CA2038428A1 - Pyrazole derivatives which are angiotensin ii receptor antagonists; their methods of preparation and pharmaceutical compositions in which they are present - Google Patents

Abstract

IN THE PATENT AND TRADEMARK OFFICE
PATENT APPLICATION
entitled: Novel pyrazole derivatives which are angio-tensin II recaptor antagonists, their methods of preparation and pharmaceutical composi-tions in which they are present in the names of: Nicole BRU-MAGNIEZ
Eric NICOLAI
Jean-Marie TEULON

Assignee: Laboratoires UPSA

ABSTRACT OF THE DISCLOSURE

The present invention relates to the deriva-tives of formula (I):

Description

2~3~

Novel pyrazole derivatives which are angiotensin II
receptor antagonists, their methods of ~reparation and pharmaceutical compositions in which _ ey are pres~nt 05 The present invention relates, by way of novel products, to the pyraæole derivatives of general for-mula (I) below and to their salts.
The compounds in question have a very valuable pharmacological profile insofar as they possess anta-lo gonistic properties towards angiotensin II receptors.
They are therefore especially indicated for the treat-ment of cardiovascular diseases and in particular for the treatment of hypertension and the treatment of cardiac insufficiency.
The present invention further relates to the method o~ preparing said products and to kheir applica-tions in therapeutics. It further relates to the novel intermediates which enable said products to be synthe-sized.
These pyrazole derivatives have general formula (I) R, N-N
R, ~ A
f~
~.~

Formula (I) in which:
R1 is a lower alkyl radical having 1 to 6 carbon atoms, a lower alkenyl radical having 2 to 6 2~3~

carbon atoms, a C~-c7 cycloalkyl radical or a C~-C7 cycloalkenyl radical;
R2 is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl 05 radical having 1 to 6 carbon atoms, a C3-C~ cycloalkyl radical, a group -(C~2)m-COOR5, a group -CH2-tCH2)m-OR5 or a group -CH2-(CH2)m-SR5, m being an integer Prom 0 to 5 and R5 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms;
A can be a group:
~(CH2)qOR~ R' being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C9-C7 cyclo-alkyl radical and q being an integer from 1 to 5, ~tCH2)qL~ L being a halogen atom, preferably chlorine or bromine, and q being as defined above, -CHO, an acetal or a dioxolan, -COOR', R' being as defined above, -CONR''R''', R'' and R~i independently being a hydro-gen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3~C7 cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attach-ed, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, -CN, -tCHa)~CN, q being as defined above, -(CH2)~COOR', R' and q being as defined above, -(CH2)~CONR''R''', R'', R''' and q being as defined abova, -(CH~)~NR''R''', R~', R''' and q being as de~ined above, ~(CH~)q~S~R~ R' and q being as defined above, or -OR3, R3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atom~, a C3-C~ cyc}oalkyl radical, a group -(CH2)n-COOR~, a group -CH2-(CH2)~-CN, a group -CH2-(CH2)~-O-R~, a group -CH2-(CH2)~-S-R~ or a group 2~3~2g -COR~, n being an integer from O to 5 and R~ beiny a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R3 can be a group -(CH2)p-CO-NR7R8 or (CH2)p-cH2-cH2NR7R8~ p being an integer from O to 5 05 and R7 and R~ independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or bein~ able to form, with the nitrogen atom to which they are attached, a hetero-cycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine; and R4 can be a nitro or amino group or a group -COORg, R~ being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R4 can be the following radicals:

R900C~ NC~3 ~ N~3 ' o2N~3 N~ ~NH
N

CF,So,NH~3 , II,N~3 ' R,OOC/~

--NH--C~ --NH--C ~1 C NH

HO,S CF,SO,HN R900C
Y Y

2~3~

~,OOC ~ ' N
05 N~N, in which Rg is as defined above, X and Y independently being a hydrogen atom, a lower alkyl radical, a halogen atomj an alkoxy radical or a trifluoromethyl radical.
In the description and the claims, lower alkyl radical is understood as meaning a linear or branched hydrocarbon chain havirlg from 1 to 6 carbon atoms. A
lower alkyl radical is, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl radical.
C3-C7 cycloalkyl radical is understood as meaning a saturated cyclic radical, preferably a cyclo-propane, cyclobutane, cyclopentane, cyclohexane or cycloheptane radical.
Lower alkenyl radical is understood as meaning a linear or branched hydrocarbon chain having from 2 to 6 carbon atoms and possessing an unsaturation. A lower alkenyl radical is, for example, an ethene, propene, isopropene, butene, isobutene, pentene, isopentenle, hexene or isoh~xene radical.
Ca-C7 cycloalkenyl radical is understood a~
meaning a cyclic radical possessing an unsaturation, pre~erably a cyclobutene, cyclopentene, cyclohexene or cycloheptene radical.
Lower halogenoalkyl radical having 1 to 6 carbon atoms is understood as meaning an alkyl radical in which 1 to 6 hydrogen atoms have been substitut2d by 1 to 6 halogen atoms. A lower halogenoalkyl radical is, ~or example, a trifluoromethyl radical or a 2,2,2-~3~2~

trifluoroethyl radical.
Alkoxy radical is understood as meaning an 0-lower alkyl group, lower alkyl being as defined above.
Heterocycle is understood as denoting a ring of 05 5 to 7 atoms containing from l to 3 heteroatoms selec-ted from oxygen, sulfur or nitrogen, which is unsubsti-tuted or substituted by a lower alkyl, lower halogeno alkyl or lower alkoxy group or by a phenyl ring which is unsubstituted or substituted by one of these groups.
In the description and the claims, halogen is understood as meaning a chlorine, bromine, iodine or fluorine atom.
Document EP-A-0323~41 to Du Pont de Nemours describes pyrroles, pyrazoles and triazoles. These compounds all possess a benzyl substituent on a nitro-gen atom:
Z--Y
R,~N `k ~ A

Now, the Applicant has discovered, surprising-ly, that in contrast to the information contained in the Du Pont de Nemours document, it is not essential for the benzyl substituent to be located on a nitrogen atom, in particular in the l-position (or 2-position) of the pyrazole ring, but that it is pvssible to obtain very effective products when this benzyl substituent is on a carbon atom in the 4-position o~ the pyrazole ring. Furthermore, the Applicant has discovered t~at the presence of a group A and especially of an oxygen ` 2~13~8 atom in the 3-position (or 5-position) of the pyrazole, in conjunction with the benzyl substituent in the 4-position, produces compounds which are particularly active as angiotensin II receptor antagonists.
05 According to one embodiment, Rl is an n-propyl group.
According to another embodiment, Rl is an n-butyl group.
According to one embodiment, R2 is a methyl group.
According to another embodiment~ R2 is a 2,2,2-trifluoroethyl group.
According to one embodiment, A is an ethoxycar-bonylmethyleneoxy group.
According to another embodiment, A is a di-methylaminocarbonyloxy group.
According to another embodiment, A is a meth-oxymethylene group.
According to ~nother embodiment, A is a 2-hydroxyethoxy group.
According to one embodiment, R~ is a 2-carboxy-3,6-dichlorobenzoylamino group.
According to another embodiment, R4 is a 2-sulfobenzoylamino group.
According to another embodiment, R~ i~ a 2-(tetrazol-5-yl)phenyl group.
The particularly pre~erred compounds oP the invention are those selected from the products o~ the ~ormulae 2~3~2~

CHJ
N--N~
~O~COOC2Hs ~NJ~J
l ll H
a COO=~OJ~N~

i S

SO~H

N N~CH' ~O~COOC~H, ~N~
3 0 1 ~N

`

2~3~8 ,GH, \~ ~CH
05 ,~,,1 .~
~N -1 ,N
H N--N/~CF, ~--' ~CH, .
~N~
N
N_N/~

N--~CF, 2 5 ~~o~f ~0~J
~N, H--N

According to the invention, it will be possible 2 ~

to prepare the compounds of formula (I) according to the ~ollowing scheme:
- the alkyl 3-oxoalkanoates of formula (II):

05 R,---C--CH~--C OOR~o Formula (II) in which Rl is as de~ined above and Rlo is a lower alkyl radical, preferably methyl or ethyl, and - th~ 1,3-diketones of formula (III):
R~ 8 - CH2~ CH~q- O-R~

Formula (III) in which Rl, R' and q are as defined above, will be prepared. These compounds of formulae (II) and (III) can be prepared by classical methods such as the Claisen reaction or the method using Meldrum's acid.
Methods of preparing this type of compound may be found in the following references:
- OIKAWA Y.; SUGANO K.; YONEMITSU O.; J. Org. Chem., 1978, ~3(10), 2087-~8, - WIERENGA W.; SKULNICK H.I.; J. Org. Chem., 1979, 44, 310, - HO~GHTON R.; LAPHAM D.; SYNI'HESIS, 1982, 6, 451-2, - BRAM G.; VILKAS M.; Bull. Soc. Chim. France, 1964 (5), 945-51, - BALYAKINA M.V.; ZHDANOVICH E.S.; PREOBRAZHENSKII
N.A.; Tr. Vses. Nauchn. Issled. Vitamin Inst., 1961, 7, 8-16, - RENARD M.; MAQUINAY A.; Bull. Soc. Chim. Belg., 1946, 2~13~2~

_ , 98-105, - BRUCE F.W.; COOVER H4W.; J. Am. Chem. Soc., 1944, 66, 2092-94, and - EBY C.J.; HAUSER C.R.; J. Am. Chem. Soc., 1957, 79, 05 723-5.
Benzylation of the compounds of formula (II) or (III) with compounds of formula (IV):
W

~

V ~

Formula (IV) in the presence of a basa such as sodium or potassium carbonate in acetone, a sodium or potassium alcoholate in an alcohol, or sodium or lithium hydride in solvents such as tetrahydrofuran, dioxane or dimethylformamide for example, at a temperature of between 50 and 100 C, or else in the presence of one equivalent of lithium chloride or bromide and two equivalents of diisopropyl-ethylamine under reflux in tetrahydrofuran, according to the reference SUNG-EUN Y00; KYU YANG YI; Bull.
Korean Chem. Soc.~ 1989, 10(1), 112, will give the compounds of formulae (V) and (VI):

R~COOR~o R~CH~q--OP~' V~ V~

35 Formula (V) Formula (VI) -~3~

The compounds of formulae (V) and (VI) can al~o be obtained by condensation of an aldehyde of ~ormula (VII):

Formula (VII) with a compound of formula (II) or formula (III), followed by catalytic hydrogenation, for example in the presence of Raney nickel, in a solvent such as an alcohol, under pressure or at ordinary pressure if the substituents pr~sent allow it.
In more general terms, methods of preparing the compounds of formula (V) or formula (VI) will be found in the following references:
- DURGESHWARI P.; CHAUDHURY N.D.; J. Ind. Chem. Soc., 1962, 39, 735-6, ~ HEINZ P.; KREGLE~SKI A.; J. Prakt. Chem., 19G3, 21(3-4), 186-197, - ZAUGG H.E.; DUNNIGAN D.A.; MICHAELS R.J.; SWETT L.R.;
J. org. Chem., 1961, 26, 644-51, - KAGAN H.B.; HENG SUEN Y.; Bull. Soc. Chim. France, 1966 (6), 1~19-22, - RATHKE M.W.; DEI~CH J.; Tetrahedron Lett., 1971 (31), 2953-6, - BORRIES KUBEL; Liebigs Ann. Chem., 1980, 1392-1401, - MARQUET J.; MORENO-MANAS M.; Chem. Lett., 1981, 2, 173-6, - IOFFE T.; POPOV E.M.; VATSURO K.V.; TULIKOVA E.K.:
KABACHNIK M.I.; Tetrahedron, 1962, 18, 923-940, and .

2 ~ 2 ~

- SHEPHERD T.M.; Chem. Ind. ~London), 1970, 17, 567.
In formula (IV), W is a halogen atom, prefer-ably chlorine or bromine.
In the same ~ormula:
05 - V can be a nitro group, in which case the derivative of formula (IV) is commercially available.
- V can be a group COORIl, R1l being a lower alkyl or benzyl radical, in which case the derivative of formula ~IV) will be prepared by chlorinating or brominating a commercially available p-methylbenzoic acid ester with N-chlorosuccinimide or N-bromosuccini-mide, in a solvent such as carbon tetrachloride or dibromoethane, according to the following reference:
- JULIA M.; CHASTRETTE F.; Bull. Soc. Chim. France, 1962 ~2), 2247.
- V can be a group R~200C~

Rl2 being a lower alkyl or benzyl radical, in which case the compounds of formula (IV) are prepared by reacting a magnesium compound of p-bromotoluene with a compound of the formula CH,O

N
:30 ~ O

to give a compound of the formula 2~13~

CH, ~

05 ~
o which is hydrolyzed to give the compound of the formula CH~ ,~, HOOC

Procedures for the three steps described above will be found in the following referenca:
- MEYERS A.I.; MIHELICH E.D.; J~ Am. Chem. Soc., 1975, 97, 7383.
The acid is then esterified with an alcohol of the formula Rl2OH, R~2 being as defined above.
These derivatives are then brominated or chlorinated, for example with N-bromosuccinimide or N-chlorosuccinimide, in a solvent such as carbon te~ra-chloride or dibromoethane, to give the compounds of formula (IV~ in which V is the group ~, R,200C ~V

- V can be the group 2~3g~

NC

in which case the compound CH~
l 11 HOOC ~

prepared above will be converted to the primary amide by reacting the acid chloride (obtained with thionyl chloride or phosphorus oxychloride) with ammonia, and this amide will be converted to the nitrile by reaction with phosphorus oxychloride in dimethylformamide or by reaction with thionyl chloride. The nitrile obtained:
CH
l~ 11 ~ ,~3 NC

will then be brominated or chlorinated under the same conditions as the above ester to give the compounds of formula ~IV) in which V is the group NC

- V can be the group -` 2~3~2~

o2N~3 in which case the compound CICH~
~
l 11 02N/~
will be prepared by chloromethylating commercially available 2-nitrobiphenyl according to the following references:
- CA : 70 (25j : 114837d, and - CA : 69 (2) : 3704t to give the compounds of formula (IV) in which V is the 20 group ~3 - V can be a group ,~3 Fl~2~ S

R12 being a lower alkyl or benzyl radical. The corres-ponding compounds of formula ~IV) are obtained in the ~ollowing manner:
Starting ~rom the compound `` 2 ~ 2 ~

CH, ~\, 05 /~~S~

whose preparation can be found in the ~ollowing refe-rence:
- FISSELMANN H.; HABITCH H.; Ger. Offen. 1,092,929 ~1960); CA : 57 : 5B94g, the compounds of the formula ~H, ~ .
)~S>
OOC

will be obtained by esterification with an alcohol of the formula R120~, R1~ being as defined above, by classical methods Xnown to those skilled in the art.
These compounds are then treated with N-chloro-succinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane for example, to give the compounds of formula ~IV) in which V is the group R"00C S

R~2 being as defined above.
- V can be the group 2 ~

NC

in which case the corresponding compowlds of ~ormula (IV) will be prepared in the following manner:
Starting ~rom the compound 3-(p methylph~nyl)-thiophene-2 carboxylic acid, whose preparation is given above, the amide compound is obtained by treatment with thionyl chloride and then ammonia, said amide compound then being dehydrated with thionyl chloride or phospho-rus oxychloride, without a solvent or in dimethylforma-mide, to give the nitrile compound CH, ~

NC

This nitrile compound is then halogenated with N-chlorosuccinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of ~ormula (IV) in which V is the group ~3 NC S

- V can be the group ~S
NC~

in which case the corresponding compounds of formula (IV) are synthesized in the following manner:
Starting from 4-chlorobutyrophenone of the formula CH, ~ CO-CH2- CH2~ CH2-CI

whose preparation can be fou~d in patent BE 577,977 of lo15 May 1959, CA : 54, 4629c, the compound o~ the formula CH~ ~ C-C -CH2 CH,-CI
Cl CHO

will be obtained by treatment with phosphorus oxy-chloride and dimethylformamide according to the con-ditions described in the following re~erence:
- VOLODINA M.A.; TERENT'EV A.P.; KUDRYASHOVA V . A ~;
KABOSHINA L.N., Khim. Geterosikl. Soedim, 1967, 5-8.
This compound is then treated with sodium sulfide, in a solvent ~uch aæ tetrahydrofuran under reflux, to give the derivative CH, ~S
I/ \
30 OHC ~

which is then converted in two ~teps to the nitrile derivative by dehydration of the oxime formed from the aldehyde and hydroxylamine. This dehydration may be carried out for example with acetic anhydride to gi~e 2~3~28 the nitrile compound CH, ~
~5 ~ S
~1 ~
NC ~

which may then be aromatized by treatment with bromine in carbon tetrachloride and then with potassium tert-butylate in tetrahydrofuran to give the compound CH, NC

This compound can then be chlorinated or bro-minated with halogenating agents such as N-chloro-succinimide or N-bromosuccinimide, in a solvent such as carbon tetrachloride or dibromoethane, to give the compounds of formula (IV) in which V is th~ group ~ S
NC

- V can ~e the group R,IOOC~

Rl~ being as de~ined above. The corresponding com-2~3~28 . .

pounds of formula (~V) may be prepared from the com-pound of the formula CH~

~S
NC~

by classical hydrolysis of the nitrile group and then esterification of the acid obtained, or by direct con-version of the nitrile group to the ester group by the methods known to those skilled in the art, followed by chlorination or bromination of the ester with N-chloro-succinimide or N-bromosuccinimide, for example in carbon tetrachloride or dibromoethane.
In formulae tv) and (VI~, Rl, R~o~ R' and q are as defined above and V is as defined in formula (IV).
Some deriYatives of formula (V) and formula (VI), when V is a 2-alkoxycarbonylphenyl, a 2-cyano-phenyl, a 2-nitrophenyl, an alkoxycarbonylthiophene or a cyanothiophene, are novel synthesis intermediates which are claimed per se.
In formula (VII), V is as defined in formula (IV), but this condensation method will only be used when V possesses a functional group unaffected by hydrogenation. In certain cases, these aldehydes may be prepared ~rom the derivatives of ~ormula (IV) according to reactions known to those skilled in the art. The Sommelet reaction (Bull. Soc. Chim. France, 1918, ~4] 23, 95) or the nitropropane reaction (organic Syntheses Collec., vol. IV, 932) may be mentioned.
Reaction of a hydrazine o~ formula (V~

, . . . .

gl 2 ~

H~N-NH-R2 Formula (VIII) 05 in which ~2 iS as defined above, with the compounds of formula (V~, by simply refluxing in an alcohol for example, will give the compounds of formula (IX):

/N-N
R, ~ OH
,~
V~

Formula (IX) in which Rl, R2 and V are as defined above.
These compounds of formula (IX) are novel syn-thesis intermediates which are claimed per se.
Alkylation of the compounds of formula (IX), performed in the presence of a base such as potassium or sodium carbonate in solvents such as acetone, butan--2-one or dimethylformamide, or in the presence of a sodium or potassium alcoholate in an alcohol, or in the presence of sodium or lithium hydride in tetrahydro-furan, with derivatives of formula (X):

~-R3 Formula ~X) Z being a bromine, chlorine or iodine atom and R9 being as de~ined above, gives the compounds of formula (XI):

2~3~

N-N
R~o~RJ

V~

For~ula (XI) in which R~, R2, R3 and V are as def.ined above.
Likewise, reaction of a hydrazine of formula tVIII)i as defined above, with a compound of formula (VI), by simply refluxing in an alcohol for example, will y7 ve a mixture of compounds of formula (XII~ and formula tXII'):

R~(CHdq ,~\(Cll~q 25 VJ~ VJ~
Formula tXII) Formula (XII') in which Rl, R2, R', q and V are as defined above.
The pure compounds of formula (XII) will be obtained from this mixture by purification by chroma-tography on silica, recryskallization or any other method of puri~ication known to those skilled in the art.
Another method of preparing the compounds of 2 ~ 2 ~

formula (XII) consists, in a first stage, in treating the compounds of formula (VI) with hydrazine hydrate under the same ~onditions to give the compounds of formula (XIII):

N-N N-N
R, ~ OR' ~ (CH,)q OR

Formula (XIII) in which R1, R', q and V are as defined above. These compounds of formula (XIII) are then alkylated in the presence of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a solvent such as acetone or acetonitrile for example, with halogenated derivatives of formula (XIV):

Z-R

Formula (XIV) in which R2 is as defined above and Z is a bromine, chlorine or iodine atom, to give a mixture of the com-pounds of formula (XII) and formula (XII'), as defined above, the compounds of formula (XII) then being ob-~30 tained pure after purification as mentioned above.
This second method of preparation can be particularly advantageous in the case where R2 is a lower alkyl group, because it makes it possible to obtain a pre-ponderant proportion of the compounds of formula (XII) relative to the compounds of formula (XII').

