IE910766A1 - Novel pyrazole derivatives which are angiotensin ii¹receptor antagonists; their methods of preparation¹and pharmaceutical compositions in which they are present - Google Patents

Abstract

Derivatives of formula (I): and their addition salts and their use in therapeutics, especially for the treatment of cardiovascular disorders, in particular for the treatment of high blood pressure and of cardiac insufficiency.

Description

Novel pvrazole 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 anta10 gonistic 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 (I): Formula (I) in which: Rx is a lower alkyl radical having 1 to 6 35 carbon atoms, a lower alkenyl radical having 2 to 6 carbon atoms, a C3-C7 cycloalkyl radical or a C4-C2 cycloalkenyl 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-C7 cycloalkyl radical, a group -(CH2)ra-COORs, a group -CH2-(CH2)m-ORs or a group -CH2-(CH2)m-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; A can be a group: -(CH2)q0Rzz Rz being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-Cv cycloalkyl radical and q being an integer from 1 to 5, — (CH2)c^L, L being a halogen atom, preferably chlorine or bromine, and q being as defined above, -CHO, an acetal or a dioxolan, -COORZ, Rz being as defined above, -CONRZZRZZZ, Rz z and Rzzz 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 heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, -CN, -(CH2)caCN, q being as defined above, -(CH2)qCOORz, Rz and q being as defined above, -(CH2)^CONR''R''', Rzz, Rzzz and q being as defined above, -(CH2)£3NRZ ZRZ z z, Rzz, Rzzz and q being as defined above, -(CH2),-S-Rz, Rz and q being as defined above, or -or3, r3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C_, cycloalkyl radical, a group -(CH2)n-COOR6, a group -CH2-(CH2)„-CN, a group -CH2-(CH2)„-O-R6, a group -CH2-(CH2)„-S-Re or a group -CORS, 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-C0-NRvRs or -(CH2)p-CH2-CH2NRvRe, p being an integer from 0 to 5 and Rv and Ra independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon 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; and Rd can be a nitro or amino group or a group -COORg, Rg being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R4 can be the following radicals: χΝΗ O X in which Rg 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-C7 cycloalkyl 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.

C4-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- trifluoroethyl radical.

Alkoxy radical is understood as meaning an 0lower alkyl group, lower alkyl being as defined above.

Heterocycle is understood as denoting a ring of to 7 atoms containing from 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, which is unsubstituted 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.

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 compounds all possess a benzyl substituent on a nitrogen atom: Z—Y // N 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 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 the presence of a group A and especially of an oxygen oo atom in the 3-position (or 5-position) of the pyrazole, in conjunction with the benzyl substituent in the 4position, produces compounds which are particularly active as angiotensin II receptor antagonists.

According to one embodiment, Rx is an n-propyl group.

According to another embodiment, Rx is an nbutyl group.

According to one embodiment, R2 is a methyl group.

According to another embodiment, R2 is a 2,2,2trifluoroethyl group.

According to one embodiment, A is an ethoxycarbony lmethyleneoxy group.

According to another embodiment, A is a dimethylaminocarbonyloxy group'.

According to another embodiment, A is a methoxymethylene group.

According to another embodiment, A is a 220 hydroxyethoxy group.

According to one embodiment, R4 is a 2-carboxy3,6-dichlorobenzoylamino group.

According to another embodiment, R4 is a 2sulfobenzoylamino group.

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 According to the invention, it will be possible BS to prepare the compounds of formula (I) according to the following scheme: - the alkyl 3-oxoalkanoates of formula (II): 05 R,—C—CHj—COOR,0 O Formula (II) in which Rx is as defined above and R1O is a lower alkyl radical, preferably methyl or ethyl, and - the 1,3-diketones of formula (III): R,—C—CHj—C—(CHJq—0—R* O 0 Formula (III) in which RlZ R' and q are as defined above, 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: - OIKAWA Y. ; SUGANO K. ; YONEMITSU O. ; J. Org. Chem., 1978, 43(10), 2087-88, - WIERENGA W. SKULNICK H.I.? J. Org. Chem., 1979, 44., 310, - HOUGHTON R.; LAPHAM D.; SYNTHESIS, 1982, 6, 451-2, - BEAM 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, - RENARD M.; MAQUINAY A.; Bull. Soc. Chim. Belg., 1946, 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): 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 diisopropylethylamine 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): Formula (V) Formula (VI) The compounds of formulae (V) and (VI) can also be obtained by condensation of an aldehyde of formula (VII): V Formula (VII) with a compound of formula (II) or formula (III), followed by catalytic hydrogenation, for example in the 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 in the following references: - DURGESHWARI P. ; CHAUDHURY N.D.; J. Ind. Chem. Soc. , 1962, 39, 735-6, - HEINZ P. ; KREGLEWSKI A.; J. Prakt. Chem., 196 3, 21(3-4), 186-197, - 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), 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M. ; Chem. Lett., 1981, 2, 173-6, - IOFFE T. ; POPOV E.M.; VATSURO K.V. ; TULIKOVA E.K.; KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and - SHEPHERD T.M.? Chem. Ind. (London), 1970, 17, 567.

In formula (IV), W is a halogen atom, preferably chlorine or bromine.

In the same formula: - V can be a nitro group, in which case the derivative of formula (IV) is commercially available.

- V can be a group COOR^, Ri;l being a lower alkyl or benzyl radical, in which case the derivative of formula (IV) will be prepared by chlorinating or brominating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, according to the following reference: - JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 1962 (2), 2247.

- V can be a group 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 compound of the formula to give a compound of the formula - 13 05 which is hydrolyzed to give the compound of the formula Procedures for the three steps described above will be found in the following reference: - MEYERS A.I.; MIHELICH E.D.; J. Am. Chem. Soc., 1975, 97, 7383.

The acid is then esterified with an alcohol of the formula RX2OH, RX2 being as defined above.

These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide or N25 chlorosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is the group R„OOC V can be the group NC in which case the compound CH, HOOC 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: CH.

NC will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula (IV) in which V is the group NC' - V can be the group 0,h in which case the compound CICH.

OjN will be prepared by chloromethylating commercially 15 available 2-nitrobiphenyl according to the following references: - CA : 70 (25) : 114837d, and - CA : 62. (2) : 3704t to give the compounds of formula (IV) in which V is the 20 group - V can be a group R12 being a lower alkyl or benzyl radical. The corresponding compounds of formula (IV) are obtained in the following manner: Starting from the compound whose preparation can be found in the following reference : - FISSELMANN H.; HABITCH H. ; Ger . Offen. 1,092, 929 (1960); CA : 57 : 5894g, the compounds of the formula 1 I 1 J A R„OOCZ 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.

• These compounds are then treated with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane for example, to give the compounds of formula (IV) in which V is the group R(JOOC Rl2 being as defined above.

- V can be the group // w 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 dimethylformamide, to give the nitrile compound 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 NC - V can be the group NC' in which case the corresponding compounds of formula (IV) are synthesized in the following manner: Starting from 4-chlorobutyrophenone of the formula CH, CH,—CH,—CH,—Cl whose preparation can be found in patent BE 577,977 of 15 May 1959, CA : 54, 4629c, the compound of the formula 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.ΐ 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 which is then converted in two steps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxy1amine. This dehydration may be carried out for example with acetic anhydride to give the nitrile compound which may then be aromatized by treatment with bromine 10 in carbon tetrachloride and then with potassium tertbutylate in tetrahydrofuran to give the compound This compound can then be chlorinated or bro20 minated with halogenating agents such as 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 30 R,jOOC •A R12 being as defined above.

The corresponding com20 pounds of formula (IV) pound of the formula may be prepared from the com 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-chloro15 succinimide or N-bromosuccinimide, for example in carbon tetrachloride or dibromoethane.

In formulae (V) and (VI), RiZ R1O, R* and 9 are as defined above and V is as defined in formula (IV).

Some derivatives of formula (V) and formula (VI), when V is a 2-alkoxycarbonylphenyl, a 2-cyanophenyl, 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 (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 art. The Sommelet reaction (Bull. Soc. Chira. 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): H2N-NH-R2 Formula (VIII) in which R2 is as defined above, with the compounds of formula (V), by simply refluxing in an alcohol for example, will give the compounds of formula (IX): Formula (IX) in which Rx, R2 and V are as defined above.

These compounds of formula (IX) are novel synthesis 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, butan25 2-one or dimethylformamide, or in the presence of a sodium or potassium alcoholate in an alcohol, or in the presence of sodium or lithium hydride in tetrahydrofuran, with derivatives of formula (X): Z-R3 Formula (X) Z being a bromine, chlorine or iodine atom and R3 being as defined above, gives the compounds of formula (XI): - 22 05 Formula (XI) in which RlZ R2, R3 and V are as defined above.

Likewise, reaction of a hydrazine of formula (VIII), as defined above, with a compound of formula 15 (VI), by simply refluxing in an alcohol for example, will give a mixture of compounds of formula (XII) and formula (XII'): Formula (XII) Formula (XII') in which Rir R2, R', q and V are as defined above.

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.

Another method of preparing the compounds of 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): Formula (XIII) 15 in which Rx, R', q 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-R2 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 (XII*), as defined above, the compounds of formula (XII) then being ob30 tained 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 (XII*).

The compounds of formula (XII) in which Rz is a hydrogen will be prepared in two steps: Treatment of the compounds of formula (XII) in which Rz is a lower alkyl group with boron tribromide will give the bromi05 nated derivatives of formula (XV): Formula (XV) 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 compounds of formula (XII) in which Rz 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 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 -(CH2)-ORz or OR3 , Rz, R3 and q being as defined above.

