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

<img file="PT97056A_D0001.tif" />

USPA LABORATORIES

PROCESS FOR THE PREPARATION OF NEW ANTIGONIST PIRAZOL DERIVATIVES FROM ANGIOTENSIN II RECEPTORS AND

PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to a process for the preparation of novel pyrazole derivatives of formula I defined below as well as their addition salts.

The compounds in question have a very interesting pharmacological profile in that they have angiotensin II receptor antagonist properties. They are therefore particularly suitable for the treatment of cardiovascular disease, in particular for the treatment of hypertension and for the treatment of heart failure.

The present invention also relates to a process for the preparation of said compounds and therapeutic applications. It further relates to novel intermediate compounds which allow the synthesis of said compounds.

These pyrazole derivatives are characterized in that they correspond to the general formula (I):

<img file="PT97056A_D0002.tif" />

(I) in which

R- represents a lower alkyl radical having 1 to 6 carbon atoms, lower alkenyl having 2 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms or C ^-C ciclo cycloalkenyl,

R 2 represents a hydrogen atom, a lower alkyl radical of 1 to 6 carbon atoms or C 1 -C 5 cycloalkyl or a group of formula

- (CH₉) -COOR ,, -CH₉- (CH₉) -OR, or -CH₉- (CH₉Wherein m represents an integer from 0 to 5, R j represents a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms,

A can represent:

- a group of formula - (CEL?) OR ', in which

<img file="PT97056A_D0003.tif" />

R 'represents a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms or C 1 -C 5 cycloalkyl, q represents an integer from 1 to 5,

- a group of general formula - (CH_?) L, where L

Z q represents a halogen atom, preferably chlorine or bromine, q has the meaning defined above,

I

- a group of formula CHO, an acetal, a dioxolane

- a group of formula COOR ', where R' has the meaning as defined above,

- a group of the formula -CONRR 'wherein R' and R '' each independently represent a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms or C1 -C5 cycloalkyl or taken together) with the nitrogen atom to which they are attached form a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or piperazine,

- a -CN group,

- a group of the formula - (CH3) CN, where qzq has the meaning given above,

- a group of formula - (CH?) COOR ', wherein zqqe R' have the meanings defined above, / - a group of formula - (CH?)₉) CONRR ', where z, R, R' and q have the meanings defined above,

- a group of general formula - (CH₉) NRR ', where zq

R ”, R '” eq have the meanings defined above,

- a group of general formula - (CH₉) -S-R ', where zq

R * eq have the meanings defined above,

- a group -ORg, wherein Rg represents a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or cycloalkyl Gg-Cy, a group of general formula

- (CH₂)_no-COOR₆, -CH₂- (CH₂)_no-CN, CH₂- (CH₂)_no-OR₆, -CH₂~ (CH₂)_no-S-Rg or -CORg, where n represents an integer from 0 to 5, Rg represents a hydrogen atom or a lower alkyl radical of 1 to 6 carbon atoms, Rg may further represent a group of formula - (CH₂) p-CO-NRyRg or - (CH₂) p-CH₂-CH₂NRyRg, where p represents an integer from 0 to 5, Ry and Rg each independently represent a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, Cg-Cy cycloalkyl or taken together with the nitrogen atom to which they are attached form a heterocycle such as pyrrolidine,

Piperidine, morpholine, thiomorpholine or a piperazine may represent a nitro or amino group or a group -COORg wherein Rg is hydrogen or lower alkyl radical of 1 to 6 carbon atoms and may be also represent the following radicals:

<img file="PT97056A_D0004.tif" />

R, OOC

<img file="PT97056A_D0005.tif" />

where Rg has the meaning defined above,

X and Y each independently of one another represent a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical or a trifluoromethyl radical.

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

By C1 -C4 cycloalkyl radical is meant a saturated cyclic radical, preferably a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane radical.

By lower alkenyl radical is meant a hydrocarbon chain having 2 to 6 straight or branched carbon atoms and having an unsaturation. A lower alkenyl radical is, for example, an ethylene, propene, isopropene, butene, isobutene, pentene, isopentene, hexenejisohexene radical.

By C1 -C5 cycloalkenyl radical is meant a cyclic radical having an unsaturation, preferably ζ

7y · * '' is a cyclobutene, cyclopentene, cyclohexene or cycloheptene radical.

By halogen-lower alkyl radical of 1 to 6 carbon atoms is meant an alkyl radical in which 1 to 6 hydrogen atoms have been replaced by 1 to 6 halogen atoms. A halo-lower alkyl radical is for example a trifluoromethyl radical or 2,2,2-trifluoroethyl radical.

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

By heterocycle is meant a cycle of 5 to 7 carbon atoms having 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, optionally substituted by a lower alkyl, halo-lower alkyl, lower alkoxy or a phenyl nucleus eventually replaced by one of these groups.

In the description and claims by halogen is meant a chlorine, bromine, iodine or fluorine atom.

European Patent EP-A-0323841 to Du Pont de Nemours describes pyrroles, pyrazols and triazois. These compounds always have the benzyl substitution on a nitrogen atom:

<img file="PT97056A_D0006.tif" />

Rj

<img file="PT97056A_D0007.tif" />

Surprisingly, however, the applicant found that, contrary to what emerges from Du Pont de Nemours' document, it was not essential that the benzyl substitution be on a nitrogen atom, in particular at position -1 (or -2) but very advantageous compounds could be obtained when this benzyl substitution was on a carbon atom at the -4 position of the pyrazole cycle. Furthermore, we have found that the presence of a group represented by the symbol A and particularly an oxygen atom at the -3 (or -5) position of pyrazole combined with benzyl substitution at the -4 position leads to particularly active compounds as antagonists. angiotensin II receptors.

In one embodiment, R 4 is n-propyl;

In another embodiment, R1 is n-butyl,

<img file="PT97056A_D0008.tif" />

according to one embodiment the symbol represents a methyl group;

according to another embodiment, R₂ represents a 2,2,2-trifluoroethyl group;

In one embodiment, A represents an ethoxycarbonylmethylenoxy group;

according to one embodiment A is dimethylamino carbonyloxy;

according to another embodiment A represents a methoxy methylene group;

in another embodiment, A is 2-hydroxyethyloxy;

in one embodiment, R3 is 2-carboxy-3,6-dichloro-benzoyl-amino;

in another embodiment, R3 is 2-sulfonic benzoylamino acid group;

in another embodiment, R3 is 2- (5-tetrazolyl) phenyl;

Particularly preferred compounds of the present invention are those corresponding to the compounds of formula:

<img file="PT97056A_D0009.tif" />

ί

'*

<img file="PT97056A_D0010.tif" />

<img file="PT97056A_D0011.tif" />

<img file="PT97056A_D0012.tif" />

Η

Ν \

Ν '/

Ν

<img file="PT97056A_D0013.tif" />

In accordance with the present invention, the compounds of formula I may be prepared according to the following reaction scheme:

prepare:

- alkyl 3-oxo alkanoates of formula (II):

^R1-J-^CH2-^COOR10 (II) wherein R3 is as defined above and R3 represents a lower alkyl radical, preferably methyl or ethyl,

- 1,3-diketones of general formula (III):

R_what —C — CH₀—C— (CH₀) —0 — R * ¹ II ² II ^{2 what}

0 (III) wherein R1, R2 and e are as defined above, these compounds of formula II and III may be prepared according to classical methods, such as the Claisen reaction or the Meldrum acid method. Methods for preparing such compounds can be found in the following references:

<img file="PT97056A_D0014.tif" />

-..- Λ— *

-OIKAWA. Y; SUGANO. K; YONEMITSU. 0; J. Org. Chem., 1978, 43 (10), 2087-88.

-WIERENGA. W; SKULNIGK. Η I; J. Org. Chem., 1979, 44, 310.-HOUGHTON. R; LAPHAM. D; SYNTHESIS, 1082, 6, 451-2.

-BRAM. G; VILKAS. M; Bull. Soc. Chim. France, 1964 (5), 945-51. -BALYAKINA. Μ V; ZHDANOVICH. E.S; PREOBRAZHENSKII. N.A;

Tr. Ye. Nauchn Issled Vitam in. Inst., 1961, 7, 8-16. -RENARD. M; MACHINAY. THE; Bull. Soc. Chim. Belg., 1946, 55, 98-105.

-Bruce. F. W; COOVER H. W; J. Am. Chem. Soc., 1944, 66, 2092-94. -EBY. C. J; eHAUSER. C.R; J. Am. Chem. Soc., 1957, 79, 723-5.

By benzylation of the compounds of formula II or III in the presence of a base such as sodium or potassium carbonate in acetone, sodium or potassium alcoholate in alcohol, sodium or lithium hydride in solvents like tetrahydrofuran, dioxane or dimethylformamide for example at 50 to 100 ° C or in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropyl ethyl amine at reflux of tetrahydrofuran according to SUNG-EUN Y00;

KYO YANG YI; Bull. Korean Chem. Soc. 1989, 10 (1), 112, with compounds of formula (IV)

<img file="PT97056A_D0015.tif" />

(IV)

<img file="PT97056A_D0016.tif" />

The compounds of general formulas (V) and (VI) are obtained:

<img file="PT97056A_D0017.tif" />

<img file="PT97056A_D0018.tif" />

The compounds of formula (V) and (VI) may also be prepared by condensation of an aldehyde of formula (VII).

CHO (Vil) with a compound of formula (II) or formula (III) followed by catalytic hydrogenation, for example in the presence of Reney Nickel in a solvent such as alcohol, under pressure or at ordinary pressure, when present substitutions allow it.

<img file="PT97056A_D0019.tif" />

More generally, methods for preparing the compounds of formula (V) or formula (VI) are found in the following references:

-DURGESHWARI. P; CHAUDHURY. N. D; J. Ind. Chem. Soc., 1962,

735-6.

-HEINZ. P; KREGLEWSKI. THE; J. Prakt. Chem. ”, 1963, 21 (3-4), 186-197.

-ZAUGG. HE; DUNNIGAN GIVES; MICHAELS R. J; SWETT L.R;

J. Org. Chem., 1961, 26, 644-51.

-KAGAN. Η B; HENG SUEN. Y; Bull. Soc. Chim. France, 1966 (6), 1819-22.

-RATHKE. M. W; DEITCH J; Tetrahedron Lett, 1971 (31), 2953-6. -BURRIES KUBEL .; Liebigs. Ann Chem., 1980, 1392-1401.

-MARQUET. J; Moreno-manas. M; Chem. Lett, 1981, 213-6.

-IOFFE. T; POPOV IN; VATSURO. K. V; TULIKOVA. E. K; KABACHNIK. Μ I; Tetrahedron, 1962, 18, 923-940.

-SHEPHERD. T.M; Chem. Ind. (London), 1970, 17, 567.

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

In the same general formula:

V may represent a nitro group and is then the derivative of commercial formula (IV).

V may represent a group of the formula wherein R 4 is lower alkyl or benzyl; The derivative of formula (IV) will then be prepared by chlorination or bromination with N-chloro succinimide or N-bromosuccinimide in a solvent such as carbon tetrachloride or dibromoethane from a p-methyl acid ester. -benzoic acid which is commercial according to the reference:

-JULIA. M; CHASTRETTE. F; Bull. Soc. Chim. France, 1962 (2), 2247.

- V may represent a group of formula

R,₂OOC, wherein R1 represents a lower alkyl or benzyl radical; The compounds of formula (IV) are then prepared by reaction of a p-bromo-toluene magnesian.

<img file="PT97056A_D0020.tif" />

to obtain a compound of formula

<img file="PT97056A_D0021.tif" />

O

<img file="PT97056A_D0022.tif" />

hydrolyzed to a compound of formula

<img file="PT97056A_D0023.tif" />

Processes for the three steps described earlier in the reference will be found:

MEYERS. THERE; MIHELICH. ED; J. Am. Chem. Soc., 1975, 97, 7383.

The acid is then esterified with an alcohol of formula wherein₂ has the meaning defined above.

These derivatives are then brominated or chlorinated with, for example, N-bromosuccinimide or N-chlorosuccinimide in a solvent such as carbon tetrachloride or dibromoethane to give the compounds of formula (IV) wherein V is a group of formula

<img file="PT97056A_D0024.tif" />

R,₂OOC

-18ζ *

- ο symbol V may represent ο group Π, in this case the compound of formula MC

<img file="PT97056A_D0025.tif" />

&gt;

previously prepared will be transformed into a primary amide by reaction of the acid chloride obtained with thionyl chloride or phosphorus oxychloride with ammonia, the amide being converted to nitrile by the action of phosphorus oxychloride in dimethylformamide or thionyl chloride . The nitrile thus obtained is then subjected to the formula

<img file="PT97056A_D0026.tif" />

bromination or chlorination according to the conditions described for the above ester to give the compounds of formula (IV) wherein V is

NC

THE/

<img file="PT97056A_D0027.tif" />

V may represent a group of formula, in this case the compound of formula '

0, N

<img file="PT97056A_D0028.tif" />

It will be prepared by chloromethylation of the commercial 2-nitrobiphenylD according to the references:

- CA: 70 (25): 114837 d

- CA: 69 (2): 3704 t to give compounds of formula (IV) wherein V is a group of formula

<img file="PT97056A_D0029.tif" />

V may represent a group of general formula

R,₂OOC- ^ ^xs in which represents a lower alkyl radical

-20or benzyl; or corresponding compounds of formula (IV) are then prepared as follows:

From the compound of formula

<img file="PT97056A_D0030.tif" />

whose preparation can be found in the reference:

-FISSELMANN. H; HABITCH. H; Ger. Offen. ”, 1,092,929 (1960); CA ”; 57: 5894 g give the compounds of general formula

<img file="PT97056A_D0031.tif" />

by esterification with an alcohol of the formula wherein R 12 is as defined above according to classical methods known to those skilled in the art.

These compounds are then reacted with N-chloro succinimide or N-bromosuccinimide in a solvent. _ΖAs carbon tetrachloride or dibromoethane for example to give compounds of formula (IV) wherein V is a group of formula. &gt; -,

R_youOOC where meaning is given above V may represent a group of general formula

<img file="PT97056A_D0032.tif" />

In this case the corresponding compounds of formula (IV) will be prepared as follows:

from the compound 3- (p-methylphenyl) -2-thiophene carboxylic acid whose preparation was previously mentioned by reaction with thionyl chloride and then with ammonia gives the amide compound which then dehydrates with thionyl chloride or phosphorous oxychloride without solvent or dimethylformamide to give the nitrile compound:

<img file="PT97056A_D0033.tif" />

This nitrile compound is then halogenated with N-chloro-succinimide or N-bromosuccinimide within

<img file="PT97056A_D0034.tif" />

- / from a solvent such as carbon tetrachloride or dibromoethane to give compounds of formula (IV) wherein V is a group of formula

NC V may represent the group of formula in which case the corresponding compounds of formula (IV) are synthesized as follows:

from 4-chloro-butyrophenone of formula

CH, //

CO-CH, -CH, -CH, -Cl, the preparation of which can be found in Belgian Patent BE 577 977 of May 15, 1859; CA: 54, 4629 and by reaction with phosphorus oxychloride and dimethylformamide according to the conditions described in the reference; -VOLODINE. Μ THE; TERENTEV. AP; KUDRYASHOVA. GO; KABOSHINA. L. N; Khim Geterosikl. Soedim; 1967, 5-8;

<img file="PT97056A_D0035.tif" />

the compound of formula is obtained

CH,

C — C — CH, —CH, —Cl Cl CHO

This compound is then reacted with sodium sulfizide in a solvent such as refluxing tetrahydrofuran to give the derivative.

<img file="PT97056A_D0036.tif" />

which then transforms into a nitrile derivative in two steps by dehydrating the oxime formed from aldehyde and hydroxylamine. This dehydration may be effected, for example, with acetic anhydride to give the nitrile compound of formula:

CH,

<img file="PT97056A_D0037.tif" />

NC

<img file="PT97056A_D0038.tif" />

which may then be flavored by reaction with bromine in carbon tetrachloride and then with tert-butylate. of potassium in tetrahydrofuran to give the compound of formula:

CH

This compound may then be chlorinated or brominated with halogenating agents such as N-chloro-succinimide or N-bromosuccinimide in a solvent such as carbon tetrachloride or dibromoethane. compounds of formula (IV) wherein V is a group of formula

NC V may represent a group of formula ξ wherein R1 is as defined above, and compounds of formula (IV) may be prepared from the compound of formula (IV).

<img file="PT97056A_D0039.tif" />

by classical hydrolysis of the nitrile function followed by esterification of the acid obtained or direct passage of the nitrile function to the ester function according to methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chloro succinimide or with N-bromosuccinimide in carbon tetrachloride or dibromoethane for example.

In the general formulas (V) and (VI), the symbols Rp Rj_q, R ', q and V have the meanings defined above.

Certain derivatives of formula (V) and formula (VI) when V is alkoxy-2-carbonyl-phenyl, 2-cyano-phenyl, 2-nitro-phenyl, alkoxy-carbonyl-thiophene or cyano-radical. Thiophene are new synthesis intermediates that are claimed.