-- . . .

2 ~

The compounds of formula (XII) in which R' is a hydrogen will be prepared in two steps: Treatment of the compounds of formula (XII) in which R' is a lower alkyl group with boron tribromide will give the bromi-05 nated derivatives of formula (XV):

N_N~RZ

R~/~\(CH~q Br ,D~

V~
Formula (XV) in which Rl, R2, q and V are as defined above. Treat-ment of these brominated derivatives of formula (XV~
with potassium or sodium carbonate under reflux in a dioxane/water mixture makes it possible to obtain tha compounds of formula (XII) in which R' is the hydrogen atom.
The derivatives of formula (XI) or formula (XII) in which V is a nitro group will be able to undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give the compounds of formula (I) in which R4 is an amino group and A is a group -(CH2)~-OR' or OR3, R', R3 and q being as defined above.
Reaction of an appropriately substituted phthalic anhydride with these derivatives will give the compounds of general formula (I) in which R4 is the group 2~3~

X
~ HN-C

05 HOOC ~

in which x and Y are as defined above and A i5 a group ~lCHa)q-OR~ or OR3, q, R~ and R3 being as defined above, it then being possible for the acid obtained to be esterified to give the group O X
--HN- C~,~
R900G~
y Likewise, reaction of the cyclic anhydride of an appropriately substituted orthosulfobenzoic acid with these amino compounds will give the compounds of general formula (Il in which R~ is the group z5 --HN--8~3 HO,S
y and A is a group -(CH2)~-OR' or OR3, g, R', R3, X and Y
b~ing as defined above.
Likewise, reaction of N-(trifluoromethyl-sulfonyl)anthranilic acid chloride, whose preparation can be found in the following references:
CA 96 (13) : 103651z, and 2 ~ 2 ~
~ 26 -CA 97 t7) : 55500w, with these amino compounds will give the compounds of general formula (I) in which Ra is the group --HN--C~, CF:~--S02--HNJ~

and A is a group ~(CH2)q~OR! or OR3, q, R' and R3 being as defined above.
The compounds of formula (XI) or ~XII) in which V is a group -COORl1 will be able to be hydrolyzed in an acidic or basic medium, or hydrogenated in the case where R~l is a benzyl so as not to affect the other ester groups present, to give the compounds of formula (I) in which R~ is a group -COOH and A is a group -(CH2)~-OR' or OR3, q, R' and R3 being as defined above.
After conversion to the acid chloride with thionyl chloride or to a mixed anhydride with ethyl chloroformate, these acid derivatives will be able to give the compounds of general formula ~I) in which R~
is the group o X
NH

R~O,C
Y

and A is a group -~CH2)~-OR' or OR~, q, R' and R~ being as defined above, by reaction with anthranilic acid derivatives of the formula 2 ~

05 RDOOC~

in which X, Y and Rg are as defined above.
In the same way, the compounds of formula (XI) or txII) in which V is a group \f~

R,200C~

will be hydrolyzed, or hydrogenated in the presence of a catalyst such as palladium-on-charcoal in the case where R12 is a benzyl, to give the compounds of formula (I) in which R~ is a group HOOC ~

and A is a group ~(CH2)q-OR~ or OR3, q, R~ and R3 being as defined above.
The compounds of formulae (XI) and (XII) in which V is a group NC~

will be able to react with one equivalent of sodium nitride in a solvent such as dimethylformamide, in the ~33~

presence of an ammonium salt such as ammonium chloride, or with a trialkyltin nitride under reflux in toluene and then with gaseous hydrochloric acid in tetrahydro-fuxan, to give the compounds of general formula (1) in 05 which R~ is a group ~, N~/
N~ ,NH
N

and A is a group -(CH~)~-OR' or OR3, q, R' and R3 being as defined above.
The compounds of formulae (XI) and (XII) in which V is a group ~3 will be able to undergo catalytic hydrogenation, for example in the presence of Raney nickel, in an alcohol, at atmospheric pressure or under pressure, to give com-pounds of general formula (I) in which R~ is a group HlN~J

and A is a group ~(CH2)q~0R~ or OR3, q, R' and R3 being as defined above~
Reaction of trifluoromethanesulfonyl chloride with the latter in a solvent such as chloroform or in an aromatic solvent such as toluene, in the presence of ~3~

a base such as triethylamine or pyr.idine, or in pyri-dine, will give the compounds of general formula (I) in which R4 is a group 05 ~

CFJ--SO2--HN~J

and A is a group -(CH2)~-OR~ or OR3, q, ~' and R3 being as defined above.
The compounds of formulae (XI) and (XII) in which V is the group NC ~ S

will be able to be treated with a trialkyltin nitride under re~lux in toluene and then with gaseous hydro-chloric acid in te~rahydrofuran to give the derivatives of formula (I) in which R~ is the group N~ ~S
N

and A is a group ~(CH2)q~OR~ or OR3, q, ~' and R3 being as defined above.
The compounds of formulae (XI) and (XII) in which V is the group R"OOC ~ S

will be able to be hydrolyzed, or hydrogenated in the ~3~

~ 30 -presence of a catalyst such as palladium-on-charcoal in the case where Rl2 is a benzyl, to give the compounds of formula (I) in which R~ is the group 05 ~
HOOC ~ S

and A is a group ~(CH2)q~0Rt or OR3, q, R' and R3 being as defined above.
The compounds of formula (I) in which A is a group CH20H will be able to be oxidized with a mild oxidizing agent such as manganese dioxide, in a solvent such as chloroform, to give the compounds of formula (I) in which A is the group CH0, which will be able to be converted, by the classical methods known to those skilled in the ar~, to an acetal or a dioxolan by heating with an alcohol or a diol, in the presence of paratoluenesulfonic acid for example (Synthesis, 1981, 501).
More rigorous oxidation of these same aldehyde compounds or of the alcohol compounds direct, for example with oxidizing agents such as potassium per-manganate, will give the compounds of formula (I) in which A is the group C02H.
The compounds of formula (I) in which A is the group CO~H will be able to be esterified by classical methods of esterification to give the compounds of formula (I) in which A is a group C02R', R' being a lower alkyl radical.
The compounds of ~ormula (I) in which A is the group C02H will also be able to be converted to the amide in several steps, if necessary after steps for protecting other functional groups, by conversion to the acid chloride and then treatment with ammonia or with an amine of the formula HNR''R''', R'' and R''' 2 ~

being as defined above, to give the compounds of formula (I) in which A is a group CONR'tR'''.
The compounds of formula tI) in which A is a group CONH2 will be able to be treated with an agent 05 such as thionyl chloride or phosphorus oxychloride to give the compounds of formula (I) in which A is the group CN.
The compounds of formula (I) in which A is a group (CH2)~0R', R' being a lower alkyl radical and q being an integer from 1 to 5, will be able to be treated with boron tribromide in chloroform to give, if necessary after steps for protecting and deprotecting other functional groups, the compounds of formula (I) in which A is the group (CH2)~Br.
The compounds of formula (I) in which A is the group (CH2)~Br will be able to be treated with sodium or potassium cyanide, in solvents such as alcohol, an alcohol/water mixture, dimethyl sulfoxide or aceto-nitrile, to give the compounds of formula (I) in which A is the group tCH2)~CN, or with amines of the formula HNR''R''', in which R'' and R''' are as defined above, to give the compounds of formula (I) in which A is (CH2)qNR~R~ or with thiols of the fo.rmula HS-R', R' being as defined above, to give the derivatives of formula (I) in which A is (CH2)~-S-R'.
The compounds of formula ~I) in which A is the group ~CH2)~CN will be able to be hydrolyzed by the classical methods of nitrile hydrolysis to give the compounds of ~ormula (I) in which A is the group (CH2)~CO2H.
These acid compounds will themselves be able to be esterified by the classical methods of esterifica-tion to give the compounds of ~ormula (I) in which A is a group ~CH2)~CO2R', R' being a lower alkyl radical and q being an integer from 1 to 5, or converted to an 2 ~ 3 ~f~

amide ~(C~2)q~CONR/~R~ as indicated above.
The compounds of formula (I) in which A is the group ~CH2)qL~ L being a halogen and q being an integer from 1 to 5, will be able to be synthesized by treating 05 the derivatives of formula (I) in which A is the group (CH2)qOH with halogenating agents such as, for example, thionyl chloride, phosphorus oxychloride or phosphorus tribromide.
In the case where R4 possesses a functional group which is not compatible with these reaction sequences, the derivative of formula (XII) will be used as the product for conversion, V subsequently being converted to the group R~ in the manner mentioned above.
It is possible to obtain addition salts of some of the compounds of formula (I), especially pharmaceu-tically acceptable addition salts. In particular, when R2, R4 or A contains an acid group, there may be mentioned the salts of sodium, potassium, calcium, an amine such as dicyclohexylamine or an amino acid such as lysine. When A or R4 contains an amine group, there may be mentioned a salt of a mineral or organic acid, such as, for example, the hydrochloride, methanesulfo-nate, acetate, maleate, succinate, fumarate, sulfate, lactate or citrate.
The novel compounds according to the invention possess remarkable pharmacological properties as angio~
tensin II receptor antagonists and can be used in therapeutics for the treatment of cardiovascular dis-~
eases and in particular for the treatment of hyperten--sion and cardiac insufficiency~
Thus the invention covers the pharm~ceutical compositions which contain, as the active principle, the drugs consistiny of a pharmaceutically effe.ctive amount of at least one compound of formula (I) as 2 ~

defined above, as well as one of its pharmaceutically acceptable addition salts if appropriate.
These compositions can be given by buccal, rectal, parenteral, percutaneous or oculax administra~
05 tion.
These compositions can be solid or liquid and presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, gelatin capsules, granules, suppositories, injectable preparations, percutaneous sys~ems and eye lotions; they are prepared by the customary methods.
In said compositions, the active principle, consisting of a pharmaceutically effective amount of at least one compound of formula (I~ as defined above, or one of its pharmaceutically acceptable addition salts, can be incorporated in excipients normally employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, polyvidone, cellulose derivatives, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous vehicles, ~ats of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, certain polymers or copolymers, preservatives, flavor-ings and colors.
The invention also covers a pharmaceutical com-position with antagonistic activity towards angiotensin II receptors, which makes it possible especially to favorably treat cardiovascular diseases, in particular hypertension and cardiac insuf f iciency, said composi-ti.on comprising a pharmaceutically effective amount o:f at least one compound of formula (I) mentioned above, or one of its pharmaceutically acceptable addition salts, which may be incorporated in a pharmaceutically acceptable excipient, vehicle or carrier.
The dosage varies especially accordinq to the ~3~

mode of administra~ion, the complaint treated and the subject in question.
For example, for an adult with an average weight of 60 to 70 kg, it can vary between 1 and 400 mg 05 of active principle administered orally in one or more daily doses, or from 0.01 to 50 mg admi:nistered paren-terally in one or more daily doses.
The invention also covers a method of preparing a pharmaceutical composition, which comprises incor-porating a pharmaceutically effective amount of atleast one compound of formula (I) as defined above, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier. According to a particular character.istic, this pharmaceutical composition is formulated as gelatin capsules or tablets containing from 1 to 400 mg of active ingradient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient.
The invention also covers a method of thera-peutic treatment for mammals, which comprises adminis-tering to this mammal a therapeutically effective a~ount of at least one compound of formula ~I) as defined above, or one o~ its pharmaceutically accept-able addition salts.
In animal therapeutics, the daily dose which can be used should normally be between 1 and 100 mg per kg.
Further characteristics and advantages of the invention will be understood more clearly from the following description of some Preparatory Examples, which in no way imply a limitation but are given by way of illustration.

2~3~3 Example_1: Ethyl 3-oxoheptanoate Formula (II): Rl = n-butyl, Rlo = ethyl 05 70 g of Meldrum's acid are dissolved in 200 ml of methylene chloride in the presence of 78.5 ml of pyridine, the mixture is cooled to 0 C and 64.5 g of valeroyl chloride are added dropwise at this tempera-ture. When the addition is complete, the mixture is left to stand at room temperature and stirred for two hours. The solution is washed with a dilute solution of hydrochloric a~id, dried over magnesium sulfate and evaporated under vacuum to give 110 g of an oil, whi~h is used as such for tAe next step. This oil is dis-solved in 400 ml of absolute ethanol and the mixture is refluxed for two hours and left to stand overnight at room temperature. The ethanol is evaporated off under vacuum and the oily residue is distilled under reduced pressure to give 63.3 g of ethyl 3-oxoheptanoate in the ~orm of a liquid o~ b.p.20 = 115-120 C.

Example 2: Ethyl 3-oxohexanoate Formula ~ Rl = n-propyl, Rlo = ethyl 5 Prepared by the same procedure as Example l.
Liquid of b.p.20 - 95-100C.

~xample 3: Ethyl 2-(4-nitrobenzyl)-3-oxohepkanoa30 Formula (V): R~ = n-butyl, V = N02, Rlo =
ethyl 57.3 g of ethyl 3-oxoheptanoate are dissolved in 300 ml of ethanol. A solution o~ sodium ethylate, 2 ~

prepared by adding 7.7 g of sodium to 50 ml of ethanol, is added and the mixture is stirred for 20 minutes at room temperature. 72 g of 4-nitrobenzyl bromide are then added in portions and the mixture is subsequently 05 stirred for two hours at room temperature and then for two hours under reflux. The ethanol is evaporated off under vacuum and the residue obtained is taken up with water and then extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The oil obtained is taken up in a mixture of ether and pentane and the crystals formed are filtered off to remove the dibenzylated derivative (m.p. = 135C); the mother liquors, ~oncentrated under vacuum at 120C to remo~e the starting unsubstituted keto-ester, give 69.2 g of ethyl 2-(4-nitrobenzyl)-3-oxoheptanoate in the form of an oil, which is used as such for the next step.

Example 4: Ethyl 2-(4-nitrobenzyl)-3-oxohexanoate Formula (V): Rl = n-propyl, V - NO2, Rlo =
ethyl Prepared by the procedure of Example 3, start-ing from the ethyl 3-oxohexanoate prepared in Example 2.
Oil used as such for the next step.

Example 5: Ethyl 2-(2'-methoxycarbonylbiphenyl-4-yl)-methyl-3-oxoheptanoate Formula (V): R1 = n-butyl, V =
MeO2C/~
R1o = ethyl 2~3~28 Prepared by the procedure of Example 3, start-ing from the ethyl 3-oxoheptanoate prepared in Example 1 and methyl (4~-bromomethylbiphenyl-2-yl)carboxylate.
Oil used as such for the n~xt step.

Preparation o~ methyl (~'-bromomethylbiphenyl-2-yl~-carboxylate A) Methyl (4'-methylbiphenyl-2-yl)carboxylate 1015 ml of acetyl chloride are added to 300 ml of methanol cooled to 0 C. The mixture is stirred for 10 minutes at this temperature and 15 g of (4'-methylbi-phenyl-2-yl)carboxylic acid (prepared according to MEYERS A.I.; MIHELICH E.D., J. Am. Chem. Soc., 1975, I5 97(25~, 7383, by reacting (4-methylphenyl)magnesium bromide with 2-(2-methoxyphenyl)-4,4-dimethyl-1,3-oxazolidine) are then added. The mixture is then refluxed for 4 hours and the solvents are evaporated off under vacuum to give 16 g of methyl (4'-methylbi-phenyl-2-yl)carboxylate in the form of an oil, which is used as such for the next step.

B) Methyl (4'-bromomethylbiphenyl-2-yl)carboxylate 16 g of methyl (4'-methylbiphenyl-2-yl)carhoxy late, prepared in A), are dissolved in 120 ml of carbon tetrachloride in the presence of 12.6 g of N-hromo-succinimide and 0.5 g of benzoyl peroxide. The mixture is refluxed for 6 hours, the crystals are filtered off and the remaining solution is washed with a solution of sodium bicarbonate and then evaporated under vacuum.
The residue is taken up with ether and the solution is then filtered on charcoal and evaporated under vacuum to give 14.5 g of methvl (4'-bromomethylbiphenyl-2-yl)carboxylate in the form of an oil, which is used as such ~or the next step.

