EP0449699A2

Pyrazole derivatives as angiotensin II-receptor antagonists, process for their preparation and pharmaceutical compositions containing them.

Abstract

Derivatives of formula (I): <IMAGE> 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.

EP0449699A2, drawing sheet 1 — Sheet 1 of 256

Term

Term ended

Projected expiry passed 18 March 2011, 15.5 years ago.

16 claims: 1 independent, 15 dependent

1
Pyrazole derivatives characterized in that they correspond to the general formula:in which :R1 is a lower alkyl radical of 1 to 6 carbon atoms, a lower alkenyl radical of 2 to 6 carbon atoms, a C cycloalkyl radical3-VS7,R2 is the hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a lower halogeroyalkyl radical of 1 to 6 carbon atoms, a Cydoalkyl radical3-VS7, a group - (CH2)mCOOR5, a CH group2- (CH2)m-GOLD5 or a grouping-CH2(CH2) m SR5, m being an integer from 0 to 5, R6 being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms,A can represent a group:- (CH2) q OR ', R' being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms or a Cydoalkyl radical3-VS7, q being an integer from 1 to 5,- (CH2)qL, L being a halogen atom, preferably chlorine or bromine, q having the same meaning as above,-CHO, an acetal, a dioxolane,-COOR ', R' being defined as above,-CONR "R" ', R "and R"' independently representing a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a Cydoalkyl radical3-VS7 or which can form, with the nitrogen atom to which they are attached, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine,-CN- (CH2)q-CN, q being defined as above,- (CH2)q-COOR ', R' and q being defined as above,- (CH2)qCONR "R" ', R ", R"' and q being defined as above,- (CH2)qNR "R" ', R ", R"' and q being defined as above,-GOLD3, R3 being a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a Cydoalkyl radical3-VS7, a group- (CH2)notCOOR6, a group- (CH2) (CH2)notCN, a grouping-CH2- (CH2)notGOLD6, a group -CH2- (CH2)not-SR6, a grouping -CO-R6, n being an integer from 0 to 5, R6 being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, R3 may still represent a group- (CH2)P-CONR7R8 or - (CH2)P-CH2-CH2NR7R8, p being an integer from 0 to 5, R7 and R8 independently representing a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a Cydoalkyl radical3-VS7 or which can form with the nitrogen atom to which they are attached a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine,R4 may represent a nitro, amino, -COOR group9, Rg being the hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, R4 can still represent the following radicals:in which Rg has the same meaning as above, X and Y independently representing a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical or a trifluoromethyl radical, as well as their addition salts, in particular the pharmaceutically acceptable addition salts. 1. Dérivés de pyrazole caractérisés en ce qu'ils répondent à la formule générale: dans laquelle : R1 est un radical alkyle inférieur de 1 à 6 atomes de carbone, un radical alkényle inférieur de 2 à 6 atomes de carbone, un radical cycloalkyle en C3-C7,R2 est l'atome d'hydrogène, un radical alkyle inférieur de 1 à 6 atomes de carbone, un radical halo- gérioalkyle inférieur de 1 à 6 atomes de carbone, un radical cydoalkyle en C3-C7, un groupement - (CH2)mCOOR5, un groupement-CH2-(CH2)m-OR5 ou un groupement-CH2(CH2)m S-R5, m étant un nombre entier de 0 à 5, R6 étant un atome d'hydrogène ou un radical alkyle inférieur de 1 à 6 atomes de carbone,A peut représenter un groupement :-(CH2)q OR', R' étant un atome d'hydrogène ou un radical alkyle inférieur de 1 à 6 atomes de carbone ou un radical cydoalkyle en C3-C7, q étant un nombre entier de 1 à 5,-(CH2)qL, L étant un atome d'halogène, préférentiellement chlore ou brome, q ayant la même signification que ci-dessus,-CHO, un acétal, un dioxolane,-COOR', R' étant défini comme ci-dessus,-CONR"R"', R" et R"' représentant indépendamment un atome d'hydrogène, un radical akyle inférieur de 1 à 6 atomes de carbone, un radical cydoalkyle en C3-C7 ou pouvant former, avec l'atome d'azote auquel ils sont rattachés un hétérocycle comme la pyrrolidine, la pipéridine, la morpholine, la thiomorpholine ou une pipérazine,-CN-(CH2)q-CN, q étant défini comme ci-dessus,-(CH2)q-COOR', R' et q étant définis comme ci-dessus,-(CH2)qCONR"R"', R", R"' et q étant définis comme ci-dessus,-(CH2)qNR"R"', R", R"' et q étant définis comme ci-dessus,-OR3, R3 étant un atome d'hydrogène, un radical alkyle inférieur de 1 à 6 atomes de carbone, un radical cydoalkyle en C3-C7, un groupement-(CH2)nCOOR6, un groupement-(CH2)(CH2)nCN, un groupement-CH2-(CH2)nO-R6, un groupement -CH2-(CH2)n-S-R6, un groupement -CO-R6, n étant un nombre entier de 0 à 5, R6 étant un atome d'hydrogène ou un radical alkyle inférieur de 1 à 6 atomes de carbone, R3 peut encore représenter un groupement-(CH2)P-CONR7R8 ou -(CH2)P-CH2-CH2NR7R8, p étant un nombre entier de 0 à 5, R7 et R8 représentant indépendamment un atome d'hydrogène, un radical alkyle inférieur de 1 à 6 atomes de carbone, un radical cydoalkyle en C3-C7 ou pouvant former avec l'atome d'azote auquel ils sont rattachés un hétérocycle comme la pyrrolidine, la pipéridine, la morpholine, le thiomorpholine ou une pipérazine,R4 peut représenter un groupement nitro, amino, -COOR9, Rg étant l'atome d'hydrogène, un radical alkyle inférieur de 1 à 6 atomes de carbone, R4 peut encore représenter les radicaux suivants : dans lesquels Rg a la môme signification que ci-dessus, X et Y représentant indépendamment un atome d'hydrogène, un radical alkyle inférieur, un atome d'halogène, un radical alkoxy ou un radical trifluorométhyl, ainsi que leurs sels d'addition, en particulier les sels d'addition pharmaceutiquement acceptables.

854 paragraphs in 44 sections, as filed

The present invention relates, as new products, to the pyrazole derivatives of general formula (1) below as well as their salts.

The compounds in question have a very interesting pharmacological profile insofar as they are endowed with antagonistic properties of the angiotensin II receptors. They are therefore particularly indicated for the treatment of cardiovascular diseases, in particular for the treatment of hypertension and for the treatment of heart failure.

The present invention also relates to the process for the preparation of said products and their therapeutic applications. It also relates to new intermediate compounds allowing the synthesis of said products.

These pyrazole derivatives are characterized in that they correspond to the general formula (1):<chemistry id="chem0001" num="0001"><img file="EP0449699A2_D0001.tif" /></chemistry>in which :<ul id="ul0001" list-style="none"><li>R1 is a lower alkyl radical of 1 to 6 carbon atoms or a lower alkenyl radical of 2 to 6 carbon atoms, or a C cycloalkyl radical3-VS7 or a C cycloalkenyl radical4-VS7,</li><li>R2 is the hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a halo lower alkyl radical of 1 to 6 carbon atoms, or a C cycloalkyl radical3-VS7, a group - (CH2)m -COOR5 or a group -CH2- (CH2)m-GOLD6 or a group -CH2- (CH2)m-SR5, m being an integer from 0 to 5, R5 being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms,</li></ul>

A can represent a group:<ul id="ul0002" list-style="none"><li>- (CH2)qOR ', R' being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, or a C cycloalkyl radical3-VS7, q being an integer from 1 to 5</li><li>- (CH2)qL, L being a halogen atom, preferably chlorine or bromine, q having the same meaning as above</li><li>-CHO, an acetal, a dioxolane,</li><li>-COOR ', R' being defined as above</li><li>-CONR "R" ', R "and R'" independently representing a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms, a Cydoalkyl radical3-VS7 or which can form with the nitrogen atom to which they are attached a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine -CN</li><li>- (CH2)qCN, q being defined as above</li><li>- (CH2)qCOOR ', R' and q being defined as above</li><li>- (CH2)q CONR "R" ', R ", R"' and q being defined as above</li><li>- (CH2)qNR "R" ', R ", R"' and q being defined as above</li><li>- (CH2)q-S-R ', R' and q being defined as above</li><li>-OR3, R3 being a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms or a C cycloalkyl radical3-VS7, a group- (CH2)not-COOR6, a CH group2- (CH2)not-CN, a group -CH2- (CH2)not-GOLD6, a CH group2- (CH2)not-SR6, a COR group4, n being an integer from 0 to 5, R6 being a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, R3 can still represent a group - (CH2)p-CO-NR7R8 or - (CH2)p-CH2-CH2NR7Rat. p being an integer from 0 to 5, R7 and R8 independently representing a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, a C3-C cycloalkyl radical7 or which can form with the nitrogen atom to which they are attached a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine,</li></ul>

R4 may represent a nitro, amino, -COORg, R group9 being the hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, R4 can also represent the following radicals:<chemistry id="chem0002" num="0002"><img file="EP0449699A2_D0002.tif" /></chemistry><chemistry id="chem0003" num="0003"><img file="EP0449699A2_D0003.tif" /></chemistry><chemistry id="chem0004" num="0004"><img file="EP0449699A2_D0004.tif" /></chemistry><chemistry id="chem0005" num="0005"><img file="EP0449699A2_D0005.tif" /></chemistry>in which Rg has the same meaning as above,<ul id="ul0003" list-style="none"><li>X and Y independently represent a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical, or a trifluoromethyl radical.</li></ul>

In the description and the claims, the term lower alkyl radical means a hydrocarbon chain having from 1 to 6 carbon atoms, linear or branched. A lower alkyl radical is for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.

By C cycloalkyl radical3-VS7means a saturated cyclic radical, it is preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane radical.

The term “lower alkenyl radical” is understood to mean a hydrocarbon chain having from 2 to 6 linear or branched carbon atoms and having unsaturation. A lower alkenyl radical is for example an ethene, propene, isopropene, butene, isobutene, pentene, isopentene, hexene, isohexene radical.

“C” cycloalkenyl radical is understood to mean4-VS7 a cyclic radical having an unsaturation, it is preferably a cydobutene, cyclopentene, cyclohexene or cydoheptene radical.

The term “halo lower alkyl radical of 1 to 6 carbon atoms” means an alkyl radical in which 1 to 6 hydrogen atoms have been substituted by 1 to 6 halogen atoms. A halogeno lower alkyl radical is for example a trifluoromethyl radical or a trifluoro-2,2,2 ethyl radical.

By alkoxy radical is meant an O-lower alkyl group, lower alkyl being defined as above.

The term “heterocycle” is intended to denote a cycle of 5 to 7 atoms comprising from 1 to 3 heteroatoms chosen from oxygen, sulfur or nitrogen, optionally substituted by a lower alkyl, lower haloalkyl, alkoxy group or a phenyl nucleus optionally substituted by one of these groupings.

In the description and the claims, halogen means a chlorine, bromine, iodine or fluorine atom.

Document EP-A-0323841 by Du Pont de Nemours describes pyrroles, pyrazoles and triazoles. These compounds always have the benzyl substitution on a nitrogen atom:<chemistry id="chem0006" num="0006"><img file="EP0449699A2_D0006.tif" /></chemistry>

However, the Applicant has surprisingly discovered that, contrary to what emerges from the Du Pont de Nemours document, it was not essential that the benzyl substitution be found on a nitrogen atom, in particular in position -1 ( or -2) of the pyrazole ring, but very efficient products could be obtained when this benzyl substitution was on a carbon atom in position -4 of the pyrazole ring. In addition, the applicant has discovered that the presence of a group A and in particular of an oxygen atom in position -3 (or -5) of pyrazole combined with the benzyl substitution in position -4 leads to particularly active compounds as angiotensin II receptor antagonists.<ul id="ul0004" list-style="none"><li>According to an alternative embodiment, R1 is an n-propyl group;</li><li>according to another alternative embodiment, R1 is an n-butyl group;</li><li>according to an alternative embodiment, R2 is a methyl group;</li><li>according to another alternative embodiment, R2 is a trifiuoro-2,2,2, -ethyl group;</li><li>according to an alternative embodiment, A is an ethoxy carbonyl methylene oxy group;</li><li>according to another alternative embodiment, A is a dimethyl amino carbonyl oxy group;</li><li>according to another alternative embodiment, A is a methoxy methylene group;</li><li>according to another alternative embodiment, A is a 2-hydroxyethyl oxy group;</li><li>according to an alternative embodiment, R4 is a 2-carboxy-3,6-dichloro-benzoyl amino group;</li><li>according to another alternative embodiment, R4 is a 2-sulfonic acid benzoyl amino group;</li><li>according to another alternative embodiment, R4 is a (tetrazol-yl-5) -2 phenyl group;</li></ul>

the particularly preferred compounds of the invention are those which are chosen from the products of formula:<chemistry id="chem0007" num="0007"><img file="EP0449699A2_D0007.tif" /></chemistry><chemistry id="chem0008" num="0008"><img file="EP0449699A2_D0008.tif" /></chemistry><chemistry id="chem0009" num="0009"><img file="EP0449699A2_D0009.tif" /></chemistry><chemistry id="chem0010" num="0010"><img file="EP0449699A2_D0010.tif" /></chemistry>

According to the invention, the compounds of formula (I) can be prepared according to the following scheme: we will prepare:<ul id="ul0005" list-style="none"><li>- the alkyl oxo-3 alkanoates of formula (II):<chemistry id="chem0011" num="0011"><img file="EP0449699A2_D0011.tif" /></chemistry>in which R1 is defined as above and R10 represents a lower alkyl radical, preferably methyl or ethyl,</li><li>- 1,3-diketones of formula (III):<chemistry id="chem0012" num="0012"><img file="EP0449699A2_D0012.tif" /></chemistry>in which R1, R ′ and q are defined as above, these compounds of formula (II) and (III) can be prepared by conventional methods, such as the Claisen reaction or the Meldrum acid method. Methods of preparing this type of compound can be found in the following references:</li><li>- OIKAWA. Y; SUGANO. K; YONEMITSU. O; J. Org. Chem., 1978, 43 (10), 2087-88.</li><li>- WIERENGA. W; SKULNICK. HI; J. Org. Chem., 1979, 44, 310.</li><li>- HOUGHTON. R; LAPHAM. D; SYNTHESIS, 1982, 6.451-2.</li><li>- BRAM. G; VILKAS. M; Bull. Soc. Chim. France, 1964 (5), 945-51.</li><li>- BALYAKINA. MV; ZHDANOVICH. ES; PREOBRAZHENSKII. N / A ; Tr. Vses. Nauchn. Issled. Vitam in. Inst., 1961, 7, 8-16.</li><li>- FOX. M; MAQUINAY. AT ; Bull. Soc. Chim. Belg., 1946, 55, 98-105.</li><li>- BRUCE. FW; COOVER HW; J. Am. Chem. Soc., 1944, 66, 2092-94.</li><li>- EBY. CJ; and HAUSER. CR; J. Am. Chem. Soc., 1957, 79, 723-5.</li></ul>

By benzylation of the compounds of formula (II) or (III) in the presence of a base such as a sodium or potassium carbonate in acetone, a sodium or potassium alcoholate in an alcohol, a sodium hydride or of lithium in solvents such as tetrahydrofuran, dioxane or dimethyl formamide for example, at a temperature between 50 and 100 ° C or alternatively, in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropyl ethyl amine at reflux of tetrahydrofuran according to the reference SUNG-EUN YOO; KYU YANG YI; Bull. Korean. Chem. Soc. 1989, 10 (1), 112, using compounds of formula (IV)<chemistry id="chem0013" num="0013"><img file="EP0449699A2_D0013.tif" /></chemistry>we will obtain the compounds of formulas (V) and (VI):<chemistry id="chem0014" num="0014"><img file="EP0449699A2_D0014.tif" /></chemistry>the compounds of formulas (V) and (VI) can also be obtained by condensation of an aldehyde of formula (VII)<chemistry id="chem0015" num="0015"><img file="EP0449699A2_D0015.tif" /></chemistry>on a compound of formula (II) or of formula (III) followed by a catalytic hydrogenation, for example in the presence of Raney nickel in a solvent such as an alcohol, under pressure or at ordinary pressure, when the substitutions present allow it.