In compounds of formula (VII) in which V is as defined above, this method of condensation will only be used when V has a function which respects hydrogenation. In some cases these aldehydes may

<img file="PT97056A_D0040.tif" />

may be prepared from derivatives of formula (IV) according to reactions known to those skilled in the art, and the reaction of Sommelet (Bull. Soc. Chim. France 1918, [4] 23, 95) may be cited. or the nitropropane reaction (Organic Syntheses Collec. vol. IV, 932).

By reaction of a hydrazine of formula (VIII)

H₂N-nh-r₂ (VIII) in which R₂ has the meaning defined above, with the compounds of formula (V), by simply refluxing an alcohol for example, the compounds of formula (IX) are obtained:

<img file="PT97056A_D0041.tif" />

where R-, R₂ and V have the meanings defined above.

<img file="PT97056A_D0042.tif" />

/^r.

These compounds of formula (IX) are novel synthesis intermediates that are claimed.

Alkylation of the compounds of formula (IX) is carried out in the presence of a base such as potassium or sodium carbonate in solvents such as acetone, 2-butanone or dimethylformamide or in the presence of sodium alcoholate. or potassium in an alcohol or in the presence of sodium or lithium hydride in tetrahydrofuran with derivatives of formula (X).

zr₃ (X) wherein Z represents a bromine, chlorine or iodine atom and has the meaning defined above to give the compounds of formula (XI):

&gt;

<img file="PT97056A_D0043.tif" />

. (XI)

28.η where Rp R £, R ^ and V have the meanings defined above.

Likewise, by reacting a hydrazine of formula (VIII) as defined above with a compound of formula (VI), by simply heating under reflux of an alcohol for example, a mixture of compounds of formula is obtained. (XII) and of formula (XII ')

<img file="PT97056A_D0044.tif" />

OR '

<img file="PT97056A_D0045.tif" />

where Rp R £, R ', and V have the meanings defined above,

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

Another method for preparing compounds of formula (XII) is by first reacting&gt; 29 compounds of formula (VI) with hydrazine hydrate under the conditions described above to obtain the compounds. of general formula (XIII):

<img file="PT97056A_D0046.tif" />

wherein R1, R2, and V have the meanings defined above, these compounds of formula (XIII) are then subjected to alkylation in the presence of DBU (1,8-diazabicyclo- [5.4.0] undec. 7-ene), in a solvent such as acetone or acetonitrile with, for example, halogenated derivatives of formula (XIV):

zr₂ (XIV) where R₂ has the meaning defined above and Z represents a bromine, chlorine or iodine atom,

<img file="PT97056A_D0047.tif" />

to give a mixture of the compounds of formula (XII) and of formula (XII¹) as defined above, and then compounds of formula (XII) are obtained pure after purification as above. This second method of preparation may be particularly advantageous in the case where the symbol represents a lower alkyl group in that it allows predominantly to obtain the compounds of formula (XII) in relation to the compounds of formula (XII ').

Compounds of formula (XII) wherein R 'is hydrogen will be prepared in two steps: by reaction with boron tribromide of compounds of formula (XII) wherein R' is lower alkyl group brominated derivatives of general formula (XV) are obtained.

<img file="PT97056A_D0048.tif" />

where Rp R2, q and V have the meanings defined above,

The reaction is reacted with potassium or sodium carbonate at reflux of the dioxane / water mixture to give the compounds of formula (XII) wherein R 'is hydrogen.

Derivatives of formula (XI) or formula (XII) wherein:.

V is a nitro group and may undergo catalytic hydrogenation, for example in the presence of Raney Nickel in an alcohol at atmospheric pressure or under pressure to give the compounds of formula (I) wherein R3 is an amino group and A is - (CH ^ j ^ -OR 'or OR ^, wherein R', R ^ and q have the meanings defined above.

Reaction of these derivatives with a suitably substituted phthalic anhydride gives the compounds of formula (I) wherein R4 is a group of formula (I).

Hn

HOOC in which X and Y have the meanings defined above, and wherein A is a group of the formula - (CI4) -RR 'or ORg, where R', R4 and q have the meanings defined above and may the acid thus obtained is then subjected to an esterification to give a group of formula

<img file="PT97056A_D0049.tif" />

Likewise, by reacting the cyclic anhydride of a suitably substituted orthosulfobenzoic acid with these amino compounds, the compounds of formula (I) in which R 1 is a group of formula are obtained.

Wherein X and Y have the meanings defined above, and wherein A is a group of the formula - (CH CH jq-OR 'or OR ^, where R', R ^ and q have the meanings defined above.

Likewise, by reaction of N- (trifluoromethylsulfonyl) anthranilic acid chloride the preparation of which can be found in the references:

CA 96 (13): 103651 z

CA 97 (7): 55500 w with these compounds are obtained the compounds of formula I wherein R4 is a group of formula

CF, —SO, —HN where X and Y have the meanings defined above, and wherein A is a group of formula

- (CI4) -R 'or ORg wherein R', R4 and q have the meanings defined above.

<img file="PT97056A_D0050.tif" />

The compounds of formula (XI) or (XII) wherein

- V is -COOR-, may be hydrolyzed in acidic or basic media or hydrogenated in the case where R4 is benzyl to fulfill the other ester functions present to give the compounds of wherein R 1 is -COOH and A is (C 1 -C 4 -OR 'or ORg wherein R', R 4 and q have the meanings defined above.

These acid derivatives, after conversion to acid chloride with thionyl chloride or mixed anhydride with ethyl chloroformate, by reaction with anthranilic derivatives of general formula

<img file="PT97056A_D0051.tif" />

wherein X1 and R2 have the meanings defined above may lead to the compounds of formula (I) wherein R2 is a general group.

<img file="PT97056A_D0052.tif" />

and A is - (CIL ·) -0R 'or zq

Where R ', R 4 and q have the meanings defined above.

Compounds of general formula (XI) or (XII) wherein:

<img file="PT97056A_D0053.tif" />

Hydrolysed R OOC V is a group of formula

J will be, according to the process described above, or hydrogenated in the presence of a catalyst such as palladium on charcoal in the case where R 4 is benzyl to give the compounds of formula (I) in which R2 represents a group of formula

<img file="PT97056A_D0054.tif" />

and A is - (CIL ·) -0R 'or zq

Where R ', R 4 and q have the meanings defined above.

The compounds of general formulas (XI) and (XII) wherein:

V may be reacted with one equivalent of sodium azide in a solvent such as dimethylformamide in the presence of an ammonium salt such as ammonium chloride or trialkyl tin azide. refluxing toluene and then gaseous hydrochloric acid in tetrahydrofuran to give compounds of formula (I) wherein R4 is a group of formula

<img file="PT97056A_D0055.tif" />

and A represents a group of the formula - (CH 2) -ORR 'zq or ORp wherein R', R 4 and q have the meanings defined above.

The compounds of general formulas (XI) and (XII) wherein:

<img file="PT97056A_D0056.tif" />

may be subjected to catalytic hydrogenation for example in the presence of Raney Nickel in an alcohol at

Atoms or under pressure to obtain compounds of formula (I) wherein R is

CF, —ONLY, —HN and A is a group of the formula - (CH?) -0R 'or zq

OR 3 wherein R ', R 4 and q have the meanings defined above.

Reaction of trifluoromethanesulfonic acid chloride with the latter in a solvent such as chloroform or in an aromatic solvent such as toluene in the presence of a base such as triethylamine or pyridine or pyridine compounds of formula (I) wherein R 4 is a group of formula

Yj

H, N and 0 A are - (CH₉) -0R 'or zq

Wherein R ', R 4 and q have the meanings defined above.

The compounds of general formulas (XI) and (XII) wherein:

<img file="PT97056A_D0057.tif" />

V is a group of formula

NC

<img file="PT97056A_D0058.tif" />

may be treated with a trialkyl tin azide in refluxing toluene and then with gaseous hydrochloric acid in tetrahydrofuran to give derivatives of formula (I) wherein R4 is a group of formula

<img file="PT97056A_D0059.tif" />

H and A is - (CH?) -OR 'or Z q

ORg, wherein q, R 'and R4 have the meanings defined above.

The compounds of general formulas (XI) and (XII) wherein:

- V is a group of formula.

They may be hydrolysed or hydrogenated in the presence of a catalyst such as palladium on carbon where Rp2 is benzyl radical to give the compounds of formula (I) wherein R4 represents a group of formula

HOOC

-39 and A is a group of the formula - (CH₉) -OR 'or zq

ORg, where R ', eq has the meanings defined above.

The compounds of formula (I) in which A is a group of the formula may be oxidized with a mild oxidizing agent such as manganese dioxide in a solvent such as chloroform to obtain the compounds of formula (I) wherein A is CHO which may be converted, according to classical methods known to those skilled in the art, to acetal or dioxolane, by heating with an alcohol or a diol in the presence of para-toluenesulfonic acid for example (Synthesis 1981, 501).

More active oxidation of these same aldehyde compounds or directly of the alcohol compounds, for example with oxidizing agents such as potassium permanganate, leads to compounds of formula (I) wherein A is a CCl H group.

Compounds of formula (I) in which A is a group may be esterified according to classical esterification methods to obtain compounds of formula (I) in which A is a group of formula CO2 R ', where R' represents a lower alkyl radical.

/ -4Q (

Compounds of formula (I) wherein A is CC 3 H may also be converted to amides in several steps, optionally after steps of protecting other functional groups if necessary by conversion to acid chloride followed by reaction with ammonia or an amine of the formula NHRR ', wherein R and R' have the meanings defined above, to obtain the compounds of formula (I) wherein A is a CONRR 'group.

Compounds of formula (I) wherein A is GONH2 may be treated with an agent such as thionyl chloride or phosphorus oxychloride to give compounds of formula (I) wherein A is CN.

Compounds of formula (I) wherein A is a group of formula (GH₉) OR ', where R' represents zq a lower alkyl radical and q represents an integer from 1 to 5, may be treated with boron tribromide in chloroform to, after possible steps for the protection and deprotection of other groups. functional if necessary to obtain compounds of formula (I) wherein A is a group of formula (CtL) Br.

zq / -41τ:

Compounds of formula (I) wherein A is a group of formula (CH₉) Br 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 a group of formula (CH 2) CN or zq still having amines of formula HNRR 'where R and R' have the meanings defined above to give the compounds of formula (I) wherein A is a group of formula (CH₉) NRR 'or with thiols of general formula

HS-R 'wherein R' is as defined above to obtain derivatives of formula (I) wherein A is a group of formula (CH₉) -S-R '.

zq

Compounds of formula (I) wherein A is this group of formula (0Η₂) May be hydrolysed according to standard nitrile hydrolysis methods to give compounds of formula (I) wherein A is a group of CH (CH₂) CO₂H.

These same compounds may be esterified by conventional esterification methods to obtain compounds of formula (I) wherein A is a group of formula (CH₂) ^ CO₂R 'where R' represents a lower alkyl radical and q represents an integer from 1 to 5 or transformed into an amide of formula

- (CH₉) -CONRR 'as defined before, zq _?Compounds of formula (I) wherein A is a group of formula (CH3, wherein L represents a halogen atom and q represents an integer from 1 to 5 may be synthesized by reaction of derivatives of formula (I) wherein A is a group of formula (CH_?OH with halogenating agents such as thionyl chloride, phosphorus oxychloride or phosphorus tribromide for example.

In the case where the symbol has a function not compatible with these reaction parameters, the derivative of formula (XII) shall be used as the transformation compound, and V shall then be transformed into the function as mentioned above.

Addition salts of certain compounds of formula (I), in particular pharmaceutically acceptable addition salts, may be obtained. Particular mention may be made when R 6, R 4 or A represent an acidic function such as sodium, potassium, calcium, amine salts such as dicyclohexylamine or amino acid salts such as lysine. When A or R4 have an amine function, an inorganic or organic acid salt such as hydrochloride, methanesulfonate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate for example.

The novel compounds prepared by the process according to the present invention have remarkable pharmacological properties as angiotensin II receptor antagonists and may be used in therapy for the treatment of cardiovascular disease in particular for the treatment of hypertension and heart failure.

Thus, the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, medicaments comprising a pharmaceutically effective amount of at least one compound of formula (I) as defined above as well as optionally one of its salts pharmaceutically acceptable addition.

These compositions may be administered orally, rectally, parenterally, transdermally or ocularly.

<img file="PT97056A_D0060.tif" />

These compositions may be solid or liquid and come in pharmaceutical forms commonly used in human medicine, such as single or dragged tablets, granules, granules, suppositories, injectable preparations, transdermal patches and eye drops. : prepare according to the usual methods. 0 Active ingredient consisting of a pharmaceutically effective amount of at least one compound of formula (I) defined above or one of its pharmaceutically acceptable addition salts may be mixed with commonly used excipients

<img file="PT97056A_D0061.tif" />

such pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semi-synthetic glycerides, aqueous or non-aqueous vehicles, animal or vegetable fat bodies, glycols, various wetting, dispersing or emulsifying agents, silicone gels, certain polymers or copolymers, preservatives, flavorings and colors.

The present invention further relates to a pharmaceutical composition having angiotensin II receptor antagonist activity which particularly enables the favorable treatment of cardiovascular disease, in particular hypertension and heart failure, characterized in that an effective amount of the mixture is mixed. pharmaceutically acceptable at least one compound of formula (I) above or one of its pharmaceutically acceptable addition salts, with a pharmaceutically acceptable excipient, vehicle or carrier.

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

For example, in the average adult weight of 60 to 70 kg, it may range from 1 to 400 mg of active ingredient in one or more daily doses orally, or 0.01 to 50 mg in one or more daily doses per parenteral route.

<img file="PT97056A_D0062.tif" />

The present invention further relates to a process for the preparation of a pharmaceutical composition wherein a pharmaceutically effective amount of at least one compound of formula (I) as defined above or a pharmaceutically acceptable addition salts thereof with a pharmaceutically acceptable excipient, carrier or carrier. According to a particular feature, this pharmaceutical composition is formulated as gels, tablets dosed between 1 and 400 mg or as injectable preparations dosed between 0.01 and 50 mg.

The present invention further relates to a method for the therapeutic treatment of mammals, wherein a therapeutically effective amount of at least one compound of formula (I) as defined above or one of its salts thereof is administered to this mammal. pharmaceutically acceptable addition.

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

Other features and advantages of the present invention will be better understood from the following reading of some by no means limiting preparation examples, but given by way of illustration.

-1&amp;-

<img file="PT97056A_D0063.tif" />

EXAMPLE 1: Ethyl 3-oxoheptanoate

General formula (II): R ^ = n-Butyl R- ^ = Ethyl

Meldrum acid 70 g is dissolved in dichloromethane 200 ml in the presence of pyridine 78.5 ml, the reaction mixture is cooled to 0 ° C and 64.5 g valeric acid chloride is added. drop by drop at this temperature. After the addition is complete, leave the reaction mixture at room temperature and stir for two hours. The solution is washed with dilute hydrochloric acid solution, dried over magnesium sulfate and evaporated in vacuo to give 110 g of an oil which is used as follows. This oil is dissolved in 400 ml of absolute ethanol and the reaction mixture is refluxed for two hours and left overnight at room temperature. Ethanol is evaporated in vacuo and the oily residue distilled under reduced pressure to give 63.3 g of ethanol.

Ethyl 3-oxoheptanoate as a boiling liquid Ρ.Ε ·._2θ : 115^O-120 ° C.

EXAMPLE 2: Ethyl 3-oxohexanoate

General formula (II): R ^ = n-Propyl R- ^ = Ethyl

Prepared according to the process described in Example 1.

Boiling point liquid Ρ.Ε.₂θ = 95-100 ° C

EXAMPLE 3: Ethyl 2- (4-nitro-benzyl) -3-oxoheptanoate

General formula (V): R 1 = n-Butyl, V = NO₂, R ^ q = Ethyl

57.3 g of ethyl 3-oxoheptanoate is dissolved in 300 ml of ethanol. A solution of sodium ethylate prepared by the addition of 7.7 g of sodium in 50 ml of ethanol is added and the reaction mixture is stirred for 20 minutes at room temperature. Then 72 g of 4-nitro-benzyl bromide is added portionwise and the reaction mixture is then stirred for two hours at room temperature and then for two hours at reflux. Ethanol is evaporated in vacuo, the residue 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 an ether / pentane mixture, the crystals formed are drained to remove the dibenzylated derivative (mp: 135 ° C) and the mother liquor is concentrated under vacuum at 120 ° C to remove the initial unsubstituted keto ester to give 69.2 g of

Ethyl 2- (4-nitro-benzyl) -3-oxoheptanoate as an oil which is used as follows.

EXAMPLE 4: Ethyl 2- (4-nitro-benzyl) -3-oxohexanoate

General formula (V): R 1 = n-Propyl, V = NO₂, R- ^ θ = Ethyl

Prepared according to the process described in Example 3 from ethyl 3-oxohexanoate prepared in Example 2.

used oil as is in the following.

