NZ237445A

NZ237445A - 4-(4-substituted phenylmethyl)pyrazoles, preparatory processes, intermediates, and pharmaceutical compositions

Info

Publication number: NZ237445A
Application number: NZ237445A
Authority: NZ
Inventors: Nicole Bru-Magniez; Eric Nicolai; Jean-Marie Teulon
Original assignee: Union Pharma Scient Appl
Priority date: 1990-03-19
Filing date: 1991-03-15
Publication date: 1993-04-28
Also published as: EP0449699A2; PT97056A; FR2659655A1; IL97576A0; ZA911925B; FR2659655B1; EP0449699A3; KR910016708A; CA2038428A1; AU7359191A; IE910766A1; JPH04234851A

Description

<div id="description" class="application article clearfix"> New Zealand Paient Spedficaiion for Paient Number £37445 237 4 4 5 Priority Date-};): .(?l.\V.?U Cojll^.ttie SpCCii'iCul.'LT: J; . IT.1>-. ?\|. ^-0^lp^\\2.2r> Co^L^j^. _ OPTTIPW?>.11£> . .^P"7WuCiil.Q/, Cp"1 p.m^^Lo,' ^Tl.Pk-oiUp- .lA(oUci,j Wvsr.Lj^,^ u^Si. Publication Date: ,. 7. ?, $PR 1993 P.O. Journal, No: C^>^7] 1AWINGS Patents Form No. 5 N.Z. PATENT OFFICE 15 MAR 1991 ' RECEIVED NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION NOVEL PYRAZOLE DERIVATIVES WHICH ARE ANGIOTENSIN II RECEPTOR ANTAGONISTS, THEIR METHODS OF PREPARATION AND PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT WE, LABORATOIRES UPSA, a Societe Anonyme organized under the laws of FRANCE of 1 bis, rue Docteur Camille Bru, 47000 Agen, 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) 237 4 - la- Novel pyrazole derivatives which are angiotensin II receptor antagonists, their methods of preparation and pharmaceutical compositions in which they are present The present invention relates, by way of novel products, to the pyrazole derivatives of general formula (I) below and to their salts. The compounds in question have a very valuable pharmacological profile insofar as they possess antagonistic properties towards angiotensin II receptors. They are therefore especially indicated for the treatment of cardiovascular diseases and in particular for the treatment of hypertension and the treatment of cardiac insufficiency. The present invention further relates to the method of preparing said products and to their applications in therapeutics. It further relates to the novel intermediates which enable said products to be synthesized. These pyrazole derivatives have general formula (X): Formula (I) in which: Rx is a lower alJcyl radical having 1 to 6 carbon atoms, a lower alkenyl radical having 2 to 6 (followed by page 2) 237 4 ■7 - 2 - carbon atoms, a C3-C7 cycloalkyl radical or a Cd-C cycloalkenyl radical; R_, is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl 05 radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)m-COOR5, a group -CH2-(CH2 )TO-0RS or a group -CH2-(CH2 )ln-SRs, m being an integer from 0 to 5 and Rs being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; 10 A can be a group: -(CH-J^OR7, R' being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical and q being an integer from 1 to 5, -(CH-J^L, L being a halogen atom, preferably chlorine 15 or bromine, and q being as defined above, -CHO, an acetal or a dioxolan, -COOR', R' being as defined above, -CONR//R///, R#/ and R''' independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon 20 atoms or a C3-Cv cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attached, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, -CN, 25 -(CH2)qCN, q being as defined above, -(CH2)e3COOR/, R' and q being as defined above, -(CHa)<gC0NR/'R' '', R' ', R''' and q being as defined above, -(CH2 )tgNR/ 'R''', R'', R''' and q being as defined 30 above, -(CH2)e3-S-R/, R' and q being as defined above, or -0R3, R3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)„-C00Rs, a group -CH2-(CH2)„-CN, a group 35 -CH2-(CH2)„-0-R6, a group -CH2-(CH2)n-S-R6 or a group 237 4 4 5 3 - o 05 10 15 -C0Rs, n being an integer from 0 to 5 and Rs being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R3 can be a group -(CH_,)E>-C0-NRvRs or - (CH2) p-CHjj-CH^NR^Rg, p being an integer from 0 to 5 and R-, and Ra independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C^ cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attached, a hetero-cycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine; and R^ can be a nitro or amino group or a group -COORg, R9 being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or Ra can be the following radicals: 20 N NH N 25 30 35 o 05 o 10 15 20 o 25 30 237 4 - 4 - in which Rs is as defined above, X and Y independently being a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical or a trifluoromethyl radical. 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-Ccycloalkyl radical is understood as meaning a saturated cyclic radical, preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane radical. Lower alkenyl radical is understood as meaning a linear or branched hydrocarbon chain having from 2 to 6 carbon atoms and possessing an unsaturation. A lower alkenyl radical is, for example, an ethene, propene, isopropene, butene, isobutene, pentene, isopentene, hexene or isohexene radical. C^-C^ cycloalkenyl radical is understood as meaning a cyclic radical possessing an unsaturation, preferably a cyclobutene, cyclopentene, cyclohexene or cycloheptene radical. Lower halogenoalkyl radical having 1 to 6 carbon atoms is understood as meaning an alkyl radical in which 1 to 6 hydrogen atoms have been substituted by 1 to 6 halogen atoms. A lower halogenoalkyl radical is, for example, a trifluoromethyl radical or a 2,2,2- 25 23 7 4 - 5 - trifluoroethyl radical. Alkoxy radical is understood as meaning an O-lower alkyl group, lower alkyl being as defined above. Heterocycle is understood as denoting a ring of 05 5 to 7 atoms containing from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, which is unsubsti-tuted or substituted by a lower alkyl, lower halogenoalkyl or lower alkoxy group or by a phenyl ring which is unsubstituted or substituted by one of these groups. 10 in the description and the claims, halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom. Document EP-A-0323841 to Du Pont de Nemours describes pyrroles, pyrazoles and triazoles. These 15 compounds all possess a benzyl substituent on a nitrogen atom: Z—Y R, ^ jx N 20 R, Now, the Applicant has discovered, surprisingly, that in contrast to the information contained in the Du Pont de Nemours document, it is not essential for the benzyl substituent to be located on a nitrogen 30 atom, in particular in the 1-position (or 2-position) of the pyrazole ring, but that it is possible to obtain very effective products when this benzyl substituent is on a carbon atom in the 4-position of the pyrazole ring. Furthermore, the Applicant has discovered that 35 the presence of a group A and especially of an oxygen a o o © 237 4 4 5 - 6 - atom in the 3-position (or 5-position) of the pyrazole, in conjunction with the benzyl substituent in the 4-position, produces compounds which are particularly active as angiotensin II receptor antagonists. 05 According to one embodiment, R1 is an n-propyl group. According to another embodiment, Rx is an n-butyl group. According to one embodiment, R2 is a methyl 10 group. According to another embodiment, R_, is a 2,2,2-trifluoroethyl group. According to one embodiment, A is an ethoxycar-bonylmethyleneoxy group. 15 According to another embodiment, A is a di- methylaminocarbonyloxy group. According to another embodiment, A is a meth-oxymethylene group. According to another embodiment, A is a 2- 20 hydroxyethoxy group. According to one embodiment, R4 is a 2-carboxy-3,6-dichlorobenzoylamino group. According to another embodiment, R4 is a 2-sulfoben2oylamino group. 25 According to another embodiment, R4 is a 2- (tetrazol-5-yl)phenyl group. The particularly preferred compounds of the invention are those selected from the products of the formulae 30 35 .)' ■•■ <•'!> i} r, J-Vi -. ^-a.i.»V, linn lUlWMldMflM - 7 - 237 4 4 5 O o 05 10 15 n—n' ,ch3 20 25 30 c00c,h, 35 237 4 4 5 - 8 - 05 10 15 " N—hK^CF, 20 25 30 35 According to the invention, it will be possible © 0 237445 - 9 - to prepare the compounds of formula (I) according to the following scheme: - the alkyl 3-oxoalkanoates of formula (II): 05 r,—c—ch2—coor,, ^ II O 0 Formula (II) 10 in which Rx is as defined above and R10 is a lower alkyl radical, preferably methyl or ethyl, and - the 1,3-diketones of formula (III): 15 r,—c—ch,—c—(chj)n o—r* II II v ycl Formula (III) in which Rx , R' and q are as defined above, 20 will be prepared. These compounds of formulae (II) and (III) can be prepared by classical methods such as the Claisen reaction or the method using Meldrum's acid. Methods of preparing this type of compound may be found in the following references: 25 - OIKAWA Y.; SUGANO K. ; YONEMITSU O.; J. Org. Chem. , 1978, 43(10), 2087-88, - WIERENGA W.; SKULNICK H.I.y J- Org. Chem., 1979, 44. 310, - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, 6, 451-2, 30 - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964 (5), 945-51, - BALYAKINA M.V.; ZHDANOVICH E.S.; PREOBRAZHENSKII N.A.; Tr. Vses. Nauchn. Issled. Vitamin Inst., 1961, 7, 8-16, 35 - RENARD M.; MAQUINAY A.; Bull. Soc. Chim. Belg., 1946, 2 3 7 4 4 5 © - 10 - CD O 05 55. 98-105, - BRUCE F.W.; COOVER H.W.; J. Am. Chem. Soc., 1944, 66, 2092-94, and - EBY C.J.; HAUSER C.R.; J. Am. Chem. Soc., 1957, 79. 723-5. Benzylation of the compounds of formula (II) or (III) with compounds of formula (IV): 10 15 20 25 Formula (IV) in the presence of a base such as sodium or potassium carbonate in acetone, a sodium or potassium alcoholate 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 chloride or bromide and two equivalents of diisopropyl-ethylamine under reflux in tetrahydrofuran, according to the reference SUNG-EUN YOO; KYU YANG YI; Bull. Korean Chem. Soc., 1989, 10(1), 112, will give the compounds of formulae (V) and (VI): 30 coor,, (chj)q—or' 35 Formula (V) Formula (VI) CD 237 4 - 11 - The compounds of formulae (V) and (VI) can also be obtained by condensation of an aldehyde of formula (VII): 05 O 10 cho Formula (VII) with a compound of formula (II) or formula (III), followed by catalytic hydrogenation, for example in the 15 presence of Raney nickel, in a solvent such as an alcohol, under pressure or at ordinary pressure if the substituents present allow it. In more general terms, methods of preparing the compounds of formula (V) or formula (VI) will be found 20 in the following references: - DURGESHWARI P.; CHAUDHURY N.D.; J. Ind. Chem. Soc., 1962, 39, 735-6, - HEINZ P.; KREGLEWSKI A.; J. Prakt. Chem., 1963, 21(3-4), 186-197, 25 - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.; J. Org. Chem., 1961, 26, 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), 30 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.; 35 KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and © o © "JT » » jr-1 £ J / 4 5 - 12 - ^ - SHEPHERD T.M.; Chem. Ind. (London), 1970, 17, 567. 'w In formula (IV), W is a halogen atom, prefer ably chlorine or bromine. In the same formula: 05 - V can be a nitro group, in which case the derivative of formula (IV) is commercially available. - V can be a group COOR1:]L, Ri;l being a lower alkyl or benzyl radical, in which case the derivative of formula (IV) will be prepared by chlorinating or 10 brominating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccini-mide, in a solvent such as carbon tetrachloride or dibromoethane, according to the following reference: - JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 15 1962 (2), 2247. - V can be a group 20 R„00C R12 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 25 compound of the formula 30 CHa0 to give a compound of the formula 35 237 44 5 - 13 - 05 10 15 which is hydrolyzed to give the compound of the formula hooc 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, 20 92, 7383. The acid is then esterified with an alcohol of the formula R120H, R12 being as defined above. These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide or N-25 chlorosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is the group 30 r„ooc' 35 - V can be the group o o 05 NC in which case the compound X) 10 HOOC' o 15 20 25 30 prepared above will be converted to the primary amide by reacting the acid chloride (obtained with thionyl chloride or phosphorus oxychloride) with ammonia, and this amide will be converted to the nitrile by reaction with phosphorus oxychloride in dimethylformamide or by reaction with thionyl chloride. The nitrile obtained: 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 35 - V can be the group ,v.... 237 4 4 5 - 15 - o OjN X) 05 in which case the compound 10 CICH. will be prepared by chloromethylating commercially 15 available 2-nitrobiphenyl according to the following references: - CA : 70 (25) : H4837d, and - CA : 69 (2) : 3704t to give the compounds of formula (IV) in which V is the 20 group 25 30 02n' - V can be a group r12ooc s >3 R12 being a lower alkyl or benzyl radical. The corresponding compounds of formula (IV) are obtained in the following manner: 35 Starting from the compound 2 3 7 4 4 5 16 05 CH. HOOC whose preparation can be found in the following reference: lO - FISSELMANN H. ; HABITCH H.; Ger. Offen. 1,092,929 (1960); CA : 52 : 5894g, the compounds of the formula 20 will be obtained by esterification with an alcohol of the formula R120H, R12 being as defined above, by classical methods known to those skilled in the art. succinimide or N-bromosuccinimide, in a solvent such as 25 carbon tetrachloride or dibromoethane for example, to give the compounds of formula (IV) in which V is the group 15 RtJOOC These compounds are then treated with N-chloro- 30 35 Rx2 being as defined above. - V can be the group 237 4 4 5 ' .»