Reaction of an appropriately substituted phthalic anhydride with these derivatives will give the compounds of general formula (I) in which R4 is the group in which X and Y are as defined above and A is a group -(CH2)q-OR' or 0R3, q, R' and R3 being as defined above, it then being possible for the acid obtained to be esterified to give the group Likewise, reaction of the cyclic anhydride of an appropriately substituted orthosulfobenzoic acid with these amino compounds will give the compounds of general formula (I) in which R4 is the group and A is a group -(CILJ^-OR' or OR3, q, R', R3, X and Y being as defined above.

Likewise, reaction of N-(trifluoromethylsulfonyl)anthranilie acid chloride, whose preparation can be found in the following references: CA 96 (13) : 103651Z, and CA 97 (7) : 55500w, with these amino compounds will give the compounds of general formula (I) in which R4 is the group and A is a group -(CH2)q-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 RX1 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 -(CH2)q-QR' 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 and A is a group -(CH2)<3-OR/ or OR3, q, R' and R3 being as defined above, by reaction with anthranilic acid derivatives of the formula in which X, Y and Rg are as defined above.

In the same way, the compounds of formula (XI) or (XII) in which V is a group 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 is a group and A is a group -(CH2)ci-OR/ or OR3, q, R' and R3 being as defined above. which V The compounds is a group of formulae (XI) and (XII) in 30 s NC‘ will be able to react with one equivalent of sodium 35 nitride in a solvent such as dimethylformamide, in the 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 which R4 is a group and A is a group -(CH2)a-0Rz or 0R3, q, Rz and R3 being as defined above.

The compounds of formulae (XI) and (XII) in which V is a group 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 com25 pounds of general formula (I) in which R4 is a group and A is a group -(CH2),3-ORZ or OR3 , q, Rz and R3 being as defined above.

Reaction of trifluoromethanesulfonyl chloride with the latter in a solvent such as chloroform or in an aromatic solvent such as toluene, in the presence of a base such as triethylamine or pyridine, or in pyridine, will give the compounds of general formula (I) in which R4 is a group CF,—SO,—HN^ and A is a group -(CH2)ta-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 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 of formula (I) in which R4 is the group N—N ί and A is a group -(CH2)-OR/ or OR3, q, R' and R3 being as defined above.

The compounds of formulae (XI) and (XII) in which V is the group R„OOC will be able to 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 R4 is the group HOOC and A is a group -(CH^J^-OR' or OR3, q, R' and R3 being as defined above.

The compounds of formula (I) in which A is a group CH2OH 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 CO2H.

The compounds of formula (I) in which A is the group CO2H will be able to be esterified by classical methods of esterification to give the compounds of formula (I) in which A is a group CO2R', Rz being a lower alkyl radical.

The compounds of formula (I) in which A is the group CO2H 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 HNRZZRZZZ, Rzz and Rzzz being as defined above, to give the compounds of formula (I) in which A is a group CONR,ZRZZZ.

The compounds of formula (I) in which A is a group C0NH2 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 (CH2)eaORz, Rz 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 (CH-J^Br.

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 acetonitrile, to give the compounds of formula (I) in which A is the group (CH2)caCN, or with amines of the formula HNRZZRZ//, in which Rz z and Rz z' are as defined above, to give the compounds of formula (I) in which A is (CH2)qNRzZRZzz, or with thiols of the formula HS-RZ, Rz being as defined above, to give the derivatives of formula (I) in which A is (CH2)q-S-Rz.

The compounds of formula (I) in which A is the group (CH2)<3CN 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 (CH^CC^H.

These acid compounds will themselves be able to be esterified by the classical methods of esterification to give the compounds of formula (I) in which A is a group (CH2)qCO2Rz, Rz being a lower alkyl radical and q being an integer from 1 to 5, or converted to an amide -(CH2^-CONR''R''' as indicated above.

The compounds of formula (I) in which A is the group (CH2)L, L being a halogen and q being an integer from 1 to 5, will be able to be synthesized by treating the derivatives of formula (I) in which A is the group (CH2)q0H with halogenating agents such as, for example, thionyl chloride, phosphorus oxychloride or phosphorus tribromide.

In the case where R4 possesses a functional 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.

It is possible to obtain addition salts of some of the compounds of formula (I), especially pharmaceutically 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 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, methanesulfonate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate.

The novel compounds according to the invention possess remarkable pharmacological properties as angiotensin II receptor antagonists and can be used in therapeutics for the treatment of cardiovascular dis30 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 amount of at least one compound of formula (I) as 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 administra05 tion.

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 composi30 tion 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 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 1 and 400 mg of active principle administered orally in one or more daily doses, or from 0.01 to 50 mg administered parenterally in one or more daily doses.

The invention also covers a method of preparing a pharmaceutical composition, which comprises incor10 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, 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 thera20 peutic treatment for mammals, which comprises administering 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.

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 following description of some Preparatory Examples, which in no way imply a limitation but are given by way of illustration.

Example 1: Ethyl 3-oxoheptanoate Formula (II): Rx = n-butyl, R1O = 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 dis15 solved 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.2O = 115-120°C.

Example 2: Ethyl 3-oxohexanoate Formula (II): Rx = n-propyl, Rxo = ethyl Prepared by the same procedure as Example 1. Liquid of b.p.2o = 95-100°C.

Example 3: Ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate Formula (V): Rx = n-butyl, V = N02, Rxo = ethyl 57.3 g of ethyl 3-oxoheptanoate are dissolved in 300 ml of ethanol. A solution of sodium ethylate, 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)-3oxoheptanoate 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, R1O = ethyl Prepared by the procedure of Example 3, start25 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-oxoheptanoate Formula (V): Rx = n-butyl, V = MeOjC Rio = ethyl 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 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'-methylbiphenyl-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,3oxazolidine) 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'-methylbi20 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 g of methyl (4'-methylbiphenyl-2-yl)carboxy25 late, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-bromosuccinimide 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-2yl)carboxylate in the form of an oil, which is used as such for the next step. β β yy Example 6: Ethyl 2-(2 '-cyanobiphenyl-4-yl)methyl-3oxoheptanoate Formula (V): Rx = n-butyl, V = Rxo = ethyl g of ethyl 3-oxoheptanoate, prepared in Example 1, are dissolved in 300 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 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 3-oxoheptanoate, giving 41 g of ethyl 2-(2'-cyanobiphenyl-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 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 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)carbox35 amide in the form of crystals melting at 128 °C. These ',': /5¾ r 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 4z-methyl-2-cyanobiphenyl in the form of crystals melting at 45-46 °C.

B) 4 *-Bromomethyl-2-cyanobipheny1 7.9 g of 4z-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 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 4z-bromomethyl-2-cyanobiphenyl in the form of crystals melting at 115-118°C.

Example 7: l-Methyl-3-n-butyl-4-(4-nitrobenzyl)-5hydroxypyrazole Formula (IX): R^ = n-butyl, R2 = CH3, V = NO2 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate, prepared in Example 3, are dissolved in 150 ml of 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 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.

The crystals are filtered off and recrystallized from 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.

Example 8: l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5hydroxypyrazole Formula (IX): R-, = n-propyl, R2 = CH3, V = NO2 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-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = Η, 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-(4nitrobenzyl)-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = CH2CO2Et, 30 V = N02 Prepared by the procedure of Example 7, starting from ethyl hydrazinoacetate.

Crystals melting at 134°C.

Example 11: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4nitrobenzyl)-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = CH2CF3, 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'-methoxycarbonylbiphenyl-4-yl)methyl-5-hydroxypyrazole Formula (IX): Rx = n-butyl, R2 = CH3, CH, 0,C V = Prepared by the procedure of Example 7, start20 ing from the ethyl 2-(2'-methoxycarbonylbiphenyl-4yl)methyl-3-oxoheptanoate prepared in Example 5. Crystals melting at 108°C.

Example 13: l-Methyl-3-n-butyl-4-(2 *-cyanobiphenyl-425 yl)methyl-5-hydroxypyrazole ch3, Prepared by the procedure of Example 7, starting from the ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3oxoheptanoate prepared in Example 6.

Crystals melting at 138°C.

Example 14: Ethyl [l-methyl-3-n-propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2CO2Et, V = NO2 22.4 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl )-5-hydroxypyrazole, prepared in Example 8, are dissolved in 200 ml of acetone, and 8.7 g of sodium 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 dryness. The residue obtained is taken up with isopropyl ether and the resulting crystals are filtered off to give 9 g of ethyl [l-methyl-3-n-propyl-4-(4nitrobenzyl)-5-oxopyrazol-2-yl]acetate melting at 62°C.

The mother liquors are concentrated and the oil 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-5yl]oxyacetate in the form of crystals melting at 60-61°C.

Example 15: Ethyl [1-methy1-3-n-buty1-4-(4-nitrobenzyl )pyrazol-5-yl]oxyacetate Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2CO2Et, V = NO2 Prepared by the procedure of Example 14.

Crystals melting at 68°C. t Example 16: Ethyl [3-n-propyl-4-(4-nitrobenzyl)pyrazol5-y1]oxyacetate Formula (XI): Rx = n-propyl, R2 = H, R3 = CH2CO2Et, V = N02 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 = CH2CO2Me, V = N02 Prepared by the procedure of Example 14. Crystals melting at 58°C.

Example 18: Methyl [1-(2,2,2-trifluoroethyl)-3-n20 propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate Formula (XI): R^ = 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 *-methoxy3 0 carbonylbiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate Formula (XI): Ra = n-butyl, R2 = methyl, R3 = CH CO Et, V = MeO,C 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'-cyanobiphenyl-4-yl)methylpyrazol-5-ylJoxyacetate Formula (XI): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 14.

Oil used as such for the next step.

Example 21: Ethyl [l-methyl-3-n-butyl-4-(4-aminobenzyl)pyrazol-5-yl]oxyacetate Formula (X): Rx = n-butyl, R2 = methyl, A = OR3, R3 = CH2CO2Et, R4 = NH2 3.4 g of ethyl [l-methyl-3-n-butyl-4-(4-nitrobenzyl)pyrazol-5-ylJoxyacetate, 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-aminobenzyl)pyrazol-5-ylJoxyacetate in the form of crystals melting at 65 °C.

