NZ249508A

NZ249508A - 6-benzylpyrazolopyrimidine derivatives and medicaments

Info

Publication number: NZ249508A
Application number: NZ249508A
Authority: NZ
Inventors: Nicole Bru-Magniez; Timur Gungor; Jean-Marie Teulon
Original assignee: Union Pharma Scient Appl
Priority date: 1992-02-24
Filing date: 1993-02-18
Publication date: 1996-07-26
Also published as: HU9402429D0; AU668544B2; KR100272922B1; JP3372040B2; EE03046B1; JPH07504177A; JPH07504178A; WO1993017023A1; FR2687677A1; FI943807A0; DE69324910T2; SK99894A3; AU668139B2; HUT70949A; FI943808A0; EP0628046A1; HUT70953A; ATE179979T1; CA2128876A1; RU94040854A

Abstract

The present invention relates to derivatives having the formula (I) and their tautomeric forms, as well as addition salts thereof and therapeutical utilization particularly for the treatment and prevention of cardiovascular diseases particularly for the treatment of hypertension, cardiac insufficiency, arterial wall diseases particularly atherosclerosis.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £49508 24$ 5 0 8 New Zealand No. 249508 International No. PCT/FR93/00160 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 1 ^ ^ "3o '14 q-2 International filing date: \"3" | "2 ) ^ 3 Classification: coTDUSi/ou.; pbiK3i/stJS /? (Ccn J> l+8Vou-; 231' oo) (col T)14-87/ou., aaq-oo) Publication date: 2. 6 JUL. 1996 Journal No.:., 14.0(0, NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of invention: Pyrazolopyrimidin derivatives as angiotensin II receptor antagonists. Name, address and nationality of applicant(s) as in international application, form: LABORATOIRES UPSA, Ibis rue Docteur-Camille-Bru, F-47000 Agen, France. ct 2 A Cm r n !■ ■; W' PYRAZOLOPYRIMIDIN DERIVATIVES AS ANGIOTENSIN II RECEPTOR ANTAGONISTS n 10 15 20 25 30 The present invention relates, by way of novel products, to the pyrazolopyrimidine derivatives of general formula (I) below and their tautomeric forms and, where appropriate, their addition salts, in particular the pharmaceutically acceptable' addition salts. The compounds in question have a very valuable pharmacological profile insofar as they possess antagonistic properties towards the angiotensin II receptors, and antiproliferative properties. They are therefore particularly indicated for the treatment and prevention of cardiovascular diseases and in particular for the treatment of hypertension, for the treatment of cardiac insufficiency and for the treatment and prevention of diseases of the arterial wall, especially atherosclerosis. The present invention further relates to the method of preparing said products and to their uses in therapeutics. These pyrazolopyrimidine derivatives and their tautomeric forms are characterized in that they have the general formula (I): Formula (I) 249508 - 2 - In formula (I): - one of the radicals Rx and R2 is - a lower alkyl radical having l to 6 carbon atoms; or _ ^ 05 - an ether radical of the formula -(CH-J^OR, in 1 which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl radical; and - the other radical Rx or R2 is 10 - the hydrogen atom; - a halogen atom; - a lower alkyl radical having 1 to 6 carbon atoms; or - a radical selected from the group comprising 15 the radicals ORA, SRA, NRBR6 and NH(CH2)„-NRBRe, in which: R4 is - the hydrogen atom; - a lower alkyl radical having 1 to 6 carbon O 20 atoms or a C3-C7-cycloalkyl radical; - a radical (CH2)ra-COOR', m being an integer from 1 to 4 and R' being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; or - a radical (CH2)m-0-R', m and R' being as 4^" 25 defined above; Rs and Rs, which are identical or different, are - the hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon 30 atoms or a C3-C.,-cycloalkyl radical; or Rs and Rs, taken together with the nitrogen atom to which they are attached, form a heterocycle selected from morpholine, pyrrolidine or piperidine; and 35 n is an integer from 1 to 4; 249508 - 3 - * - X, in the 2- or 3-position of the pyrazolo[l,5-a]-pyrimidine ring, is - the hydrogen atom; - a lower alkyl radical having 1 to 6 carbon 05 atoms; or - a radical selected from the group comprising the hydroxyl radical and the radical COOR', R' being as defined above; and 10 15 - R3 is a radical of the formula *12 or R„ R in which: - Z is CH or N or Z' is S or O; - RX1 is the hydrogen atom or a halogen atom; and O 20 - ri2 is a tetrazole radical, CN, COOH or CONH2. Advantageously, the derivatives according to the invention are the derivatives of formula (I) given above in which: 25 - one of the radicals Rx and R= is - a lower alkyl radical having 1 to 6 carbon atoms; and - the other radical Rx or Ra is - the hydrogen atom; 30 - a halogen atom; - a lower alkyl radical having 1 to 6 carbon atoms; or - a radical selected from the group comprising the radicals OH, NRSRS and NH(CH2)„-NR5R6, 35 in which: 249 5 08 - 4 ~ Rs and R6, which are identical or different, are - the hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon atoms; or Rs and R6, taken together with the nitrogen atom to which they are attached, form a heterocycle selected from morpholine or pyrrolidine; and n is an integer from 2 to 4; - X, in the 2- or 3-position of the pyrazolo[l, 5-a]-pyrimidine ring, is - the hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon atoms; and - R3 is one of the following radicals: The above-mentioned derivatives of formula (I) must also be considered in their tautomeric form. The above-mentioned derivatives of formula (I) can take the form of addition salts, in particular the pharmaceutically acceptable addition salts. In the description and the claims, lower alkyl radical is understood as meaning a linear or branched hydrocarbon chain having from 1 to 6 carbon atoms. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical. C3-C7-Cycloalkyl radical is understood as meaning a saturated cyclic hydrocarbon radical, preferably a cyclopropyl, cyclobutyl, cyclohexyl or cyclo- 249 5 0 8 - 5 - heptyl radical. Halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom. In one embodiment, is an n-propyl group. 05 in another embodiment, Rx is a hydroxyl group. In another embodiment, Rx is a morpholinoethyl-amino group. In another embodiment, Rx is an amino group. In another embodiment, R^ is a diethylamino 10 group. In one embodiment, Ra is a hydroxyl group. In another embodiment, R2 is an n-propyl group. In one embodiment, X is the hydrogen atom. In one embodiment, R3 is a 2-(lH-tetrazol-5- 15 yl)phenyl group. The particularly preferred compounds of the invention are selected from the products of the formulae 20 25 30 35 - 6 - 2 4 9 5 0 8 N—CH2—CH, In general terms, the method of preparing the compounds of formula (I) is characterized in that it comprises: a) preparing a compound of formula (a): B Formula (a) 15 20 24 9 5 0 - 7 - in which: - X and R3 are as defined above; and - A and B are in one case a hydroxyl group or a lower alkyl radical having 1 to 6 carbon atoms and in the 05 other case a lower alkyl radical having 1 to 6 carbon atoms or an ether radical of the formula -(CHa)^-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl radical, 10 by condensing a 3-aminopyrazole of formula (II): N NH |l •NHa Formula (II) in which X is as defined above, with a derivative of formula (p) : 25 Formula (£) 30 in which R'^ is a lower alkyl radical having 1 to 6 carbon atoms or an ether radical of the formula -(CH2)p-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl radical, Ra is a lower alkyl radical having 1 35 to 6 carbon atoms or a lower 0-alkyl group having 1 to 249 5 0 8 - 8 - 6 carbon atoms, preferably methyl or ethyl, and R3 is as defined above, in an aprotic solvent such as dichloro- or trichloro-benzene, or in an acid solvent such as acetic acid, or 05 else in an alcohol in the presence of the corresponding sodium or potassium alcoholate, or else in pyridine or 2-methyl-5-ethylpyridine in the presence or absence of 4-dimethylaminopyridine, at a temperature of between 50" and 200°C; 10 b) if appropriate, protecting the group carried by R3 using a method known per se? c) heating the derivative thus obtained from the derivative of formula (0) , when the latter is a ketoester, in an appropriate reagent such as, for example, P0C13, 15 to convert the hydroxyl group represented by A or B to a chlorine atom; d) heating this chlorinated derivative in the presence of a nucleophile containing nitrogen, oxygen or sulfur, under reflux in an alcohol or in an autoclave at 100"c, 20 in the presence or absence of a base such as, for example, NaaC03, to give a derivative of formula (a) in which A and B have the same meanings as Rx and R2 respectively; e) if appropriate, deprotecting the group carried by 25 R3; ej converting this group to an acid group, for example by hydrolysis in the case where this group is a nit-rile; or e2) converting this group to a tetrazole group, for 30 example, in the case where this group is a nitrile, by reaction with a trialkyltin azide with heating in toluene or xylene, followed by a treatment with gaseous hydrochloric acid in tetrahydrofuran; or e3) converting this group to an amide group, for 35 example, in the case where this group is a nitrile, by 24 9 5 08 - 9 - reaction with sulfuric acid, or by reaction with hydrogen peroxide, or else by reaction with polyphosphoric acid; and f) if appropriate, converting the resulting derivative 05 to an addition salt, preferably a pharmaceutically acceptable addition salt. According to the invention, it will be possible to synthesize the compounds of formula (I) in accordance with the following reaction sequence: 10 Methods known per se, such as, for example, the Claisen reaction or the method using Meldrum's acid, which methods can be found in the following literature references: - HAUSER C.R.; SWAMER F.W.; ADAMS J.T.; Org. Reaction, 15 vol. VIII, 1954, 59-196, - HENNE A.L. ; TEDDER J.M.; J. Cl.am. Soc., 1953, 3628, - BRESLOW D.S.; BAUMGARTEN E.; HAUSER C.R.; J. Am. Chem. Soc., 1944, 66, 1286, - OIKAWA Y.; SUGANO K. ; YONEMITSU O. ; J. Org. Chem., 20 1978, .12(10), 2087-88, - WIERENGA W.; SKULNICK H.I.; J. Org. Chem., 1979, 44/ 310 , - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, 6, 451-2, - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964(5), 25 945-51, - BALYAKINA M.V.; ZHDANOVICH E.S.; PREOBRAZHENSKII N. A. ; Tr. Vses. Nauchn. Issled. Vitam in. Inst., 1961, 7, 8-16, - RENARD M.; MAQUINAY A.; Bull. Soc. Chim. Belg., 1946, 30 55, 98-105, - BRUCE F.W.; COOVER H.W.; J. Am. Chem. Soc., 1944, 2092-94, and - EBY C.J. and HAUSER C.R. ; J. Am. Chem. Soc., 1957, 79, 723-5, 35 will be used to prepare the compounds of formula (III): 249 5 - 10 - 05 30 R\—C—CHj—C—R. II II o o Formula (III) in which R' r is a lower alkyl radical having 1 to 6 carbon atoms or an ether radical of the formula -(CH2)p-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or 10 a benzyl radical, and Ra is a lower alkyl radical having 1 to 6 carbon atoms or a lower O-alkyl group having 1 to 6 carbon atoms, preferably methyl or ethyl. The compounds of the formula 15 20 Formula (V) will be obtained by benzylating the compounds of for-25 mula (III) with compounds of formula (IV): Formula (IV) in the presence of a base such as sodium or potassium 3 5 carbonate in acetone, a sodium or potassium alcoholate £4 9 in an alcohol, or sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide, for example, at a temperature of between 50 and 100*C, or else in the presence of one equivalent of lithium 05 chloride or bromide and two equivalents of diisopropyl-ethylamine in tetrahydrofuran under reflux,'according to the following reference: - SUNG-EUN YOO; KYU YANG YI; Bull. Korean Chem. Soc., 1989, ifi(l), 112. 10 These compounds of formula (V) can also be obtained by condensation of an aldehyde of formula (VI): CHO V 20 Formula (VI) with the compounds of formula (III), followed by hydro-genation in the presence of a catalyst such as Raney nickel, palladium-on-charcoal or platinum oxide, in a 25 solvent such as an alcohpl or tetrahydrofuran, under pressure or at ordinary pressure if the substituents-present allow it. In more general terras, methods of preparing the compounds of formula (V) will be found in the following 30 references: ^ - DURGESHWARI P.; CHAUDHURY N.D.; J.Indian Chem. Soc., 1962, 22, 735-6, - HEINZ P.; KREGLEWSKI A.; J. Prakt. Chem., 1963, 21f3-4), 186-197, 35 - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.; 249 5 08 - 12 - J. Org. Chem., 1961, 2f>, 644-51, - KAGAN H.B.; HENG SUEN Y.; Bull. Soc. Chim. France, 1966(6), 1819-22, - RATHKE M.W.; DEITCH J.; Tetrahedron Lett., 1971(31), 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M. ? Chem. Lett., 1981, 2., 173-6, - IOFFE T.; POPOV E.M.; VATSURO K.V.; TULIKOVA E.K. ; KABACHNIK M.I.; Tetrahedron, 1962, lj£, 923-940, and - SHEPHERD T.M.; Chem. Ind. (London), 1970, 12, 567. In formula (IV), W is a halogen atom, preferably chlorine or bromine. In the same formula: V can be a group R9 being a lower alkyl or benzyl radical, in which case the compounds of formula (IV) are prepared by reacting a magnesium compound of p-bromotoluene with a compound of the formula to give a compound of the formula 249 5 0 8 13 CH3 which is then hydrolyzed to give the compound of the formula Procedures for the three steps described above will be found in the following reference: - MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97, 7383. The acid is then esterified with an alcohol of the formula R^OH, Rg being as defined above. These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide, N-chlorosuccinimide or bromine, in a solvent such as carbon tetrachloride, dibromoethane or dichloroethane, to give the compounds of formula (IV) in which V is the group ch3 hooc RgOOC - 14 - 249 5 08 V can be the group no in which case the compound ch3 hooc prepared above will be converted to the primary amide by reacting the acid chloride, obtained with thionyl chloride or phosphorus oxychloride, with aqueous ammonia, and this amide will be converted to the nitrile by reaction with phosphorus oxychloride in dimethylforma-mide or with thionyl chloride. Likewise, the compound obtained above may be converted directly to the carbo-nitrile derivative by treatment in pyridine in the presence of POCl3. The resulting nitrile derivative of the formula ch3 249508 15 ch3 NC will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula (IV) in which V is the group in which case the corresponding compounds of formula (IV) are synthesized in the following manner: The magnesium compound prepared by a conventional Grignard reaction, is converted to the zinc derivative by reaction with zinc chloride. This zinc derivative is condensed with 2-chloronicotinonitrile, in the presence of Ni(P$3)Cl2, to give the derivative of the formula V can be a group - 16 - 249 5 08 05 This compound, treated with boron tribromide in chloroform, will give the compounds of formula (IV) in which W is the bromine atom and V is the group V can be a group 15 20 Rg being as defined above, in which case the corresponding compounds of formula (IV) may be prepared from the nitrile prepared above of the formula by conventional hydrolysis of the nitrile group fol-30 lowed by esterification of the acid obtained, or direct conversion of the nitrile group to the ester group by the methods known to those skilled in the art, followed by a treatment with boron tribromide in chloroform, to give the compounds of formula (IV) in which W is the 35 bromine atom and V is the group 2 4 9 5 17 RgOOC 05 V can be a group NC 10 in which case the corresponding compounds of formula (IV) are synthesized in the following manner?. The compound of the formula will be obtained from 4-chloro-4'-methylbutyrophenone 20 of the formula 25 the preparation of which is described in Belgian patent 577,977 of 15th May 1959, CA : Ji4, 4629c, by treatment with phosphorus oxychloride and dimethylformamide under the conditions described in the following reference: - VOLODINA M.A.; TENENT'EV A.P.; KUDRYASHOVA V.A. ; 30 KABOSHINA L.N.; Khim. Geterosikl. Soedim; 1967, 5-8. This compound is then treated with sodium sulfide in a solvent such as tetrahydrofuran, under reflux, to give the derivative 15 oo-ch2—ch2—ch2-c i 35 - 18 - 2 A 9 5 0 8 which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxy1amine. This dehydration may be carried out for example with acetic anhydride to give the nitrile compound which may then be aromatized by treatment with bromine in carbon tetrachloride to give the compound This compound can then be chlorinated or bro-mimated with halogenating agents such as N-chlorosuc-cinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is the group 2 4 9 5 0 8 - 19 - V can be a group R9 being as defined above, in which case the corresponding compounds of formula (IV) may be prepared from the nitrile prepared above of the formula by conventional hydrolysis of the nitrile group followed by esterification of the acid obtained, or direct conversion of the nitrile group to the ester group by the methods known to those skilled in the art, fpllowed by chlorination or bromination of the ester with N-chlorosuccinimide or N-bromosuccinimide, for example in carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which W is the bromine atom or the chlorine atom and V is the group V can be a group 249 5 0 8 - 20 - 05 Rg being as defined above, in which case the corresponding compounds of formula (IV) may be prepared by reacting the diazotized derivative of p-toluidine with 3-furoic acid to give the compounds of the formula 15 by the method described in the following literature reference: - A. JURASEK et al., Collect. Czech. Chem. Commun., 1989, £4, 215. 20 This compound will then be esterified by the conventional methods known to those skilled in the art to give the compound 30 in which Ra is as defined above, this derivative then being brominated or chlorinated by reaction with N-bromosuccinimide or N-chlorosuccinimide, for example in carbon tetrachloride or 1,2-dichloroethane, to give the derivative of formula (IV) in which W is the bromine 35 atom or the chlorine atom and V is the group - 21 - 2 49508 V can be a group in which case the acid prepared above will be converted to the acid chloride by reaction with thionyl chloride and then to the amide by reaction with ammonia. The amide obtained will be converted to the nitrile by reaction with phosphorus oxychloride in dimethylformamide to give the compounds of the formula This derivative will then be brominated or chlorinated by reaction with N-bromosuccinimide or N-chlorosuccinimide, for example in carbon tetrachloride or 1,2-dichloroethane, to give the compounds of formula 2 4 9 5 0 8 22 - (IV) in which W is the bromine atom or the chlorine atom and V is the group NC or NC XX Br In formula (V), R'^ and R3 are as defined above and V is as defined in formula (IV). However, the compounds of formula (V) in which V is a group will react with one equivalent of sodium azide in a solvent such as dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, or by heating in toluene or xylene with a trialkyltin azide, to give the compounds of formula (V) in which V is the group In formula (VI), V is as defined in formula (IV), but this condensation method will only be used when V possesses a group unaffected by hydrogenation. Thus reaction of a 3-aminopyrazole of formula (II): 2 A 9 5 0 8 23 N NH NHj X 05 Formula (II) in which X is as defined above - these products being commercially available or capable of being prepared by the methods known to those skilled in the art by 10 reaction of hydrazine hydrate with a ketoacetonitrile of the formula X-CO-CH=-CN, in which X is as defined above, or by other methods described in the following literature reference: Comprehensive Heterocyclic Chemistry, Pergamon Press, volume 5, pages 280 and 281 -15 with the compounds of formula (V), in which R'^ and Ra are as defined above and V is one of the following groups: 20 25 30 M—M 35 249 5 - 24 - 05 RgOOC NC O 10 RgOOC N-N N. 