EXAMPLE 5: Ethyl (methoxy-2'-carbonyl-4-biphenyl) -2-ethylethyl-3-oxoheptanoate

General formula (V): R3 = Butyl

MeO, C = Ethyl

Prepared according to the procedure described in Example 3 from ethyl 3-oxoheptanoate prepared in Example 1 and methyl (4'-bromomethyl-2-biphenylyl) -carboxylate.

Oil used as follows.

Preparation of methyl (4'-bromomethyl-2-biphenylyl) carboxylate.

A) Methyl (4'-Methyl-2-biphenylyl) carboxylate.

To 300 ml of methanol cooled to 0 ° C is added 15 ml of acetyl chloride. Stir the reaction mixture for 10 minutes at this temperature and then add 15 g of (4'-Methyl-2-biphenylyl) carboxylic acid [prepared according to MEYERS. THERE; MIHELICH ED, J. Am. Chem. Soc., 1975, 97 (25), 7383 by reaction of (4-methylphenyl) -megnesium bromide with 2- (2-methoxyphenyl) -4,4-dimethyl-1,3-oxozolidine]. The reaction mixture is then heated at reflux for 4 hours and evaporated.

<img file="PT97056A_D0064.tif" />

solvents in vacuo to give 16 g of methyl (4'-methyl-2-biphenylyl) carboxylate as an oil used as follows.

B) Methyl (4'-bromomethyl-2-biphenylyl) carboxylate.

16 g of methyl (4'-methyl-2-biphenylyl) carboxylate prepared in A) is dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-bromosuccinimide and 0.5 g of benzoyl peroxide. The reaction mixture is refluxed for 6 hours, the crystals are filtered off and the remaining solution washed with sodium hydrogen carbonate solution and then evaporated in vacuo. The residue is taken up in ether, then the solution is filtered over charcoal and evaporated in vacuo to give 14.5 g of methyl (4'-bromomethyl-2-biphenylyl) -carboxylate as a oil that is used as is in the following.

EXAMPLE 6;

Ethyl (2'-Cyano-4-biphenyl) -2-methyl-3-oxoheptanoate.

Formula (V): R3 = Butyl, V =

R₁₀ = Ethyl

<img file="PT97056A_D0065.tif" />

30 g of ethyl 3-oxoheptanoate prepared in Example 1 is dissolved in 300 ml of tetrahydrofuran. 31.6 g of 4'-bromomethyl-2-cyano-biphenyl as well as 40 ml of N, N-diiso-50propyl amine and 10 g of lithium bromide are added. The reaction mixture is heated at reflux for 15 hours, then concentrated under vacuum and ice water and dilute hydrochloric acid are added before extracting with ethyl acetate. The organic phase is washed with water, then dried and evaporated in vacuo. The residue obtained under vacuum is heated to 130 ° C to remove residual ethyl 3-oxoheptanoate to give 41 g of (2'-cyano-4-biphenylyl) -2-methyl-3-oxohexane. crude ethyl heptanoate as an oil which is used as follows.

Preparation of 4'-Bromomethyl-2-cyano-biphenyl:

A) 4'-Methyl-2-cyano-biphenyl:

18.5 g of (4'-methyl-2-biphenylyl) carboxylic acid prepared according to the procedure described in Example 5A) is heated to reflux in 60 ml of thionyl chloride for two hours. The thionyl chloride is concentrated in vacuo and the residue is poured into 28% ammonium hydroxide solution, the reaction is stirred for 30 minutes, the crystals obtained are isolated and washed with ether and dried. thereafter to give 14.5 g of (4'-methyl-2-biphenylyl) carboxamide as melting crystals 128 ° C. These crystals are taken up in 50 ml of thionyl chloride and the reaction mixture is heated at reflux for 3 hours and then concentrated under vacuum to give 9 g of 4'-methyl-2-cyano-biphenyl as of melting point crystals 45 ° -46 ° C.

(51) 4'-Bromomethyl-2-cyano-biphenyl:

7.9 g of 4'-methyl-2-cyano-biphenyl prepared in A) is dissolved in 100 ml of carbon tetrachloride in the presence of 7.3 g of N-bromosuccinimide and 0.3 g of peroxide. of benzoyl. Reflux the reaction mixture for 6 hours, filter the crystals, concentrate the remaining solution in vacuo and crystallize the residue from ether to give 4'-bromomethyl-2-cyano 6.6 g biphenyl as crystals melting point: 115 ° -118 ° C.

EXAMPLE 7: 1-Methyl-3n-butyl-4- (4-nitro-benzyl) -5-hydroxy-pyrazole.

General formula (IX): R1 = n-Butyl, R2 = CH3,

V = N0₂

20 g of ethyl 2- (4-nitro-benzyl) -3-oxoheptanoate prepared in Example 3 is dissolved in 150 ml of ethanol and 4 ml of methylhydrazine is added. The reaction mixture is heated at reflux for 6 hours. Ethanol is evaporated in vacuo and the residue taken up in water, then extracted with ethyl acetate, the organic phase is then washed several times with a dilute sodium hydroxide solution and the aqueous fractions are acidified. combined with sulfur dioxide and then extracted with chloroform.

The chloroform phase is dried over magnesium sulfate and evaporated in vacuo to give a residue which crystallizes from ether. The crystals are isolated and recrystallized from ethyl acetate to give 10.9 g of 1-methyl-3-n-butyl-4- (4-nitro-benzyl) -5-hydroxy-pyrazole as melting crystals 136 ° C.

EXAMPLE 8: 1-Methyl-3-n-propyl-4- (4-nitro-benzyl) -5-hydroxy-pyrazole

General formula (IX): R1 = n-Propyl, R1₂ = CH ^,

V = N0₂

Prepared according to the process described in Example 7 from ethyl 2- (4-nitro-benzyl) -3-oxohexanoate prepared in Example 4.

Melting crystals 174 ° C.

EXAMPLE 9: 3-n-Propyl-4- (4-nitro-benzyl) -5-h.hydroxy-pyrazole

General formula (IX): R1 = n-Propyl, R1₂ = Η, V = N0₂

Prepared according to the procedure described in Example 7 from ethyl 2- (4-nitro-benzyl) -3-oxohexanoate prepared in Example 4 and hydrazine

Melting crystals 196 ° C.

/-53,,

EXAMPLE 10:

1- (Ethoxycarbonylmethyl) -3-n-propyl-4- (nitro-4-benzyl) -5-hydroxypyrazole

General formula (IX): = n-Propyl, R₂ = CH₂C0₂Et,

V = N0₂

Prepared according to the process described in Example 7 from diethyl hydrazinoacetate.

&gt;

Melting point crystals 134 ° C.

EXAMPLE 11: 1- (2,2,2-Trifluoro-ethyl) -3-n-propyl-4- (4-nitro-benzyl) -5-hydroxy-pyrazole

General formula (IX): R1 = n-Propyl, R1₂ = CH ^ CF ^,

V = no₂

Prepared according to the process described in Example 7 | from 2,2,2- (trifluoroethyl) hydrazine.

Melting point crystals 160 ° C.

EXAMPLE 12: 1-Methyl-3-n-Butyl- (methoxy-2'-carbonyl-4-biphenylyl-4) -4-methyl-5-hydroxypyrazole

General formula (IX): R1 = n-Butyl, R1₂ = CH ^,

V = CH, O₂Ç

Prepared according to the process described in Example 7 from ethyl (methoxy-2-carbonyl-4-biphenylyl-4) -2-methyl-3-oxoheptanoate prepared in Example 5.

Melting point crystals 108 ° C.

EXAMPLE 13: 1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-hydroxypyrazole

General formula (IX): R = CH_3&gt; V = n-Butyl, R₂ =

NC

<img file="PT97056A_D0066.tif" />

Prepared according to the procedure described in Example 7 from ethyl (2-cyano-4-biphenylyl-4) -2-methyl-3-oxoheptanoate prepared in Example 6.

Melting point crystals 138 ° C.

EXAMPLE 14: [1-Methyl-3-n-propyl-4- (4-nitro-benzyl) -5-pyrazolyl]

-oxyacetate ethyl

General formula (XI): R1 = n-Propyl, R1₂ = Methyl,

R₃ = CH₂CO₂Et, V = NO₂

22.4 g of 1-methyl-3-n-propyl-4- [4-nitro-benzyl) -5-hydroxypyrazole prepared in Example 8 is dissolved in 200 ml of acetone and 8 is added, 7 g of sodium carbonate as well as 9.2 ml of ethyl bromo acetate. The reaction mixture is refluxed for 5 hours and the solvents 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 with isopropyl ether and the crystals obtained are isolated to give 9 g of [1-methyl-3-η-propyl-4- (4-nitro-benzyl) -5-oxo-2-pyrazolyl ] ethyl acetate-melting point 62 ° C.

The mother liquor is concentrated and the oil obtained is chromatographed on silica gel eluting with dichloromethane / acetone (90/10) to give 10 g of [1-methyl-3-n-propyl-4-yl). Ethyl (4-nitro-benzyl) -5-pyrazolyl] -oxyacetate as melting crystals 60 ° -61 ° C.

EXAMPLE 15: Ethyl [1-Methyl-3-n-Butyl-4- (4-nitro-benzyl) -5-pyrazolyl-5] oxyacetate

General formula (XI): R1 = n-Butyl, R1₂ = Methyl,

R₃ = CH₂CO₂Et, V = NO₂

Prepared according to the process described in Example 14

Melting point crystals 68 ° C.

-56/

X

Example 16; Ethyl [3-n-propyl-4- (4-nitro-benzyl) -5-pyrazolyl-5] oxyacetate

General formula (XI): = n-Propyl, R₂ = H,

R₃ = CH₂CO₂Et, V = NO₂

Prepared according to the process described in Example 14.

Melting point crystals 116 ° C.

EXAMPLE 17: [1-Methyl-3-n-propyl-4- (4-nitro-benzyl) -5-pyrazolyl]

methyl oxyacetate

General formula (XI): Ry = n-Propyl, R₂ = methyl,

R₃ = CH₂CO₂ Me, V = NO₂

Prepared according to the process described in Example 14.

Melting point crystals 58 ° C.

EXAMPLE 18: methyl d (2,2,2-trifluoroethyl) -3-n-propyl-4- (4-nitro-benzyl) -5-pyrazolyl] oxyacetate

General formula (XI): R1 = n-Propyl, R1₂ = CH₂CF₃,

R₃ = CH₂CO₂ Me, V = NO₂

Prepared according to the process described in Example 14.

Melting point crystals 73 ° C.

EXAMPLE 19: [1-Methyl-3-n-butyl- (methoxy-2'-carbonyl-4-biphenylyl)

Ethyl 4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R1 = n-Butyl, R1₂ = Methyl,

R₃ = CHjCO_sEt, V = MeOjC

<img file="PT97056A_D0067.tif" />

Prepared according to the process described in Example 14.

used oil as is following,

EXAMPLE 20 Ethyl [1-methyl-3-n-butyl-2 * - (eiano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R1 '= n-Butyl, R1₂ = Methyl,

R₃ = CHjCO₂Et, V = NC '

Prepared according to the process described in Example 14, oil used as follows.

EXAMPLE 21:

_ [1-Methyl-3-n-butyl-4- (4-amino-benzyl) -5-pyrazylyl] -oxy-acetate

General formula (I): R 1 = n-Butyl, R 2 = Methyl,

A = OR ^, R ^ = CH₂CO₂Et, -NH₂

3.4 g of ethyl [1-methyl-3-n-butyl-4- [4-nitro-benzyl) -5-pyrazolyl] oxyacetate prepared in Example 15 is dissolved in 50 ml of absolute ethanol in the presence of 500 mg Raney Nickel. The reaction mixture is hydrogenated at atmospheric pressure and room temperature and when hydrogenation is complete the catalyst is filtered off, the ethanol is evaporated in vacuo and the residue taken up with pentane to give 2.9 g. Ethyl [1-methyl-3-n-butyl-4- (4-amino-benzyl) -5-pyrazolyl] oxyacetate as melting crystals 65 ° C.

EXAMPLE 22: [1-Methyl-3-n-propyl-4- (4-amino-benzyl) -5-pyrazolyl]

-oxy ethyl acetate

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

A = ORg, Rg = CH₂C0₂ Et, r₄= nh₂

Prepared according to the process described in Example 21.

Melting crystals 103 ° C.

-59/

V

EXAMPLE 23: [1-Methyl-3-n-propyl-4- (4-amino-benzyl) -5-pyrazolyl]

methyl oxyacetate

General formula (I): = n-Propyl, R₂ = Methyl,

A = 0R₃, R₃ = CH₂CO₂ Me, Rf = NH

Prepared according to the process described in Example 21.

used oil as is in the following.

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

General formula (I): R1 = n-Propyl, R1₂ = CH₂CF₃,

A = 0R₃, R₃ = CH₂CO₂ Me, Rf = NH₂

Prepared according to the process described in Example 21.

Melting point crystals 63 ° C.

EXAMPLE 25: 1- (Ethoxycarbonyl-methyl) -3-n-propyl-4- (4-amino-benzyl) -5-hydroxy-pyrazole

General formula (I): R- = n-Propyl, R₂ = CH₂CO₂ Et,

A = 0R₃, R₃ = H, R3 = NH₂

<img file="PT97056A_D0068.tif" />

Prepared according to the process described in Example 21.

Oil used as is following.

EXAMPLE 26 Ethyl 1- [3-n-prapyl-4- (4-amino-benzyl) -5-pyrazolyl] -oxyacetate

General formula (I): R1 = n-Propyl, R2 = H,

A = ORg, Rg = CH2CO2 Et, R3 = NH2

Prepared according to the process described in Example 21.

Oil used as follows.

EXAMPLE 27 Ethyl α-1-Methyl-3-n-butyl-4- [4- (2-carboxy-benzoyl-amino) -benzyl] -5-pyrazolyl-oxiacetate

General formula (I): = n-butyl, R2 = methyl,

<img file="PT97056A_D0069.tif" />

3 g of ethyl [1-methyl-Bn-butyl-α- (4-amino-benzyl) -5-pyrazolyl] oxyacetate, prepared in Example 21, is dissolved in 50 ml.

-61 of acetonitrile. Add 1.3 g of phthalic anhydride and leave the reaction mixture at room temperature overnight. The crystals obtained are isolated, washed with isopropyl ether and dried to give 2.5 g of 1-Methyl-3-n-butyl-4- [4- (2-carboxy-benzoyl-amino) Ethyl 4-benzyl] -5-pyrazolyl] oxyacetate as melting crystals 140 ° -141 ° C.

According to the process described above, the following compounds were prepared:

EXAMPLE 28: Methyl N-1-Methyl-3-n-propyl-4- [1- (2-carboxy-benzoyl-amino) -benzyl] -4-pyrazolyl-oxiacetate

General formula (I): R1 = n-Propyl, R1₂ = CH ^

<img file="PT97056A_D0070.tif" />

Crystals in the form of dicyclohexylamine salt, mp 173-174 ° C.

EXAMPLE 29: | Ethyl 1-methyl-3-n-propyl-4- [4- (2-carboxy-benzoyl-amino) -benzyl] -5-pyrazolyl} -oxyacetate

General Formula (I): = n-Propyl, R₂ = CHg, A = ORg

O

II

NH— &lt;λ

R ^CHjCOjEt.R. »

HOjC

Melting crystals 139 ° -140 ° C,

EXAMPLE 30: | Ethyl 1-methyl-3-n-propyl-4- [4- (2-carboxy-3,6-dichloro-benzoyl-amino) -benzyl] -5-pyrazolyl] -oxyacetate

General formula (I): R1 = n-Propyl, R1₂ = CHg, A = ORg

<img file="PT97056A_D0071.tif" />

From 3,6-dichlorophthalic anhydride.

Crystals in the form of dicyclohexylamine salt, mp 199 ° -200 ° C.

EXAMPLE 31:

| Methyl 1-methyl-3-n-propyl-4- [4- (2-carboxy-3,6-dichloro-benzoyl-amino) -benzyl] -5-pyrazolyl} -oxyacetate

General formula (I); = n-Propyl, Rg = Methyl,

<img file="PT97056A_D0072.tif" />

From 3,6-dichloro-phthalic anhydride.

Melting point crystals 150 ° -151 ° C.

EXAMPLE 32: | 1- (2,2,2-trifluoro-ethyl) -3-n-propyl-4- [4- (2-carboxy-3,6-dichloro-benzoyl-amino) -benzyl] -5-pyrazolyl] -oxyacetate methyl

General formula (I): R 1 = n-Propyl, R g = CH 3 CF 3,

<img file="PT97056A_D0073.tif" />

<img file="PT97056A_D0074.tif" />

From 3,6-dichlorophthalic anhydride.

Melting crystals 169 ° -170 ° C.

EXAMPLE

33; | 1- (2,2,2-trifluoroethyl) -3-n-propyl-4- [4- (2-carboxy

methyl-benzoyl-amino) -benzyl] -5-pyrazolyl] -oxyacetate

General formula (I): R- = n-Propyl, R₂ = CH ^ CF ^, A ⁼ OR ^,

<img file="PT97056A_D0075.tif" />

Melting crystals 189 ° -192 ° C.