**» - 17 - o 05 10 15 >3 NC in which case the corresponding compounds of formula (IV) will be prepared in the following manner: Starting from the compound 3-(p-methylphenyl)-thiophene-2-carboxylic acid, whose preparation is given above, the amide compound is obtained by treatment with thionyl chloride and then ammonia, said amide compound then being dehydrated with thionyl chloride or phosphorus oxychloride, without a solvent or in dimethylforma-mide, to give the nitrile compound 20 © 25 30 This nitrile compound is then halogenated with N-chlorosuccinimide 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 - V can be the group 35 O T "7 /' / 'C 4.) / H 4 y - 18 - D 05 in which case the corresponding compounds of formula (IV) are synthesized in the following manner: Starting from 4-chlorobutyrophenone of the formula CH, ^ / co—ch,—ch,—ch,—ci whose preparation can be found in patent BE 577,977 of 10 15 May 1959, CA : 54, 4629c, the compound of the formula 15 CH, * n c=c—ch2-I I ci cho -CK—CI 3 20 25 will be obtained by treatment with phosphorus oxychloride and dimethylformamide according to the conditions described in the following reference: - VOLODINA M.A.; TERENT'EV A.P.; KUDRYASHOVA V.A.; 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 30 35 which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxylamine. This dehydration may be carried out for example with acetic anhydride to give 237 4 4 5 TW - 19 - o n the nitrile compound 05 which may then be aromatized by treatment with bromine 10 in carbon tetrachloride and then with potassium tert-butylate in tetrahydrofuran to give the compound 15 This compound can then be chlorinated or bro-20 minated with halogenating agents such as N-chloro-succinimide 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 25 -A? 30 - V can be the group y~\ RtJOOC^X^ 35 R12 being as defined above. The corresponding com- f) - 20 - . pounds of formula (IV) may be prepared from the com- * pound of the formula 10 by classical hydrolysis of the nitrile group and then esterification of the acid obtained, or by direct conversion of the nitrile group to the ester group by the methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chloro-15 succinimide or N-bromosuccinimide, for example in carbon tetrachloride or dibromoethane. In formulae (V) and (VI), Rx, R10, R' and q are as defined above and V is as defined in formula (IV). Some derivatives of formula (V) and formula 20 (VI), when V is a 2-alkoxycarbonylphenyl, a 2-cyano-phenyl, a 2-nitrophenyl, an alkoxycarbonylthiophene or a cyanothiophene, are novel synthesis intermediates which are claimed per se. In formula (VII), V is as defined in formula 25 (IV), but this condensation method will only be used when V possesses a functional group unaffected by hydrogenation. In certain cases, these aldehydes may be prepared from the derivatives of formula (IV) according to reactions known to those skilled in the 30 art. The Sommelet reaction (Bull. Soc. Chim. France, 1918, [4] 23., 95) or the nitropropane reaction (Organic Syntheses Collec., vol. IV, 932) may be mentioned. Reaction of a hydrazine of formula (VIII): 35 D o Cf 10 237 - 21 - H2N-NH-R2 Formula (VIII) 05 in which R2 is as defined above, with the compounds of i(^s formula (V), by simply refluxing in an alcohol for ^ example, will give the compounds of formula (IX): 15 Formula (IX) in which Ri; Ra and V are as defined above. 20 These compounds of formula (IX) are novel syn thesis intermediates which are claimed per se. Alkylation of the compounds of formula (IX) , performed in the presence of a base such as potassium or sodium carbonate in solvents such as acetone, butan-25 2-one or dimethylformamide, or in the presence of a V-/ sodium or potassium alcoholate in an alcohol, or in the presence of sodium or lithium hydride in tetrahydrofuran, with derivatives of formula (X): 30 Z-R3 Formula (X) Z being a bromine, chlorine or iodine atom and R3 being 35 as defined above, gives the compounds of formula (XI): 2 3 7 4 4 5 - 22 - 05 10 Formula (XI) 15 in which R1( R2, R3 and V are as defined above. Likewise, reaction of a hydrazine of formula (VIII), as defined above, with a compound of formula (VI), by simply refluxing in an alcohol for example, will give a mixture of compounds of formula (XII) and formula (XII7): 20 25 OR' r, \ n—n (CHX .or* Formula (XII) Formula (XII') in which Rx, R2, R', g and V are as defined above. 30 The pure compounds of formula (XII) will be obtained from this mixture by purification by chromatography on silica, recrystallization or any other method of purification known to those skilled in the art. 35 Another method of preparing the compounds of £> 237 4 4 5 - 23 05 10 formula (XII) consists, in a first stage, in treating the compounds of formula (VI) with hydrazine hydrate under the same conditions to give the compounds of formula (XIII): .OR* O1 15 20 in which R i' Formula (XIII) g and V are as defined above. These compounds of formula (XIII) are then alkylated in the presence of DBU (l,8-diazabicyclo[5.4.0]undec-7-ene), in a solvent such as acetone or acetonitrile for example, with halogenated derivatives of formula (XIV): Z-R. 25 30 35 Formula (XIV) in which R2 is as defined above and Z is a bromine, chlorine or iodine atom, to give a mixture of the compounds of formula (XII) and formula (XII7), as defined above, the compounds of formula (XII) then being obtained pure after purification as mentioned above. This second method of preparation can be particularly advantageous in the case where R2 is a lower alkyl group, because it makes it possible to obtain a preponderant proportion of the compounds of formula (XII) relative to the compounds of formula (XII7). o L (L -J a "t H - 24 - The compounds of formula (XII) in which R# is a hydrogen will be prepared in two steps: Treatment of the compounds of formula (XII) in which R' is a lower alkyl group with boron tribromide will give the bromi-05 nated derivatives of formula (XV): Formula (XV) 15 in which Rx, R2, q and V are as defined above. Treatment of these brominated derivatives of formula (XV) with potassium or sodium carbonate under reflux in a dioxane/water mixture makes it possible to obtain the 20 compounds of formula (XII) in which R' is the hydrogen atom. The derivatives of formula (XI) or formula (XII) in which V is a nitro group will be able to undergo catalytic hydrogenation, for example in the 25 presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give the compounds of formula (I) in which R4 is an amino group and A is a group -(CH^^-OR' or 0R3, R', R3 and q being as defined above. 30 Reaction of an appropriately substituted phthalic anhydride with these derivatives will give the compounds of general formula (I) in which R4 is the group 35 . «F<rr'Jrt?iT. r** 237 4 4 5 TV#*' - 25 - o n 05 10 HN—C' HOOC in which X and Y are as defined above and A is a group -(CH^^-OR' or 0R3, g, R' and R3 being as defined above, it then being possible for the acid obtained to be esterified to give the group 15 R.00C Likewise, reaction of the cyclic anhydride of 20 an appropriately substituted orthosulfobenzoic acid with these amino compounds will give the compounds of general formula (I) in which Rd is the group 25 0 II -HN—C H0,S 30 and A is a group -(CH-J^-OR' or 0R3, g, R', R3, X and Y being as defined above. Likewise, reaction of N-(trifluoromethyl-sulfonyl)anthranilic acid chloride, whose preparation can be found in the following references: 35 CA 96 (13) : 103651Z, and 23 7 lx e i-i- - 26 - n CA 97 (7) : 55500W, with these amino compounds will give the compounds of general formula (I) in which R4 is the group 05 HN cf,—so, 10 15 20 25 and A is a group - (CH_,) ^-OR' or 0R3, q, R' and R3 being as defined above. The compounds of formula (XI) or (XII) in which V is a group -COORi;l will be able to be hydrolyzed in an acidic or basic medium, or hydrogenated in the case where Rx;l is a benzyl so as not to affect the other ester groups present, to give the compounds of formula (I) in which R4 is a group -COOH and A is a group -(CH-J^-OR' or 0R3/ q, R' and R3 being as defined above. After conversion to the acid chloride with thionyl chloride or to a mixed anhydride with ethyl chloroformate, these acid derivatives will be able to give the compounds of general formula (I) in which R4 is the group -nh R,OjC 30 and A is a group -(CH=)^-OR' or 0R3, q, R' and R3 being as defined above, by reaction with anthranilic acid derivatives of the formula 35 © 237 4 4 5 - 27 - Cw*^ o 05 r9ooc in which X, Y and Rs are as defined above. In the same way, the compounds of formula (XI) 10 or (XII) in which V is a group 15 20 r„ooc will be hydrolyzed, or hydrogenated in the presence of a catalyst such as palladium-on-charcoal in the case where R12 is a benzyl, to give the compounds of formula (I) in which RA is a group hooc 25 and A is a group -(CHaJ^-OR' or OR3, q, R' and R3 being as defined above. The compounds of formulae (XI) and (XII) in which V is a group 30 will be able to react with one equivalent of sodium 35 nitride in a solvent such as dimethylformamide, in the n 4 4 - 28 - presence of an ammonium salt such as ammonium chloride, or with a trialkyltin nitride under reflux in toluene and then with gaseous hydrochloric acid in tetrahydrofuran, to give the compounds of general formula (I) in 05 which is a group 10 and A is a group -(CH2)ca-0R/ or OR3, q, R' and R3 being as defined above. 15 The compounds of formulae (XI) and (XII) in which V is a group 20 o2n 25 will be able to undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give compounds of general formula (I) in which R4 is a group and A is a group -(CH-, J^-OR' or OR3, q, R' and R3 being as defined above. Reaction of trifluoromethanesulfonyl chloride with the latter in a solvent such as chloroform or in 35 an aromatic solvent such as toluene, in the presence of 237 4 4 5 - 29 - a base such as triethylamine or pyridine, or in pyridine, will give the compounds of general formula (I) in which R4 is a group 05 CF,—SOa—HN' and A is a group -(CH2J^-OR' or OR3, q, R' and R3 being 10 as defined above. The compounds of formulae (XI) and (XII) in which V is the group NC^S 15 will be able to be treated with a trialkyltin nitride under reflux in toluene and then with gaseous hydrochloric acid in tetrahydrofuran to give the derivatives 20 of formula (I) in which Rd is the group Qb H and A is a group -(CH2)<a-OR/ or OR3, q, R' and R3 being as defined above. The compounds of formulae (XI) and (XII) in which V is the group 25 30 ^OOC-f^j ^/S 35 will be able to be hydrolyzed, or hydrogenated in the 3 7 4 4 5 - 30 - presence of a catalyst such as palladium-on-charcoal in the case where RX2 is a benzyl, to give the compounds of formula (I) in which RA is the group and A is a group -(CH2)c3-OR/ or 0R3, g, R' and R3 being as defined above. The compounds of formula (I) in which A is a group CH_,OH will be able to be oxidized with a mild oxidizing agent such as manganese dioxide, in a solvent such as chloroform, to give the compounds of formula (I) in which A is the group CHO, which will be able to be converted, by the classical methods known to those skilled in the art, to an acetal or a dioxolan by heating with an alcohol or a diol, in the presence of paratoluenesulfonic acid for example (Synthesis, 1981, 501). More rigorous oxidation of these same aldehyde compounds or of the alcohol compounds direct, for example with oxidizing agents such as potassium permanganate, will give the compounds of formula (I) in which A is the group C02H. The compounds of formula (I) in which A is the group C02H will be able to be esterified by classical methods of esterification to give the compounds of formula (I) in which A is a group CO..R', R' being a lower alkyl radical. The compounds of formula (I) in which A is the group C02H will also be able to be converted to the amide in several steps, if necessary after steps for protecting other functional groups, by conversion to the acid chloride and then treatment with ammonia or with an amine of the formula HNR"R"', R'' and R'" 237 4 4 5 - 31 - being as defined above, to give the compounds of formula (I) in which A is a group CONR'/R///. The compounds of formula (I) in which A is a group CONH2 will be able to be treated with an agent such as thionyl chloride or phosphorus oxychloride to give the compounds of formula (I) in which A is the group CN. The compounds of formula (I) in which A is a group (CH=J^OR', R' being a lower alkyl radical and q being an integer from 1 to 5, will be able to be treated with boron tribromide in chloroform to give, if necessary after steps for protecting and deprotecting other functional groups, the compounds of formula (I) in which A is the group (CH2)e3Br. The compounds of formula (I) in which A is the group (CH2)caBr will be able to be treated with sodium or potassium cyanide, in solvents such as alcohol, an alcohol/water mixture, dimethyl sulfoxide or aceto-nitrile, to give the compounds of formula (I) in which A is the group (CH2)<aCN, or with amines of the formula HNR' 'R''', in which R" and R'" are as defined above, to give the compounds of formula (I) in which A is (CH2)<3NR"R'" , or with thiols of the formula HS-R', R' being as defined above, to give the derivatives of formula (I) in which A is (CH2)<g-S-R/. The compounds of formula (I) in which A is the group (CH2)qCN will be able to be hydrolyzed by the classical methods of nitrile hydrolysis to give the compounds of formula (I) in which A is the group (CH2 )<gCO=H. These acid compounds will themselves be able to be esterified by the classical methods of esterifica-tion to give the compounds of formula (I) in which A is a group (CH2 )eaC02R', R' being a lower alkyl radical and q being an integer from 1 to 5, or converted to an n 4 j 5 - 32 - amide -(CH2i^-CONR''R''' as indicated above. The compounds of formula (I) in which A is the group (CH2)caL/ L being a halogen and q being an integer from 1 to 5, will be able to be synthesized by treating 05 the derivatives of formula (I) in which A is the group (CH2)<30H with halogenating agents such as, for example, thionyl chloride, phosphorus oxychloride or phosphorus tribromide. In the case where R4 possesses a functional 10 group which is not compatible with these reaction sequences, the derivative of formula (XII) will be used as the product for conversion, V subsequently being converted to the group R4 in the manner mentioned above. 15 It is possible to obtain addition salts of some of the compounds of formula (I), especially pharmaceu-tically acceptable addition salts. In particular, when R2, R4 or A contains an acid group, there may be mentioned the salts of sodium, potassium, calcium, an 20 amine such as dicyclohexylamine or an amino acid such as lysine. When A or R4 contains an amine group, there may be mentioned a salt of a mineral or organic acid, such as, for example, the hydrochloride, methanesulfo-nate, acetate, maleate, succinate, fumarate, sulfate, 25 lactate or citrate. The novel compounds according to the invention possess remarkable pharmacological properties as angiotensin II receptor antagonists and can be used in therapeutics for the treatment of cardiovascular dis-30 eases and in particular for the treatment of hypertension and cardiac insufficiency. Thus the invention covers the pharmaceutical compositions which contain, as the active principle, the drugs consisting of a pharmaceutically effective 35 amount of at least one compound of formula (I) as 237 44 5 - 33 - defined above, as well as one of its pharmaceutically acceptable addition salts if appropriate. These compositions can be given by buccal, rectal, parenteral, percutaneous or ocular administration. These compositions can be solid or liquid and presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, percutaneous 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 compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, can be incorporated in excipients normally employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, 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 colors. The invention also covers a pharmaceutical composition with antagonistic activity towards angiotensin II receptors, which makes it possible especially to favorably treat cardiovascular diseases, in particular hypertension and cardiac insufficiency, said composition comprising a pharmaceutically effective amount of at least one compound of formula (I) mentioned above, or one of its pharmaceutically acceptable addition salts, which may be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier. The dosage varies especially according to the 237 4 4 5 O o o - 34 - mode of administration, the complaint treated and the subject in question. For example, for an adult with an average weight of 60 to 70 kg, it can vary between l and 400 mg 05 of active principle administered orally in one or more daily doses, or from 0.01 to 50 mg administered paren-terally in one or more daily doses. The invention also covers a method of preparing a pharmaceutical composition, which comprises incor-10 porating a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier. According to a particular characteristic, 15 this pharmaceutical composition is formulated as gelatin capsules or tablets containing from 1 to 400 mg of active ingredient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient. The invention also covers a method of thera-20 peutic treatment for mammals, which comprises adminis-tering to this mammal a therapeutically effective amount of at least one compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts. 25 In animal therapeutics, the daily dose which can be used should normally be between 1 and 100 mg per kg. Further characteristics and advantages of the invention will be understood more clearly from the 30 following description of some Preparatory Examples, which in no way imply a limitation but are given by way of i1lustration. 