'N H Br 15 where R9 is as defined above, will give the compounds of formulae (Vila) and/or (Vllb): 20 Formula (Vila) Formula (Vllb) and their tautomeric forms, in which R'x, X and V are 25 as defined above and Rxo is the hydroxyl group when the compounds of formula (V) are 0-ketoesters and a lower alkyl radical having 1 to 6 carbon atoms in the case where these same compounds of formula (V) are 0-di-ketones, by condensation in an aprotic solvent such as 30 dichloro- or trich1oro-benzene, or in an acid solvent such as acetic acid, or else in an alcohol in the presence of the corresponding sodium or potassium alcoholate, or else in pyridine or 2-methyl-5-ethyl-pyridine in the presence or absence of 4-dimethylamino-35 pyridine, at a temperature of between 50° and 200°C. 2 4 9 5 0 8 - 25 - In the case where V possesses a tetrazole group, the reaction temperatures should not exceed 140°C so as not to decompose the tetrazole. The reactions of aminopyrazoles or similar 05 heteroaromatic amines with 0-ketoesters and 0-diketone derivatives are described well in the literature and, according to the operating conditions, the forms obtained are identified. Examples which may be cited are the studies by 10 - J. A. VAN ALLAN et al. , J. Org. 801 (1959), and by - L.A. WILLIAMS, J. Chem. Soc., p. - L.A. WILLIAMS, J. Chem. Soc., p. 15 Thus the compounds Vila and Vllb will be iden tified for separate treatment. The Applicant has discovered, however, that 2-methyl-5-ethylpyridine, in the presence or absence of 4-dimethylaminopyridine, is a preferred solvent for 20 orientating the reaction towards the formation of the derivatives of formula (Vllb); in fact, the temperature (170-180°C) and the pH which are necessary for this orientation can be achieved using this solvent. For example, if the derivatives of formulae 25 (Vila) and (Vllb) in which R10 is a hydroxyl group are Chem. , p. 779 to p. 1829 (1960), and 3046 (1961). heated in POCl and (VHIb) : 3 9 the derivatives of formulae (Villa) 30 35 Formula (Villa) Formula (VHIb) 249 5 08 - 26 - will be obtained, in which R'x, X and V are as defined above. Hydrogenation of the derivatives of formulae (Villa) and (VHIb), in the presence of a catalyst such as palladium-on-charcoal, will make it possible to replace the chlorine with a hydrogen atom, and the derivatives of formula (IX): Formula (IX) in which Rlf R2, X and V are as defined above, will be obtained by heating the derivatives of formulae (Villa) and (VIIlb), in the presence of a nucleophile containing nitrogen, oxygen or sulfur, under reflux in an alcohol, in the presence or absence of a base such as Na2C03, or in an autoclave at 100°C. The compounds of formula (IX) in which V possesses an ester group COOR., may be hydrolyzed in an acid or basic medium, or hydrogenated in the case where Rg is a benzyl, to give the compounds of formula (I) in which R3 possesses an acid group. The compounds of formula (IX) in which V possesses a nitrile group will react with one equivalent of sodium azide in a solvent such as dimethylformamide, in the presence of an ammonium salt such as ammonium chloride, or by heating in toluene or xylene with a trialkyltin azide, for example trimethyltin or tributyltin azide, followed by an acid treatment, for example with gaseous hydrochloric acid in tetrahydro- - 27 - furan, to give the compounds of general formula (I) in which R3 possesses a tetrazol-5-yl group. These same compounds in which V possesses a nitrile group may be converted by reaction with sulfuric acid, or by reaction with hydrogen peroxide, or else by reaction with polyphosphoric acid, to derivatives of general formula (I) in which R3 possesses an amide group. The derivatives in which V possesses a nitrile group or an amide group may also be converted by basic or acid hydrolysis to derivatives of general formula (I) in which R3 possesses an acid group. It is possible to obtain addition salts of some of the compounds of formula (I), especially pharma-ceutically acceptable addition salts. In particular, when the compounds of formula (I) contain an acid or tetrazole group, there may be mentioned the salts of sodium, potassium, calcium, an amine such as dicyclo'-hexylamine or an amino acid such as lysine. When they contain an amine group, there may be mentioned the salts of an inorganic or organic acid, such as, for example, the hydrochloride, methanesulfonate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate. The novel compounds according to the invention possess remarkable pharmacological properties as angiotensin II receptor antagonists and antiproliferatives and can be used in therapeutics for the treatment and prevention of cardiovascular diseases and in particular for the treatment of hypertension, cardiac insufficiency and diseases of the arterial wall, especially atherosclerosis. Thus the invention covers the pharmaceutical compositions which contain as the active principle the drugs consisting of a pharm&c.eut ically effective amount 2 4 9 5 01 28 of at least one compound of formula (I) as defined above, as well as one of its pharmaceutically acceptable addition salts where appropriate. These compositions can be administered by the 5 buccal, rectal, parenteral, transdermal or ocular route. These compositions can be solid or liquid and can take the pharmaceutical forms . 'commonly used in human medicine, such as, for example, simple or coated 10 tablets, gelatin capsules, granules, suppositories, injectable preparations, transdermal systems and eye lotions. They are prepared by the customary methods. In said compositions, the active principle; consisting of a pharmaceutically effective amount of at least one 15 compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition ,sa^lt^v can be incorporated with excipients normally "%mploye& in these pharmaceutical compositions, such as talc, gum arabiq, lactose, starch, magnesium stearate, polyvidone, cellu-20 lose derivatives, cacao butter, semisynthetic glyce-rides, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavorings and 25 colors. The invention also covers a pharmaceutical composition with antagonistic activity towards angiotensin II receptors, and/or antiproliferative activity, which permits especially a favorable treatment or prevention 30 of cardiovascular diseases, in particular hypertension, cardiac insufficiency and diseases of the arterial wall, especially atherosclerosis, characterized in that it comprises a pharmaceutically effective amount of at least one compound of formula (I) given above, or one 35 of its pharmaceutically acceptable addition salts. 29 2 A 9 5 which may be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier. The dosage varies especially according to the route of administration, the complaint treated and the 5 subject in question. For example, for an adult with an average weight of 60 to 70 kg, it can vary between 1 and 400 mg of active principle, administered orally in one or more daily doses, or from 0.01 to 50 mg, administered paren-10 terally in one or more daily doses. The invention also covers a method of preparing a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its 15 pharmaceutically acceptable addition salts, is incorporated into a pharmaceutically acceptable excipient, vehicle or carrier. This pharmaceutical composition can be formulated as gelatin capsules or' tablets containing from 1 to 400 mg of active 20 principle, or as injectable preparations containing from 0.01 to 50 mg of active principle. The invention also covers a method of therapeutic treatment for mammals, characterized in that a therapeutically effective amount of at least one 25 compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, is administered to this mammal. In animal therapeutics, the daily dose which can be used should normally be between 1 and 100 mg per 30 kg. Further characteristics and advantages of the invention will be understood more clearly from the following description of some Preparatory Examples, which in no way imply a limitation but are given by way 35 of illustration. 249 5 08 - 30 - Example 1; Ethyl 3-oxohexanoate Formula (III): R'x = n-propyl, Ra = O-ethyl 176 g of 2,2—dimethyl-4,6-dioxo—1,3—dioxane (Meldrum's acid) are dissolved in 550 ml of dichloro-methane and 188 ml of pyridine; the mixture is cooled to 5°C with a bath of water and ice and 133 ml of butyryl chloride are added dropwise. When the addition is complete, the mixture is stirred for three hours at room temperature. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give an oil. This oil is dissolved in 700 ml of ethanol and the mixture is refluxed for six hours. The ethanol is evaporated off under vacuum and the residue obtained is distilled to give 145.4 g of ethyl 3-oxohexanoate in the form of an oil. Boiling point (20 mm of mercury): 98°-100°C. The compound of Example 2 was prepared by the procedure of Example 1. Example 2: Ethyl 3-oxoheptanoate Formula (III): R'^ = n-butyl, Ra = O-ethyl Boiling point (20 mm of mercury): 115°-120°C. Example 3: Ethyl 4-benzyloxy-3-oxobutanoate Formula (III): R'x = CH2—0—CH2 RB = O-ethyl -<3 249508 - 31 - 80 g of 60% NaH are added in portions to 800 ml of anhydrous THF. The medium is cooled to 10 °C and maintained at this temperature. 