EXAMPLE 34:

3-n-propyl-4- [4- (2-carboxy-benzoyl-amino) -benzyl] -5-pyrazolyl} -oxyacetic acid

General formula (I): R1 = n-Propyl, R1₂ = Η, A = OR ^

O

II

NH — C.

R₃ = CHjCOjH, R₄ =

<img file="PT97056A_D0076.tif" />

0.9 g of ethyl [3-n-propyl-4- (4-amino-benzyl) -5-pyrazolyl] oxyacetate prepared in Example 26 is dissolved in 20 ml of acetonitrile in the presence of 0.45 g of phthalic anhydride. The reaction mixture is left at room temperature overnight. The acetonitrile is evaporated in vacuo and the residue taken up in an ethyl acetate / ether mixture to give isolated crystals. These crystals are dissolved in dichloromethane and the solution is washed several times with 1 N sodium hydroxide solution. The combined aqueous phases are acidified by bubbling with sulfur dioxide and the crystals obtained are isolated and dried to give 3-n-propyl-4- [4- (2-carboxy-benzoyl) -acid. amino) benzyl] -5-pyrazolyl] oxiacetic as melting crystals 170 ° -171 ° C.

EXAMPLE 35: [1-Methyl-3-n-propyl-4- [4- (2-sulfo-benzoyl-amino) -benzyl] -5-pyrazolyl] -oxyacetic acid

General formula (I): = n-Propyl, R₂ = CHg, A = 0R ^

O

II

NH — C

<img file="PT97056A_D0077.tif" />

Prepared according to the process described in Example 34 from ortho sulfobenzoic acid cyclic anhydride.

Melting point crystals 168 ° -170 ° C.

EXAMPLE 36: [1-Methyl-3-n-butyl-5-hydroxy-4-pyrazolyl] -4'-methyl-2-biphenyl carboxylic acid

General formula (I): = n-Butyl, R₂ = Methyl,

A = OR ^&gt; R3 ⁼ H,

<img file="PT97056A_D0078.tif" />

1.5 g of 1-methyl-3-n-butyl-5-hydroxy- (2'-methoxycarbonyl-4-biphenylyl) -4-methylpyrazole prepared in Example 12 is suspended in 15 ml of a solution of 1N sodium hydroxide and stir for one hour at 40 ° C. The solution is washed with dichloromethane and then acidified by sulfur dioxide bubbling and extracted with dichloromethane. The organic phase is dried over magnesium sulfate and then evaporated in vacuo. The residue is diluted with ethyl acetate, extracted with sodium hydrogen carbonate solution, then acidified with sulfur dioxide and the crystals isolated to give 1.1 g of [1-Methyl-3 acid. -n-butyl-5-hydroxy-4-pyrazolyl] -4'-methyl-2-biphenylcarboxylic as melting crystals 228 ° -230 ° C

EXAMPLE 37: [1-Methyl-3-n-butyl- (2'-carboxy-4-biphenylyl) -4-acid

-methyl-5-pyrazolyl] -oxyacetic

<img file="PT97056A_D0079.tif" />

General formula (I): = n-Butyl, R₂ = CHg, A = ORg (VCHjCO / f R &lt;=

HOjC

2.6 g of ethyl [1-Methyl-3-n-butyl- (2'-methoxycarbonyl-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate prepared in Example 19 is dissolved in 30 ml of ethanol. 1 g of sodium hydroxide in pellets as well as 10 ml of water are added, the reaction mixture is stirred at room temperature for two hours and then heated at reflux 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 sulfur dioxide bubbling and extracted with chloroform. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give a residue which crystallizes from an ethyl acetate / ether mixture to give 2 g of [1-Methyl-3-n-butyl acid). (2'-Carboxy-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetic as melting crystals 153 ° -154 ° C.

EXAMPLE 38: 1-Methyl-3-n-butyl-4- (4-nitro-benzyl) -methoxycarbonyl-5-oxypyrazole

General formula (I): R1 = n-Butyl, R1₂ = Methyl,

A = OR-, R- = C OMe, R, = NO_O ’ 3 || 4 2

<img file="PT97056A_D0080.tif" />

12 g of 1-Methyl-3-n-butyl-4- (4-nitro-benzyl) -5-hydroxypyrazole prepared in Example 7 is dissolved in 120 ml of 1,2-dichloroethane in the presence of 6 ml of triethylamine. Is added

3.3 g of methyl chloroformate dropwise and the reaction mixture is stirred for 2 hours at room temperature and then for 4 hours at reflux. The solution is washed with water after cooling, then dried over magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel eluting with dichloromethane / acetone (95: 5) to give 6.6 g of 1-methyl-3-n-butyl-4- (4-nitro-benzyl). methoxycarbonyl-5-oxypyrazole as melting crystals 44 ° -47 ° C.

EXAMPLE 39: 1-Methyl-3-n-butyl-4- (4-amino-benzyl) -methoxycarbonyl-5-oxypyrazole

General formula (XII): R 1 = n-Butyl, R 2 = Methyl,

R_O = C-OMe, V = NH₀³ II ²

Prepared according to the process described in Example 21.

used oil as is in the following.

EXAMPLE 40: [[1-Methyl-3-n-butyl-5-hydroxy-4-pyrazolyl] methyl-4-phenylyl] amino-2-carbonyl-3,6-dichloro benzoic acid

<img file="PT97056A_D0081.tif" />

General formula (I): = n-Butyl, R₂ = Methyl,

<img file="PT97056A_D0082.tif" />

Prepared according to the process described in Example 27 from 3,6-dichloro-phthalic anhydride.

Melting crystals 172 ° -174 ° C.

EXAMPLE 41: [[Ethoxycarbonyl-1-methyl-3-n-propyl-5-hydroxy-4-pyrazolyl] methyl-4-phenylyl] amino-2-carbonyl-3,6-dichloro benzoic acid

General formula (I): R1 = n-propyl, R1₂ = CH₂CO₂ Et,

<img file="PT97056A_D0083.tif" />

Prepared according to the process described in Example 27 from 3,6-dichloro-phthalic anhydride.

70 Melting crystals 150 ° -153 ° C.

EXAMPLE 42: Ethyl [ethoxycarbonyl-1-methyl-3-n-propyl-4- (4-nitro-benzyl) -5-pyrazolyl] -oxyacetate

General formula (XI): = n-propyl, R₂ = CH₂CO₂ Et,

R₃ = CH₂C0₂ Et, V = NO₂

Prepared according to the process described in Example 14.

Oil used as follows.

EXAMPLE 43: Ethyl [Ethoxycarbonyl-1-methyl-3-n-propyl-4- (4-amino-benzyl) -5-pyrazolyl] -oxyacetate

General formula (I): R1 = n-propyl, R1₂ = CH₂CO₂ Et,

A = ORp R ^ = CH₂CO₂ Et, Rf = NH₂

Prepared according to the process described in Example 21.

used oil as is in the following.

EXAMPLE 44: [[1- (Ethoxycarbonyl-1-methyl) -3-n-propyl-5- (Ethoxycarbonylmethyloxy) -4-pyrazolyl-4] methyl-4-phenyl] amino-2-carbonyl-3,6-dichloro benzoic

<img file="PT97056A_D0084.tif" />

General formula (I): = n-propyl, R₂ = CH₂CO₂ Et,

A = 0R₃,

<img file="PT97056A_D0085.tif" />

Prepared according to the process described in Example 27 from 3,6-dichloro-phthalic anhydride.

Melting crystals 189 ° -191 ° C as dicyclohexylamine salt.

EXAMPLE 45 ·. [[1-Methyl-3-n-propyl-5- (Ethoxycarbonylmethyloxy) -4-pyrazolyl] methyl-4-phenylylamino-2-carbonylbenzenesulfonic acid

General formula (I): R1 = n-propyl, R1₂ - Methyl, A = 0R_O

<img file="PT97056A_D0086.tif" />

Prepared according to the procedure described in Example 27 but with ortho-sulfobenzoic acid cyclic anhydride.

Melting crystals 203 ° -205 ° C,

EXAMPLE 46: N - [[1-Methyl-3-n-butyl-4- (4-nitro-benzyl) -5-pyrazolyl] -oxyacetyl] -morpholine

General formula (XI): R1 = n-butyl, R2 = methyl R1

R₃ = CH, —C — NO, V = NO_: ΰ w

Prepared according to the process described in Example 14 from N- (chloroacetyl) morpholine.

Melting point crystals 98 ° C.

Preparation of N- (chloroacetyl) morpholine:

21.7 g of morpholine is dissolved in 250 ml of dichloromethane and the solution obtained is cooled with an ice / water mixture.

Add 14.1 g of chloroacetyl chloride dropwise while maintaining the temperature at 0 ° C, then stir the reaction mixture.

For 3 hours at room temperature and wash with a dilute hydrochloric acid solution. The organic phase is dried over magnesium sulfate and evaporated in vacuo to give 29.8 g of N- (chloroacetyl) morpholine as an oil of sufficient purity to follow.

EXAMPLE 47: N - [[1-Methyl-3-n-butyl-4- (4-amino-benzyl) -5-pyrazolyl] -oxyacetyl] -morpholine

I

General formula (I): = n-butyl, R₂ = Methyl,

THE ^— or₃ ,

Rj = CH_;

<img file="PT97056A_D0087.tif" />

Rf = NHj

Prepared according to the process described in Example 21.

Melting point crystals 130 ° C.

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

General formula (I): = n-butyl, R₂ = Methyl,

A = 0R₃,

<img file="PT97056A_D0088.tif" />

Ζ

<img file="PT97056A_D0089.tif" />

Prepared according to the procedure described in Example 27 and using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 236 ° -237 ° C.

EXAMPLE 49: [1-Methyl-3-n-butyl-4- (4-nitro-benzyl) -5-pyrazolyl] -2-oxyethanol

General formula (XI): = n-butyl, R₂ = Methyl,

Rg = CH₂CH₂OH, V = NO₂

12 g of 1-methyl-3-n-butyl-4- (4-nitro-benzyl) -5-hydroxy) pyrazole prepared in Example 7 is dissolved in 150 ml of 2-butanone. Sodium carbonate (4.6 g) and 2-bromoethanol (6 g) are added and the reaction mixture is heated at reflux for 12 hours. After cooling the solution is concentrated, then taken up with water and made basic by the addition of dilute sodium hydroxide. After extraction with dichloromethane the organic phase is dried over magnesium sulfate and then evaporated to dryness. The residue obtained is subjected to gel chromatography.⁷⁵ % Silica eluting with ethyl acetate / acetone (6/4) to give 5 g of [1-methyl-3'-n-butyl-4- (4-nitro-benzyl) -5-pyrazolyl] -2-oxo ethanol as crystals of melting point 81 ° C.

EXAMPLE 50: [1-Methyl-3-n-butyl-4- (4-amino-benzyl) -5-pyrazolyl] -2-oxyethanol

General formula (I): = n-butyl, Rg = methyl,

A = ORg, R₃ = CHgCHgOH, R4 = ΝΗ_£

Prepared according to the process described in Example 21.

Oil used as follows.

EXAMPLE 51: [[1-Methyl-3-n-butyl-5- (2-hydroxyethoxy) -4-pyrazolyl] methyl-4-phenylyl] amino-2-carbonylbenzenesulfonic acid

General formula (I): R 2 n-butyl, R g = Methyl, A = OR 4

<img file="PT97056A_D0090.tif" />

Prepared according to the procedure described in Example 27 but using the ortho sulfobenzoic acid cyclic anhydride.

Melting point crystals 170 ° -171 ° C.

EXAMPLE 52:

1-Methyl-4- (4-nitro-benzyl) -3-n-propyl- (N, N-dimethylcarbamoyl) -5-oxypyrazole

General formula (XI): R1 = n-Propyl, R1₂ = Methyl, /^H3

C — N

10 g of 1-Methyl-4- (4-nitro-benzyl) -3-n-propyl-5-hydroxypyrazole prepared in Example 8 is dissolved in 100 ml of dichloromethane and 5 ml of triethylamine. Add 3.2 ml of α-β-dimethyl carbamoyl chloride dropwise and then heat the reaction to reflux for 10 hours. After cooling the reaction mixture is taken up in water and washed with a potassium hydrogen carbonate solution. The chloroform phase is dried over magnesium sulfate and then evaporated in vacuo to give 9.1 g of 1-methyl-4- (4-nitro-benzyl) -3-n-propyl- (N, N- dimethylcarbamoyl) -5-oxypyrazole as crystals melting at 90 ° C.

EXAMPLE 53:

1-Methyl-4- (4-amino-benzyl) -3-n-Propyl- (N, N-dimethylcarbamoyl) -5-oxypyrazole

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

A = 0R_what, Ro = C — N ^{3 3} II 'the tea₃ ch₃, ^r4 - NH₂

Prepared according to the process described in Example 21.

Melting point crystals 138 ° C.

EXAMPLE 54; [[1-Methyl-3-n-propyl- (N, N-dimethylcarbamoyl) -5-oxy-4-pyrazolyl] methyl-4-phenylyl] -2-aminocarbonylbenzenesulfonic acid

General Formula (I)

R1 = n-Propyl, R1₂ = Methyl, A = ORg

<img file="PT97056A_D0091.tif" />

Prepared according to the procedure described in Example 27 and using ortho sulfobenzoic acid cyclic anhydride.

Melting point crystals 210 ° -2 ° C.

EXAMPLE 55:

1-Methyl-3-n-Propyl-4- (4-nitro-benzyl) - (N, N-diethylcarbamoyl) -5-oxypyrazole

General formula (XI): R1 = n-Propyl, R1₂ = Methyl,

Ç₂H_s

R₃ = C — N

V = no₂

<img file="PT97056A_D0092.tif" />

Prepared according to the process described in Example 52.

Oil used as follows.

EXAMPLE 56: 1-Methyl-3-n-Propyl-4- (4-amino-benzyl) - (N, N-diethyl

-carbamorl) -5-oxypyrazole

General formula (I): R4 ⁼ n-Propyl, R₂ = Methyl

A = ORo, R₃ = C — n; ^J II

R₄ = nh₂⁰ c h₅ c h₃

Prepared according to the process described in Example 21.

Melting point crystals 100 ° C.

EXAMPLE 57: [[1-Methyl-3-n-Propyl- (N, N-diethyl carbamoyl) acid

-5-oxy-4-pyrazolyl] methyl-4-phenyl] amino-2-carbonylbenzenesulfonic

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

THE ⁼ OR ^,

C, H_s

FVC— N

R. =

Ç₂H₅

O

II

NH — C,

HO, S '

Prepared according to the procedure described in Example 27 and using ortho-sulfobenzoic acid cyclic anhydride.

Melting crystals 216 ° -217 ° C.

EXAMPLE 58: 1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl- (N, N-dimethylcarbamoyl) -5-oxy-4- (4-nitro-benzyl) -pyrazole

General formula (XI): R1 = n-Propyl, R1₂ = CH₂CFg,

CH,

R, = C — N

CH,

Prepared according to the process described in Example 52.

Melting point crystals 70 ° C.

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

General formula (I): R1 = n-Propyl, R1₂ = CI ^ CFg,

CH,

Á - ORq, r -C — N^Z »&amp; Δ” ^NH?

O ^CH3

Melting point crystals 82 ° C.

Prepared according to the process described in Example 21.

EXAMPLE 60: [[1- (2,2,2-Trifluoro-ethyl) -3-propyl- (N, N-dimethylcarbamoyl) -5-oxy-4-pyrazolyl] -methyl 4-4-phenyl] -acetic acid amino-2-carbonylbenzenesulfonic

General formula (I): Rf = n-Propyl, Rf = Ct4 CF4,

Rf = C

-N

Ά -

CH,

CH,

<img file="PT97056A_D0093.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 159 ° -161 ° C.

EXAMPLE 61; 1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl-4- (4-nitro-benzyl) -5- (hydroxy-ethoxy) -pyrazole

General formula (XI): R · = n-Propyl, R₂ = CI ^ CF ^,

GO₃ = CH₂CH₂OH, V = NO₂

Prepared according to the process described in Example 49.

Melting point crystals 71 ° C.

EXAMPLE 62: 1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl-4- (4-amino-benzyl) -5- (2-hydroxy-ethoxy) -pyrazole

<img file="PT97056A_D0094.tif" />

General formula (I): R1 = n-Propyl, R1₂ = C ^ CFg, a = or₃r₃ = ch₂ch₂oh r₄ = nh₂

Prepared according to the process described in Example 21.

Oil used as follows.

EXAMPLE 63: [[1- (2,2,2-Trifluoroethyl) -3-n-Propyl-5- (hydroxyethoxy) -4-pyrazolyl] -4-methyl-4-phenylyl] amino acid 2 - carbonylbenzene sulfonic

General formula (I): R1 = n-Propyl, R1₂ = C ^ CF ^,

A = 0R₃, R₃ = CH₂CH₂OH,

<img file="PT97056A_D0095.tif" />

Prepared according to the procedure described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 211 ° -213 ° C.