35 237 4 4 5 - 35 - Example 1: Ethyl 3-oxoheptanoate Formula (II): Rx = n-butyl, Rxo = ethyl 70 g of Meldrum's acid are dissolved in 200 ml of methylene chloride in the presence of 78.5 ml of pyridine, the mixture is cooled to 0°C and 64.5 g of valeroyl chloride are added dropwise at this temperature. When the addition is complete, the mixture is left to stand at room temperature and stirred for two hours. The solution is washed with a dilute solution of hydrochloric acid, dried over magnesium sulfate and evaporated under vacuum to give 110 g of an oil, which is used as such for the next step. This oil is dissolved in 400 ml of absolute ethanol and the mixture is refluxed for two hours and left to stand overnight at room temperature. The ethanol is evaporated off under vacuum and the oily residue is distilled under reduced pressure to give 63.3 g of ethyl 3-oxoheptanoate in the form of a liquid of b.p.2Q = 115-120°C. Example 2: Ethyl 3-oxohexanoate Formula (II): R^ = n-propyl, Rxo = ethyl Prepared by the same procedure as Example 1. Liquid of b.p.20 = 95-100°C. Example 3: Ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate Formula (V): Rx = n-butyl, V = N02, R10 = ethyl 57.3 g of ethyl 3-oxoheptanoate are dissolved in 300 ml of ethanol. A solution of sodium ethylate, o - 36 - prepared by adding 7.7 g of sodium to 50 ml of ethanol, is added and the mixture is stirred for 20 minutes at room temperature. 72 g of 4-nitrobenzyl bromide are then added in portions and the mixture is subsequently stirred for two hours at room temperature and then for two hours under reflux. The ethanol is evaporated off under vacuum and the residue obtained is taken up with water and then extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The oil obtained is taken up in a mixture of ether and pentane and the crystals formed are filtered off to remove the dibenzylated derivative (m.p. = 135°C); the mother liquors, concentrated under vacuum at 120°C to remove the starting unsubstituted keto-ester, give 69.2 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate in the form of an oil, which is used as such for the next step. Example 4: Ethyl 2-(4-nitrobenzyl)-3-oxohexanoate Formula (V): Rx = n-propyl, V = N02, R10 = ethyl Prepared by the procedure of Example 3, start-25 ing from the ethyl 3-oxohexanoate prepared in Example © 2. Oil used as such for the next step. Example 5: Ethyl 2-(2'-methoxycarbonylbiphenyl-4-yl)-3 0 methyl - 3 -oxohept anoate ~ T £ O i* t J I <£ *4 0 05 10 15 237 4 4 5 - 37 - Prepared by the procedure of Example 3, starting from the ethyl 3-oxoheptanoate prepared in Example 1 and methyl (4'-bromomethylbiphenyl-2-yl)carboxylate. Oil used as such for the next step. Preparation of methyl (4'-bromomethylbiphenyl-2-yl)-carboxylate A) Methyl (4'-methylbiphenyl-2-yl)carboxylate 15 ml of acetyl chloride are added to 300 ml of methanol cooled to 0°C. The mixture is stirred for 10 minutes at this temperature and 15 g of (4 '-methylbi-phenyl-2-yl)carboxylic acid (prepared according to MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97(25), 7383, by reacting (4-methylphenyl)magnesium bromide with 2-(2-methoxyphenyl)-4,4-dimethyl-l,3-oxazolidine) are then added. The mixture is then refluxed for 4 hours and the solvents are evaporated off under vacuum to give 16 g of methyl (4' -methylbi-phenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step. B) Methyl (4'-bromomethylbiphenyl-2-yl)carboxylate 16 g of methyl (4'-methylbiphenyl-2-ylCarboxylate, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-bromo-succinimide and 0.5 g of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum. The residue is taken up with ether and the solution is then filtered on charcoal and evaporated under vacuum to give 14.5 g of methyl (4 '-bromomethylbiphenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step. o 237 4 - 38 - Example 6: Ethyl 2-(27-cyanobiphenyl-4-yl)methy1-3-oxoheptanoate 30 g of ethyl 3-oxoheptanoate, prepared in 10 Example 1, are dissolved in 3 00 ml of tetrahydrofuran. 31.6 g of 4'-bromomethyl—2-cyanobiphenyl are added together with 40 ml of N,N-diisopropylamine and 10 g of lithium bromide. The mixture is refluxed for 15 hours and then concentrated under vacuum, iced water and 15 dilute hydrochloric acid are added and the mixture is then extracted with ethyl acetate. The organic phase is washed with water and then dried and evaporated under vacuum. The residue obtained is heated under vacuum at 130°C in order to remove the residual ethyl 20 3-oxoheptanoate, giving 41 g of ethyl 2-(2'-cyanobi-phenyl-4-yl)methyl-3-oxoheptanoate in the form of an oil, which is used as such for the next step. Preparation of 4'-bromomethyl-2-cyanobiphenyl 25 A) 4'-Methyl-2-cyanobiphenyl 18.5 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared as in Example 5 A), are refluxed in 60 ml of thionyl chloride for two hours. The thionyl 30 chloride is concentrated under vacuum, the residue is poured into a 28% solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are filtered off, washed with ether and then dried to give 14.5 g of (4/-methylbiphenyl-2-yl)carbox-35 amide in the form of crystals melting at 128°C. These -ft •at*/' n o o 05 237 4 4 5 - 39 - crystals are taken up in 50 ml of thionyl chloride and the mixture is refluxed for 3 hours and then concentrated under vacuum to give 9 g of 4'-methyl-2-cyanobi-phenyl in the form of crystals melting at 45-46°C. B) 4'-Bromomethyl-2-cyanobiphenyl 7.9 g of 4'-methyl-2-cyanobiphenyl, prepared in A), are dissolved in 100 ml of carbon tetrachloride in the presence of 7.3 g of N-bromosuccinimide and 0.3 g 10 of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off, the remaining solution is concentrated under vacuum and the residue is crystallized from ether to give 6.6 g of 4'-bromo-methyl-2-cyanobiphenyl in the form of crystals melting 15 at 115-118 °C. Example 7: l-Methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole 20 Formula (IX): Rx = n-butyl, R_, = CHa, V = N02 20 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate, prepared in Example 3, are dissolved in 150 ml of 25 ethanol, and 4 ml of methylhydrazine are added. The mixture is refluxed for 6 hours. The ethanol is evaporated off under vacuum, the residue is taken up with water and then extracted with ethyl acetate, the organic phase is then washed several times with a 30 dilute solution of sodium hydroxide and the combined aqueous fractions are acidified with sulfur dioxide and then extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated under vacuum to give a residue which crystallizes from ether. 35 The crystals are filtered off and recrystallized from 237 4 4 5 o - 40 - o ethyl acetate to give 10.9 g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole in the form of crystals melting at 136°C. 05 Example 8: l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5- hydroxypyrazole Formula (XX): Rx = n-propyl, R_, = CH3, V = NO. 10 15 20 25 2 Prepared by the procedure of Example 7, starting from the ethyl 2-(4-nitrobenzyl)-3-oxohexanoate prepared in Example 4. Crystals melting at 174°C. Example 9: 3-n-Propyl-4~(4-nitrobenzyl) -5-lxydroxy-pyrazole Formula (IX): = n-propyl, Rz = H, V = N02 Prepared by the procedure of Example 7, starting from the ethyl 2-(4-nitrobenzyl)-3-oxohexanoate prepared in Example 4 and hydrazine. Crystals melting at 196°C. Example 10: l-Ethoxycarbonylmethyl-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = CH_.CO_.Et, 30 V = NO, 35 Prepared by the procedure of Example 7, start ing from ethyl hydrazinoacetate. Crystals melting at 134°C. o o n 10 15 23 7 4 - 41 - Example 11: l-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = CH_,CF3 , 05 V = N02 Prepared by the procedure of Example 7, starting from 2,2,2-trifluoroethylhydrazine. Crystals melting at 160°C. Example 12: l-Methyl-3-n-butyl-4-( 2 ' -methoxycarbonyl— biphenyl-4-yl) methyl-5-hydroxypyrazole Formula (IX): Rx = n-butyl, R_, = CH3, X) V = CH, 0aC' Prepared by the procedure of Example 7, start-20 ing from the ethyl 2-(2'-methoxycarbonylbiphenyl-4-^ yl)methyl-3-oxoheptanoate prepared in Example 5. Crystals melting at 1086C. Example 13: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-25 yl)methyl-5-hydroxypyrazo1e 30 Formula (IX): Rx = n-butyl, R2 = CH , Prepared by the procedure of Example 7, starting from the ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxoheptanoate prepared in Example 6. 35 Crystals melting at 138°C. 237445 n o o - 42 - Example 14: Ethyl [l-methyl-3-n-propyl-4-(4-nitrobenzyl )pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, 05 R3 = CH2C02Et, V = N02 22.4 g of l-methyl-3-n-propyl-4-(4-nitro-benzyl)-5-hydroxypyrazole, prepared in Example 8, are dissolved in 200 ml of acetone, and 8.7 g of sodium 10 carbonate and 9.2 ml of ethyl bromoacetate are added. The mixture is refluxed for 5 hours and the solvents are concentrated to dryness. The residue is taken up with water and then extracted with ether. The organic phase is dried over magnesium sulfate and evaporated to 15 dryness. The residue obtained is taken up with iso-propyl ether and the resulting crystals are filtered off to give 9 g of ethyl [l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-oxopyrazol-2-yl]acetate melting at 62°C. The mother liquors are concentrated and the oil 20 obtained is chromatographed on silica gel in a methylene chloride/acetone eluent (90/10) to give 10 g of ethyl [l-methyl-3-n-propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate in the form of crystals melting at 60-61°C. 25 Example 15: Ethyl [l-methyl-3-n-butyl-4-(4-nitrobenzyl ) pyrazol-5-yl ] oxyacetate Formula (XI): Rx = n-butyl, R2 = methyl, 30 • R3 = CH2C02Et, V = N02 Prepared by the procedure of Example 14. Crystals melting at 68°C. 35 - 43 - Example 16: Ethyl [3-n-propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R= = H, R3 = CH2C02Et, V = N0= Prepared by the procedure of Example 14. Crystals melting at 116°C. Example 17: Methyl [l-methyl-3-n-propyl-4-( 4-nitrobenzyl )pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2CO;sMe, V = N02 Prepared by the procedure of Example 14. Crystals melting at 58°C. Example 18: Methyl [1-(2,2,2-trifluoroethyl)-3-n- propyl-4- (4-nitrobenzyl) pyrazol-5-yl ] oxyacetate Formula (XI): Rx = n-propyl, R2 = CH2CF3, R3 = CH2C02Me, V = N02 Prepared by the procedure of Example 14. Crystals melting at 73°C. Example 19: Ethyl [ l-methyl-3-n-butyl-4-( 2'-methoxy- carbonylbiphenyl-4-yl) methylpyrazol-5-yl]-oxyacetate Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2C02Et, V = MeOjC' 237 4 4 5 - 44 - Prepared by the procedure of Example 14. Oil used as such for the next step. Example 20: Ethyl [l-methyl-3-n-butyl-4-(2'-cyanobi-pheny 1-4—yl )methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2C02Et, V Prepared by the procedure of Example 14. Oil used as such for the next step. Example 21: Ethyl [1-methyl-3-n-butyl-4-(4-amino-benzyl)pyrazol-5-yl]oxyacetate Formula (I): R1 = n-butyl, Rz = methyl, A = OR3, R3 = CH3CO=Et, R4 = NH2 3.4 g of ethyl [l-methyl-3-n-butyl-4-(4-nitrobenzyl )pyrazol-5-yl] oxyacetate, prepared in Example 15, are dissolved in 50 ml of absolute ethanol in the presence of 500 mg of Raney nickel. The mixture is hydrogenated at atmospheric pressure and room temperature and, when the uptake of hydrogen has ceased, the catalyst is filtered off, the ethanol is evaporated off under vacuum and the residue is taken up with pentane to give 2.9 g of ethyl [l-methyl-3-n-butyl-4-(4-amino-benzyl)pyrazol-5-yl]oxyacetate in the form of crystals melting at 65°C. 237 4 4 5 O o - 45 - Example 22: Ethyl [l-methyl-3-n-propyl-4-(4-amino-benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, 05 A = 0R3/ R3 = CH2C0=Et, RA = nh2 Prepared by the procedure of Example 21. Crystals melting at 103"C. 10 Example 23: Methyl [1-methyl-3-n-propy1-4-(4-amino-benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, 15 A = OR3/ R3 = CH2C02Me, R4 = NH2 Prepared by the procedure of Example 21. Oil used as such for the next step. 20 Example 24: Methyl [l-(2f2/2-trifluoroethyl)-3-n- propyl-4-(4-aminobenzyl)pyrazol-5-yl]oxyacetate 25 Formula (I): Rx = n-propyl, R2 = CH3CF3, A = OR3, R3 = CH2C02Me, R4 = NH2 Prepared by the procedure of Example 21. 30 Crystals melting at 63°C. 35 237 4 - 46 - Example 25: l-Ethoxycarbonylmethyl-3-n-propyl—4-(4-aminobenzyl) -5-hydroxypyrazole Formula (I): Rx = n-propyl, R2 = CH2C02Et, 05 A = OR3, R3 = H, R4 = NH2 Prepared by the procedure of Example 21. Oil used as such for the next step. 10 Example 26: Ethyl [3-n-propyl-4-(4-aminobenzyl)pyrazol- 5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = H, A = OR3, R3 = CH2C02Et, R4 = NH2 15 Prepared by the procedure of Example 21. Oil used as such for the next step. Example 27: Ethyl [1-methy1-3-n-butyl-4-(4-(2-carboxy-20 benzoylamino)benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-butyl, R2 = methyl, A = 0R3, R3 = CH2C02Et, C0,H NH—C, R. = 4 O 25 30 3 g of ethyl [ l-methyl-3-n-butyl-4-( 4-amino- benzyl)pyrazol-5-yl]oxyacetate, prepared in Example 21, are dissolved in 50 ml of acetonitrile. 