500 ml of benzyl alcohol are then introduced dropwise. A solution of 05 65.8 g of ethyl 4-chloroacetoacetate in 200 ml of benzyl alcohol is then added. The mixture is stirred at room temperature for 20 h. It is neutralized by the slow addition of acetic acid (120 ml) while being cooled with an ice bath. The whole is then poured into 10 a mixture of water and ice and extracted with ether. The organic phase is washed with a solution of sodium bicarbonate, dried over MgS04 and then concentrated to give an orange oil. The product is purified by two successive distillations to give a yellow oil. 15 Boiling point (under 0.05 mm of mercury): 126- 13 2 ° C. Example 4: 4'-Bromomethyl-2-cyanobiphenyl 20 Formula (IV): W = Br, V = 25 a) Preparation of 2-cvano-4'-methvlbiphenvl 563.8 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared according to MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, £Z(25), 7383, are added in small portions to 800 ml of thionyl chloride. The mix-30 ture is refluxed for two hours. The thionyl chloride is concentrated under vacuum and the residue is poured into a 28% solution of ammonium hydroxide cooled beforehand with a bath of water and ice. The mixture is stirred for 30 minutes and the crystals obtained are 35 filtered off, washed with water followed by ether and 2 A 9 5 0 8 - 32 - then dried to give 554.8 g of (4'-methylbiphenyl-2-yl)-carboxamide in the form of crystals melting at 128°-132" C. These crystals are taken up in 1300 ml of thionyl chloride and the mixture is refluxed for 3 05 hours and then concentrated under vacuum to give an orange oil. This is taken up in two liters of chloroform and washed with water and the organic phase is then dried and concentrated to give 509.8 g of an oil, which crystallizes from pentane to give 467.3 g of 2-10 cyano-4'-methylbiphenyl. Melting point: 46°-48°C. b) 4'-Bromomethv1-2-cvanobiphenv1 The 467.3 g of 2-cyano-4'-methylbiphenyl pre-15 pared above are dissolved in 4.7 1 of 1,2-dichloro-ethane in the presence of 467.3 g of N-bromosuccinimide and 9.3 g of benzoyl peroxide. The mixture is heated very gradually so as to have good control over the exothermic effect. It is subsequently refluxed for 20 4 h, cooled to 50°C and then washed 3 times with hot water and dried and the organic phase is concentrated to give cream-colored crystals. Recrystallization from isopropanol gives 451 g of white crystals of 4'-bromomethyl-2-cyanobiphenyl. 25 Melting point: 128°C. Example 5: Ethyl 2-[ (2'-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate 30 Formula (V): R'x = n-propyl, Ra = O-ethyl, V = 35 249 5 - 33 - 2 3 g of ethyl 3-oxohexanoate, prepared in Example 1, are dissolved in 120 ml of tetrahydrofuran. 30.3 g of 4'-bromomethyl-2-cyanobiphenyl, prepared in Example 4, and 4.7 g of lithium chloride are added and 05 the mixture is stirred at room temperature. 39 ml of diisopropylethylamine are then introduced dropwise, causing a slight exothermic effect. The mixture is subsequently stirred for three hours at room temperature and then for ten hours under reflux. The solvents 10 are evaporated off under vacuum and the residue is taken up in water and then extracted with chloroform. The organic phase is decanted and then washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give 38 g 15 of an orange oil. Purification by chromatography on silica gel (eluent: CHC13) gives 32.3 g of ethyl 2-[ (2'-cyano-biphenyl-4-yl)methyl]-3-oxohexanoate. 20 The compounds of Examples 6 to 10 are obtained by the procedure of Example 5 using the appropriate p-ketoester. Example 6: Ethyl 2-[ (2'-cyanobiphenyl-4-yl)methyl]-3-2 5 oxoheptanoate Formula (V): = n-butyl, Ra = O-ethyl, Oil used as such in the next step. 35 ?4 9 5 0 8 34 Example 7: Ethyl 2-[ (2'-cyanobiphenyl-4-yl)methyl]-3-oxobutanoate Formula (V): R'^ = methyl, Ra = O-ethyl, Yellow oil purified by chromatography on silica gel (eluent: chloroform 95%/ether 5%). Example 8: Ethyl 2-[ (2'-cyanobiphenyl-4-yl)methyl]-3-oxopentanoate Formula (V): R'^ = ethyl, Ra = O-ethyl, (eluent: CHC13 95%/ether 5%). Example 9: Ethyl 2-[ ( 2'-cyanobiphenyl-4-yl)methyl]-4- Oil purified by chromatography on silica gel methoxy-3-oxobutanoate Formula (V): R'x = methoxymethyl, Ra O-ethyl, CN 249 5 08 - 35 - Yellow oil purified by chromatography on silica gel (eluent: CHC13 95%/ether 5%). Example 10: Ethyl 4-benzyloxy-2-[ (2'-cyanobiphenyl-4-yl)methyl]-3-oxobutanoate Formula (V): R'x = CH2—O—CH2 / ^ V = 6r , Ra = O-ethyl Oil purified by chromatography twice in succession (eluents: chloroform, then cyclohexane 80%/ethyl acetate 20%). Example 11: Ethyl 2-[4-(3-cyano-2-pyridyl)benzyl]-3-oxohexanoate Formula (V): R'x = CH2-CH2-CH3, V = U Ra = O-ethyl a) Preparation of 4-bromobenzvl methvl ether A solution of sodium methylate, prepared from 11.8 g of sodium and 350 ml of methanol, is introduced dropwise into a suspension of 117.7 g of 4-bromobenzyl bromide in 350 ml of methanol. The mixture is stirred for 2 h at room temperature and left to stand overnight. The methanol is evaporated off, the residue is taken up in ether and the organic phase is washed with 2 A 9 5 0 8 - 36 - water and then dried and concentrated to give a yellow oil, which is purified by distillation to give 102 g of bromobenzyl methyl ether as a colorless liquid. Boiling point under 17 mm of mercury: 112- 05 114 ° C. b) Synthesis of 3-cvano-2-(4-methoxvmethvlphenvl)pyridine 2 g of the compound 4-bromobenzyl methyl ether, 10 prepared above, are added to a suspension of 18 g of magnesium in 50 ml of anhydrous THF. The formation of the magnesium compound is initiated with a few crystals of iodine and, if necessary, by heating with a bath of warm water. A solution of 121.8 g of 4-bromobenzyl 15 methyl ether in 200 ml of anhydrous THF is introduced dropwise so that the temperature does not exceed 40°C. The components are reacted for 1 h at room temperature and 800 ml of a solution of zinc chloride in ether are then introduced under excess nitrogen pressure. A 20 white precipitate forms. The components are reacted for 1 h 30 min at room temperature. 800 mg of the coupling catalyst bis(triphenylphosphine)nickel(II) chloride, [NiP(phenyl)3]aCla/ are added and a solution of 76.9 g of 2-chloronicotinonitrile in 300 ml of THF 25 is then introduced. The mixture is stirred overnight at room temperature and concentrated under vacuum. The concentrate is taken up in a mixture of 1 1 of di-chloromethane, 1 1 of water and 1 1 of the disodium salt of EDTA. The emulsion is filtered on C61ite 545. 30 The organic phase is decanted, washed with water, dried and concentrated to give 133.6 g of an orange oil, which is purified by chromatography twice in succession (eluent: chloroform 95%/ether 5%). 69.4 g of 3-cyano-2-(4-methoxymethylphenyl)pyridine are thus isolated in 35 the form of an orange oil, which crystallizes. 2 49 5 37 Melting point: 74°C. c) Preparation of 3-cvano-2-f4-broroomethvlPhenvl)pvri- pyridine, prepared in the previous step, are dissolved in 700 ml of chloroform stabilized with amylene. The solution is cooled to -10°C. A solution of 66 ml of 15 BBr3 in 200 ml of chloroform stabilized with amylene is introduced dropwise so that the temperature does not exceed 5"C, The mixture is left for 1 h 30 min in an ice bath. It is hydrolyzed with ice and then with water. It is filtered and the suspension is taken up 20 in a mixture of water and chloroform. After decanta-tion, the organic phases are combined, dried and then concentrated to give 78.2 g of cream-colored crystals of 3-cyano-2-(4-bromomethylphenyl)pyridine. di ne 05 Formula (IV): W = Br, V 10 69.4 g of 3-cyano-2-(4-methoxymethylphenyl)- Melting point: 118°C. 25 d) Preparation of ethvl 2-T4-f3-cvano-2-Pvridvl benzvl1-3-oxohexanoate 30 Formula (V): R'x = CH2-CH2-CH3, V Ra = O-ethyl 35 Following the procedure of Example 5, the 249 5 - 38 - expected derivative is obtained in the form of an orange oil, which is used as such in the next step. Example 12: Ethyl 2-[4-(3-cyano-2-thienyl)benzyl]—3-05 oxohexanoate 10 ,CN s^V^( Formula (V): R'^ = CH2-CH2-CH3, V = \ J , Rs = O-ethyl a) Preparation of 4-chloro-l-U-methvlPhenvl^butanone A mixture of 560 ml of 4-chlorobutyryl chloride 15 and 550 ml of toluene is added dropwise to a suspension of 740 g of A1C13 in 2 1 of dichloromethane, the temperature being maintained at between 10° and 15°C. The reaction mixture is stirred for 30 min at room temperature and poured on to ice. After decantation, the 20 organic phase is separated off and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water and then dried and concentrated under vacuum to give 994.5 g of 4-chloro-l-(4-methylphenyl)butanone in the form of an oil, which is 25 used in the next step without further purification. b) Preparation of 3-chloro-2-f2-chloroethvl^-3-C4-iaethvlphenvllprop-2-en-l-al 390 ml of POCI3 are introduced dropwise, at a 30 temperature of between 7° and 12°C, into a solution of 352.5 g of 4-chloro-l-(4-methylphenyl)butanone, prepared above according to Example 12 a), in 450 ml of DMF. The temperature is raised gradually, in the first instance to 50°C over 2 h and then to 75°C over 45 min. 35 The mixture is poured on to ice and extracted three 249508 - 39 - times with ether and the organic phases are combined, washed with water and then dried and evaporated to give 387.8 g of 3-chloro-2-(2-chloroethyl)-3-(4-methyl-phenyl)prop-2-en-l-al in the form of an oil, which is 05 used as such in the next step. c) Preparation of 4.5-dihvdro-3-formvl-2-(4-methvl-phenvl)thiophene A mixture of 200 g of 3-chloro-2-(2-chloro-10 ethyl)-3-(4-methylphenyl)prop-2-en-l-al, prepared in Example 12 b) , 2.2 1 of THF, 276.5 g of NaaS'9H20 and 373 ml of water is refluxed for 6 h. It is concentrated under vacuum and the concentrate is taken up in water and extracted 3 times with ether. The organic 15 phases are combined, washed with water, dried and concentrated to give 170.3 g of an oil, which crystallizes. Melting point: below 50'c. 20 d) Preparation of 4.5-dihvdro-3-formvl-2-(4-methvl-phenvl1thiophene oxime 132.1 g of hydroxylamine hydrochloride are added in portions to a solution of 323.5 g of the aldehyde prepared according to 12 c) in 800 ml of 25 ethanol. A solution of sodium carbonate, prepared from 100.5 g of Na2C03 and 700 ml of water, is then added dropwise. The mixture is heated at 40°C for 5 min and the reaction is then left to proceed at room temperature for l h. The mixture is cooled to 15°C and the 30 solid is filtered off and washed with water and then with a mixture of isopropyl ether 50%/petroleum ether 50% to give 252 g of oxime. Extraction of the filtrate with dichloromethane gives a 2nd crop of 99 g of the expected oxime. 