EXAMPLE 64; 1- (Methoxy-phenyl) - [1-methyl-3-n-Propyl-4- (4-nitro-benzyl) -5-pyrazolyl] -oxy-4-acetyl-piperazine

General formula (XI); R1 = n-Propyl, R1₂ = Methyl,

-82/

II

CH, O.

Ο

R, = CH, - C — N

<img file="PT97056A_D0096.tif" />

// \ AT THE,

Prepared according to the process described in Example 14 from 1- (chloroacetyl) -4- (2-methoxyphenyl) piperazine.

used oil as is in the following.

The preparation of 1- (chloroacetyl) -4- (2-methoxyphenyl) piperazine is prepared according to the operative method used for the synthesis of N-chloroacetyl morpholine described in Example 46.

EXAMPLE 65: 1- (Methoxy-phenyl) - [1-methyl-3-n-Propyl-4- (4-amino-benzyl) -5-pyrazolyl] -oxy-4-acetyl-piperazine

General formula (I): = n-Propyl, R₂ = Methyl,

A = 0R₃

CH, O,

I read it

R, = CH, —C — N

<img file="PT97056A_D0097.tif" />

Prepared according to the process described in Example 21.

*** O

145 C. melting crystals

EXAMPLE 66: 1- (2-Methoxy-phenyl) -4 - [[1-methyl-3-n-propyl-4- [4- (2-sulfo-benzoyl-amino) -benzyl] -5-pyrazolyl ] -oxyacetyl] -4-piperazine

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

<img file="PT97056A_D0098.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 226 ° -227 ° C.

EXAMPLE 67:

► (2'-Cyano-4-biphenylyl) -2-methyl-3-oxohexanoate

General formula (V): R1 = n-Propyl, V

<img file="PT97056A_D0099.tif" />

R ^ O ⁼ Ethyl

Prepared according to the process described in Example 6.

Oil used as is in the following.

EXAMPLE 68; 1-Methyl-3-n-Propyl- (2¹-cyano-4-biphenylyl) -4-methyl-5-hydroxypyrazole

General formula (IX): R1 = n-Propyl, V =

R₂ = Methyl

NC '

Prepared according to the process described in Example 7,

Melting point crystals 164 ° C.

EXAMPLE 69: Ethyl [1-methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R1 = n-Propyl, R1₂ = Methyl,

<img file="PT97056A_D0100.tif" />

Prepared according to the process described in Example 14 oil used as follows.

EXAMPLE 70:

Ethyl [1-methyl-3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] oxy acetate.

General formula (I): R1 = n-Propyl, R1₂ = Methyl, A = ORg, Rg = CH₂CO₂ Et,

85ζ

-. 'Λ

<img file="PT97056A_D0101.tif" />

11 g of ethyl [1-methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate prepared in Example 69 is dissolved in 75 ml of toluene. 6.5 g of trimethyl tin azide are added and the reaction mixture is heated at reflux for 24 hours. Evaporate the solvent in vacuo and subject the residue to silica gel chromatography, eluting with 9: 1 chloroform / methanol to give 6.7 g of [1-methyl-3-η-propyl]. Ethyl [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] oxy acetate as melting crystals 187-189 ° C.

EXAMPLE 71;

1-Methyl-3-n-propyl-5-hydroxy- [2 '- (5-tetrazolyl] -4-biphenylyl] -4-methylpyrazole

General formula (I): R · = n-Propyl, R₂ = Methyl,

A = OH,

<img file="PT97056A_D0102.tif" />

5 g of 1-Methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-hydroxypyrazole prepared in Example 68 is dissolved in 50 ml of toluene. 4 g of trimethyl tin azide are added and the reaction mixture is heated at reflux for 14 hours. After cooling, 10 ml of methanol and 10 ml of chloroform are added, the crystals formed are isolated and then taken up with 40 ml of toluene and 10 ml of tetrahydrofuran. Gaseous hydrochloric acid is bubbled into the reaction mixture for 10 minutes and then the reaction mixture is stirred for 1 hour at room temperature. The solvents are evaporated in vacuo, the residue taken up as a dilute sodium hydroxide solution and then washed with ethyl acetate. The aqueous phase is neutralized by bubbling with sulfur dioxide and the residue slowly crystallizes from water to give 3.1 g of 1-methyl-3-n-propyl-5-hydroxy- [2 '] after washing with acetone. - (5-Tetrazolyl) -4-biphenylyl] -4-methylpyrazole as melting crystals 150 ° -153 ° C.

| EXAMPLE 72: 1-Methyl-3-n-Butyl-5-hydroxy- [2 * - (5-tetrazolyl) -4-biphenylyl] -4-methylpyrazole

General formula (I): R1 = n-Butyl, R1₂ = Methyl,

<img file="PT97056A_D0103.tif" />

<img file="PT97056A_D0104.tif" />

7Prepared according to the process described in Example 71.

Melting crystals 176 ° -7 ° C.

EXAMPLE 73: 1- (2,2,2-Trifluoro-ethyl-3-n-Propyl-5-hydroxy- (2'-cyano-4-biphenylyl) -4-methyl-pyrazole

General formula (IX): R-, = n-Propyl, R₉ = CI-UCF ^,

<img file="PT97056A_D0105.tif" />

Prepared according to the process described in Example 7 from (2,2,2-trifluoroethyl) hydrazine.

Crystals

EXAMPLE 74:

melting point 154 ° C.

1- (2,2,2-trifluoroethyl) -3-n-propyl-5-hydroxy- [2 * (5-tetrazolyl) -4-biphenylyl] -4-methylpyrazole

General formula (I): R- = n-Propyl, R₂ = CH₂CF₂, A = OH,

<img file="PT97056A_D0106.tif" />

Prepared according to the process described in Example 71.

Melting point crystals 218 ° -220 ° C.

<img file="PT97056A_D0107.tif" />

EXAMPLE 75: [1-Methyl-3-n-Butyl- (2¹-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (XI): R1 = n-Butyl, R1₂ = Methyl,

R₃ = CH₂CH₂OH,

<img file="PT97056A_D0108.tif" />

Prepared according to the process described in Example 49.

used oil as is in the following.

EXAMPLE 76: [1-Methyl-3-n-Butyl- [2 '(5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (I): R 1 = n-Butyl

<img file="PT97056A_D0109.tif" />

R₂ = Methyl, ch₂ch₂oh

Prepared according to the process described in Example 70.

Melting crystals 105 ° -8 ° C.

<img file="PT97056A_D0110.tif" />

EXAMPLE 77:

Ethyl [1- (2,2,2-trifluoroethyl) -3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R1 = n-Butyl, R1₂ = CH₂CF_3&gt;= CH₂CO₂ Et,

<img file="PT97056A_D0111.tif" />

Prepared according to the process described in Example 14.

Oil used as is in the following.

EXAMPLE 78: [[1- (2,2,2-Trifluoro-ethyl) -3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -oxy ethyl acetate | General formula (I): R 1 = n-Butyl

<img file="PT97056A_D0112.tif" />

^R2 ^CH2^CF3 CH₂CO₂ Et,

Prepared according to the process described in Example 70.

Melting point crystals 140 ° -1 ° C.

EXAMPLE 79: 1- (2,2,2-Trifluoro-ethyl) -3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl- (β, Ν-dimethylcarbamoyl) -5 -oxypyrazole

General formula (XI): R 1 = n-Butyl, R 2 = Cl 2 CF 3,

<img file="PT97056A_D0113.tif" />

I

Prepared according to the process described in Example 52.

Oil used as follows.

EXAMPLE 80: 1- (2,2,2-Trifluoroethyl) -3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl- (Δ, Ν-dimethylcarbamoyl) ) -5-oxypyrazole

General Formula (I):

CH,

R1 = CN

CH,

<img file="PT97056A_D0114.tif" />

CH₂CF₃,

A = ORp

Prepared according to the process described in Example 70

Melting crystals 151 ° -2 ° C.

<img file="PT97056A_D0115.tif" />

EXAMPLE 81:

1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-N, β-dimethyl carbamoyl) -5-oxypyrazole

General formula (XI): R 1 = n-Butyl, R 2 = Methyl,

<img file="PT97056A_D0116.tif" />

Prepared according to the process described in Example 52.

used oil as is in the following.

EXAMPLE 82: 1-Methyl-3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl]

-methyl- (Ν, Ν-dimethyl carbamoyl) -5-oxypyrazole

General formula (I): R 1 = n-Butyl, R 2 = Methyl,

A = 0RCH,

R1 = C- N

CH₃

<img file="PT97056A_D0117.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 160 ° C.

EXAMPLE 83:

<img file="PT97056A_D0118.tif" />

Ethyl 1- (2,2,2-trifluoroethyl) -3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R1 = n-Propyl, R1₂ = CH₂CF Rg = CHgCOg Et,

<img file="PT97056A_D0119.tif" />

Prepared according to the process described in Example 14.

used oil as is in the following.

EXAMPLE 84: [1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -oxy- ethyl acetate

General formula (I): R1 = n-Propyl, R1₂ = CH₂CFg, A - ORg, Rg ⁼ CH₂CO₂ ET,

<img file="PT97056A_D0120.tif" />

Prepared according to the process described in Example 70.

<img file="PT97056A_D0121.tif" />

Melting point crystals 146 ° C.

EXAMPLE 85: 1-Methyl-3-n-Propyl- (2'-cyano-4-biphenylyl) -4-methyl- (α, β-dimethylcarbamoyl) -5-oxypyrazole

General formula (XI): R 1 = n-Propyl, R g = Methyl, r₃= cII • N ch,

CH,

<img file="PT97056A_D0122.tif" />

Prepared according to the process described in Example 52.

Oil used as is in the following.

EXAMPLE 86: 1-Methyl-3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl]

-4-methyl- (Ν, Ν-dimethyl carbamoyl) -5-oxypyrazole

I

General formula (I): R 1 = n-Propyl, R g = Methyl,

A = ORg

Ro

<img file="PT97056A_D0123.tif" />

CH,

CH,

<img file="PT97056A_D0124.tif" />

/

Prepared according to the process described in Example 70.

Melting crystals 103 ° -5 ° C.

EXAMPLE 87; [1-Methyl-3-n-Propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (XI): R1 = n-Propyl, R1₂ = Methyl, R₃ = CH₂CH₂OH,

<img file="PT97056A_D0125.tif" />

Prepared according to the process described in Example 49.

Oil used as follows.

EXAMPLE 88: [1-Methyl-3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl]

-4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

A = 0R₃, R₃ = CH₂CH₂OH,

<img file="PT97056A_D0126.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 120 ° -122 ° C.

EXAMPLE 89: Ethyl [1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI) = n-Butyl, R₂ = Methyl,

R₂ = CH₂CO₂ Et,

<img file="PT97056A_D0127.tif" />

Prepared according to the process described in Example 14.

used oil as is in the following.

EXAMPLE 90: [1-Methyl-3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl) | Ethyl 4-methyl-5-pyrazolyl] oxyacetate

General formula (I): R1 = n-Butyl, R1₂ = Methyl,

A = ORg, Rg = CHgCOg Et,

<img file="PT97056A_D0128.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 142 ° -3 ° C.

EXAMPLE 91: [1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (XI): R1 = n-Propyl, R1₂ = CH₂CF₃r₃ = ch₂ch₂oh

<img file="PT97056A_D0129.tif" />

Prepared according to the process described in Example 49.

Oil used as follows.

EXAMPLE 92:

[1- (2,2,2-Trifluoroethyl) -3-n-Propyl- [2 '- (5-tetrazolyl) biphenylyl] -4-methyl-5-pyrazolyl-2-oxyethanol

General formula (I) = n-Propyl, R₂ = CH₂CF_3&gt;A = 0R₃, R₃ = CH₂CH₂OH,

<img file="PT97056A_D0130.tif" />

Prepared according to the process described in Example 70.

Melting crystals 167 ° C.

EXAMPLE 93: 1-Methoxyoctane-2,4-dione

General formula (III): R 1 = n-Butyl, R '= CH 2, q = 1

200 ml of 2-hexanone and 102 ml of methyl methoxy acetate are added dropwise to 400 ml of toluene containing 26.9 g of hotly divided sodium. On addition the temperature is maintained between 60 ° and 70 ° C. After addition is complete, the reaction is stirred for 2 hours at 55 ° C. After cooling, 20 ml of methanol is added. The reaction mixture is stirred, then taken up in dilute sodium hydroxide solution, the aqueous phase is washed with ether, then acidified with dilute hydrochloric acid and extracted with ether. Evaporate the organic phase under vacuum at 30 ° C after drying over magnesium sulfate and distill the residue under reduced pressure to give 98.6 g of 1-methoxyoctane-2,4-dione as a boiling liquid PE: 115 ° -120 ° C.

EXAMPLE 94: 1-Methoxyheptane-2,4-dione

General formula (III): R 1 = n-Propyl, R '= CH 2, q = 1

<img file="PT97056A_D0131.tif" />

Prepared according to the process described in Example 93 from 2-pentanone.

PE boiling liquid ₂θ: 100 ° -111 ° C.

EXAMPLE 95: 1-Methoxy-3- (4-nitro-benzyl) -heptane-2,4-dione

General formula (VI): R1 = n-Propyl, R1 = CH3,

V = N0₂, q = 1

135 g of 1-methoxyheptane-2,4-dione prepared in Example 94 is dissolved in 1.5 liters of tetrahydrofuran. Is added

123.3 g of 4-nitro-benzyl bromide, 197 ml of N, N-diisopropylethylamine and 49.5 g of lithium bromide and the reaction mixture is heated at reflux for 15 hours. Evaporate the solvent in vacuo, take up the residue with dilute hydrochloric acid and extract with ethyl acetate. The organic phase is evaporated to dryness and the crystals obtained are washed several times with ether and then with hot methanol. The filtrates are combined, evaporated to dryness and the residue 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 3- (4-nitro-benzyl) -1-methoxyheptane-2,4-dione under 55 ° C crystals.

The following compounds were prepared according to the process described.

<img file="PT97056A_D0132.tif" />

EXAMPLE 96:

1-Methoxy- (2'-cyano-4-biphenylyl) -3-methylheptane-2,4-dione

General formula (VI): R1 = n-Propyl, R1 = CH3,

<img file="PT97056A_D0133.tif" />

Oil used as follows.

I

EXAMPLE 97: 1-Methoxy- (2'-cyano-4-biphenylyl) -3-methyl-octane-2,4-dione

Formula¹ (VI): R1 = n-Butyl, R1 = CH3,

<img file="PT97056A_D0134.tif" />

Oil used as follows.

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

General formula (XIII): R1 = n-Propyl, R '= CHg, q = 1, V = NO₂

3- (4-Nitro-benzyl) -1-methoxy-heptane-2,4-dione, 20 g, prepared in Example 95, is dissolved in 400 ml of ethanol, added.

-100-

<img file="PT97056A_D0135.tif" />

400 hydrazine hydrate and the reaction mixture is refluxed for 2 hours. Evaporate the solvent to dryness under vacuum and take up the residue with isopropyl ether; The crystals obtained are isolated to give 4- (4-nitro-benzyl) -n-3-propyl-methoxy-5-methyl-pyrazole 19.5 g as crystals of melting point 124 ° C.

The following compounds were prepared according to the described process:

EXAMPLE 99: 3-n-Propyl- (2'-cyano-4-biphenylyl) -4-methylmethoxy-5-methylpyrazole

General formula (XIII): Ry = n-Propyl, R 'ch₃

<img file="PT97056A_D0136.tif" />

used oil as is in the following.

I

EXAMPLE 100: 3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methylmethoxy-5-methylpyrazole

General formula (XIII): Ry = n-Butyl, R '= CH_3&gt;

7NC

-101-

<img file="PT97056A_D0137.tif" />

used oil as is in the following.

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

General formula (XII): = n-Butyl, R₂ = CEL ^ CF ^,

Rg = CHg, q = 1

NC '

Prepared according to the process described in Example 98 from (2,2,2-trifluoroethyl) hydrazine.

After chromatography on silica gel, the desired compound is obtained by elution with 2/8 ethyl acetate / cyclohexane as an oil which is used as follows.

EXAMPLE 102 1-Methyl-3-n-propyl-4- (4-nitro-benzyl) methoxy-5-methylpyrazole

General formula (XII): R1 = n-Propyl, R1₂ = Methyl, R '= Methyl, V = NO₂, q = 1

5 g of 3-n-propyl-4- (4-nitro-benzyl) -methoxy-5-methylpyrazole prepared in Example 98 is dissolved in 50 ml of acetone in the

-102-

<img file="PT97056A_D0138.tif" />

3 ml of methyl iodide and 3 ml of DBU (1,8-diazabicyclo- [5.4.0] -7-undecene) are present. The reaction mixture is heated for 8 hours at 45 ° C and then the solvent is evaporated.