1.3 g of phthalic anhydride are added and the mixture is left to stand at room temperature overnight. The crystals 35 obtained are filtered off, washed with isopropyl ether 23 7 4 o - 47 - o 0 and dried to give 2.5 g of ethyl [l-methyl-3-n-butyl-4-(4-(2-carboxybenzoylamino)benzyl)pyrazol-5-yl]oxyacetate in the form of crystals melting at 140-141°C. 05 The following Examples were prepared by the same procedure: Example 28: Methyl [l-methyl-3-n-propyl-4-(4-(2-carboxybenzoylamino )benzyl)pyrazol-5-yl]oxy-10 acetate Formula (I): Rx = n-propyl, R= = CH3, A = OR3, R3 = CHjjCOjjMe, 0 m II 15 NH—C. R*= Tj) 20 Crystals, in the form of the dicyclohexylamine salt, melting at 173-174°c. Example 29: Ethyl [1-methyl-3-n-propy1-4-(4- (2-carboxybenzoylamino) benzyl )pyrazol-5-yl]oxyacetate 25 Formula (X): Rx = n-propyl, R2 = CH3, A = 0R3, R3 = CH=C02Et, O II NH—C. 30 R4 = HOjC Crystals melting at 139-140°C. 35 237445 48 Example 30: Ethyl [ l-methy 1-3-n-propy 1-4-(4-(2-carboxy-3 , 6-dichlorobenzoylami.no ) benzyl) pyrazol-5-y1]oxyacetate CI From 3,6-dichlorophthalic anhydride. Crystals, in the form of the dicyclohexylamine 15 salt, melting at 199-200°C. Example 31: Methyl [l-methyl-3-n-propyl-4-(4-(2-car- 05 Formula (I): Rx = n-propyl, R2 = CH3, A 0R3, R3 = CH2CO=Et, O CI 10 boxy-3,6-dichlorobenzoylamino)benzyl)-pyrazol-5-yl]oxyacetate 20 Formula (I): Rx - n-propyl, R2 = methyl A = 0R3, R3 = CH2C0=Me, O CI 25 CI 30 From 3,6—dichlorophthalic anhydride Crystals melting at 150-151°C. 35 o o o •Akwi*^ 10 25 237 4 4 5 - 49 - Example 32: Methyl [1-(2,2,2-trifluoroethyl)-3-n- propyl-4-(4-(2-carboxy-3,6-dichlorobenzoyl-amino)benzyl)pyrazol-5-y1]oxyacetate 05 Formula (I): = n-propyl, Ra = CH2CF3, A = 0R3, R3 = CH2C02Me, O CI II NH—C> R* = From 3,6-dichlorophthalic anhydride. Crystals melting at 169-170°C. 15 Example 33: Methyl [l-(2,2,2-trifluoroethyl)-3-n- propyl-4-(4-(2-carboxybenzoylamino)benzyl) ■ pyrazol-5-yl]oxyacetate 20 Formula (I): Rx = n-propyl, R_, = CHaCF3, '\D A = 0R3, R3 = CHaCOaMe, 0 II nh—cs ra = hojc Crystals melting at 189-192°C. AJ 30 35 23 7 4 - 50 - Example 34: [ 3-n-Propyl-4-(4-(2-carboxybenzoylamino)■ benzyl)pyrazol-5-yl]oxyacetic acid Formula (I): Rx = n-propyl, R2 = H, A = 05 OR3, R3 = CH2C0_,H, O II nh—c 10 ho2c 0.9 g of ethyl [3-n-propyl-4-(4-aminobenzyl)-pyrazol-5-yl]oxyacetate, prepared in Example 26, is dissolved in 20 ml of acetonitrile in the presence of 15 0.45 g of phthalic anhydride. The mixture is left to stand at room temperature overnight. The acetonitrile is evaporated off under vacuum and the residue is taken up in an ethyl acetate/ether mixture to give crystals, which are filtered off. These crystals are dissolved 20 in methylene chloride and the solution is washed several times with a 1 N solution of sodium hydroxide. The combined aqueous phases are acidified by having sulfur dioxide bubbled through them and the crystals obtained are filtered off and dried to give 0.5 g of 25 [3-n-propyl-4-(4-(2-carboxybenzoylamino)benzyl)pyrazol-?j) 5-yl ]oxyacetic acid in the form of crystals melting at 170-171°c. 30 35 237 4 4 5 - 51 - Example 35: [1-Methy1-3-n-propy1-4-[4-(2-sulfobenzoyl-amino)benzyl]pyrazol-5-yl]oxyacetic acid Formula (I): Rx = n-propyl, R3 = CH3, A = 05 0R3, R3 = CH2C02H, O 10 R* = hojs nh—a AJ Prepared by the procedure of Example 34, starting from the cyclic anhydride of orthosulfobenzoic acid. 15 Crystals melting at 168-170°C. Example 36: 4'-[l-Methyl-3-n-butyl-5-hydroxypyrazol-4-yl]methylbiphenyl-2-carboxylic acid 20 Formula (I): Rx = n-butyl, R2 = methyl, A = OR3, R3 = H, 1.5 g of l-methyl-3-n-butyl-5-hydroxy-4-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrazole, prepared in Example 12, are suspended in 15 ml of a 1 N solution 30 of sodium hydroxide and the suspension is stirred for one hour at 40°C. The solution is washed with methylene chloride and then acidified by having sulfur dioxide bubbled through it and extracted with methylene chloride. The organic phase is dried over magnesium 35 sulfate and then evaporated under vacuum. The residue 237 4 - 52 - is diluted in ethyl acetate, extracted with a solution of sodium bicarbonate and then acidified with sulfur dioxide and the crystals obtained are filtered off and then dried to give l.i g of 4'-[l-methyl-3-n-butyl-5-hydroxypyrazol-4-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 228-30°C. Example 37: [l-Methyl-3-n-butyl-4-(2'-carboxybiphenyl-4-yl)methylpyrazol-5-y1]oxyacetic acid Formula (I): rx = n-butyl, r2 = ch3, A = 0r3, r3 = ch2co2h, 2.6 g of ethyl [l-methyl-3-n-butyl-4-( 2' -methoxycarbonylbiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate, prepared in Example 19, are dissolved in 30 ml of ethanol. 1 g of sodium hydroxide pellets and 10 ml of water are added and the mixture is stirred at room temperature for two hours and then heated for 3 hours at 50—55°C. After cooling, the solution is diluted with water and washed with ether and the aqueous phase is acidified by having sulfur dioxide bubbled through it and extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give a residue which crystallizes from an ethyl acetate/ether mixture to give 2 g of [l-methyl-3-n-butyl-4-(2'-carboxybiphenyl-4-yl)methylpyrazol-5-yl]oxyacetic acid in the form of crystals melting at 153-154"C. 237445 <0 - 53 - Example 38: 1-Methyl-3-n-butyl-4-(4-nitrobenzyl)-5— methoxycarbonyloxypyrazole Formula (I): Rx = n-butyl, R_, = methyl, A = 05 OR3, R3 = C-OMe, Rd = N02 12 g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole, prepared in Example 7, are dissolved 10 in 120 ml of 1,2-dichloroethane in the presence of 6 ml of triethylamine. 3.3 g of methyl chloroformate are added dropwise and the mixture is stirred for 2 hours at room temperature and then for 4 hours under reflux. After cooling, the solution is washed with water and 15 then dried over magnesium sulfate and concentrated under vacuum. The oily residue is chromatographed on silica gel in a methylene chloride/acetone eluent (95/5) to give 6.6 g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-methoxycarbonyloxypyrazole in the form 20 of crystals melting at 44-47°C. © Example 39: 1-Methyl-3-n-butyl-4-(4-aminobenzyl)-5-methoxycarbonyloxypyrazole 25 Formula (XI): Rx = n-butyl, R2 = methyl, © r3 = c-OMe, v = nh2 o Prepared by the procedure of Example 21. 30 Oil used as such for the next step. 35 o T1KH.~LZT o 10 30 23 7 4 - 54 - Example 40: 2-[ [l-Methyl-3-n-butyl-5-hydroxypyrazol-4-yl ]methy 1 phenyl-4-yl ] aminocarbonyl-3 ,6-dichlorobenzoic acid 05 Formula (I): Rx = n-butyl, R2 = methyl, A OR3, R3 = H, HOjC Prepared by the procedure of Example 27, start-15 ing from 3,6-dichlorophthalic anhydride. Crystals melting at 172-174°C. Example 41: 2- [ [ 1-Ethoxycarbonylmethyl-3-n-propy 1-5-hydroxypyrazol-4-yl ] methy lphenyl-4-yl ] -20 aminocarbonyl-3,6-dichlorobenzoic acid Formula (I): Rx = n-propyl, Rz = CH^CO^Et, A = ORR3 = H, 25 R* = Prepared by the procedure of Example 27, starting from 3,6-dichlorophthalic anhydride. Crystals melting at 150-153°C. 35 2 3 7 -A - 55 - Example 42: Ethyl [l-ethoxycarbonylmethyl-3-n-propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = CH2C02Et, R3 = CH2COaEt, V = N02 Prepared by the procedure of Example 14. Oil used as such for the next step. Example 43: Ethyl [l-ethoxycarbonylmethyl-3-n-propyl-4 (4-aminobenzyl) pyrazol-5-yl ] oxyacetate Formula (I): Rx = n-propyl, R2 = CH2C02Et, A = OR3, R3 = CH2CO_,Et, R4 = NH2 Prepared by the procedure of Example 21. Oil used as such for the next step. Example 44: 2- [ (1-Ethoxycarbonylmethyl-3-n-propy 1-5-ethoxycarbony lmethoxypyr a zol-4-yl) methyl-phenyl-4-yl ] aminocarbonyl-3 r 6-dichlorobenzoic acid Formula (I): Rx = n-propyl, R2 = CH2C02Et, A = 0R3, R3 = CH2C02Et, O CI Prepared by the procedure of Example 27. starting from 3,6-dichlorophthalic anhydride. 237 4 4 5 56 Crystals, in the form of the dicyclohexylamine salt, melting at 189-191°C. Example 45: 2- [ (l-Methyl-3-n-propyl-5-ethoxycarbonyl-methoxypyrazol-4-y 1) methylpheny 1-4-yl ] -aminocarbonylbenzenesulfonic acid Prepared by the procedure of Example 27, but with the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 203-205°C. Example 46: N-[[l-Methyl-3-n-butyl-4-(4-nitrobenzyl)-pyrazol-5-yl ]oxyacetyl ]morpholine Prepared by the procedure of Example 14, start ing from N-(chloroacetyl)morpholine. Crystals melting at 98°C. Preparation of N-(chloroacetyl)morpholine Formula (I): Rx = n-propyl, R_, = methyl, A = 0R3, R3 = CH2C02H, o II Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH,—C—N O , V = N02 'I \ / O N— 21.7 g of morpholine are dissolved in 250 ml of methylene chloride and the solution obtained is cooled 237445 - 57 - n with an ice/water mixture. 14.1 g of chloroacetyl chloride are added drop-wise with the temperature being kept at 0°C, and the mixture is then stirred for 3 hours at room temperature 05 and washed with a dilute solution of hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 29.8 g of N-(chloroacetyl )morpholine in the form of an oil of sufficient purity for the next step. 10 15 30 Example 47: N-[ [ 1-Methyl-3-n-butyl-4-(4-aminobenzyl)-pyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, A 0R3, R3 = CH,—C—H \> , R< NH= 20 Prepared by the procedure of Example 21. Crystals melting at 130°C. Example 48: N-[[l-Methyl-3-n-butyl-4-[4—(2-sulfo-benzoylamino)benzyl]pyrazol-5-yl]oxy-2 5 acetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, A = OR3 , R3 = CH,—C—H , » v_y 35 hojs o J On 25 237 4 4 5 - 58 - ^ Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 236-237°C. 05 Example 49; 2-[l-Methyl-3-n-butyl-4-(4-nitrobenzyl)- pyrazol-5-yl]oxyethanol Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2CH20H, V = NO2 10 12 g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole, prepared in Example 7, are dissolved in 150 ml of butan-2-one. 4.6 g of sodium carbonate and 6 g of 2—bromoethanol are added and the mixture is 15 refluxed for 12 hours. After cooling, the solution is concentrated and then taken up with water and the pH is rendered alkaline by the addition of dilute sodium hydroxide solution. After extraction with methylene chloride, the organic phase is dried over magnesium 20 sulfate and then evaporated to dryness. The residue obtained is chromatographed on silica gel in an ethyl acetate/acetone eluent (6/4) to give 5 g of 2-[l-methyl-3-n-butyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxy-ethanol in the form of crystals melting at 81°C. Example 50: 2-[l-Methyl-3-n-butyl-4-(4-aminobenzyl)-pyrazol-5-yl]oxyethanol Formula (I): Rx = n-butyl, R2 = methyl, A = 30 0R3, R3 = CH2CH20H, R4 = NH2 Prepared by the procedure of Example 21. Oil used as such for the next step. 35 n 237445 - 59 - Example 51: 2-[[1-Methy1-3-n-buty1-5-(2—hydroxyethoxy) ■ pyrazol-4-yl]methylphenyl-4—yl]aminocar— bonylbenzenesulfonic acid 05 10 Formula (I): Rx = n-butyl, R2 = methyl, A 0R3, R3 = CH2CH20H, R. = ho3s Prepared by the procedure of Example 27, but using the cyclic anhydride of orthosulfobenzoic acid. 15 Crystals melting at 170-171°C. Example 52: l-Methyl-4-(4-nitrobenzyl)-3-n-propyl-5-(N, N-dimethylcarbamoyl) oxypyrazole Formula (XI): Rx = n-propyl, R_, = methyl, ch, = 9,~K , V = no, 6 CH> 25 10 g of l-methyl-4-(4-nitrobenzyl)-3-n-propyl- 5-hydroxypyrazole, prepared in Example 8, are dissolved in 100 ml of methylene chloride and 5 ml of triethyl-amine. 3.2 ml of N,N-dimethylcarbamoyl chloride are added dropwise and the mixture is then refluxed for 10 30 hours. After cooling, the mixture is taken up with water and washed with a solution of potassium bicarbonate. The chloroform phase is dried over magnesium sulfate and then evaporated under vacuum to give 9.1 g of l-methyl-4-(4-nitrobenzyl)-3-n-propyl-5-(N,N-di-35 methylcarbamoyl) oxypyrazole in the form of crystals © 20 O 237445 o n 05 20 25 - 60 - melting at 90°C. Example 53: l-Methyl-4-(4-aminobenzyl)-3-n-propy1-5-(M,N-dimethylcarbamoyl)oxypyrazole Formula (I): Rx = n-propyl, R2 = methyl, O A = OR3 , R3 = M ch, C—N' nch, 10 R„ = NH. Prepared by the procedure of Example 21. Crystals melting at 138"c. 15 Example 54: 2-[[l-Methyl-3-n-propyl-5-(N,N-dimethylcarbamoyl )oxypyrazol-4-yl]methylphenyl-4-yl]-aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, ch, ho,s Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. 30 Crystals melting at 210-2°C. 35 23 7 4 o - 61 - Example 55; l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5-(N, N-diethylcarbamoyl) oxypyrazole Formula (XI): = n-propyl, R2 = methyl, 05 ^CjHJ _ R_ = C—N , V = NO. O Jl CjH. i 20 35 Prepared by the procedure of Example 52. 10 Oil used as such for the next step. Example 56: 1-Methyl-3-n-propyl-4-(4-aminobenzyl) -5-(N, N-diethylcarbamoyl) oxypyrazole 15 Formula (I): Rx = n-propyl, R2 = methyl, C4Hs A = OR , R = C f/ 3 3 ii V o CSHS R. = NH2 Prepared by the procedure of Example 21. Crystals melting at 100°C. Example 57: 2- [ [ l-Methyl-3-n-propyl-5-(N, N-diethylcar-25 bamoyl) oxypyrazol-4-yl ]methylphenyl-4-yl ] - aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, 30 ^ = OR3, R3 = NCaHs O R = II NH—C HO,S o 237 4 4 5 n - 62 - Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 216-217°C. 05 Example 58; l-(2,2,2-Trifluoroethyl)-3-n-propyl-5-(N,N- dimethylcarbamoyl)oxy-4-(4-nitrobenzyl)-pyrazole 10 Formula (XI): Rx = n-propyl, R2 = CH2CF3, CHj R3 = c—N( , V = NO; J! ch3 Prepared by the procedure of Example 52. 15 Crystals melting at 70°C. Example 59: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-5-( N , N-dimethylcarbamoyl)oxy-4-(4-aminobenzyl)-pyrazole 20 30 35 Formula (I): Rx = n-propyl, R2 = CH=CF3, ch, A = 0R3, R3 = C-N( 11 ch, O 25 R4 = NH, Prepared by the procedure of Example 21. Crystals melting at 82°C. ,"1 n 237 445 - 63 - o o 05 10 15 Example 60: 2-[[1—(2,2,2-Trifluoroethyl)-3-n-propyl-5-(N,N-dimethylcarbamoyl)oxypyrazol-4-yl]-methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (X): R1 = n-propyl, R2 0 A = 0R3, R3 = Jl = ch2cf3, ch, -N / "s ch, ~ nh hojs Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 159-161°C. 20 Example 61: l-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4-nitrobenzyl)-5-(2-hydroxyethoxy)pyrazole Formula (XI): rx = n-propyl, r2 = ch2cf3, r3 = ch_.ch_.oh, v = no2 25 Prepared by the procedure of Example 49, Crystals melting at 71°C. 30 Example 62: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4-aminobenzyl)-5-(2-hydroxyethoxy)pyrazole Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CH20H, R4 = NH, 35 Prepared by the procedure of Example 21. n nun?" - 64 - 237 4 4 5 O r\ Oil used as such for the next step. Example 63: 2-[[l-(2,2,2-Trifluoroethyl)-3-n-propyl-5-(2-hydroxyethoxy)pyrazol-4-yl]methylphenyl-05 4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH_,CH2OH, 10 R. _ NH HOsS 15 Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 211-3°C. Example 64: 1-(2-Methoxyphenyl)-4-[1-methyl-3-n-propyl-20 4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetyl- piperazine Formula (XI): Rx = n-propyl, R2 = methyl, CHaO 25 0 \ R3 = CH,— C— H \ , v = no2 30 Prepared by the procedure of Example 14, start ing from l-chloroacetyl-4-(2-methoxyphenyl)piperazine. Oil used as such for the next step. l-Chloroacetyl-4-(2-methoxyphenyl)piperazine is prepared by the procedure used to synthesize N-chloro-35 acetylmorpholine, described in Example 46. o 2 3 7 4 4 5 - 65 Example 65: 1-(2-Methoxyphenyl)-4-[ 1-methy1-3-n-propyl-4-(4-aminobenzyl)pyrazol-5-yl]oxyacetyl-piperazine 05 Formula (I): Rx = n-propyl, R2 = methyl, A = OR3/ 10 15 25 R* = NH2 Prepared by the procedure of Example 21. Crystals melting at 145°C. Example 66: l-(2-Methoxyphenyl)-4-[ [l-methyl-3-n- propyl-4-[4-(2-sulfobenzoylamino)benzyl]-pyrazol-5-yl]oxyacetyl]piperazine 20 Formula (I): R^ = n-propyl, R_, = methyl, A = 0Ra, CH30^ R3 = CH2—C—b/ ^M—/\ / o NH- *•' io Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 226-227°C. 35 o o o 15 25 30 2 3 7 4 4 - 66 - Example 67: Ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxohexanoate 05 Formula (V): Rx = n-propyl, V = || R10 = ethyl Prepared by the procedure of Example 6. 