35 249 5 0 8 - 40 - e) Preparation of 3-cvano-4.5-dihvdro-2-f4-methvl-phenvl)thiophene A solution of 171.8 g of the oxime prepared in Example 12 d) in 680 ml of acetic anhydride is refluxed 05 for 3 h. It is concentrated to remove the excess anhydride and then distilled to give 115.3 g of nitrile derivative. Boiling point under 0.05 mm of mercury: 140- 150 °C. 10 f) Preparation of 3-cvano-2-f4-methvlPhenvl)thiophene 62 ml of bromine are introduced dropwise into a solution, preheated to 50°C, of 191.3 g of the nitrile prepared according to Example 12 e) in 1.85 1 of CC14. 15 The whole is refluxed until the evolution of HBr ceases. The CC14 is evaporated off and the residue is distilled to give 115.3 g of 3-cyano-2-(4-methylphe-ny1)thiophene. Boiling point under 0.05-0.1 mm of mercury: 20 130-150 ° C. g) 2-(4-Bromomethv1Phenv11-3-cvanothiophene 25 .CN Formula (IV): W = Br, V = y / 3^V( 182.2 g of the compound obtained in Example 12 30 f) are brominated according to Example 4 to give 133.7 g of 2-(4-bromomethylphenyl)-3-cyanothiophene. Melting point: 80-84°C. 35 2 A 9 5 0 8 - 41 - h) Ethvl 2-r4-(3-cvano-2-thienvl)benzvl1-3-oxohexanoate 3-^V' S" ^CN Formula (V): R'^ = CH.2-CHa.-CH3, V = \ / Ra = O-ethyl A mixture of 50 g of 2-(4-bromomethylphenyl)-3-cyanothiophene, prepared above, 40 g of ethyl 3-oxohexanoate, prepared in Example 1, 300 ml of THF, 62 ml of diisopropylethylamine and 15.6 g of LiBr is refluxed for 15 h. It is concentrated under vacuum, a dilute solution of hydrochloric acid is added and the mixture is extracted with ethyl acetate. The organic phases are combined, washed with water, dried and evaporated to give 62.4 g of ethyl 2-[4-(3-cyano-2-thienyl)-benzyl]-3-oxohexanoate in the form of an oil, which is used without further purification. Example 13: Ethyl 2-[4-(3-cyano-2-fury1)benzyl]-3-oxohexanoate oVCN Formula (V): R'^ = CH2-CH_.-CH3, V = \ / Ra = O-ethyl a) Preparation of 2-(4-methvlphenvl)-3-furanoic acid 70.7 g of p-toluidine, cooled with a bath of water and ice, are treated with 205 ml of 36% HC1. The mixture is then stirred at 55a-60°C for 30 min before being cooled to 0°C again. A solution of 45 g of NaNO= in 220 ml of water is then introduced. The mixture is 249 5 08 - 42 - stirred for 1 h at 0°C. This cold solution is introduced into a mixture of 49.3 g of 3-furanoic acid, 220 ml of acetone, 23.4 g of CuCl2 and 6.3 g of water, cooled to -5°C. The whole is stirred at 0°C for 2 h 05 and then at room temperature for 48 h. It is extracted twice with ether and the organic phase is decanted, dried and concentrated to give an oil, which gives crystals when treated with water. The crystals are filtered off and washed with 50 ml of a 50% methanol/ 10 water mixture to give 13.4 g of 2-(4-methylphenyl)-3-furanoic acid. Melting point: 166"C. b) Preparation of 2-(4-methvlphenvl1furan-3-carbox-15 amide 20 ml of S0C12 are added to a solution of the 13.4 g of furanoic acid prepared above in 70 ml of toluene. The mixture is refluxed for 3 h and the excess S0C12 and the toluene are then distilled to give 20 an oil, which is reacted at 5°C with a solution of 100 ml of 1,2-dimethoxyethane saturated with ammonia. The precipitate is filtered off and washed with water and then with isopropyl alcohol to give 7 g of white crystals of amide. 25 Melting point: 174°C. c) Preparation of 3-cvano-2-M-methvlphenvHfuran A mixture of 12.2 g of the amide prepared above and 65 ml of S0C12 is refluxed for 3 h and concentrated 30 under vacuum. The oil obtained is taken up in chloroform, and water and ice are then added. After decanta-tion, the aqueous phase is extracted with chloroform and the organic phases are combined, dried and evaporated to give an oil. Purification by chromatography on 35 silica gel (eluent: toluene) gives 7.5 g of an oil, 249 5 08 43 which crystallizes. Melting point: 66°C. d) 2-(4-Bromomethylphenvl1-3-cvanofuran Formula (IV) : W = Br, V CN The 7.5 g of compound obtained in Example 13 c) are brominated according to Example 4 to give, after purification by chromatography on silica gel (eluent: pentane 50%/toluene 50%), 4.6 g of 5-bromo-3-cyano-2-(4-methylphenyl)furan (melting point: 88°C), 2.2 g of 5-bromo-3-cyano-2-(4-bromomethyIpheny1)furan (melting point: 114°C) and 2 g of 2-(4-bromomethylphenyl)-3-cyanofuran. phenyl)furan is subjected to a further bromination reaction according to Example 4 to give 5-bromo-2-(4-bromomethylphenyl)-3-cyanofuran, which constitutes the compound of Example 13 d) bis. e) Ethvl 2-r4-(3-cvano-2-furvl)benzvl1-3-oxohexanoate Melting point: 108°C. The compound 5-bromo-3-cyano-2-(4-methyl- CN Formula (V): R'x = CH2-CHS-CH3, V = \ Ra = O-ethyl The resulting derivative 2-(4-bromomethyl-phenyl)-3-cyanofuran is treated according to Example 5 2 4 9 5 0 8 44 to give ethyl 2-[4-(3-cyano-2-furyl)benzyl]-3-oxo-hexanoate in the form of an oil, which is used in the crude state in the next step. . Likewise, the derivative 5-bromo-2-(4-bromo-05 methylphenyl)-3-cyanofuran of Example 13 d) bis is treated according to Example 5 to give ethyl 2-[4-(5-bromo-3-cyano-2-furyl)benzyl]-3-oxohexanoate in the form of an oil, which constitutes the derivative of Example 13 bis. 10 Example 14: 3-[ (2'-Cyanobiphenyl-4-yl)methyl]-2,4-dioxopentane 20 methyl-2-cyanobiphenyl, prepared in Example 4, 88 ml of diisopropylamine and 10.6 g of anhydrous lithium chloride in 300 ml of tetrahydrofuran are refluxed for 27 h. The mixture is cooled and the precipitate is filtered off. The organic phase is concentrated to 25 dryness to give 88.5 g of crystals. These are taken up in isopropanol and the mixture is filtered to isolate 38.8 g of unreacted 4'-bromomethyl-2-cyanobiphenyl. The concentrated mother liquors yield 26.5 g of an oil which, when purified on silica gel (eluent: chloro-30 form), gives a further 5.3 g of 4'-bromomethyl-2-cyano-biphenyl and 12.2 g of the expected 3-[ (2'-cyanobi-phenyl-4-yl)methyl]-2,4-dioxopentane in the form of a yellow oil. 15 Formula (V): R'x = CH3, Ra = CH3, V 32.8 g of 2,4-dioxopentane, 68 g of 4'-bromo- 35 249508 - 45 - Example 15: 5-[ (2'-Cyanobiphenyl-4-yl)methyl]-4,6-dloxononane Formula (V): R'x = CH2-CH3-CH3, V = Rb = CH2-CH2-CH3 15.6 g of 4,6—dioxononane, prepared from methyl propyl ketone and ethyl butyrate in the presence of lithium amide (according to CA 42 : 4129 f), are dissolved in 160 ml of anhydrous DMF. 4 g of 60% NaH are added in portions. When the exothermic effect has subsided, the mixture is cooled to room temperature and a solution of 27.2 g of 4'-bromomethyl-2-cyanobiphenyl, prepared in Example 4, in 90 ml of DMF is introduced dropwise. The mixture is stirred for 30 min at room temperature and then heated at 60°C for 2 h. It is concentrated under vacuum and the concentrate is taken up in a water/dichloromethane mixture and acidified with a dilute solution of HCl. After decantation, the aqueous phase is extracted twice with dichloromethane. The organic phases are washed with water, dried and then concentrated to give 36.3 g of an oil, which is purified by chromatography twice in succession (eluent: chloroform, then cyclohexane 90%/ethyl acetate 10% respectively) to give a solid identified by NMR as being the enol tautomer melting at 105°C, and an oil corresponding to the diketone tautomeric form. Example 16: 2,4-Dioxo-3—[ (2'-(lH-tetrazol-5-yl)bi— phenyl-4-yl)methyl]pentane Formula (V): R'^ = CH3, RB = CH3 , 2 4 9 5 0 8 - 46 - 05 A mixture of 11.8 g of 3-[ (2'-cyanobiphenyl-4-yl)methyl]-2,4-dioxopentane, prepared in Example 14, 200 ml of xylene and 9.3 g of trimethyltin azide is 10 refluxed for 50 h. After 24 h, a second equivalent of trimethyltin azide is added. The mixture is cooled and concentrated to give a viscous oil which, when chromatographed on silica gel (eluent: chloroform 90%/methanol 10%), gives 9.3 g of 15 crystals. An additional treatment with acetonitrile gives 6.2 g of analytically pure 2,4-dioxo-3-[ (2'-( lH-tetra-zol-5-yl)biphenyl-4-yl)methyl]pentane. Empirical formula: CxoH:LeN<103. 20 Melting point: 166°C. Example 17: Ethyl 2-[ [2'-(lH-tetrazol-5-y2 )biphenyl-4-yl]methyl]-3-oxohexanoate 25 Formula (V): R'^ = n-propyl, Ra = O-ethyl, 30 A mixture of 69.9 g of ethyl 2-[ (2'-cyanobi-phenyl-4-yl)methyl]-3-oxohexanoate, prepared according to Example 5, 700 ml of anhydrous toluene and 47.5 g of 35 trimethyltin azide, prepared from sodium azide and tri- 249 5 08 - 47 - methyltin chloride, is refluxed for 24 h. A further 47.5 g of trimethyltin azide are added and reflux is continued for 16 h. The mixture is concentrated to 50%. The orange solution obtained is purified by chromatography twice in succession (eluent: chloroform 90%/methanol 10%, then chloroform 95%/methanol 5%) to give 58 g of an orange oil, which crystallizes. Melting point: 65°C. Example 18 (method A): 6— [ ( 2'-Cyanobiphenyl-4-yl ) methyl ] -7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine Formula (Vila): R'x = n-propyl, X = H, Rxo = OH, V = A mixture of 5 g of 3-aminopyrazole, 20.6 g of the 0-ketoester of Example 5 and 90 ml of acetic acid is refluxed for 1 h 30 min. The precipitate obtained is filtered off and washed with ether and then with ethanol to give 12.7 g of 6-[ (2'-cyanobiphenyl-4-yl)-methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine. Melting point: 251°C. XH NMR (DMSO-de): 2.65 (t, 2H, propyl CHa); 3.96 (s, 2H, benzyl. CHa) ; 6.1 (d, 1H, H3); 7.85 (d, 1H, H2, J(H2-H3): 2Hz). 