Example 6: Ethyl ~-(2~-cyanobiphenyl-4-yl)methyl-3-oxoheptanoate 05 Formula (V): Rl = n-butyl, v =

Rlo - ethyl g of ethyl 3-oxoheptanoata, prepared in Exa~ple 1, are dissolved in 300 ml of tetrahydrofuran.
31.6 g of 4'-bromomethyl-2-cyarlobiphenyl are added together with 40 ml of N,N-diisopropylamine and 10 g of lithium bromide. The mixture is refluxed or 15 hours and then concentrated under vacuum, iced water and dilute hydrochloric acid are added and the mixture is then extracted with ethyl acetate. Tha organic phase is washed with water and then dried and evaporated under vacuum. The residue obtained is heated under vacuum at 130 C in order to remove the residual ethyl 3-oxoheptanoate, giving 41 g of ethyl 2-(2t-cyanobi-phenyl 4-yl)methyl-3-oxoheptanoate in the form of an oil, which i8 used as such for the next step.

Preparation of 4'-bromomethyl-2-cyanobiphenyl A) 4'-Methyl-2-cyanobiphenyl 18.5 g of (4'-methylbiphenyl-2-yl)carboxylic acid, prepared as in Example 5 A), are refluxed in 60 ml of thionyl chloride for two hours. The thionyl chloride is concentrated under vacuum, the residue is poured into a 28~ solution of ammonium hydroxide, the mixture is stirred for 30 minutes and the crystals obtained are filtered off, washed with ether and then dried to give 14.5 g of (4'-methylbiphenyl-2-yl)carbox-amide in the form of crystals melting at 128C. These ~ 3~ _ .

?
cryst~ re ~akan u~ in 50 m~ o~ thionyl ~hlorl~a and the mlxture 1~ re~lux~d ~or 3 hour~ and then ~naen~r~-tad un~ar vaauum to ~lv~ 9 . ~ o~ 4'~ethyl-2=ay~nobi-phe~yl in the ~orm o~ ory~a~ melti~ a~ 45-~6 C.

B) 4'-Bromo~t~yl-~-cyano~lph~nyl 7.~ 4'-m~thyl-?-~yanobiphenyl, prepa~d ln A), ~re.~ o~ve~ in 1~0 m} o~ a~rbDn t~r~ch~o~ide in t~ pr~38~nae o~ 7 . 3 g o~ N-br~mo~u~cinintidG ~nd O . 3 4~
o~ b~n20yl peroxid~. The mix~-ure i~ re:Elux~d ~or ~
hours, th~ cry~ are ~ D~ he ~emainin~
~olution 1~ conce~t~ted under ~auum and th~ r~ ue i~ ~rystalli~d ~ro~ ~ther ~o glve 6.6 g of 4'-bromo-me~hyl-2-~r~nobiphen~l ~n th~ ~orm of cry~al~ m~l~ing 15 ~ 115-118 C

~Xhm~ hyl~3~n-butyl-~ 14-~ltr~n~yl~
. hyd~oxypy~801 For~ula ~IX~: R~ ~ n-butyl, Ra ' CH~ ~ V

~0 g oP ~hy~ 2-(4-nitrobenzyl)~3-oxoh~p~no~
at~, pr~p~rad in Ex~mpl~ 3, 4~ dlssolved in 150 ml o~
~t~nol, ~nd 4 ml o~ me~hylhyd~azina a~ ~dded. ~h~
mixture i~ r~luxa~ ~or ~ hou~. The. ~ hanol i&
ev~porAt~d o~ und~r va~uum, ~h~ r~ ue i~ tak~n Up wi~h w~ter ~nd ~h~ ~x~raot~d wl~h ~hyl ~etate, ~h~
organiG pha~ hen wash~d ~ver~ tim~s w~th dilute ~olu~ion o~ ~odlum hyA~oxi~ and the aom~lnad a~ueou~ ~ractlon~ ar~ acid~ with eul~ur dioxide and th~n extra~t~d wl~h chloro~orm. The ~hloro~orm pha~e i~ ~risd o~ar m~ne6~um sul~t~ ~nd e~flporat~d under vacuum ~o glve a re~i~Ue WhlCh cry~tAllize~ ~rom ~th~r.
~h~ ~ryR~ are ~iltered o~ and re~ry~t~ ed ~rom .

203~2~

ethyl acetate to give 10~9 g of 1-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole in the form of crystals melting at 136C~

05 Example 8: 1-Methyl-3-n-propyl~4 (4-nitrobenzyl~-5~
hydroxypyrazole Formula (IX): R~ = n-propyl, R2 = CH3, V =

Prepared by the procedure of Example 7, start-ing from the ethyl 2-~4-nitrobenzyl)-3-oxohexanoate prepared in Example 4.
Crystals melting at 174C.
Example 9: 3-n-Propyl-4-(4-nitrobenzyl~-5-hydroXy-pyrazole Formula (IX): R1 = n-propyl, R~ = H, V = N02 2~
Prepared by the procedure of Example 7, start-ing from the ethyl 2-(4-nitrobenzyl)-3-oxohexanoate prepared in Example 4 and hydrazine.
Crystals melting at 196C.
Example 10: 1-Ethoxycarbonylmethyl-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxypyrazole Formula (IX): ~l = n-propyl, R2 = CH2C02Et, V ~ N0z Prepared by the procedure of Example 7, start ing from ethyl hydrazinoacetate.
Crystals melting at 134C.

2~3~2~

- 4~ -Example 11: 1-(2,2,2-Trî~luoroethyl)-3-n propyl-4-(4- -.nitrobenzyl)-5-hydroxypyrazole Formula (IX): R1 = n-propyl, ~2 = CH2CF3, 05V = N02 Prepared by the procedure of Example 7, start-ing from 2,2,2-tri~luoroethylhydrazine.
Crystals melting at 160C.
Example 12: 1-~ethyl-3-n~butyl-4-(2'-mathoxycarbonyl-biphenyl-4-yl)methyl-5-hydroxypyrazole Formula (IX~: Rl = n-butyl, R2 = CH3, :15 ~
V= 1 11 CH,O,C ~
Prepared by the procedure of Example 7, start-ing from the ethyl 2-(2' methoxycarbonylbiphenyl-4-yl)methyl-3-oxoheptanoate prepared in Example 5.
Crystals melting at 108C.

Examplç_13: 1-~ethyl-3-n-butyl-4-(2'-cyanobiphenyl-4-25yl)methyl-5-hydroxypyrazole Formula (IX): R~ = n-butyl, R2 = CH3, V= 1 11 30NC ~

Prepared by the procedure of Example 7, start-ing from the ethyl 2-(2'-cyanobiphenyl-4-yl)methyl-3-oxoheptanoate prepa~ed in Example 6.
35Crystals melting at 138~C.

~38~2~

Example 14: Ethyl [l-methyl-3 n-propyl-~-(4-nitro-benzyl)pyrazol-~-yl]oxyacetate Formula (Xl): R1 = n-propyl, R2 = methyl, 05 R3 = CH2C02Et, V = NO2 22.4 g of 1-methyl-3-n-propyl-4-~4-nitro-benzyl)-5-hydroxypyrazole, prepared in Example 8, are dissolved in 200 ml of acetone, and 8.7 g of sodium ~o carbonate and 9.2 ml of ethyl bromoacetate are added.
The mixture is refluxed for 5 hours and the solvents are concentrated to dryness. The residue is taken up with water and then extracted with ether. The organic phase is dried over magnesium sulfate and evaporate~ to dryness. The residue obtained is taken up with iso-propyl ether and the resulting crystals are filtered of f to give 9 g of ethyl [1-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-oxopyrazol-2-yl]acetate melting at 62C.
The mother liquors are concentrated and the oil obtained is chromatographed on silica gel in a methy-lene chloride/acetone eluent (90/10) to give lO g of ethyl [l-methyl 3 n-propyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxyacetate in the form of crystals melting at 60-61 C.
Example 15: ~thyl [l-methyl 3-n-butyl-4-~4-nitro-benzyl)pyrazol-5-yl~oxyacetate Formula (XI): R1 = n-butyl, R2 = methyl, ~3 -- CH2C2Et l V = N02 Prepared by the procedure of Example 14.
Crystals melting at 68C.

2~3~28 Example 16: Ekhyl [3-n-propyl-4~ nitrobenzyl~pyrazol-5-yl~oxyacetate ~ormula (XI): R1 = n-propyl, R2 = H, R3 =
05 CH2Co2Et~ V = N02 Prepare~ by the procedure o~ Example 14.
Crystals melting at 116C.

Example 17: ~ethyl ~1-methyl-3-n-p~opyl-4-(4-nitro-benzyl)pyrazol-5-yl]oxyacetat~

Formula ~XI): R1 = n-propyl, R2 = methyl, R3 = CH2C02Me, V = N02 Prepared by the procedure of Example 14.
Crystals melt.ing at 58C.

Example 18: Methyl Cl-l2,2,2-tri~luoroethyl)-3-n-prupyl-4-(4-nitrobenzyl)pyrazol-5~yl]oxy-acetate ~o~mula ~XI): R1 = n-propyl, R2 = CH2CF3, R3 = CH2C02Me, V = N02 Prepared by the procedure of Example 14.
Crystals melting at 73C.

E~am~le 1~: Ethyl tl-methyl-3-n-butyl-4-(2'-methoxy-carbonylbiphenyl-~-yl)methylpyrazol-5-yl3-oxyacetate For~ula (X~): Rl = n-~utyl, R2 = methyl, -- CH2C02Et, V =
. ~.

2~3~8 - ~4 -Prepared by the procedure of Example 14.
oi 1 used as such for the next step.

Example 20: Ethyl t1-methyl-3-n-butyl-4-(2~-cy~nobi-05 phenyl-4-yl)~ethylpyrazol-s-yl~oxyacetate Formula (XI3: R1 = n~butyl, R2 ~ methyl, R3 = CH2CO2Et, V =
NC~

Prepared by the procedure of Example 14.
Oil used as such for the next step.

Example 21: Ethyl [l-methyl-3-n-butyl-4-(4-amino-benzyl~pyrazol-5-yl]oxyacetate Formula (I~ Rl = n-butyl, R2 = methyl, A =
OR3, R3 = cH2C02Et, Ra = NH2 3.4 g o~ ethyl [1-methyl-3 n butyl-4-~4-nitro-benzyl)pyrazol-5-yl]oxyacetate, prepared in Example 15, are dissolved in 50 ml of absolute ethanol in the presence of 500 mg of Raney nickel. The mixture is hydrogenated at atmospheric pressure and room tempera-ture and, when the uptake of hydrogen has ceased, tha catalyst is filtered off, the ethanol is evaporated off under vacuum and the residue is taken up with pentane to give 2.9 g of ethyl [1-methyl-3-n-butyl-4-(4-amino-ben2yl)pyrazol-5-yl]oxyacetata in the form of crystals melting at 65C.
.

~3~8 Example 22: ~khyl [1-methyl-3-n-propyl-~-(4-amino-benzyl)pyrazol-5~yl]oxyacetate Formula (I): Rl = n-propyl, R2 = methyl, 05 A = OR3, R3 = CH2CO2Et, R~ =
NH~

Prepared by the procedure of Example 21.
Crystals melting at 103C.
. "
Example_23: Methyl [1-methyl-3-n-propyl-4-(~-a~ino-~enzyl~pyrazol-5-yl~oxyacetate Formula (I): R1 = n-propyl, R2 = methyl, A = OR3, R3 = CH2CO2Me, R~ =

Prepared by the procedure of Example 21.
Oil used as sUch for the next step.
Example 24: Methyl [1-(2,2,2-trifluoroethyl)-3-n-propyl-4-(4-aminobenzyl)pyrazol-5-yl]oxy-acekate Formula (I): Rl = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CO2Me, R4 =
NHa Prepared by the procedure o~ Example 21.
Crystals melting at 63~C.

3~42~

Examp~e 25~ thoxycarbonylmet~lyl-3-n-propyl 4-(4-aminobenzyl)-5-hydroxyp~razole Formula (I): Rl = n-propyl, Ra = CH2CO2Et, 05 A = OR3, R = H, R - NH

Prepared by the procedure of Example 21.
Oil used as such for the next step.

Example_26: Ethyl ~3-n-propyl-4-(~-aminobenzyl)pyrazol-5-ylloxyacetate F~rmula (I): Rl = n-propyl, R2 = ~, A =
OR3, R~ = CH2C02Et, R4 = NH2 Prepared by the procedure of Example 21.
oi l used as such for the next step.

Exampla ~7: E~hyl [l-methyl-3~n-butyl 4-(4-(2-carbo~y-~enzoylamino)benzyl)pyrazol-5-yl]oxyacetate Formula (I): Rl = n-butyl, R2 = methylj A =
OR3, R3 = CH~Co2Et, ~H-C ~

3 g of ethyl [1-methyl-3-n-butyl~4-(4-amino-benzyl)pyrazol-5-yl]oxyacetate, prepared in Example 21, are dissolved in 50 ml of acetonitrile. 1.3 g o~
phthalic anhydride are added and the mixture is left to stand at room temperature overnight. The crystals obtained are filtered off, washed with isopropyl ether `` 2~3~8 and dried to give 2.5 g of ethyl [1-methyl-3-n-butyl-4-(4-(2-carboxybenzoylamino~benzyl)pyrazol-5-yl]oxy-acetate in the form of crystals melting at 140-141 C.

05 The following Examples were prepared by the same procedure:

Example 28: ~ethyl tl-methyl-3-n-propyl-4-(4-(2-car-boxybenzoylamino)benzyl)pyrazol-5-yl]oxy-ace$ate For~ula (I) R1 = n-propyl, R2 = CH3, A =
OR3, R3 = CH2CO2Me, o NH--C~

Crystals, in the form of the dicyclohexylamine salt, melting at 173-174C.

Example 29: Ethyl tl-~ethyl-3-n-propyl-4-(4-(2-carboxy b~nzoylamino)benæyl)pyrazol-5-yl]oxyacetate Formula (I) Rl = n-propyl, R2 = CH9, A =
OR~, R3 = CH2CO2Et, ~4 =
HO,C

Crystals melting at 139-140C.

~-` 2~38428 Example 30: ~thyl [1-methyl-3-n-propyl-4-(4-(2-carbOXy-3,6-dichloro~enzoylamino)benzyl)pyrazol-5 yl]oxyacetate 05 Formula ( I ): Rl = n-propyl t ~a a CH3, A =
OR3, R3 = CHzCO2Et, O Cl NH--C~
R4 =

Ct From 3,6-dichlorophthalic anhydride.
Crystals, in the form of the dicyclohexylamina salt, melting at 199-200C.

~amnl~ 31: ~e~hyl [1-~ethyl-3-n-propyl-4-(4-~2-car-~oxy-3,6-dichloxobenzoyla~ino)benzyl)~
pyrazol-5-yl]oxyace~ate For~ula lI): Rl = n-propyl, R2 = mathyl, A = OR3, R3 = CH2CO2Me, O Cl Il I
NH - C~

Cl From 3,6-dichlorophthalic anhydride.
Crystals mel~ing at 150-151C.

:

.

-` 2038~28 ~9 Example 32: ~ethyl Ll-(2,2,2-trifluoroethyl)~3-n-propyl-4-(4-~2-carbo~y-3,6-dichlorobenzoyl-amino)benzyl)pyrazol-5-yl]oxyacetate 05 Formula ~ Rl = n-propyl, R2 = CH2CF3, A = OR3 ~ R3 = CH2COaMe, O Cl NH-C

~4= 1~
Ho2~ T
Cl From 3,6-dichlorophthalic anhydride~
Crystals melting at 169-170C~
Example 33: ~ethyl [1-(2,2,2-trifluoroethyl)-3-n-propyl-4-(4-(2-carboxybenzoyla~ino)benzyl)-pyrazol-5-yl]oxyacetate Formula ~ R~ = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CO2Me, NH-C

Crystals melting at 189-192C.

03~28 Example 34: [3-n-Propyl-4-(~ [2-carboxyben~oylamino)-be~zyl)pyrazol-5-yl]oxyacetic acid For~ula (I). Rl = n-propyl, Rz = H, A -05 VR3, R3 = CH2C02H, ll NH--C~

0.9 g of ethyl ~3-n-propyl-4-(4-aminobenzyl)-pyrazol-5-yl~oxyacetate, prepared in Example 26, is dissolved in 20 ml of acetonitrile in the presence of 0.45 g o~ phthalic anhydride. The mixture is left to stand at room temperature overnight. The acetonitrile is evaporated off under vacuum and the residue is taken up in an ethyl acetate/ether mixture to give crystals, which are filtered off. These crystals are dissolved in methylene chloride and the solution is washed several times with a 1 N solution of sodium hydroxide.
The combined aqueous phases are acidified by having sulfur dioxide bubbled through them and the crystals obtained are filtered off and dried to give 0.5 g of [3-n-propyl-4-(4-t2-carboxybenzoylamino)benzyl)pyrazol-5-yl]oxyacetic acid in the form of crystals melting at 170-171 C.

203~

Example 35~ Methyl-3-n-propyl-4~ (2-sulfobenzoyl-a~ino)benzyl]pyrazol-5~yl]oxyacetic acid Formula (I): R1 - n-propyl, Rz = CH3, A =
05 OR3, R3 -NH--C
R~ = \~

1 O HOJS~

Prepared by the procedure of Example 34, start-ing from the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 16~-170C.

Example 36: 4'-[1-~ethyl-3-n-butyl-5-hydroxypyrazol-4-yl]methylbiphenyl-2-carboxylic acid Formula (I): R1 = n-butyl, R2 = methyl, A =
OR3 ~ R~ = H, \~ .
R" =
HO,C ~ ~

1.5 g of l~methyl-3-n-butyl-5-hydroxy-4-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrazole, prepared in Example 12, are suspended in 15 ml of a 1 N solution o~ sodium hydroxide and the suspension is stirred ~or one hour at 40~C. The solution is washed with methy-lene chloride and then acidified by having sulfur dioxide bubbled through it and extracted with methylene chloride. The organic phase is dried over magnesium sul~ake and then evaporated under vacuum. The residue 38~

is diluted in ethyl acetate, extracted with a solution of sodium bicarbonate and then acidified with sulfur dioxide and the crystals obtained are filtared off and then dried to give 1.1 g of 4'-[1-methyl-3-n-butyl-5-05 hydroxypyrazol-4-yl]methylbiphenyl-2-carboxylic acid in the form of crystals melting at 228-30 C.