More generally, methods for preparing the compounds of formula (V) or of formula (VI) can be found in the following references:<ul id="ul0006" list-style="none"><li>- DURGESHWARI. P; CHAUDHURY. ND; J. Ind. Chem. Soc., 1962,39,735-6.</li><li>- HEINZ. P; KREGLEWSKI. AT; J. Prakt. Chem., 1963.21 (3-4), 186-197.</li><li>- ZAUGG. HEY; DUNNIGAN. DA; MICHAELS. RJ; SWETT. LR; J. Org. Chem., 1961, 26, 644-51.</li><li>- KAGAN. HB; HENG SUEN. Y; Bull. Soc. Chim. France, 1966 (6), 1819-22.</li><li>- RATHKE. MW; DEITCH. J; Tetrahedron Lett, 1971 (31), 2953-6.</li><li>- BORRIES KUBEL. ; Liebigs. Ann. Chem., 1980, 1392-1401.</li><li>- MARQUET. J; MORENO-MANAS. M; Chem. Lett, 1981,2,173-6.</li><li>- IOFFE. T; POPOV. EM; VATSURO. KV; TULIKOVA. EK; KABACHNIK. MID; Tetrahedron, 1962, 18, 923-940.</li><li>- SHEPHERD. TM; Chem. Ind. (London), 1970, 17, 567.</li></ul>

In formula (IV), W represents a halogen atom, preferably chlorine or bromine. In the same formula:<ul id="ul0007" list-style="none"><li>- V can be a nitro group, the derivative of formula (IV) is then commercial.</li><li>- V can be a COOR group11, R11 being a lower alkyl or benzyl radical, the derivative of formula (IV) will then be prepared by chlorination or bromination using N-chloro succinimide or N-bromosuccinimide in a solvent such as carbon tetrachloride or dibromoethane d '' an ester of p-methyl benzoic acid which is commercial, according to the reference:</li><li>- JULIA. M; CHASTRETTE. F; Bull. Soc. Chim. France, 1962 (2), 2247.<chemistry id="chem0016" num="0016"><img file="EP0449699A2_D0016.tif" /></chemistry>R12 being a lower alkyl or benzyl radical, the compounds of formula (IV) are then prepared by reaction of a magnesian of p-bromo toluene with a compound of formula:<chemistry id="chem0017" num="0017"><img file="EP0449699A2_D0017.tif" /></chemistry>to obtain a compound of formula:<chemistry id="chem0018" num="0018"><img file="EP0449699A2_D0018.tif" /></chemistry>which is hydrolyzed to yield the compound of formula:<chemistry id="chem0019" num="0019"><img file="EP0449699A2_D0019.tif" /></chemistry></li></ul>

Procedures for the three steps described above are found in the reference:<ul id="ul0008" list-style="none"><li>- MEYERS. HAVE ; MIHELICH. ED; J. Am. Chem. Soc., 1975, 97, 7383.</li></ul>

The acid is then esterified with an alcohol of formula R120H, R12 being defined as above. These derivatives are then brominated or chlorinated for example by N-bromo succinimide or N-chloro succinimide in a solvent such as carbon tetrachloride or dibromoethane to yield the compounds of formula (IV) where V is the group<chemistry id="chem0020" num="0020"><img file="EP0449699A2_D0020.tif" /></chemistry><chemistry id="chem0021" num="0021"><img file="EP0449699A2_D0021.tif" /></chemistry>in this case the compound:<chemistry id="chem0022" num="0022"><img file="EP0449699A2_D0022.tif" /></chemistry>previously prepared will be transformed into primary amide by action of the acid chloride, obtained with thionyl chloride or phosphorus oxychloride, on ammonia and this amide will be transformed into nitrile by action of phosphorus oxychloride in dimethylformamide or thionyl chloride. The nitrile obtained:<chemistry id="chem0023" num="0023"><img file="EP0449699A2_D0023.tif" /></chemistry>will then be brominated or chlorinated under the same conditions as the previous ester to yield the compounds of formula (IV) where V is the group<chemistry id="chem0024" num="0024"><img file="EP0449699A2_D0024.tif" /></chemistry><chemistry id="chem0025" num="0025"><img file="EP0449699A2_D0025.tif" /></chemistry>in this case the compound<chemistry id="chem0026" num="0026"><img file="EP0449699A2_D0026.tif" /></chemistry>will be prepared by chloromethylation of commercial 2-nitrobiphenyl, according to the references:<ul id="ul0009" list-style="none"><li>- CA: 70 (25): 114837 d</li><li>- Turnover: 69 (2): 3,704 t</li></ul>to lead to the compounds of formula (IV) where V is the group<chemistry id="chem0027" num="0027"><img file="EP0449699A2_D0027.tif" /></chemistry><chemistry id="chem0028" num="0028"><img file="EP0449699A2_D0028.tif" /></chemistry>

R12 being a lower alkyl or benzyl radical, the corresponding compounds of formula (IV) are obtained in the following way:<ul id="ul0010" list-style="none"><li>From the compound:<chemistry id="chem0029" num="0029"><img file="EP0449699A2_D0029.tif" /></chemistry>which preparation can be found in the reference:</li><li>- FISSELMANN. H; HABITCH. H; Ger. Offen .: 1,092,929 (1960); CA: 57: 5894 g the compounds of formula will be obtained:<chemistry id="chem0030" num="0030"><img file="EP0449699A2_D0030.tif" /></chemistry>by esterification using an alcohol of formula R120H, R12 being defined as above by conventional methods known to those skilled in the art.</li></ul>

These compounds are then treated with N-chloro succinimide or N-bromo succinimide in a solvent such as carbon tetrachloride or dibromoethane for example, to give the compounds of formula (IV) in which V represents the<chemistry id="chem0031" num="0031"><img file="EP0449699A2_D0031.tif" /></chemistry>

R12 being defined as above.<chemistry id="chem0032" num="0032"><img file="EP0449699A2_D0032.tif" /></chemistry>in this case, the corresponding compounds of formula (IV) will be prepared as follows:

starting from the acidic compound (p-methyl phenyl) -3 thiophene-2 carboxylic whose preparation is given above, by treatment with thionyl chloride then ammonia one obtains the amide compound which is then dehydrated by the chloride of thionyl or phosphorus oxy chloride without solvent or in dimethyl formamide to lead to the nitrile compound:<chemistry id="chem0033" num="0033"><img file="EP0449699A2_D0033.tif" /></chemistry>

This nitrile compound is then halogenated with N-chloro succinimide or N-bromo succinimide in a solvent such as carbon tetrachloride or dibromoethane to give the compounds of formula (IV) in which V represents the group<chemistry id="chem0034" num="0034"><img file="EP0449699A2_D0034.tif" /></chemistry><chemistry id="chem0035" num="0035"><img file="EP0449699A2_D0035.tif" /></chemistry>in this case, the corresponding compounds of formula (IV) are synthesized as follows: from 4-chloro-butyrophenone of formula:<chemistry id="chem0036" num="0036"><img file="EP0449699A2_D0036.tif" /></chemistry>whose preparation can be found in patent BE: 577,977 of May 15, 1959, CA: 54, 4629 c, by treatment with phosphorus oxychloride and dimethyl formamide according to the conditions described in the reference:<ul id="ul0011" list-style="none"><li>- VOLODINA. MY; TERENTEV. AP; KUDRYASHOVA. GOES; KABOSHINA. LN; Khim. Geterosikl. Soe-dim; 1967, 5-8;</li></ul>we will obtain the compound of formula:<chemistry id="chem0037" num="0037"><img file="EP0449699A2_D0037.tif" /></chemistry>

This compound is then treated with sodium sulfide in a solvent such as tetrahydrofuran at reflux to give the derivative<chemistry id="chem0038" num="0038"><img file="EP0449699A2_D0038.tif" /></chemistry>which is then transformed in two stages into a nitrile derivative by dehydration of the oxime formed from the aldehyde and the hydroxylamine. This dehydration can be carried out for example using acetic anhydride to give the nitrile compound:<chemistry id="chem0039" num="0039"><img file="EP0449699A2_D0039.tif" /></chemistry>which can then be flavored by treatment with bromine in carbon tetrachloride and then with potassium tert-butoxide in tetrahydrofuran to give the compound:<chemistry id="chem0040" num="0040"><img file="EP0449699A2_D0040.tif" /></chemistry>

This compound can then be chlorinated or brominated by halogenating agents such as N-chloro succinimide or N-bromo succinimide in a solvent such as carbon tetrachloride or dibromoethane to give the compounds of formula (IV) in which V represents the group<chemistry id="chem0041" num="0041"><img file="EP0449699A2_D0041.tif" /></chemistry><chemistry id="chem0042" num="0042"><img file="EP0449699A2_D0042.tif" /></chemistry>

R12 being defined as above, they can be prepared from the compound of formula<chemistry id="chem0043" num="0043"><img file="EP0449699A2_D0043.tif" /></chemistry>by conventional hydrolysis of the nitrile function then esterification of the acid obtained or passage directly from the nitrile function to the ester function according to the methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chloro succinimide or N-bromo succinimide in carbon tetrachloride or dibromo ethane for example.

In formulas (V) and (VI), R1, Rio, R 'and are defined as above and V has the same meaning as in formula (IV).

Certain derivatives of formula (V) and of formula (VI) when V represents a 2-alkoxycarbonylphenyl, 2-cyanophenyl, 2-nitrophenyl, alkoxycarbonyl-thiophene or cyano-thiophene are new synthetic intermediates which are claimed in themselves.

In formula (VII) V with the same definition as in formula (IV) but this method of condensation will only be used when V has a function which the hydrogenation respects. In certain cases these aldehydes can be prepared from the derivatives of formula (IV) according to reactions known to those skilled in the art, the Sommelet reaction can be cited (Bull. Soc. Chim. France 1918, [4] 23, 95) or that with nitropropane (Organic Syntheses Collec. Vol. IV, 932). By the action of a hydrazine of formula (VIII)<chemistry id="chem0044" num="0044"><img file="EP0449699A2_D0044.tif" /></chemistry>in which R2 is defined as above, on the compounds of formula (V), by simple heating under reflux of an alcohol for example, the compounds of formula (IX) will be obtained:<chemistry id="chem0045" num="0045"><img file="EP0449699A2_D0045.tif" /></chemistry>in which R1, R2 and V have the definitions given above.

These compounds of formula (IX) are new synthetic intermediates which are claimed in themselves.

The alkylation of the compounds of formula (IX) carried out in the presence of a base such as potassium or sodium carbonate in solvents such as acetone, butanone-2 or dimethyl formamide or in the presence of alcoholate sodium or potassium in an alcohol or in the presence of sodium or lithium hydride in tetrahydrofuran by derivatives of formula (X)<chemistry id="chem0046" num="0046"><img file="EP0449699A2_D0046.tif" /></chemistry>

Z being a bromine, chlorine or iodine atom, R3 being defined as above leads to the compounds of formula (XI):<chemistry id="chem0047" num="0047"><img file="EP0449699A2_D0047.tif" /></chemistry>in which R1, R2, R3 and V are defined as above.

Likewise, by the action of a hydrazine of formula (VIII), defined as above, on a compound of formula (VI), by simple heating under reflux of an alcohol for example, a mixture of compounds of formula will be obtained. (XII) and of formula (XII ')<chemistry id="chem0048" num="0048"><img file="EP0449699A2_D0048.tif" /></chemistry>in which R1, R2, R ', q and V are defined as above.

From this mixture, the pure compounds of formula (XII) will be obtained by purification either by chromatography on silica or by recrystallization or any other purification process known to those skilled in the art.

Another method for preparing the compounds of formula (XII) consists in first treating the compounds of formula (VI) with hydrazine hydrate according to the same conditions in order to obtain the compounds of formula (XIII):<chemistry id="chem0049" num="0049"><img file="EP0449699A2_D0049.tif" /></chemistry>in which R1, R ', q and V are defined as above, these compounds of formula (XIII) are then alkylated in the presence of DBU (1,8-diazabicydo- [5.4.0] undec-7- ene), in a solvent such as acetone or acetonitrile for example, by halogenated derivatives of formula (XIV):<chemistry id="chem0050" num="0050"><img file="EP0449699A2_D0050.tif" /></chemistry>in which R2 has the same meaning as above and Z being a bromine, chlorine or iodine atom to lead to the mixture of the compounds of formula (XII) and of formula (XII ') as defined above, the compounds of formula (XII) then being obtained pure after purification as mentioned. This second preparation method can be particularly advantageous in the case where R2 is a lower alkyl group since it makes it possible to predominantly obtain the compounds of formula (XII) compared to the compounds of formula (XII ').

The compounds of formula (XII) in which R 'is hydrogen will be prepared in two stages: by treatment with boron tribromide of the compounds of formula (XII) in which R' is a lower alkyl group, the brominated derivatives of formula will be obtained (XV)<chemistry id="chem0051" num="0051"><img file="EP0449699A2_D0051.tif" /></chemistry>in which R1, R2, q and V are defined as above, the treatment of these brominated derivatives of formula (XV) with potassium or sodium carbonate at the reflux of the dioxane-water mixture makes it possible to obtain the compounds of formula (XII) in which R 'is the hydrogen atom.

The derivatives of formula (XI) or of formula (XII) in which:<ul id="ul0012" list-style="none"><li>- V is a nitro group may undergo catalytic hydrogenation, for example in the presence of Raney nickel in an alcohol at atmospheric pressure or under pressure to yield the compounds of formula (I) where R4 is an amino group and A a group - (CH2)q-OR 'or OR3, R ', R3 and q being defined as above.</li></ul>

By acting on these derivatives of a suitably substituted phthalic anhydride, the compounds of general formula (I) where R will be obtained4 represents the group<chemistry id="chem0052" num="0052"><img file="EP0449699A2_D0052.tif" /></chemistry>where X and Y are defined as above and where A is a group - (CH2)q-OR 'or OR3, q, R'and R3 being defined as above, the acid obtained can then be esterified to obtain the group<chemistry id="chem0053" num="0053"><img file="EP0449699A2_D0053.tif" /></chemistry>

Similarly, by the action of the cyclic anhydride of a suitably substituted orthosulfobenzoic acid on these amino compounds, the compounds of general formula (I) are obtained in which R4 represents the group<chemistry id="chem0054" num="0054"><img file="EP0449699A2_D0054.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R ', R3, X and Y being defined as above.

Likewise by the action of N- (trifluoromethyl sulfonyl) anthranilic acid chloride, the preparation of which can be found in the references:<ul id="ul0013" list-style="none"><li>CA 96 (13): 103651 z</li><li>CA 97 (7): 55500 w</li></ul>

on these amino compounds we will obtain the compounds of general formula (I) where R4 represents the group<chemistry id="chem0055" num="0055"><img file="EP0449699A2_D0055.tif" /></chemistry>

and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above. The compounds of formulas (XI) or (XII) in which:<ul id="ul0014" list-style="none"><li>- V is a group-COOR11 may be hydrolyzed in an acidic or basic medium or hydrogenated in the case where R11 is a benzyl in order to respect the other ester functions present, to lead to the compounds of formula (I) where R4 is a group -COOH and A is a group - (CH2) q-OR 'or OR3, q, R 'and R3 being defined as above.</li></ul>

These acid derivatives may lead, after having been transformed into acid chloride with thionyl chloride or into mixed anhydride with ethyl chloroformate, by reaction on anthranilic derivatives of formula<chemistry id="chem0056" num="0056"><img file="EP0449699A2_D0056.tif" /></chemistry>where X, Y and R9 are defined as above, to the compounds of general formula (I) where R4 represents the group:<chemistry id="chem0057" num="0057"><img file="EP0449699A2_D0057.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.

The compounds of formulas (XI) or (XII) in which:<chemistry id="chem0058" num="0058"><img file="EP0449699A2_D0058.tif" /></chemistry>in the same way will be hydrolyzed or hydrogenated in the presence of a catalyst such as palladium on carbon in the case where R12 is a benzyl, to lead to the compounds of formula (I) where R4 is a group:<chemistry id="chem0059" num="0059"><img file="EP0449699A2_D0059.tif" /></chemistry>and to a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.

The compounds of formulas (XI) and (XII) in which:<chemistry id="chem0060" num="0060"><img file="EP0449699A2_D0060.tif" /></chemistry>may react with an equivalent of sodium azide in a solvent such as dimethyl formamide in the presence of an ammonium salt such as ammonium chloride or with a trialkyl tin azide at the reflux of toluene then with hydrochloric acid gas in tetrahydrofuran to lead to the compounds of general formula (I) where R4 represents a group:<chemistry id="chem0061" num="0061"><img file="EP0449699A2_D0061.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.

The compounds of formulas (XI) and (XII) in which:<chemistry id="chem0062" num="0062"><img file="EP0449699A2_D0062.tif" /></chemistry>may undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol at atmospheric pressure or under pressure to yield compounds of general formula (I) where R4 represents a group:<chemistry id="chem0063" num="0063"><img file="EP0449699A2_D0063.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.