10 Oil used as such for the next step. Example 68: 1-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxypyrazole Formula (IX): Rx = n-propyl, V = | R2 = methyl 20 Prepared by the procedure of Example 7. Crystals melting at 164"C. Example 69: Ethyl [l-methyl-3-n-propyl-4-(2'-cyanobi-phenyl-4-yl)methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 14. Oil used as such for the next step. 35 o o 30 237 4 4 5 - 67 - Example 70: Ethyl [1—methyl-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetate 05 Formula (I): = n-propyl, R2 = methyl, A = 0R3/ R3 = CH2C02Et, R. = 10 11 g of ethyl [l-methyl-3-n-propyl-4-(2'-cyano-biphenyl-4-y1)methylpyrazol-5-y1]oxyacetate, prepared 15 in Example 69, are dissolved in 75 ml of toluene. 6.5 g of trimethyltin nitride are added and the mixture is refluxed for 24 hours. The solvent is evaporated off under vacuum and the residue is chromatographed on silica gel in a chloroform/methanol eluent (9/1) to 20 give 6.7 g of ethyl [l-methyl-3-n-propyl-4-[2/-(tetra-zol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetate in the form of crystals melting at 187-189°C. Example 71: l-Methyl-3-n-propyl-5-hydroxy-4-[2'-(tet-25 razol-5-yl)biphenyl-4-yl]methyIpyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = OH, R. = 5 g of l-methyl-3-n-propyl-4-(2'-cyanobiphenyl-35 4-yl)methyl-5-hydroxypyrazole, prepared in Example 68, 2 1 7 68 are dissolved in 50 ml of toluene. 4 g of trimethyltin nitride are added and the mixture is refluxed for 14 hours. After cooling, 10 ml of methanol and 10 ml of chloroform are added and the crystals formed are filtered off and then taken up in 40 ml of toluene and 10 ml of tetrahydrofuran. Gaseous hydrochloric acid is bubbled through the reaction mixture for 10 minutes and the mixture is then stirred for 1 hour at room temperature. The solvents are evaporated off under vacuum and the residue is taken up with a dilute solution of sodium hydroxide and then washed with ethyl acetate. The aqueous phase is neutralized by having sulfur dioxide bubbled through it and the residue crystallizes slowly from water to give, after washing with acetone, 3.1 g of l-methyl-3-n-propyl-5-hydroxy-4-[2'-(tetrazol-5-yl)biphenyl-4-yljmethylpyrazole in the form of crystals melting at 150-153°C. Example 72: 1-Methyl-3-n-butyl-5-hydroxy-4-[2'-(tet-razol-5-yl)biphenyl-4-yl]methylpyrazole Formula (I): Rx = n-butyl, R., = methyl A = OH, R4 Prepared by the procedure of Example 71. Crystals melting at 176-7°C. r\ 23744! - 69 - Example 73: 1- ( 2,2,2-Trif luoroethyl) -3-n-propyl-5- hydr oxy-4- (2 ' -cyanobipheny 1-4-yl )methyl-pyrazole n 05 Formula (IX): R^ = n-propyl, R2 = CH2CF3, V = 10 Prepared by the procedure of Example 7, start ing from 2,2,2-trifluoroethylhydrazine. Crystals melting at 154°C. Example 74; 1— (2,2,2-Trifluoroethyl)— 3-n—propyl-5-15 hydroxy-4-[ 2 ' - (tetrazol-5-yl) biphenyl-4- yl]methylpyrazole 20 Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OH, Ra = 25 Prepared by the procedure of Example 71. Crystals melting at 218-220°C. 30 Example 75: 2- [ 1 -Methyl-3-n-butyl-4- ( 2' -cyanobiphenyl-4-yl) methy lpyrazol-5-yl ]oxyethanol Formula (XI): Rx = n-butyl, R2 = methyl, R_ = CH_CH2OH, V = 35 n 237 4 4 5 - 70 - Prepared by the procedure of Example 49. Oil used as such for the next step. Example 76: 2-[1-Methyl-3-n-butyl-4-[ 2' - (tetrazol-5-05 yl)biphenyl-4-yl]methylpyrazol-5-yl]oxy- ethanol Formula (I): Rx = n-butyl, R2 = methyl, A = 0R3, R3 = CH2CH20H, 10 15 Prepared by the procedure of Example 70. Crystals melting at 105-8°C. Example 77: Ethyl [l-(2,2,2—trifluoroethyl)-3-n-butyl-20 4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5- yl]oxyacetate Formula (XI): Rx = n-butyl, R2 = CH2CF3/ 25 R3 = CH2C02Et, V = NC Prepared by procedure 14. Oil used as such for the next step. 30 35 n 23 7 4 4 5 - 71 - Example 78: Ethyl [1-(2,2,2-trifluoroethyl)-3-n-butyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrazol-5-yl]oxyacetate n 05 10 Formula (I): Rx = n-butyl, R2 = CH2CF3, A OR3, R3 = CH2C02Et, R. = 15 Prepared by the procedure of Example 70. Crystals melting at 140-1°C. Example 79: l-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2'-cyanobiphenyl-4-yl) methyl-5- (N, N-dimethylcarbamoyl )oxypyrazole 0 20 Formula (XI): Rx = n-butyl, R2 = CH2CF3, ch, r3 = c—n' , v = J! ch, o 25 Prepared by the procedure of Example 52. Oil used as such for the next step. 30 35 v';. v; r> 237 4 4 5 - 72 - Example 80: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-5-(N,N-dimethylcarbamoyl)oxypyrazole 05 Formula (I): Rx = n-butyl, R_, = CH2CF3, A CH3 OR3, R3 = c N O CHa 10 N H 15 Prepared by the procedure of Example 70. Crystals melting at 151-2°c. Example 81: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl) methy 1-5- ( N, N-dimethylcarbamoyl) oxy-20 pyrazole Formula (XI): Rx = n-butyl, R2 = methyl, CH3 R3 = C—N' ll v 25 Prepared by the procedure of Example 52. Oil used as such for the next step. 30 35 n 237445 - 73 - Example 82: l-Methyl-3-n-butyl-4-[ 2 ' - (tetrazol-5-yl )bi-phenyl-4-yl]methyl-5-(N,N-dimethylcarbamoyl )oxypyrazole 05 Formula (I): Rx = n-butyl, Ra = methyl, a = or_ , r3 = c—n; ch, / nch1 10 n h O 15 Prepared by the procedure of Example 70. Crystals melting at 160°C. Example 83: Ethyl [l-(2,2,2-trifluoroethyl)-3-n-propyl-4- (2 '-cyanobiphenyl—4-yl)methylpyrazol-5-20 y 1 ] oxyacetate Formula (XI): Rx = n-propyl, R2 = CH2CF3, 25 Prepared by the procedure of Example 14. Oil used as such for the next step. 30 35 237445 o "v - 74 - 30 Example 84: Ethyl [l-(2,2,2-trifluoroethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrazol-5-yl]oxyacetate 05 10 Formula (I): R^ = n-propyl, R_, = CH2CF3, A = 0R3, R3 = CH_,C0=Et, = 15 Prepared by the procedure of Example 70. Crystals melting at 146°C. Example 85: 1-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-y1)methyl—5—(N,N-dimethylcarbamoyl)oxypyrazole 20 Formula (XI): Rx = n-propyl, R2 = methyl, CH, R3 = C—N' , V = 3 ii v CH, 25 Prepared by the procedure of Example 52. Oil used as such for the next step. 35 237 4 4 - 75 - O Example 86: 1—Methyl-3-n-propyl-4-[2'-(tetrazol-5- yl)biphenyl-4-yl]methy1-5-(N,N-dimethylcarbamoyl )oxypyrazole 05 Formula (I): Rx = n-propyl, r2 = methyl, a = 0r_, r_ = c n ch, CH, 10 R„ = N H 15 Prepared by the procedure of Example 70. Crystals melting at 103-5°C. Example 87: 2-[1-Methy1-3-n-propy1-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyethanol 20 25 30 Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 49. Oil used as such for the next step. 35 237445 - 76 - o Example 88: 2-[1-Methy1-3-n-propy1-4-[2'-(tetrazol-5-yl)biphenyl-4-yl ]methylpyrazol-5-yl ]oxy-ethanol 05 10 Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, R = CH_CH_0H, R. = 15 Prepared by the procedure of Example 70. Crystals melting at 120-122°C. Example 89: Ethyl [1-methyl-3-n-buty1-4-(2'-cyanobi-phenyl-4-yl)methylpyrazol-5-yl]oxyacetate 20 Formula (XI): Rx = n-butyl, R_. = methyl, R3 = CH2C02Et, V 25 Prepared by the procedure of Example 14. Oil used as such for the next step. 30 35 ' ' -) 217 4 4 - 77 - o Example 90: Ethyl [l-methyl-3-n-butyl-4-[2 *—(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl ]oxy-acetate O 05 10 Formula (I): R^ = n-butyl, R2 = methyl, A 0R3, R3 = CH2C02Et, R* = 15 Prepared by the procedure of Example 70. Crystals melting at 142-3°C. Example 91; 2-[l-(2,2,2-Trifluoroethyl)-3-n-propy1-4-( 2 ' -cyanobiphenyl-4-yl )methylpyrazol-5-yl ] ■ oxyethanol 20 Formula (XI): R^ = n-propyl, R2 = CHaCF R3 = CH,CH,0H, V = 3 / 25 Prepared by the procedure of Example 49. Oil used as such for the next step. 30 35 o o 237 4 - 78 - Example 92: 2-[1-(2,2,2-Trifluorethyl)-3-n-propyl-4-[ 2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrazol-5-yl]oxyethanol 05 Formula (I): = n-propyl, R2 = CH3CF3, A = 0R3, R3 = CH2CHa0H, R. = 10 Prepared by the procedure of Example 70. Crystals melting at 167°C. 15 Example 93: l-Methoxyoctane-2,4-dione Formula (III): Rx = n-butyl, R' = CH3, q = 1 20 200 ml of hexan-2-one and 102 ml of methyl methoxyacetate are added dropwise to 400 ml of toluene containing 26.9 g of divided sodium, with heating. The temperature during the addition is kept between 60°C 25 and 70°C. When the addition is complete, the mixture is stirred for 2 hours at 55°C. After cooling, 20 ml of methanol are added. The mixture is stirred and then taken up with a dilute solution of sodium hydroxide and the aqueous phase is washed with ether and then acidi-30 fied with dilute hydrochloric acid and extracted with ether. The organic phase is evaporated under vacuum at 30°C after drying over magnesium sulfate and the residue is distilled under reduced pressure to give 98.6 g of l-methoxyoctane-2,4-dione in the form of a liquid of 35 b.p.1S = 115-120 ° C. ,y ■. v o 237445 - 79 ^ Example 94: l-Methoxyheptane-2,4-dione Formula (III): Rx = n-propyl, R' = CH3, q = 1 05 ^ Prepared by the procedure of Example 93, start ing from pentan-2-one. Liquid of b.p.20 = 100-110°C. 10 Example 95: l-Methoxy-3-(4-nitrobenzyl)heptane-2,4- dione Formula (VI): Rx = n-propyl, R' = CH3, V = N02, q = 1 15 135 g of l-methoxyheptane-2,4-dione, prepared in Example 94, are dissolved in 1.5 liters of tetrahydrofuran. 123.3 g of 4-nitrobenzyl bromide, 197 ml of N,N-diisopropylethylamine and 49.5 g of lithium 20 bromide are added and the mixture is refluxed for 15 hours. The solvent is evaporated off under vacuum and the residue is taken up with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is evaporated to dryness and the crystals obtained are 25 washed with ether several times and then methanol, with heating. The filtrates are combined and evaporated to dryness and the residue is then taken up with isopropyl ether. The crystals obtained are washed with isopropyl ether and dried at 30°C under vacuum to give 85.7 g of 30 3-(4-nitrobenzyl)-l-methoxyheptane-2,4-dione in the form of crystals melting at 55°C. The following two Examples were prepared by the same procedure: 35 n 237 4 4 5 - 80 - o Example 96: l-Methoxy-3- (2 ' -cyanobiphenyl-4-yl) methyl-heptane-2,4-dione 05 Formula (VI): Rx = n-propyl, R' = CH3, V = , q = i 10 Oil used as such for the next step. Example 97: l-Methoxy-3 - (2 ' -cyanobiphenyl-4-yl) methyl-octane-2,4-dione 15 Formula (VI): R^ = n-butyl, R' = CH3, V = , q = i 20 Oil used as such for the next step. Example 98: 3-n-Propyl-4-(4-nitrobenzyl)-5-methoxy-methylpyrazole 25 Formula (XIII): R^ = n-propyl, R' q = 1, V = N02 CH 3 ' 20 g of 3-(4-nitrobenzyl)-l-methoxyheptane-2,4-dione, prepared in Example 95, are dissolved in 400 ml of ethanol, 4 ml of hydrazine hydrate are added and the 30 mixture is refluxed for 2 hours. The solvent is evaporated off to dryness under vacuum, the residue is taken up with isopropyl ether and the crystals obtained are filtered off to give 19.5 g of 4-(4-nitrobenzyl)-3-n-propyl-5-methoxymethylpyrazole in the form of crystals 35 melting at 124°C. O 237445 - 81 - The following two Examples were prepared by the o same procedure: Example 99: 3-n-Propyl-4-(2 '-cyanobiphenyl-4-yl )methy1-05 5-methoxymethylpyrazole Formula (XIII): Rx = n-propyl, R' = CH3, v = ,1-1 Oil used as such for the next step. Example 100: 3 -n-Butyl-4- (2' -cyanobiphenyl-4-yl) methyl -15 5-methoxymethylpyrazole Formula (XIII): Rx = n-butyl, R' = CH3, V. , q. 1 Oil used as such for the next step. Example 101: l-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2 ' -25 cyanobiphenyl-4-yl) methyl-5-methoxymethyl pyrazole Formula (XII): Rx = n-butyl, R2 = CH2CF3, R3 = CH3, q = l, 30 v= Y) Prepared by the procedure of Example 98, start-35 ing from 2,2,2-trifluoroethylhydrazine. 237 - 82 - After chromatography on silica gel in an ethyl acetate/cyclohexane eluent (2/8), the desired product is obtained in the form of an oil, which is used as such for the next step. 05 Example 102: 1-Methyl-3-n-propyl- 4 -(4-nitrobenzyl)-5-methoxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = methyl, 10 R' = methyl, V = N02, q = 1 5 g of 3-n-propyl-4-(4-nitrobenzyl)-5-methoxymethylpyrazole, prepared in Example 98, are dissolved in 50 ml of acetone in the presence of 3 ml of methyl 15 iodide and 3 ml of DBU (l,8-diazabicyclo[5.4.0]undec-7-ene). The mixture is heated for 8 hours at 45 °C and the solvent is then evaporated off. The residue is taken up with dilute hydrochloric acid and then extracted with ether. The organic phase is dried over mag-20 nesium sulfate and then evaporated under vacuum to give an oily residue, which is chromatographed on silica gel in an ether/cyclopentane eluent (7/3) to give 2.5 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-methoxymethyl-pyrazole in the form of crystals melting at 73°C. 25 The following two Examples were prepared by the procedure of Example 102: 30 O o 237445 05 - 83 - Example 103: l-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-methoxymethylpyrazole Formula (XII): Rx = n-propyl, R_> = methyl, R' = methyl, V = jf |) , n ^ NC q = 1 10 Oil used as such for the next step. Example 104: l-Methyl-3-n-butyl-4-(2*-cyanobiphenyl-4-yl)methyl-5-methoxymethylpyrazole 15 Formula (XII): Rx = n-butyl, R2 = methyl, X> R' = methyl, V = NC' q = 1 20 25 Oil used as such for the next step. Example 105: l-Methyl-3-n-propyl-4-(4-aminobenzyl)-5-methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = CH2OCH3, R4 = NH2 Prepared by the procedure of Example 21, 30 Oil used as such for the next step. 35 84 - 237 4 4 5 o C) Example 106: 3-n-Propyl-4-(4-aminobenzyl)-5-methoxy-methylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = 05 CH20CH3, R4 = NH2 Prepared by the procedure of Example 21. Crystals melting at 126°C. 10 Example 107; 2-[ (l-Methyl-3-n-propyl-5-methoxymethyl- pyrazol-4-yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid 15 20 30 35 Formula (I): Rx = n-propyl, R2 = methyl, O NH A = CH2OCH3, R4 = HOjS ^V) Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 126°C. 25 Example 108: 2-[(3-n-Propyl-5-methoxymethylpyrazol-4- yl) methylphenyl-4-yl ] aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = H, A = O NH- CH20CH3, r4 = hojs io 237 4 4 5 - 85 - Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 253-256°C. Example 109; l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5-bromomethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = CH2Br, R4 = N0= 4.5 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-methoxymethylpyrazole, prepared in Example 102, are dissolved in 140 ml of chloroform. 2.8 ml of boron tribromide are added dropwise at a temperature of between 0°C and 5°C and the mixture is subsequently stirred for one hour at this temperature and then for 2 hours at room temperature. A dilute solution of sodium hydroxide is added to the mixture and the organic phase is decanted, dried and evaporated under vacuum to give 5 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-bromo-methylpyrazole in the form of an oil, which is used as such for the next step. Example 110: 3-n-Propyl~4-(4-nitrobenzyl)-5-bromo-methylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = CH2Br, R4 = N02 Prepared by the procedure of Example 109. Crystals melting at 120°C. o 2-37 4 4 5 - 86 - o r^i Example 111; l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxymethylpyra zo1e Formula (XII): = n-propyl, R2 = methyl, 2 f 05 R' = H, V = NC>2, q = 1 6.5 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-bromomethylpyrazole, prepared in Example 109, are dissolved in a mixture composed of 50 ml of dioxane and 10 50 ml of water. 