Exam~le 37O tl-Methyl-3-n-butyl-4-(2'-carboxybiphenyl-4-yl)methylpyrazol-5-yl]oxyacetic acid Fo~mula (I): R = n-butyl, R2 = CH3, A =
OR3, R3 = CH2CO2H, \~ :
R4 =
HO~C ~ ~

2.6 g of ethyl [1-methyl-3-n-butyl-4-(2'-methoxycarbonylbiphenyl-4-yl)methylpyrazol-5-yl]oxy-acetate, prepared in Example 19, are dissolved in 30 mlof ethanol. 1 g of sodium hydroxide pellets and 10 ml of water are added and the mixture is stirred at room temperature for two hours and then heated for 3 hours at 50-55C. After cooling, the solution is diluted with water and washed with ether and the aqueous phase is acidified by having sulfu.r dioxide bubbled through it and extracted with chloroformO The organic phase is dried over magnesium sulfate and evaporated under vacuum to give a residue which crystallizes from an ethyl acetate/ether mixture to give 2 g of ~1-methyl-3-n-butyl-4-(2'-carboxybiphenyl-4-yl)methylpyrazol-5-yl]oxyacetic acid in the form of crystals melting at153-154 C.

2~38~28 Exampla 38: 1-Methyl-3-n-butyl-~-(4-nitrobenzyl)-5-methoxycarbonyloxypyra201e Formula (I): Rl = n-butyl, R2 = methyl, A =
05 OR3, R3 - Il-OMe, R~ = NO2 o 12 g of 1-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole, prepared in Example 7, are dissolved in 120 ml of 1,2-dichloroethane in ~he presence of 6 ml of triethylamine. 3.3 g of methyl chloroformate are added dropwise and the mixture is stirred for 2 hours at room temperature and then for 4 hours under reflux.
After cooling, the solution is washed with water and then dried over magnesium sulfate and concentrated under vacuum. The oily residue is chromatographed on silica gel in a methylene chloride/acetone eluent t95/5) to give 6.6 g of 1-methyl-3-n-butyl-4~(4-ni~robenzyl~-5-methoxycarbonyloxypyrazole in the form of crystals melting at ~4-47C.
.
Example 39~ ethyl-3-n-butyl-4-~4-aminobenzyl)-5-methoxycarbonyloxypyrazole Formula (XI3: R~ = n-butyl, R2 = methyl, R3 = I-OMe, V = NH2 Prepared by the procedure of Example 21.
oi l used as such for the next step.

~3~2~

Example ~0: 2-E[1-Methyl-3-n~butyl-5-hydroxypyrazol-4 yl]methylphenyl-4-yl]aminocar~onyl-3,6-dichloroben~oic acid 05 Formula (I): Rl = n-hutyl, Ra = methyl, A =
OR3, R3 = H, O Cl NH--C~
R4 =
HOzC Cl Prepared by the procedure of Example 27, start-ing Prom 3,6-dichlorophthalic anhydride.
Crystals melting at 172-174C.

E~ample 41: 2-[~1-EthoxycarbDnyl~ethyl-3-n-propyl-5-hydroxypyrazol-4-yl~methylphenyl-4-yl]-a~inocar~onyl-3~6-dichlorobenzoic acid Form~la (I): Rl - n-propyl, R2 = CH2CO2Et, A Q OR3, R3 = H, NH-C

R -HOlC

Prepared by the procedure of Example 27, start~
ing Prom 3,6-dichlorophthalic anhydride.
Crystals melting at 150-153C.

2~38~L2~

Example 4?: Ethyl ~l-ethoxycarbonylmethyl-3-n-propyl-4-(4-nitrobenzyl)pyx~zol-~5-yl]oxyacetate For~ula (XI): Rl = n-propyl, R2 = CH2CO2Et, 05 R3 = CH2CO2Et, V = NO~

Prepared by the procedure of Example 14.
Oil used as such for the next step.
0 Example 43: Ethyl [l-ethoxycarbonylmethyl-3-n-propyl-4-(4-aminobenzyl)pyrazol-5 yl]oxyacetate Formula (I3: R1 = n-propyl, R2 = CH~CO2Et, A = OR3, R3 = CH2CO2Et, R4 =

Prepared by the procedure of Example 21.
Oil used as such for the next step.

Example 44: 2-[(1-Ethoxycarbonylmethyl-3-n-propyl-5-ethoxycarbonylmethox~pyra~ol-4-yl3methyl-phenyl-4-yl~aminocarbonyl-3,6-dichloro-be~zoic acid Formula (I): R1 = n-propyl, R2 = CH2CO2Et, A = OR3, R3 = CH2Co2Et, O Ct NH--C~
3 0 R" =
HO,C

Prepared by the procedure of Example 27. start-ing from 3, 6-dichlorophthalic anhydride.

2~38~28 Crystals, in the form of the dicyclohexylamine salt, melting at 189-l91~C.

~xample 45- 2-t(l-Methyl-3-n-propyl-~-ethoxycarbonyl-05 methoxypyrazol-4-yl)methylphenyl~4-yl]-aminocarbonylbenzenesulfonic a~id Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, R3 =

NH--C~3 HO,S

Prepared by the procedure of Example 27, but with the cyclic anhydride of orthosulfobenzoic acid.
Crystals meltinq at 203-20sC.

20 Example 46: N-[rl-~ethyl-3-n-butyl-4-(4-nitrobenzyl)-pyrazol-5-yl~oxyacetyl]morpholine Formula (XI): ~1 = n-butyl, R2 = methyl, / \ ' R~ = CHI- C-N O , V = NO2 Prepared by the procedure of Example 14, start-ing from N-tchloroacetyl)morpholine.
Crystals melting at 98C.

Preparation o~ N-(chloroacetyl)morpholine 21.7 g of morpholine are dissolved in 250 ml of methylene chloride and the solution obtained is cooled 2~3~428 with an ice/water mixture.
14.1 g of chloroacetyl chloride are added drop wise with the temperature being kept at 0C, and the mixture is then stirred for 3 hours at room temperature 05 and washed with a dilute solution of hydrochloric acid.
The organic phase is dried over magnesium sulfate and evaporated under vacuum to yive 29.8 g of N-~chloro-acetyl)morpholine in the form of an oil of sufficient purity for the next step.
Example 47: N-[[l-Methyl-3-n-butyl-4-~4-aminobenzyl)-pyrazol-5-yl]oxyacetyl]morpholine Formula (I): Rl = n-butyl, R2 = methyl, A =
~
OR3, R3 = CH~- C-N O, R4 =

Prepared by the procedure of Example 21.
Crystals melting at 130C.

Example 48: N-[tl-Methyl-3-n-butyl-4-[4-(2-sulfo-benzoylamino)benzyl]pyrazol-5-yl]oxy-acetyl]morpholine Formula (I): R1 = n-butyl, R2 = methyl~ A -r~
OR3, R~ = CH,- C-N 0, R4 = ~
~3 HQ~S

~038~2~

Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 236-237C.

05 Example 49: 2-[1-~ethyl-3-n-butyl-4-(4-nitrobenzyl)-pyrazol-5-yl]oxyethanol Formula (XI): R1 = n-butyl, R2 = methyl, R3 = CH2CH20H, V = NO2 12 g of 1-methyl-3-n-butyl-4-(4-nitrobenzyl)-5-hydroxypyrazole, prepared in ~xample 7, are dissolved in 150 ml of butan~2-ons. 4.6 g of sodium carbonate and 6 g of 2-bromoethanol are addad and the mixture is refluxed for 12 hours. After cooling, the solution is concentrated and then taken up with water and the pH is rendered alkaline by the addition of dilute sodium hydroxide solution. After extraction with methylene chloride, the organic phase is dried over magnesium sulfate and then evaporated to dryness. ~he residue obtained is chromatographed on silica gel in an ethyl acetate/acetone eluent (6/4) to give 5 g of 2 methyl-3-n-butyl-4-(4-nitrobenzyl)pyrazol-5-yl]oxy-ethanol in the form of crystals melting at 81C.
Example 50: 2-[1-Methyl-3-n-butyl-4-(4-aminobenzyl)-pyrazol-5-yl]oxy~thanol Formula (I): Rl = n-butyl, R2 = methyl, A =
OR3, R3 = CH2CH20H, R4 = NH2 Prepared by the procedure o~ Example 21.
oi l used as such for the next step.

2~3~

Example 51; 2-~[1-~ethyl-3-n-butyl-5-(2-hydxoxyethoxy~-pyrazol-4-yl~ethylphenyl 4-yl}aminocar-bonylbenzenesulfonic acid 05 Form~la (I): R1 2 n-butyl, R2 - methyl r A =
OR3, R3 = CH2CH20H, O
NH

HO,S
1'.
Prepared by the procedure of Example 27, but using the cyclic anhydride o~ orthosulfobenzoic aci~.
~rystals melting at 170-171C.

Exam~le 52: 1-M~thyl-4-(4-nitrobenzyl)-3-n-propyl-5-(N,N-dimethylcarbamoyl30xypyrazole .
Formula (XI): Rl = n-propyl, R2 = methyl, R = C - N~ , V = NO, CH, I
10 g o~ 1-methyl-~-(4-nitrobenzyl)-3-n-propyl-5-hydroxypyrazole, prepared in Example 8, are dissolved in 100 ml o~ methylene chloride and 5 ml of triethyl-amine. 3.2 ml of N,N-dimethylcarbamoyl chloride are addad dropwise and the mixture is then ref~uxed for 10 hours. A~ter cooling, the mixture is taken up with water and washed with a solution o~ potassium bicarbo-nate. The chloro~orm phase is dried over magnesium sul~ate and then evaporated under vacuum to give 9.1 g o.~ 1-methyl-4-(4-nitrobenzyl)-3-n-propyl-5-(N,N-di-methylcarbamoyl)oxypyrazole in the form of crystals 2~3~2~

melting at 90C.

Example 53: 1-~ethyl-4-(4-a~inobenzyl)-3-n-propyl-5 (N,N-di~ethylcarbamoyl)oxypyrazole ~ormula (~): Rl = n-propyl, R2 = methyl, A = OR3, R3 = C - N~
R4 = NH2 Prepared by the procedure of Example 21.
Crystals melting at 138C.

15 Example 54: 2-[[1-~ethyl-3-n-prop~1-5-(N,N-dimethylcar-ba~oyl)oxypyr~zol-4-yl]methylpheny~-4-yl~-aminocar~onylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 = methyl, CH, A = OR~, R3 = C - N~
O CH, R~ = NH

HO~S ~
Prepared by the procedure of Example 27 u~ing the cyclic anhydride of orthosulfobenzoic acid.
Cry~tals melting at 210-2~C.

2~38428 ~ample 55: 1-~ethyl~3-n-propyl-4-(4-nitrob~nzyl~-5-~,N-diethylcarbamoyl)oxypyrazole Formula (XI): R1 = n-propyl, R2 = methyl, C,Hs R = C--N~ , V = NO2 o C2Hs Prepared by the procedure of ~xample 52.
lo Oil used as such for the next step.

Example 56: 1-Methyl-3-n-propyl-4-[4-amino~enzyl)~5-(N,N-diethylcarbamoyl~oxypyrazole Formula (I): Rl = n-propyl, R2 = methyl, ,c2Hs A = OR3, R3 = C - N~
O C~, R4 = N~2 Prepared by the procedure of Exampl~ 21.
Crystals melting at lOO~C.

~xample 57: 2-[[1-Methyl-3-n-propyl-~-(N,N-diethylcar-bamoyl)oxypyrazol-~-yl]methylphenyl-4-yl]-aminocarbonylbenzenesul~onic acid Formula (I): R1 = n-propyl, R2 = methyl, A = OR3, R~ N~
C2H, o NH--C~

HO~S~

2~3~

Prepared by the procedure o~ Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 216-217C.

05 Example 58: 1-(2,2,2-Trifluoroethyl)-3-n~-propyl-5-(N,N-dimethylcarba~oyl)oxy-4-~4-ni.trobenzyl)-pyrazole Formula (XI): R1 = n-propyl, R2 = CH2CF3, CH, R9 = 11--N~ , V = NO2 o CH, Prepared by the procedure of Example 52.
Crystals melting at 70C.

~x~ple ~ 2~2,2-Trifluoroethyl)-3-n-propyl-5-(N,~-di~ethylcarbamoyl)oxy-4-(4 aminobenzyl)-pyrazole Formula (I): R1 = n-propyl, R2 = CH2CF3, ,CHJ
A = OR3, R3 = Il-N~
O CH, R4 = NH2 Prepared by the procedure of Example 21.
Crystals melting at 82~C.

`` 2~3~2~

Example 60: 2~ (2,2,2-Trifluoroethyl)-3-n-propyl-5-(N,N-dimethylcarbamoyl)oxypyrazol-4-yl]-methylphenyl-4-yl]aminocarbonylbenzene-sul~onic acid ~ormula (I~: Rl = n propyl, ~2 = CH2CF3, A = OR3, R3 = C - N~ , R a NH

HO~S ~
Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 159-161~C.

Ex~mp~e 61~ 1-(2,2,2-Tri~luoroethyl~-3-n-propyl-4-~4-nitrobenzyl)-5-~2-hydroxyethoxy)pyrazole Formula (XI): Rl = n-propyl, R2 = CH2CF3, R3 = CH2CH~o~, V = NO2 . ~
Prepared by the procedure of Example 49.
Crystals melting at 71C.

xa~le 6?: 1-(2,2,2-Trifluoroe~hyl)-3-n-propy~-4-(4-aminobenzyl)-5-(2-hydroxyethoxy)pyra201e For~ula (I): ~1 = n-propyl, R2 = CH2CF3, A - OR3, R3 = CH2CH20H, R4 =

Prepared by the procedure of Example 21.

2~3~2~

- 6~ -Oil used as such for the next step.

Exam~le 63: 2-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-5-(2 hydroxyethoxy)pyrazol-4-yl]me~hylphenyl-05 4-yl]aminocarbonylbenzenesul~onic acid For~ula (I): Rl = n-propyl, R2 = CH2CF3, A = OR3, R3 = C~2~Hz~H, R~ = NH

HO~S ~

Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 211 3C.

Example 64: 1-(2-~sthoxyphenyl)-4-tl-~e~hyl-3-n-propyl 4-(4-nitrobenzyl)pyrazol-5-yl30xyacetyl-piperazine F~rmula ~XI~: Rl = n-propyl, R2 = methyl, CH,O
R9 = C~ C-N N ~ , V = NO~

Prepared by the procedure o~ Example 14, start-ing from l-chloroacetyl-4-(2-methoxyphenyl)piperazine.
Oil used as such ~or the next step.
1-Chloroacetyl-4-(2~methoxyphenyl)piperazine is prepared by the procedure used to synthesize N-chloro-acetylmorpholine, described in Example 460 ~3~

Example 65~ 2-~ethvxyphenyl)-4-[1-methyl-3-n-propy~-4-(4-aminobenzyl)pyrazol-5-yl]oxyacetyl~
piperazine 05 Formula (I): Rl - n-propyl, R2 ~ methyl, A = OR3, CH,O

R3 = CH2- C~N N
R~ = NH2 Prepared by the procedure of Example 21.
Crystals melting at 145C.
Example 66: 1~(2-Metho~yphenyl~-~-E[1-~ethyl-3-n-propyl-4-[4-(2-sulfobenzoylamino)benzyl]-pyraæol-5-yl~oxyacetyl]piperazine Formula (I): Rl = n-propyl, R2 = methyl, A = OR~, CHO
R3 = CH2-C N N~, R~ = NH~3 Prepared by ~he procedure of Example 27 using ~he cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 226-227C.

203~2~

Z: Ethyl 2-(2~-cyanobiphenyl-4-yl)methyl-3-oxohexanoate ~, 05 ~ormula ~V): Rl ~ n-propyl, V =
NC
Rlo = ethyl Prepared by the procedure of Example 6.
Oil used as such for the next step.

Examp~e 68: 1-Me~hyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxypyrazole For~ula (IX): Rl = n-propyl, V =
NC
R2 = met~yl Prepared by the procPdure of Example 7.
Crystals melting a~ 1~4C.

Example 69: Ethyl rl-methyl-~-n-propyl-4-(2'-cyano~i-phenyl-4-yl)methylpyrazol-5-yl]oxyacetate ~or~ula (~ Rl = n-propyl, R2 = methyl, R3 = CH2CO2Et, R4 =
NC
Prepared by the procedure of Example 14.
Oil used as such for the next step.

" ~03~2g Example 70: Ethyl [l-methyl-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl 4-yl]methylpyrazol-5-yl~o~y-acetate 05 Formula (I): Rl = n propyl~ R2 = methyl, A = OR3, R3 = CH2CO2Et, R4 =

N/ =~
N H

11 g of ethyl [1-methyl-3-n-propyl-4-(2'-cyano-biphenyl-4-yl)methylpyrazol-5-yl]oxyacetate, prepared in Example 69, are dissolved in 75 ml of toluene.
6.5 g of trimethyltin nitride are added and the mixture is refluxed for 24 hours. The solvent is evaporated off under vacuum and the residue is chromatographed on silica gel in a chloroform/methanol eluent (9/1) to give 6~7 g of ethyl ~1-methyl-3-n-propyl-4-[2i-(tetra-zol 5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxyacetate in the form of crystals melting at 187-189C.

Exa~ple 71: 1-Methyl-3-n-propyl-5-hydroxy-4-t2'-(tet-razol-5-yl)~iphenyl-4-yl]methylpyrazole Formula (I): Rl - n-propyl, R2 = methyl, A = OH, R4 =
N
N\~N'HN

5 g of 1-methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxypyrazole, prepared in Example 68, ~Q3~4~8 are dissolved in 50 ml of toluene. 4 g of trimethyltin nitride are added and the mixture is refluxed for 14 hours. After cooli~g, ~0 ml of methanol and 10 ml of chloroform are added and the crystals formed are fil-05 tered off and then taken up in 40 ml of ~oluene and 10ml of tetrahydrofuran. Gaseous hydrochloric acid is bubbled through the reaction mixture for 10 minutes and the mixture is then stirred for 1 hour at room tempera-ture. The solvents are ~vaporated off under vacuum and the residue is taken up with a dilute sol~tion of sodium hydroxide and then washed with ethyl acetate.
The aqueous phase is neutralized by having sulfur di-oxide bubbled through it and the residue crystallizes slowly from water ~o give, after washing with acetone, 3.1 g of 1-methyl-3-n-propyl-5-hydroxy-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazole in the form of crys-tals melting at 150-153C.