By the action of the chloride of trifluoromethane sulfonic acid on 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, the compounds of general formula (I) where R4 represents a group:<chemistry id="chem0064" num="0064"><img file="EP0449699A2_D0064.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.

The compounds of formulas (XI) and (XII) in which:<ul id="ul0015" list-style="none"><li>- V represents the grouping<chemistry id="chem0065" num="0065"><img file="EP0449699A2_D0065.tif" /></chemistry>may be treated with a trialkyl tin azide in toluene at reflux and then with gaseous hydrochloric acid in tetrahydrofuran to yield the derivatives of formula (I) in which R4 represents the group<chemistry id="chem0066" num="0066"><img file="EP0449699A2_D0066.tif" /></chemistry>and A is a group - (CH2)qOR 'or OR3, q, R 'and R3 being defined as above.</li></ul>

The compounds of formulas (XI) and (XII) in which:<ul id="ul0016" list-style="none"><li>- V represents the grouping<chemistry id="chem0067" num="0067"><img file="EP0449699A2_D0067.tif" /></chemistry>can be hydrolyzed or hydrogenated in the presence of a catalyst such as Palladium on carbon in the case where R12 is a benzyl, to lead to the compounds of formula (1) in which R4 represents the group<chemistry id="chem0068" num="0068"><img file="EP0449699A2_D0068.tif" /></chemistry>and A is a group - (CH2)q-OR 'or OR3, q, R 'and R3 being defined as above.</li></ul>

The compounds of formula (I) in which A represents a CH group20H can be oxidized by a mild oxidizing agent such as manganese dioxide in a solvent such as chloroform to give the compounds of formula (I) in which A represents the CHO group which can be transformed according to the conventional methods known to man of art in acetal or in dioxolane, by heating with an alcohol or a diol in the presence of paratoluene sulfonic acid for example (Synthesis 1981, 501).

Further oxidation of these same aldehyde compounds or directly of the alcohol compounds, for example with oxidizing agents such as potassium permanganate will lead to the compounds of formula (I) in which A represents the group C02H.

The compounds of formula (I) in which A represents the group C02H may be esterified by conventional esterification methods to give the compounds of formula (I) in which A represents a group CO2R ', R' being a lower alkyl radical.

The compounds of formula (I) in which A represents the group CO2H may also be converted into amide in several stages, optionally after stages of protection of other functional groups if necessary, by transformation into acid chloride then treatment with ammonia or with an amine of formula HN R "R" ' , R "and R" 'being defined as above to lead to the compounds of formula (I) in which A represents a group CON R "R"'.

The compounds of formula (I) in which A represents a CONH group2 may be treated with an agent such as thionyl chloride or phosphorus oxychloride to give the compounds of formula (I) in which A represents the group CN.

The compounds of formula (1) in which A represents a group (CH2)qOR ', R' being a lower alkyl radical and q an integer from 1 to 5 can be treated with boron tribromide in chloroform to give, after optionally steps of protection and deprotection of other functional groups if necessary, compounds of formula (I) in which A represents the group (CH2) qBr.

The compounds of formula (I) in which A represents the group (CH2)qBr may be treated with sodium or potassium cyanide in solvents such as alcohol, or an alcohol-water mixture, dimethyl sulfoxide or acetonitrile, to give the compounds of formula (I) in which A represents the grouping (CH2)qCN or also by amines of formula HNR "R" 'in which R "and R"' are defined as above to lead to the compounds of formula (I) where A represents (CH2)q NR "R" 'or also by thiols of formula HS-R', R 'being defined as above to lead to the derivatives of formula (I) where A represents (CH2) qS-R '.

The compounds of formula (I) in which A represents this group (CH2) qCN can be hydrolyzed according to conventional nitrile hydrolysis methods to give the compounds of formula (I) in which A represents the group (CH2)qCO2H.

These acidic compounds can themselves be esterified by conventional esterification methods to yield the compounds of formula (I) in which A represents a group (CH2)qCO2R ', R' being a lower alkyl radical and q an integer from 1 to 5 or transformed into amide - (CH2)q-CONR "R" as indicated previously.

The compounds of formula (I) in which A represents the group (CH2)qL, L being a halogen and q an integer from 1 to 5, can be synthesized by treatment of the derivatives of formula (1) in which A represents the group (CH2)qOH by halogenating agents such as thionyl chloride, phosphorus oxychloride or phosphorus tribromide for example.

In the case where R4 has a function not compatible with these reaction sequences, the derivative of formula (XII) will be used as transformation product, V then being transformed into function R4 as mentioned above.

Addition salts of certain compounds of formula (I) can be obtained, in particular pharmaceutically acceptable addition salts. We can cite in particular when R2, R4 or A have an acid function the sodium, potassium, calcium, amine salts such as dicyclohexylamine or amino acid such as lysine. When A or R4 have an amine function, a mineral or organic acid salt such as hydrochloride, methane sulfonate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate, for example.

The new compounds according to the invention have remarkable pharmacological properties as angiotensin II receptor antagonists and can be used therapeutically for the treatment of cardiovascular diseases, in particular for treating hypertension and heart failure.

Thus, the invention extends to pharmaceutical compositions containing as active principle, the drugs consisting of a pharmaceutically effective amount of at least one compound of formula (I), as defined above, as well as possibly one of its salts d 'pharmaceutically acceptable addition.

These compositions may be administered by the oral, rectal, parenteral, transdermal or ocular route.

These compositions can be solid or liquid and can be presented in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets, capsules, granules, suppositories, injections, transdermal systems and eye drops: they are prepared according to the usual methods. The active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (1) defined as above or one of its pharmaceutically acceptable addition salts can be incorporated therein into excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavors and colorings.

The invention also covers a pharmaceutical composition with angiotensin II receptor antagonist activity which makes it possible in particular to favorably treat cardiovascular diseases, in particular hypertension and heart failure, characterized in that it comprises a pharmaceutically effective amount of at least one aforementioned compound of formula (I) or one of its pharmaceutically acceptable addition salts which can be incorporated into an excipient, pharmaceutically acceptable vehicle or carrier.

The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

For example, in adults of average weight 60 to 70 kg, it can vary between 1 and 400 mg of active principle in one or more daily doses by the oral route, or from 0.01 to 50 mg in one or more daily doses. parenterally.

The invention also covers a process for the preparation of a pharmaceutical composition, characterized in that a pharmaceutically effective amount of at least one compound of formula (I) as defined above, or one of its addition salts is incorporated. pharmaceutically acceptable, in a pharmaceutically acceptable excipient, vehicle or carrier. According to a particular characteristic, this pharmaceutical composition is formulated in the form of capsules, tablets dosed from 1 to 400 mg or in the form of injectable preparations dosed from 0.01 to 50 mg.

The invention also covers a method of therapeutic treatment of mammals, characterized in that a therapeutically effective amount of at least one compound of formula (I) as defined above or one of its addition salts is administered to this mammal pharmaceutically acceptable.

In animal therapy, the usable daily dose should usually be 1 to 100 mg per kg.

Other characteristics and advantages of the invention will be better understood on reading which will follow from a few examples of preparation which are in no way limitative, but given by way of illustration.

Example 1: ethyl oxo-3 heptanoate

Formula (II): R

= n-Butyi R

= Ethyl

70 g of Meldrum acid are dissolved in 200 ml of dichloromethane in the presence of 78.5 ml of pyridine, the mixture is cooled to 0 ° C. and 64.5 g of valeric acid acid chloride are added dropwise. this temperature. At the end of the addition, the mixture is left at room temperature and stirred for two hours. The solution is washed with a dilute hydrochloric acid solution, dried over magnesium sulfate and evaporated in vacuo to give 110 g of an oil used as it is for the following. This oil is dissolved in 400 ml of absolute ethanol and the mixture is heated under reflux for two hours and left overnight at room temperature. The ethanol is evaporated in vacuo and the oily residue is distilled under reduced pressure to give 63.3 g of ethyl oxo-3 heptanoate in the form of a liquid of boiling point Eb20 = 115-120 ° C.

Example 2: ethyl oxo-3 hexanoate

Formula (II): R

= n-Propyl, R

= Ethyl

Prepared according to the same procedure as Example 1.

Boiling point liquid Eb20 = 95-100 ° C

Example 3: (nltro-4 bonzyl) -2 ethyl oxo-3 heptanoate

Formula (V): R

= n-Butyl, V = N0

, R

= Ethyl

57.3 g of ethyl oxo-3 heptanoate are dissolved in 300 ml of ethanol. A solution of sodium ethylate prepared by adding 7.7 g of sodium in 50 ml of ethanol is added and the mixture is stirred for 20 minutes at room temperature. 72 g of 4-nitro-benzyl bromide are then added in portions and the mixture is then stirred for two hours at room temperature and then two hours at reflux. The ethanol is evaporated in vacuo and the residue obtained is taken up in water and then extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The oil obtained is taken up in a pentane ether mixture and the crystals formed are drained in order to remove the dibenzyl derivative (F = 135 ° C), the mother liquors concentrated in vacuo at 120 ° C to remove the unsubstituted keto-ester starting, give 69.2 g of (4-nitro-benzyl) -2 3-oxo-ethyl heptanoate in the form of an oil used as it is for the continuation.

Example 4: (4-nitro benryl) -2 ethyl oxo-3 hexanoate

Formula (V): R

= n-Propyl, V = N0

, R

= Ethyl

Prepared according to the procedure of Example 3 starting from ethyl oxo-hexanoate prepared in Example 2.

Oil used as it is for the continuation.

Example 5: (Methoxy carbonyl-2'biphenyl yl-4) 2-methyl-3-oxo-ethyl heptanoate

Prepared according to the procedure of Example 3 from ethyl oxo-3 heptanoate prepared in Example 1 and methyl (4-bromomethyl biphenyl-yl-2) carboxylate.

Oil used as it is for the continuation.

Preparation of methyl (4-bromomethyl biphenyl-yl-2) carboxylate

A) (methyl-4 'biphenyl-yl-2) methyl carboxylate.

To 300 ml of methanol cooled to 0 ° C., 15 ml of acetyl chloride are added. The mixture is stirred for 10 minutes at this temperature then 15 g of (methyl-4 'biphenyl-yl-2) carboxylic acid (prepared according to MEYERS.A.1; MIHELICH ED, J.Am.Chem.Soc, 1975, 97 ( 25), 7383 by the action of (4-methylphenyl) magnesium bromide on (2-methoxyphenyl) -2 dimethyl-4,4-oxazolidine-1,3) are added. The mixture is then heated at reflux for 4 hours, the solvents are evaporated under vacuum to give 16 g of (methyl-4 'biphenyl-yl-2) carboxylate in the form of an oil used as it is for the following.

B) (methyl bromomethyl-4 'biphenyl-yl-2) carboxylate.

16g of methyl (4'-biphenyl-yl-2) methyl carboxylate prepared in A) are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6g of N-bromo succinimide and 0.5g of peroxide benzoyl. The mixture is brought to reflux for 6 hours, the crystals are filtered and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum. The residue is taken up in ether then the solution is filtered on charcoal and evaporated under vacuum to give 14.5 g of methyl (4-bromomethyl biphenyl-yl-2) carboxylate in the form of an oil used as it is for after.

Example 6: (Cyano-2 'biphenyl-yl-4) ethyl-2-methyl-3-oxo heptanoate

<chemistry id="chem0070" num="0070"><img file="EP0449699A2_D0070.tif" /></chemistry>30 g of ethyl oxo-3 heptanoate, prepared in Example 1, are dissolved in 300 ml of tetrahydrofuran. 31.6 g of 4-bromomethyl-2-cyano-biphenyl are added as well as 40 ml of N, N-diisopropyl amine and 10 g of lithium bromide. The mixture is heated for 15 hours at reflux, then concentrated under vacuum and added with ice water and dilute hydrochloric acid before being extracted with ethyl acetate. The organic phase is washed with water and then dried and evaporated in vacuo. The residue obtained is heated under vacuum to 130 ° C. in order to remove the residual ethyl oxo-3 heptanoate, to give 41 g of (2-cyano-biphenyl-yl-4) methyl-2 oxo-3 heptanoate crude ethyl in the form of an oil used as such for the following.

Preparation of 4-bromomethyl-2-cyano-biphenyl:

A) 4-methyl-2-cyano-biphenyl:

18.5 g of (methyl-4 'biphenyl-yl-2) carboxylic acid prepared as in Example 5 A) are heated to reflux in 60 ml of thionyl chloride for two hours. The thionyl chloride is concentrated in vacuo and the residue is poured onto a 28% solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are drained and washed with ether then dried to give 14 , 5g of (methyl-4 'biphenyl-yl-2) carboxamide in the form of crystals with a melting point of 128 ° C. These crystals are taken up in 50 ml of thionyl chloride and the mixture is heated for 3 hours at reflux then concentrated in vacuo to give 9 g of methyl-4 '2-cyano-biphenyl in the form of crystals of melting point 45-46 ° C.

B) 4-bromomethyl-2-cyano-biphenyl:

7.9 g of methyl 4 '2-cyano-biphenyl prepared in A) are dissolved in 100 ml of carbon tetrachloride in the presence of 7.3 g of N-bromo succinimide and 0.3 g of benzoyl peroxide. The mixture is heated at reflux for 6 hours and the crystals are filtered, the remaining solution is concentrated in vacuo and the residue is crystallized from ether to give 6.6 g of bromomethyl-4 '2-cyano-biphenyl in the form of crystals of melting point 115-118 ° C.

EXAMPLE 7 Methyl-1 n-Butyl-3 (4-nitro-benzyl) -4 5-hydroxy-pyrazole

Formula (IX): R

= n-Butyl, R

= CH

, V = NO

20 g of (4-nitro-benzyl) -2 3-oxo-ethyl heptanoate prepared in Example 3 are dissolved in 150 ml of ethanol and 4 ml of methyl hydrazine are added. The mixture is heated at reflux for 6 hours. The ethanol is evaporated in vacuo and the residue is taken up in water and then extracted with ethyl acetate, the organic phase is then washed several times with dilute sodium hydroxide solution and the combined aqueous fractions are acidified with dioxide. of sulfur, then extracted with chloroform. The chloroform phase is dried over magnesium sulfate and evaporated in vacuo to give a residue which crystallizes in ether. The crystals are drained and recrystallized from ethyl acetate to give 10.9 g of methyl-1 n-butyl-3 (4-nitro benzyl) -4 hydroxy-5 pyrazole in the form of crystals of melting point 136 ° C. .

EXAMPLE 8 Methyl-1 n-Propyl-3 (4-nitro-banryl) -4 5-hydroxy-pyrazole

Formula (IX): R

= n-Propyl, R

= CH

, V = NO

Prepared according to the procedure of Example 7 starting from ethyl (4-nitro-benzyl) -2 3-oxo-hexanoate prepared in Example 4.

Melting point crystals 174 ° C.

Example 9: n-Propyl-3 (nltro-4 benzyl) -4 hydroxy-5 pyrazole

Formula (IX): R

= n-Propyl, R

= H, V = NO

Prepared according to the procedure of Example 7 starting from (4-nitro benzyl) -2 3-oxo ethyl hexanoate prepared in Example 4 and hydrazine.

Melting point crystals 196 ° C.

Example 10: (Ethoxy carbonyl methyl) -1 n-propyi-3 (4-nitro benzyl) -4 5-hydroxy-pyrazole

Formula (IX): R1 = n-Propyl, R2 = CH2C02And, V = N02

Prepared according to the procedure of Example 7 from ethyl hydrazinoacetate.

Melting point crystals 134 ° C.

Example 11: (2,2,2,2-Trifluoroethyl) -1 n-propyl-3 (4-nitro-benzyl) -4 5-hydroxy-pyrazole

Formula (IX): R1 = n-Propyl, R2 = CH2CF3, V = NO2

Prepared according to the procedure of Example 7 from (trifluoro-2,2,2 ethyl) hydrazine.

Melting point crystals 160 ° C.

Example 12: Methyl-1 n-Butyl-3 (methoxy carbonyl-2 'biphenyl-yl-4) methyl-4 hydroxy-5 pyrazole

Formula (IX): R1 = n-Butyl,<chemistry id="chem0071" num="0071"><img file="EP0449699A2_D0071.tif" /></chemistry>

Prepared according to the procedure of Example 7 from ethyl (2-methoxy carbonyl-2 'biphenyl-yl-4)-methyl-3-oxo-heptanoate prepared in Example 5.

Melting point crystals 108 ° C.

Example 13: Methyl-1 n-Butyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-5-hydroxy-pyrazole

Formula (IX): R1 = n-Butyl, R2 = CH3,<chemistry id="chem0072" num="0072"><img file="EP0449699A2_D0072.tif" /></chemistry>

Prepared according to the procedure of Example 7 starting from ethyl (2-cyano-biphenyl-yl-4) -methyl-2-oxo-3 heptanoate prepared in Example 6.

