), (cH2)z N 2 O | H in which R is a C1-C4 alkyl, R' is hydrogen or a C1-C4 10 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. 15 The compound £1 are known compounds or are prepared by known methods. The compounds iLL 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 20 Active Alpha-aminoacids, R.M. Williams, Pergamon Press, 1989". 11 244258 5 20 According to another procedure, the compound 2 can be prepared by reacting an aminoalkylamide (5' M with an alkyl ortho-ester (1Q.) in an acid medium in accordance with the following reaction scheme: r4 (CH2)z-CONH2 v/ ^ +Rj-C(OR)2 ► 2 R5 (CH2)t-NH2 it 5_ 10 in which R is a C1-C4 alkyl. Using a procedure described by H. Takenaka et 10 al. (Heterocycles, 1989, 22(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 15 the derivative 5' ' ; the cyclization of the diamine is then carried out in a basic medium. If z ■ t « 0, a derivative 5JL can be prepared from a ketone by a procedure described in US patent 4 017 blO or in Swiss patent 540 271 : cyanure H+ ou OH- R4-CO ► R4-C-CN ► 5 nh4oh \Nh2 nh4ci tt 5 Itt 12 244258 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 5 hydrolyzed to 5 . either in a strongly acidic medium or in a basic medium. If appropriate, the aminonitrile' 5"' can be resolved with an optically active acid by the procedure in European patent 158 000, in which case it is possible to prepare the compound 5J1. and then the 10 compound 2. in optically pure form. More particularly, according to another ubject of the present invention, the compound 2. is prepared by a method which comprises reacting a compound of the formula 15 R3-B ii. in which B is - a group C(OR)3 HN - a group 20 RO - a group COHal R being a C1-C4 alkyl and Hal denoting a halogen atom, preferably chlorine, with a compound of the formula R4 (CH2)zCOA ^cr 13 25 ^ ^ (CH2)tNH2 in which A is an OH group, an NH^ group or a group OR', R' being hydrogen or a C1-C4 alkyl. The (biphenyl - 4-yl) methyl derivative (3.) is p-r<ap»rp.d by a method described in European patent 30 application 324 377. — OFFICE 13 244258 The conversion of a group R'^ and/or R'2 "to a group 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 0 carboxyl, 5 R'i and/or R'2 are an esterified carboxyl group. If the compound (I) to be prepared possesses a group and/or R2 ■ tetrazolyl, R'i 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 10 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 azida. It is also possible to use groups R'i and/or 15 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 Ri and/or R2 as defined for the compound (I). Thus, if R'i and/or R'2 are a carboxyl, they 20 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)acetamide. The group R'i and/or R'2 in the form of an acid chloride can be converted to R^ and/or R2 in the form 25 of N-hydroxyacetamide, N-cyanoacetamide, ureido or 2-cyanoguanidinocarbonyl. The group R'i 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-30 methylsulfonylamino or trifluoromethylsulfonylamino-methyl. The group R'i and/or R'2 in the form of a cyano 14 c H ** z 0 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 5 (according to R.W. Turner, Synthesis, 1975, 332). Step al) is carried out in an inert solvent such as DMF, DMSO or THF, in a basic medium, for example in the presence of potassium hydroxide, a metal alcoholate, a metal hydride, calcium carbonate or 10 triethylamine. Step bl) is carried out by heating under nitrogen in a oolvent such as toluene, according to the method described by M.P. Cava et al., Tetrahedron, 1985, 41, 22, 5061. 15 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: 20 a2) an amino acid of the formula R4 ^ (CH2)r NHPr R 1 5 <™2>z COOH in which z, t, R4 and R5 are as defined above for (I), 25 and of which the amine group is protected by the Pr group, is reacted with a (biphenyl-4-yl)methylamlne derivative of the formula 15 2 4 4 2 5 8 h2n- ch2 R'2 R'l /"\ / 8 in which R' i and R' 2 are respectively either R^ and R2 or a precursor group of Rj. and R2; 5 b2) after deprotection of the amine, the resulting compound of the formula R1' r'i r, r ;c-(ch2)z-c-nh-ch2 5' (ch2)t-nh2 10 15 is then treated with an alkyl ortho-ester of the formula R3C(OR>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 R/ (CH2)* X, o CH' is treated with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disul-20 fide]; 16 244258 and d2) th3 compound thus obtained in b2 or c2, of the fozrmula r4 R 5—^—(SH2)t <ch2)z v 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 ; 10 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 2. are known or are prepared by known methods (Chemistry of the Amino Acids, Greenstein 15 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-20 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 25 of BOP and DIPEA. Step b2), which is the cyclization of the 17 2 4 4 2 5 8 compound 2. in the presence of 10 r is carried out according to Jacquier et al. (Bull. Soc. Chlm. France, 1971, (3), 1040-1051) and according to Brunken and Bach (Chem. Ber., 1956, fi2, 1363-1373). 