The residue is taken up in dilute hydrochloric acid and then extracted with ether. The organic phase is dried over magnesium sulfate and then evaporated in vacuo to give an oily residue which is chromatographed on silica gel with an ether / cyclopentane (7: 3) eluent to give 2.5 g of 1-methyl-3-n-propyl-4- (4-nitro-benzyl) -methoxy-5-methyl-pyrazole as melting crystals 73 ° C.

The following two Examples were prepared according to the process described in Example 102:

EXAMPLE 103: 1-Methyl-3-n-propyl- (2'-eiano-4-biphenylyl) -4-methyl-methoxy-5-methyl-pyrazole

General formula (XII): R1 = n-Propyl, R1₂ = Methyl, R '= methyl,

NC

Oil used as is following

EXAMPLE 104: 1-Methyl-3-n-butyl- (2'-cyano-4-biphenylyl) -4-methylmethoxy-5-methylpyrazole

-103General formula (XII): = n-Butyl

R '= methyl,

R₂ = Methyl,

V =

<img file="PT97056A_D0139.tif" />

, q = 1

Oil used as follows.

EXAMPLE 105: 1-Methyl-3-n-propyl-4- (4-amino-benzyl) methoxy-5-methylpyrazole

General formula (I): R · = n-Propyl, R₂ = Methyl, A = CH₂OCH₃, R₄ = NH₂

Prepared according to the process described in Example 21.

Oil used as follows.

Example 106:

»

3-n-Propyl-4- (4-amino-benzyl) methoxy-5-methylpyrazole

General formula (I): = n-Propyl, R₂ = H,

A = CH₂0CH₃, R₄ = NH₂

Prepared according to the process described in Example 21.

Melting crystals 126 ° C.

104

EXAMPLE 107: [(1-Methyl-3-n-propyl-methoxy-5-methyl-4-pyrazolyl) -methyl-4-phenyl] -amino-2-carbonyl-benzene sulfonic acid

General formula (I): = n-Propyl, R₂ = Methyl,

A = CH₂OCH₃.

<img file="PT97056A_D0140.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 126 ° C.

EXAMPLE 108: [(3-n-Propyl-methoxy-5-methyl-4-pyrazolyl) -methyl-4-phenyl] -amino-2-carbonyl-benzene sulfonic acid&gt;

General formula (I): R1 = n-Propyl, R1₂ = H,

A = CH₂OCH₃,

<img file="PT97056A_D0141.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

-105 Melting crystals 253 ° -256 ° C.

EXAMPLE 109: 1-Methyl-3-n-propyl-4- (4-nitro-benzyl) -bromo-5-methyl-pyrazole

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

A = CH₂Br, R4 = NO₂

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

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

General formula (I): R1 = n-Propyl, R1₂ = H,

A = CH₂Br, R₄ = N0₂

Prepared according to the process described in Example 109.

** O

Melting point crystals 120 C.

<img file="PT97056A_D0142.tif" />

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

General formula (XII): R1 = n-Propyl, R1₂ = Methyl,

R '= Η, V = N0₂, q = 1

6.5 g of 1-methyl-3-n-propyl-4- (4-nitro-benzyl) -5-bromomethyl pyrazole prepared in Example 109 is dissolved in a mixture of 50 ml dioxane and 50 ml. ml of water. Sodium carbonate (5 g) is added and the reaction mixture is heated at reflux for 3 hours. Evaporate the solvents in vacuo, take up the residue with water and extract with ether. The organic phase is dried over magnesium sulfate and then evaporated in vacuo to give a residue which crystallizes from isopropyl ether to give

3.8 g of 1-methyl-3-n-propyl-4- (4-nitro-benzyl) hydroxy-5-methylpyrazole as melting crystals 134 ° C.

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

General formula (XIII): R 1 = n-Propyl, R '= H,

V = N0₂, q = 1

Prepared according to the process described in Example 111.

Melting point crystals 125 ° C.

-107-

<img file="PT97056A_D0143.tif" />

EXAMPLE 113; 1-Methyl-3-n-Propyl-4- (4-amino-benzyl) hydroxy-5-methyl-pyrazole

General formula (I): R- = n-Propyl, R₂ = Methyl,

A = CH₂OH, Rf = NH₂

Prepared according to the process described in Example 21.

Melting point crystals 133 ° C.

EXAMPLE 114: 3-n-Propyl-4- (4-amino-benzyl) hydroxy-5-methylpyrazole

General formula (I): R1 = n-Propyl, R1₂ = H,

A = CH₂OH, R₄ = NH₂

Prepared according to the process described in Example 21.

used oil as is in the following.

EXAMPLE 115: [(1-Methyl-3-n-propylhydroxy-5-methyl-4-pyrazolyl) -methyl-4-phenyl] -amino-2-carbonyl-benzene sulfonic acid

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

A = CH₂OH

<img file="PT97056A_D0144.tif" />

<img file="PT97056A_D0145.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 255 ° -257 ° C.

EXAMPLE 116: [(3-n-Propylhydroxy-5-methyl-4-pyrazolyl) methyl-4-phenylyl] amino-2-carbonylbenzene sulfonic acid

General formula (I): = n-Propyl, Rg - H,

A = CHgOH

<img file="PT97056A_D0146.tif" />

Prepared according to the process described in Example 27 using ortho sulfobenzoic acid cyclic anhydride.

Melting crystals 168 ° -170 ° C,

EXAMPLE 117:

1-Methyl-3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methylmethoxy-5-methylpyrazole

General formula (I): R 1 = n-Propyl, R g = Methyl,

<img file="PT97056A_D0147.tif" />

Prepared

Crystals

EXAMPLE 118;

according to the process described in Example 71.

mp 128 ° -130 ° C.

1-Methyl-3-n-Butyl [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methylmethoxy-5-methylpyrazole

General formula (I): R 1 = n-Butyl, R g = Methyl,

A = CHgOCHg,

<img file="PT97056A_D0148.tif" />

Prepared according to the process described in Example 71.

Melting point crystals 134 ° -135 ° C.

-110ζ

EXAMPLE 119: 1- (2,2,2-Trifluoro-ethyl) -3-n-butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-methoxy-5-methyl-pyrazole

General formula (I): R- = n-Butyl, Rg = CHgCF ^,

A = CH₂OCH₃

<img file="PT97056A_D0149.tif" />

Prepared according to the process described in Example 71.

Melting crystals 172 ° -173 ° C.

EXAMPLE 120: Ethyl 3-Oxo-5-methylhexanoate

General formula (II): Rf = 2-methylpropyl,

R ^ q = Ethyl

I

Prepared according to the process described in Example 1.

Boiling point liquid Ρ.Ε. ^ θ: 100 ° -110 ° C.

EXAMPLE 121: Ethyl (2'-Cyano-4-biphenylyl) -2-methyl-3-oxo-5-methylhexanoate

-111ζ

General formula (V): R- = 2-Methyl-Propyl, R ^q = Ethyl

<img file="PT97056A_D0150.tif" />

Prepared according to the process described in Example 6.

Oil used as follows.

EXAMPLE 122: 1-Methyl-3- (2-methylpropyl) - (2¹-cyano-4-biphenylyl) -4-methyl-5-hydroxypyrazole

General formula (IX): Rf = 2-Methyl-Propyl,

R₂ = Methyl,

<img file="PT97056A_D0151.tif" />

Prepared according to the process described in Example 7.

Melting point crystals 163 ° C.

EXAMPLE 123: 1- (2,2,2-Trifluoro-ethyl) -3- (2-methyl-propyl) - (2'-cyano-4-biphenylyl) -4-methyl-5-hydroxy-pyrazole

-112General formula (IX): =

2-Methyl-Propyl, ch₂cf₃,

<img file="PT97056A_D0152.tif" />

Prepared according to the process described in Example 7.

used oil as is in the following.

EXAMPLE 124: [1-Methyl-3- (2-methylpropyl) - (2¹-cyano-4-biphenylyl)

Ethyl 4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): Rf = 2-Methyl-Propyl,

R₂ = Methyl, R₃ = CH₂CO₂ Et,

<img file="PT97056A_D0153.tif" />

Prepared according to the process described in Example 14.

used oil as is in the following.

<img file="PT97056A_D0154.tif" />

EXAMPLE 125: Ethyl [1-Methyl-3- (2-methylpropyl) - [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] oxy-acetate

General formula (I): = 2-Methyl-Propyl,

R2 = Methyl, A = ORp

<img file="PT97056A_D0155.tif" />

Prepared according to the process described in Example 70.

Melting crystals 172 ° -173 ° C.

EXAMPLE 126: [1- (2,2,2-Trifluoro-ethyl) -3- (2-methyl-propyl) - (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxy- ethyl acetate

General formula (XI): Rf = 2-Methyl-Propyl,

R2 ⁼ CF3, Rg = CH2 CO2 Et,

<img file="PT97056A_D0156.tif" />

Prepared according to the process described in Example 14.

Oil used as follows.

EXAMPLE 127: [1- (2,2,2-Trifluoro-ethyl) -3- (2-methyl-propyl) - [2 * - (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl ] -oxy-ethyl acetate

General formula (I): R1 = 2-Methyl-Propyl,

R₂ = CH₂CF₃, A = OR ^,

<img file="PT97056A_D0157.tif" />

Prepared according to the process described in Example 70.

Melting crystals 114 ° -115 ° C.

&gt;

EXAMPLE 128: [1- (2,2,2-Trifluoro-ethyl) -3- (2-methyl-propyl) - (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2- oxyethanol

General formula (XI): Rf = 2-Methyl-Propyl,

R₂ = CH₂CF₃, R₃ = CH₂CH₂OH,

<img file="PT97056A_D0158.tif" />

V

-115/

Prepared according to the process described in Example 49.

Melting point crystals 116 ° C.

EXAMPLE 129: [1- (2,2,2-Trifluoro-ethyl) -3- (2-methylpropyl) - [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl ] -2-oxyethanol

Formula (I): Rf = 2-Methyl-Propyl,

<img file="PT97056A_D0159.tif" />

Prepared according to the process described in Example 70.

Melting crystals 145 ° -146 ° C.

EXAMPLE 130: N - [[1-Methyl-3-n-butyl-4 - [(trifluoromethylsulfonyl-2-amino-benzoyl) -4-amino-benzyl] -5-pyrazolyl] -oxy-acetyl] -morpholine

General formula (I): R1 = n-Butyl, R1₂ = Methyl,

THE ⁼ ORg,

<img file="PT97056A_D0160.tif" />

/ / -166 4.3 g of N - [[1-Methyl-3-n-butyl-4- (4-amino-benzyl) -5-pyrazolyl] -oxy-acetyl] -morpholine prepared in the Example 47, in 20 ml of chloroform in the presence of 1.54 ml of triethylamine 3.52 g of N- (trifluoromethylsulfonyl) -antranylic acid chloride [prepared according to CA references: 96 (13 ): 103651 z and CA 97 (7): 55500 When dissolved in 10 ml of chloroform dropwise at room temperature, the reaction mixture is then heated for 2 hours at 50 ° C and left in. rest 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 dilute sodium hydroxide solution. It is acidified to pH 2 and extracted with ethyl acetate, the organic phase is dried over magnesium sulfate, then evaporated to dryness and the oil is crystallized from ether to give 4.6 g of N - [[1-methyl-3-n-butyl-4 - [(trifluoromethylsulfonyl-2-amino-benzoyl) -4-amino-benzyl] -5-pyrazolyl] -oxy-acetyl] -morpholine as a melting crystals 190 ° C.

&gt;

EXAMPLE 131: (2¹Ethyl -Nitro-4-biphenylyl) -2-methyl-3-oxohexanoate

General formula (V): = n-Propyl, R 4 q = Ethyl,

Λ¹⁷ ζ

. -ϊ

Prepared according to the process described in Example 6 from 2'-nitro-chloro-4-methyl-biphenylyl.

Oil used as such and following.

2'-nitro-chloro-4-methyl-biphenyl was prepared by chloromethylation of 2-nitro-biphenyl according to references: CA 70 (25): 114837 d

CA 69 (2): 3704 t

EXAMPLE 132: 1-Methyl-3-n-Propyl- (2 * -Nitro-4-biphenylyl) -4-methyl-5-hydroxypyrazole

General formula (IX): = n-Propyl, R 2 = Methyl,

V = o₂no

Prepared according to the process described in Example 7.

Crystals

EXAMPLE 133:

mp 179-182 ° C.

Methyl [1-methyl-3-n-propyl- (2'-nitro-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (XI): R 1 = n-Propyl, R 2 = Methyl,

Rg = CH2CO2Me,

-118-

<img file="PT97056A_D0161.tif" />

<img file="PT97056A_D0162.tif" />

Prepared according to the process described in Example 14.

used oil as is in the following.

I

EXAMPLE 134: Methyl [1-methyl-3-n-propyl- (2'-amino-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

General formula (I): R1 = n-Propyl, Rg = Methyl, A = ORg, Rg = CHgCOgMe,

R =

H₂N 'according to the process described in Example 21.

Prepared used oil as is following.

EXAMPLE 135; Methyl [1-methyl-3-n-propyl- (trifluoromethylsulfonyl-2'-amino-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate

<img file="PT97056A_D0163.tif" />

General formula (I): = n-Propyl, Rg = Methyl,

A = ORg, Rg = CHgCOgMe,

R

CF, SO₂NH

1 g of ethyl [1-methyl-3-n-propyl- (2'-amino-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate prepared in Example 134 is dissolved in 30 g. ml of chloroform in the presence of 0.4 ml of triethylamine; The reaction mixture is cooled to 0 ° C and 0.43 ml of trifluoromethanesulfonic anhydride is added dropwise. The reaction 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 is crystallized from isopropyl ether to give 0.7 g of [1-methyl-3-n-propyl- (trifluoromethylsulfonyl-2)¹ethyl-amino-4-biphenylyl) -4-methyl-5-pyrazolyl] oxyacetate as melting crystals 114 ° -116 ° C.

EXAMPLE 136: [1-Methyl-3-n-Propyl- (2'-carbethoxy-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (XI): R 1 = n-Propyl, R g = Methyl,

Rg = CHgCHgOH, v =

EtOjC

<img file="PT97056A_D0164.tif" />

-120-

<img file="PT97056A_D0165.tif" />

Prepared according to the process described in Example 49.

used oil as is in the following.

EXAMPLE 137: [1-Methyl-3-n-Propyl- (2'-carboxy-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (I): Rf = n-Propyl, = methyl, A = 0R₃, R₃ = CH₂CH₂OH

<img file="PT97056A_D0166.tif" />

Prepared according to the process described in Example 37.

Melting crystals 168 ° -170 ° C.

EXAMPLE 138: Ethyl 2- [4- (2-cyano-3-thienyl) benzyl] -3-oxohexanoate

General formula (V): = n-Propyl, R = ^ θ = Ethyl, v = NC

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

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

A) 3- (4-Methyl-phenyl) -2-thiophene carboxylic acid:

25 g of 3- (4-methylphenyl) -2-thiophene carboxylate is dissolved | ethyl alcohol prepared according to reference FISSELMANN. H;

HABITCH. H; Ger. Offen. ”: 1092 929 (1960), CA”: 57, 5894 g, in 580 ml of ethanol and 50 ml of water. Sodium hydroxide (6.2 g) is added to the tablets and the reaction mixture is heated at reflux for 2 hours, poured into water and acidified with concentrated hydrochloric acid. The crystals that form are isolated and dried to give 20.7 g of 3- (4-methylphenyl) -2-thiophene carboxylic acid as melting crystals 172 ° C.

IB) 3- (4-Methyl-phenyl) -2-thiophene carboxamide:

20.7 g of 3- (4-Methyl-phenyl) -2-thiophene carboxylic acid prepared in A) is dissolved in 200 ml of anhydrous toluene with

10.4 ml of thionyl chloride. The reaction mixture is refluxed for three hours and then evaporated to dryness. The oily residue is added dropwise to a 28% ammonia solution at 25 ° C. After one hour of stirring, the reaction mixture is extracted with chloroform, the organic phase is washed with water, dried over magnesium sulfate and evaporated in vacuo to give 3-4- (4-18 g) methylphenyl) -2-thiophene carboxamide as melting crystals 128 ° -130 ° C.

C) 3- (4-Methyl-phenyl) -2-thiophene carbonitrile:

18 g of 3- (4-methylphenyl) -2-thiophene carboxamide (prepared in B) is dissolved in 36 ml of phosphorus oxychloride and the reaction mixture is refluxed for one hour. Phosphorous oxychloride is concentrated in vacuo and the residue taken up in water and ethyl acetate. Extract the organic phase, dry and filter over animal black and then evaporate under vacuum to give 12 g of 3- (4-methylphenyl) -2-thiophene carbonitrile as a used oil as is in the following.

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

12 g of 3- (4-methylphenyl) -2-thiophene carbonitrile, prepared in C), is dissolved in 100 ml of carbon tetrachloride. Is added

11.3 g of N-bromosuccinimide as well as 10 mg of benzoyl peroxide. The reaction mixture is heated to reflux until succinimide passes completely over the top of the solution. The crystals are filtered off and the solvent concentrated in vacuo to give 16 g of 4- (2-cyano-3-thienyl) benzyl bromide as an oil which is used as follows.