Melting point crystals 138 ° C.

Example 14: [Methyl-1 n-propyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R

= n-Propyl, R

= Methyl, R

= CH

CO

And, V = N0

22.4 g of methyl-1 n-propyl-3 (4-nitro-benzyl) -4 hydroxy-5 pyrazole prepared in Example 8 are dissolved in 200 ml of acetone and 8.7 g of sodium carbonate are added as well 9.2 ml of ethyl bromo acetate. The mixture is brought to reflux for 5 hours and the solvents are concentrated to dryness. The residue is taken up in water and then extracted with ether. The organic phase is dried over magnesium sulfate and evaporated to dryness. The residue obtained is taken up in isopropyl ether and the crystals obtained are drained to give 9g of [methyl-1 n-propyl-3 (4-nitro-benzyl) -4 5-oxo-pyrazol-yl-2] ethyl acetate melting point 62 ° C.

The mother liquors are concentrated and the oil obtained is chromatographed on silica gel in a dichloromethane / acetone eluent (90/10) to give 10 g of [methyl-1 n-propyl-3 (4 nitro-4 benzyl) -4 pyrazol -yl-5] ethyl oxyacetate in the form of crystals of melting point 60-61 ° C.

EXAMPLE 15 [1-methyl-n-Butyl-3 (4-nitro-benzyl) -4 pyrazoi-yl-5] ethyl oxyacetate

Formula (XI): R1 = n-Butyl, R2 = Methyl, R3 = CH2 CO2 And, V = NO2

Prepared according to the procedure of Example 14.

Melting point crystals 68 ° C.

Example 16: [n-propyl-3 (nltro-4 benzyl) -4 pyrazol-yl-5] ethyl oxyacetate

Formula (XI): R1 = n-Propyl, R2 = H, R3 = CH2 CO2 And, V = N02

Prepared according to the procedure of Example 14.

Melting point crystals 116 ° C.

Example 17: [Methyl-1 n-propyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] methyl oxy acetate

Formula (XI): R1 = n-Propyl, R2 = methyl, R3 = CH2 CO2 Me, V = NO2

Prepared according to the procedure of Example 14.

Melting point crystals 58 ° C.

EXAMPLE 18 Methyl [(trffluoro-2,2,2 ethyl) -1 n-propyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] oxyacetate

Fonmule (XI): R1 = n-Propyl, R2 = CH2 CF3, R3 = CH2 CO2 Me, V = N02

Prepared according to the procedure of Example 14.

73 ° C melting point crystals.

EXAMPLE 19 [1-methyl-n-butyl-3 (methoxy carbonyl-2 'b lphenyl-yl4) methyl-4 pyrazol-yl-5] ethyl oxyacetate

Formula (XI): R

= n-Butyl, R

= Methyl,

<chemistry id="chem0073" num="0073"><img file="EP0449699A2_D0073.tif" /></chemistry>Prepared according to the procedure of Example 14.

Oil used as it is for the continuation.

Example 20: (methyl-1 n-butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] ethyl oxyacetate

Formula (XI): R

= n-Butyl, R

= Methyl, R

= CH

CO

And,

Prepared according to the procedure of Example 14.

Oil used as it is for the continuation.

Example 21: [Methyl-1 n-butyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] oxy ethyl acetate

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, R3 = CH2 CO2 And, R4 = NH2

3.4 g of [methyl-1 n-butyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] ethyl oxyacetate prepared in Example 15 are dissolved in 50 ml of absolute ethanol in the presence of 500 mg of Raney Nickel. The mixture is hydrogenated at atmospheric pressure and at ambient temperature and when the hydrogen uptake has ceased, the catalyst is filtered, the ethanol is evaporated in vacuo and the residue is taken up in pentane to give 2.9 g of [methyl-1 n-butyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] ethyl oxyacetate in the form of crystals with a melting point of 65 ° C.

Example 22: [Methyl-1 n-propyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] oxy ethyl acetate

Fonmule (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2 CO2 And, R4 = NH2

Prepared according to the procedure of Example 21.

Melting point crystals 103 ° C.

Example 23: (Methyl-1 n-propyl-3 (4-amino benryl) -4 pyrazol-yl-5] oxy methyl acetate

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3= CH2CO2 Sea4 = NH2

Prepared according to the procedure of Example 21.

Oil used as it is for the continuation.

EXAMPLE 24: [(2,2,2,2-trifluoroethyl) -1 n-propyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] methyl oxyacetate

Formula (I): R1 = n-Propyl, R2 = CH2 CF3, A = OR3, R3 = CH2 CO2 Sea4 = NH2

Prepared according to the procedure of Example 21.

Melting point crystals 63 ° C.

Example 25: (Ethoxy carbonyl methyl) -1 n-propyl-3 (4-amino benzyl) -4 hydroxy-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = CH2 CO2 And, A = OR3, R3 = H, R4= NH2

Prepared according to the procedure of Example 21.

Oil used as it is for the continuation.

Example 26: ethyl n-propyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] oxyacetate

Formula (I): R1 = n-Propyl, R2 = H, A = OR3, R3 = CH2 C02 And, R4 = NH2

Prepared according to the procedure of Example 21.

Oil used as it is for the continuation.

EXAMPLE 27 [1-methyl-n-butyl-3 ((2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] ethyl oxyacetate

Formula (I): R

= n-butyl, R

= Methyl, A = OR

R

= CH

CO

And,

<chemistry id="chem0075" num="0075"><img file="EP0449699A2_D0075.tif" /></chemistry>3 g of [Methyl-1 n-butyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] ethyl 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 at room temperature overnight. The crystals obtained are drained, washed with isopropyl ether and dried to give 2.5 g of [1-methyl-3-n-butyl ( (2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] ethyl oxyacetate in the form of crystals of melting point 140-141 ° C.

According to the same procedure, we have prepared the following examples:

Example 28: [Methyl-1 n-propyl-3 ((2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] methyl oxyacetate

Formula (I): R

= n-Propyl, R

= CH

, A = OR

, R

= CH

CO

Me,

Crystals, in the form of a dicyclohexylamine salt, with a melting point of 173-174 ° C.

Example 29: [1-methyl-n-propyl-3 ((2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] ethyl oxyacetate

Formula (I): R

= n-Propyl, R

= CH

, A = OR

, R

= CH

CO

And,

Melting point crystals 139-140 ° C.

Example 30: [1-methyl-n-propyl-3 ((2-carboxy-dichloro-3,6-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] ethyl oxyacetate

Formula (I): R1 = n-Propyl, R2 = CH3, A = OR3 R3 = CH2 CO2 And,<chemistry id="chem0078" num="0078"><img file="EP0449699A2_D0078.tif" /></chemistry>

From 3,6-dichlorophthalic anhydride.

Crystals in the form of dicydohexylamine salt, melting point 199-200 ° C.

Example 31: [Methyl-1 n-propyl-3 ((2-carboxy-3-chloro-3,6-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] methyl oxyacetate

Formula (I): R

= n-Propyl, R

= Methyl, A = OR

, R

= CH

CO

Me,

From 3,6-dichlorophthalic anhydride.

Melting point crystals 150-151 ° C.

Example 32: methyl [(trifluoro-2,2,2 ethyl) -1 n-propyl-3 ((2-carboxy-dichloro-3,6-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5]

Formula (I): R

= n-Propyl, R

= CH

CF

, A = OR

, R

= CH

CO

Me,

From 3,6-dichlorophthalic anhydride.

Melting point crystals 169-170 ° C.

Example 33: [(trifluoro-2,2,2 ethyl) -1 n-propyl-3 ((2-carboxy benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] methyl oxyacetate

Formula (I): R

= n-Propyl, R

= CH

CF

, A = OR

, R

= CH

CO

Me,

<chemistry id="chem0081" num="0081"><img file="EP0449699A2_D0081.tif" /></chemistry>Melting point crystals 189-192 ° C.

Example 34 Acid [n-propyl-3 ((2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] oxyacetic

Formula (I): R

= n-Propyl, R

= H, A = OR

, R

= CH

CO

H,

<chemistry id="chem0082" num="0082"><img file="EP0449699A2_D0082.tif" /></chemistry>0.9 g of [n-propyl-3 (4-amino-benzyl) -4 pyrazolyl-5] ethyl oxyacetate prepared in Example 26 are dissolved in 20 ml of acetonitrile in the presence of 0.45 g of phthalic anhydride . The mixture is left at room temperature overnight. The acetonitrile is evaporated in vacuo and the residue is taken up in an ethyl acetate / ether mixture to give crystals which are filtered off. These crystals are dissolved in dichloromethane and the solution is washed several times with a 1N sodium hydroxide solution. The combined aqueous phases are acidified by bubbling sulfur dioxide and the crystals obtained are drained and dried to give 0.5 g of acid. [n-propyl-3 ((2-carboxy-benzoyl amino) -4 benzyl) -4 pyrazol-yl-5] oxyacetic in the form of crystals of melting point 170-171 ° C.

Example 35 Acid [Methyl-1 n-propyl-3 [(2-sulfo benzoyl amino) -4 benzyl] -4 pyrazol-yl-5] oxy acetic

Formula (I): R

= n-Propyl, R

= CH

, A = OR

, R

= CH

CO

H,

Prepared according to the procedure of Example 34 from the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 168-170 ° C.

Example 36 Acid [1-methyl-3-n-butyl-5-hydroxy-pyrazol-yl-4] methyl-4 '2-biphenyl carboxylic

Formula (I): R

= n-Butyl, R

= Methyl, A = OR

, R

= H,

<chemistry id="chem0084" num="0084"><img file="EP0449699A2_D0084.tif" /></chemistry>1.5 g of methyl-1 n-butyl-3 hydroxy-5 (methoxycarbonyl-2 'biphenyl-yl-4) methyl-4 pyrazole prepared in Example 12 are suspended in 15 ml of a 1N sodium hydroxide solution and stirred for one hour at 40 ° C. The solution is washed with dichloromethane and then acidified by bubbling sulfur dioxide and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then evaporated in vacuo. The residue is diluted in ethyl acetate and extracted with a sodium bicarbonate solution, then the aqueous phase is acidified with sulfur dioxide and the crystals obtained are drained and then dried to give 1.1 g of acid [Methyl -1 n-butyl-3-hydroxy-5 pyrazol-yl-4] methyl-4 '2-biphenyl carboxylic in the form of crystals of melting point 228-30 ° C.

EXAMPLE 37 Acid [methyl-1 n-butyl-3 (carboxy-2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxyacetic

Formula (1): R

= n-Butyl, R

= CH

, A = OR

, R

= CH

CO

H,

<chemistry id="chem0085" num="0085"><img file="EP0449699A2_D0085.tif" /></chemistry>2.6 g of [methyl-1 n-butyl-3 (methoxycarbonyl-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] ethyl oxyacetate prepared in Example 19 are dissolved in 30 ml of ethanol . 1 g of sodium hydroxide tablet is added as well as 10 ml of water and the mixture is stirred at room temperature for two hours then heated for 3 hours at 50-55 ° C. After cooling, the solution is diluted with water and washed with ether, the aqueous phase is acidified by bubbling sulfur dioxide and extracted with chloroform. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give a residue which crystallizes in an ethyl acetate / ether mixture, giving 2 g of [Methyl-1 n-butyl-3 (2-carboxy-2'-biphenyl-) acid. yl-4) methyl-4 pyrazol-yl-5] oxyacetic in the form of crystals of melting point 153-154 ° C.

Example 38: 1-methyl-3-butyl (4-nitro-benzyl) -4 methoxy carbonyl 5-oxy pyrazole

Formula (I): R

= n-Butyl, R

= Methyl, A = OR

<chemistry id="chem0086" num="0086"><img file="EP0449699A2_D0086.tif" /></chemistry>12 g of Methyl-1 n-butyl-3 (4-nitro-benzyl) -4 hydroxy-5 pyrazole prepared in Example 7 are dissolved in 120 ml of 1,2-dichloro-ethane 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 4 hours at reflux. The solution is washed with water after cooling, then it is dried over magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel in a dichloromethane / acetone eluent (95/5) to give 6.6 g of methyl-1 n-butyl-3 (nitro-4 benzyl) -4 methoxy carbonyl oxy-5 pyrazole in the form of melting point crystals 44-47 ° C.

Example 39: Methyl-1 n-butyl-3 (4-amino benzyl) -4 methoxy carbonyl oxy-5 pyrazole

Formula (XI): R

= n-Butyl, R

= Methyl

<chemistry id="chem0087" num="0087"><img file="EP0449699A2_D0087.tif" /></chemistry>Prepared according to the procedure of Example 21. Oil used as it is for the following.

Example 40 Acid [(1-Methyl-3-n-butyl-5-hydroxy-pyrazolyl-4] Methyl phenyl-4-yl] 2-amino carbonyl-3,6-dichloro-benzoic acid

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, R3 = H,<chemistry id="chem0088" num="0088"><img file="EP0449699A2_D0088.tif" /></chemistry>

Prepared according to the procedure of Example 27 from 3,6-dichlorophthalic anhydride. Melting point crystals 172-174 ° C.

EXAMPLE 41 Acid [[ethoxy carbonyl methyl-1 n-propyl-3 hydroxy-5 pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl-2-dichloro-3,6 benzoic

Formula (I): R

= n-propyl, R

= CH

CO

And, A = OR

, R

= H,

<chemistry id="chem0089" num="0089"><img file="EP0449699A2_D0089.tif" /></chemistry>Prepared according to the procedure of Example 27 from 3,6-dichlorophthalic anhydride. Melting point crystals 150-153 ° C.

EXAMPLE 42 Ethyl carbonyl-methyl-1 n-propyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] ethyl oxyacetate

Formula (XI): R1 = n-propyl, R2 = CH2 CO2 And, R3 = CH2 CO2 And, V = NO2 Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 43: [Ethoxy carbonyl methyl-1 n-propyl-3 (4-amino benzyl) - 4 pyrazol-yl-5] ethyl oxyacetate

Formula (1): R1 = n-propyl, R2 = CH2 CO2 And, A = OR3, R3 = CH2 CO2 And, R4 = NH2 Prepared according to the procedure of Example 21. Oil used as it is for the following.

Example 44 Acid [[(Ethoxy carbonyl methyl) -1 n-propyl-3 (Ethoxy carbonyl methyl oxy) - 5 pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl-2 dlchloro-3,6-benzoic acid

Formula (1): R

= n-propyl, R

= CH

CO

And, A = OR

, R

= CH

CO

And,

<chemistry id="chem0090" num="0090"><img file="EP0449699A2_D0090.tif" /></chemistry>Prepared according to the procedure of Example 27 from 3,6-dichlorophthalic anhydride. Melting point crystals 189-191 ° C. In the form of dicydohexylamine salt.

Example 45: Acid [[1-methyl-n-propyl-3 (Ethoxy carbonyl methyl oxy) - 5 pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonlque.

Formula (I): R

= n-propyl, R

= Methyl, A = OR

, R

= CH

CO

H,

Prepared according to the procedure of Example 27 but with the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 203-205 ° C.

Example 46: N - [[Methyl-1 n-butyl-3 (4-nitro-benzyl) - 4 pyrazol-yl-5] oxyacetyl] morphollne

Formula (XI): R

= n-butyl, R

= Methyl,

<chemistry id="chem0092" num="0092"><img file="EP0449699A2_D0092.tif" /></chemistry>Prepared according to the procedure of Example 14 from N- (chloro acetyl) morpholine. Melting point crystals 98 ° C.

Preparation of N- (chloro acetyl) morpholine:<ul id="ul0017" list-style="none"><li>21.7 g of morpholine are dissolved in 250 ml of dichloromethane and the solution obtained is cooled by an ice / water mixture.</li><li>14.1 g of chloroacetyl chloride are added dropwise while maintaining the temperature at 0 ° C., then the mixture is stirred for 3 hours at room temperature and washed with a dilute solution of hydrochloric acid. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 29.8 g of N- (chloro acetyl) morpholine in the form of an oil of sufficient purity for the following.</li></ul>

Example 47: N - [[Methyl-1 n-butyl-3 (4-amino benryl) - 4 pyrazol-yl-5] oxyacetyl] morpholine

Formula (I): R

= n-butyl, R

= Methyl, A = OR

<chemistry id="chem0093" num="0093"><img file="EP0449699A2_D0093.tif" /></chemistry>Prepared according to the procedure of Example 21. Crystals of melting point 130 ° C.