5 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 3.L of the formula 10 r'2 r\ R4 ^ c-(ch2>2 c0 " nh_ ch2 R*/ I 5 (ch2)t-nh-co-r3 and then to prepare the compound 4. by cyclization in an acid or alkaline medium. 15 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. 20 In Biochem. J., 1982, 208. 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 25 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 18 2 4 4 2 5 8 (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, 5 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 10 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. 15 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 20 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, 25 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 30 prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms for oral administration, such as tablets, 19 244258 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 arable 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 20 2 4 4 2 5 8 ■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. 5 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. 10 Rectal administration is effected using suppositories prepared with binders which melt at the rectal temperature, for example cacao1 butter or polyethylene glycols. Parenteral administration is effected using 15 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. 20 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 25 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 30 pharmaceutical compositions containing several active principles in association, one being a compound according to the invention and it being possible for 21 24 4 2 58 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 5 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 10 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 15 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]j) are measured 20 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 25 sb : broad singlet d : doublet t : triplet q : quadruplet quint : quintuplet 30 sext : sextuplet m : unresolved signals or multiplet In addition, im denotes imidazole. 24 4 2 example 1 (R,S)-2-n-Butyl-l-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-4-methyl-2-imidazolin-5-one tri-fluoroacetate 5 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 10 29.4 g of sodium cyanide and 192 g of ammonium carbonate ir. 400 ml of water. The mixture is heated at 55-60* C for 4 hours and then evaporated to half its volume under vacuum end left to stand overnight at +4* C. The precipitate formed is filtered off, washed 15 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 NMR spectra. M.p. - 220* C. B) (R,S)-2-Amino-2-cyclohexylpropionic acid 20 This compound is prepared according to J. Org. Chem., I960, 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 25 160* 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 30 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350* C with decomposition. 23 c.. / ' • ''7, ;"•? £ 4 C J O C) Ethyl ester of (R,S)-2-amino-2-cyclohexylprop±onic acid 3 g of the acid prepared in the previous step are added to 40 ml of absolute alcohol saturated with 5 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 10 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. 15 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 20 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 25 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 30 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 24 2 4 4 2 5 8 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 5 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): 10 1720 cm-1 : C=0 1640 cm~l : C=N - NMR consistent. F) 4-Bromomethyl-21-tert-butoxycarbonylbiphenyl This compound is prepared by the method 15 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 20 previous step are dissolved in 20 ml of DMF. 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. 25 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 30 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. 