249 5 0 8 - 48 - Example 19 (method B): 6- [ (2'-Cyanobiphenyl-4-yl)methyl ]-5-hydroxy- 7-propylpyrazolo[1,5-a]pyrimidine 05 Formula (Vllb): R'^ = n-propyl, X = H, R10 OH, 10 A mixture of 5 g of 3-aminopyrazole and 50 ml of 5-ethyl-2-methylpyridine is heated to 175°C. A 15 solution of 21 g of the ^-ketoester compound of Example 5 in 50 ml of 5-ethyl-2-methylpyridine is introduced dropwise. The reaction mixture is heated for 6 h at 175°C. The precipitate of 11.9 g obtained is filtered 20 off and identified as being the derivative of Example 18 described above. The concentrated mother liquors are taken up in a mixture of water and chloroform. After decantation, the aqueous phase is extracted with chloroform and the 25 organic phases are combined, dried and concentrated to give 10.7 g of amorphous crystals. Chromatography on silica gel (eluent: CHC13 95%/methanol 5%) makes it possible to isolate 4.1 g of crystals of the compound 6— [ (2'-cyanobiphenyl-4-yl)methyl]-5-hydroxy-7-propyl-30 pyrazolo[l,5-a]pyrimidine. Melting point: 236°C. 1H NMR (DMSO—ds): 2.99 (t, 2H, n-propyl CHa); 3.95 (s, 2H, benzyl CHa); 5.85 (d, 1H, H3, J(Ha-H3): 35 1.5 H2); 7.75 (m, 2H, Ha with 249 5 0 8 - 49 - an aromatic proton). The following derivatives of Examples 20 to 26 were prepared by one of the two procedures of Examples 05 18 or 19 using the appropriate /9-ketoester compounds described in Examples 5 to 15. Example 20: 6-[ (2'-Cyanobiphenyl-4-yl)methyl ]-7- hydroxy-2-methyl-5-propylpyrazolo[1,5-10 a]pyrimidine Formula (Vila): R'^ = n-propyl, X = 2-CH3, R10 = OH, 15 20 Melting point: 210*0. 1H NMR (DMSO-ds): 2.3 (s, 3H, CH3); 2.6 (t, 2H, propyl CHa); 5.9 (s, 1H, H3). Example 21: 5-Butyl-6-[ (2'-cyanobiphenyl-4-yl)methyl]-25 7-hydroxypyrazolo[l,5-a]pyrimidine Formula (Vila): R'x = n-butyl, X = H, Rxo = OH, 30 35 249508 - 50 - Melting point: 216°C. ^ NMR (CHC13): 2.8 (t, 2H; n-butyl CHa); 4.07 (s, 2H, benzyl CHa); 6.14 (d, 1H, H3); 7.75 (d, 1H, Ha, J(Ha-05 H3): 2.3 HZ). Example 2 2: 6-[4-(3-Cyano-2-thienyl)benzyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine 10 Formula (Vila): R'x= n-propyl, X = H, R10 = OH, V = 15 NC Melting point: 252°C. *H NMR (DMS0-de): 2.64 (t, 2H, n-propyl CHa); 3.96 (s, 2H, benzyl CHa); 20 6.12 (d, 1H, H3, J(Ha-H3): 1.2 Hz). Example 23: 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-5,7-di-propylpyrazolo[1,5-a]pyrimidine 25 Formula (Vllb): R'^ = n-propyl, X = H, Rio = n-propyl, 30 35 Melting point: 125°C. XH NMR (CHC13): 2.74 (t, 2H, n-propyl CHa); 249 5 0 8 - 51 - 05 3.23 (q, 2H, n-propyl CH2); 4.21 (s, 2H, benzyl CH2); 6.61 (d, 1H, H3); 8.09 (d, 1H, H2, J(H2-H3) : 2.2 Hz).. Example 24: 6-[4-(3-Cyano-2-pyridyl)benzyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine Formula (Vila): R'x = n-propyl, X = H, 10 Rto = OH, 25 30 15 Melting point: 248°C. XH NMR (DMSO-ds): 2.65 (t, 2H, n-propyl CHa); 3.99 (s, 2H, benzyl CHa); 6.12 (d, 1H, H3) ; 7.87 (d, 20 1H, H2/ J(H2-H3): 1.7 Hz). Example 25: Ethyl [6-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimi-din-2-yl]carboxylate Formula (Vila): R'^ = n-propyl, X = 3—COOCH2CH3, R10 - OH, 35 Melting point: 160°C. XH NMR (DMS0-d6) : 2.83 (t, 2H, n-propyl CH=!) ; 249 5 0 8 - 52 - 05 3.99 (s, 2H, benzyl CH3); 8.21 (s, 1H, H2). Example 26: 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-2,7-di-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine Formula (Vila): R'^ = n-propyl, X = 2-OH, Rxo = OH, 10 V 15 The following compounds will be obtained by reacting the ^-ketoesters of Examples 9, 10, 13-13 bis and 14 with 3-aminopyrazole by one of the procedures of Examples 18 or 19: 6- [ ( 2'-cyanobiphenyl-4-yl)methyl]-7-hydroxy-5-methoxy-methylpyrazolo[1,5-a]pyrimidine 5-benzyloxymethyl-6-[ (2'-cyanobiphenyl-4-yl)methyl ]-7-hydroxypyrazolo[1,5-a]pyrimidine 6-[4-(3-cyano-2-furyl)benzyl]-7-hydroxy-5-propylpyra-zolo[1,5-a]pyrimidine 6—[4—(5-bromo-3-cyano-2-furyl)benzyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine 6- [ ( 2'-cyanobiphenyl-4-yl)methyl]-5,7-dimethylpyrazolo-[1,5-a]pyrimidine Example 27: 7-Chloro-6-[ (2'-cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine Formula (Villa): R'^ = n-propyl, X = H, 35 249 5 08 - 53 - NC. 05 10 15 20 27 g of 6— [ (2'—cyanobiphenyl—4—yl)methyl ] -7— hydroxy-5-propylpyrazolo[l,5-a]pyrimidine, prepared in Example 18, are added in portions to 540 ml of P0C13. The mixture is refluxed for 3 h. It is concentrated under vacuum. The oil obtained is taken up in dichloromethane and washed twice with a solution of water and ice. The organic phase is decanted, dried and concentrated. The yellow oil is taken up in ether to give 25.6 g of crystals of 7-chloro-6-[(2'-cyanobi-phenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine. Melting point: 137°C. ^-H NMR (CDC13) : 2.8 (t, 2H, propyl CHa) ; 6.7 (d, 1H, H3); 8.2 (d, 1H, H,, J(Ha-H3): 2.2 Hz). Example 28: 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-7-[2-(morpholin-4-y1)ethylamino]-5-propylpyrazolo [1,5-a]pyrimidine 25 Formula (IX): R, = NH—CH,—ChL—N O, = n-propyl, X = H, 30 NC V = ~0 35 A mixture of 5 g of the chlorinated derivative prepared in Example 27, 1.8 g of 4 -(2-aminoethyl)mor- 30 249508 - 54 - pholine, 1.5 g of NaaC03 and 100 ml of ethanol is refluxed for 7 h. A further 1.8 g of 4-(2-aminoethyl)-morpholine are added and the mixture is refluxed for 8 h. It is concentrated under vacuum and taken up in a mixture of water and dichloromethane. The aqueous phase is decanted and extracted with dichloromethane. The organic phases are combined and dried. Evaporation of the solvent gives 5.9 g of a brown oil which is sufficiently pure for the next step. NMR (CDC13): 2.5 (t, 2H, propyl CHa); 6.4 (d, 1H, H3); 7.9 (d, 1H, Ha, J(Ha-H3): 2.4 Hz). Example 29; 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-7-math-oxy-5-propylpyrazolo[1,5-a]pyrimidine Formula (IX): Rx = OCH3, X = H, Ra = n-propyl, 7.7 g of the chlorinated compound prepared in Example 27 are reacted at room temperature, for 6 h, with a solution of sodium methylate and 1,2-dimethoxy-ethane prepared from 0.6 g of sodium, 25 ml of methanol and 50 ml of 1,2-dimethoxyethane. The reaction mixture is concentrated. The concentrate is taken up in a mixture of water and ethyl acetate. The precipitate obtained (1.4 g) is identified as 6-[ ( 2'-cyanobiphenyl-4-yl)methyl l-^-hydroxy-S-propylpyrazoloCl ,5-a]pyrimidine, obtained in Example 18. The organic phase is chromatographed on silica - 55 - gel (eluent: dichloromethane 90%/acetone 10%) to give 4 g of 6-[ ( 2'-cyanobipheny1-4-yl)methyl]-7-methoxy-5-propylpyrazolo[1,5-a]pyrimidine. Melting point: 110°C. XH NMR (CDC13): 2.75 (q, 2H, propyl CHa); 4.18 (s, 2H, ben2yl CHa); 4.29 (s, 3H, OCH3); 6.60 (d, 1H, H3); 8.07 (d, 1H, H2/ J(H2-H3): 2.3 HZ). Example 30: 6-[ (2'-Cyanobiphenyl-4-yl)methyl ]-5-propylpyrazolo [1,5-a]pyrimidin-7-yl] 2-methoxy-ethyl ether Formula (IX): Rx = 0CHaCH20CH3, X = H, R2 = n-propyl, 0.6 g of 60% NaH is added in portions to a mixture of 25 ml of 2-me thoxy ethanol and 50 ml of 1,2-dimethoxyethane. After 15 min, 5 g of the chlorinated compound prepared in Example 27 are introduced in portions, followed by 50 ml of 1,2-dimethoxyethane. The mixture is stirred for 3 h at room temperature and then for 3 h at 60°C. It is concentrated under vacuum and the concentrate is taken up in a mixture of water and ethyl acetate. After decantation, the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried and evaporated to give 6.3 g of an oil, which is purified by chromatography on silica gel (eluent: dichloromethane 90%/acetone 10%) to give 4.2 g 20 25 30 2 4 9 5 0 8 - 56 - of 6- [ (2'-cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo-[1,5-a]pyrimidin-7-yl] 2-methoxyethyl ether. Melting point: 106"C. 05 The compounds of Examples 31 to 34 were ob tained by one of the procedures of Examples 28 to 30 using the appropriate nucleophiles. Example 31: 6-[ (2'-Cyanobiphenyl-4-yl)methy 1]-7-(N-10 morpholino)-5-propylpyrazolo[lf5-a]- pyrimidine Formula (IX): = N-morpholino, Ra = n-propyl, X = H, 15 V = Melting point: 140°C. XH NMR (DMSO-de): 2.6 (t, 2H, propyl CHa); 6.6 (d, 1H, H3); 8.1 (d, 1H, Ha/ J(H3-H3): 2.4 Hz). Example 3 2: 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-5-propyl-7-[2-(pyrrolidin-l-yl)ethylamino]pyrazolo-[1,5-a]pyrimidine Formula (IX): rx = nh—ch2—ch2—n R2 = n-propyl, X = H, 35 - 57 - 249 5 0 8 Oil purified by chromatography on silica gel (eluent: CHC13 90%/methanol 10%). XH NMR (CDC13): 2.6 (m, 4H, propyl CHa + pyrrolidine CH=); 6.4 (d, 1H, H3, J(H2-H3): 2.1 Hz); 7.9 (d, 1H, H2). Example 33: 6-[ (2'-Cyanobipheny 1-4-yl)methyl]-7- (piperidin-l-yl)-5-propylpyrazolo[1,5-a]-pyrimidine Crystallization from isopropyl ether. Melting point: 118'C. Example 34: Ethyl [6-[ (2'-cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidin-7-yl]-mercaptoacetate Formula (IX): R1 = S-CH3COOEt, X = H, NC. R2 = n-propyl, V = 249 5 08 - 58 - Melting point: 126°C. The compounds of Examples 35 and 36 were obtained by the procedure of Example 28, except that 05 the reaction was carried out in an autoclave at 100°C for 48 h. Example 35: 6-[ (2'-Cyaviobiphenyl-4-yl)methyl]-7-N,N-diethylamiiio-5-propylpyrazolo[ 1,5-a ] -10 pyrimidine v = ' 15 ch2 chg • R_, = n-propyl, X = H Formula (IX): Rx = ch2-ch3 Oil purified by chromatography on silica gel (eluent: CH2C12 95%/ethyl acetate 5%). 