Example 48: N - [[Methyl-1 n-butyl-3 [(2-sulfo benzoyl amino) - 4 benzyl] -4 pyrazol-yl-5] oxyacetyl] morpholine

Formula (I): R1 = n-butyl, R2 = Methyl, A = OR3, <chemistry id="chem0094" num="0094"><img file="EP0449699A2_D0094.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 236-237 ° C.

Example 49: [Methyl-1 n-butyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] oxy-2 ethanol

Formula (XI): R1 = n-butyl, R2 = Methyl, R3 = CH2CH20H, V = N02

12 g of methyl-1 n-butyl-3 (4-nitro-benzyl) -4 hydroxy-5 pyrazole prepared in Example 7 are dissolved in 150 ml of butanone-2. 4.6 g of sodium carbonate and 6 g of 2-bromo ethanol are added and the mixture is heated for 12 hours at reflux. After cooling, the solution is concentrated and then taken up in water and the pH is made alkaline by the addition of dilute sodium hydroxide. After extraction with dichloromethane, the organic phase is dried over magnesium sulphate and then evaporated to dryness. The residue obtained is chromatographed on silica gel in an eluent of ethyl acetate / acetone (6/4) to give 5g of [methyl-1 n-butyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] 2-oxy ethanol in the form of crystals with a melting point of 81 ° C.

Example 50: [Methyl-1 n-butyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] 2-oxy ethanol

Formula (1): Ri = n-butyl, R2 = Methyl, A = OR3, R3 = CH2CH2OH, R4= NH2 Prepared according to the procedure of Example 21. Oil used as it is for the following.

EXAMPLE 51 Acid [[Methyl-1 n-butyl-3 (2-hydroxyethoxy) -5 pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonic acid

Formula (I): R

= n-butyl, R

= Methyl, A = OR

, R

= CH

-CH

-OH ,

Prepared according to the procedure of Example 27 but using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 170-171 ° C.

Example 52: Methyl-1 (4-nitro benzyl) -4 n-Propyl-3 (N, N-dimethyl carbamoyl) 5-oxy pyrazole

Formula (XI): R, = n-Propyl, R2 = Methyl, IV = NO2<chemistry id="chem0096" num="0096"><img file="EP0449699A2_D0096.tif" /></chemistry>10 g of Methyl-1 (4-nitro-benzyl) -4 n-Propyl-3-hydroxy-5 pyrazole, prepared in Example 8, are dissolved in 100 ml of dichloromethane and 5 ml of triethylamine. 3.2 ml of N, N-dimethyl carbamoyl chloride are added dropwise and the mixture is then heated for 10 hours at reflux. After cooling, the mixture is taken up in water and washed with a solution of potassium bicarbonate. The chloroform phase is dried over magnesium sulphate and then evaporated under vacuum to give 9.1 g of methyl-1 (4-nitro-benzyl) -4 n-propyl-3 (N, N-dimethyl carbamoyl) oxy-5 pyrazole in the form of crystals with a melting point of 90 ° C.

Example 53: Methyl-1 (4-amino benzyl) -4 n-Propyl-3 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

<chemistry id="chem0097" num="0097"><img file="EP0449699A2_D0097.tif" /></chemistry>Prepared according to the procedure of Example 21. Crystals of melting point 138 ° C.

Example 54 Acid [[Methyl-1 n-propyl-3 (N, N-dimethyl carbamoyl) 5-oxy pyrazol-yl-4] methyl phenyl-yl-4] 2-aminocarbonyl benzene sulfonic acid

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0098" num="0098"><img file="EP0449699A2_D0098.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 210-2 ° C.

Example 55: Methyl-1 n-Propyl-3 (nltro-4 benzyl) -4 (N, N-diethyl carbamoyl) oxy-5 pyrazole

<chemistry id="chem0099" num="0099"><img file="EP0449699A2_D0099.tif" /></chemistry>Prepared according to the procedure of Example 52. Oil used as it is for the following.

Example 56: Methyl-1 n-Propyl-3 (4-amino benzyl) -4 (N, N-diethyl carbamoyl) oxy-5 pyrazole

<chemistry id="chem0100" num="0100"><img file="EP0449699A2_D0100.tif" /></chemistry>Prepared according to the procedure of Example 21. Crystals with a melting point of 100 ° C.

Example 57 Acid [[Methyl-1 n-Propyl-3 (N, N-diethyl carbamoyl) oxy-5 pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonic acid

Formula (I): Ri = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0101" num="0101"><img file="EP0449699A2_D0101.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 216-217 ° C.

Example 58: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 (N, N-dlmethyl carbamoyl) oxy-5 (4-nitro benzyl) -4 pyrazole

Formula (XI): R1 = n-Propyl, R2 = CH2CF3, V = NO2<chemistry id="chem0102" num="0102"><img file="EP0449699A2_D0102.tif" /></chemistry>Prepared according to the procedure of Example 52. Crystals of melting point 70 ° C.

Example 59: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 (N, N-dimethyl carbamoyl) oxy-5 (4-amino-benzyl) -4 pyrazole

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0103" num="0103"><img file="EP0449699A2_D0103.tif" /></chemistry>Prepared according to the procedure of Example 21. Crystals of melting point 82 ° C.

Example 60 Acid [[(2,2,2-trifluoroethyl) -1 n-Propyl-3 (N, N-dimethyl carbamoyl) 5-oxy pyrazol-yl-4] methyl phenyl-yl-4] amino carbonyl- 2 benzene sulfonic

Formula (I): R1 = n-Propyl, R2 = CH2CF3, AT = GOLD3, <chemistry id="chem0104" num="0104"><img file="EP0449699A2_D0104.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 159-161 ° C.

Example 61: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 (4-nitro-benzyl) -4 (2-hydroxyethoxy) -5 pyrazole

Formula (XI): R1 = n-Propyl, R2 = CH2CF3, R3 = CH2CH2OH, V = N02 Prepared according to the procedure of Example 49.

71 ° C melting point crystals.

Example 62: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 (4-amino benzyl) -4 (2-hydroxy ethoxy) -5 pyrazole

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, R3 = CH2CH2OH, R4 = NH2 Prepared according to the procedure of Example 21. Oil used as it is for the following.

EXAMPLE 63 Acid [[(2,2,2,2-trffioroethyl) -1 n-Propyl-3 (2-hydroxyethoxy) -5 pyrazol-yl-4] 4-methylphenyl-yl-4] amino carbonyl-2 benzene sulfonic

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, R3 = CH2CH20H,<chemistry id="chem0105" num="0105"><img file="EP0449699A2_D0105.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 211-3 ° C

Example 64: (2-Methoxyphenyl) -1 [1-methyl-n-Propyl-3 (4-nitro-benzyl) -4 pyrazol-yl-5] oxy-acetyl-4 piperazine

Formula (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0106" num="0106"><img file="EP0449699A2_D0106.tif" /></chemistry>

Prepared according to the procedure of Example 14 from (chloro acetyl) -1 (2-methoxyphenyl) -4 piperazine.

Oil used as it is for the continuation.

The preparation of (chloro acetyl) -1 (2-methoxyphenyl) -4 piperazine is carried out according to the procedure used for the synthesis of N-chloro acetyl morpholine described in Example 46.

Example 65: (2-Methoxyphenyl) -1 [1-methyl-n-Propyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] oxy acetyl-4 piperazine

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0107" num="0107"><img file="EP0449699A2_D0107.tif" /></chemistry>Prepared according to the procedure of Example 21. Crystals with a melting point of 145 ° C.

Example 66: (2-Methoxyphenyl) -1 [[1-methyl-n-propyl-3 [(2-sulfo benzoyl amino) -4 benzyl] -4 pyrazol-yl-5] oxyacetyl] -4 piperazine

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0108" num="0108"><img file="EP0449699A2_D0108.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 226-227 ° C.

Example 67: (Cyano-2 'blphenyl-yl-4) 2-methyl-3-oxo-ethyl hexanoate

Formula (V): R1 = n-Propyl,<chemistry id="chem0109" num="0109"><img file="EP0449699A2_D0109.tif" /></chemistry>Prepared according to the procedure of Example 6. Oil used as it is for the following.

Example 68: Methyl-1 n-Propyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 hydroxy-5 pyrazole

Formula (IX): R1 = n-Propyl,<chemistry id="chem0110" num="0110"><img file="EP0449699A2_D0110.tif" /></chemistry>Prepared according to the procedure of Example 7. Crystals of melting point 164 ° C.

Example 69: [1-methyl-n-Propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = n-Propyl, R2= Methyl, R3 = CH2CO2And,<chemistry id="chem0111" num="0111"><img file="EP0449699A2_D0111.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 70: [Methyl-1 n-Propyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (1): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CO2 And,<chemistry id="chem0112" num="0112"><img file="EP0449699A2_D0112.tif" /></chemistry>

11 g of [Methyl-1 n-Propyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy ethyl acetate prepared in Example 69 are dissolved in 75 ml of toluene. 6.5 g of trimethyl tin azide are added and the mixture is heated under reflux for 24 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel, in an eluent Chloroform / Methanol 9/1, to give 6.7 g of [Methyl-1 n-Propyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy ethyl acetate in the form of crystals with melting point 187-189 ° C.

Example 71: Methyl-1 n-Propyl-3 hydroxy-5 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazole

Formula (1): R1 = n-Propyl, R2 = Methyl, A = OH,<chemistry id="chem0113" num="0113"><img file="EP0449699A2_D0113.tif" /></chemistry>5 g of Methyl-1 n-Propyl-3 (cyano-2 'biphenyl-yl-4) methyl-4-hydroxy-5 pyrazole, prepared in Example 68, are dissolved in 50 ml of toluene. 4 g of trimethyl tin azide are added and the mixture is heated under reflux for 14 hours. After cooling 10 ml of methanol and 10 ml of chloroform are added, the crystals formed are drained, 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, then the mixture is stirred for 1 hour at room temperature. The solvents are evaporated in vacuo and the residue is taken up with a dilute sodium hydroxide solution, then washed with ethyl acetate. The aqueous phase is neutralized by bubbling sulfur dioxide, the residue slowly crystallizes in water to give, after washing with acetone, 3.1 g of 1-methyl-3-propyl-3-hydroxy-5 [(5-tetrazolyl) -2 'biphenyl-yl-4] methyl-4 pyrazole in the form of crystals of melting point 150-153 ° C.

Example 72: Methyl-1 n-Butyl-3 hydroxy-5 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OH,<chemistry id="chem0114" num="0114"><img file="EP0449699A2_D0114.tif" /></chemistry>

Prepared according to the procedure of Example 71.

Melting point crystals 176-7 ° C.

Example 73: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 hydroxy-5 (2-cyano 'biphenyl-yl-4) 4-methyl-pyrazole

Formula (IX): R1 = n-Propyl, R2 = CH2CF3, <chemistry id="chem0115" num="0115"><img file="EP0449699A2_D0115.tif" /></chemistry>Prepared according to the procedure of Example 7 from (trifluoro-2,2,2-ethyl) hydrazine. Melting point crystals 154 ° C.

Example 74: (2,2,2,2-Trifluoroethyl) -1 n-Propyl-3 hydroxy-5 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazole

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OH,<chemistry id="chem0116" num="0116"><img file="EP0449699A2_D0116.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 218-220 ° C.

Example 75: [Methyl-1 n-Butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy-2 ethanol

Formula (XI): R1 = n-Butyl, R2 = Methyl, R3 = CH2CH2OH,<chemistry id="chem0117" num="0117"><img file="EP0449699A2_D0117.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 76: [Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazole-yl-5] oxy-2 ethanol

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, R3 = CH2CH2OH,<chemistry id="chem0118" num="0118"><img file="EP0449699A2_D0118.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 105-8 ° C.

Example 77: [(Trifluoro-2,2,2 ethyl) -1 n-Butyl-3 (2-cyano-biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = n-Butyl, R2 = CH2CF3, R3 = CH2CO2And,<chemistry id="chem0119" num="0119"><img file="EP0449699A2_D0119.tif" /></chemistry>Prepared according to procedure 14. Oil used as it is for the continuation.

Example 78: [(2,2,2,2-trifluoro) -1 n-Butyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (I): R1 = n-Butyl, R2 = CH2CF3, A = OR3, R3 = CH2CO2And,<chemistry id="chem0120" num="0120"><img file="EP0449699A2_D0120.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 140-1 ° C.

Example 79: (2,2,2,2-Trifluoroethyl) -1 n-Butyl-3 (2-cyano-biphenyl-yl-4) methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (XI): R1 = n-Butyl, R2 = CH2CF3, <chemistry id="chem0121" num="0121"><img file="EP0449699A2_D0121.tif" /></chemistry>Prepared according to the procedure of Example 52. Oil used as it is for the following.

Example 80: (2,2,2,2-Trifluoroethyl) -1 n-Butyl-3 [(tetrazolyl-5) -2'biphenyl -yl-4] methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (1): R1 = n-Butyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0122" num="0122"><img file="EP0449699A2_D0122.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 151-2 ° C.

Example 81: Methyl-1 n-Butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (XI): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0123" num="0123"><img file="EP0449699A2_D0123.tif" /></chemistry>Prepared according to the procedure of Example 52. Oil used as it is for the following.

Example 82: Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, <chemistry id="chem0124" num="0124"><img file="EP0449699A2_D0124.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 160 ° C.

Example 83: [(Trifluoro-2,2,2 ethyl) -1 n-Propyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = n-Propyl, R2 = CH2CF3, R3 = CH2CO2And,<chemistry id="chem0125" num="0125"><img file="EP0449699A2_D0125.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

EXAMPLE 84

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, R3 = CH2CO2And,<chemistry id="chem0126" num="0126"><img file="EP0449699A2_D0126.tif" /></chemistry>Prepared according to the procedure of Example 70. Charcoal point crystals 146 ° C.

Example 85: Methyl-1 n-Propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0127" num="0127"><img file="EP0449699A2_D0127.tif" /></chemistry>Prepared according to the procedure of Example 52. Oil used as it is for the following.

Example 86: Methyl-1 n-Propyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4] methyl-4 (N, N-dimethyl carbamoyl) oxy-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0128" num="0128"><img file="EP0449699A2_D0128.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 103-5 ° C.

Example 87: [1-methyl-n-Propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = n-Propyl, R2 = Methyl, R3 = CH2CH20H,<chemistry id="chem0129" num="0129"><img file="EP0449699A2_D0129.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 88: [Methyl-1 n-Propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy-2 ethanol

Formula (1): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CH20H,<chemistry id="chem0130" num="0130"><img file="EP0449699A2_D0130.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 120-122 ° C.

Example 89: [Methyl-1 n-Butyl-3 (cyano-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = n-Butyl, R2 = Methyl, R3 = CH2CO2And,<chemistry id="chem0131" num="0131"><img file="EP0449699A2_D0131.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 90: [Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2'blphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, R3 = CH2CO2And,<chemistry id="chem0132" num="0132"><img file="EP0449699A2_D0132.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 142-3 ° C.

Example 91: [(2,2,2,2-trifluoro) -1 n-Propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = n-Propyl, R2 = CH2CF3, R3 = CH2CH2OH,<chemistry id="chem0133" num="0133"><img file="EP0449699A2_D0133.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 92: [(2,2,2-trifluoroethyl) -1 n-Propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy-2 ethanol

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, R3 = CH2CH2OH,<chemistry id="chem0134" num="0134"><img file="EP0449699A2_D0134.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 167 ° C.

Example 93: Methoxy-1 octane dlone-2,4

Formula (III): R1 = n-Butyl, R '= CH3, q = 1

200 ml of hexanone-2 and 102 ml of methyl methoxy acetate are added dropwise to 400 ml of toluene containing 26.9 g of sodium, divided hot. The temperature during the addition is maintained between 60 ° C and 70 ° C. At the end of the addition, 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 in a dilute sodium hydroxide solution, the aqueous phase is washed with ether 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, the residue is distilled under reduced pressure to give 98.6 g of methoxy-1 octane-2,4-dione in the form of a liquid of point d 'boil Eb16 = 115-120 ° C.

Example 94: 1-Methoxy-2,4-heptane dlone

Formula (III): R1 = n-Propyl, R '= CH3, q = 1 Prepared according to the procedure of Example 93 from pentanone-2. Boiling point liquid Eb20 = 100-110 ° C.

Example 95: Methoxy-1 (4-nitro benryl) -3 heptane dione-2,4

Formula (VI): R1 = n-Propyl, R '= CH3, V = N02, q = 1

135 g of 1-methoxy-heptane-2,4-dione prepared in Example 94, are dissolved in 1.5 liters of tetrahydrofuran. 123.3 g of 4-nitro-benzyl bromide, 197 ml of N, N-diisopropyl ethylamine and 49.5 g of lithium bromide are added and the mixture is heated under reflux for 15 hours. The solvent is evaporated in vacuo and the residue is taken up in 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, then with hot methanol. The filtrates are combined and evaporated to dryness, then the residue is taken up in isopropyl ether. The crystals obtained are washed with isopropyl ether and dried at 30 ° C. under vacuum to give 85.7 g of (4-nitro-benzyl) -3-methoxy-1-heptane-2,4-dione in the form of crystals of melting point. 55 ° C.