Example 22: Ethyl [l-methyl-3-n-propyl-4-(4-aminobenzyl )pyrazol-5-yl ] oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, R3 = CH2CO2Et, R4 nh2 Prepared by the procedure of Example 21. Crystals melting at 103°C.

Example 23: Methyl [l-methyl-3-n-propyl-4-(4-aminobenzy1)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, R3 = CH2CO2Me, R4 NH2 Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 24: Methyl [l-(2,2,2-trifluoroethyl)-3-npropyl-4-(4-aminobenzyl)pyrazol-5-yl]oxy acetate Formula (I): Rx = n-propyl, R2 = CH2CF3, A = 0R3, R3 = CH2C02Me, R4 NH2 Prepared by the procedure of Example 21. Crystals melting at 63°C.

Example 25: l-Ethoxycarbonylmethyl-3-n-propyl-4-(4aminobenzyl)-5-hydroxypyrazole Formula (I): Rx = n-propyl, R2 = CH2CO2Et, A = 0R3, R3 = H, R4 = NH2 Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 26: Ethyl [3-n-propyl-4-(4-aminobenzyl)pyrazol5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = H, A = OR3, R3 = CH2CO2Et, R4 = NH2 Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 27: Ethyl [l-methyl-3-n-butyl-4-(4-(2-carboxy^ 20 benzoylamino)benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-butyl, R2 = methyl, A OR3, R3 = CH2CO2Et, R„ 3 g of ethyl [l-methyl-3-n-butyl-4-(4-aminobenzyl)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 obtained are filtered off, washed with isopropyl ether 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.

The following Examples were prepared by the same procedure: Example 28: Methyl [l-methyl-3-n-propy1-4-(4-(2-carboxybenzoylamino )benzyl)pyrazol-5-yl]oxyacetate Formula (I): Ι\ = n-propyl, R2 = CH3, A 0R3, R3 = CH2CO2Me, = Crystals, in the form of the dicyclohexylamine salt, melting at 173-174’C.

Example 29: Ethyl [l-methyl-3-n-propyl-4-(4-(2-carboxybenzoylamino )benzyl)pyrazol-5-yl]oxyacetate Formula (I): Ra = n-propyl, R2 = CH3, A = OR3, R3 = CH2CO2Et, Crystals melting at 139-140°C.

Example 30: Ethyl [l-methyl-3-n-propyl-4-(4-(2-carboxy 3,6-dichlorobenzoylamino)benzyl)pyrazol-5y1]oxyacetate Formula (I): = n-propyl, R2 = CH3, A = 0R3, R3 = CH2CO2Et, From 3,6-dichlorophthalic anhydride.

Crystals, in the form of the dicyclohexylamine salt, melting at 199-200°c.

Example 31: Methyl [1-methyl-3-n-propy1-4-(4-(2-carboxy- 3,6-dichlorobenzoylamino)benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, R3 = CH2CO2Me, From 3,6-dichlorophthalic anhydride. 30 Crystals melting at 150-151 °C.

Example 32: Methyl [1-(2,2,2-trifluoroethyl)-3-npropyl-4-(4-(2-carboxy-3,6-dichlorobenzoyl amino)benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CO2Me, = From 3,6-dichlorophthalic anhydride.

Crystals melting at 169-170°C.

Example 33: Methyl [1-(2,2,2-trifluoroethyl)-3-npropyl-4-(4-(2-carboxybenzoylamino)benzyl) pyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = CH2CF3, A = 0R3, R3 = CH2CO2Me, = Crystals melting at 189-192°C.

Example 34: [3-n-Propy1-4-(4-(2-carboxybenzoylamino)benzyl)pyrazol-5-yl]oxyacetic acid Formula (I): Rr = n-propyl, R2 = H, A = OR3, R3 = CH2CO2H, 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 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 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 [3-n-propyl-4-(4-(2-carboxybenzoylamino)benzyl)pyrazol5-yl]oxyacetic acid in the form of crystals melting at 170-171°C.

Example 35: [1-Methy1-3-n-propy1-4-[4-(2-sulfobenzoylamino)benzyl]pyrazol-5-y1]oxyacetic acid Formula (I): Rx = or3, n-propyl, R2 R3 = ch2co2h, ch3, a = Prepared by the procedure of Example 34, starting from the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 168-170°C.

Example 36: 4 * -[l-Methyl-3-n-butyl-5-hydroxypyrazol-4yl]methylbiphenyl-2-carboxylic acid Formula (I): Rx = n-butyl, R2 = methyl, A = or3, R3 = H, = HO,C 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 sulfate and then evaporated under vacuum. The residue 91766 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 1.1 g of 4'-[l-methyl-3-n-butyl-505 hydroxypyrazol-4-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 228-30°C.

Example 37: [1-Methyl-3-n-buty1-4-(2 *-carboxybiphenyl4-yl)methylpyrazol-5-yl]oxyacetic acid Formula (I): Rx = n-butyl, R2 = CH3 , A = OR3, R3 = CH2CO2H, 2.6 g of ethyl [l-methyl-3-n-butyl-4-(2'methoxycarbonylbiphenyl-4-yl )methylpyrazol-5-yl ]oxy20 acetate, 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-3n-butyl-4-(2'-carboxybiphenyl-4-yl)methylpyrazol-5yl]oxyacetic acid in the form of crystals melting at 153—154°C.

IE 91766 - 53 Example 38: l-Methyl-3-n-butyl-4-(4-nitrobenzyl)-5methoxycarbonyloxypyrazole Formula (I): Rx = n-butyl, R2 = methyl, A = OR3, R3 = C-OMe, R4 = NO2 o g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5hydroxypyrazole, prepared in Example 7, are dissolved 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 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-(4nitrobenzyl)-5-methoxycarbonyloxypyrazole in the form of crystals melting at 44-47°C.

Example 39: 1-Methyl-3-n-butyl-4-(4-aminobenzyl)-5methoxycarbonyloxypyrazole Formula (XI): Rx = n-butyl, R2 = methyl, R3 = C-OMe, V = NH2 O Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 40: 2-[[l-Methyl-3-n-butyl-5-hydroxypyrazol-4 yl]methylphenyl-4-yl]aminocarbonyl-3,6dichlorobenzoic acid Formula (I): Rx = n-butyl, R2 = methyl, A 0R3, R3 = H, 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-Ethoxycarbonylmethy1-3-n-propy1-5hydroxypyrazol-4-yl]methylphenyl-4-yl]20 aminocarbonyl-3,6-dichlorobenzoic acid Formula (I): R3 = n-propyl, R2 = CH2CO2Et, A = OR3, R3 = H, Prepared by the procedure of Example 27, start ing from 3,6-dichlorophthalic anhydride.

Crystals melting at 150-153°C.

IE 91766 - 55 Example 42: Ethyl [l-ethoxycarbonylmethyl-3-n-propyl-4 (4-nitrobenzyl)pyrazol-5-yl]oxyacetate Formula (XI): = n-propyl, R2 = CH2CO2Et R3 = CH2CO2Et, V = NO2 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 = CH2CO2Et, A = 0R3, R3 = CH2CO2Et, RA = NH2 Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 44: 2-[(l-Ethoxycarbonylmethyl-B-n-propyl-Sethoxycarbonylmethoxypyrazol-^-yl )methylphenyl-4-yl]aminocarbonyl-3,6-dichlorobenzoic acid Formula (I): = n-propyl, R2 = CH2CO2Et, A = OR3, R3 = CH2CO2Et, Prepared by the procedure of Example 27. start 35 ing from 3,6-dichlorophthalic anhydride.

IE 91766 Crystals, in the form of the dicyclohexylamine salt, melting at 189-191°C.

Example 45: 2-[(l-Methyl-3-n-propyl-5-ethoxycarbonyl05 methoxypyrazol-4-yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx A : n-propyl, R2 = methyl, or3, r3 = ch2co2h, O Ra 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 Formula (XI): R-l = n-butyl, R2 = methyl, Prepared by the procedure of Example 14, starting from N-(chloroacetyl)morpholine.

Crystals melting at 98°C.

Preparation of N-(chloroacetyl)morpholine 21.7 g of morpholine are dissolved in 250 ml of 35 methylene chloride and the solution obtained is cooled - 57 IE 91766 with an ice/water mixture. 14.1 g of chloroacetyl chloride are added dropwise with the temperature being kept at O’C, and the mixture is then stirred for 3 hours at room temperature 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 ) morphol ine in the form of an oil of sufficient purity for the next step.

Example 47: N-[[1-Methyl-3-n-butyl-4-(4-aminobenzyl)pyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, A = OR R„ = CH.—C R. = NH2 Prepared by the procedure of Example 21. Crystals melting at 130°C.

Example 48: N-[[l-Methyl-3-n-butyl-4-[4-(2-sulfobenzoylamino)benzyl]pyrazol-5-yl]oxy25 acetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, A = IE 91766 Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 236-237°C.

Example 49: 2-[1-Methy1-3-n-buty1-4-(4-nitrobenzyl)pyrazol-5-ylJoxyethanol Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2CH2OH, V = N02 g of l-methyl-3-n-butyl-4-(4-nitrobenzyl)-5hydroxypyrazole, 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 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 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-[lmethyl-3-n-butyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyethanol 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 = OR3, R3 = CH2CH2OH, R4 = NH2 Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 51: 2-[[l-Methyl-3-n-butyl-5-(2-hydroxyethoxy)pyrazol-4-yl]methylpheny1-4-y1]aminocarbony Ibenzenesu If on ic acid Formula (I): Rx = n-butyl, R2 = methyl, A = 0R3, R3 = CH2CH2OH, Prepared by the procedure of Example 27, but using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 170-171 °C.