5 g of sodium carbonate are added and the mixture is refluxed for 3 hours. The solvents are evaporated off under vacuum and the residue is taken up with water and extracted with ether. The organic phase is dried over magnesium sulfate and then evaporated 15 under vacuum to give a residue, which crystallizes from isopropyl ether to give 3.8 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxymethylpyrazole in the form of crystals melting at 134°C. 20 Example 112: 3-n-Propy1-4-(4-nitrobenzyl)-5-hydroxy- methylpyrazole Formula (XIII): Rx = n-propyl, R' = H, V = N02, q = 1 25 Prepared by the procedure of Example 111. Crystals melting at 125°C. Example 113: l-Methyl-3-n-propyl-4-(4-aminobenzyl)-5-3 0 hydroxymethylpyrazole Formula (I): R^ = n-propyl, Ra = methyl, A = CH20H, = NH2 35 Prepared by the procedure of Example 21. o o 'u 05 15 20 30 35 2 3 7 4 4 5 - 87 - Crystals melting at 133°C, Example 114: 3-n-Propy1-4-(4-aminobenzyl)-5-hydroxymethylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = CH20H, R4 = NH2 Prepared by the procedure of Example 21. 10 Oil used as such for the next step. Example 115: 2-[(l-Methyl-3-n-propyl-5-hydroxymethyl-pyrazol-4-yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, O nh- A = CH2OH, R4 = hojs ,io Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. 25 Crystals melting at 255-257°C. Example 116: 2-[(3-n-Propyl-5-hydroxymethylpyrazol-4- yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R_, = H, A = O NH- CH20H, R4 = HO,S 237 4 4 5 88 Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid. Crystals melting at 168-170°C. Example 117: l-Methyl-3-n-propyl-4-[2'-(tetrazol-5- yl)biphenyl-4-yl]methyl-5-methoxymethylpyrazole Example 118: 1-Methyl-3-n-butyl-4-[2'-(tetrazol-5-yl)-biphenyl-4-yl ] methyl-5-methoxymethyl-pyrazole Formula (I): R.^ = n-propyl, R_. = methyl, Prepared by the procedure of Example 71. Crystals melting at 128-130°C. Formula (I): Rx = n-butyl, R2 = methyl N H Prepared by the procedure of Example 71. Crystals melting at 134-135°C. o o w' o 25 30 23 7 4 - 89 - Example 119: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2' ■ (tetrazol-5-y1)bipheny1-4-yl]methyl-5-methoxymethylpyrazole 05 Formula (I): Rx = n-butyl, R_, = CH2CF3, A = CH-.OCH-, R4 = 10 Prepared by the procedure of Example 71. Crystals melting at 172-173°C. 15 Example 120: Ethyl 3-oxo-5-methylhexanoate Formula (II): Rx = 2-methylpropyl, Rxo = ethyl 20 Prepared by the procedure of Example 1. Liquid of b.p.xo = 100-110°C. Example 121: Ethyl 2-(2'-cyanobiphenyl-4-y1)methyl-3-oxo-5-methylhexanoate Formula (V): Rx = 2-methylpropyl, Rxo = x> ethyl, v = NC' Prepared by the procedure of Example 6, Oil used as such for the next step. 35 o o O 05 15 20 30 237 4 4 5 - 90 - Example 122: l-Methyl-3- (2-methylpropyl) -4- (2' -cyano-biphenyl-4-yl)methyl-5-hydroxypyrazole Formula (IX): Rx = 2-methylpropyl, R2 = methyl, V = Prepared by the procedure of Example 7. 10 Crystals melting at 163°C. Example 123: l-(2,2,2-Trifluoroethyl)-3-(2-methyl- propyl) -4- ( 2' -cyanobiphenyl-4-yl) methyl-5-hydroxypyrazole Formula (IX): Rx = 2-methylpropyl, R3 = X3 CH2CF3, V = nc' Prepared by the procedure of Example 7. Oil used as such for the next step. Example 124: Ethyl [l-methyl-3-(2-methylpropyl)-4-(2' • 2 5 cyanobiphenyl-4-yl)methylpyrazol-5-yl]- oxyacetate Formula (XI): Rx = 2-methylpropyl, R_, = methyl, R3 = CH_.C0-.Et, v = nc' .XJ 35 Prepared by the procedure of Example 14. Oil used as such for the next step. o 237 4 4 5 o c - -> - 91 - Example 125: Ethyl [l-methyl-3-(2-methylpropyl)-4-[ 2 ' -(tetrazol-5-yl) biphenyl-4-yl ]methylpyra-zol—5-yl]oxyacetate 05 Formula (I): Rx = 2-methylpropyl, R2 = methyl, A = 0R3, R3 = CH2C02Et, 10 20 25 30 J N^h Prepared by the procedure of Example 70. 15 Crystals melting at 172-173°C. Example 126: Ethyl [l-(2,2,2-trifluoroethyl)-3-(2- methylpropyl) -4- ( 2' -cyanobiphenyl-4-yl) ■ methylpyrazol-5-yl ] oxyacetate Formula (XI): Rx = 2-methylpropyl, Ra CH2CF3, R3 = CH2C02Et, V = JsJ NC Prepared by the procedure of Example 14, Oil used as such for the next step. 35 o 237 4 4 5 - 92 - o Example 127; Ethyl [l-(2,2,2-trifluoroethyl)-3-(2-methylpropyl)-4-[2'-(tetrazol-5-yl)bi-phenyl-4-yl]methylpyrazol-5-yl]oxyacetate 05 10 Formula (I): Rx = 2-methylpropyl, R2 = CH2CF3, A = 0R3, R3 = CH2C02Et, Ra = n h 15 Prepared by the procedure of Example 70. Crystals melting at 114-115°C. Example 128: 2-[l-(2,2,2-Trifluoroethyl)-3-(2-methylpropyl )-4-(2'-cyanobiphenyl-4-yl)methyl -pyrazol-5-yl]oxyethanol 20 25 Formula (XI): r.^ = 2-methylpropyl, r2 ch2cf3, r3 = ch2ch2oh, v = X) Prepared by the procedure of Example 49 Crystals melting at 116°C. 30 35 o 237 4 4 5 - 93 - O Example 129: 2-[1-(2,2,2-Trifluoroethyl)-3-(2-methylpropyl )-4-[2'-(tetrazol-5-yl)biphenyl-4-yl ] methylpyrazol-5-yl ] oxyethanol O 05 10 Formula (I): R^ = 2-methylpropyl, R2 CH2CF3, A = 0R3, R3 = CH2CH20H, 15 Prepared by the procedure of Example 70. Crystals melting at 145-146°C. m 20 25 30 Example 130: N-[[l-Methyl-3-n-butyl-4-[4-(2-trifluoro-methylsulf onylaminobenzoyl) aminobenzyl ]-pyrazol-5-yl]oxyacetyl]morpholine Formula (I): R^^ = n-butyl, R= = methyl, 35 CFjSOJN H 4.3 g of N-[[l-methyl-3-n-butyl-4-(4-aminobenzyl )pyrazol-5-yl ] oxyacetyl ]morpholine, prepared in Example 47, are dissolved in 20 ml of chloroform in the presence of 1.54 ml of triethylamine. A solution of 3.52 g of N-trifluoromethylsulfonylanthranilic acid c 237 4 4 5 - 94 - o rx chloride (prepared according to the references CA : 96(13) : 1036512 and CA : 97(7) : 55500w) in 10 ml of chloroform is added dropwise at room temperature and the mixture is then heated for 2 hours at 50°C and left 05 to stand overnight at room temperature. The solution is washed with dilute hydrochloric acid, dried and evaporated under vacuum. The residue is taken up with methylene chloride and extracted with a dilute solution of sodium hydroxide. The aqueous phase is acidified to 10 pH 2 and extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and then evaporated to dryness and the oil obtained crystallizes from ether to give 4.6 g of N-[ [l-methyl-3-n-butyl-4-[4-(2-trifluoromethylsulfonylaminobenzoyl)aminobenzyl]pyra-15 zol-5-yl]oxyacetyl]morpholine in the form of crystals melting at 190°C. ^ 20 0 Example 131: Ethyl 2-(2'-nitrobiphenyl-4-yl)methyl-3-oxohexanoate Formula (V): Rx = n-propyl, R10 = ethyl, 25 Prepared by the procedure of Example 6, starting from 2/-nitro-4-chloromethylbiphenyl. Oil used as such for the next step. 2'-Nitro—4—chloromethylbiphenyl was prepared by 30 chloromethylating 2-nitrobiphenyl according to the following references: - CA 70(25) : 114837d, and - CA 69(2) : 3704t. 35 o 237 4 - 95 - n Example 132: l-Methyl-3-n-propyl-4- (2 '-nitrobiphenyl-4-y 1)methy1-5-hydroxypyrazole 05 Formula (IX): Rx = n-propyl, R2 = methyl, "JO 10 Prepared by the procedure of Example 7 Crystals melting at 179-182°C. Example 133: Methyl [l-methyl-3-n-propyl-4-(2'-nitrobi-phenyl-4-yl )methylpyrazol-5-yl ] oxyacetate 15 20 Formula (XI): R1 = n-propyl, R2 = methyl, R3 = CHaC02Me, O 25 Prepared by the procedure of Example 14. Oil used as such for the next step. Example 134: Methyl [l-methyl-3-n-propyl-4-(2'-aminobi-phenyl-4-yl) methy lpyrazol-5-yl ] oxyacetate 30 Formula (I): Rx = n-propyl, R2 — methyl, A = 0R3, R3 = CH_,C02Me, = H,N 35 Prepared by the procedure of Example 21. Q 237 4 4 5 - 96 - o 05 Oil used as such for the next step. Example 135: Methyl [1-methy1-3-n-propy1-4-(2'-tri- fluoromethylsulfonylaminobiphenyl-4-yl)-methylpyrazol-5-yl]oxyacetate 10 Formula (I): R., n-propyl, R2 = methyl, A = 0R3/ R3 = CH2C02Me, = CFjSOJNH l g of methyl [l-methyl-3-n-propyl-4-(2'-amino-biphenyl-4-yl)methylpyrazol-5-y1]oxyacetate, prepared 15 in Example 134, is dissolved in 30 ml of chloroform in the presence of 0.4 ml of triethylamine; the mixture is cooled to 0°C and 0.43 ml of trifluoromethanesulfonic anhydride is added dropwise. The mixture is then stirred for one hour at room temperature and the organic 20 phase is washed with water, dried over magnesium sulfate and evaporated under vacuum. The residue obtained crystallizes from isopropyl ether to give 0.7 g of methyl [l-methyl-3-n-propyl-4-(2'-trifluoromethylsul-fonylaminobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate 25 in the form of crystals melting at 114-116°C. 30 35 Example 136; 2-[l-Methyl-3-n-propyl-4-(2'-carbethoxy-biphenyl-4-yl)methylpyrazol-5-yl]oxy-ethanol Formula (XI): Rx = n-propyl, R= = methyl, R3 = CH2CH20H, V = EtOjC o 237 4 4 5 - 97 - O Prepared by the procedure of Example 49. Oil used as such for the next step. Example 137: 2-[l-Methyl-3-n-propyl-4-(2'-carboxy-05 biphenyl-4-yl)methylpyrazol-5-yl]oxy- ethanol Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, R3 = CH2CH2OH, 10 R* = H0,C Prepared by the procedure of Example 37. 15 Crystals melting at 168-170°C. Example 138: Ethyl 2-[4-(2-cyanothien-3-yl)benzyl]-3-oxohexanoate 20 Formula (V): Rx = n-propyl, R10 = ethyl, io V = NC^ ^S" 25 Prepared by the procedure of Example 6, start ing from 4-(2-cyanothien-3-yl)benzyl bromide. * Preparation of 4-(2-cyanothien-3-yl)benzyl bromide 30 A) 3-(4-Methylphenyl)thiophene-2-carboxylic acid 25 g of ethyl 3-(4-methylphenyl)thiophene-2-carboxylate, prepared according to the reference FISSELMANN H.; HABITCH H.? Ger. Offen. 1,092,929 (1960), CA : 57, 5894g, are dissolved in 580 ml of 35 ethanol and 50 ml of water. 6.2 g of sodium hydroxide Jj 237 4 4 5 - 98 - pellets are added and the mixture is refluxed for 2 hours, poured into water and acidified with concentrated hydrochloric acid. The crystals obtained are filtered off and dried to give 20.7 g of 3-(4-methyl-05 phenyl) thiophene-2-carboxylic acid in the form of crystals melting at 172°C. B) 3-(4-Methylphenyl)thiophene-2-carboxamide 20.7 g of 3-(4-methylphenyl)thiophene-2-car-10 boxylic acid, prepared in A), are dissolved in 200 ml of anhydrous toluene with 10.4 ml of thionyl chloride. The mixture is refluxed for three hours and then evaporated to dryness. The oily residue is added dropwise to a 28% solution of ammonia at 25 °C. After stirring 15 for one hour, the mixture is extracted with chloroform and the organic phase is washed with water, dried over magnesium sulfate and evaporated under vacuum to give 18 g of 3—(4—methylphenyl)thiophene—2—carboxamide in the form of crystals melting at 128-130°C. 20 C) 3-(4-Methylphenyl)thiophene-2-carbonitrile 18 g of 3-(4-methylphenyl)thiophene-2-car-boxamide, prepared in B), are dissolved in 36 ml of phosphorus oxychloride and the mixture is refluxed for 25 one hour. The phosphorus oxychloride is concentrated under vacuum and the residue is taken up in water and ethyl acetate. The organic phase is extracted, dried, filtered over animal charcoal and then evaporated under vacuum to give 12 g of 3-(4-methylphenyl)thiophene-2-30 carbonitrile in the form of an oil, which is used as such for the next step. 35 D) 4-(2-Cyanothien-3-yl)benzyl bromide 12 g of 3-(4-methylphenyl)thiophene-2-carbo-nitrile, prepared in C), are dissolved in 100 ml of o 237 A A 5 99 carbon tetrachloride. 11.3 g of N-bromosuccinimide and 10 mg of benzoyl peroxide are added. The mixture is refluxed until all the succinimide has come out of solution. The crystals are filtered off and the sol-05 vent is concentrated under vacuum to give 16 g of 4-(2-cyanothien-3-yl)benzyl bromide in the form of an oil, which is used as such for the next step. Example 139: 1-Methy1-3-n-propy1-4-[4-(2-cyanothien-10 3-yl)benzyl]-5—hydroxypyrazole 20 Example 140; Ethyl [l-methyl-3-n-propyl-4-[4-(2-cyano- Formula (IX): = n-propyl, R2 = methyl, 15 Prepared by the procedure of Example 7. Crystals melting at 110-115°C. thien-3-yl)benzyl]pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2C03Et, 25 30 Prepared by the procedure of Example 14. Oil used as such for the next step. 35 n 15 20 237445 - 100 - Example 141; Ethyl [l-methyl-3-n-propyl-4-[4-[2-(tet-razol-5-yl )thien-3-yl ]benzyl ]pyrazol-5-yl]oxyacetate 05 Formula (I): Rx = n-propyl, R_, - methyl, A = OR3, R3 = CH=C02Et, R. = 10 Prepared by the procedure of Example 71. Crystals melting at 201°C. Example 142: Ethyl 2-[4-(2-carbethoxythien-3-yl)-benzyl]-3-oxohexanoate Formula (V): Rx = n-propyl, R1Q = ethyl, V = Et02C" "S' Prepared by the procedure of Example 6, start-25 ing from 4-(2-carbethoxythien-3-yl)benzyl bromide. Oil used as such for the next step. Preparation of 4-(2-carbethoxythien-3-yl)benzyl bromide 30 43.4 g of ethyl 3-(4-methylphenyl)thiophene-2- carboxylate, prepared according to the reference FISSELMANN H.; HABITCH; Ger. Offen. 1,092,929 (1960); CA : 52, 5894g, are dissolved in 250 ml of carbon tetrachloride. 33 g of N-bromosuccinimide and 10 mg of 35 benzoyl peroxide are added, the mixture is refluxed for o 2 3 7 4 4 5 101 one hour, the crystals of succinimide are filtered off and the solvent is evaporated off under vacuum to give 56.6 g of 4-(2-carbethoxythien-3-yl)benzyl bromide in the form of crystals melting at 55°C. 05 Example 143: 1-Methy1-3-n-propy1-4-[4-(2-carbethoxy-thien-3-yl)benzyl]-5-hydroxypyrazole Example 144: 2-[1-Methyl-3-n-propyl-4-[4-(2-carbethoxy-thien-3-yl) benzyl ] pyrazol-5-yl ] oxyethanol Formula (IX): = n-propyl, R2 = methyl 10 15 Prepared by the procedure of Example 7. Crystals melting at 130-132°C. © 20 Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CHaCH20H, 25 Prepared by the procedure of Example 49. Oil used as such for the next step. 30 Example 145: 2-[1-Methyl-3-n-propyl-4-[4-(2-carboxy- thien-3-yl)benzyl]pyrazol-5-yl]oxyethanol Formula (I): Rx = n-propyl, R_, = methyl A = 0R3, R3 = CH2CH20H, 35 V = 'Q 237 4 4 5 - 102 - o Prepared by the procedure of Example 37, Crystals melting at 118-120°C. r\ 05 10 15 Example 146; l-(2-Methoxyphenyl)-4-[l-(2,2,2-trifluoroethyl )-3-n-propyl-4-( 2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetylpiperazine Formula (XI): R.^ = n-propyl, R2 = CH_,CF3, R V = Prepared by the procedure of Example 64. Oil used as such for the next step. 20 Example 147: l-(2-Methoxyphenyl)-4-[l-(2,2,2-trifluoroethyl )-3-n-propyl-4-[ 2' - (tetrazol-5-yl)-biphenyl-4-yl]methylpyrazol-5-yl]oxyacetylpiperazine /5=* 25 30 35 Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, r3 = 9 = 237 4 4 5 o - 103 - n Prepared by the procedure of Example 70. Crystals melting at 158-160°C. /T"-. Example 148: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-05 4—(2'—cyanobiphenyl—4—yl)methylpyrazol-5- yl]oxyacetyl]morpholine 10 Formula (XI): Rr = n-propyl, R2 = CH2CF3, R3 = V ch,c0 n o 15 Prepared by the procedure of Example 46. Oil used as such for the next step. Example 149: N-[[l-(2,2,2-Trifluoroethyl)-3-n-propyl-20 4—[2#—(tetrazol-5-yl)biphenyl-4-yl]- methylpyrazol-5-yl]oxyacetyl]morpholine 25 Formula (I): Ra = n-propyl, R_, = CH2CF3, A = OR3, R3 = CHjCO N / \ O , 30 35 Prepared by the procedure of Example 70. Crystals melting at 129-31°C. C<) 237 4 4 5 O o - 104 - Example 150: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-5- hydroxy-4-[ 2' - (tetrazol-5-yl)biphenyl-4-yl]methylpyrazole 05 Formula (I): Rx = n-butyl, R2 = CH2CF3, A = OH, R4 = 10 Prepared by the procedure of Example 71. Crystals melting at 210-11°C. 15 Example 151: 1-Methy1-3-n-butyl-4-(2'-cyanobiphenyl-4- yl )methyl-5-bromomethy lpyrazole Formula (I): Rx = n-butyl, R2 = methyl, 20 17- <! v_y Prepared by the procedure of Example 109, starting from the l-methyl-3-n-butyl-4-(2'-cyanobi-25 phenyl-4-yl)methyl-5-methoxymethylpyrazole prepared in Example 104. Oil used as such for the next step. 30 35 o O r*\ 05 237 - 105 - Example 152: 1-Methyl-3-n-buty1-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxymethy1pyrazo1e Formula (XII): Rx = n-butyl, R2 = methyl, * «X) • q = 1 10 Prepared by the procedure of Example 111. Oil used as such for the next step. Example 153: l-Methyl-3-n-butyl-4-[ 2 ' - (tetrazol-5- yl)biphenyl-4-yl]methyl-5-hydroxymethyl-15 pyrazole Formula (I): Rx = n-butyl, R2 = methyl, A = CH2OH, Ra = 20 N H Prepared by the procedure of Example 71. 