20 AH NMR (DMSO-ds): 2.6 (t, 2H, propyl CHZ); 6.6 (d, 1H, H3, J(H2-H3): 2.1 Hz); 8.1 (d, 1H, Ha). Example 36: 7-Amino-6- [ ( 2'-cyanobiphenyl-4-yl)methyl ]-25 5-propylpyrazolo[1,5-a]pyrimidine Formula (IX): Rx = NH2, R2 = n-propyl, X = H, 30 35 Oil purified by chromatography on silica gel 249 - 59 - (eluent: CH2C12 95%/acetone 5%). Crystallizes slowly. Melting point: 158°C. XH NMR (CDC13): 2.7 (t, 2H, propyl CH2)? 6.4 (d, 1H, H3); 7.9 (d, 1H, H2/ J(H2-H3): 2 Hz). Example 37 : 6-[ (2'-Cyanobiphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine Formula (IX): Rx = H, X = H, NC R2 = n-propyl, V = A solution of 5.4 g of the chlorinated compound prepared in Example 27 in 110 ml of 2-methoxyethanol containing 1.2 g of anhydrous sodium acetate is hydro-genated, at atmospheric pressure and ambient temperature, in the presence of 1.4 g of 5% Pd-on-charcoal. The system is purged with nitrogen. The catalyst is filtered off on C61ite 545 and washed with 2-methoxyethanol. The filtrate is concentrated and taken up in ether to give 5.2 g of crude product. Purification by chromatography on silica gel (eluent: dichloromethane 90%/acetone 10%) gives 4 g of 6-[ (2'-cyanobiphenyl-4-y1)methyl]-5-propylpyrazolo[1,5-a]pyrimidine. Melting point: 154°C. Example 38: 7-Hydroxy-5-propy 1 -6-[ (2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methy1]pyrazolo[1,5-a]-pyrimidine Formula (I): Rx = OH, R_, = n-propyl, X = H, 2 4^5 - 60 - 05 A mixture of 0.8 g of 3-aminopyrazole, 3.9 g of the 0-ketoester of Example 17 and 25 ml of acetic acid is refluxed for 6 h. A further 0.4 g of aminopyrazole 10 is added and the mixture is refluxed for a period of 6 h. It is concentrated under vacuum. The oil obtained is taken up in water to give 3.8 g of a solid, which is purified a first time by chromatography on silica gel (eluent: chloroform 80%/methanol 20% to 15 remove the less polar products, then chloroform 70%/ methanol 30% to elute the pyrazolopyrimidine compound). The resulting solid is treated with a normal solution of sodium hydroxide. The insoluble materials are removed and the clear solution is acidified to pH 4 20 by bubbling SOa to give a white precipitate. The compound is crystallized from ethanol to give 0.6 g of 7-hydroxy-5-propyl-6-[ (2'-( lH-tetrazol-5-yl )biphenyl-4-y1)methyl]pyrazolo[1,5-a]pyrimidine. Empirical formula: C=.3H2iN70» 2HaO. 25 Melting point: >320°C with decomposition. XH NMR (DMSO-ds): 2.5 (m, 2H, propyl CHa + DMSO-ds); 6 (d, 1H, H3); 7.8 (d, 1H, H2, J(H2-H3): 1.9 Hz) . 30 Example 39 : 5-Hydroxy-7-propyl-6- [ (2'-(lH-tetrazol-5-y1)biphenyl-4-y1)methyl]pyrazolo[1,5-a]-pyrimidine 35 Formula (X): Rx = n-propyl, X = H, R2 = OH, 2 49508 61 N-NH n". N R 3 A mixture of 5 g of the derivative prepared in Example 19, 150 ml of xylene, 6 ml of DMF and 7 g of trimethyltin azide is heated at 115°C for 50 h. The organic phase is decanted. The precipitate is taken Up in THF. Gaseous hydrochloric acid is bubbled in until the precipitate dissolves. The solution is concentrated under vacuum and the concentrate is taken up in water and triturated. The gum obtained is crystallized in the presence of acetonitrile. Recrystallization from isopropanol gives 0.7 g of 5-hydroxy-7-propyl-6-[ (2'-(lH-tetrazol-5-yl)-bipheny1-4-y1)methy1]pyrazolo[1,5-a]pyrimidine. Empirical formula: C^H^N^O. Melting point: 260'c. XH NMR (DMS0-ds): 2.93 (t, 2H, n-propyl CHa); 3.86 (s, 2H, benzyl CHa); 5.83 (d, 1H, H3); 7.74 (d, 1H, H2, J(H3-H3): 1.9 Hz). Example 40: 7-[(N-Morpholinoethyl)amino]-5-propyl-6-[ ( 2'-(lH-tetrazol-5-yl)biphenyl-4-yl) — methyl]pyrazolo[1,5-a]pyrimidine Formula (I): Rx = NH—CH2—CH2—N / \ O , \ / Ra = n-propyl, X = H 249 5 0 8 - 62 - A mixture of 5.9 g of 6-[ (2'-cyanobipheny1-4-y1)methyl]-7-[2-(morpholin-4-y1)ethylamino]-5-propyl-pyrazolo[l,5-a]pyrimidine, prepared in Example 28, 3.1 g of trimethyltin azide and 120 ml of xv&ene is brought to the reflux point. After 15 h, a ."furttver 3.1 g of . 'I trimethyltin azide are added and the reflux reaction is 't. continued for 20 h. The thick oil is decanted from the xylene and taken up in THF. Acidification with gaseous hydrochloric acid gives a gummy precipitate, which is taken up in acetonitrile to give 4.7 g of a solid. The base is freed by treatment with a solution of triethylamine/ethyl acetate. The compound is purified a first time by chromatography on silica gel (eluent: chloroform 80%/methanol 20%). Recrystallization from ethanol, gives 2.5 g of white crystals of 7-[(N-morpholinoethyl)amino]-5-propyl-6- [ (2'- (lH-tetrazol-5-yl)biphenyi-4-yl)methyl ] -pyrazolo[l,5-a]pyrimidine. Empirical formula: C2aH33No0«0.lHaO. Melting point: 210°C. 3-H NMR (DMSO-d6): 2.6 (t, 2H, propyl CHa); 6.3 (d, 1H, H3); 8 (d, 1H, H2, J(H2-H3): 2.2 Hz). The following compounds of Examples 41 to 49 were prepared by any one of the methods described in Examples 38, 39 or 40. 2 4 9 5 0 8 - 63 - Example 41: 7-Hydroxy-2-xnethy 1 -5-propy 1 -6- [ ( 2'- (1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-pyrazolo[1,5-a]pyrimidine hydrochloride 05 Formula (I): Rx = OH, R2 = n-propyl, X = 2-CH3, 10 R„ = 15 Empirical formula: CaAHa3N70»HCl«0.2H20. Melting point: 230-232°C with decomposition. AH NMR (DMS0-ds): 2.6 (t, 2H, propyl CH2); 6 (s, 1H, H3 ). 20 Example 42: 7-Chloro-5-propyl-6-[ (2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]pyrazolo[1,5-a]-pyrimidine Formula (I): Rx = CI, Ra = n-propyl, X = H, 25 Empirical formula: C23HaoClN7,. 30 Melting point: 234°C. XH NMR (DMS0-ds): 2.7 (t, 2H, propyl CH2); 6.8 (d, 1H, H3); 8.3 (d, 1H, H2, J(H3-H3): 2.3 Hz). 35 2 4 9 5 0 8 - 64 - Example 43: 7-(N-Morpholino)-5-propyl-6-[ (2'-(lH-tetra-zol-5-yl)biphenyl-4-yl)methyl]pyrazolo-[1,5-a]pyrimidine hydrochloride 05 Formula (I): Rx = -N Ra = n-propyl, X = H, 10 15 20 Empirical formula: C27H2aNs0«HCl. Melting point: 210°-212°C. NMR (DMSO-d6): 2.8 (t, 2H, propyl CH2) ; 6.6 (d, 1H, H3); 8.2 (d, 1H, H2, J(H2-H3): 2.2 Hz). Example 44: 5-Propyl-7-[(N-pyrrolidinoethyl)amino]-6-[ (2'-(lH-tetrazol-5-yl)biphenyl-4-yl)-methy1]pyrazolo[1,5-a]pyrimidine 25 Formula (I): R, = NH—CH2—CH2—N 30 X = H, R_, = n-propyl, N-NH R-. = 35 Empirical formula: C2S,H33NS. - 65 - 249 5 08 Melting point: 200°-201°C. XH NMR (DMSO-ds): 2.6 (t, 2H, propyl CH2); 6.4 (d, 1H, H3); 8 (d, 1H, H2, J(H2-H3): 2 Hz). 05 Example 45: 7-Amino-6-[ (2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine 10 Formula (I): Rx = NH2, R2 = n-propyl, X = H, 15 R„ = Empirical formula: C23H22NB. Melting point: 255°C. 20 iH NMR (DMSO-ds): 2.5 (m, 2H, propyl CH2 + DMSO-ds); 6.3 (d, 1H, H3); 8 (d, 1H, H2, J(H2-H3): 2 Hz). Example 46: 7-N,N-Diethylamino-5-propy1-6-[(2'-( 1H-2 5 tetrazol-5-yl)bipheny1-4-y1)methyl]- pyrazolo[1,5-a]pyrimidine hydrochloride /CH2—CH3 Formula (I): R1 = N 30 CH2-CH3 ' R2 = n-propyl, X = H, N-NH i * N 35 R3 = - 66 - 249 5 08 Empirical formula: C27HaoNB*HCl. Melting point: 192"C. NMR (DMSO-ds): 2.68 (t, 2H, propyl CHa) ; 6.63 (d; 1H, H3)? 8.21 (d, 05 1H, Ha). Example 47: 5-Butyl-7-hydroxy-6-[ ( 2'-( lH-tetrazol-5-y1)biphenyl-4-y1)methyl]pyrazolo[1,5-a]-pyrimidine 10 Formula (I): Rx = OH, Ra = n-butyl, X = H, 15 Purified by chromatography on silica gel (eluent: dichloromethane 90%/methanol 10%). 20 Empirical formula: C24Ha3N_,0. Melting point: >370°C with decomposition. XH NMR (DMS0-de): 2.51 (m, n-propyl CHa/DMS0- de); 5.99 (d, 1H, H3); 7.8 (d, 1H, Ha, J(H2-H3): 1.8 25 Hz). Example 48: 5-Propyl-6-[ (2'-(lH-tetrazol-5-yl)bi- pheny1-4-y1)methyl]pyrazolo[1,5-a]pyrimidine 30 35 Formula (I): Rx = H, Ra = n-propyl, X = H, 249508 - 67 - Purified by crystallization from acetonitrile. Empirical formula: Ca3HaiN7. Melting point: 196°C. ^-H NMR (DMSO-d6): 2.64 (t, 2H, n-propyl CHa) ; 05 4.05 (s, 2H, benzyl CHa); 6.58 (d, 1H, H3); 8.11 (d, 1H, Ha/ J(H3-H3): 1.8 Hz); 8.89 (s, 1H, H7). 10 Example 49: 5f 7-Dipropyl-6-[ (2'-(lH-tetrazol-5-yl)bi-- pheny1-4-y1)methyl]pyrazolo[1,5-a]pyrimidine Formula (I): Rx = n-propyl, Ra = n-propyl, 15 X = H, 20 Purification by recrystallization from iso-propyl acetate. Empirical formula: Ca6Ha7N7. 25 Melting point: 188°C. *H NMR (DMSO-de): 2.64 (t, 2H, n-propyl CHa); 3.17 (t, 2H, n-propyl CHa); 4.16 (s, 2H, benzyl CHa); 6.59 (s, 1H, H3); 8.13 (s, 30 1H, H ) . 35 - 68 - 249508 Example 50: 6-[ ( 2'-Aminocarbonylbiphenyl-4-yl)methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine 05 Formula (I): Rx = OH, Ra = n-propyl, X = H, 0 R3 = H2N^ 10 7.4 g of the compound of Example 18 in a solution of NaOH, prepared from 29.6 g of sodium hydroxide pellets and 700 ml of water, are refluxed for 3 h. The 15 white precipitate is filtered off and treated with a dilute solution of acetic acid. Purification by recrystallization from 2-methoxyethanol gives 3.4 g of 6-[ (2'-aminocarbonylbiphenyl-4-yl)methyl]-7-hydroxy-5-propylpyrazolo[1,5-a]pyrimidine. 20 Empirical formula: C33H22N404. Melting point: 264°C. XH NMR (DMSO-ds): 2.64 (t, 2H, n-propyl CHa); 3.9 (s, 2H, benzyl CHa); 6.09 (d, 1H, H3); 7.85 (d, 1H, H2, 25 J(Ha-H3): 1.7 Hz). Example 51: 6-[ (2'-Carboxybiphenyl-4-yl)methyl]-7- hydroxy-5-propylpyrazolo[1,5-a]pyrimidine 30 Formula (I): Rx = OH, R_, = n-propyl, X = H, HOOC R3 = 35 20 249 5 08 - 69 - A mixture of 7.4 g of the compound of Example 18 in a solution of NaOH, prepared from 40 g of sodium hydroxide pellets and 500 ml of water, is refluxed for 6 h. The white precipitate, melting at 230-240°C, 05 obtained after treatment with dilute acetic acid is refluxed again for 18 h with a mixture of 6 g of NaOH, 6 ml of water and 200 ml of ethylene glycol. The resulting mixture is concentrated under vacuum and taken up in water. Treatment with a solution of acetic 10 acid gives a precipitate which, when purified by recrystallization from 2-methoxyethanol, gives 4 g of 6- [ (2'-carboxybiphenyl-4-yl)methyl]-7-hydroxy-5-propyl-pyrazolo[1,5-a]pyrimidine. Empirical formula: C23H2XN303. 