Example 52: 1-Methyl-4-(4-nitrobenzyl)-3-n-propy1-5(N,N-dimethylcarbamoy1)oxypyrazole Formula (XI): Rx = n-propyl, R2 = methyl, CH, R3 = C—Ν' , V = NO ΰ NH, g of 1-methyl-4-(4-nitrobenzyl)-3-n-propyl5-hydroxypyrazole, prepared in Example 8, are dissolved in 100 ml of methylene chloride and 5 ml of triethylamine. 3.2 ml of Ν,Ν-dimethylcarbamoyl chloride are added dropwise and the mixture is then refluxed for 10 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-di35 methylcarbamoyl)oxypyrazole in the form of crystals melting at 90°C.

Example 53: 1-Methyl-4-(4-aminobenzyl)-3-n-propyl-5(N,N-dimethylcarbamoyl)oxypyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, R3 R4 = NH2 Prepared by the procedure of Crystals melting at 138°C.

II C-N CH, 'CH, Example 21.

Example 54: 2-[[l-Methyl-3-n-propy1-5-(N,N-dimethylcarbamoyl )oxypyrazol-4-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 210-2°C.

Example 55: l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5(Ν,N-diethylcarbamoyl)oxypyrazole Formula (XI): Rx = n-propyl, R2 = methyl, C,HS , V = no2 ./ r = C—N' Prepared by the procedure of Example 52. Oil used as such for the next step.

Example 56: 1-Methy1-3-n-propy1-4-(4-aminobenzyl)-5(Ν,N-diethylcarbamoyl)oxypyrazole Formula (I): Rx = n-propyl, R2 = methyl, CsH5 A = OR, R3 = C—n' 3 3 ii \ R4 = nh2 C,HS Prepared by the procedure of Example 21. Crystals melting at 100°C.

Example 57: 2-[[l-Methyl-3-n-propyl-5-(Ν,N-diethylcar2 5 bamoyl)oxypyrazol-4-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): R-l = n-propyl, R2 = methyl, A = OR,, R, = N_nz C,H, 'CaH, R = II 4 NH—C.

HOsS 1E91766 - 62 Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 216-217°C.

Example 58; 1—(2,2,2-Trifluoroethyl)—3—n—propyl—5—(N,N— dimethylcarbamoyl)oxy-4-(4-nitrobenzyl)pyrazole Formula (XI): Rx = n-propyl, R2 = CH2CF3, CH, R-. = C—N II x o CH, , V = no2 Prepared by the procedure of Example 52. Crystals melting at 70°C.

Example 59: 1-(2,2,2-Trifluoroethyl) -3-n-propyl-5- (N,Ν'dimethylcarbamoyl )oxy-4-(4-aminobenzyl)pyrazole Formula (I): RT = n-propyl, R2 = CH2CF3, CH, A = OR3, R3 = C—N ch, R4 = NH2 Prepared by the procedure of Example 21. Crystals melting at 82°C.

Example 60: 2-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-5(N,N-dimethylcarbamoyl)oxypyrazol-4-yl]methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 159-161°C.

Example 61: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4nitrobenzyl)-5-(2-hydroxyethoxy)pyrazole Formula (XI): Rx = n-propyl, R2 = CH2CF3, R3 = ch2ch2oh, v = no2 Prepared by the procedure of Example 49.

Crystals melting at 71 °C.

Example 62: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(4aminobenzyl)-5-(2-hydroxyethoxy)pyrazole Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CH2OH, R4 = NH2 Prepared by the procedure of Example 21.

SE 91766^^ - 64 Oil used as such for the next step.

Example 63: 2-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-5(2-hydroxyethoxy)pyrazol-4-yl]methylpheny14-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = CH2CF3, A = 0R3, R3 = CH2CH2OH, Π = 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-[l-methyl-3-n-propyl20 4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetylpiperazine Prepared by the procedure of Example 14, starting 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-chloro35 acetylmorpholine, described in Example 46.

IE 91766 - 65 Example 65: 1-(2-Methoxyphenyl)-4-[l-methyl-3-n-propyl 4-(4-aminobenzyl)pyrazol-5-yl]oxyacetylpiperazine Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 21. Crystals melting at 145°C.

Example 66: l-(2-Methoxyphenyl)-4-[[l-methyl-3-npropy1-4-[4-(2-sulfobenzoylamino)benzyl]pyrazol-5-yl]oxyacetyl]piperazine Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 226-227°C.

Example 67: Ethyl 2-(2*-cyanobiphenyl-4-yl)methyl-3oxohexanoate Formula (V): Rx = n-propyl, V = N R1O = ethyl Prepared by the procedure of Example 6. Oil used as such for the next step.

Example 68: l-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4yl)methyl-5-hydroxypyrazole Formula (IX): Rx = n-propyl, V = NC' R2 = methyl Prepared by the procedure of Example 7 Crystals melting at 164°C.

Example 69: Ethyl [l-methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-ylJoxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 14. Oil used as such for the next step. 5E 91766 - 67 05 Example 70: Ethyl [l-methyl-3-n-propyl-4-[2'-(tetrazol5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, A = OR3, R3 = CH2CO2Et, g of ethyl [l-methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate, prepared 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 give 6.7 g of ethyl [l-methyl-3-n-propyl-4-[2'-(tetrazol-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'-(tet2 5 razol-5-yl)biphenyl-4-yl]methylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, g of l-methyl-3-n-propyl-4-(2'-cyanobiphenyl35 4-yl)methyl-5-hydroxypyrazole, prepared in Example 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 fil05 tered 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'-(tetrazol5-yl)biphenyl-4-yl]methylpyrazole in the form of crystals melting at 150-153°C.

Example 72: l-Methyl-3-n-butyl-5-hydroxy-4-[2'-(tet20 razol-5-yl)biphenyl-4-yl]methylpyrazole Formula (I): Rx = n-butyl, R2 = methyl, N— / Prepared by the procedure of Example 71. Crystals melting at 176-7°C.

IE 91766 - 69 Example 73: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-5hydroxy-4-(2'-cyanobiphenyl-4-yl)methylpyrazole Formula (IX): Rx = n-propyl, R2 = CH2CF3, 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-propy1-515 hydroxy-4-[2 *-(tetrazol-5-y1)bipheny1-4yllmethylpyrazole Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OH, Ra Prepared by the procedure of Example 71. Crystals melting at 218-220°C.

Example 75: 2-[l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl4-yl)methylpyrazol-5-ylJoxyethanol Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH2CH20H, V NC Prepared by the procedure of Example 49.

Oil used as such for the next step.

Example 76: 2-[l-Methyl-3-n-buty1-4-[2 * -(tetrazol-5yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyethanol Formula (I): Rx = n-butyl, R_. = methyl, Prepared by the procedure of Example 70. Crystals melting at 105-8 °C.

Example 77: Ethyl [1-(2,2,2-trifluoroethyl)-3-n-butyl 4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5yl]oxyacetate Formula (XI): = n-butyl, R2 = CH2CF3, R3 = CH2CO2Et, V = Prepared by procedure 14.

Oil used as such for the next step.

Example 78; Ethyl [1-(2,2,2-trifluoroethyl)-3-n-butyl 4—[2 * — (tetrazol-5-yl)biphenyl-4-yl]methyl pyrazol-5-yl]oxyacetate Formula (I): Rx = n-butyl, R2 = CH2CF3, A 0R3, R3 = CH2CO2Et, Prepared by the procedure of Example 70. Crystals melting at 140-1 °C.

Example 79: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2 *cyanobiphenyl-4-yl)methyl-5-(N,N-dimethyl carbamoyl)oxypyrazole Formula (XI): Rx = n-butyl, R2 = CH2CF3, CH, R3 = c—N ΰ CH.

Prepared by the procedure of Example 52. Oil used as such for the next step. Ί2 - Example 80: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2Z(tetrazol-5-yl)biphenyl-4-yl]methy1-5(N,N-dimethylcarbamoyl)oxypyrazole Formula (I): Rx = n-butyl, R2 = CH2CF3, A Prepared by the procedure of Example 70.

Crystals melting at 151-2°C.

Example 81: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4yl)methyl-5-(N,N-dimethylcarbamoyl)oxypyrazole Formula (XI): Rx = R. = n-butyl, R2 CH CII o -N CH, methyl, 00 Prepared by the procedure of Example 52. Oil used as such for the next step.

Example 82: i-Methyl-3-n-butyl-4-[2 * -(tetrazol-5-yl)bi phenyl-4-yl]methyl-5-(N,N-dimethylcarbamoyl)oxypyrazole Formula (I): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 70.

Crystals melting at 160°C.

Example 83: Ethyl [1-(2,2,2-trifluoroethyl)-3-n-propyl 4—(2 *-cyanobiphenyl-4-yl)methylpyrazol-520 yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = CH2CF3, R3 = CH2CO2Et, V = NC' Prepared by the procedure of Example 14. Oil used as such for the next step.

Example 84: Ethyl [1-(2,2,2-trifluoroethyl)-3-n-propyl4-[2 '-(tetrazol-5-yl)biphenyl-4-ylJmethylpyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = CH2CF3, A = 0R3, R3 = CH2CO2Et, Prepared by the procedure of Example 70. Crystals melting at 146°C.

Example 85: l-Methyl-3-n-propyl-4-(2 *-cyanobiphenyl-4yl)methyl-5-(N,N-dimethylcarbamoyl)oxypyrazole Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 52.

Oil used as such for the next step.

Example 86: l-Methyl-3-n-propyl-4-[2 * -(tetrazol-5yl)biphenyl-4-yl]methyl-5-(N,N-dimethylcarbamoy1)oxypyrazole Formula (I): Rx = n-propyl, R2 = methyl, CH, CH, Prepared by the procedure of Example 70. Crystals melting at 103-5°C.