25 Crystals melting at 110-12°C. Example 154: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-formylpyrazole 30 Formula (I): Rx = n-butyl, R2 = methyl, X) A = CHO, R4 = > NC' 35 2.3 g of 2-nitropropane are dissolved in a 'O n 25 237445 - 106 - solution of sodium methylate prepared from 0.7 g of sodium and 40 ml of methanol. 10 g of l-methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-bromomethyl-pyrazole, prepared in Example 151, are dissolved in 30 05 ml of methanol and this solution is added dropwise to the reaction mixture. The mixture is stirred for two hours at 50°C, water is then added and the resulting mixture is extracted with ethyl acetate. The organic phase is evaporated to dryness under vacuum and the 10 residue obtained is chromatographed on silica gel to give 4.3 g of l-methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-formylpyrazole in the form of an oil, which is used as such for the next step. 15 Example 155: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl- 4-yl)methyl-5—(dioxolan-2-yl)pyrazole Formula (I): Rx = n-butyl, R2 = methyl, 0. 20 A = CHJ s o- O ' n— R*= Y) NC- 4.3 g of l-methyl-3-n-butyl-4-(2'-cyanobi-phenyl-4-yl)methyl-5-formylpyrazole, prepared in Example 154, are dissolved in 50 ml of toluene. 1 g of ethylene glycol and 10 mg of paratoluenesulfonic acid 30 are added. The mixture is brought to the reflux temperature and the water is removed for 3 hours by means of a Dean-Stark apparatus. The mixture is subsequently taken up with water and extracted with ether and the extract is then dried over magnesium sulfate and eva-35 porated under vacuum to give 4 g of 1-methyl-3-n-butyl- "O 237 44 5 - 107 - n 4-(2'-cyanobiphenyl-4-yl)methyl-5-(dioxolan-2-yl)-pyrazole in the form of an oil, which is used as such for the next step. 05 Example 156; l-Methyl-3-n-butyl-4-[2/ — (tetrazol-5-yl)- biphenyl-4-yl ] methyl-5- (dioxolan-2-yl) -pyrazole 10 Formula (I): Rx = n-butyl, R_, = methyl, 0. A = CH" o- <3 ■ 15 /N N H 20 Prepared by the procedure of Example 70, Crystals melting at 144-6°C. 25 30 Example 157: 2- [ 1- (2,2,2-Trif luoroethyl) -3-n-butyl-4-( 2' -cyanobiphenyl-4-yl) methylpyrazol-5-yl]oxyethanol Formula (XI): Rx = n-butyl, R_. = CH2CF3, R_ = CH2CH_OH, V = Prepared by the procedure of Example 49, Oil used as such for the next step. 35 .... •O o 10 15 20 237445 - 108 - Example 158; 2-[1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-pyrazol-5-yl]oxyethanol 05 Formula (I): Rx = n-butyl, R2 = CH2CF3, A = 0R3, R3 = CH_,CH20H, N Vh Prepared by the procedure of Example 71. Crystals melting at 107-10°C. Example 159: Ethyl 3-oxo-2-[4-(3-cyanothien-2-yl)-benzyl]heptanoate Formula (V): Rx = n-butyl, R10 = ethyl, V = nc' 1.1 g of ethyl 3-oxoheptanoate, prepared in 25 Example 1, 1.2 g of 4-(3-cyanothien-2-yl)benzyl bro-(v) mide, 0.6 g of lithium bromide and 2.2 ml of diiso- propylethylamine are added to 15 ml of tetrahydrofuran. i. The mixture is stirred under reflux for 20 hours, taken up with water and extracted with ether. The organic 30 phase is dried over magnesium sulfate and then evaporated. The excess ethyl 3-oxoheptanoate is evaporated off using a vane pump and 1.5 g of ethyl 3-oxo-2-[4-(3-cyanothien-2-yl)benzyl]heptanoate are obtained in the form of an oil, which is used as such for the next 35 step. 237445 •n - 109 - o D o Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'—Methyl-4-chlorobutyrophenone 53 ml of toluene and 70.5 g of 4-chlorobutyroyl 05 chloride are dissolved in 100 ml of methylene chloride and the solution is added at 10°C to a suspension of 74 g of aluminum chloride in 200 ml of methylene chloride. The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with iced 10 water. The organic phase is dried over magnesium sulfate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used as such for the next step. 15 B) a-Chloro-6-(2-chloroethyl)cinnamaldehyde 130 ml of phosphorus oxychloride are added slowly, at 0°C, to 130 ml of dimethylformamide, and a solution of 117.5 g of 4'-methyl-4-chlorobutyrophenone, prepared in A) , in 50 ml of dimethylformamide is then 20 added dropwise. The mixture is subsequently stirred at room temperature for one hour and then at 50 °c for 2 hours and at 70°C for 1 hour. The mixture is then poured on to ice and taken up with ether and the ether phase is washed with a saturated solution of sodium bi-25 carbonate, dried over sodium sulfate and evaporated under vacuum to give 133.8 g of a-chloro-6-(2-chloro-ethyl)cinnamaldehyde in the form of an oil, which is used as such for the next step. 30 c) 2-(4-Methylphenyl)-4,5-dihydrothiophene-3-carbox-aldehyde 15.9 g of a-chloro-B-(2-chloroethyl)cinnamaldehyde, prepared in B), and 22 g of sodium sulfide (9HZ0) are added to 200 ml of THF. A sufficient amount 35 of water is added for all the sodium sulfide to pass o 237445 - 110 - into solution, and the mixture is subsequently refluxed for 3 hours, cooled and then taken up with ether. The organic phase is decanted, washed with water and then dried over magnesium sulfate and evaporated under 05 vacuum to give 13.5 g of 2-(4-methylphenyl)-4,5-di-hydrothiophene-3-carboxaldehyde in the form of an oil, which is used as such for the next step. D) 2 - (4-Methylphenyl)-3-cyano-4,5-dihydrothiophene 10 15 g of 2-(4-methylphenyl)-4,5-dihydrothio- phene-3-carboxaldehyde, prepared in C), and 6.5 g of hydroxylamine hydrochloride are mixed with 40 ml of ethanol and 10 ml of water. A solution of 4.7 g of sodium carbonate in 10 ml of water is added. The mix-15 ture is stirred at room temperature for half an hour and then extracted with ether. The ether phase is washed with water and then dried over sodium sulfate and evaporated under vacuum to give 15.2 g of a gummy yellow residue. This residue is added to 13 ml of 20 acetic anhydride and the mixture warms up slightly, turns brown and becomes liquid. The mixture is subsequently refluxed for 1 hour and then poured on to ice and extracted with methylene chloride, the extract is washed with a saturated solution of sodium bicarbonate, 25 the organic phase is then dried over magnesium sulfate and evaporated under vacuum and the residue obtained is chromatographed on silica gel in methylene chloride to give 10 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydro-thiophene in the form of an oil, which is used as such 30 for the next step. E) 2-(4-Methylphenyl)-3-cyanothiophene 49.9 g of 2-(4-methylphenyl)-3-cyano-4,5-dihydrothiophene, prepared in D), are dissolved in 200 ml 35 of carbon tetrachloride, the mixture is heated to the 237 445 T) ) 05 o 10 15 20 30 reflux temperature and, after two hours, a solution of 11 g of bromine in 200 ml of carbon tetrachloride is added dropwise. Reflux is continued until the evolution of hydrobromic acid has ceased, and the solvent is then evaporated off under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is refluxed for one hour and then cooled, water and sodium chloride are added and the mixture is extracted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl)-3-cyanothiophene in the form of an oil, which is used as such for the next step. F) 4-(3-Cyanothien-2-yl)benzyl bromide 24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide are added. The mixture is refluxed for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept in a refrigerator for 24 hours. The crystals formed are filtered off to give 14 g of 4-(3-cyanothien-2-yl)benzyl bromide in the form of crystals melting at 80°C. Example 160: 1-Methyl-3-n-butyl-4-[4-(3-cyanothien-2-yl)benzyl]-5-hydroxypyrazo1e Formula (IX): Rx = n-butyl, R2 = methyl "O 237445 112 ■sw^ 1.4 g of ethyl 2-[4-(3-cyanothien-2-yl)benzyl]- 3-oxoheptanoate, prepared in Example 159, are dissolved in 10 ml of ethanol. 2.2 ml of methylhydrazine are added, the mixture is refluxed for 13 hours, water is 05 added and the resulting mixture is extracted with ether and then with ethyl acetate. The organic phases are combined and evaporated under vacuum to give an oily residue, which, after chromatography on silica gel in a methylene chloride/methanol eluent (95/5), gives 0.8 g 10 of l-methyl-3-n-butyl-4-[4-(3-cyanothien-2-yl)benzyl]-5-hydroxypyrazole in the form of crystals melting at 120°C. Example 161: i-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-15 4-yl) methyl-5- (N, N-diethylcarbamoyl) oxypyrazole Formula (XX): R1 = n-propyl, R2 = methyl, 20 R 3 25 O Prepared by the procedure of Example 52. Oil used as such for the next step. 30 35 o 237445 - 113 - o Example 162: l-Methyl-3-n-propyl-4-[ 2 ' - (tetrazol-5-yl)■ biphenyl-4-yl]methyl-5-(N,N-diethylcarbamoyl )oxypyrazole 05 v_y 10 15 Formula (I): = n-propyl, R2 = methyl, A = 0R3, c5h5 R3 = C nn Jl cjHS n h Prepared by the procedure of Example 70, Crystals melting at 134-135°C. Example 163: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-20 4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5- yl]oxyacetyl]thiomorpholine Formula (XI): Rx = n-propyl, R2 = CH2CF 3 ' 25 R3 = chj co n s , v_/ 30 V = Prepared by the procedure of Example 46, starting from N-(chloroacetyl)thiomorpholine. Oil used as such for the next step. 35 237445 n - 114 - r\ Example 164: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl -pyrazol-5-yl]oxyacetyl]thiomorpholine 05 10 15 Formula (I): Rx = n-propyl, R_, = CH2CF3, A = 0R3, / \ R3 = CH, CO N S , R„ = N— N^ N N H Prepared by the procedure of Example 70, Crystals melting at 127-128°C. © Example 165: 1-(2-Methoxyphenyl)-4-[1-methy1-3-n-2 0 propyl-4-(2'-cyanobiphenyl-4-yl)methyl- pyrazol-5-yl]oxyacetylpiperazine 25 30 Formula (XI): RA = n-propyl, R2 = methyl, t NC Prepared by the procedure of Example 64, Oil used as such for the next step. 35 10 15 20 25 30 237445 - 115 - Example 166: 1-(2-Methoxyphenyl)-4-[l-methyl-3-n- propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetylpiperazine Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3/ Prepared by the procedure of Example 70. Crystals melting at 139-141°C. Example 167: 3-n-Propyl-l-methyl-4-(2'-cyanobiphenyl-4-yl) methy 1-5- (2-dimethylaminoethoxy) -pyrazole Formula (XI): Rx = n-propyl, Ra = methyl, CH, / "CH, *-«X) 10 g of 3-n-propyl-l-methyl-4-(2/-cyanobi-phenyl-4-yl)methyl-5-hydroxypyrazole, prepared in Example 68, are dissolved in 100 ml of butan-2-one in the presence of 10 g of sodium carbonate and 8.6 g of R3 = CH,CH2N^ "O o 15 20 237445 - 116 - N,N-dimethyl-2-chloroethylamine hydrochloride. The ^ mixture is refluxed for 20 hours and then concentrated under vacuum, taken up with water and extracted with ether. The ether phase is washed with water, dried and 05 then evaporated under vacuum. The residue is chromatographed on silica gel in a chloroform/methanol eluent CD (95/5) to give 4.6 g of 3-n-propyl-l-methyl-4-(2'- cyanobiphenyl-4-yl)methyl-5-(2-dimethylaminoethoxy)-pyrazole in the form of an oil, which is used as such 10 for the next step. Example 168: 3-n-Propyl-l-methyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-5-(2-dimethylaminoethoxy )pyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, ch, R3 = ch,ch,n' ch, = 25 N H 30 Prepared by the procedure of Example 70, Crystals melting at 88-90°C. 35 'O 237 4 4 3 - 117 - o Example 169: N-[2-[l-Methyl-3-n-propyl-4-(2'-cyanobi-phenyl-4-yl)methylpyrazol-5-yl]oxyethyl]-morpholine 05 Formula (XI): Ra = n-propyl, R2 = methyl, 10 r_ = chj ch2 n o , \ / V = X) 15 Prepared by the procedure of Example 167, starting from N-(2-chloroethyl)morpholine. Oil used as such for the next step. 20 Example 170: N-[2-[1-Methyl-3-n-propy1-4-[2'—(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]-oxyethyl]morpholine Formula (I): R, = n-propyl, R, methyl, A = OR 3 ' O 25 30 R3 = CHjCHJ N 0 , R. = n— nh Prepared by the procedure of Example 70. Crystals melting at 132-134°C. 35 "r> 20 237445 - 118 - Example 171: l-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2'-cyanobiphenyl-4-y1)methyl-5-hydroxymethy1-pyrazole 05 Formula (XII): Rx = n-butyl, R2 = CH2CF3, R' = H, , q = 1 10 Prepared by the procedure of Example ill, starting from the l-(2,2,2-trifluoroethyl)-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-bromomethylpyrazole prepared by the procedure of Example 109. 15 Oil used as such for the next step. Example 172: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2'-(tetrazol-5-yl )biphenyl-4-yl ]methyl-5-hydroxymethy lpyrazole Formula (I): Rx = n-butyl, Ra = CH3CF3, A = CH..0H, R. = 25 / N^h Prepared by the procedure of Example 71. 30 Crystals melting at 114-117°C. 35 o o 10 2374 - 119 - Example 173; 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(2 *-cyanobiphenyl-4-y 1) methy 1-5-methoxymethyl-pyrazole 05 Formula (XII): Rx = n-propyl, R= = CH2CF3, R' = CH3, q = 1, X) v = NC' Prepared by the procedure of Example 101. Oil used as such for the next step. Example 174: 1- (2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'• 15 (tetrazol-5-yl) biphenyl-4-yl ]methyl-5- methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = CH_,CF3, 20 A = CH20CH3, Ra = 25 Prepared by the procedure of Example 71. Crystals melting at 177-178°C. 30 35 237445 - 120 - ^ Example 175: N-[[1-Methy1-3-n-butyl-4-(2'-cyanobi- phenyl-4-yl )methylpyrazol-5-yl ] oxyacetyl ] -morpholine 05 Formula (XI): Rx = n-butyl, R_, = methyl, B /—\ ^ r3 = ch2co n o , 10 Prepared by the procedure of Example 46. Oil used as such for the next step. 15 Example 176: N-[[1-Methyl-3-n-propyl-4-(2'-cyanobi- phenyl-4-yl )methylpyrazol-5-yl ] oxyacetyl ]■ morpholine 20 Formula (XI): Rx = n-propyl, R2 = methyl, / V R3 = chjco n v-«X) Prepared by the procedure of Example 46 Oil used as such for the next step. 30 35 •»>—"UUUfcAIMf J 237445 - 121 - o Example 177: N-[ [l-Methyl-3-n-butyl-4-[2'-(tetrazol-5-yl )biphenyl-4-yl ]methylpyrazol-5-yl ] oxyacetyl ]morpholine 05 10 15 Formula (I): Rx = n-butyl, R2 = methyl, A = 0R3, R3 = CH,CO N N H Prepared by the procedure of Example 70, Crystals melting at 140-141°C. Example 178: N-[ [l-Methyl-3-n-propyl-4-[2'-(tetrazol-5-20 yl )biphenyl-4—yl ]methylpyrazol-5-yl ]oxy- acetyl]morpholine 25 30 Formula (I): Rx = n-propyl, R_, = methyl, A = 0R3, / \ R3 = CHjCO N O , \—/ Prepared by the procedure of Example 70. 35 Crystals melting at 106-110°C. o 02 20 25 2 3 7 4 4 5 - 122 - Example 179: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxymethyl-pyrazole 05 Formula (XII): Ra = n-propyl, R2 = CH2CF3, R# = H, , q = 1 10 Prepared by the procedure of Example 111, starting from the 1-(2,2,2-trifluoroethyl)-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-bromomethylpyrazole prepared by the procedure of Example 109. 