According to the same procedure, the following two examples were prepared:

Example 96: Methoxy-1 (cyano-2'biphenyl-yl-4) methyl-3 heptane dlone-2,4

Formula (VI): R1 = n-Propyl, R '= CH3, <chemistry id="chem0135" num="0135"><img file="EP0449699A2_D0135.tif" /></chemistry>Oil used as it is for the continuation.

Example 97: Methoxy-1 (Cyano-2 'biphenyl-yl-4) methyl-3 octane dlone-2,4

Formula (VI): R1 = n-Butyl, R '= CH3, <chemistry id="chem0136" num="0136"><img file="EP0449699A2_D0136.tif" /></chemistry>

Oil used as it is for the continuation.

Example 98: n-Propyl-3 (nitro-4 benzyl) -4 methoxy methyl-5 pyrazole

Formula (XIII): R1 = n-Propyl, R '= CH3, q = 1, V = NO2

20 g of (4-nitro-benzyl) -3-1-methoxy-heptane-2,4-dione, prepared in Example 95, are dissolved in 400 ml of ethanol and 4 ml of hydrazine hydrate are added, the mixture is heated at reflux for 2 hours. The solvent is evaporated to dryness under vacuum and the residue is taken up in isopropyl ether, the crystals obtained are drained to give 19.5 g of (4-nitro-benzyl) -4 n-3-propyl-methoxy-5-methyl-pyrazole under form of crystals with a melting point of 124 ° C.

According to the same procedure, the following two examples were prepared:

Example 99: n-Propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole

Formula (XIII): R1 = n-Propyl, R '= CH3, <chemistry id="chem0137" num="0137"><img file="EP0449699A2_D0137.tif" /></chemistry>

Oil used as it is for the continuation.

Example 100: n-Butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole

Formula (XIII): R1 = n-Butyl, R '= CH3, <chemistry id="chem0138" num="0138"><img file="EP0449699A2_D0138.tif" /></chemistry>

Oil used as it is for the continuation.

Example 101: (Trifluoro-2,2,2-ethyl) -1 n-butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole

Formula (XII): R1 = n-Butyl, R2 = CH2CF3, R3 = CH3, q = 1 <chemistry id="chem0139" num="0139"><img file="EP0449699A2_D0139.tif" /></chemistry>Prepared according to the procedure of Example 98 from (trifluoro-2,2,2-ethyl) hydrazine.

After chromatography on silica gel, the desired product is obtained with the eluent ethyl acetate / cyclohexane 2/8 in the form of an oil used as it is for the following.

Example 102: Methyl-1 n-Propyl-3 (4-nitro-benzyl) -4 methoxy 5-methyl-pyrazole

Formula (XII): R1 = n-Propyl, R2 = Methyl, R '= Methyl, V = NO2, q = 1

5 g of n-Propyl-3 (4-nitro-benzyl) -4 methoxy-methyl-5 pyrazole, 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-7 ene). The mixture is heated for 8 hours at 45 ° C, then the solvent is evaporated. The residue is taken up in dilute hydrochloric acid, then extracted with ether. The organic phase is dried over magnesium sulphate then evaporated under vacuum to give an oily residue which is chromatographed on silica gel with an eluent of ether / cyclopentane (7/3) to give 2.5 g of methyl-1 n-propyl-3 ( 4-nitro benzyl) -4 5-methoxy methyl-pyrazole in the form of crystals with a melting point of 73 ° C. The following two examples were prepared according to the procedure of Example 102:

Example 103: Methyl-1 n-propyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole

Formula (XII): R1 = n-Propyl, R2 = Methyl, R '= Methyl,<chemistry id="chem0140" num="0140"><img file="EP0449699A2_D0140.tif" /></chemistry>

Oil used as it is for the continuation.

Example 104: Methyl-1 n-butyl-3 (cyano-2'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole

Formula (XII): R1 = n-Butyl, R2 = Methyl, R '= Methyl,<chemistry id="chem0141" num="0141"><img file="EP0449699A2_D0141.tif" /></chemistry>

Oil used as it is for the continuation.

Example 105: Methyl-1 n-propyl-3 (4-amlno benryl) -4 methoxy 5-methyl-pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH2OCH3, R4 = NH2 Prepared according to the procedure of Example 21. Oil used as it is for the following.

Example 106: n-Propyl-3 (4-amino-benzyl) -4 methoxy-methyl-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = H, A = CH20 CH3, R4 = NH2 Prepared according to the procedure of Example 21. Crystals of melting point 126 ° C.

EXAMPLE 107 Acid [(1-Methyl-3-propyl-3-methoxy-5-methyl-pyrazol-yl-4) Methyl-4-phenyl] Amino-2-carbonyl benzene sulfonyl

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH20CH3, <chemistry id="chem0142" num="0142"><img file="EP0449699A2_D0142.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 126 ° C.

Example 108 Acid [(n-propyl-3 methoxy-methyl-5 pyrazol-yl-4) methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonic acid

Formula (I): R1 = n-Propyl, R2 = H, A = CH20CH3, <chemistry id="chem0143" num="0143"><img file="EP0449699A2_D0143.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 253-256 ° C.

Example 109: Methyl-1 n-Propyl-3 (4-nitro-benryl) -4 bromo-methyl-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH2Br, R4 = N02

4.5 g of Methyl-1 n-Propyl-3 (4-nitro-benzyl) -4 methoxy-methyl 5-pyrazole, prepared in Example 102, are dissolved in 140 ml of chloroform. 2.8 ml of boron tribromide are added dropwise at a temperature between 0 ° C and 5 ° C, the mixture is then stirred for one hour at this temperature, then 2 hours at room temperature. A dilute sodium hydroxide solution is added to the mixture and the organic phase is decanted, dried and evaporated in vacuo to give 5 g of methyl-1 n-propyl-3 (4-nitro-benzyl) -4-bromomethyl-5 pyrazole in the form of an oil used as it is for the continuation.

Example 110: n-Propyl-3 (4-nitro-benzyl) -4 bromomethyl-5 pyrazole

Formula (1): R1 = n-Propyl, R2 = H, A = CH2Br, R4 = N02 Prepared according to the procedure of Example 109. Crystals of melting point 120 ° C.

Example 111: Methyl-1 n-Propyl-3 (4-nitro-benzyl) -4 hydroxy-5-methyl-pyrazole

Formula (XII): R1 = n-Propyl, R2 = Methyl, R '= H, V = NO2, q = 1

6.5 g of methyl-1 n-propyl-3 (4-nitro-benzyl) -4-bromomethyl-5 pyrazole, 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 heated for 3 hours at reflux. The solvents are evaporated under vacuum and the residue is taken up in water and extracted with ether. The organic phase is dried over magnesium sulphate and then evaporated under vacuum to give a residue which crystallizes in isopropyl ether to give 3.8 g of methyl-1 n-propyl-3 (4-nitro-benzyl) -4 hydroxy methyl- 5 pyrazole in the form of crystals with a melting point of 134 ° C.

Example 112: n-Propyl-3 (4-nitro-benzyl) -4 hydroxy-methyl-5 pyrazole

Formula (XIII): R1 = n-Propyl, R '= H, V = N02, q = 1 Prepared according to the procedure of Example 111. Crystals with a melting point of 125 ° C.

Example 113: Methyl-1 n-Propyl-3 (4-amino benryl) -4 hydroxy-5-methyl-pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH20H, R4 = NH2 Prepared according to the procedure of Example 21. Crystals of melting point 133 ° C.

Example 114: n-Propyl-3 (4-amino benzyl) -4 hydroxy methyl-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = H, A = CH20H, R4 = NH2 Prepared according to the procedure of Example 21. Oil used as it is for the following.

Example 115 Acid [(1-methyl-n-propyl-3-hydroxy-5-methyl-pyrazol-yl-4) methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonic acid

Fonmule (I): R1 = n-Propyl, R2 = Methyl, A = CH2OH,<chemistry id="chem0144" num="0144"><img file="EP0449699A2_D0144.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 255-257 ° C.

Example 116 Acid ((n-Propyl-3 hydroxy-methyl-5 pyrazol-yl-4) methyl phenyl-yl-4] amino carbonyl-2 benzene sulfonic acid

Formula (I): R1 = n-Propyl, R2 = H, A = CH20H<chemistry id="chem0145" num="0145"><img file="EP0449699A2_D0145.tif" /></chemistry>

Prepared according to the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.

Melting point crystals 168-170 ° C.

Example 117: Methyl-1 n-propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 methoxy methyl-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH20CH3<chemistry id="chem0146" num="0146"><img file="EP0449699A2_D0146.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 128-130 ° C.

EXAMPLE 118 1-methyl-n-Butyl-3 [(tetrazolyl-5) 2 ′ biphenyl-yl-4] methyl-4 methoxy methyl-5 pyrazole

Formula (1): R1 = n-Butyl, R2 = Methyl, A = CH2OCH3<chemistry id="chem0147" num="0147"><img file="EP0449699A2_D0147.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 134-135 ° C.

Example 119: (2,2,2,2-Trifluoroethyl) -1 n-butyl-3 [(5-tetrazolyl) -2 'biphenyl-yl-4] 4-methyl-5-methoxy methyl-pyrazole

Formula (I): R1 = n-Butyl, R2 = CH2CF3, A = CH2OCH3<chemistry id="chem0148" num="0148"><img file="EP0449699A2_D0148.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 172-173 ° C.

EXAMPLE 120 3-Oxo-5-methylhexanoate

Formula (II): R1 = 2-methyl propyl, R10 = Ethyl Prepared according to the same procedure of Example 1. Boiling point liquid Eb10 = 100-110 ° C.

Example 121: (2-Cyano-biphenyl-yl-4) 2-methyl-3-oxo-5-methyl-hexanoate

Formula (V): R1 = 2-Methyl Propyl, R10 = Ethyl,<chemistry id="chem0149" num="0149"><img file="EP0449699A2_D0149.tif" /></chemistry>Prepared according to the procedure of Example 6. Oil used as it is for the following.

Example 122: Methyl-1 (2-methyl propyl) -3 (2-cyano-biphenyl-yl-4) 4-methyl-5-hydroxy-pyrazole

Formula (IX): R1 = 2-Methyl Propyl, R2 = Methyl,<chemistry id="chem0150" num="0150"><img file="EP0449699A2_D0150.tif" /></chemistry>Prepared according to the procedure of Example 7. Crystals of melting point 163 ° C.

Example 123: (Trif

uoro-2,2,2 ethyl) -1 (2-methyl propyl) -3 (2-cyano-biphenyl-yl-4) 4-methyl-5-hydroxy-pyrazole

Formula (IX): R1 = 2-Methyl Propyl, R2 = CH2CF3, <chemistry id="chem0151" num="0151"><img file="EP0449699A2_D0151.tif" /></chemistry>Prepared according to the procedure of Example 7. Oil used as it is for the following.

Example 124: [Methyl-1 (2-methyl propyl) -3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = 2-Methyl Propyl, R2 = Methyl, R3 = CH2C02 And,<chemistry id="chem0152" num="0152"><img file="EP0449699A2_D0152.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 125: [Methyl-1 (2-methyl propyl) -3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy ethyl acetate

Formula (1): R1 = 2-Methyl Propyl, R2 = Methyl, A = OR3, R3 = CH2C02And,<chemistry id="chem0153" num="0153"><img file="EP0449699A2_D0153.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 172-173 ° C.

Example 126: [(2,2,2,2-Trifluoroethyl) -1 (2-methylpropyl) -3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = 2-Methyl Propyl, R2 = CH2CF3, R3 = CH2CO2And,<chemistry id="chem0154" num="0154"><img file="EP0449699A2_D0154.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 127: [(2,2,2,2-Trifluoro) -1 (2-methyl-propyl) -3 [(5-tetrazolyl) -2'biphenyl-yl-4] 4-methyl pyrazol-yl-5] oxy acetate d 'ethyl

Formula (I): R1 = 2-Methyl Propyl, R2 = CH2CF3, A = OR3<chemistry id="chem0155" num="0155"><img file="EP0449699A2_D0155.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 114-115 ° C.

Example 128: [(2,2,2,2-Trifluoroethyl) -1 (2-methyl-propyl) -3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = 2-Methyl Propyl, R2 = CH2CF3, R3 = CH2CH2OH,<chemistry id="chem0156" num="0156"><img file="EP0449699A2_D0156.tif" /></chemistry>Prepared according to the procedure of Example 49. Crystals with a melting point of 116 ° C.

Example 129: [(2,2,2 Trifluoroethyl) -1 (2-methyl propyl) -3 [(5-tetrazolyl) -2'biphenyl-yl-4] 4-methyl pyrazol-yl-5] oxy- 2 ethanol

Formula (1): R1 = 2-Methyl Propyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0157" num="0157"><img file="EP0449699A2_D0157.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 145-146 ° C.

Example 130: N - [[Methyl-1 n-Butyl-3 [(trifluoro methyl sulfonyl-2 amino benzoyl) 4-amino benryl] -4 pyrazol-yl-5] oxy acetyl] morpholine

Formula (1): R1 = n-Butyl, R2 = Methyl, A = OR3, <chemistry id="chem0158" num="0158"><img file="EP0449699A2_D0158.tif" /></chemistry>4.3 g of N - [[Methyl-1n-Butyl-3 (4-amino-benzyl) -4 pyrazol-yl-5] oxy acetyl] morpholine, prepared in Example 47, are dissolved in 20 ml of chloroform as presence of 1.54 ml of triethylamine. 3.52 g of N- (trifluoromethyl sulfonyl) anthranilic acid chloride (prepared according to references CA: 96 (13): 103651 z and CA 97 (7): 55500 w) dissolved in 10 ml of chloroform, are added drop by drop at room temperature, then the mixture is heated for 2 hours at 50 ° C. and left overnight at room temperature. The solution is washed with dilute hydrochloric acid, dried and evaporated in vacuo. The residue is taken up in dichloromethane and extracted with a dilute sodium hydroxide solution. 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, the oil obtained crystallizes from ether to give 4.6 g of N- [[methyl-1 n-butyl-3 [(trifluoromethyl sulfonyl-amino 2-benzoyl) amino-4 benzyl] -4 pyrazol-yl-5] oxy acetyl] morpholine in the form of crystals of melting point 190 ° C.

Example 131: (Nltro-2 'biphenyl-yl-4) methyl-2 oxo-3 ethyl hexanoate

Formula (V): R1 = n-Propyl, R10 = Ethyl,<chemistry id="chem0159" num="0159"><img file="EP0449699A2_D0159.tif" /></chemistry>Prepared according to the procedure of Example 6, starting from 4-nitro-2'chloro-methyl-biphenyl. Oil used as it is for the continuation.

2-nitro-4-chloro-methyl biphenyl was prepared by chloromethylation of 2-nitro-biphenyl according to the references:<ul id="ul0018" list-style="none"><li>- CA 70 (25): 114837 d</li><li>- CA 69 (2): 3704 t</li></ul>

Example 132: Methyl-1 n-Propyl-3 (Nitro-2'biphenyl-yl-4) methyl-4hydroxy-5 pyrazole

Formula (IX): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0160" num="0160"><img file="EP0449699A2_D0160.tif" /></chemistry>Prepared according to the procedure of Example 7. Crystals of melting point 179-182 ° C.

Example 133: [Methyl-1 n-Propyl-3 (2-nitro-2'biphenyl-yl-4) methyl-4pyrazol-yl-5] oxy methyl acetate

Formula (XI): Ri = n-Propyl, R2 = Methyl, R3 = CH2CO2Me,<chemistry id="chem0161" num="0161"><img file="EP0449699A2_D0161.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 134: [1-methyl-n-propyl-3 (2'-amino-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy methyl acetate

Formula (I): Ri = n-Propyl, R2 = Methyl, A = OR3 R3 = CH2CO2Me,<chemistry id="chem0162" num="0162"><img file="EP0449699A2_D0162.tif" /></chemistry>Prepared according to the procedure of Example 21. Oil used as it is for the following.