Example 87: 2-[l-Methyl-3-n-propy1-4-(2'-cyanobiphenyl4-yl)methylpyrazol-5-yljoxyethanol Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2CH2OH, V NC Prepared by the procedure of Example 49. Oil used as such for the next step.

Example 88: 2-[l-Methyl-3-n-propyi-4-[2 · - (tetrazol-5yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyethanol Formula (I): R3 = n-propyl, R2 = methyl, Prepared by the procedure of Example 70. Crystals melting at 120-122°C.

Example 89: Ethyl [l-methyl-3-n-butyl-4-(2 ‘-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = n-butyl, R2 R3 = CH2CO2Et, V Prepared by the procedure of Example 14. Oil used as such for the next step.

Example 90: Ethyl [l-methyl-3-n-butyl-4-[2#-(tetrazol -yl)biphenyl-4-yl]methylpyrazol-5-yl)oxyacetate Formula (I): Rx OR R. = n-butyl, R2 = methyl, A Prepared by the procedure of Example 70. Crystals melting at 142-3°C.

Example 91: 2-[1-(2,2,2-Trifluoroethyl)-3-n-propyl-4(2 cyanobiphenyl—4—yl)methylpyrazol—5—yl] oxyethanol Formula (XI): Rx = n-propyl, R2 = CH2CF3, R3 = CH2CH2OH, V NC Prepared by the procedure of Example 49. Oil used as such for the next step.

Example 92: 2-(1-(2,2,2-Trifluorethyl)-3-n-propy1-4(2·-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyethanol Formula (I): Rx = n-propyl, R2 = CH2CF3, a = or3, r3 = ch2ch2oh, Prepared by the procedure of Example 70.

Crystals melting at 167 °C.

Example 93: 1-Methoxyoctane-2,4-dione Formula (III): Rx = n-butyl, R' = CH3, q = 1 200 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 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 acidified 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 b.p.xs = 115—120°C. - 79 Example 94: 1-Methoxyheptane-2,4-dione Formula (III): Rx = n-propyl, R' = CH3, q = 1 Prepared by the procedure of Example 93, starting from pentan-2-one.

Liquid of b.p.2O = 100-110°C.

Example 95: l-Methoxy-3-(4-nitrobenzyl)heptane-2,4dione Formula (VI): Rx = n-propyl, Rz = CH3, V = N02, q = 1 135 g of 1-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 Ν,Ν-diisopropylethylamine and 49.5 g of lithium 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 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 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: Example 96: l-Methoxy-3-(2'-cyanobiphenyl-4-yl)methylheptane-2,4-dione Formula (VI): Rx = n-propyl, R' = CH3, V , q = i Oil used as such for the next step.

Example 97: l-Methoxy-3-(2'-cyanobiphenyl-4-yl)methy1octane-2,4-dione Formula (VI): Rx = n-butyl, R' NC V = CH3, Oil used as such for the next step.

Example 98: 3-n-Propyl-4-(4-nitrobenzyl)-5-methoxymethylpyrazole Formula (XIII): Rx = n-propyl, R' = CH3, 25 q = 1, V = N02 g of 3-(4-nitrobenzyl)-1-methoxyheptane—2,4dione, prepared in Example 95, are dissolved in 400 ml of ethanol, 4 ml of hydrazine hydrate are added and the 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-npropyl-5-methoxymethylpyrazole in the form of crystals melting at 124°C.

The following two Examples were prepared by the same procedure: Example 99: 3-n-Propyl-4-(2'-cyanobiphenyl-4-yl)methyl05 5-methoxymethylpyrazole Formula (XIII): Rx = n-propyl, R' = CH3, , q = i Oil used as such for the next step.

Example 100: 3-n-Butyl-4-(2#-cyanobiphenyl-4-yl)methyl15 5-methoxymethylpyrazole Formula (XIII): Rx = n-butyl, R' = CH3, v = , q = 1 Oil used as such for the next step.

Example 101: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2# cyanobiphenyl-4-yl)methyl-5-methoxymethylpyrazole Formula (XII): Rx = n-butyl, R2 = CH2CF3, Prepared by the procedure of Example 98, starting from 2,2,2-trifluoroethylhydrazine. , - 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.

Example 102: l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5methoxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = methyl, 10 R' = methyl, V = NO2, q = 1 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 iodide and 3 ml of DBU (1,8-diazabicyclo[5.4.0]undec-7ene). 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 mag20 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-methoxymethylpyrazole in the form of crystals melting at 73°C.

The following two Examples were prepared by the procedure of Example 102: Example 103: l-Methyl-3-n-propyl-4-(2*-cyanobiphenyl4-yl)methyl-5-methoxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = methyl, Oil used as such for the next step.

R' = methyl, V = Example 104: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl4-yl)methyl-5-methoxymethylpyrazole Formula (XII): Rx = n-butyl, R2 = methyl, R' = methyl, V = q = 1 Oil used as such for the next step.

Example 105: l-Methyl-3-n-propyl-4-(4-aminobenzyl)-5methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = CH2OCH3, R4 = NH2 Prepared by the procedure of Example 21, Oil used as such for the next step.

IE 91?66 Example 106: 3-n-Propyl-4-(4-aminobenzyl)-5-methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = CH2OCH3, R4 = NH2 Prepared by the procedure of Example 21. Crystals melting at 126°C.

Example 107: 2-[(1-Methyl-3-n-propy1-5-methoxymethylpyrazol-4-yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx A Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 126°C.

Example 108: 2-[(3-n-Propyl-5-methoxymethylpyrazol-4yl)methylphenyl-4-yl]aminocarbonylbenzenesulfonic acid Formula (I): Rx = n-propyl, R2 — H, A = ΙΕ 91766 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)-5bromomethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = CH2Br, R4 = NO2 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 g of 1-methyl-3-n-propy1-4-(4-nitrobenzyl)-5-bromomethylpyrazole in the form of an oil, which is used as such for the next step.

Example 110: 3-n-Propyl-4-(4-nitrobenzyl)-5-bromo25 methylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = CH2Br, R4 = N02 Prepared by the procedure of Example 109.

Crystals melting at 120°C. - 86 IE Example 111: l-Methyl-3-n-propyl-4-(4-nitrobenzyl)-5hydroxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = methyl, Rz = Η, V = N02, 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 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 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.

Example 112: 3-n-Propyl-4-(4-nitrobenzyl)-5-hydroxymethylpyrazole Formula (XIII): Rx = n-propyl, Rz = H, V = N02, q = 1 Prepared by the procedure of Example 111. Crystals melting at 125 °C.

Example 113: l-Methyl-3-n-propyl-4-(4-aminobenzyl)-530 hydroxymethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, a = ch2oh, r4 = nh2 Prepared by the procedure of Example 21.

Crystals melting at 13 3 °C.

Example 114: 3-n-Propyl-4-(4-aminobenzyl)-5-hydroxymethylpyrazole Formula (I): Rx = n-propyl, R2 = H, A = ch2oh, r4 = nh2 Prepared by the procedure of Example 21. 10 Oil used as such for the next step.

Example 115: 2-[(1-Methyl-3-n-propyl-5-hydroxymethylpyrazol-4-yl)methyIpheny1-4-yl]aminocarbony Ibenzenesulfonic acid Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Crystals melting at 255-257°C.

Example 116: 2-[(3-n-Propyl-5-hydroxymethylpyrazol-4yl)methylphenyl-4-yl]aminocarbonyIbenzenesulfonic acid Formula (I): Rx n-propyl, R2 = H, A = CH20H, R4 IE 9 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-5yl)biphenyl-4-yl]methyl-5-methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 71. Crystals melting at 128-130°C.

Example 118: l-Methyl-3-n-butyl-4-[2'-(tetrazol-5-yl)20 biphenyl-4-yl]methy1-5-methoxymethylpyrazole Formula (I): Rx = n-butyl, R2 A = CH2OCH3, Rd Prepared by the procedure of Example 71. Crystals melting at 134-135°C.

Example 119: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2 (tetrazol-5-yl)biphenyl-4-yl]methyl-5methoxymethylpyrazole Formula (I): Rx = n-butyl, R2 = CH2CF3, A = CH20CH3, R„ = | N-s' / Prepared by the procedure of Example 71. Crystals melting at 172-173°C.

Example 120: Ethyl 3-oxo-5-methylhexanoate Formula (II): Rx = 2-methylpropyl, Rxo ethyl 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 = ethyl, V Prepared by the procedure of Example 6. Oil used as such for the next step.

IE 91766 Example 122: 1-Methyl-3-(2-methylpropyl)-4-(2'-cyano biphenyl-4-yl)methyl-5-hydroxypyrazole Formula (IX): Rx = 2-methylpropyl, R2 = methyl, V NC Prepared by the procedure of Example 7. Crystals melting at 163 °C.

Example 123: 1-(2,2,2-Trifluoroethyl)-3-(2-methylpropyl)-4-(2'-cyanobiphenyl-4-yl)methyl -hydroxypyrazole Formula (IX): = 2-methylpropyl, R2 = CH2CF3, V 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 25 cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = 2-methylpropyl, R2 = methyl, R3 = CH2CO2Et, Prepared by the procedure of Example 14. 35 Oil used as such for the next step.

Example 125: Ethyl [1-methy1-3-(2-methylpropyl)-4-[2 (tetrazol-5-yl)biphenyl-4-yl]methylpyra zol-5-yl]oxyacetate Formula (I): Rx = 2-methylpropyl, R2 = methyl, A = OR3, R3 = CH2CO2Et, Prepared by the procedure of Example 70.

Crystals melting at 172-173°C.

Example 126: Ethyl [1-(2,2,2-trifluoroethyl)-3-(2methylpropyl)-4-(2'-cyanobiphenyl-4-yl) methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = 2-methylpropyl, R2 = CH2CF3, R3 = CH2CO2Et, Prepared by the procedure of Example 14. Oil used as such for the next step.