Example 72: 1-Methyl-3-n~butyl-5-hydroxy-4-[2'-(tet-razol-5-yl)biphenyl-4-yl~methylpyrazole Formula (I): R1 = n-butyl, R~ = methyl, A = OH, R~
N
N~N~H

Prepared by the procedure of Example 71.
Crystals melting at 176-7C.

2~3~28 -- 6g Exa~ple 73: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-5-hydroxy-4-(2'-cyanobiphenyl-4-yl)methyl-pyrazole 05 For~ula (IX)~ Rl = n-propyl, R2 = CH2CF3, \~ .

NC ~

Prepared by the procedure of Example 7, start-ing from 2,2,2-trifluoroethylhydrazine.
Crystals melting at 154C.

Bxample 74: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-5-hydroxy-4-[2'-ttetrazol-5-yl)biphenyl-4-yl]methylpyrazole Formula (I): Rl = n-propyl, R2 = CH2CF3, A = OH, R4 =
N
N\~N'N

Prepared by the procedure of Example 71.
Crystals melting at 218-220C.

Example 75: 2-tl Methyl-3-n-butyl-4-~2'-cyanobiphenyl-4-yl)~ethylpyra~ol-5-yl]oxyethanol Formula (XI): Rl = n-butyl, R2 = methyl, R3 = CH2CH20H~ V ~
NC

.

.~
2~3~2~

Prepared by the procedure of Example 49.
Oil used as such for the next stap.

Example 76~ ~ethyl-3-n-butyl-4-[2~tetrazol-5-05 yl)biphenyl-4-yl]methyl~yrazol-5-yl]oxy-etha~ol Yormula (~): R1 = n butyl, R~ = methyl, A = OR3, R3 = CH2CH20H, R~ =
N

N~H

Prepared by the procedure of Example 70.
Crystals melting at 105-8~C.

Example 77: Ethyl [1-(2,2,2-triflu~roethyl)-3-n butyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl lo~yac~tate Formula (XI): R~ = n-butyl, R2 = CH2CF3, R3 = CH2CO2Et, V =
NC
Prepared by procedure 14.
Oil used as such ~or the next step.

03~2~

Example 78: Ethyl [1-(2,2~ trifluoroethyl)-3 n-~utyl-4-~2'-(tetrazol-5-yl)biphenyl-~-yl]methyl-pyrazol-5~yl]oxyacetate For~ula (I): Rl = n-butyl, R2 = CH2CF3, A =
OR3, R3 = CH~CO2Et, N~
~ _ N''H

Prepared by the procedure of Example 70.
Crystal~ melting at 140 1C.
Example 79: 1-(2,2,2 Trifluoroethyl)-3-n-butyl-4-~2'-cyanobiphenyl-4-yl)meth~1-5-(N,N-di~ethyl-aarb~moyl)oxypyrazole Pormula (XI): R1 = n butyl, R2 = CH2CF3, CH
ll CHJ ~CJ~

Prepared by the procedure of Example 52.
oi 1 used as such for the next step.

203~2~

Example 800 1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-[2'~
(tetrazol-5-yl)biphenyl-4-yl]methyl-5-(~,N-di~ethylcar~a~oyl)oxypyrazole 05 Form~la (I): Rl = n-butyl, R2 = CHzCF3~ A =
CH, OR3, R9 = C - N~ , Il CH, R"
N~ ~/
N~ N
N~ H

Prepared by the procedure of Example 70.
Crystals melting at 151-2C.

Examp~e 81: 1-Met~yl-3-n-butyl-4-(2'-cyanobiphenyl~4-yl~methyl-5-(N,~-di~ethylcarbamoyl)oxy-pyrazole For~ula (XI): Rl = n-butyl, R2 ~ methyl, CH

Prepared by the procedure of Example 52.
Oil used as such for the next step.

, " ' ~ ' ~ .

---` 20~42~

Example 8?: 1-Methyl-3-n-butyl-4-[2'-~tetrazol-5-yl)bi-phenyl-4-yl]~ethyl-5~(N,N-di~ethylcarba-moyl)oxypyra201e 05 Formula (I): R1 = n butyl, R2 = methyl, ~CH~
A = OR3, R3 = C - N~

R.s = ¦ ¦¦

I
N~ ~N
N H

Prepared by the procedure of Example 70.
Crystals melting at 160C.

Examp~e 83: ~thyl [1-(2,2,2-tri~luoroethyl~-3-n~propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol 5-yl~oxyacetate Formula (XI): Rl = n-propyl, R2 = CH2CF3, R3 = CH2C02Et, V =
NC

Prepared by the procedure of Example 14.
Oil used as such ~or the next step.

38~2~

Example 84: ~thyl ~1-(2~2,2-trifluoroethyl~-3-n-propyl-4-[2'-~tetrazol-5-yl)~iphenyl-4-yl]methyl-pyrazol-5-yl]oxyaaetate 05 Formula ~ Rl = n-propyl, R2 = CH2CF3, A = OR3, R3 = C~2CO2Et~
\~
R~ - l IJ
N
N'H

Prepared by the procedure of Example 70.
Crystals melting at 146C.
Example 85~ ethyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-(N,N-dimethylcarbamoyl)oxy-pyrazole Formula (XI~ Rl = n-propyl, R2 = methyl, ~CH, Prepared by the procedure of Example 52.
Oil used as such ~or the next step.

---` 2~13~28 Examp1e 86: 1-Methyl-3~n-propyl-4-~2'-ttetrazol-5-yl)biphenyl-4-yl]methyl-5 (N,N-di~ethyl-carba~oyl)oxypyrazole 05 Formula (I): R = n-propyl, R2 = methyl, CH, A = OR3 ~ R3 = C - N
O CH, p~4= l ll N
N~N~H

Prepared by the procedure of Example 70.
Crystals melting at 103-5C.

Example 87: 2-jl-Methyl-3-n~propyl-4-(2'-cyanobiphenyl-4-yl)~ethylpyrazol-5~yl]oxyethanol ~0 Formula (XI3: Rl = n-propyl, R2 = methyl, R3 = CH2CH2OH, V =
NC
Prepared by the procedure of Example 4~.
Oil used as such for the next step.

, :

`

-`` 2~3~28 Example 88: 2-~l~Nethyl-3-n-propyl~ 2'-~tetra201-5-yl)~iphenyl-~-yl~methylpyrazol-5-yl]oxy-ethanol 05 Formula (I~: Rl = n-propyl, ~2 = methyl, A = OR3, R3 = CH2CH20H, `
~`~
R". =

N~ N
N H

Prepar~d by the procedure of Example 70.
Crystals melting at 120-122C.

Example 89: Ethyl [l-methyl~3-n-butyl-4-(2~-cyanobi-phenyl-4-yl)methylpyra~ol-5-yl]oxyacetate ~ormula ~XI): Rl = n-butyl, R2 = methyl, R3 = CH2~02Et, V =
NC

Prepared by the procedure of Example 14.

Oil used as such for the next step.

-" 2~3~28 Example 90: Ethyl ~l~methyl-3-n-butyl-4-~2'-(tetra~ol-5-yl~biphenyl-4-yl}methylpyrazol-5-yl~oxy-acetate 05 Formula (I): Rl = n-butyl, R2 = methyl, A =
OR3, R3 = CH2CO2Et, R" =
N~
N H

Prepared by the procedure of Example 70.
Crystals melting at 142-3C.

Example 91: 2-[1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-~2'-cyanubiphenyl-4-yl)methylpyrazol-5-yl]-oxyethanol Formula ~XI~: R - n-propyl, R2 = CH2CF3, R3 = CH2C~2OH, V = ¦ ¦¦
NC

Prepared by the procedure of Example 49.
Oil used as such for the next step.

~3$~2~

Example g2: 2~ (2,2,2-Trifluorethyl)-3 n-propyl 4-[2'- r tekrazol-5~yl)biphenyl 4-yl~ethyl-pyrazol-5-yl]oxyethanol 05 Formula ~ Rl a n-propyl, R~ = CH2CF3, A = OR3, R3 = CH~CH20H, R =
N
1 0 N~H

Prepared by the procedure of Example 70.
Crystals melting at 167C.
Example 93~ ethoxyoctane-2,4-dione Formula (III): Rl = n-butyl, R' = CH3 t q = 1 200 ml o~ hexan-2-one and 102 ml of methyl methoxyacetate are added dropwise to ~00 ml of tolu~ne containing 26.9 g of divided sodium, with heating. The temperature during the addition is kept between 60 C
and 70 C. When the addition is complete, the mixture is stirred for 2 hours at 55C. After cooling, 20 ml of methanol are a~ded. The mixture is stirred and then taken up with a dilute solution of sodium hydroxide and the aqueous phase is washed with ether and then acidi-fied with dilute hydrochloric acid and extracted withether. The organic phase is evaporated under vacuum at 30 C after drying over magnesium sulfate and the resi-due is distilled under reduced pressure to give 98.6 g of l-methoxyoctane-2,4-dione in the form of a liquid of 3s b.p.l5 = 115-120C.

-`` 2~3~28 Example 94~ ethoxyhep~ane 2,4-dione Formula (III~: Rl = n-propyl, R' = CH3, q = 1 Prepared by the procedure of Example 93, start-ing from pentan-2-one.
Liquid of b.p. 20 = 100-110 C .

10xample 95: 1-~ethoxy-3-(~-nitroben~yl]heptane-2,4-dione Formula (VI): Rl = n-propyl, R' = CH3, V =
NO~, q = 1 135 g of 1-methoxyheptane-2,4-dione, prepared in Example 94, are dissolved in 1.5 liters of tetra-hydrofuran. 123.3 g of 4-nikrobenzyl bromide, 197 ml of N,N-diisopropylethylamine and 49.5 g of lithium bromide are added and the mixture is refluxed for 15 hours. The solvent is evaporated off under vacuum and the residue is taken up with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase is evaporated to dryness and the crystals obtained are washed with ether several times and then methanol, with heating. The filtrates are combined and evaporated to dryness and the residue is then taken up with isopropyl ether. Tha crystals obtained are washed with isopropyl ether and dried at 30 C under vacuum to give 85.7 g of 3-(4-nitrobenzyl)-1-methoxyheptane-2,~-dione in thle form of crystals melting at 55C.

~ he following two Examples were prepared by the same procedure:

`` 2V38~28 ~xample 96~ ethoxy-3~ cyanobiphenyl-4-yl)~ethyl-heptane-2,4-dione Formula ~VI): Rl = n-propyl, ~ - CH3, V = ~ 3 , q = l NG
Oil used as such for the next step.
Example 97: 1-Methoxy-3-(2'-cyanobiphenyl 4-yl~methyl-octane-2,4-dione Formula ~VI): R1 = n-butyl, R' = CH3, V = ~ , q = 1 NC
Oil used as such for the next step.
Example 98: 3-n-Propyl-4-(4-nitrobenzyl)-5-~ethoxy-methylpyrazole For~ula (XIII): R1 = n-propyl, R' = CH3, q = 1, V = NO2 20 g of 3 (4-nitrobenzyl)-l-methoxyhsptane-2,4-dione, prepared in Example 95, are dissolved in 400 ml of ethanol, 4 ml of hydrazine hydrate are added and the mixture is refluxed for 2 hours. The solvent is evapo-rated off to dryness under vacuum, the residue is taken up with isopropyl ether and the crystals obtained are filtered off to give 19.5 g of 4-~4-nitrobenzyl)-3-n-propyl-5-methoxymethylpyrazole in the form of crystals melting at 124~C.

` 2~38~28 The following two Examples were prepared by the same procedure:

Ex~mple 99: 3-n-Propyl-4-~2'-cyano~iphenyl-4-yl)methyl-05 5-methoxy~ethylpyrazole For~ula (XIII): R1 = n-propyl, R' = CH3, V=~, q=l Oil used as such for the next step.
Example 100: 3-n-Butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-methoxy~ethylpyrazole Formula (XIII): R~ = n-butyl, R' = CH3, v= ~ ,q=l NC ~

Oil used as such for the next step.

Example 10.~ (2,2,~-Trifluoroethyl)-3-n-butyl-4-(2'--cyanobiphenyl-4-yl)methyl-5-methoxy3ethyl-pyrazole Formula (XII3: R1 = n-butyl, R2 = CH2CF~, R3 = CH3, q = 1, ~
V= I I
NC ~

Prepared by the procedure of Example 98, start-ing from 2,2,2-trifluoroethylhydrazine.

.

2~3~42~ `

After chromatography on silica gel in an ethyl acetate/cyclohexane eluent ~2/8), the desired product is obtained in the form of an oil, which is used as such for the next step.

Example 102~ 1-Methyl-3-n-propyl-4-(~-nitrobenzyl)-5-methoxymethylpyrazole Formula (XII): R1 = n-propyl, R2 = methyl, 10R' = methyl, v = N02, q = 1 5 g of 3-n-propyl-4-(4-nitrobenzyl)-5-methoxy-methylpyrazole, prepared in Example 98, are dissolved .in 50 ml of acetone in the presence of 3 ml of methyl 15iodide and 3 ml of DBU ~1,8-diazabicyclo[5.4.0~undec-7-ene). The mixture is heated for 8 hours at 45 C and the solvent is then evaporated off. The residue is ta~en up with dilute hydrochloric acid and then extrac~
ted with ether. The organic phase is dried over mag-nesium sulfate and then evaporated under vacuum to give an oily residue, which is chromatographed on silica gel in an ether/cyclopentane eluent (7/3) to give 2.5 g of l-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-methoxym0thyl pyrazole in the form of crystals melting at 73C.
The following two Examples were prepared by the procedure of Example 102:

2~38~28 xample 103: 1-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl~methyl-s-methoxymethylpyrazole Formula ~XII)~ Rl = n-propyl, R2 = methyl, R' = methyl, V =
NC
q = 1 Oil used as such for the next step.

Example 104: 1-Methyl-3-n-~utyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-methoxymethylp~razole FQr~U1a ~X~ Rl - n-~utyl, R2 = methyl, R~ = methyl, V =
NC~ ~
q = 1 Oil used as such for the next step.

Example 105: 1-Methyl-3-n-propyl-4-(4-aminohenzyl)-5-methoxymethylpyrazole Formula (I). Rl = n-propyl, Ra = methyl, A = CH20CH~, R4 = ~H2 Prepared by the procedure of Example 21.
Oil used as such for the next step.

`` 2 ~

Example 106: 3-n-Propyl-4~ aminobenzyl) 5-methoxy-methylpy~azole Formula (~ = n-propyl, R2 = H, A =
05 CH2OCH3, R~ = NH2 Prepared by the procedure of Example 21.
Crystals melting at 126C.

Example 107: 2-[(1-~ethyl-3-n-propyl-5-~ethoxymethyl-pyrazol-4-yl~methylphenyl-~-yl]aminocar-bonylbenzenesulfonic acid Formula (I): Rl = n-propyl, R2 - methyl, O

A = cH2OCH3, R4 =
HO,S

Preparad by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 126C.

25 ~ sLl~: 2-[(3-n-Propyl-5-methoxymethylpyrazol-4-yl)m~thylphenyl-4-yl]a~inocarbonylbenzene-sulfonic acid Formula ~ Rl = n-propyl, R2 = H, A =
O

CH2OCH3, R~ =
HOJS

`` 2~3~2~

Prepared by ths procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 253-256C.

05 Example 109: 1-Methyl-3-n~prop~1-4-(4-nitr~benzyl~-5-br~momethylpyrazole Yormula (I): Rl = n-propyl, R2 = methyl, A = C~I2Br, R4 = N02 4.5 g of 1-methyl-3~n-propyl-4-(4-nitrobenzyl)-5-methoxymethylpyrazole, prepared in Example 102, are dissolved in 140 ml o chloroform. 2.8 ml of boron tribromide are added dropwise at a temperature of between 0 C and 5 C and the mixture is subsequently stirred for one hour at this temperature and then for 2 hours at room temperatura. A dilute solution o~ sodium hydroxide is added to the mixture and t~e organic phase is decanted, dried and evaporated under vacuum to give 5 g of 1-methyl-3-n-propyl-4-(~-nitrobenzyl)-5 bromo-methylpyra201e in the form of an oil, which is used as such for the next step.

Example 110: 3-n-Propyl-4-(4-nitrobenzyl)-5-bro~o methylpyrazole Formula ~ R - n-propyl, R2 a ~ t A =
CH2Br, R~ = N0z Prepared by the procedure of Example 109.
Crystals melting at 120C.

-`- 2~3842~

Example 111: 1-Methyl-3-n-propyl-4-~4-nitrobenzyl~-5-hydroxymethylpyrazole Formula ~XI~): R1 = n-propyl, R2 = methyl, 05 R' = H, V = N02, q = 1 6.5 g of 1-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-bromomethylpyrazole, prepared in Example 109, are dissolved in a mixture composed of 50 ml of dioxane and 1~ 50 ml of water. 5 g of sodium carbonate are added and the -mixture is refluxed for 3 hours. The solvents are evaporated off under vacuum and the resldue is taken up with water and extracted with ether~ The organic phase is dried over magnesium sulfate and ~hen evaporated under vacuum to give a residue, which crystallizes from isopropyl ether t.o give 3.8 g of 1-methyl-3-n-propyl-4-(4-nitrobenzyl)-5-hydroxymethylpyrazole in the form of crystals melting at 134C~

Exam~le 112: 3-n-Propyl 4-(4-nitrobenzyl~-5-hydroxy-methylpyrazole Formula ~XIII): Rl = n-prcpyl, R' = H, V = N2~ q = 1 Prepared by the procedure of Example 111.
Crystals melting at 125C.

Exam~le 113~ ethyl-3-n-propyl-4-(4-aminobenzyl)-5-hydroxymethylpyrazole Formula (I): R1 = n-propyl, R2 = methyl, A = CH20H, R~ = NH2 Prepared by the procedure of Example 21.

2~3$~28 - ~7 -Crystals melting at 133C.

Example 114: 3-n-Propyl-4-(4-a~ino~enzyl~-5-hydroxy-methylpyrazole Formula ~ R1 = n-propyl, R2 = H, A =
CH20H, R4 = NH2 Prepared by the procedure of Example 21.
Oil used as such for the next step.