25 244251 - IR (chloroform): 1710-1730 cm-1 : ester and imldazolinone C=0 1630 cm-1 : C=N H) (R,S)-2-n-Butyl-l-[(2'-carboxybiphenyl-4-yl)methyl]-5 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 10 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. 15 MH+ : 447. - nmr: 7.10-7.70 ppm : m : 8 aromatic H 4.45 ppm : s : 2 H : N-CH2~c6h4~ 1.25 ppm : s : CH3 in the 4 position 20 EXAMPLE 2 (R,S)-2-n-Butyl-l-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclohexyl-methyl-4-methyl-2-iraidazolin-5-one trifluoroacetate 25 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. 30 B) (R,S)-2-Amino-3-cyclohexyl-2-methylpropionic acid Characterized by its IR and NMR spectra. 26 244258 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-2-5 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 : imldazolinone C=0 10 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 15 compound of step D with 4-bromomethy1-2'-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. 20 Yield : 51%. M.p. = 73-75* C. - IR (KBr): 1700-1730 cm""1 : imldazolinone and ester C=0 1630 cm-1 : C«N 25 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. 30 - NMR: 7.20-7.80 ppm : 8 H : aromatic protons 4.85 ppm : m : 2 H : N-CH2_c6h4- 27 24 4 2 58 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 5 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-10 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 15 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 20 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 25 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 30 give 2.87 g of product, which becomes pasty at 120* C. Identification by IR and NMR. - IR of the free base: 244258 2220 cm-1 : C»N B) (R, S) -2-Arnino-2-cyclohexylbutyramide 2.84 g of -the nitrile obtained in step A are added over 30 minutes to 6 ml of pure sulfuric acid. 5 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 10 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 15 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 20 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 25 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. 30 m - 2.62 g. M.p. = 80-85* C. Identification by NMR and IR (chloroform and KBr). 29 24 4 2 58 D) (R, S )-2-n-Butyl-l- C (2' -ter£-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-21-tert-butoxycarbonylbiphenyl . - IR (chloroform): 1700-1720 cm-1 : imldazolinone 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 tri fluoroacetate 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%. M.p. » 159-161* C. - NMR: 7.10-7.70 ppm : m : 8 H : aromatic protons 4.75 ppm : s : 2 H : -N-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 21-Cyano-4-methylbiphenyl is prepared according 30 24 4 2 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 5 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 10 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. 15 M.p. = 146-148' C after recrystallization from ethyl acetate. B) 4-Methyl-21 -(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 20 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 25 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) 30 biphenyl A mixture containing 11 g of the compound prepared in step B, 140 ml of carbon tetrachloride, 31 244258 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 5 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-10 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-2-15 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 20 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 chromatographed on silica using an ethyl acetate/hexane mixture (1/3; v/v) as the eluent. After evaporation 25 of the solvents, 3.45 g of the expected product are obtained in the form of a solid foam. - NMR (CDC13): 0.9 ppm : m : 3 H : -CH2-CH2-CH2-CH3 1-1.8 ppm : m : 18 H : 4-methyl + 4-cyclohexyl + 30 CH2-CH2-CH2-CH3 2.35 ppm : distorted t : 2 H : CH2-CH2"CH2-CH3 4.5 ppm : s : 2 H : N-CH2-C6H4- 24 4 2 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 5 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 10 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 15 sodium sulfate and evaporated to dryness to give 1.72 g of the expected product in the form of a white solid foam. - NMR (CDCI3): 0.9 ppm : t : 3 H : CH2-CH2-CH2-CH3 20 0.95-2.7 ppm : m : 18 H : 4-cyclohexyl + 4-methyl + -ch2-ch2-ch2-ch3 2.1 ppm : t : 2 H : -CH2CH2-CH2-CH3 4.4-4.7 ppm : AB system : 2 H : N-CH2-C6H4-6.95-7.1 ppm : q : 4 H : aromatic protons 25 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-[(2'-(tetra-30 zol-5-yl)biphenyl-4-yl)methyl]-2-imidazolih-5-one, levorotatory A) 5-Methyl-5-phenylhydantoin 33 244258 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 5 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 10 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 15 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 20 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 25 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 30 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 34 24 4 2 58 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. 