Example 127: Ethyl [1-(2,2,2-trifluoroethyl)-3-(2methylpropyl)-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetate Formula (I): Rx = 2-raethylpropyl, R2 = CH2CO2Et, R4 Prepared by the procedure of Example 70. Crystals melting at 114-115°C.

Example 128: 2-[1-(2,2,2-Trifluoroethyl),-3-(2-methylpropyl)-4-(2 *-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyethanol Formula (XI): Rx = 2-methylpropyl, R2 = ch2cf3, r3 = ch2ch2oh, Prepared by the procedure of Example 49. Crystals melting at 116°C.

Example 129: 2-(1-(2,2,2-Trifluoroethyl)-3-(2-methyl propyl)-4-(2e-(tetrazol-5-yl)biphenyl-4 yl]methylpyrazol-5-y1]oxyethanol Formula (I) Rx = 2-methylpropyl, R2 = CH2CF3, A = 0R3, R3 = Prepared by the procedure of Example 70. Crystals melting at 145-146°C.

Example 130: N-[[l-Methyl-3-n-butyl-4-[4-(2-trifluoromethylsulfonylaminobenzoyl)aminobenzyl]pyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, 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 IE 91766 chloride (prepared according to the references CA : 9£(13) : 103651Z 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 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 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-(2trifluoromethylsulfonylaminobenzoyl)aminobenzyl]pyra15 zol-5-ylJoxyacetylJmorpholine in the form of crystals melting at 190°C.

Example 131: Ethyl 2-( 2 '-nitrobiphenyl-4-yl)methyl-3oxohexanoate 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 chloromethylating 2-nitrobiphenyl according to the following references: - CA 70(25) : 114837d, and - CA 69(2) : 3704t.

Example 132: l-Methyl-3-n-propyl-4-(2 ·-nitrobiphenyl4-yl)methyl-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 7. 10 Crystals melting at 179-182°C.

Example 133: Methyl [l-methyl-3-n-propyl-4-(2'-nitrobi phenyl-4-yl)methylpyrazol-5-yl]oxyacetate Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2CO2Me, 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)methylpyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, 30 A = 0R3, R3 - CH2CO2Me, Prepared by the procedure of Example 21.

Oil used as such for the next step.

Example 135; Methyl [l-methyl-3-n-propyl-4-(2'-trifluoromethylsulfonylaminobiphenyl-4-yl)05 methyIpyrazol-5-yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, g of methyl [l-methyl-3-n-propyl-4-(2/-aminobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetate, prepared in Example 134, is dissolved in 30 ml of chloroform in the presence of 0.4 ml of triethylamine; the mixture is cooled to O’C and 0.43 ml of trif luoromethanesulfonic anhydride is added dropwise. The mixture is then stirred for one hour at room temperature and the organic 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'-trifluoromethylsulfonylaminobiphenyl-4-y1)methylpyrazol-5-y1]oxyacetate in the form of crystals melting at 114-116 °C.

Example 136: 2-[l-Methyl-3-m-propyl-4-(2'-carbethoxybiphenyl-4-yl)methylpyrazol-5-yl]oxyethanol Formula (XI): Rx = n-propyl, R2 = methyl, R3 = CH2CH2OH, v= ΥΊ EtOjC Prepared by the procedure of Example 49. Oil used as such for the next step.

Example 137: 2-[i-Methyl-3-n-propyl-4-(2'-carboxy05 biphenyl-4-yl)methylpyrazol-5-yl]oxyethanol Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 37. Crystals melting at 168-170°C.

Example 138: Ethyl 2-[4-(2-cyanothien-3-yl)benzyl]-3oxohexanoate Formula (V): Rx = n-propyl, R1O = ethyl, Prepared by the procedure of Example 6, starting from 4-(2-cyanothien-3-yl)benzyl bromide.

Preparation of 4-(2-cyanothien-3-yl)benzyl bromide A) 3-(4-Methylphenyl)thiophene-2-carboxylic acid g of ethyl 3-(4-methylphenyl)thiophene-2carboxylate, prepared according to the reference FISSELMANN H.; HABITCH H. ; Ger. Offen. 1,092,929 (1960), CA : 57, 5894g, are dissolved in 580 ml of ethanol and 50 ml of water. 6.2 g of sodium hydroxide 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-methyl05 phenyl) thiophene-2-carboxylic acid in the form of crystals melting at 172°C.

B) 3-(4-Methylphenyl)thiophene-2-carboxamide .7 g of 3-(4-methylphenyl)thiophene-2-car10 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 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.

C) 3-(4-Methylphenyl)thiophene-2-carbonitrile g of 3-(4-methylphenyl)thiophene-2-carboxamide, prepared in B), are dissolved in 36 ml of phosphorus oxychloride and the mixture is refluxed for 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-230 carbonitrile in the form of an oil, which is used as such for the next step.

D) 4-(2-Cyanothien-3-yl)benzyl bromide g of 3-(4-methylphenyl)thiophene-2-carbo35 nitrile, prepared in C), are dissolved in 100 ml of 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 solvent is concentrated under vacuum to give 16 g of 4-(2cyanothien-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-cyanothien3-yl)benzyl]-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 7. Crystals melting at 110-115°C.

Example 140: Ethyl [l-methyl-3-n-propyl-4-[4-(2-cyanothien-3-yl)benzyl]pyrazol-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. 100 Example 141: Ethyl [l-methyl-3-n-propyl-4-[4-[2-(tetrazol-5-yl)thien-3-ylJbenzyl)pyrazol-5yl]oxyacetate Formula (I): Rx = n-propyl, R2 = methyl, 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, Rxo = ethyl, V = EtO2C b Prepared by the procedure of Example 6, starting 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 43.4 g of ethyl 3-(4-methylphenyl)thiophene-2carboxylate, prepared according to the reference FISSELMANN H.,' HABITCH; Ger. Offen. 1,092,929 (I960); CA : 57. 5894g, are dissolved in 250: ml of carbon tetrachloride. 33 g of N-bromosuccinimide and 10 mg of benzoyl peroxide are added, the mixture is refluxed for 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.

Example 143: l-Methyl-3-n-propyT-4-[4-(2-carbethoxythien-3-yl)benzyl]-5-hydroxypyrazole Formula (IX): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 7.

Crystals melting at 130-132°C.

Example 144: 2-[l-Methyl-3-n-propyl-4-[4-(2-carbethoxythien-3-yl)benzyl]pyrazol-5-yl]oxyethanol Formula (XI): Rx = n-propyl, R2 = methyl, r3 = ch2ch2oh, v= Vi Prepared by the procedure of Example 49.

Oil used as such for the next step.

Example 145: 2-[l-Methyl-3-n-propyl-4-[4-(2-carboxy3 0 thien-3-yl)benzyl]pyrazol-5-yl]oxyethanol Formula (I): Rx = n-propyl, R2 = methyl, a = or3, r3 = ch2ch2oh, ll HO,C 102 Prepared by the procedure of Example 37. Crystals melting at 118-120°C.

Example 146: 1-(2-Methoxyphenyl)-4-[1-(2,2,2-trifluoro ethyl)-3-n-propyl-4-(2 '-cyanobiphenyl-4yl)methylpyrazol-5-yl]oxyacetylpiperazine Formula (XI): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 64. Oil used as such for the next step.

Example 147: 1-(2-Methoxyphenyl)-4-(1-(2,2,2-trifluoro ethyl)-3-n-propyl-4-[2·-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetylpiperaz ine Formula (I): Rx = n-propyl, R2 = CH2CF3, 103 Prepared by the procedure of Example 70. Crystals melting at 158-160°C.

Example 148: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl05 4-(2z-cyanobiphenyl-4-yl)methylpyrazol-5yl]oxyacetyl]morpholine Formula (XI): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 46. Oil used as such for the next step.

Example 149: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl20 4—[2 z — (tetrazol-5-yl)bipheny1-4-yl]methylpyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-propyl, R2 = CH2CF3, A = OR3, Prepared by the procedure of Example 70.

Crystals melting at 129-31°C. 104 Example 150: 1-(2,2,2-Trifluoroethyl)-3-n-butyl-5hydroxy-4-[2'-(tetrazol-5-yl)biphenyl-4yl]methylpyrazole Formula (I): Rx = n-butyl, R2 = CH2CF3, Prepared by the procedure of Example 71. Crystals melting at 210-11°C.

Example 151: l-Methyl-3-n-buty1-4-(2’-cyanobipheny1-4yl)methyl-5-bromomethylpyrazole Formula (I): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 109, starting from the 1-methy1-3-n-butyl-4-(2'-cyanobi25 phenyl-4-yl)methyl-5-methoxymethylpyrazole prepared in Example 104.

Oil used as such for the next step. 105 Example 152: l-Methyl-3-n-butyl-4-(2 *-cyanobiphenyl-4 y1)methyl-5-hydroxymethy1pyrazole Formula (XII): Rx = n-butyl, R2 = methyl R' = Η, V = q = 1 Prepared by the procedure of Example ill.

Oil used as such for the next step.

Example 153: l-Methyl-3-n-butyl-4-[2'-(tetrazol-5yl)biphenyl-4-yl]methy1-5-hydroxymethy115 pyrazole Prepared by the procedure of Example 71. Crystals melting at 110-12°C.

Example 154: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4 yl)methyl-5-formylpyrazole Formula (I) Rx = n-butyl, A = CHO, R4 = 2.3 g of 2-nitropropane are dissolved in SE 91766 - 106 solution of sodium methylate prepared from 0.7 g of sodium and 40 ml of methanol. 10 g of l-methyl-3-nbutyl-4-(2·-cyanobiphenyl-4-yl)methyl-5-bromomethylpyrazole, prepared in Example 151, are dissolved in 30 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 residue obtained is chromatographed on silica gel to give 4.3 g of l-methyl-3-n-butyl-4-(2z-cyanobiphenyl-4yl)methyl-5-formylpyrazole in the form of an oil, which is used as such for the next step.