Example 115: 2-[~1-Nethyl-3-n-propyl-5-hydroxymethyl-pyrazol-4-yl)~ethylphenyl-4-yl]aminocar-bonylbenzenesulfonic acid For~ula (I): R1 = n propyl, R2 = methyl, o A = CH20H, R4 =
HO,S

Prepared by t~e procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid.
Crystals melting at 255-257C.

Example 116: 2-[(3-n-Propyl-5-hydroxymethylpyraz~1-4-yl)methylphenyl-4-yl]aminocarbonylbenzene-sulfonic acid For~ula (I): R1 = n-propyl, R2 = H, A =
o CH20H, R~ =
HO,S

2~38~2~

Prepared by the procedure of Example 27 using the cyclic anhydride of orthosulfobenzoic acid~
Crystals melting at 168-170C.

05 Example 117: 1-~ethyl-3-n-propyl-~-~2'-~tetrazol-5-yl)biphenyl-4-yl]methyl-5-methoxymethyl-pyrazole Formula ~ Rl = n-propyl, R2 = methyl, A = CH20CH3, R~
r~
N~`N''N

Prepared by the procedure of Example 710 Crystals melting at 128-130C.

~rnlQ~ 1 Methyl-3-n-butyl-4-[2'-(tetra201-5-yl)-~iphenyl-4-yl]methyl-5-me~hoxymeth pyrazole Formula (X): Rl = n-butyl, Rz = methyl, A = CH20CH " R~ =
N
N~ N

Prepared by the procedure of Example 71.
Crystals melting at 134-135C.

` 2~3~28 ~9 le 119~ 2,2,2-Trifluoroethyl~-3-n-butyl~4-~2'-(tetrazol-5-yl)biphenyl~4-yl]methyl-5-~etho~ymethylpyrazole 05 For~la (I): Rl = n-butyl~ R2 = CH2CF~, A = CH2OCH3 ~
r~
N~N,N

Prepared by the procedure of Example 71.
Crystals melting at 172-173C.

15 Example 120: Ethyl 3-oxo-5-~ethylhexanoate ~ormula (II~: R~ = Z-methylpropyl, Rlo =
ethyl Prepared by the procedure of Example 1.
Liquid of b.p.1o = 100-110 C.

Example 121: Ethyl 2-(2'-cyanobiphenyl 4-yl)methyl-3-oxo-5-~ethylhexanoate For~ula ~V): R1 = 2-methylpropyl, Rlo =

ethyl, V =
NC
Prepared by the procedure of Example 6.
Oil used as such for the next step.

`"` ~03~28 Examp~e 122: l~Methyl~3-(2-methylpropyl)-4 (2'-cyano-biph~nyl-4-yl)methyl-5-hydroxypyrazole Form~la (IX): Rl = 2-methylpropyl, R2 ~

methyl, V =
NC~

Prepared by the procedure of Example 7.
Cry~tals melting at 163C.

Example 1~3: 1-(2~2,2-Trifluoroethyl)-3-(2-methyl-pro W 1~-4-(2'-cyanobiphenyl-4-yl)methyl~
5-h~droxypyrazole Formula (IX): Rl = 2-methylpropyl J R2 =

CH2CF3, V = ~3 NC
Prepared by the procedure of Example 7.
Oil used as such for the next step.

~ Example 124: E~hyl ~l~m~thyl-3-(2-methylpropyl)-4-~2~-: 25 cyanobiphenyl~4-yl)methylpyrazol-5-yl]-oxyacetate ~or~ula (XI): Rl = 2-methylpropyl, Rz =
methyl, R~ = CH2CO2Et, V= L 11 NC ~;~"

Prepared by the procedure of Example 14.
Oil used as such for the next step.

- 203~42~

E~ample 125: E~hyl [l-methyl-3-(2-methylpropyl)~4-[2'-(tetrazol-5-yl)biphenyl~4~yl]methylpyra-zol-5-yl~o~yacetate 05 E~or~ula (T): Rl = 2-methylpropyl, R~ =
methyl, A = OR9, R3 =
CH2co2E

Ra~
}O N~

N\~N~H

Preparsd by the procedure of Example 70.
Crystals melting at 172 173C.

~xample 126: Ethyl ~1-(2,2,2-trifluoroethyl)-3-(2-mekhylpropyl)-4-~2'-cyanobiphenyl-4-yl~-methylpyrazol-5-yl]oxyacetate 2~
For~ula (XI): Rl = 2-methylpropyl, R2 ~
CH2CF3, R3 = CH2C02Et, V= ~
NC `~"

Prepared by the procedure of Example 14.
Oil used as such for the next step.

293~2~

g ;~ -- ' Exampla 127: Ethyl L 1- ( 2,2,2-trifluoroethyl)-3-(2-~ethylpropyl)-4-[2'-(tetrazol-5 yl~bi-phenyl-4-yl]methylpyrazol-5-yl]oxyacetate 05 Formula (I): Rl = 2-methylpropyl, R2 =
CH2CF3, A = OR3, R3 =

CH2CO2E~ R4 =

I
N~H

Prepared by the procedure of Example 70.
Crystals melting at 114-115C.
Example 1~: 2-[1-(2,2,2-Tri~luoroethyl)-3-(Z-methyl-propyl)-4-(2'-cyanobiphenyl-4~yl)~ethyl-pyra201-5-yl ]oxyethanol ~ormula ~XI): Rl = 2-methylpropyl, R2 =
CH2CF3, R3 = CH2CH2OH, NC ~
Prepared by the procedure of Example 49.
Crystals melting at 116C.

2~3~

xample 129: 2~ (2,~,2-Trifluoroethyl)-3-(2-~ethyl-propyl~-4-[2'-(tetra201-5-yl)biphenyl-4-yl]methylpyrazol-5-yl~oxyethanol 05 Formula ~ R1 = 2-methylpropyl, R2 =
CH2CF3, A = OR3, ~3 --CH2CH ~OH, R4 =
N~/

N~H

Prepared by the procedure of Example 70.
Crystals melting at 145-146~C.

Example 130: N-~ Methyl~3-n-butyl-4-[4-~2-trifluoro-~methylsulfonylamino~nzoyl~aminobenzyl]-pyra201-5-yl]oxyacetyl]morpholinQ 0 Formula ~ Rl = n-butyl, R2 = methyl, A = OR3, R3 = CH2- C-N 0, R NH ~3 CF,SO2N

4.3 g oP N-[[1-methyl-3-n-butyl-4-(4-amino-benzyl)pyrazol-5-yl]oxyacetyl]morpholine, prapared in Example 47, are dissolved in 20 ml of chloro~orm in the presence of 1.54 ml of triethylamine. A solution of 3.52 g of N-trifluoromethylsulfonylanthranilic acid 2038~28 chloride (prepared according to the references CA :
96(13) : 103651z and CA : 9~(7) : 55500w) in 10 ml of chloroform is added dropwise at room temperature and the mixture is then heated for 2 hours at 50C and left 05 to stand overnight at room temperature. The solution is washed with dilute hydrochloric acid, dried and evaporated under vacuum. The residue is taken up with methylene chloride and extracted with a dilute solution of sodium hydroxide. The aquevus phase is acidified to pH 2 and extracted with ethyl acetate, the organic phase is dried over magnesium sulfate and then evapora-ted to dryness and ths oil obtained crystallizes from ether to give 4.6 g of N-[[1-methyl-3-n-butyl-4-[4-(2-trifluoromethylsulfonylaminobenzoyl)aminobenzyl]pyra-zol-5-yl]oxyacetyl]murpholine in the form of crystals melting at 190C.

Example 131- Ethyl 2- f 2'-nitrobiphenyl-4-yl)methyl-3-oxohexanoate 0 ~ormula (V): Rl = n-propyl, R1o = ethyl, V= 1 11 O,N
Prepared by the procedure of Example 6, start-ing from 2'-nitro-4-chloromethylbiphenyl.
oi l used as such for the next step.
2'-Nitro 4-chloromethylbiphenyl was prepared by chloromethylating 2-nitrobiphenyl according to the following references:
- CA 7Q(25) : 114837d, and - CA 69(2) 3704t.

2~3~

Exam~le 132: 1-Methyl-3-n-propyl-4-(~'-nitrv~iphenyl~
4-yl3~ethyl-5-hydroxypyrazole Formula (IX): Rl = n-propyl, R2 = methyl, 05 ~
V= 1 11 02N~

Prepared by the procedure of Example 7.
Crystals melting at 179-182C.

Example 133: ~e~hyl [1-methyl-3-n-propyl-4-(2'-nitrobi-phenyl-~-yl)methylpyrazol-5-ylJoxyacetat~

Formula ~XI): Rl = n-propyl, R2 = methyl., R3 = CH2CO2Me, R4 =
N~
N/,h N ~

Prepared by the procedure of Example 14.
Oil used as such for the next step~

Example 134: ~ethyl [1-~ethyl-3-n-propyl~~-(2'-aminobi-phenyl-4-yl)m~thylpyrazol-5-yl]oxyacetate Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, R3 = CH2CO2Me, ~, R" =
H2N~/
Prepared by the procedure of Example 21.

2~842~

Oil used as such for the next step.

Example 135: Methyl [l-methyl-3-n-propyl-4-l2~-tri-fluoro~ethylsulfonylaminobiphenyl-4-yl)-05 methylp~r~zol-5-yl]oxyacetate Formula ~ Rl = n-propyl, Ra = methyl, A = OR3, R3 = cH2~O2Me~
\r~ .
P~
CF,SO2NH~/

1 g of methyl [1-methyl-3-n-propyl-4-(2'-aminO-biphenyl-4-yl)methylpyrazol-5-yl]oxyacetate, prepared in Example 134, is dissolved in 30 ml of chloroform in the presence of 0.4 ml of triethylamine; the mixture is cooled to 0C and 0.43 ml of trifluoromethanesulfonic anhydride is added dropwise. The mixture is then stir-red for one hour at room temperature and the organic phase is washed with water, dried over magnesium sul-fate and evaporated under vacuum. The residue o~tained crystallizes from isopropyl ether to give 0.7 g of methyl E1-methyl-3-n-propyl-4-(2'-trifluoromethylsul-fonylaminobiphenyl-4-yl)methylpyrazol-5 yl]oxyacetate in the form of crystals melting at 114-116C.

Example 136: 2-tl-Methyl-3-n-propyl-4-(2'-carkethoxy biphenyl-4~yl3methylpyrazol-5-yl]oxy-ethanol Formula (XI): Rl = n-propyl, R2 = methyl, R9 = CH2CH2OH, V = 11 EtO2C ~ ~

`` 2~3~8 Prepared by the procedure of Example 49.
Oil used as such for the next step.

Example 137: 2-[1-Methyl-3-n-propyl-4-(2'-carboxy-05 biphenyl-4-yl)methylpyrazol-5-yl~oxy-ethanol Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, R3 = CH2CH2OH, Ra =
)~O,C~
Prepared by the procedure of Example 37.
Crystals melting at 168-170C.

Example 138: ~thyl 2-~-(2-cyanothien-3-yl)benzyl]-3-oxohe~anoate Forcula tv): R1 = n-propyl, Rlo = ethyl, V = ~
NC S

Prepared by the procedure of Example 6, start-ing from 4-(2-cyanothien-3-yl)benzyl bromide.

Preparation of 4-t2 cyanothien-3-yl)benzyl bromide A) 3-(4-Methylphenyl)thiophene-2-carboxylic acid g of ethyl 3-~4-methylphenyl)thiophene-2-carboxylate, prepared according to the reference FISSELMANN H.; HABITCH H.; Ger. Offen. 1,092,929 (1960), CA : 57, 5894g, are dissolved in 580 ml of ethanol and 50 ml of water. 6.2 g of sodium hydroxide pellets are added and the mixture is refluxed for 2 hours, poured into water and acidified with concentra-ted hydrochloric acid. The crystals obtained are fil-tered off and dried to give 20.7 g of 3-(4-methyl-05 phenyl)thiophene 2-carboxylic acid in the form of crystals melting at 172C.

B) 3-(4-Methylphenyl~thiophene-2 carboxamide 20.7 g of 3-(4-methylphenyl)thiophene-2-car-boxylic acid, prepared in A), are dissolved in 200 mlof anhydrous toluene with 10.4 ml of thionyl chloride.
The mixture is refluxed for three hours and then eva-porated to dryness. The oily residue is added dropwise to a 28% solution of ammonia at 25C. After stirring for one hour, the mixture is extracted with chloroform and the organic phase is washed with water, dried over magnesium sulfate and evaporated under vacuum to give 18 g of 3-(4-methylphenyl)thiophene-2-carboxamide in the form of crystals melting at 128-130 C.
C) 3-(4-Methylphenyl)thiophene-2-carbonitrile 18 g of 3-(4-methylphenyl)thiophene-2-car-boxamide, prepared in B), are dissolved in 36 ml of phosphorus oxychloride and the mixture is refluxed for one hour. The phosphorus oxychloride is concentrated under vacuum and the residue is taken up in water and ethyl acetate. The oryanic phase is extracted, dried, filtered over animal charcoal and then evaporated under vacuum to give 12 g of 3-(4-methylphenyl)thiophene-2-carbonitrile in the form of an oil, which is used assuch for the next step.

D) 4-(2-Cyanothien-3-yl)benzyl bromide 12 g of 3-(4-methylphenyl)thiophene-2-carbo-nitrile, prepared in C), are dissolved in 100 ml of `` 2~3~2~

carbon tetrachloride. 11.3 g of N-bromosuccinimide and 10 mg of benzoyl peroxide are added. The mixture is refluxed until all the succinimide has come out of solution. ~he crystals are filtered off and the sol-05 vent is concentrated under vacuum to give 16 g o~ 4-(2-cyanothien-3-yl)benzyl bromide in the form of an oil, which is used as such for the next step.

Example 139: 1-~ethyl-3-n-propyl-4-~4-(2-cyanothian-3-yl)benzyl3-5-hydroxypyrazole ~ormula (IX): R~ = n-propyl, R2 = methyl, V = ~3 NC S

Prepared by the procedure of Example 7.
Crystals melting at 110-115C.

Example 140: Ethyl ~ thyl-3-n-propyl-4-~4-(2-cyano-thien-3-yl)benzyl~pyrazoI-5-yl]oxyacetate Form~la (XI): Rl = n-propyl, R2 = methyl, R3 = CH2C02Et, V = ~
NC S/

Prepared by the procedure of Example 14.
Oil used as such for the next step.

~3~
- 1~0 -Example 141: ~thyl ~1-methyl-3-n-propyl-4-[4-[~-(tet-razol-5-yl~thien-3-yl]benzyl~pyrazol-5 yl]oxyacetate 05 For~ula (I): ~1 = n-propyl, R2 - methyl, A = OR3, R3 - CH~CO~Et, R.
N~
N~ ,N
N t~

Prepared by the procedure of Example 71.
Crystals melting a~ 201C.
~xam~le l~: Eth~l 2-t4-(~-carbethoxythien-3-yl)-benzyl]-3-oxohexanoate For~ula (~: Rl - n-propyl, R1o - ethyl, 2~
V= ~3 ~tO~C S
Prepared by the procedure of Example 6, start- 5 i~g from 4-(2-carbethoxythien-3-yl)benzyl bromide.
Oil used as such for the next step.

Preparation of 4-~2-carbethoxythien-3-yl)benzyl bromide 43.4 g of ethyl 3-(4-methylphenyl)thiophene-2-carboxylate, prepared according to the reference FISSELMANN H.; HABITCH; Ger. Offen. 1,092,929 (~960);
CA : 57, 5894g, are dissolved in 250 ml o~ carbon tetrachloride. 33 g of N-bromosuccinimide and 10 mg of benzoyl peroxide are added, the mixture is refluxed for ~03~2~

-- lo~ --one hour, the crystals of succinimide are filtered off and the solvent is evaporated of~ under vacuum to give 56.6 g of 4-(2-carbethoxythien-3-yl)benzyl bromide in the form of crystals melting at 55C.

Example 143: 1-~ethyl-3-n-propyl-~-[4-~2-carbethoxy-thien-3~-yl)benzyl]-5-hydroxypyrazole For~ula (IX): Rl - n-propyl, R2 = methyl, V= ~3 EIO,C S

Prepared by the procedure of Example 7.
Crystals melting at 130-132C.

~BLQ~ 2-tl-~ethyl-3-n-propyl-4-[4-(2-carbeth thien-3-yl)benzyl~pyrazol-5-yl]oxyethanol Fo~m~la (XI): Rl = n-propyl, R~ = methyl, R3 = CH2CH20~, V= ~3 E~02C S
Prepared by the procedure of Example 49.
Oil used as such for the next step.

Example 145: 2-[1-Methyl-3-n-propyl-4-~4--(2-carboxy-thien-3-yl)benzyl]pyrazol-5-yl~oxyethanol Formula (I): R1 = n-propyl, R2 = methyl, A = OR3, R~ = CH2CH20H, 3S V =
HO,C S

-`` 2~3~28 ~ 102 -Prepared by the procedure of Example 37.
Crystals melting at 118-120C.

Example 146: 1-(2-Methoxyphenyl)-4-~1-(2,~,2-triflu~ro-05 ethyl)-3-n-propyl-4-~2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl3oxyacetylpiperazine For~ula (XI~: Rl = n-propyl, R2 = CH2CF3, CH,O
R3 = CH,CO N N

V= ~

Prepared by the procedure of Example 64.
Oil used as such for the next step.

Example I47~ 2-Methoxyphenyl)-4-[1-(~,2,2~trifluoro-ethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl)-biphenyl 4-yl]me~hylpyrazol-5~yl]0xy-acetylpiperazine : 25 Formula (~): Rl = n-propyl, R2 = CH2CF3, A = OR3, R3 = CH2CO N N

CH,O

R~ =

~N_N

::

~138~8 - 1~3 -Prepared by the procedure o~ Example 70.
Crystals melting at 158-160C.

Example 148: N-[~1-(2,2,2-Trifluoroethyl)-3-n-propyl-oS ~-~2'-cyanobiphanyl-4-yl~ethylpyrazol-5-yl]o~yacetyl]~orpholine Formula (XI): Rl = n-propyl, R2 = CH2CF3, R3 = C~O N 3 V= 1 11 NC

Prepared by the procedure of Example 46.
Oil used as such for the next step.