Example 135: [methyl-1 n-propyl-3 (trifluoro methyl sulfonyl amlmo-2'blphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy methyl acetate

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CO2Me,<chemistry id="chem0163" num="0163"><img file="EP0449699A2_D0163.tif" /></chemistry>1 g of [Methyl-1 n-Propyl-3 (amino-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy ethyl acetate, 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 0 ° C. and 0.43 ml of trifluoro methane sulphonic anhydride are added dropwise. The mixture is then stirred for one hour at room temperature, the organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue obtained crystallizes from isopropyl ether to give 0.7 g of [Methyl-1 n-Propyl-3 (trifluoro methyl sulfonyl-amino 2 'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy acetate ethyl as crystals of melting point 114-116 ° C.

Example 136: [1-methyl-n-Propyl-3 (2-carbethoxy-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = n-Propyl, R2 = Methyl, R3 = CH2CH2OH,<chemistry id="chem0164" num="0164"><img file="EP0449699A2_D0164.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 137: [Methyl-1 n-Propyl-3 (carboxy-2'blphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy-2 ethanol

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CH2OH,<chemistry id="chem0165" num="0165"><img file="EP0449699A2_D0165.tif" /></chemistry>Prepared according to the procedure of Example 37. Crystals with a melting point of 168-170 ° C.

Example 138: [(Cyano-2-thlenyl-3) -4 benzyl] -2 ethyl oxo-3 hexanoate

Formula (V): Ri = n-Propyl, R10 = Ethyl,<chemistry id="chem0166" num="0166"><img file="EP0449699A2_D0166.tif" /></chemistry>

Prepared according to the procedure of Example 6 from (2-cyano-3-thienyl) -4 benzyl bromide.

Preparation of (2-cyano-3-thienyl) -4-benzyl bromide:

A) (4-methylphenyl) -3 thiophene-2 carboxylic acid:

25 g of ethyl (4-methylphenyl) -3 thiophene-2 carboxylate prepared according to the reference, FISSELMANN. H; HABITCH. H; Ger. Offen. : 1,092,929 (1960), CA: 57, 5894 g, are dissolved in 580 ml of ethanol and 50 ml of water. 6.2 g of sodium hydroxide tablet are added and the mixture is heated for 2 hours at reflux, poured into water and acidified with concentrated hydrochloric acid. The crystals obtained are drained and dried to give 20.7 g of (4-methylphenyl) -3 thiophene-2 carboxylic acid in the form of crystals with a melting point of 172 ° C.

B) (4-methylphenyl) -3 thiophene-2 carboxamide:

20.7 g of (4-methylphenyl) -3 thiophene-2 carboxylic acid, prepared in A), are dissolved in 200 ml of anhydrous toluene with 10.4 ml of thionyl chloride. The mixture is brought to reflux for three hours and is then evaporated to dryness. The oily residue is added dropwise to a 28% ammonia solution at 25 ° C. After one hour of stirring, the mixture is extracted with chloroform, the organic phase is washed with water, dried over magnesium sulfate and evaporated under vacuum to give 18 g of (4-methylphenyl) -3 thiophene-2 carboxamide in the form of crystals with melting point 128-130 ° C.

C) (4-methylphenyl) -3 thiophene-2 carbonitrile:

18 g of (4-methylphenyl) -3 thiophene-2 carboxamide, prepared in B), are dissolved in 36 ml of phosphorus oxychloride and the mixture is heated at reflux 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 and filtered on animal black and then evaporated under vacuum to give 12 g of (4-methylphenyl) -3 thiophene-2 carbonitrile in the form of an oil used as it is for the following.

D) (2-cyano-3-thienyl) -4 benzyl bromide:

12 g of (4-methylphenyl) -3 thiophene-2 carbonitrile, prepared in C), are dissolved in 100 ml of carbon tetrachloride. 11.3 g of N-bromo succinimide are added as well as 10 mg of benzoyl peroxide. The mixture is heated to reflux until the succinimide has completely passed over the solution. The crystals are filtered and the solvent concentrated in vacuo to give 16 g of (2-cyano-3-thienyl) -4-benzyl bromide in the form of an oil used as such for the following.

Example 139: Methyl-1 n-propyl-3 [(Cyano-2 thienyl-3) -4 benzyl] -4 hydroxy-5 pyrazole

Formula (IX): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0167" num="0167"><img file="EP0449699A2_D0167.tif" /></chemistry>Prepared according to the procedure of Example 7. Crystals with a melting point of 110-115 ° C.

Example 140: [Methyl-1 n-propyl-3 [(Cyano-2 thienyl-3) -4 benryl] -4 pyrazol-yl-5] oxy ethyl acetate

Formula (XI): R1 = n-Propyl, R2 = Methyl, R3 = CH2C02And,<chemistry id="chem0168" num="0168"><img file="EP0449699A2_D0168.tif" /></chemistry>Prepared according to the procedure of Example 14. Oil used as it is for the following.

Example 141: [Methyl-1 n-propyl-3 [[(tetrazolyl-5) -2 thienyl-3] -4 benzyl] -4 pyrazol-yl-5] oxy ethyl acetate

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CO2And,<chemistry id="chem0169" num="0169"><img file="EP0449699A2_D0169.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 201 ° C.

Example 142: [(2-carbethoxy-3-thienyl) -4 benzyl] -2 3-oxo ethyl hexanoate

Formula (V): R1 = n-Propyl, R10 = Ethyl,<chemistry id="chem0170" num="0170"><img file="EP0449699A2_D0170.tif" /></chemistry>Prepared according to the procedure of Example 6 from (2-carbethoxy-3-thienyl) -4 benzyl bromide. Oil used as it is for the continuation.

Preparation of benzyl (2-carbethoxy-3-thienyl) -4-bromide:<ul id="ul0019" list-style="none"><li>43.4 g of ethyl (4-methylphenyl) -3 thiophene-2 carboxylate, prepared according to the reference, FISSELMANN. H; HABITCH. ; Ger. Offen .: 1,092,929 (1960); CA: 57, 5894 g, are dissolved in 250 ml of carbon tetrachloride. 33 g of N-bromo succinimide and 10 mg of benzoyl peroxide are added and the mixture is heated under reflux for one hour, the succinimide crystals are drained and the solvent is evaporated in vacuo to give 56.6 g of (carbethoxy bromide) -2 thienyl-3) -4 benzyl in the form of crystals with a melting point of 55 ° C.</li></ul>

Example 143: Methyl-1 n-Propyl-3 [(2-carbethoxy-3-thienyl) -4 benryl] -4 hydroxy-5 pyrazole

Formula (IX): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0171" num="0171"><img file="EP0449699A2_D0171.tif" /></chemistry>Prepared according to the procedure of Example 7. Crystals of melting point 130-132 ° C.

Example 144: [1-Methyl-propyl-3 [(2-carbethoxy-3-thienyl) -4 benryl] -4 pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = n-Propyl, R2 = Methyl, R3 = CH2CH2OH,<chemistry id="chem0172" num="0172"><img file="EP0449699A2_D0172.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 145: [1-Methyl-propyl-3 [(2-carboxy-3-thienyl) -4 benzyl] -4 pyrazol-yl-5] 2-oxy ethanol

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, R3 = CH2CH20H,<chemistry id="chem0173" num="0173"><img file="EP0449699A2_D0173.tif" /></chemistry>Prepared according to the procedure of Example 37. Crystals of melting point 118-120 ° C.

Example 146: (2-Methoxy-phenyl) -1 [(2,2,2-trifluoro-ethyl) -1 n-Propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy 4-acetyl plperazine

Formula (XI): R1 = n-Propyl, R2 = CH2 CF3, <chemistry id="chem0174" num="0174"><img file="EP0449699A2_D0174.tif" /></chemistry>Prepared according to the procedure of Example 64. Oil used as it is for the following.

Example 147: (2-Methoxyphenyl) -1 [(2,2,2-trifluoroethyl) -1 n-Propyl-3 [(tetrazolyl-5) -2 'biphenyl-yl-4) methyl-4 pyrazol-yl -5] oxy acetyl-4 piperazine

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0175" num="0175"><img file="EP0449699A2_D0175.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 158-160 ° C.

Example 148: N - [((2,2,2-trifluoroethyl) -1 n-Propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy acetyl] morpholine

Formula (XI): R1 = n-Propyl, R2 = CH2CF3, <chemistry id="chem0176" num="0176"><img file="EP0449699A2_D0176.tif" /></chemistry>Prepared according to the procedure of Example 46. Oil used as it is for the following.

Example 149: N - [[(2,2,2-trifluoroethyl) -1 n-Propyl-3 [(tetrazolyl-5) -2'biphenyi-yl-4] methyl-4 pyrazol-yl-5] oxy acetyl ] morpholine

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0177" num="0177"><img file="EP0449699A2_D0177.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 129-31 ° C.

Example 150: (2,2,2,2-Trifluoroethyl) -1 n-Butyl-3 hydroxy-5 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazole

Formula (I): R1 = n-Butyl, R2 = CH2 CF3, A = OH,<chemistry id="chem0178" num="0178"><img file="EP0449699A2_D0178.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 210-11 ° C.

Example 151: Methyl-1 n-Butyl-3 (cyano-2'blphenyl-yl-4) methyl-4 bromomethyl-5 pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl, A = CH2Br,<chemistry id="chem0179" num="0179"><img file="EP0449699A2_D0179.tif" /></chemistry>

Prepared according to the procedure of Example 109 from methyl-1 n-Butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 methoxy methyl-5 pyrazole prepared in Example 104.

Oil used as it is for the continuation.

Example 152: Methyl-1 n-Butyl-3 (cyano-2'biphenyl-yl-4) methyl-4 hydroxy methyl-5 pyrazole

Formula (XII): R1 = n-Butyl, R2 = Methyl, R '= H,<chemistry id="chem0180" num="0180"><img file="EP0449699A2_D0180.tif" /></chemistry>Prepared according to the procedure of Example 111. Oil used as it is for the following.

Example 153: Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 hydroxy methyl-5 pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl, A = CH20H,<chemistry id="chem0181" num="0181"><img file="EP0449699A2_D0181.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 110-12 ° C.

Example 154: Methyl-1 n-Butyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-5-formyl pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl, A = CHO,<chemistry id="chem0182" num="0182"><img file="EP0449699A2_D0182.tif" /></chemistry>

2.3 g of 2-nitro propane are dissolved in a sodium methylate solution, prepared from 0.7 g of sodium and 40 ml of methanol. 10 g of methyl-1 n-butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 bromomethyl-5 pyrazole, prepared in Example 151, are dissolved in 30 ml of methanol and this solution is added dropwise dropwise to the reaction mixture. The mixture is stirred for two hours at 50 ° C. then added with water and 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 Methyl-1 n-Butyl-3 (cyano-2 'biphenyl-yl-4) methyl-4 formyl- 5 pyrazole in the form of an oil used as it is for the following.

Example 155: Methyl-1 n-Butyl-3 (cyano-2'biphenyl-yl-4) methyl-4 (dioxolane-yl-2) -5 pyrazole

Formula (I): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0183" num="0183"><img file="EP0449699A2_D0183.tif" /></chemistry>4.3 g of methyl-1 n-Butyl-3 (cyano-2'biphenyl-yl-4) methyl-4-formyl-5 pyrazole, prepared in Example 154, are dissolved in 50 ml of toluene. 1 g of ethylene glycol is added as well as 10 mg of para-toluene sulfonic acid. The mixture is brought to reflux and the water is removed for 3 hours using a Dean-Stark. The mixture is then taken up in water and extracted with ether, then dried over magnesium sulfate and evaporated in vacuo to give 4 g of methyl-1 n-butyl-3 (cyano-2'biphenyl-yl-4) methyl-4 (dioxolane-yl-2) -5 pyrazole in the form of an oil used as such for the following.

Example 156: Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2'blphenyl-yl-4] methyl-4 (dioxotane-yl-2) -5 pyrazole

Formula (1): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0184" num="0184"><img file="EP0449699A2_D0184.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 144-6 ° C.

Example 157: ((2,2,2,2-Trifluoroethyl) -1 n-Butyl-3 (2'-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 2-oxy ethanol

Formula (XI): R1 = n-Butyl, R2 = CH2CF3, R3 = CH2CH20H,<chemistry id="chem0185" num="0185"><img file="EP0449699A2_D0185.tif" /></chemistry>Prepared according to the procedure of Example 49. Oil used as it is for the following.

Example 158: [(2,2,2,2-Trifluoroethyl) -1 n-Butyl-3 [(tetrazoiyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy-2 ethanol

Formula (I): R1 = n-Butyl, R2 = CH2CF3, A = OR3, R3 = CH2CH2OH,<chemistry id="chem0186" num="0186"><img file="EP0449699A2_D0186.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 107-10 ° C.

Example 159: Oxo-3 [(3-cyano-thényl-yl-2) -4 benryl] -2 ethyl heptanoate

Formula (V): R1 = n-Butyl, R10 = Ethyl,<chemistry id="chem0187" num="0187"><img file="EP0449699A2_D0187.tif" /></chemistry>1.1 g of ethyl oxo-3 heptanoate, prepared in Example 1.1.2 g of (3-cyano-thienyl-yl-2) -4 benzyl bromide, 0.6 g of lithium bromide and 2.2 ml of di-isopropyl ethyl amine are added to 15 ml of tetrahydrofuran. The mixture is stirred at reflux for 20 hours, taken up in water and extracted with ether. The organic phase is dried over magnesium sulfate and then evaporated. The excess ethyl oxo-3 heptanoate is evaporated with a vane pump and 1.5 g of oxo-3 (cyano-3 thienyl-yl-2) -4 ethyl benzyl-2 heptanoate are obtained in the form of an oil used as it is for the following.

Preparation of (3-cyano-2-thienyl) -4-benzyl bromide:

A) 4-methyl-4-chloro-butyrophenone:

53 ml of toluene and 70.5 g of 4-chloro-butyric acid chloride are dissolved in 100 ml of dichloromethane and the solution is added at 10 ° C. to a suspension of 74 g of aluminum chloride in 200 ml of dichloromethane . The temperature is then allowed to rise for a quarter of an hour, the mixture is treated with ice water. The organic phase is dried over magnesium sulphate and evaporated under vacuum to give 96.9 g of 4-methyl-4-chloro-butyrophenone in the form of an oil used as it is for the following.

B) a-chloro β- (chloro-2ethyl) cinnamaldehyde:

130 ml of phosphorus oxychloride are added slowly, at 0 ° C., to 130 ml of dimethyl formamide, then 117.5 g of 4-methyl-4-chloro-butyrophenone, prepared in A), dissolved in 50 ml of dimethyl formamide are added dropwise. The mixture is then stirred at room temperature for one hour, then at 50 ° C for 2 hours and at 70 ° C for 1 hour. The mixture is then poured onto ice and taken up in ether, the ethereal phase is washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated in vacuo to give 133.8 g of a-chloro β- (2-chloroethyl) cinnamaldehyde in the form of an oil used as it is for the following.

C) (4-methylphenyl) -2 4,5-dihydro-3-thiophene carboxaldehyde:

15.9 g of a-chloro β- (2-chloro-ethyl) cinnamaldehyde prepared in B) and 22 g of sodium sulfide (9 H20) are added to 200 ml of THF. Sufficient water is added so that the sodium sulphide goes completely into solution and the mixture is then heated for 3 hours at reflux, cooled and then taken up in ether. The organic phase is decanted, washed with water and then dried over magnesium sulphate and evaporated under vacuum to give 13.5 g of (4-methylphenyl) -2 dihydro-4,5-thiophene-3 carboxaldehyde in the form of an oil used as it is for the continuation.

D) (4-methylphenyl) -2 cyano-3 dihydro-4,5-thiophene:

15 g of (4-methylphenyl) -2 4,5-dihydro-3-thiophene-carboxaldehyde, prepared in C) and 6.5 g of hydroxylamine hydrochloride are mixed in 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 mixture is stirred at room temperature for half an hour, then extracted with ether. The ethereal phase is washed with water, then dried over sodium sulfate and evaporated in vacuo to give 15.2 g of a gummy yellow residue. This residue is added to 13 ml of acetic anhydride and the mixture slightly heats, turns brown and becomes liquid. The mixture is then heated for 1 hour at reflux, then poured onto ice and extracted with dichloromethane and washed with a saturated solution of sodium bicarbonate, then the organic phase is dried over magnesium sulphate and evaporated under vacuum, the residue obtained is chromatographed on silica gel in dichloromethane to give 10 g of (4-methylphenyl) -2 cyano-3 dihyro-4,5-thiophene in the form of an oil used as it is for the following.