15 Melting point: 300°C. i-H NMR (DMS0-d6): 2.63 (t, 2H, n-propyl CH2) ; 3.91 (s, 2H, benzyl CH2); 6.09 (d, 1H, H3); 7.85 (d, 1H, H2, J(H2-H3): 1.9 Hz). PHARMACOLOGY A • Study of the adrenal angiotensin II receptors 25 i. principle The affinity of the products of the Examples for the angiotensin II receptors is evaluated by the technique of displacing a radioligand specifically 30 bound to rat adrenal angiotensin II receptors. II. Procedure An aliquot of a rat adrenal gland homogenate 35 incubates in the presence of a single concentration of 10 lb 20 25 30 249 5 08 - 70 - [X2Si]—SIAII (Sar1,Tyr4,Ilea-angiotensin II), which is an angiotensin II receptor antagonist, and two concentrations of competing agents (10_s M, 10-7 M) for 60 min at 25°C. The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper filters. The non-specific binding is determined in the presence of angiotensin II. III. Expression of the results The results are expressed, for the concentrations tested, as the percentage displacement of the radioligand specifically bound to the adrenal angiotensin II receptors. IV. Results Product of % displacement of the labeled ligand 1E-7M 1E-5M Example 38 65 39 Example 40 70 51 Example 41 68 40 Example 4 2 68 38 Example 43 65 21 Example 44 72 48 Example 45 64 46 Example 46 72 49 B • Measurement of the inhibition of the cell proliferation induced by a growth factor (example: Platelet-Derived Growth Factor, or PDGF) in rat aorta smooth muscle cells 30 249 5 0 8 - 71 - I. Principle The inhibition of the cell proliferation induced by a growth factor (example: PDGF) is evaluated 05 by measuring the incorporation of 3H-thymidine in rat aorta smooth muscle cells (VSMC). II. Procedure 10 The VSMC are cultivated at 37°C in 5% COa until subconfluence is reached, and are then placed for 24 hours at rest in a serum-poor medium. They are subsequently pretreated for one hour with the test molecule (10-* M) and then stimulated for 22 hours with a growth 15 factor (example: PDGF). 3H-Thymidine is incorporated during the last 4 hours. All these steps are performed at 37°C in 5% C02. The reaction is terminated by sucking off the reaction medium, detaching the cells and then filtering 20 the lyzed cells through glassfiber filters. III. Expression of the results The results are expressed as the percentage 25 inhibition of the stimulation of incorporation of 3H-thymidine due to the action of the growth factor. Under these conditions, the tested products of formula (I) of the Examples have an antiproliferative activity at 100 nM. TOXICOLOGY 35 The products of the Examples described have an excellent tolerance after oral administration. Their 50% lethal dose in rats was found to be </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 249 5 0 8 - 72 - greater than 300 mg/kg. CONCLUSION 05 The products of the Examples described have a good affinity for the angiotensin II receptors. In this respect they may be used beneficially for the various pathological conditions in which angiotensin II is involved, in particular for the treatment of arte-10 rial hypertension and cardiac insufficiency, in dosages of l to 400 mg by oral administration and of 0.01 to 50 mg by intravenous administration, in one or more dosage units per day. Furthermore, some of the compounds also have an antiproliferative activity and in this respect 15 are of potential value in the treatment of proliferative diseases such as atherosclerosis. 30 35 2-4 9 5 0 IB 73 WHAT WE CLAIM IS;

1. Pyrazolopyrimidine derivatives characterized in that they have the general formula (I): 5 Formula (I) in which: - one of the radicals and R2 is 10 - a lower alkyl radical having 1 to 6 carbon atoms; or - an ether radical of the formula -(CH2)p-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl 15 radical; and - the other radical R^ or R2 is - a hydrogen atom; - a halogen atom; - a lower alkyl radical having 1 to 6 carbon 20 atoms; or - a radical selected from the group comprising the radicals 0R4, SR4, NR5R6 and NH(CH2)n~NR5R6' in which: R4 is 25 - a hydrogen atom; - a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical; - a- radical (CH2)m-COOR', m being an integer from 1 to 4 and R' being a hydrogen atom or a lower 30 alkyl radical having 1 to 6 carbon atoms; or ft. % 249508 74 - a radical (CH2)m-0-H', m and R' being as defined above; R5 and Rg, which are identical or different, are 5 - a hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical; or R5 and Rg, taken together with the nitrogen atom to which they are attached, form a heterocycle 10 selected from morpholine, pyrrolidine and piperidi'ne; and n is an integer from 1 to 4; - X, in the 2- or 3-position of the pyrazolo[l,5-a]-pyrimidine ring, is 15 - a hydrogen atom; - a lower alkyl radical having 1 to 6 carbon atoms; or - a radical selected from the group comprising the hydroxyl radicals and the radical COOR', R' being 20 as defined above; and - R3 is a radical of the formula R12- z Ri2 or TV 25 in which: - Z is CH or N or Z' is S or 0; - R11 is a hydrogen atom or a halogen atom; and - R^2 is a tetrazole radical, CN, COOH or C0NH2; 30 and its tautomeric forms and its addition .salts. f" . . ■4 V* ^ 1/ 75 ■>1,9 50

2. Derivatives of formula (I) according to claim 1, characterized in that: - one of the radicals and R2 is - a lower alkyl radical having 1 to 6 carbon 5 atoms; and - the other radical R^ or R2 is - a hydrogen atom; - a halogen atom; - a lower alkyl radical having 1 to 6 carbon 10 atoms; or - a radical selected from the group comprising the radicals OH, NR5R5 and NH(CH2)n-NR5R6/ in which: R5 and Rg, which are identical or different, 15 are - a hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon atoms; or R5 and Rg, taken together with the nitrogen 20 atom to which they are attached, form a heterocycle selected from morpholine or pyrrolidine; and n is an integer from 2 to 4; - X, in the 2- or 3-position of the pyrazolo[1,5-a]-pyrimidine ring, is 25 - a hydrogen atom; or - a lower alkyl radical having 1 to 6 carbon atoms; and ^ / - R3 is one of the following radicals: ,y tt^NOC 30 HOOC 249 508 76 and its tautomeric forms and its addition salts, 0^ particular—the—pharmaooutioally—aoooptoblo ■ addition-aalto.-

3. Derivatives according to claim 1 or 2, 5 characterized in that Ri is an n-propyl, hydroxyl, morpholinoethylamino, amino or N-diethylamino group.

4. Derivatives according to any one of claims 1 to 3, characterized in that R2 is an n-propyl or hydroxyl group. 10

5. Derivative according to any one of claims 1 to 4, characterized in that X is the hydrogen atom.

6. Derivatives according to any one of claims 1 to 5, characterized in that R3 is a 2-( lH-tetrazol-5-yl)phenyl group. 15

7. Derivatives according to claim 1 or 2, characterized in that they are selected from the derivatives of the formulae 77 2^ g 5 0 $ r D V A I y N CH,—CH,V \

8. Method of preparing compounds of formula (I) according to any one of claims 1 to 7, characterized in that i't comprises: """■ a) preparing a compound of Formula (a): 10 Formula (a) 78 10 in which: - X and R3 are as defined in claim 1 or 2; and - A and B are in one case a hydroxyl group or a lower alkyl radical having 1 to 6 carbon atoms and in the other case a lower alkyl radical having 1 to 6 carbon atoms or an ether radical of the formula -(CH2)p-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl radical, by condensing a 3-aminopyrazole of formula (II): N NH V NH, Formula (II) 15 20 25 with a derivative of Formula ((3): 0 0 Formula (3) Riassh in which R'^ is a lower alkyl radical having 1 to ~ carbon atoms or an ether radical of the formula -(CH2)p-OR, in which p is an integer from 1 to 6 and R is a lower alkyl radical having 1 to 6 carbon atoms or a benzyl radical, Rs is a lower alkyl radical having 1 to 6 carbon atoms or a lower 0-alkyl group having 1 to 6 carbon atoms, and R3 is as defined in claim 1 or 2, in an aprotic solvent or in an acid solvent, or else in an alcohol in the presence of the corresponding sodium *VA/v. 2* 9 5 0 8 79 or potassium alcoholate, or else in pyridine or 2-methyl-5-ethylpyridine in the presence or absence of 4-dimethylaminopyridine, at a temperature of between 50* and 200*C; 5 b) if appropriate, protecting the .group' carried by R3 using a method known per se; . v c) heating the derivative thus ©Brained- from the derivative of formula (P), when the latter is a ketoester, in an appropriate reagent to convert the 10 hydroxyl group represented by A or B to a chlorine atom; d) heating this chlorinated derivative in the presence of a nucleophile containing nitrogen, oxygen or sulfur, under reflux in an alcohol or in an autoclave at 100*C, 15 in the presence or absence of a base to give a derivative of formula (a) in which A and B have the same meanings as and R2 respectively; e) if appropriate, deprotecting the group carried by 20 e^) converting this group to an acid group, or e2) converting this group to a tetrazole group, or 63) converting this group to an amide group, and f) if appropriate, converting the resulting derivative to an addition salt. 25

9. Pharmaceutical composition, which permits a favorable treatment and prevention of cardiovascular diseases, characterized in that it contains "-a-pharmaceutically effective amount of at least or0 compound of formula (I) as defined in any one of claim 30 1 to 7, or one of its pharmaceutically acceptab addition salts, which may or may not be incorporated a pharmaceutically acceptable excipient, vehicle carrier. I ^ LAB0RAT0IRES UtfSA By its Attorney DON HOPKINS ft ASSOCIATE! per: </div>