Example 149: N-[[1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl]-m~thylpyrazol 5-yl~oxy~cetyl]morpholine Formula (I): Rl = n-propyl, R2 = CH2CF3, A = OR3, R3 = C~CO N o , R4 =
~N
N N

Prepared by the procedure of ~xample 70 Crystals melting at 129-31C.

- 2~3~28 Example 150: 1-(2,2,2-Trifluoroethyl~-3-n-bU~yl-5-hydroxy-~-~2'-(tetrazol-5-yl)biphenyl-4-yl]methylpyrazole 05 Formula (I): Rl = n-butyl, R2 = CH2CF3, A = OH, ~4 = l ll r~
1 0 N~N~H

Prepared by the procedure of Example 71.
Crystal~ melting at 210-11C.

Example 151: 1-~ethyl-3-n-butyl-~-(2~-cyanobiphenyl-4-yl)~ethyl-5-bromomethylpyrazole Form~la (I): R~ = n-butyl, R2 = methyl, A = CH2Br, Ra =
NC ~

Prepared by the procedure of Example los, starting from the l-methyl-3-n-bu~yl~4-~2'-cyanobi-phenyl~4-yl)methyl-5-methoxymethylpyrazole prepared in Example 104.
Oil used as such for the next step.

" ~3~2~

Example 152: 1-~ethyl-3-n-butyl-~-(2'-cyanobiphenyl-4-yl)~ethyl-5-hydroxymethylpyrazole Formula ~XII): Rl = n-butyl, R2 = methyl, R ' = H, V =
NC~:/
q = 1 ~0 Prepared by the procedure of Example 111, Oil used as such for the next step.

Example 153: 1-Me~hyl-3-n-~utyl-4-[2'-(tetrazol-5-yl~biphenyl-4-yl~ethyl-5-hydroxymethyl pyra201e For~ula (I): Rl = n-butyl, Rz = methyl, A = CH20H, Ra =
N

N~H

Prepared by the procedure o~ Example 71.
Crystals melting at 110-12C.

Example ~54: l-~ethyl-3-n-~utyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-formylpyraxole Formula (I): Rl = n-butyl, R2 = methyl, A = CH0, R4 =
~K:
2.3 g vf 2-nitropropane are dissolved in a ``` 2~3~28 solution of sodium methylate prepared from 0.7 g of sodium and 40 ml of me~hanol. 10 of 1-methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-s-bromomethyl-pyrazole, prepared in ~xample 151, are dissolved in 3005 ml of methanol and this solution is ad~ed dropwise to the reaction mixture. The mixture is stirred for two hours at 50 C, water is then added and the resulting mixture is extracted with ethyl acetate. The organic phase is evaporated to dryness under vacuum and the residue obtained is chromatographed on silica gel to give 4.3 g of 1-methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-formylpyrazole in the form of an oil, which is used as such for the next step.

Example 155: 1-Methyl-3-n-butyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-(dioxolan~2~yl)pyrazole Formula (I): Rl = n-butyl, R2 - methyl, A = C~

R = ~
4.3 g of 1-methyl-3-n-butyl-4-(2'-cyanobi-phenyl-4-yl)methyl-5-formylpyrazole, prepared in Example 154, are dissolved in 50 ml of toluene. 1 g of ethylene glycol and 10 mg of paratoluenesulfonic acid are added. The mixture is brought to the reflux tem-perature and the water is removed for 3 hours by means of a Dean-Stark apparatus. The mixture is subsequently taken up with water and extracted with ether and the extract is then dried over magnesium sulfate and eva-porated under vacuum to give 4 g o~ 1-methyl-3-n-butyl--`` 2~3~

4-(2'-cyanobiphenyl-~-yl)methyl-5-(dioxolan-2-yl)-pyrazole in ths form of an oil, which is used as such for khe next step.

05 Example 15 6: 1-~ethyl-3-n-butyl-4- L 2 ~ - ( tetrazol -5-yl ) -biphenyl-4-yl]methyl-5-(dioxolan-~-yl)-pyrazol~

Formula (I): Rl = n-butyl, R2 = methyl, o A = CH

N~ N
N''H
Prepared by the procedure of Example 70.
Crystals melting at 144 6C.

Example 157: 2-~1-(2,2,2-Trifluoroethyl)-3-n-butyl-4-(2'-cyanobiphenyl-4~yl)methylpyrazol-5-ylloxyethanol ~ormula (XI): Rl = n-butyl, ~z = CH7CF3, R3 = CH2CH20H, V= 1 11 NC ~

Prepared by the procedure of Example 49.
oi l used as such for the next step.

2~3~ 8 Example 158: 2~ (2,2,2-Trifluoroethyl)-3-n-butyl-4-~2'-(tetrazol-s-yl)biphenyl-4-yll~ethyl-pyrazol-5-yl]oxyeth~nQl 05 Formula (I): Rl = n-butyl, R2 = CH~CF~, A = OR3, R3 - CH2CHzOH, R4 =

N~N~N

Prepared by the procedure of Example 71.
Crystals melting at 107-10C.
e_L~: Ethyl 3-oxo-2-[4-(3-cyanothien-2-yl]-banzyl]heptanoate For~ul~ (V): Rl = n-butyl, Rlo = ethyl, ` ~ S

NC ~
1.1 g of ethyl 3-oxoheptanoate, prepared in Example 1, 1.2 g of 4-(3-cyanothien-2-yl)benzyl bro-mide, 0.6 g of lithium bromide and 2.2 ml of diiso-propylethylamine are added to 15 ml of tetrahydrofuran.
The mixture is stirred under reflux for 20 hoursj taken up with water and extracted with ether. The organic phase is dried over magnesium sulfate and then evapora-ted. The excess ethyl 3-oxoheptanoate is evaporated off using a vane pump and 1.5 g of ethyl 3-oxo-2-[4-(3-cyanothien-2-yl)~enzyl]heptanoate are obtained in the form of an oilj which is used as such for the next step.

2 ~ 2 8 Preparation of 4-(3-cyanothien-2-yl)benzyl bromide A) 4'-Methyl-4-chlorobutyrophenone 53 ml of toluene and 70O5 g of 4-chlorobutyroyl 05 chloride are dissolved in 100 ml of methylene chloride and the solution is added at 10C to a suspension of 74 g of aluminum chloride in 200 ml of methylene chlo-rideO The temperature is then allowed to rise for a quarter of an hour and the mixture is treated with iced water. The organic phase is dried over magnesium sul-fate and evaporated under vacuum to give 96.9 g of 4'-methyl-4-chlorobutyrophenone in the form of an oil, which is used as such for the next step.

B) ~-Chloro-B-(2-chloroethyl)cinnamaldehyde 130 ml of phosphorus oxychloride are added slowly, at 0 C, to 130 ml o~ dimethylformamide, and a solution of 117.5 g of 4' me~hyl-4-chlorobutyrophenone, prepared in A), in 50 ml of dimethylformamide is then added dropwise. The mixture is subsequently stirred at room temperature for one hour and then at 50 C for 2 hours and at 70~C for 1 hour. The mixture is then poured on to ice and taken up with ether and the ether phase is washed with a saturated solution of sodium bi-carbonate, dried over sodium sulfate and evaporatedunder vacuum to give 133.8 g of ~-chloro-B-~2-chloro-ethyl)cinnamaldehyde in the form of an oil, which is used as such for the next step.

30C) 2-(4-Methylphenyl)-4 r 5-dihydrothiophene-3-carbox-aldehyde 15.9 g of Q-chloro-B-(2-chloroethyl)cinnam-aldehyde, prepared in B), and 22 g of sodium sulfide (9H2O) are added to 200 ml of THF. A sufficient amount of water is added for all the sodium sulfide to pass 2Q3~28 into solution, and the mixture is subsequently refluxed for 3 hours, cooled and then takan up with ether. The organic phase is decanted, wa~hed with water and then dried over magnesium sulfate and evaporated under 05 vacuum to give 13.5 g of 2-(4-methylphsnyl)-~,s-di-hydrothiophene-3-carboxaldehyde in the form of an oil, which is used as such for the next step.

D) 2-(4 Methylphenyl)-3-cyano-4,5-dihydrothiophene ~0 15 g of 2-(4-methylphenyl)-4,5-dihydrothio-phene-3-carboxaldehyde, prepared in C), and 6.5 g of hydroxylamine hydrochloride are mixed with 40 ml of ethanol and 10 ml of water. A solution of 4.7 g of sodium carbonate in 10 ml of water is added. The mix-ture is stirred at room temperature for half an hour and then ~xtracted with ether. The ether phase is washed with water and ~hen dried over sodium sulfate and evaporated under vacuum to give 15~2 g of a gummy yellow residue. This re~idue is added to 13 ml of acetic anhydride and the mixture warms up slightly, turns brown and becomes liquid. The mixture is sub-sequently refluxed for 1 hour and then poured on to ice and extracted with methylene chloride, the extract is washed with a saturated solution of sodium bicarbonate, the organic phase is then dried over magnesium sulfate and evaporated under vacuum and ~he residue obtained is chromatographed on æilica gel in methylene chloride to give 10 g of 2-(4-methylphenyl~-3-cyano-4,5-dihydro-thiophene in the form of an oil, which is used as such for the next step.

E) 2-(4-Methylphenyl)-3-cyanothiophene 49.9 g of 2-(4-methylphenyl)-3-cyano 4,5-di-hydrothiophene, prepared in D), are dissolved in 200 ml of car~on tetrachloride, the mixture is heated to the 2038~28 reflux temperature and, after two hours, a solution of 11 g of bromine in 200 ml of carbon tetrachloride is added dropwise. Reflux is continued until the evolu-tion of hydrobromic acid has ceas~d, and the solvent is 05 then evaporated off under vacuum. The residue is taXen up in 200 ml of anhydrous tetrahydrofuran, and 28 g of potassium tert-butylate are added. The mixture is re-fluxed for one hour and then cooled, water and sodium chloride are added and the mixture is extr~cted with ether. The organic phase is evaporated under vacuum to give 31.8 g of 2-(4-methylphenyl~-3-cyanothiophene in the form of an oil, which is used as such for the next step.

F) 4-(3-Cyanothien-2-yl)benzyl bromide 24.5 g of 2~(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide and 0.1 g of benzoyl peroxide are added. The mixture is refluxed for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum.
The residue is taken up in a mixture of hexane an~
ethyl acetate and the solution is kept in a refriqera-tor for 24 hours. The crystals formed are filtered off to give 14 g of 4-(3-cyanothian-2-yl)benzyl bromide in the form of crystals melting at ~0C.

Example 160: 1-Methyl-3-n-butyl-4-[4-(3-cyanothien-2-yl)benzyl]-5-hydroxypyrazole Formula (IX): Rl = n-butyl, R2 = methyl, V= ~

-- 2~38~28 1.4 g of ethyl 2-[4-(3 cyanothien-2-yl)benzyl]-3-oxoheptanoate, prepared in Example 159, are dissolved in 10 ~1 o~ ethanol. 2.2 ml of methylhydrazine are added, the mixture is re1uxed for 13 hours, water is 05 added and the resu~ting mixture is extracted with ether and then with ethyl acetate. The organic phases are combined and evaporated under vacuum to give an oily residue, whicht after chromatography on silica gel in a methylene chloride/methanol eluent (95/5), gives 0.8 g 1~ of 1-methyl~3-n-butyl-4-~4-(3-cyanothien-2-yl)benzyl]-5-hydroxypyrazole in the form of crystals melting at 120 C.

Example 161: ~-Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-~,N-diethylcar~amoyl~oxy-pyrazole Formula (IX): R = n-propyl, R2 = methyl, C,H, R3 = ll N~
o C2 ~.
V= 1 1~
NC

Prepared by the procedure of Example 52.
Oil used as such for the next step.

2~38~28 xampl~_162: 1-Methyl-3-n-propyl-~ [2'-(tetrazol-5-yl)-biphenyl-4 yl]methyl-5-(N/N diethylcar-bamoyl)oxypyrazole 05 Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, ,~,H5 R3 = 1I N~
o C2H, R~ =
N
/ \
N~ ~N
N H

Prepared by the procedure of Example 70.
Crystals melting at 134-135~C.

Exam~le 163: N-~[l ~2,~,2-Tri~luoroethyl)-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methylpyrazol-5-yl30xyacetyl]thiomorpholine Formula (XI): Rl = n-propyl, R2 = CH~CF3, R3 = C~CO N S ~

V= 1 11 .
NC

Prepared by the procedure of Example 46, start-ing from N~(chloroacetyl)thiomorpholina.
Oil used as such for the next step.

~`` 2~3~28 Example 164- N-ttl-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-[tetrazol-5-yl)biphenyl-4-yl]methyl-pyrazol-5-yl~oxyacetyl]thio~orpholine 05 Formula ~ R1 = n-propyl, R2 = CH2CF
A = OR3, r~
R~ = CHICO N ~ S, \~ `
R =

N~H

Prepared by the procedure of Example 70.
Crystals melting at 127-128C.

Example 165: 1-(2-Methoxyphenyl)-4-[1-methyl-3-n-propyl-4~(2~-cyanobiphenyl-4-yl)methyl-pyrazol-5-yl]oxyacetylpiperazine ForMula (XI): Rl = n-propyl, R2 = methyl, ~ R3 = CH2CO N ~ N

CHJO
V= ~3 NC

Prepared by the procedure of Example 64.
Oil used as such for the next step.

- 2~3~28 Example 166: 1 ~2-~ethvxyphenyl)-4-[l-methyl-3-n~
propyl-4-~2~-(tetrazol~5-yl~biphenyl-4-yl]m~thylpyrazol-5-yl~oxyacetylpip~razine 05 Formula (I): R1 = n-propyl, R2 = methyl, A = ~3 R3 = CH,C0 N N

lo CH,0 V= l 11 N~/
N~, N
1 5 N~H

Prepared by the procedure of Example 70.
Crystals melting at 139-141C.

Example 167: 3-n-Propyl-l-methyl-4-~2'-cyanobiphenyl~
4-yl)nethyl-5-(2-dimethylaminoethoxy)-pyrazGle Formula ~XI): R1 = n-propyl, R2 = methyl, C~13 R3 = CH2CH2N~
CH, V ~

g of 3-n-propyl-1-methyl-4-(2'-cyano~i-phenyl-4-yl)methyl-5-hydroxypyrazole, prepared in Example 68, are dissolved in 100 ml of butan-2-one in the presence of lO g of sodium carbonate and 8.6 g of 2l338~8 N,N-dimethyl-2-chloroethylamine hydrochloride. The mixture is refluxed ~or 20 hours and then concentrated under vacuum, taken up with water and extracted with ether. The ether phase is washed with water, dried and 05 then evaporated under vacuum. The residue is chromato-graphed on silica gel in a chloroform/methanol eluent ~95/5) to give ~.6 g of 3-n-propyl-1-methyl-4-~2'-cyanobiphenyl-4-yl)methyl-5-(2-dimethylaminoethoxy~-pyrazole in the form of an oil, which is used as such for the next step.

Example 168: 3-n-Propyl-1-methyl-4-[2'-(tetrazol-5-yl)biphenyl-4-yl~me~hyl-5-(2-dimethyl-a~inoethoxy)pyra~ole Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, CH, R3 = C~C~N~
CH, ~, Ra = 1 IJ
N
N~ ~N
N H

Prepared by the procedure of Example 70.
Crystals melting at 88-90C.

' "
2~3~28 Example 169: N-[2-[1-Methyl-3-n propyl-4-~2'-cyanobi-phenyl-4-yl)~ethylpyraxol-5-yl~oxyethyl~-~orpholine 05 Formula (XI): R~ = n-propyl, Ra ~ methyl, r~ .
R~ = C~ CH2N ~ O , V= 1 1 NC~

Prepared by the procedure of Example 167, starting from N-(2-chloroethyl)morpholine.
Oil used as such for the next step.

E~ample 170: N- L 2~ ethyl-3~n-propyl-4-C2'-(tetrazol-5-yl)biphenyl-4-yl]m~thylpyrazol-5-yl~-oxyethyl~morpholine Formula (I): Rl = n-propyl, R2 = methyl, A = OR3, r~
R3 = C~CH2N ~ O , R4 =
/
N~ N
N~H

Prepared by the procedure of Example 70.
Crystals melting at 132-134C.

21~3~8 ~xample 171: 1-(2,2,2-Trifluoroe~hyl) 3-n-~utyl-4-[2'-cyanobiphenyl-4-yl)methyl-5-hydroxymethyl-pyrazola 05 Formula (XII): Rl = n-butyl, Rz = CH2CF3 r R' = H, V = ~ 3 , q = l NC

Prepared by the procedure of Example 111, starting from the 1-(2,2,2-tri~luoroethyl)-3-n~bu~yl-4-(2'-cyanobiphenyl-4-yl)methyl-5-bromomethylpyrazole prepared by the procedure of Example lo9.
Oil uæed as such for the next step.

Exa~ LjL7~: 1-(2~2~2-Trifluoroethyl) 3-n-butyl-4-[2'--(tetrazol-5-yl)~iphenyl-4-yl]methyl-5-hydroxymethylpyrazole F~rmula ~ R~ = n-butyl, R2 = CH2CF3, A = CH20H, R.,~
N~
N\~N~N

Prepared by the procedure of Example 71.
Crystals melting at 114-117C.

-2~8~28 Example 173: 1-(2,2,2-Trifluoroe~hyl~-3-n propyl-4-(2 7 -cyanobiphenyl-4-yl)methyl-5~ethoxym~thyl-pyrazole 05 ~ormula (XII): Rl = n-propyl, R2 = CH2CF3, R' = CH3, ~ = 1, ~ .
V= 1~ IJ
Nc~V
Prepared by the procedure of Example 101.
oi 1 used as such for the next step.

Example 174: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-(tetrazol-5-yl~biph~nyl-4-yl]~e~hyl-5-methoxyme~hylpyrazole Formula (I): R~ z n-propyl, R2 - CH2CF3, A = CH20CH~, ~4 =
N
N\~ ,N

Prepared by the proeedure of Example 71.
Crystals melting at ~77-178C.