Example 155: l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl4-yl)methyl-5-(dioxolan-2-yl)pyrazole Formula (I): Rx = n-butyl, R2 = methyl, 4.3 g of l-methyl-3-n-butyl-4-(2'-cyanobiphenyl-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 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 eva35 porated under vacuum to give 4 g of l-methyl-3-n-butyl1 107 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.

Example 156; l-Methyl-3-n-butyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl-5-(dioxolan-2-yl)pyrazole Formula (I): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 70.

Crystals melting at 144-6°C.

Example 157: 2-[1-(2,2,2-Trifluoroethyl)-3-n-buty1-4(2'-cyanobiphenyl-4-yl)methylpyrazol-5yl]oxyethanol Formula (XI): Rx = n-butyl, R2 = CH2CF3, R3 = CH2CH2OH, Prepared by the procedure of Example 49.

Oil used as such for the next step. 108 Example 158: 2-[1-(2,2,2-Trifluoroethyl)-3-n-butyl-4[2'—(tetrazol—5—yl)biphenyl—4—yl]methylpyrazol-5-yl]oxyethanol Formula (I): Rx = n-butyl, R2 = CH2CF3, 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, R1O = ethyl, 1.1 g of ethyl 3-oxoheptanoate, prepared in Example 1, 1.2 g of 4-(3-cyanothien-2-yl)benzyl bromide, 0.6 g of lithium bromide and 2.2 ml of diisopropylethylamine are added to 15 ml of tetrahydrofuran. The mixture is stirred under reflux for 20 hours, taken up with water and extracted with ether. The organic 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-(3cyanothien-2-yl)benzyl]heptanoate are obtained in the form of an oil, which is used as such for the next step. 109 Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'-Methyl-4-chlorobutyrophenone 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 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.

B) a-Chloro-β-(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 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 bi25 carbonate, dried over sodium sulfate and evaporated under vacuum to give 133.8 g of a-chloro-B-(2-chloroethyl )cinnamaldehyde in the form of an oil, which is used as such for the next step.

C) 2-(4-Methylphenyl)-4,5-dihydrothiophene-3-carboxaldehyde .9 g of a-chloro-B-(2-chloroethyl)cinnamaldehyde, prepared in B), and 22 g of sodium sulfide (9H20) are added to 200 ml of THF. A sufficient amount of water is added for all the sodium sulfide to pass 110 Έ91766 I 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 vacuum to give 13.5 g of 2-(4-methylphenyl)-4,5-dihydrothiophene-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 g of 2-(4-methylphenyl)-4,5-dihydrothiophene-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 mix15 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 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, 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-dihydrothiophene in the form of an oil, which is used as such 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 of carbon tetrachloride, the mixture is heated to the Ill 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: l-Methyl-3-n-butyl-4-[4-(3-cyanothien-2yl)benzyl]-5-hydroxypyrazole Formula (IX): Rx = n-butyl, R2 = methyl, 112 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 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 of l-methyl-3-n-buty1-4-[4-(3-cyanothien-2-yl)benzyl]5-hydroxypyrazole in the form of crystals melting at 120°C.

Example 161: 1-Methyl-3-n-propyl-4-(2 ·-cyanobiphenyl15 4-yl)methyl-5-(Ν,N-diethylcarbamoyl)oxypyrazole Formula (IX): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 52. Oil used as such for the next step. 113 IE 91766 Example 162: 1-Methyl-3-n-propyl-4-[ 2' - (tetrazol-5-yl) biphenyl-4-yl]methyl-5-(N,N-diethylcarbamoyl)oxypyrazole Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, zc2h5 r3 Prepared by the procedure of Example 70. Crystals melting at 134-135°C.

Example 163: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl20 4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5yl]oxyacetyl]thiomorpholine Formula (XI): Rx = n-propyl, R2 = CH2CF3, R3 = CHjCO N S , NC Prepared by the procedure of Example 46, starting from N-(chloroacetyl)thiomorpholine.

Oil used as such for the next step. 114 Example 164: N-[[l-(2,2,2-Trifluoroethyl)-3-n-propyl4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl pyrazol-5-yl]oxyacetyl]thiomorpholine Formula (I): Rx = n-propyl, R2 = CH2CF3, A = 0R3, Prepared by the procedure of Example 70. Crystals melting at 127-128°C.

Example 165: 1-(2-Methoxyphenyl)-4-[l-methyl-3-n20 propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetylpiperazine Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 64. Oil used as such for the next step. 115 Example 166: 1-(2-Methoxyphenyl)-4-[l-methyl-3-npropyl-4-[2'-(tetrazol-5-yl)biphenyl-4yl]methylpyrazol-5-yl]oxyacetylpiperazine Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 70. Crystals melting at 139-141 °C.

Example 167: 3-n-Propyl-l-methyl-4-(2’-cyanobiphenyl4-yl)methyl-5-(2-dimethylaminoethoxy)pyrazole Formula (XI): Rx = n-propyl, R2 = methyl, g of 3-n-propyl-l-methyl-4-(2'-cyanobiphenyl-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 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 then evaporated under vacuum. The residue is chromatographed on silica gel in a chloroform/methanol eluent (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 for the next step.

Example 168: 3-n-Propyl-l-methyl-4-[ 2' - (tetrazol-5yl)biphenyl-4-yl]methyl-5-(2-dimethylaminoethoxy )pyrazole Formula (I): Rx = n-propyl, R2 = methyl A = or3, CH.

Prepared by the procedure of Example 70. Crystals melting at 88-90°C. 117 Example 169: N-[2-[l-Methyl-3-n-propyl-4-(2 '-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyethyl]morpholine Formula (XI): Rx r3 n-propyl, R2 = methyl, /~y CH,CH2 N 0 NC Prepared by the procedure of Example 167, starting from N-(2-chloroethyl)morpholine.

Oil used as such for the next step.

Example 170: N-[2-[l-Methyl-3-n-propyl-4-[2'-(tetrazol* -yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyethyl]morpholine Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, R3 = CH,CH2 N O , Prepared by the procedure of Example 70, Crystals melting at 132-134°C. 118 Example 171: 1-(2,2,2-Trifluoroethyl)-3-n-buty1-4-(2 * — cyanobiphenyl-4-yl)methyl-5-hydroxymethylpyrazole Formula (XII): Rx = n-butyl, R2 = CH2CF3, R·' = H, Prepared by the procedure of Example 111, starting from the 1-(2,2,2-trifluoroethyl)-3-n-butyl-4(2·-cyanobiphenyl-4-y1)methyl-5-bromomethylpyrazole prepared by the procedure of Example 109.

Oil used as such for the next step.

Example 172: 1-(2,2,2-Trifluoroethyl)-3-n-buty1-4-(2 ' (tetrazol-5-yl)biphenyl-4-yl]methyl-5hydroxymethylpyrazole Formula (I): Rx = n-butyl, R2 = CH2CF3, Prepared by the procedure of Example 71. 30 Crystals melting at 114-117°C. 119 Example 173: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-(2'cyanobiphenyl-4-yl)methyl-5-methoxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = CH2CF3, io 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-5methoxymethylpyrazole Formula (I): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 71.

Crystals melting at 177-178°C. 120 Example 175: N-[[l-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetyl]morpholine Formula (XI): Rx = n-butyl, R2 = methyl, R3 = CH,CO N Ο , v= NC' Prepared by the procedure of Example 46 Oil used as such for the next step.

Example 176: N-[[1-Methy1-3-n-propy1-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetyl]morpholine Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 46. Oil used as such for the next step. 121 Example 177: Ν-[[l-Methyl-3-n-butyl-4-[2'-(tetrazol-5yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 70. Crystals melting at 140-141°C.

Example 178: N-[[l-Methyl-3-n-propyl-4-[2 * - (tetrazol-520 yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rx = n-propyl, R2 = methyl, A = 0R3, R_ = CHjCO Ν O , R.

Prepared by the procedure of Example 70. Crystals melting at 106-110°C. 122 Example 179: 1-(2,2,2-Trifluoroethyl)-3-n-propy1-4-(2'cyanobiphenyl-4-yl)methyl-5-hydroxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 111, starting from the 1-(2,2,2-trifluoroethyl)-3-n-propyl4-(2'-cyanobiphenyl-4-yl)methyl-5-bromomethylpyrazole prepared by the procedure of Example 109.

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-5hydroxymethylpyrazole Formula (I): Rx = n-propyl, R2 = CH2CF3, Prepared by the procedure of Example 71. 30 Crystals melting at 110-2°C. 123 Example 181: l-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4yl)methy1-5-hydroxymethylpyrazole Formula (XII): Rx = n-propyl, R2 = methyl, 05 Rz = Η, V = q = 1 Prepared by the procedure of Example 111.

Oil used as such for the next step.

Example 182: l-Methyl-3-n-propyl-4-[2'-(tetrazol-5-yl)bipheny1-4-yl]methyl-5-hydroxymethy115 pyrazole Formula (I): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 71. Crystals melting at 136-9 °C. 124 Example 183: 1-(2-Methoxyphenyl)-4-[l-methyl-3-n-butyl4—(2#-cyanobiphenyl-4-yl)methylpyrazol-5yl]oxyacetylpiperazine Formula (XI): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 64. Oil used as such for the next step.

Example 184: 1-(2-Methoxyphenyl)-4-[l-methyl-3-n-butyl4-[2 * -(tetrazol-5-yl)biphenyl-4-yljmethylpyrazol-5-yl]oxyacetylpiperazine Formula (I): Rx = n-butyl, R2 = methyl, Prepared by the procedure of Example 70. Crystals melting at 153-5°C. 125 Example 185: N-[[l-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl]oxyacetyl] thiomorpholine Formula (XI): Rx = n-propyl, R2 = methyl, Prepared by the procedure of Example 46, start ing from N-(chloroacetyl)thiomorpholine. oil used as such for the next step.