5 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 10 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 15 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 20 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. 25 [o]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 30 200 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 35 244258 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 5 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 10 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 15 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 20 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 , 23., 25 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 30 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. 36 24 4 2 58 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 5 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 10 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. [<x]d = -57.2* (C = 1, chloroform). 15 - IR (chloroform): 1720 cm-1 : 00 1640 cm-1 : C=N The IR spectrum confirms the 5-one form of the imldazolinone in solution. 20 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 25 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. 30 H) 2-n-Butyl-4-cyclohexyl-4-methyl-l-[(2'-(tetrazol-5-yl) biphenyl-4-yl)methyl]-2-imidazolin-5-one, levorotatory 37 4 2 This compound is prepared from the product prepared in step G by following the procedure described in Example 4, step E. Yield : 85%. 5 [<i]d = -25.9* (C - 1, methanol). - NMR: superimposable on that of the compound of Example 4, step E. EXAMPLE 6 10 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 15 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 20 600 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 25 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 30 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 38 4 4 2 give 16.3 g of the tartaric acid salt of the expected product. M.p. - 172-173* C. [a]d = -45.2* (C = 1, water). 5 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 10 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-15 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). 20 C) 2-n-Butyl-4-cyclohexyl-4-methyl-2-imidazolin-5-one, dextrorotatory The procedure of Example 5, step F), is followed. [a]o 3 +56.9* (C » 1, chloroform). 25 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-30 zolin-5-one, dextrorotatory The procedure described in Example 5, step 6), is followed to give 2.3 g of the expected product in 39 244258 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 5 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, 10 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 15 the compound prepared in Example 4. Likewise, the following compounds according to the invention were prepared according to the procedure described in Example 3: 20 EXAMPLE 7 (R,S)-2-n-Butyl-l-[(2'-carboxybiphenyl-4-yl)-methyl]-4-cyclopropyl-4-methyl-2-imidazolin-5-one trifluoroacetate M.p. - 149-150* C. 25 - 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 30 in the 4 position + cyclopropane CH 0.70 ppm : t : 3 R : CH3-(CH2)3- 244258 0.05-0.45 ppm : m : 4 H : 2 cyclopropane CH2 EXAMPLE 8 (R, S)-2-n-Butyl-l-[(2'-carboxybiphenyl-4-yl)-5 methyl]-4,4-dicyclopropyl-2-imidazolin-5-one trifluoroacetate M.p. - 132-134* C. - Mass spectrum: MH+ : 431 10 - 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 cyclo-15 propane CH 0.80 ppm : t : 3 H : (CH2)3-CH3 0.10-0.80 ppm : m : 8 H : 4 cyclopropane CH2 EXAMPLE 9 20 (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: 25 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~ 30 CH2-CH3 0.80 ppm : t : 3 H : CH3-(CH2)3- </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 41 244258 EXAMPLE 10 (R,S)-2-n-Birtyl-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 : (CDCI3) 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- 42 244258 WHAT ^WE CLAIM IS:-flftW is. etHMBa >g:

1. A compound of the formula ^H2)t (C X (I) in which: - Ri and R2 are similar or different and are each independently hydrogen or a group selected from a C1-C5 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-cyanoacetamide, an N-hydroxyacetamide, an N-(4-carboxy- 1,3-thiazol-2-yl) acetamide, 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 proviso that at least one of the substituents or R2 is other than hydrogen; - r3 is a hydrogen ; a C^-Cg alkyl which is unsubstituted or substituted by one or more halogen atoms ; a C2-Cg alkenyl, a c3-c7 cycloalkyl, a phenyl, a phenylalkyl in which the alkyl is C1-C3, or a phenylalkenyl in which the 43 244258 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 5 hydroxy1 or a C1-C4 alkoxy; and - R4 is a Ci-Cg alkyl which is unsubstituted or substituted by one or more halogen atoms; and - R5 is a cycloalkyl or a cycloal kylmethyl, the cycloalkyl being C3-C7, which is unsubstituted or 10 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; 15 and its salts.

2. A compound according to claim 1 wherein R^ is in the ortho position and is a carboxyl or tetrazolyl group and R2 is hydrogen.

3. A compound according to claim 1 or claim 2 wherein 20 R4 is methyl and R5 is cyclohexyl.

4. A compound according to any one of claims 1 to 3 wherein R3 is a linear C^-Cg alkyl group.

5. A compound according to any one of claims 1 to 4 wherein X is oxygen. 25

6. A compound according to any one of claims 1 to 5 wherein z = t = 0.

7. A compound according to claim 1 which is 2-n-butyl-4 -methyl-4-cyclohexyl-1-[(2'-(tetrazol-5-yl)biphenyl-4-yl )methyl]-2-imidazolin-5-one or one of its salts 30 with acids or bases.

8. A method of preparing a compound (I) according to 244258 any one of claims 1 to 7, wherein: al) a heterocyclic derivative of the formula R, R5-^_(CH2)t (C"2)Z J? ■A N-^"R3 o | H in which z, t, R^, R^ and Rj. are as defined for (I) in claim 1, is reacted with a (biphenyl-4-yl) methyl derivative of the formula 10 R' R'. Hal-CH' 2 1X1 \ /"A 15 in which Hal is a halogen atom and R'i and R'2 are respectively either R^ and R2 or a precursor group of R1 and R2? bl) if appropriate, the resulting compound of the formula R, R <CH2>Z f A-N^R3 R'. O CFL O R' 1 > | n.Z. patent ui-no 10 APR 1995 RECEIVED 45 24 4 2 58 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. . A method of preparing a compound (1) according to any one of claims 1 to 7, wherein: a2) an amino acid of the formula R 5^>-(CH2)t (CH2)t- NHPr 7 cooh in which z„ t, R4 and R5 are as defined for (1) in claim 1, and of which the amine group is protected 244258 by the N-protecting group Pr, is reacted with a (biphenyl-4-yl) metl'iylciinine derivative of the formula RS r* h2n- ch -^>0 10 in which r' ]_ and r'2 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 r'< r' ^c-(ch2)z-c-nh-ch2 l5 (ch2)t-nh2 w 1 A is then treated with an alkyl ortho-ester of the formula R3C(OR>3 (10), in which R3 is as defined 15 for (I) in claim 1 and R is a C1-C4 alkyl; c2) if appropriate, the resulting compound of the formula r4 r- ' 20 5~7^(ch2), (ch2)z I r'- CH0 -f\ r' \ U.7.. PATENT OFFICE 10 APR 1995 47 24425 is treated with Lawesson's reagent [2,4-bis(4-methoxy-phenyl) -1,3-dithia-2,4-diphosphetane 2,4-disulfide]; and d2) the compound thus obtained in b2 or c2, of the formula R4 R5 <CH2> z (CH2)t N J- R is then treated under suitable conditions for preparing the compound (I) by conversion of the groups R'2 and/or R11 to the groups R2 and/or Ri respectively e2) the compounds so obtained is converted, if appropriate, into one of its salts. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present as the active principle. A pharmaceutical composition in which a compound according to any one of the claims 1 to 7 is present in association with a beta-blocking compound. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a diuretic. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a non-steroidal antiinflammatory* A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a. *"•a 1r*"«■-.«»~•*-°* =*■. HZ. PATENT OFFICE . 2 JUN BS5 <* 24 48

15. A pharmaceutical composition in which a compound according to any one of claims 1 to 7 is present in association with a tranquilizer.

16. A compound according to any one of claims 1-7, substantially as herein described.

17. A compound according to claim 1, substantially as described with reference to any one of the Examples.

18. A method according to claim 8 or claim 9, substantially as herein described.

19. A method according to claim 8 or claim 9, substantially as herein described with reference to any Example thereof.

20. A pharmaceutical composition according to any one of claims 10-15, substantially as herein described. ELF SAHQF1 ^By Their Attorneys B&LDWJH. SOW & CAREY </div>