, Λ²³EXAMPLE 139:

1-Methyl-3-n-propyl-4- [4- (2-Cyano-3-thienyl) -benzyl] -5-hydroxy-pyrazo

General formula (IX): R1 = n-Propyl, R1₂ = Methyl,

<img file="PT97056A_D0167.tif" />

Prepared according to the process described in Example Ί

Melting crystals 110 ° -115 ° C.

EXAMPLE 140: Ethyl [1-Methyl-3-n-propyl- [4- (2-Cyano-3-thienyl) -benzyl] -5-pyrazolyl] -oxyacetate

General formula (XI): R1 = n-Propyl, R1₂ = Methyl. R ^ = CH₂CO₂Et,

NC- ^ s /

Prepared according to the process described in Example 14 used oil as is in the following.

-124-

<img file="PT97056A_D0168.tif" />

EXAMPLE 141:

Ethyl [1-methyl-3-n-propyl-4- [4- [2- (5-tetrazolyl) -3-thienyl] benzyl] -5-pyrazolyl] oxyacetate

General formula (I): Ry = n-Propyl, R₂ = Methyl

<img file="PT97056A_D0169.tif" />

Prepared according to the process described in Example 71,

Melting point crystals 201 ° C.

EXAMPLE 142: Ethyl 2- [4- (2-carbethoxy-3-thienyl) benzyl] -3-oxohexanoate.

General formula (V): R ^ = n-Propyl, R- ^ = Ethyl,

v. Et \\ Et 0/7

Prepared according to the process described in Example 6 from 4- (2-carbethoxy-3-thienyl) benzyl bromide.

used oil as is in the following.

125-125 i JÍ

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

43.4 g of ethyl 3- [4-methylphenyl) -2-thiophene carboxylate, prepared according to the reference, FISSELMANN.

H; HABITCH .; Ger. Offen : 1,092,929 (1960); CA: 57, 5894 g, in 250 ml of carbon tetrachloride. 33 g of N-bromosuccinimide and 10 mg of benzoyl peroxide are added and the reaction mixture is refluxed for one hour, the succinimide crystals are isolated and the solvent evaporated in vacuo to give

56.6 g of 4- (2-carbethoxy-3-thienyl) benzyl bromide as melting crystals 55 ° C.

EXAMPLE 143: 1-Methyl-3-n-Propyl-4- [4- (2-carbethoxy-3-thienyl) benzyl] -5-hydroxypyrazole

General formula (IX): R1 = n-Propyl, R1₂ = Methyl,

EtO₂C ^^Xs^X

Prepared according to the process described in Example 7.

Melting point crystals 130 ° -132 ° C.

EXAMPLE 144:

<img file="PT97056A_D0170.tif" />

[1-Methyl-3-n-Propyl-4- [4- (2-carbethoxy-3-thienyl) -benzyl] -5-pyrazolyl] -2-oxyethanol

General formula (XI): R1 = n-Propyl, R1₂ = Methyl, r₃ = ch₂ch₂oh

Prepared according to the process described in Example 49 used oil as it follows.

EXAMPLE 145: [1-Methyl-3-n-Propyl-4- [4- (2-earboxy-3-thienyl) -benzyl] -5-pyrazolyl] -2-oxyethanol

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

<img file="PT97056A_D0171.tif" />

Prepared according to the process described in Example 37

Melting crystals 118 ° -120 ° C.

/127

EXAMPLE 146:

- (2-Methoxy-phenyl) - [1- (2,2,2-trifluoro-ethyl) -3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxy-4-acetyl piperazine

General formula (XI): = n-Propyl, = CH 2 CF 4,

<img file="PT97056A_D0172.tif" />

Prepared according to the process described in Example 64.

used oil as is in the following.

EXAMPLE 147: 1- (2-Methoxy-phenyl) - [1- (2,2,2-trifluoroethyl) -3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl) -4 -methyl-5-pyrazolyl] -oxy-4-acetyl piperazine

I

General formula (I): R · = n-Propyl, R₂ = CH₂CF₃, A - OR ^ '

<img file="PT97056A_D0173.tif" />

<img file="PT97056A_D0174.tif" />

<img file="PT97056A_D0175.tif" />

Prepared according to the process described in Example 70.

Melting crystals 158 ° -160 ° C.

EXAMPLE 148: N - [[1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxy-acetyl ] -morpholine

General formula (XI): R1 = n-Propyl, R1₂ = Ct ^ CF ^,

<img file="PT97056A_D0176.tif" />

Prepared according to the process described in Example 46.

Oil used as follows.

) EXAMPLE 149: N - [[1- (2,2,2-Trifluoro-ethyl) -3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl ] -oxy-acetyl] -morpholine

General formula (I): = n-Propyl, R₂ = CH ^ CF ^,

A = 0R₃,

<img file="PT97056A_D0177.tif" />

-129/

Prepared according to the process described in Example 70

Melting crystals 129 ° -31 ° C,

EXAMPLE 150:

1- (2,2,2-Trifluoro-ethyl) -3-n-Butyl-5-hydroxy- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-pyrazole

General formula (I): R1 = n-Butyl, R1₂ = CH₂CF₃, A = OH,

<img file="PT97056A_D0178.tif" />

Prepared according to the process described in Example 71,

Melting crystals 210 ° -11 ° C,

EXAMPLE 151: 1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-bromomethyl-pyrazole

General Formula (I): - n-Butyl, R₂ = Methyl,

A = CH₂Br,

<img file="PT97056A_D0179.tif" />

-130

Prepared according to the process described in Example 109 from 1-methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methylmethoxy-5-methylpyrazole prepared in Example 104.

used oil as is in the following.

EXAMPLE 152: 1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methylhydroxy-5-methylpyrazole

General formula (XII): R1 = n-Butyl, R1₂ = Methyl, R '= H,

<img file="PT97056A_D0180.tif" />

Prepared according to the process described in Example 111.

used oil as is in the following.

EXAMPLE 153: 1-Methyl-3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl]

- 4 me ti 1-hydroxy - 5 me ti 1-p go az o 1

General formula (I): = n-Butyl, R₂ = Methyl,

A = CH₂OH,

PV

<img file="PT97056A_D0181.tif" />

Prepared according to the process described in Example 71.

Melting crystals 110 ° -12 ° C.

EXAMPLE 154: 1-Methyl-3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-formylpyrazole

General formula (I): R1 = n-Butyl, R1₂ = Methyl, A = CHO,

<img file="PT97056A_D0182.tif" />

2-nitropropane (2.3 g) is dissolved in a sodium methylate solution prepared from 0.7 g sodium and 40 ml methanol. 10 g of 1-Methyl-3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-bromomethylpyrazole, prepared in Example 151, is dissolved in 30 ml of methanol and added. this solution is added dropwise to the reaction mixture. Stir the reaction for two at 50 ° C, then add water and extract 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 1-methyl-3-n-butyl- (2'-cyano-4). (biphenylyl) -4-methyl-5-formylpyrazole as an oil which is used as follows.

<img file="PT97056A_D0183.tif" />

EXAMPLE 155:

1-Methyl-3- n -butyl- (2'-cyano-4-biphenylyl) -4-methyl-5- (2-dioxolanyl) -pyrazole

General formula (I): = n-Butyl, R₂ = Methyl

A = CH

I

4.3 g of 1-methyl-3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-formylpyrazole prepared in Example 154 is dissolved in 50 ml of toluene. 1 g of ethylene glycol as well as 10 mg of para-toluenesulfonic acid are added. The reaction mixture is refluxed and the water is removed for 3 hours by means of a Dean-Stark separator. The reaction mixture is then taken up with water and extracted with ether, then dried over magnesium sulfate and evaporated in vacuo to give 4 g of 1-methyl-3-n-butyl- ( 2'-cyano-4-biphenylyl) -4-methyl-5- (2-dioxalanyl) pyrazole I as an oil which is used as follows.

EXAMPLE 156: 1-Methyl-3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5- (2-dioxolanyl) -pyrazole

General formula (I): = n-Butyl, R₂ = Methyl,

A =

<img file="PT97056A_D0184.tif" />

<img file="PT97056A_D0185.tif" />

<img file="PT97056A_D0186.tif" />

Prepared according to the process described in Example 70.

Melting crystals 144 ° -6 ° C.

Example 157: [1- (2,2,2-Trifluoroethyl) -3-n-Butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxyethanol

General formula (XI): R1 = n-Butyl, R1₂ = CH ^ CF ^, r₃ = ch₂ch₂oh

<img file="PT97056A_D0187.tif" />

Prepared according to the process described in Example 49.

used oil as is in the following.

EXAMPLE 158: [1- (2,2,2-Trifluoro-ethyl-3-n-Butyl- [2- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -2-oxo ethanol

General formula (I): = n-Butyl, R₂ = CH₂CF₃,

A = 0R₃, R₃ = CH₂CH₂0H,

<img file="PT97056A_D0188.tif" />

Prepared according to the process described in Example 71.

-134Ζ

Melting crystals 107 ° -10 ° C.

EXAMPLE 159: Ethyl 3-Oxo -2- [4- (3-cyano-2-thienyl) -benzyl] -heptanoate

General formula (V): R ^ = n-Butyl, R- ^ = Ethyl,

I

<img file="PT97056A_D0189.tif" />

Add 1.1 g of ethyl 3-oxoheptanoate prepared in Example 1, 1.2 g of 4- (3-cyano-2-thienylyl) benzyl bromide, 0.6 g of lithium bromide and 2.2 ml diisopropyl ethyl amine to 15 ml tetrahydrofuran. The reaction mixture is stirred at reflux for 20 hours, taken up with water and extracted with ether. The organic phase is dried over magnesium sulfate and then evaporated. Excess ethyl 3-oxoheptanoate is evaporated with a vane pump to give 1.5 g of ethyl 3-oxo-4- (3-cyano-2-thienylyl) -2-benzylheptanoate under the form of an oil that is used as is in the following.

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

-135/

THE)

4'-Methyl-4-chloro-butyrophenone:

Dissolve 53 ml of toluene and 70.5 g of acid chloride

4-Chlorobutyric acid in 100 ml of dichloromethane and the solution at 10 ° C is added 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 and the reaction mixture is treated with ice water. The organic phase is dried over magnesium sulfate and evaporated in vacuo to yield 96.9 g of 4'-methyl-4-chloro-butyrophenone as an oil which is used as follows.

B)-Chloro - ^ - (2-chloroethyl) cinnamaldehyde:

Phosphorous oxychloride (130 ml) is slowly added at 0 ° C over dimethylformamide (130 ml) and then added dropwise 117.5 g of 4'-methyl-4-chloro-butyrophenone prepared in A ) in solution in 50 ml of dimethylformamide. The reaction 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 over ice and taken up in ether, the ether phase is washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and evaporated in vacuo to give 133.8 g. N-chloro- (2-chloroethyl) cinnamaldehyde as an oil which is used as follows.

-136/

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

15.9 g of (2-chloro- (2-chloroethyl) cinnamaldehyde prepared in B) and 22 g of sodium sulfide (910%) are added to 200 ml of THF. Sufficient water is added to bring the sodium sulphide completely into solution and the reaction mixture is then heated for 3 hours at reflux, cooled and then taken up with ether. Decant the organic phase, wash with water, then dry over magnesium sulfate and evaporate in vacuo to give 2- (4-methylphenyl) -4,5-di (13.5 g). -hydro-3-thiophene carboxaldehyde as an oil which is used as follows.

D) 2- (4-Methyl-phenyl) -3-cyano-4,5-dihydro-thiophene

Mix 15 g of 2- (4-methylphenyl) -4,5-dihydro-3-thiophene carboxaldehyde prepared in C) and 6.5 g of hydroxylamine hydrochloride with 40 ml ethanol and 10 ml. ml of water. A solution of 4.7 g of sodium carbonate in 10 ml of water is added. The reaction mixture is stirred at room temperature for half an hour and then extracted with ether. The ether 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 light brownish reaction mixture becomes slightly warmed. The reaction mixture is then refluxed for 1 hour, then poured onto ice and extracted with dichloromethane and washed with saturated sodium hydrogen carbonate solution; The organic phase is then dried over magnesium sulfate and evaporated in vacuo. The residue obtained is chromatographed on silica gel eluting with dichloromethane to give 10 g of 2- (4-methylphenyl) -3-cyano-4,5-dihydro-thiophene as a silica gel. oil that is used as is in the following.

E) 2- (4-Methyl-phenyl) -3-cyano-thiophene:

Dissolve 49.9 g of 2- (4-methylphenyl) -3-cyano-4,5-dihydro-thiophene, prepared in D), in 200 ml of carbon tetrachloride, warm the mixture After two hours, 11 g of bromine in solution in 200 ml of carbon tetrachloride are added dropwise. Reflux is continued until the hydrobromic acid release is complete and then the solvent is evaporated under vacuum. The residue is taken up in anhydrous tetrahydrofuran (200 ml) and tert-butylate (28 g) is added. potassium The reaction mixture is refluxed for one hour, then cooled and water and sodium chloride are added and extracted with ether. Evaporate the organic phase under vacuum to give 31.8 g of 2- (4-methylphenyl) -3-cyanothiophene as an oil which is used as follows.

F) 4- (3-Cyano-2-thienylyl) benzyl bromide:

-138-

<img file="PT97056A_D0190.tif" />

24.5 g of 2- (4-methylphenyl) -3-cyanothiophene, prepared in E), is dissolved in 200 ml of carbon tetrachloride. Is added

21.9 g of N-bromosuccinimide as well as 0.1 g of benzoyl peroxide. The reaction mixture is heated at reflux for 24 hours. Succinimide crystals are filtered off and the solvent is evaporated under vacuum. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is stored for 24 hours in the freezer. The crystals formed are isolated to give 14 g of 4- (3-cyano-2-thienylyl) benzyl bromide as 80 ° C melting crystals.

EXAMPLE 160: 1-Methyl-3-n-butyl-4- [4- (3-cyano-2-thienylyl) benzyl] -5-hydroxypyrazole

General formula (IX): R 1 = n-Butyl, R 2 = Methyl,

<img file="PT97056A_D0191.tif" />

<img file="PT97056A_D0192.tif" />

1.4 g of ethyl 2- [4- (3-cyano-2-thienylyl) benzyl] -3-oxoheptanoate prepared in Example 159 is dissolved in 10 ml of ethanol. Methylhydrazine (2.2 ml) is added and the reaction mixture is refluxed for 13 hours; Water is then added and extracted with ether and then ethyl acetate. Evaporate the combined organic phases under vacuum to give a

-139

<img file="PT97056A_D0193.tif" />

oily residue which gives, after chromatography on silica gel eluting with dichloromethane / methanol 95: 5, 0.8 of 1-Methyl-3-η-butyl-4- [4- (3-cyano-2-thienylyl) - benzyl] -5-hydroxypyrazole as melting crystals 120 ° C.

EXAMPLE 161: 1-Methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4- (β, β-diethylcarbamoyl) -5-oxypyrazole

General formula (IX): R 1 = n-Propyl, R g = Methyl,

R1 = CN^z

Ç₂H, v =

NC '

Prepared according to the process described in Example 52.

used oil as is following

EXAMPLE 162: 1-Methyl-3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl]

-4-methyl- (β, β-diethylcarbamoyl) -5-oxypyrazole

General formula (I); R1 = n-Propyl, Rg = Methyl,

R1 = CN

<img file="PT97056A_D0194.tif" />

-140-

<img file="PT97056A_D0195.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 134 ° -135 ° C.

*

EXAMPLE 163: N - [[1 H -Z-trifluoroethyl] -1H-propyl-1 H¹ -cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxy-acetyl] -thiomorpholine

General Formula (XI):

n-Propyl, R₂ = CH₂CF₃

Rf = 04.00

<img file="PT97056A_D0196.tif" />

<img file="PT97056A_D0197.tif" />

Prepared according to the process described in Example 46 from N- (chloroacetyl) thiomorpholine.

used oil as is in the following.

I

EXAMPLE 164: N - [[1- (2,2,2-Trifluoro-ethyl) -3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -oxy-acetyl thiomorpholine

General formula (I): R1 = n-Propyl, R1₂ = CH₂CF₃,

<img file="PT97056A_D0198.tif" />

-141

<img file="PT97056A_D0199.tif" />

Prepared according to the process described in Example 70.

. .V »

Melting crystals 127 ° -128 ° C.

EXAMPLE 165: 1- (2-Methoxy-phenyl) - [1-methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxy-4-acetyl piperazine

Formula (XI): R1 n-Propyl, Rg = Methyl,

<img file="PT97056A_D0200.tif" />

Prepared according to the process described in Example 64.

used oil as is in the following.

EXAMPLE 166: 1- (2-Methoxy-phenyl) - [1-methyl-3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -oxy- 4-acetyl piperazine

General Formula (I)

R1 = n-Propyl, Rg = Methyl, A = ORg,

R₃ = CH₂CO N

<img file="PT97056A_D0201.tif" />

<img file="PT97056A_D0202.tif" />

142 Prepared according to the process described in Example 70.

<img file="PT97056A_D0203.tif" />

Melting crystals 139 ° -141 ° C.