E) (4-methylphenyl) -2 cyano-3 thiophene:

49.9 g of (4-methylphenyl) -2 cyano-3 dihydro-4,5-thiophene, prepared in D) are dissolved in 200 ml of carbon tetrachloride, the mixture is heated to reflux and, after two hours, 11 g of bromine in solution in 200 ml of carbon tetrachloride are added dropwise. The reflux is continued until the evolution of hydrobromic acid is stopped, then the solvent is evaporated under vacuum. The residue is taken up in 200 ml of anhydrous tetrahydrofuran and 28 g of potassium tert-butoxide are added. The mixture is heated for one hour at reflux then cooled and aspirated with water and sodium chloride and extracted with ether. The organic phase is evaporated under vacuum to give 31.8 g of (4-methylphenyl) -2 cyano-3 thiophene in the form of an oil used as it is for the following.

F) Benzyl (3-cyano-thienyl-yl-2) -4 bromide:

24.5 g of (4-methylphenyl) -2 cyano-3 thiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromo succinimide are added as well as 0.1 g of benzoyl peroxide. The mixture is heated for 24 hours at reflux. The succinimide crystals are filtered and the solvent evaporated in vacuo. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept in the freezer for 24 hours. The crystals formed are drained to give 14 g of (3-cyano-thienyl-yl-2) -4 benzyl bromide in the form of crystals with a melting point of 80 ° C.

Example 160: Methyl-1 n-Butyl-3 [(3-cyano-thényl-yl-2) -4 benryl] -4 hydroxy-5 pyrazole

Formula (IX): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0188" num="0188"><img file="EP0449699A2_D0188.tif" /></chemistry>1.4 g of [(3-cyano-thienyl-yl-2) -4 benzyl] -2 3-oxo ethyl heptanoate prepared in Example 159, are dissolved in 10 ml of ethanol. 2.2 ml of methyl hydrazine are added and the mixture is brought to reflux for 13 hours, then added with water and extracted with ether and then with ethyl acetate. The organic phases are combined and evaporated under vacuum to give an oily residue which gives, after chromatography on silica gel in an eluantdichloromethanelmethanol 9515.0.8 g of Methyl-1 n-Butyl-3 [(3-cyano thienyl-yl- 2) -4 benzyl] -4 hydroxy-5 pyrazole in the form of crystals with a melting point of 120 ° C.

Example 161: Methyl-1 n-propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 (N, N-diethyl carbamoyl) oxy-5 pyrazole

Formula (IX): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0189" num="0189"><img file="EP0449699A2_D0189.tif" /></chemistry>Prepared according to the procedure of Example 52. Oil used as it is for the following.

Example 162: Methyl-1 n-propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 (N, N-diethyl carbamoyl) oxy-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0190" num="0190"><img file="EP0449699A2_D0190.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 134-135 ° C.

Example 163: N - [[(2,2,2-trlfluoroethyl) -1 n-propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy acetyl] thiomorpholine

Formula (XI): R1 = n-Propyl, R2 = CH2CF3<chemistry id="chem0191" num="0191"><img file="EP0449699A2_D0191.tif" /></chemistry>Prepared according to the procedure of Example 46 from N- (chloro acetyl) thiomorpholine. Oil used as it is for the continuation.

Example 164: N - [((2,2,2-trifluoroethyl) -1 n-propyl-3 ((tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy acetyl ] thiomorphoiine

Formula (I): R1 = n-Propyl, R2 = CH2CF3, A = OR3, <chemistry id="chem0192" num="0192"><img file="EP0449699A2_D0192.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 127-128 ° C.

Example 165: (2-Methoxyphenyl) -1 [1-methyl-n-propyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] oxy acetyl-4 piperazine

Fonmule (XI): Ri = n-Propyl, R2 = Methyl,<chemistry id="chem0193" num="0193"><img file="EP0449699A2_D0193.tif" /></chemistry>Prepared according to the procedure of Example 64. Oil used as it is for the following.

Example 166: (2-Methoxyphenyl) -1 (1-methyl-n-propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy acetyl-4 piperazine

Fonmule (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0194" num="0194"><img file="EP0449699A2_D0194.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 139-141 ° C.

Example 167: n-Propyl-3 methyl-1 (2-cyano-biphenyl-yl-4) methyl-4 (2-dimethylamino ethoxy) -5 pyrazole

Fonmule (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0195" num="0195"><img file="EP0449699A2_D0195.tif" /></chemistry>10 g of n-Propyl-3 methyl-1 (2-cyano-biphenyl-yl-4) methyl-4 hydroxy-5 pyrazole, prepared in Example 68, are dissolved in 100 ml of butanone-2 in the presence of 10 g sodium carbonate and 8.6 g of N, N hydrochloride 2-dimethyl chloro ethyl amine. The mixture is brought to reflux for 20 hours then concentrated under vacuum, taken up in water and extracted with ether. The ethereal phase is washed with water, dried and then evaporated under vacuum. The residue is chromatographed on silica gel in a 95/5 chloroform / methanol eluent to give 4.6 g of n-propyl-3 methyl-1 (2-cyano 'biphenyl-yl-4) methyl-4 (dimethylamino-2 ethoxy) -5 pyrazole in the form of an oil used as it is for the following.

Example 168: n-Propyl-3 methyl-1 [(tetrazolyl-5) -2'biphenyl-yl-4j methyl-4 (dimethylamina2 ethoxy) -5 pyrazole

Formula (I): R1 = n-Propyl, R2= Methyl, A = OR3, <chemistry id="chem0196" num="0196"><img file="EP0449699A2_D0196.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 88-90 ° C.

Example 169: N - [[Methyl-1 n-propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] 2-oxy ethyl] morpholine

Formula (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0197" num="0197"><img file="EP0449699A2_D0197.tif" /></chemistry>Prepared according to the procedure of Example 167 from N- (2-chloro-ethyl) morpholine. Oil used as it is for the continuation.

Example 170: N - [[Methyl-1 n-propyl-3 ((tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy-2 ethyl] morpholine

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0198" num="0198"><img file="EP0449699A2_D0198.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 132-134 ° C.

Example 171: (2,2,2,2-Trifluoroethyl) -1 n-butyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-5-hydroxy methyl 5-pyrazole

Fortnule (XII): R1 = n-Butyl, R2 = CH2CF3, R '= H,<chemistry id="chem0199" num="0199"><img file="EP0449699A2_D0199.tif" /></chemistry>Prepared according to the procedure of Example 111 from (trifluoro-2,2,2 ethyl) -1 n-butyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-5-bromomethyl pyrazole which is prepared according to the procedure of Example 109. Oil used as it is for the following.

Example 172: (2,2,2,2-Trifluoroethyl)] - 1 n-butyl-3 ((5-tetrazolyl) -2 'biphenyl-yl-4] 4-methyl-5-hydroxy methyl 5-pyrazole

Formula (I): R1 = n-Butyl, R2 = CH2CF3, A = CH20H,<chemistry id="chem0200" num="0200"><img file="EP0449699A2_D0200.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 114-117 ° C.

Example 173: (2,2,2,2-Trifluoroethyl) -1 n-propyt-3 (2-cyano-biphenyl-yl-4) 4-methyl-5-methoxy methyl-5 pyrazole

Formula (XII): R1 = n-Propyl, R2 = CH2CF3, R '= CH3, q = 1,<chemistry id="chem0201" num="0201"><img file="EP0449699A2_D0201.tif" /></chemistry>Prepared according to the procedure of Example 101. Oil used as it is for the following.

EXAMPLE 174

Formula (I): R1 = n-Propyl, R2 = CH2CF3 A = CH20CH3, <chemistry id="chem0202" num="0202"><img file="EP0449699A2_D0202.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 177-178 ° C.

Example 175: N - ([Methyl-1 n-butyh3 (cyano-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy acetyl] morpholine

Formula (XI): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0203" num="0203"><img file="EP0449699A2_D0203.tif" /></chemistry>Prepared according to the procedure of Example 46. Oil used as it is for the following.

Example 176: N - [(Methyl-1 n-propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5] oxy acetyl] morphollne

Formula (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0204" num="0204"><img file="EP0449699A2_D0204.tif" /></chemistry>Prepared according to the procedure of Example 46. Oil used as it is for the following.

Example 177: N - [(Methyl-1 n-Butyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 pyrazol-yl-5] oxy acetyl] morpholine

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, <chemistry id="chem0205" num="0205"><img file="EP0449699A2_D0205.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 140-141 ° C.

Example 178: N - ((Methyl-1 n-Propyl-3 ((tetrazolyl-5) -2'b (phenyl-yl-4] methyl-4 pyrazol-yl-5] oxy acetyl] morpholine

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3,<chemistry id="chem0206" num="0206"><img file="EP0449699A2_D0206.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 106-110 ° C.

Example 179: (2,2,2,2-Trifluoroethyl) -1 n-Propyh3 (2-cyano-biphenyl-yl-4) 4-methyl-5-hydroxy methyl 5-pyrazole

Formula (XII): R1 = n-Propyl, R2 = CH2CF3, R '= H<chemistry id="chem0207" num="0207"><img file="EP0449699A2_D0207.tif" /></chemistry>

Prepared according to the procedure of Example 111 from (trifluoro-2,2,2 ethyl) -1 n-propyl-3 (2-cyano-biphenyl-yl-4) methyl-4 bromomethyl-5 pyrazole which is prepared according to the procedure of Example 109.

Oil used as it is for the continuation.

Example 180: (2,2,2,2-Trifluoroethyl) -1 n-propyl-3 [(5-tetrazolyi) -2 'biphenyl-yl-4] 4-methyl-5-hydroxy methyl 5-pyrazole

Formula (1): R1 = n-Propyl, R2 = CH2CF3, A = CH20H,<chemistry id="chem0208" num="0208"><img file="EP0449699A2_D0208.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 110-2 ° C.

Example 181: Methyl-1 n-propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 hydroxy methyl-5 pyrazole

Formula (XII): R1 = n-Propyl, R2 = Methyl, R '= H,<chemistry id="chem0209" num="0209"><img file="EP0449699A2_D0209.tif" /></chemistry>Prepared according to the procedure of Example 111. Oil used as it is for the following.

Example 182: Methyl-1 n-propyl-3 [(tetrazolyl-5) -2'biphenyl-yl-4] methyl-4 hydroxymethyl-5 pyrazole

Formula (I): R1 = n-Propyl, R2 = Methyl, A = CH20H,<chemistry id="chem0210" num="0210"><img file="EP0449699A2_D0210.tif" /></chemistry>Prepared according to the procedure of Example 71. Crystals of melting point 136-9 ° C.

Example 183: (2-Methoxyphenyl) -1 [1-methyl-n-butyl-3 (2-cyano-biphenyl-yl-4) 4-methyl-pyrazol-yl-5] 4-oxyacetyl

Formula (XI): R1 = n-Butyl, R2 = Methyl,<chemistry id="chem0211" num="0211"><img file="EP0449699A2_D0211.tif" /></chemistry>Prepared according to the procedure of Example 64. Oil used as it is for the following.

Example 184: (2-Methoxyphenyl) -1 [1-methyl-n-butyl-3 [(5-tetrazolyl) -2'biphenyl-yl-4] 4-methyl pyrazol-yl-5] 4-oxyacetyl

Formula (I): R1 = n-Butyl, R2 = Methyl, A = OR3, <chemistry id="chem0212" num="0212"><img file="EP0449699A2_D0212.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 153-5 ° C.

Example 185: N - ((methyl-1 n-propyl-3 (cyano-2'biphenyl-yl-4) methyl-4 pyrazol-yl-5) oxyacetyl] thiomorpholine

Formula (XI): R1 = n-Propyl, R2 = Methyl,<chemistry id="chem0213" num="0213"><img file="EP0449699A2_D0213.tif" /></chemistry>Prepared according to the procedure of Example 46, starting from N- (chloroacetyl) thiomorpholine. Oil used as it is for the continuation.

Example 186: N - [[methyl-1 n-propyl-3 [(tetrazolyl-5) -2'blphenyl-yl-4] methyl-4 pyrazol-yl-5] oxyacetyl] thiomorphollne

Formula (I): R1 = n-Propyl, R2 = Methyl, A = OR3, <chemistry id="chem0214" num="0214"><img file="EP0449699A2_D0214.tif" /></chemistry>Prepared according to the procedure of Example 70. Crystals of melting point 140-1 ° C.<tables id="tabl0001" num="0001"><img file="EP0449699A2_D0215.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0449699A2_D0216.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0449699A2_D0217.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0449699A2_D0218.tif" /></tables><tables id="tabl0005" num="0005"><img file="EP0449699A2_D0219.tif" /></tables><tables id="tabl0006" num="0006"><img file="EP0449699A2_D0220.tif" /></tables><tables id="tabl0007" num="0007"><img file="EP0449699A2_D0221.tif" /></tables><tables id="tabl0008" num="0008"><img file="EP0449699A2_D0222.tif" /></tables><tables id="tabl0009" num="0009"><img file="EP0449699A2_D0223.tif" /></tables><tables id="tabl0010" num="0010"><img file="EP0449699A2_D0224.tif" /></tables><tables id="tabl0011" num="0011"><img file="EP0449699A2_D0225.tif" /></tables><tables id="tabl0012" num="0012"><img file="EP0449699A2_D0226.tif" /></tables><tables id="tabl0013" num="0013"><img file="EP0449699A2_D0227.tif" /></tables><tables id="tabl0014" num="0014"><img file="EP0449699A2_D0228.tif" /></tables><tables id="tabl0015" num="0015"><img file="EP0449699A2_D0229.tif" /></tables><tables id="tabl0016" num="0016"><img file="EP0449699A2_D0230.tif" /></tables>

PHARMACOLOGY

I. Principle

The affinity of the products of the examples for the angiotensin II receptors is evaluated by technique of displacement of a radioligand specifically fixed on the adrenal receptors of angiotensin II, in the rat.

II. Procedure

An aliquot of a homogenate of adrenal rats incubated in the presence of a single concentration of [125I] -SIAII (Sar1, Tyr4, Isle8 - angiotensin II), an angiotensin II receptor antagonist, and two concentrations of competing agents (10-5 M, 10-7 M) for 60 min at 25 ° C.

The reaction is completed by adding buffer, then rapid filtration through sandpaper filters. Nonspecific binding is determined in the presence of angiotensin II.

III. Expression of results

The results are expressed, for the concentrations tested, as a percentage of displacement of the radioligand specifically fixed on the adrenal receptors of angiotensin II.

. Results

TOXICOLOGY

The products of the examples described exhibit, after oral administration, excellent tolerance.

Their lethal dose 50 in rats has been estimated to be greater than 300 mglkg.

CONCLUSION

The products of the examples described have a good affinity for the Angiotensin II receptors. As such, they can be used with benefit in the various pathologies where Angiotensin II is involved, in particular in the treatment of arterial hypertension and heart failure, in dosages of 1 to 400 mg orally. and 0.01 to 50 mg intravenously, in one or more doses per day.

Contents44

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Every citation, both ways

Citations
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Document	Office	Kind	Date
9003485	France	A	1990-03-19
9003485	France	A	1990-03-19
9003485	France	–	1990-03-19
9003485	–	–	–
FR19900003485	–	–	–

Members13

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Document	Office	Kind
AU7359191A	Australia	A	1991-09-19
CA2038428A1	Canada	A1	1991-09-20
FR2659655A1	France	A1	1991-09-20
IE910766A1	Ireland	A1	1991-09-25
EP0449699A2This record	European Patent Office (EPO)	A2	1991-10-02
PT97056A	Portugal	A	1991-10-31
KR910016708A	Republic of Korea	A	1991-11-05
ZA911925B	South Africa	B	1992-03-25
IL97576A0	Israel	A0	1992-06-21
FR2659655B1	France	B1	1992-07-24
JPH04234851A	Japan	A	1992-08-24
EP0449699A3	European Patent Office (EPO)	A3	1993-04-07
NZ237445A	New Zealand	A	1993-04-28

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	Event	Code
1996-04-03	Application deemed to be withdrawnWithdrawn18D	18D
1996-02-16	Information on the status of an ep patent application or granted ep patentGrantedSTATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWNSTAA	STAA
1993-12-01	Request for examination filed17P	17P
1993-04-07	Designated contracting statesAK	AK
1993-02-12	Search report despatchedORIGINAL CODE: 0009013PUAL	PUAL
1991-10-02	Designated contracting statesAK	AK
1991-08-15	Public reference made under article 153(3) epc to a published international application that has entered the european phaseORIGINAL CODE: 0009012PUAI	PUAI

Abstract

Term

, R

, R

CO

CO

R

CO

, R

CO

, R

CO

, R

CO

CF

, R

CO

CF

, R

CO

, R

CO

H,

, R

CO

H,

, R

, R

CO

H,

CO

, R

CO

, R

CO

, R

CO

H,

, R

-CH

-OH ,

EXAMPLE 84

EXAMPLE 174

PHARMACOLOGY

TOXICOLOGY

CONCLUSION

Priority claims5

Members13

Over the term

Events

Numbers

Titles6

Classification

Designated states14