15 Oil used as such for the next step. Example 180: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-5-hydroxymethylpyrazole Formula (I): Rx = n-propyl, R2 = CH_,CF3, A = CH20H, Prepared by the procedure of Example 71, 30 Crystals melting at 110-2°C. 35 o 237 4 4 5 - 123 - O Example 181: 1-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxymethylpyrazole 05 Formula (XIX): R^ = n-propyl, R2 = methyl, R' = H, V = q = 1 10 Prepared by the procedure of Example 111, Oil used as such for the next step. 15 Example 182: 1-Methy1-3-n-propyl-4-[ 2 ' - (tetrazol-5-yl) • biphenyl-4-yl]methy1-5-hydroxymethy1-pyrazole 20 Formula (I): Rx = n-propyl, Ra = methyl, A = CH OH, R = ^0 / n-^h 25 Prepared by the procedure of Example 71. Crystals melting at 136-9°C. 30 35 ■n 237445 - 124 O Example 183: l- (2-Methoxyphenyl) -4- [ l-methyl-3-n-butyl-4—(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetylpiperazine 05 10 Formula (XI): R^ = n-butyl, R2 = methyl, / 15 Prepared by the procedure of Example 64, Oil used as such for the next step. 20 25 30 Example 184: l-(2-Methoxyphenyl) -4- [ 1 -methy 1-3-n-butyl-4—[2'-(tetrazol-5-yl)biphenyl—4—yl]methyl-pyrazol—5-yl]oxyacetylpiperazine Formula (I): Rx = n-butyl, R2 = methyl, A = 0R3, R3 / R. 35 Prepared by the procedure of Example 70. Crystals melting at 153-5°C. jjgfgjpjpnam*!*'*" — »*vuww;rf,«vr**^" ~r>: 237445 - 125 - o Example 185: N-[[1-Methy1-3-n-propyl-4-(2'-cyanobi— phenyl-4-yl)methylpyrazol-5-y1]oxyacetyl]■ thiomorpholine 05 Formula (XI): Rx = n-propyl, R_, = methyl, 10 r3 = chjc n s , II \ / o — V = «X) 15 Prepared by the procedure of Example 46, starting from N-(chloroacetyl)thiomorpholine. Oil used as such for the next step. o 20 25 Example 186: N-[[l-Methyl-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetyl ]thiomorpholine Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, / \ R3 = CHjC N S , o — 30 N H Prepared by the procedure of Example 70. Crystals melting at 140-1°C. 35 237445 - 126 - o o 05 Example 27 10 Example 28 15 Example 29 20 Example 30 25 30 Example 31 TABLE N-N' CH, O CH, CO, Et UP 221-1 O CH, CO, Me UP 221-6 O CH, CO, Et UP 221-11 O CH, C0a Et UP 221-13 0 CH, CO, Me UP 221-12 35 _ —vrMrr^'^"i t> :.rrv nv-v^rv,,-, »rj ,r y ,. 'O V..^1 23 7 4 4 5 - 127 - o V / 05 Example 32 10 Example 33 15 Example 34 20 Example 35 25 Example 36 30 ^X^SO,H N-N -CF, 0 CH, CO, Me UP 221-7 OCH, CO, Me UP 221-4 0 CH, CO, H UP 221-16 N-N ^ —0 CH, CO, H UP 221-14 N—N CH, UP 221-15 'COOH 35' 237445 •w' - 128 - o j V 05 Example 37 10 Example 40 15 Example 41 20 Example 44 25 Example 45 30 n-n' CH, O CH. CO, H CO,Et UP 221-17 UP 221-18 UP 221-19 COjEt 0 CH, CO, Et UP 221-20 T^XJOOH a n-n' O CH, CO, Et UP 221-21 SO,H 35 'O 2 3 7 4 4 5 - 129 - n Vw^ ■fP Viy O 05 Example 48 10 Example 51 15 Example 54 20 Example 57 25 Example 60 30 CC1"" ^^SO,H OC^ O CH, CHj OH UP 221-22 OCON ,CH, 'CH, UP 221-23 UP 221-27 UP 221-28 UP 221-30 35 237 4 4 5 'O - 130 - n o 05 Example 63 10 Example 66 15 Example 70 20 Example 71 25 Example 72 30 35 o ch, ch, oh UP 221-32 ch3 ch5o n-n' 9 ^^ \. o ch, c n n—v v \_y \=J O CH, CO, Et UP 221-33 UP 221-34 UP 221-43 UP 221-59 23 7 4 4 131 - O o © o1 05 Example 74 10 15 20 Example 76 Example 78 25 Example 80 30 n-n H N N-N M '/ H N N-N' -CF, 0 CH, CO, Et ocorC CH, CH, UP 221-56 UP 221-57 UP 221-54 UP 221-55 35 V» -T-*- «-r •"•■ innr. n 237445 - 132 - o rr\ 05 Example 82 10 Example 84 15 20 Example 86 25 Example 88 30 OCHjCHJOH UP 221-51 UP 221-44 UP 221-45 UP 221-46 35 237 4 o - 133 - 05 Example 90 10 Example 92 15 Example 107 20 25 Example 108 30 Example 115 n-n' CH, 35 UP 221-47 UP 221-50 UP 221-38 UP 221-36 UP 221-42 i-Wf ^s~-,- ,.,-wj«wj"|r'W;r^v'fv<' 237445 - 134 - Q W O Example 116 05 Example 117 10 15 Example 118 20 Example 119 25 Example 125 30 N-N' .H UP 221-40 UP 221-48 UP 221-52 UP 221-53 UP 221-58 35 "n 237445 - 135 - o Example 127 05 O CH, CO, Et UP 221-61 10 Example 129 15 20 Example 130 O CH, CH, OH UP 221-60 UP 221-25 I II H ^^NH SOjCF, 25 Example 135 30 0 CH, CO, Me UP 221-26 NH SO, CF, 35 o 237445 - 136 - o Example 137 05 10 Example 141 15 Example 145 20 25 Example 147 30 O CH, CH,OH UP 221-29 O CH, CO, Et UP 221-35 35 237445 - 137 - n Example 149 05 10 Example 150 15 Example 153 20 25 Example 156 30 UP 221-63 UP 221-64 UP 221-65 UP 221-66 35 'O O O Example 158 05 OCHjCKOH H N CHj N-n' 10 Example 162 15 Example 164 20 0 CON x c3Hs C3HS OCHgCO N s W Example 166 N ✓ N h"N' CH, n-n 25 30 ochjco n chjo \—^ 35 237445 o - 139 - (T it**?, \ Example 168 05 10 Example 170 15 Example 172 20 25 Example 174 30 UP 221-71 UP 221-72 UP 221-73 UP 221-74 35 - 140 - 237445 o 0 05 Example 177 10 15 25 Example 178 20 Example 180 Example 182 30 N-N -CF, UP 221-76 UP 221-77 UP 221-78 UP 221-79 35 W*WT»r**y^»S(Vwv <•l,l.,■■■.r^v|t^tl^^l^:r■W^^^W,^'^^B^'llt^*,'y*^y^^^rr~•/*•■••^^^•• D 23 7 4 4 5 - 141 - o o 05 10 15 20 /" UP 221-80 OCH, UP 221-81 ."C-A cD 25 30 35 237 4 - 142 -PHARMACOLOGY I. Principle 05 The affinity of the products of the Examples for angiotensin II receptors is evaluated by the technique of displacing a radioligand specifically bound to rat adrenal angiotensin II receptors. 10 II. Procedure An aliquot of a rat adrenal gland homogenate incubates in the presence of a single concentration of [i25i]-SIAII (Sar1,Tyr4,lie3-angiotensin II), which is 15 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 20 filters. The non-specific binding is determined in the presence of angiotensin II. Ill. Expression of the results 25 The results are expressed, for the concentra tions tested, as the percentage displacement of the radioligand specifically bound to the adrenal angiotensin II receptors. 35 'ij. :> * ■- i ' 237 4 45 - 143 - o IV. Results 05 10 15 20 /M^'\ 30 35 Product of Example % displacement of the labeled ligand 1E-5 M 1E-7 M 27 92 39 28 82 34 29 80 40 30 96 63 31 93 60 32 98 52 33 94 26 35 85 48 36 62 10 37 58 9 40 83 0 41 85 2 44 96 9 45 92 60 48 80 58 51 83 60 54 77 62 57 80 60 60 84 49 63 91 64 66 92 63 70 67 49 71 58 24 74 66 58 78 73 58 80 69 48 82 71 47 84 65 51 86 58 41 88 60 38 90 64 40 92 75 70 107 83 62 108 86 19 115 80 57 116 82 12 117 61 35 118 67 35 119 70 54 130 74 33 135 65 34 137 63 5 141 64 9 145 53 0 </div>

Claims

<div id="claims" class="application article clearfix printTableText"> 237445 V", i ^ ji - 144 - o 1 TOXICOLOGY v.- The products of the Examples described have an excellent tolerance after oral administration. 05 Their 50% lethal dose in rats was found to be greater than 300 mg/kg. CONCLUSION 10 The products of the Examples described have a good affinity for angiotensin II receptors. In this respect, they will be able to be used beneficially for the various pathological conditions in which angiotensin II is involved, in particular in the treatment 15 of arterial hypertension and cardiac insufficiency, in dosages of 1 to 400 mg by oral administration and 0.01 to 50 mg by intravenous administration, in one or more dosage units per day. ^ 25 30 35 o - 145 237 4 WW g. Ci»nro *6: WHATVWE CLAIM IS:,;1. A pyrazole derivative of the general formula;Formula (I);in which:;Rx is a lower alkyl radical having 1 to 6 carbon atoms, a lower alkenyl radical having 2 to 6 carbon atoms or a C3-C7 cycloalkyl radical;;R2 is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having 1 to 6 carbon atoms, a C3-Cv cycloalkyl radical, a group -(CH2)m-COORs, a group -CH^-fCII-, )m-OR^ or a group -CH2-(CH3)Jn-S-Rs, m being an integer from 0 to 5 and Rs being a hydrogen atom or a lower alkyl radical having l to 6 carbon atoms;;A can be a group:;-(CH2)<30R/, R' being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical and q being an integer from 1 to 5, -(CHa)qL, L being a halogen atom, preferably chlorine or bromine, and q being as defined above,;-CHO, an acetal or a dioxolan,;-COOR7, R' being as defined above,;-CONR''R''', R'' and R/#/ independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon;r* • O 237445 - 146 - atoms or a C3-C7 cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attached, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, -CN, -(CH2)^-CN, q being as defined above, -(CH-J^-COOR', R' and q being as defined above, — (CH2)taCONR/ 'R''', R'', R''' and q being as defined above, -(CH2)qNR/'R''', R'', R'" and q being as defined above, or —0R3, R3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)n-COOR6, a group -(CH2)-(CHa)n-CN, a group -CH,,— (CH2) 0-Re, a group -CH2-(CH2)„-S-R6 or a group -co-Rs, n being an integer from 0 to 5 and R6 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R3 can be a group -(CH2 )]p-CONRT7RB or -(CH2)E>-CH2-CH2NR7.RS, p being an integer from 0 to 5 and R7 and Rs independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attached, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine; and Rd can be a nitro or amino group or a group -COORs, Rs being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R4 can be the following radicals: o - 147 - 237 4 R.OOC Yj! N NH N R.OOC rP N NH N in which R3 is as defined above, X and Y independently being a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical or a trifluoromethyl radical, and its addition salts, in particular the pharmaceutically acceptable addition salts. 2. A derivative according to claim 1 of formula (I) in which: is a lower alkyl radical having 1 to 6 carbon atoms which is preferably selected from n-propyl, n-butyl and 2-methylpropyl; R2 is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, a lower halogenoalkyl radical having 1 to 6 carbon atoms, pre- 237445 - 148 - ■Oi ferably 2,2 ,2-trif luoroethyl, or a group - (CH2) ^-COOR,., m and Rs being as defined in claim 1, preferably a group CH_,-COOEt; A is a group: -(CH.jgOR', r' being selected from a hydrogen atom and a lower alkyl group having 1 to 6 carbon atoms, preferably methyl, and q being an integer from l to 5, preferably equal to 1, -(CH2)qL, L and q being as defined in claim 1, preferably -CH2Br, -CHO, an acetyl or a dioxolan, or —OR3, R3 being selected from a hydrogen atom, a group -(CH2)n-COORs or -CH2-(CH2)„-0R6, n being an integer from 0 to 5, preferably equal to 0 or 1, and Rs being a hydrogen atom or a lower alkyl radical having l to 6 carbon atoms, preferably methyl or ethyl, or a group -(CH2^-CONR^Rq, p being an integer from 0 to 5, preferably equal to 0 or 1, and R_, and Re independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, or R,, and Ra, taken together with the nitrogen atom to which they are attached, forming a heterocycle which is preferably selected from morpholine, piperazine and l-(2-methoxyphenyl)piperazine; and R4 is as defined in claim 1, and its addition salts, in particular the pharmaceutically acceptable addition salts. 3. A derivative according to claim 1 or claim 2, wherein Rx is a group selected from n-butyl and n-propyl. 4. A derivative according to any one of claims 1 to 3, wherein R2 is a group selected from methyl and 2,2,2-trifluoroethyl. 5. A derivative according to any one of claims 1 to 4, wherein A is a group selected from ethoxycarbonyl-methyleneoxy, dimethylaminocarbonyloxy, methoxymethy- 237 4 4 5" 11. .•'' - 149 - lene and 2-hydroxyethoxy. 6. A derivative according to any one of claims 1 to 5, wherein RA is a group selected from 2-carboxy-3,6-di-chlorobenzoylamino, 2-sulfobenzoylamino and 2-(tetra-zol-5-yl)phenyl. 7. A derivative according to claim 1 which is selected from the derivatives of the formulae / rrTTtrimnMKaiwiarm.ffnTO, -irrmrnr- v, nt ' ,r,v" ' o 237 4 - 150 - 0 oh 2 n 7 4 ^ - 151 - O 8. A method of preparing the derivatives of formula (I) according to any one of claims 1 to 7, which comprises reacting a hydrazine of the formula H2N-NH-R3, R= being as defined above, with a keto-ester of formula (V) or a diketone of formula (VI): V (CH2)q—OR' Formula (V) Formula (VI) in which Rx, R' and q are as defined above, Rxo is a C-^-Cg alkyl, preferably ethyl or methyl, and V is a functional group selected from N02; COORx;L, Rxx being a C^-Cg alkyl radical or benzyl; RI2OOC X) Rla being a C--Cc alkyl radical or benzyl; A 0 RX2 being as defined above; and Vl ;VSV ; VS\ NC^^S R.-OOCn^ , V Ol ^ MAR I99J - 152 - R12 being as defined above, or reacting hydrazine hydrate with a diketone of formula (VI) as mentioned above, this being followed by alkylation in the presence of DBU (1,8-diazabicyclo-[5.4.0]undec-7-ene) with halogenated derivatives of the formula Z-R2/ in which R2 is as defined above and Z is a bromine, chlorine or iodine atom. 9. A method according to claim 8, wherein the keto-ester of formula (V) mentioned above is obtained: - by benzylation of an alkyl 3-oxoalkanoate of formula in which Rx and R10 are as defined above, with a compound of formula (IV): (II): Formula (II) W Formula (IV) in which W is a halogen atom, preferably chlorine or bromine, and V is as defined above; - or by condensation of an aldehyde of formula (VII): 237445 - 153 - CHO V Formula (VII) in which V is as defined above, with said alkyl 3-oxoalkanoate of formula (II), followed by catalytic hydrogenation. 10. A method according to claim 8, wherein the diketone of formula (VI) mentioned above is obtained: - by benzylation of a 1,3-diketone of formula (III): R, P CH, C—(CHJg O—R' II II M 0 O Formula (III) in which Rx, R' and q are as defined above, with a compound of formula (IV): W Formula (IV) in which W is a halogen atom, preferably chlorine or bromine, and V is as defined above; - or by condensation of an aldehyde of formula (VII): - 154 - cho V Formula (vii) in which V is as defined above, with said 1,3-diketone of formula (III), followed by catalytic hydrogenation. 11. A synthesis intermediate for the preparation of derivatives of formula (I) according to any one of claims 1 to 7, useful especially for carrying out the method according to claim 8, said intermediate having formula (IX), (XI) or (XII): 23 7 4 - 155 - Formula (XII) in which Rx, Ra, R3, v, q and R' are as defined above. 12. A pharmaceutical composition which comprises a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 7, or one of its pharmaceutically acceptable addition salts, in association with a pharmaceutically acceptable excipient, vehicle or carrier. 13. A pharmaceutical composition with antagonistic activity towards angiotensin II receptors, which comprises a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims l to 7, or one of its pharmaceutically acceptable addition salts, in association with a pharmaceu- / ^ o\ /v ^ s\ ^ MAR /993 <J \ A '! r. O .y - 156 - 23 7 A 4 U tically acceptable excipient, vehicle or carrier. 14. A method of preparing a pharmaceutical composition, which comprises incorporating a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 7, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier. 15. A method according to claim 14, wherein the pharmaceutical composition is formulated as gelatin capsules or tablets containing from 1 to 400 mg of active ingredient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient. 16. A compound as claimed in claim 1 specifically set forth herein. 17. A process for producing a compound as claimed in claim 1 substantially as herein described with reference to any one of the Examples. LABORATOIRES UPSA {J f. By Their Attorneys BALDWIN SON S CAREY </div>