EXAMPLE 167: 3-n-Propyl-1-methyl- (2'-cyano-4-biphenylyl) -4-methyl-5- (2-dimethylamino-ethoxy) -pyrazole

General formula (XI): R1 = n-Propyl, R1₂ = Methyl,&gt;

CH,

R₃ = CH, CH₂1 /, V = ^CHj NC

10 g of 3-n-propyl-1-methyl- (2'-cyano-4-biphenylyl) -4-methyl-5-hydroxypyrazole prepared in Example 68 is dissolved in 100 ml of 2-butanone in the 10 g of sodium carbonate and 8.6 g of N, N-dimethyl-2-chloroethylamine hydrochloride. The reaction mixture is refluxed for 20 hours and then concentrated under vacuum, taken up with water and extracted with ether. The ether phase is washed with water, dried and then evaporated under vacuum. The residue is chromatographed on silica gel eluting with 95: 5 chloroform / methanol to give 4.6 g of 3-n-propyl-1-methyl- (2'-cyano-4-biphenyl) - 4-Methyl-5- (2-dimethylaminoethoxy) pyrazole as an oil which is used as follows.

EXAMPLE 168:

n-Propyl-1-methyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5- (2-dimethylamino-ethoxy) -pyrazole

General formula (I): = n-Propyl, R₂ = Methyl,

THE ⁼ OR ^,

R₃ = CHjCHjN

CH,

CHj

<img file="PT97056A_D0204.tif" />

Prepared according to the process described in Example 70

Melting point crystals 88 ° -90 ° C.

EXAMPLE 169:

N - [[1-Methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxy-ethyl] -morpholine

General formula (XI): R1 = n-Propyl, R1₂ = Methyl

Γ \

R1 CH3 CH, NΟ, V

NC

Prepared according to the process described in Example 167 from N- (2-chloroethyl) morpholine.

-144used oil as is following.

EXAMPLE 170: N - [[1-Methyl-3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl) -4-methyl-5-pyrazolyl] -2-oxy-ethyl] -morpholine

General formula (I): = n-Propyl, R₂ = Methyl,

A = OR ^,&gt;

/—\

R₃ = CH, CH, Ν O \ _ /

<img file="PT97056A_D0205.tif" />

Prepared according to the process described in Example 70.

Melting crystals 132 ° -134 ° C.

EXAMPLE 171: 1- (2,2,2-Trifluoro-ethyl) -3-n-butyl- (2'-cyano-biphenylyl) -4-methylhydroxy-5-methyl-pyrazole

General formula (XII): = n-Butyl, R₂ = CH₂CF₃,

R '= H,

<img file="PT97056A_D0206.tif" />

.q = i

-145ζ /

•faith

Prepared according to the procedure described in Example 111 from 1- (2,2,2-trifluoro-ethyl) -3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5- bromomethyl pyrazole which is prepared according to the process described in Example 109.

used oil as is in the following.

EXAMPLE 172: 1- (2,2,2-Trifluoro-ethyl) -3-n-butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-hydroxy-5-methyl-2-one pyrazole

General formula (I): R1 = n-Butyl, R1₂ = CH₂CF₃,

A = CH₂OH,

<img file="PT97056A_D0207.tif" />

Prepared according to the process described in Example 71.

Melting crystals 114 ° -117 ° C.

EXAMPLE 173: 1- (2,2,2-Trifluoro-ethyl) -3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-methoxy-5-methyl-pyrazole

General formula (XII): R- = n-Propyl, R₂ = CH₂CF₃,

R '= CHp q = 1,

-146ζ ν- ΥΊ

Prepared according to the process described in Example 101.

used oil as is in the following.

EXAMPLE 174: 1- (2,2,2-Trifluoro-ethyl) -3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-methoxy-5-methyl-pyrazole

General formula (I): Rf = n-Propyl, Rf = C1 -C4,

<img file="PT97056A_D0208.tif" />

Prepared according to the process described in Example 71.

Melting crystals 177 ° -178 ° C.

EXAMPLE 175

N - [[1-Methyl-3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxy-acetyl] -morpholine

General formula (XI): Rf = n-Butyl, Rf = Methyl.

-147R, = CH, CO N

<img file="PT97056A_D0209.tif" />

<img file="PT97056A_D0210.tif" />

<img file="PT97056A_D0211.tif" />

Prepared according to the process described in Example 46.

used oil as is in the following.

EXAMPLE 176: N - [[1-Methyl-3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] oxy-acetyl] -morpholine

General formula (XI): = n-Propyl, R ^ = methyl, / λ

R, * CB, CON 0 V \ _v ' _NC»

Prepared according to the process described in Example 46.

Oil used as follows.

EXAMPLE 177: N - [[1-Methyl-3-n-Butyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] oxy-acetyl] -morpholine

-148

General formula (I): = n-Butyl, R₂ = Methyl,

A = ORg,

R, CH, CO No.

<img file="PT97056A_D0212.tif" />

Prepared according to the process described in Example 70.

Melting crystals 140 ° -141 ° C.

EXAMPLE 178: N - [[1-Methyl-3-n-Propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] oxy-acetyl] -morpholine

General formula (I): R1 = n-Propyl, R1₂ = Methyl, A = ORg, ►

<img file="PT97056A_D0213.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 106 ° -110 ° C.

EXAMPLE 179:

<img file="PT97056A_D0214.tif" />

1- (2,2,2-Trifluoro-ethyl) -3-n-propyl- (2 * -cyano-4-biphenylyl) -4-methylhydroxy-5-methyl-pyrazole

General formula (XII): Rf = n-Propyl, Rg = CHgCFg, R '= H

V = NC

<img file="PT97056A_D0215.tif" />

Prepared according to the procedure described in Example 111 from 1- (2,2,2-trifluoro-ethyl) -3-n-propyl- (2'-cyano-4-biphenylyl) -4-methyl-5- bromomethyl pyrazole which is prepared according to the process described in Example 109.

used oil as is in the following.

EXAMPLE 180: 1- (2,2,2-Trifluoro-ethyl) -3-n-propyl- [2 '- (5-tetrazolyl) -4-biphenylyl] -4-methylhydroxy-5-methyl-2-one pyrazole

General formula (I): Rf = n-Propyl, Rg = CHgCFg, A = CHgOH,

<img file="PT97056A_D0216.tif" />

150 Prepared according to the process described in Example 71.

Melting point crystals 110 ° -2 ° C

EXAMPLE 181:

1-Methyl-3-n-propyl- (2¹-cyano-4-biphenylyl) -4-methylhydroxy-5-methylpyrazole

General formula (XII): = n-Propyl, R₂ = Methyl.

R '= H,

V-Yj), q.1

Prepared according to the process described in Example 111,

Oil used as is in the following.

EXAMPLE 182: 1-Methyl-3-n-propyl- (2 '- (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-hydroxymethylpyrazole

General formula (I): R1 = n-Propyl, R1₂ = Methyl,

<img file="PT97056A_D0217.tif" />

Prepared according to the process described in Example 71.

-151Ζ

Melting crystals 136 ° -9 ° C.

EXAMPLE 183: 1- (2-Methoxy-phenyl) - [1-methyl-3-n-butyl- (2'-cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -4-oxyacetyl piperazine

General formula (XI): R1 = n-Butyl, R1₂ = Methyl,

<img file="PT97056A_D0218.tif" />

Prepared according to the process described in Example 64.

Oil used as follows.

EXAMPLE 184: 1- (2-Methoxy-phenyl) - [1-methyl-3-n-butyl- [2 * - (5-tetrazolyl) -4-biphenylyl] -4-methyl-5-pyrazolyl] -4 -oxyacetyl piperazine

<img file="PT97056A_D0219.tif" />

= Methyl,

Prepared according to the process described in Example 70.

Melting crystals 153 ° -5 ° C.

EXAMPLE 185:

N - [[1-methyl-3-n-propyl- (2 * -cyano-4-biphenylyl) -4-methyl-5-pyrazolyl] -oxyacetyl] -thiomorpholine

General formula (XI): = n-Propyl, R₂ = Methyl, / - \ r₃= ch, cns, v =

NC '

Prepared according to the process described in Example 46 from N- (chloroacetyl) thiomorpholine.

used oil as is in the following.

EXAMPLE 186: N - [[1-Methyl-3-n-propyl [2 '- (5-tetrazolyl) -4-biphenyl] -4-methyl-5-pyrazolyl] oxyacetyl] thiomorpholine

General Formula (I)

R1 = n-Propyl, R1₂ = Methyl, A = OR ^,

R₃ = CH, CN \ _v

R.

<img file="PT97056A_D0220.tif" />

-153-

<img file="PT97056A_D0221.tif" />

Prepared according to the process described in Example 70.

Melting point crystals 140 ° -1 ° C.

I

-154-

<img file="PT97056A_D0222.tif" />

PAINTING

Example 27

Example 28

Example 29

Example 30

<img file="PT97056A_D0223.tif" />

UP 221-1

UP 221-6

UP 221-11

UP 221-13

UP 221-12

Example 31

-155Example 32 ₁ θ Example 33

Example 34

Example 35

Example 35

<img file="PT97056A_D0224.tif" />

The CH, CO, Me

CH, CO, H, COOH, -CF,

NN

Q-Q CH. Eats

NN JUO CH, CO, H

UP 221-7

UP 221-4

UP 221-16

UP 221-14

UP 221-15

-156-

<img file="PT97056A_D0225.tif" />

Example 37

Example 4Q

Example 41

Example 44

<img file="PT97056A_D0226.tif" />

UP 221-17

UP 221-18

UP 221-19

UP 221-20

UP 221-21

Example 45

-157Example 48

Example 51

Example 54

Example 57

Example 60

<img file="PT97056A_D0227.tif" />

UP 221-23

UP 221-27

UP 221-28

UP 221-22

UP 221-30

-158Z

Example 63

Example 66

CF.

Example 70

Example 71

Example 72

NN

<img file="PT97056A_D0228.tif" />

-159-

<img file="PT97056A_D0229.tif" />

Example 74

Example 75

Example 73

Example 30

CF,

NN

<img file="PT97056A_D0230.tif" />

UP 221-56

UP 221-57

UP 221-54

UP 221-55

-160-

<img file="PT97056A_D0231.tif" />

Example32

CH,

NN^z

<img file="PT97056A_D0232.tif" />

OCON

<img file="PT97056A_D0233.tif" />

UP 221-51

Example 8S

Example 8S

Example 84

N — N / -CF,

<img file="PT97056A_D0234.tif" />

UP 221-44

UP 221-45

UP 221-46

-161-

<img file="PT97056A_D0235.tif" />

Example 90

Example 92

Example 107

Example 108

Example 115

<img file="PT97056A_D0236.tif" />

UP 221-38

UP 221-36

UP 221-42

UP 221-47

UP 221-50

-162

Example 116 ζ

, · Ϊ́ί^Λ

Example 117

Example 118

Example 119

Example 125

Η

Ν — Ν

<img file="PT97056A_D0237.tif" />

UP 221-40

UP 221-48

UP 221-52

UP 221-53

UP 221-58

-163-

<img file="PT97056A_D0238.tif" />

Example 127

<img file="PT97056A_D0239.tif" />

UP 221-61 ►

Example 129

Example 130

<img file="PT97056A_D0240.tif" />

UP 221-60

UP 221-25

Example 135

<img file="PT97056A_D0241.tif" />

UP 221-26

-164-

<img file="PT97056A_D0242.tif" />

<img file="PT97056A_D0243.tif" />

Ν

Η

UP 221-29

UP 221-35

Ν-Ν^ζ

CH,

Example 145

Example 147

<img file="PT97056A_D0244.tif" />

<img file="PT97056A_D0245.tif" />

Example 156

UP 221-63

UP 221-64

UP 221-65

UP 221-66

-166-

<img file="PT97056A_D0246.tif" />

^ -CF,

Ν-Ν

<img file="PT97056A_D0247.tif" />

UP 221-68

UP 221-69

UP 221-67

UP 221-70

-167

<img file="PT97056A_D0248.tif" />

\

<img file="PT97056A_D0249.tif" />

CH,

<img file="PT97056A_D0250.tif" />

UP 221-71

UP 221-72

UP 221-73

UP 221-74

-168-

<img file="PT97056A_D0251.tif" />

CH

Example 177

Example 178

<img file="PT97056A_D0252.tif" />

Example 180

<img file="PT97056A_D0253.tif" />

Example 182

<img file="PT97056A_D0254.tif" />

OH

UP 221-75

UP 221-77

UP 221-78

UP 221-79

-169-

<img file="PT97056A_D0255.tif" />

<img file="PT97056A_D0256.tif" />

CCH₃

UP 221-80

UP 221-81

-170 PHARMACOLOGY

I Principle

The affinity of the compounds prepared by the process according to the present invention for angiotensin II receptors is assessed by the technique of displacing a radioligand specifically fixed to the angiotensin II adrenal receptors in the rat.

II Realization Process

An aliquot of a rat adrenal homogenate is incubated in the presence of a single concentration of [I] -SIA II 146 (Sar, Tyr \ Ile-angiotensin II), angiotensin II receptor antagonist and two concentrations. of competing agent (10 µM, 10 µM) for 60 minutes at 25 ° C. The reaction is completed by the addition of buffer followed by rapid filtration through glass paper filters. Non-specific binding is determined in the presence of angiotensin II.

III Expression of results

Results are expressed, at the concentrations tested, in percent displacement of the radioligand specifically fixed on the angiotensin II adrenal receptors.

-171-

<img file="PT97056A_D0257.tif" />

Results

<td rowspan="2">COMPOSITE OF EXAMPLE</td><td colspan="2">% Of displacement of the ligand MARKED</td>

<td>1E-5M</td><td>1E-7M</td>

<td> 27</td><td> 92</td><td> 39</td>

<td> 28</td><td> 82.</td><td> 34</td>

<td> 29</td><td> 80</td><td> 40</td>

<td> 30</td><td> 96</td><td> 63</td>

<td> 31</td><td> 93</td><td> 60</td>

<td> 32</td><td> 98</td><td> 52</td>

<td> 33</td><td> 94</td><td> 26</td>

<td> 35</td><td> 85</td><td> 48</td>

<td> 36</td><td> 62</td><td> 10</td>

<td> 37</td><td> 58</td><td> 9</td>

<td> 40</td><td> 83</td><td> 0</td>

<td> 41</td><td> 85</td><td> 2</td>

<td> 44</td><td> 96</td><td> 9</td>

<td> 45</td><td> 92</td><td> 60</td>

<td> 48</td><td> 80</td><td> 58</td>

<td> 51</td><td> 83</td><td> 60</td>

<td> 54</td><td> 77</td><td> 62</td>

<td> 57</td><td> 80</td><td> 60</td>

<td> 60</td><td> 84</td><td> 49</td>

<td> 63</td><td> 91</td><td> 64</td>

<td> 66</td><td> 92</td><td> 63</td>

<td> 70</td><td> 67</td><td> 49</td>

<td> 71</td><td> 58</td><td> 24</td>

/

-172 ^ lf&gt; ·

<td rowspan="2">COMPOSITE OF EXAMPLE</td><td colspan="2">7TH DISPLACEMENT OF CONNECTION MARKED</td>

<td>1E-5M</td><td>1E-7M</td>

<td> 74</td><td> 66</td><td> 58</td>

<td> 78</td><td> 73</td><td> 58</td>

<td> 80</td><td> 69</td><td> 48</td>

<td> 82</td><td> 71</td><td> 47</td>

<td> 84</td><td> 65</td><td> 51</td>

<td> 86</td><td> 58</td><td> 41</td>

<td> 88</td><td> 60</td><td> 38</td>

<td> 90</td><td> 64</td><td> 40</td>

<td> 92'</td><td> 75</td><td> 70</td>

<td> 107</td><td> 83</td><td> 62</td>

<td> 108</td><td> 86</td><td> 19</td>

<td> 115</td><td> 80</td><td> 57</td>

<td> 116</td><td> 82</td><td> 12</td>

<td> 117</td><td> 61</td><td> 35</td>

<td> 118</td><td> 67</td><td> 35</td>

<td> 119</td><td> 70</td><td> 54</td>

<td> 130</td><td> 74</td><td> 33</td>

<td> 135</td><td> 65</td><td> 34</td>

<td> 137</td><td> 63</td><td> 5</td>

<td> 141</td><td> 64</td><td> 9</td>

<td> 145</td><td> 53</td><td> 0</td>

TOXICOLOGY

The compounds of the Examples described above, after oral administration, exhibit excellent tolerance.

Its rat lethal dose 50 is estimated to be greater than 300 mg / kg.

I

CONCLUSION

Compounds prepared according to the described Examples show good affinity for angiotensin II receptors. Δ this title may be used to benefit in the various conditions in which Angiotensin II is implicated, in particular in the treatment of hypertension and heart failure, in dosages ranging from 1 to 400 mg orally and from 0.01 to 50 intravenously, once or several times a day.