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, Prepared by the procedure of Example 70. Crystals melting at 140-1 °C. - 126 TABLE Example 27 TO Example 28 Example 30 Example 29 N-N ZCH3 UP 221-6 UP 221-11 Cl .CH.

UP 221-1 UP 221-13 Example 31 N—N UP 221-12 Cl 127 UP 221-7 ζ Example 32 Example 33 N-N -CF, Cl Cl UP 221-4 Example 34 'COOH N—NH OCH, CO, H UP 221-16 Example 35 CH, OCH,CO,H UP 221-14 Example 36 30 UP 221-15 128 Example 37 Example 40 Example 41 Example 44 Example 45 30 UP 221-17 UP 221-18 UP 221-19 UP 221-20 UP 221-21 129 Example 48 Example 51 Example 54 Example 57 Example 60 UP 221-22 UP 221-23 UP 221-27 UP 221-28 UP 221-30 - 130 z- CF, N-N Example 63 Example 66 Example 70 Example 71 Example 72 /- CF, N-N Example 74 io Example 76 Example 78 Example 80 UP 221-56 UP 221-57 UP 221-54 UP 221-55 Example 82 CH, CH, /—CF, UP 221-51 ίο Example 84 Example 86 Example 88 N—N UP 221-44 UP 221-45 UP 221-46 - 133 IE 91766 Example 90 io Example 92 Example 107 Example 108 Example 115 UP 221-47 UP 221-50 UP 221-38 UP 221-36 UP 221-42 (Pht - 134 UP 221-40 n-n-h Example 116 Example 117 io Example 118 Example 119 Example 125 UP 221-48 UP 221-52 UP 221-53 UP 221-58 - 135 y—CF, Example 135 30 UP 221-26 ZCH’ N-N Example 141 Example 145 Example 147 - 137 05 Example 156 Example 149 Example 150 Example 153 UP 221-63 UP 221-64 UP 221-65 UP 221-66 138 ^CF, N-N Example Example Example Example UP 221-67 UP 221-68 UP 221-69 UP 221-70 139 Example 168 05 Example 170 Example 172 Example 174 UP 221-71 UP 221-72 UP 221-73 UP 221-74 140 05 Example 177 Example 178 UP 221-76 UP 221-77 Example 182 Example 180 UP 221-78 UP 221-79 141 142 PHARMACOLOGY I. Principle 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.

II. Procedure An aliquot of a rat adrenal gland homogenate incubates in the presence of a single concentration of [125I]-SIAII (Sar1,Tyrd,Iles-angiotensin II), which is an angiotensin II receptor antagonist, and two concentrations of competing agents (10_s Μ, 10--7 M) for 60 min at 25°C.

The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper filters. The non-specific binding is determined in the presence of angiotensin II.

Ill. Expression of the results The results are expressed, for the concentrations tested, as the percentage displacement of the radioligand specifically bound to the adrenal angiotensin II receptors. 143 IV. Results Product of Example % displacement of the labeled ligand IE-5 M IE-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 0 144 TOXICOLOGY The products of the Examples described have an excellent tolerance after oral administration.

Their 50% lethal dose in rats was found to be greater than 300 mg/kg.

CONCLUSION 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 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.

Claims (21)

WHAT IS CLAIMED IS:

1. A pyrazole derivative of the general formula Formula (I) in which: R x is a lower alkyl radical having 1 to 6 carbon atoms, a lower alkenyl radical having 2 to 6 carbon atoms or a C 3 -C v cycloalkyl radical; R 2 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 C 3 -C v cycloalkyl radical, a group -(CH 2 ) m -COOR 5 , a group -CH 2 -(CH 2 ) m -OR R or a group -CH 2 -(CH 2 ) m -S-R s , m being an integer from 0 to 5 and R s being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms; A can be a group: -(CH 2 ) ta OR / , R z being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C 3 -C, z cycloalkyl radical and q being an integer from 1 to 5, -(CH 2 ) L, L being a halogen atom, preferably chlorine or bromine, and q being as defined above, -CHO, an acetal or a dioxolan, -COOR Z , R z being as defined above, -CONR ZZ R ZZZ , R z ' and R zzz independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon 146 Satoms or a C 3 -C 7 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, -(CH 2 ) -CN, q being as defined above, -(CH 2 ) q -COOR z , R z and q being as defined above, -(CH 2 )^CONR z Z R Z ' ' , R, R zzz and q being as defined above, R zz , R z z z and q being as defined above, or -0R 3 , R 3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C 3 -C v cycloalkyl radical, a group -(CH 2 )„-COOR 6 , a group -(CH 2 )-(CH 2 )„-CN, a group -CH 2 -(CH 2 ) ri -O-R e , a group -CH 2 -(CH 2 )„-S-R 6 or a group -CO-R 6 , n being an integer from 0 to 5 and R 6 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R 3 can be a group -(CH 2 ) E> -CONR v R a or - (CH 2 ) p -CH 2 -CH 2 NR 7 ,R e , p being an integer from 0 to 5 and R v and R s independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C 3 -C v 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 R 4 can be a nitro or amino group or a group -COORg, R g being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R 4 can be the following radicals: - 147 - Y in which R g 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: R x is a lower alkyl radical having 1 to 6 carbon atoms which is preferably selected from n-propyl, n-butyl and 2-methylpropyl; R 2 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- 148 ferably 2,2,2-trifluoroethyl, or a group -(CH 2 ) m -COOR 5 , m and R s being as defined in claim 1, preferably a group CH 2 -COOEt; A is a group: -(CH 2 ) <3 OR / , 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 1 to 5, preferably equal to 1, -(CH a )^L, L and q being as defined in claim 1, preferably -CH 2 Br, -CHO, an acetyl or a dioxolan, or -0R 3 , R 3 being selected from a hydrogen atom, a group -(CH 2 )„-COOR 6 or -CH 2 -(CH 2 ) n -OR e , n being an integer from 0 to 5, preferably equal to 0 or 1, and R s being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, or a group -(CH 2 ) p -CONR v R s , p being an integer from 0 to 5, preferably equal to 0 or 1, and R 7 and R e independently being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, or R v and Rg, taken together with the nitrogen atom to which they are attached, forming a heterocycle which is preferably selected from morpholine, piperazine and 1-(2methoxyphenyl)piperazine; and R 4 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 R x is a group selected from n-butyl and n-propyl.

4. A derivative according to any one of claims 1 to 3, wherein R 2 is a group selected from methyl and 2,2,2trifluoroethyl.

5. A derivative according to any one of claims 1 to 4, wherein A is a group selected from ethoxycarbonylmethyleneoxy, dimethylaminocarbonyloxy, methoxymethy- CSjJ -ito. . ./ § £' Ob 149 lene and 2-hydroxyethoxy.

6. A derivative according to any one of claims 1 to 5, wherein R 4 is a group selected from 2-carboxy-3,6-dichlorobenzoylamino, 2-sulfobenzoylamino and 2-(tetrazol-5-yl)phenyl.

7. A derivative according to claim 1 which is selected from the derivatives of the formulae « COOC/I, 151 8. -10 or 18.

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 H 2 N-NH-R 2 , R 2 being as defined above, with a keto-ester of formula (V) or a diketone of formula (VI): (. R> 3 COOR 10 0 0 R ^XCHJq—OR* I I V z 1 1 Formula (V) Formula (VI) in which R x , R / and q are as defined above, R 1O is lower alkyl, preferably ethyl or methyl, and Visa functional group selected from N0 2 ; COOR X1 , R lx being a lower alkyl radical or benzyl; r 12 ooc R 12 being a lower alkyl radical or benzyl; R 12 being as defined above; and R 12 OOC 152 R 12 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-R 2 , in which R 2 is as defined above and Z is a bromine, chlorine or iodine atom.

9. A method according to claim 8, wherein the ketoester of formula (V) mentioned above is obtained: - by benzylation of an alkyl 3-oxoalkanoate of formula (II): Formula (II) in which R x and R iO are as defined above, with a compound of formula (IV): 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): 153 Formula (VII) in which V is as defined above, with said alkyl 3oxoalkanoate 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,—C—CH,—C—(CHJ n —O—R‘ II II q 0 O Formula (III) in which R x , R z and q are as defined above, with a compound of formula (IV): 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 Formula (VII) in which V is as defined above, with said 1,3-diketone of formula (III), followed by catalytic hydrogenation, ll.

11. A synthesis intermediate for the preparation of the 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 (V) or (VI): Formula (VI) Formula (V) in which R x , R 1O , V, q and R' are as defined above.

12. A synthesis intermediate for the preparation of derivatives of formula (I) accordinq to any one of claims 1 to 7, useful especially for carryinq out the method accordinq to claim 8, said intermediate havinq formula (IX), (XI) or (XII): 155 - Formula (IX) Formula (XI) Formula (XII) in which R x , R 2 , R 3 , V, q and R' are as defined above.

13. 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.

14. 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 1 to 7, or one of its pharmaceutically acceptable addition salts, in association with a pharmaceurawcs tically acceptable excipient, vehicle or carrier.

15. 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.

16. A method according to claim 15, 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.

17. A pyrazole derivative of the general formula (I) given and defined in claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified.

18. A method of preparing a pyrazole derivative of the general formula (I) given and defined in claim l.or an addition salt thereof, substantially as hereinbefore described and exemplified.

19. A pyrazole derivative of the general formula (I) given and defined in claim l.or an addition salt thereof, whenever prepared by a method claimed in any one of claims

20. A synthesis intermediate according to claim 11 or 12, substantially as hereinbefore described and exemplified.

21. A pharmaceutical composition according to claim 13 or 14, substantially as hereinbefore described.