2 ~

Example 175: N-[t1-Methyl-3-n-butyl-4-(2'-cyanobi-phenyl-4-yl)methylpyrazol-5-yl]oxyac~tyl]-m~rpholine 05For~ula (XI): R1 = n-butyl, R2 = methyl, r~
R9 = C~CO N ~ O I

V= ~
NC
Prepared by the procedure of Example 46.
Oil used as such for the next step.
Example 176- ~r [1-Methyl-3-n-propyl-4 (2'-cyanobi-phenyl-4-yl~me~hylpyrazol-~-yl~o~yac~t~
morpholine 20Pormula ~XI~- Rl = n-propyl, R2 = methyl, R3 = C~cO N ~ O , V = l 11 NC ~

Prepared by the procadure of Example 46.
Oil us~d as such for the next step.

2~3~'~28 Example 177: N-[[l-~ethyl-3-n-butyl-4-[2'-~tetrazol-5-yl)biphenyl-4-yl~methylpyrazol-5-yl~oxy-acetyl~orpholine 05 Formula (I): Rl = n-butyl, R2 = methyl, A = OR3, ~3 = CH2CO N 3 , R" =

I
N~ ~N
N H

Prepared by the procedure of Example 70.
Crystals meIting at 140-141C.

Exa~ple 178: N-[[l-~ethyl-3-n-propyl-4-C2'-(tetrazol 5-yl)biphenyl-4-yl]methylpyrazol-5-yl]oxy-acetyl]norpholine Formula ~ R~ propyl, ~2 = methyl, A = OR3, A
R~ = C~ ~0 N O , R~ =

N~N~N

Prepared by the procedure of Example 70.
Crystals melting at 106-110~C.

-34~

Example 179: 1-(2,2,2-Trifluoroethyl~-3-n-propyl~4-~2t-cyanobiphenyl-4-yl)~ethyl-5-h~drox~methyl-pyrazole 05 Form~la (XII~: Rl = n-propyl, R2 = CHaCF3 Rt = H, V = X 3 ' q = l NC

Prepared by the procedure of Exa~ple 111, starting from the 1-(2,2,2-trifluoroethyl)-3-n-propyl-4-(2'-cyanobiphenyl-4-yl~methyl-5-bromomethylpyrazole prepared by the procedure of Example 109.
Oil used as such for the next step.

Exam~le 180: 1-(2,2,2-Trifluoroethyl)-3-n-propyl-4-[2'-~tetrazol-5--yl~bipheny:L-4~yl~ethyl-5-hydroxymethylpyrazole ~0 Formula (I3: Rl = n-propyl, R2 = ~H2CF
A = CH20H, ~, R4 = ¦ ~¦
/ ~

N~N'~

Prepared by the procedure of Example 71.
Crystals melting at 110-2C.

2~38~8 xample 1~ Methyl-3-n-propyl-4-(2'-cyanobiphenyl-4-yl)methyl-5-hydroxymethylpyra201e For~ula (XII): R1 = n-propyl, R2 = methyl, R' = H, V =

q = 1 Prepared ~y the procedure of Example lll.
Oil used as such for the next step.

Example 182. l-~ethyl-3-nrpropyl-4-[2'-(~etrazol-5-yl~-biphenyl-4-yl]methyl-5~hydroxy~ethyl-pyrazole Formula (I): Rl = n-propyl, R2 = methyl A - CH2oH~ R4 =
N
N\~N~N

Prepared by the procedure of Example 71.
Crystals melting at 136-9~C.

2~3~2~

Example 183: 1-(2-~e~hoxyphenyl)-4-~1-methyl-3-n-butyl-4-(2'-cyanobiphenyl-~-yl)~ethylpyra201-5-yl]oxyacetylpiperazine 05Formula (XI): Rl = n-butyl, R2 = methyl, CH~O
~
v= 1 11 NC "'~

Prapared by the procedure of Example 64.
15Oil used as such for the next step.

Example 184~ 2-~ethoxyphenyl)-4 [1-methyl-3-n-butyl-4-r2~-(tetrazol-5-yl)biphenyl-4-yl~eth pyrazol-5-yl]oxyacetylp.ip~razine Formula (I): R1 = n-butyl, R2 = methyl, A = OR3, R~3 = CH,CO N ~ N

N--N~ ~N

Prepared by the procedure of Example 70.
Crystals melting at 153-5C.

- 2~38~28 Example 185: N-[[l-Me~hyl-3-n-propyl-4-~2'-cyanobi~
phenyl-4-yl)methylpyrazol-5-yl]oxyacetyl]-thiomorpholin~ -05 For~ula (XI)- R = n-propyl, R2 = methyl, R, = t:H2G N 5, V= ~
~C
Prepared by the procedure of Example 46, s~art-ing from N-(chloroacetyl)thiomorpholine.
Oil used as such for the next s~ep.
Example 186: ~-[[1-~e~hyl-3~n-propyl-4-[2'-~t~tra~ol-5-yl)biphenyl-4-yl]methylpyrazol-5-yl]ox~r-acetyl]thiomorpholine For~ula (I): Rl = n-propyl, R2 - mathyl, A = OR3, r~
R3 = C~C N ~ 5 , R =

N~ N
N~H

Prepared by the procedure o~ Example 70.
Crystals melting at 140-1C.

-" 2038~8 TAE~LE
CH, N--N
~ O CH2 C02 Et 05 Example 27 `~ UP ~21-1 [~H N--N'CH' COOH~~O CH2 CO2 Me P 2~1-6 Example 28 T u ~H CH~
COOH N--N' ~O CH2 CO2 Et Example 29 O ,~3J UP 221-11 ~N
~COOH N N,CH, 2 0 ~O CH2 C 2 Et Exanple 30 ~ ~ UP 221-13 COOH
Cl N N,CH~
~kOCH2CO,Me Cl O ~J
Example 31 ~ J~ UP 221-12 ~COOH
Cl 2~3~2~

rCF, ~ OcH2co2M~
05 Example 32 ¦ UP 221-7 ~N~
H CFJ
~COOH N--N
Cl /~0 CH, CO2 h~e Example 33 O ~ UP 221-4 COOH N-NH
~ ~ OGH2CO2H

Example 34 o ~ UP 221-16 ~ N
~ COOH N-N
~OCH,CO2H

Example 35 ~ ~ UP 221-1 ~ so,HH ,CH~
N--N
~OH
Example 36 ~ UP 221-15 ~ COOH

---" 2~3~2~

,CH, ~` ,~0 CH2 CO, H

05 Example 37 ~ ~J UP 221-17 b~COOH N--N'CH' ,l~OH

Exnmple 40 ~ J UP 2~1-18 COOH N_N CO2Et ~5 ~O~l Example 41 ~ ~0J UP 221-19 2U COOH CO2Et ~~0 CH2 CO2 Et Example 44 ~N~J UP 221-20 l 1I H
~COOH ,CHJ
~ ~, ,4~0 CH2 C02 Et Example 45 O ~ UP 221-21 3 [~N~

SO,H

" 2~38~28 ,CH, ~0 Cl~ C N~O
05 Example 48 ~ UP 221-22 ~N~J
SO,H N--N~CH~
~ ~0CH2CH~OH
Example 51 ,~J UP 221-23 f~N
~SO,H ,CH, ~~0 CO N' Example 54 0 ~ UP ~21-27 ~N
~60,H OCO~

Example 57 0 ,~3J UP 221-28 ~N
1 ll~ H
~V SO,H rCFJ
N--N ,~"
~0 CO N"
Example 60 ~ UP 221-30 SO,H

.
.~ ' ,.

, -` 2~3~28 rCFJ
N--N
~O CH2 CH2 OH
O ~
05 Example 63 ~ ,,l~J UP 221-32 o CH2 C N~

Example 66 ~N~J UP 221-3 3 W `SO,H N--N
~0 CH2 CO2 Et ~

Exampla 70 ~ UP 221-34 ~N~
N
H N -N' ~OH
Example 71 ~J UP 221-43 ~ ll ~N
N~N' CH, H N - N
Exa~nple 72 ~0~ ~ UP 221-59 ~N~
N
N~

` ~038~28 rCF, ~ OH
05Example 74 ~ UP 221-56 ~N CH
~ OCH,CH20H

Example 76 ~ UP 221 57 ~ N~

H~N N-N r CF~
~ OCH2COjEt Example 78 ~ UP 221-54 N
N_~' r CF, ~ N-N CH, ~_~0 CO ~C

Example 80 ~ UP 221-55 ~ ;

,, ~ ~ - ;

-`` 203~2g ~0 CO N~H

05 Example 82 (~/ 13P 221-51 N

H--N'N CF, N~N
~0 CH2 1::0, E~t Example 84 ~J UP 221-44 ,~W
~N

N "N

Bxampl~ 86 ~~OC0 N~ U}? 221-45 @$~
N
H--N' CH, N--N
Example 88 ~OCH2CH~OH UP 221-46 ~,~J

~N
HN--N

- 2~38~2g N N,CH3 ~0 CH, l ;2 Et 05 Example 90 ~J UP 221-47 ,~

~N
H N--N
/~0 CH2 CH, OH
Example 92 ~ UP 221-50 ~

N~ "N ,CH, H N N--N
Example 107 ~OCH~ UP 221-38 ~S0 H ,H

2 5 ~OCH, Example 10~ o ~ UP 221-36 ~NJ~
~SO,H N_N,CH, 3 0 ~C~H

l~xample 115 ~ ~ UP 221-~2 3 5 SO,H

2~3~28 N-N' ~ OH
Example 116 0 ~ UP 221-40 05 ~ N ~

~ OCH, Example 117 ~ UP 221-48 ~
N
N-N' N N,CH, ~ OCH, Example 118 ~ UP 221-52 ~j ` ~ N

H-N N-N ~ CF, ~ OCH, Example 119 ~ UP 221-53 ~ N~
N

Example 125 N_N~ UP 221-58 ~ OCH,CO2Et ~
,~
~N~ .
N

N_N' 2~3~8 -- 135 -~

rCF~
N--N
~ ~--O CH2 CO2 Et Example 127 T UP 221-61 ~N
N_N~

N--N
~O CH2 CH2 OH
Example 129 ~ UP 221-60 ~N~

H N
C~, ~OCH2C N 0 Example 130 ~l UP 221-~5 G~H
NH S02CF~
CH~
N--N
~OCH2COzM~
Example 135 ~l UP 2 21-26 ~

NH SO, CF, 2~38~

CH, N--N
Example 137 ~OCH2CH,OH UP 221-29 05 f~J

CH, N--N
~~ ~0 CH2 CO, Et Example 141 `~ UP 221-35 ~

N~N~r CH, N--N
E~ample 14~ /~0 CH~ CH, ~H UP ~21-39 ~
: ~ , , CO,H

~~ C~C0 N N~

Example 147 ~ UP 221-62 ~N

N~N~N

.

2~38~2~

--CF, ~OCH~CO N~ ~O
Example 149 ¦ UP 221-63 ~N
N "N rCF
n J~OH

Example 150 ,~,J UP 221-64 f~
~N
H~N"N ,CH, Example 153 ~OH UP 221-65 ~J

~N
N "N
H~N ,GHs N--N
O~
Exampl~ 156 ~J UP 221-66 ~N
H~N"N

203~2~

CF, N--N
~---0 CH2 ~H2 OH

Exampla 158 ~3J UP 221-67 05 ~

N , N C2H, /^ ~0CON~

EYaDP1e 162 ~ UP 22L--68 H N N--N ~

Example 164 /~OCH2CO N~S UP 221-69 ~
~r~ h ,CH, C~,O
Example 166 ~/~-OCH2CON N~3 UP 221-70 1~ .
G~
N~,N~,N

38~2~

CH, ~ OCH,CH,N~
Example 168 ~ CH, UP 221-71 0~
~N
N , N CH
~OCHzCH2 N O

Example 170 ~ UP 221-72 ~J

~N
~`N' N--N--CF~
Example 172 ~ Otl UP 221-73 ~

,: HN~N'~N rCF, ~ OCH, Example 174 ¦ UP 221-74 f~
~N
H`N"N

2~33 ~28 ,CH~
N - N ,_~
~O CH2CO N O
~ . ' .
05 Example 177 l ll UP 221-76 ~N
N`N~N CH, N - N / - - ~
~O CH2CO N O
Example 178 J UP 221-77 ~ ',.
W~N

H``N"N
rCF~
N - N
Example 180 ~OH UP 221-78 ~ .' ~ CH, N -N
Example 182 ~OH UP 221-79 ~N
N~N

203~28 ~H, ~ ~ O CH2CO N\lN $~
05 Example 1~4 ~ OCH UP 221-~0 ,~
~N~
N~ "N
H N
,CHJ
N~N ~
Example 186 ~--OCH,CON S UP 221-81 ~N
N`N~N

2~3~28 PHARMACOLOGY

I. Principle 05 The affinity o the products of the Examples for angiotensin II receptors is evaluated ~y the techni~ue of displacing a radioligand specifically ~ound to rat adrenal angiotensin II receptors.

II. Procedure An aliquot of a rat adrenal gland homogenate incubates in the presence of a single concentration of ~`25I]-SIAII (Sarl,Tyr~,Ile~-angiotensin II), which is an angiotensin II receptor antagonist, and two concen trations of competing agents (10-5 M, 10-7 M) for 60 min at 25C.
The reaction is completed by the addition of a buffer, followed by rapid filtration through glasspaper filters. The non-specific binding is determined in the presence of angiotensin II.

III. Expression of the results The results are expressed, for the concentra-tions tested, as the percentage displacement of the radioligand specifically bound to the adrenal angio-tensin II receptors.

20~28 IV. Results _ Product of ~ displacemant of the labeled ligand Example .
05 lE-5 M lE-7 M
_ _ _ _, 29 80 ~0 63 91 ~4 "` 2~3~28 TOXICOLOGY

The products o~ the Examples described have an excellent ~olerance after oral administration~
05Their 50% lethal dose in rats was found to be greater than 300 mg/kg.

CONCLUS ION
~ .
10The products of the Examples described have a good affinity for angiotensin II receptors. In this respect, they will be able to be used bene~icially for the various pathological conditions in which angio-tensin II is involved, in particular in the treatment of arterial hypertension and cardiac insuf~ciency, in dosages of 1 to 400 mg by oral administration and 0.01 to 50 mg by intravenous administration, in one or more dosage units per day.

Claims (16)

1. A pyrazole derivative of the general formula Formula (I) in which:
R1 is a lower alkyl radical having 1 to 6 carbon atoms, a lower alkenyl radical having 2 to 6 carbon atoms or a C9-C7 cycloalkyl radical;
R2 is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower halogenoalkyl radical having l to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)m-COOR5, a group -CH2-(CH2)m-OR5 or a group -CH2-(CH2)m-S-R5, m being an integer from 0 to 5 and R5 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms;
A can be a group:
-(CH2)qOR', R' being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cyclo-alkyl radical and q being an integer from 1 to 5, -(CH2)qL, L being a halogen atom, preferably chlorine or bromine, and q being as defined above, -CHO, an acetal or a dioxolan, -COOR', R' being as defined above, -CONR''R''', R'' and R''' independently being a hydro-gen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attach-ed, a heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine, -CN, -(CH2)q-CN, q being as defined above, -(CH2)q-COOR', R' and q being as defined above, -(CH2)qCONR''R''', R'', R''' and q heing as defined above, -(CH2)qNR''R''', R'', R''' and q being as defined above, or -OR3, R3 being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a C3-C7 cycloalkyl radical, a group -(CH2)n-COOR6, a group -(CH2)-(CH2)n-CN, a group -CH2-(CH2)n-O-R6, a group -CH2-(CH2)n-S-R6 or a group -CO-R6, n being an integer from 0 to 5 and R6 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R3 can be a group -(CH2)p-CONR7R8 or -(CH2)p-CH2-CH2NR7R3, p being an integer from o to s and R7 and R8 independently being a hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms or a C3-C7 cycloalkyl radical, or being able to form, with the nitrogen atom to which they are attached, a hetero-cycle such as pyrrolidine, piperidine, morpholine, thiomorpholine or a piperazine; and R4 can be a nitro or amino group or a group -COOR9, R9 being the hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, or R4 can be the following radicals:

, , , , , , , , , in which R9 is as defined above, X and Y independently being a hydrogen atom, a lower alkyl radical, a halogen atom, an alkoxy radical or a trifluoromethyl radical, and its addition salts, in particular the pharmaceuti-cally acceptable addition salts.

2. A derivative according to claim 1 of formula (I) in which:
R1 is a lower alkyl radical having 1 to 6 car-bon atoms which is preferably selected from n-propyl, n-butyl and 2-methylpropyl;
R2 is the hydrogen atom, a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl, a lower halogenoalkyl radical having 1 to 6 carbon atoms, pre-ferably 2,2,2-trifluoroethyl, or a group -(CH2)m-COOR5, m and R5 being as defined in claim 1, preferably a group CH2-COOEt:
A is a group:
-(CH2)qOR', R' being selected from a hydrogen atom and a lower alkyl group having 1 to 6 carbon atoms, pre-ferably methyl, and q being an integer from 1 to 5, preferably equal to 1, -(CH2)qL, L and q being as defined in claim 1, pre-ferably -CH2Br, -CHO, an acetyl or a dioxolan, or -OR3, R3 being selected from a hydrogen atom, a group -(CH2)n-COOR6 or -CH2-(CH2)n-OR6, n being an integer from 0 to 5, preferably equal to 0 or 1, and R6 being a hydrogen atom or a lower alkyl radical having 1 to 6 carbon atoms, preferably methyl or ethyl, or a group -(CH2)p-CONR7R8, p being an integer from 0 to 5, pre-ferably equal to 0 or l, and R7 and R8 independently being a hydrogen atom or a lower alkyl radical having l to 6 carbon atoms, preferably methyl or ethyl, or R7 and R8, taken together with the nitrogen atom to which they are attached, forming a heterocycle which is pre-ferably selected from morpholine, piperazine and 1-(2-methoxyphenyl)piperazine; and R4 is as defined in claim 1, and its addition salts, in particular the pharmaceuti-cally acceptable addition salts.

3. A derivative according to claim 1 or claim 2, where in R1 is a group selected from n-butyl and n-propyl.

4. A derivative according to any one of claims 1 to 3, wherein R2 is a group selected from methyl and 2,2,2-trifluoroethyl.

5. A derivative according to any one of claims l to 4, wherein A is a group selected from ethoxycarbonyl-methyleneoxy, dimethylaminocarbonyloxy, methoxymethy-lene and 2-hydroxyethoxy.

6. A derivative according to any one of claims 1 to 5, wherein R4 is a group selected from 2-carboxy-3,6-di-chlorobenzoylamino, 2-sulfobenzoylamino and 2-(tetra-zol-5-yl)phenyl.

7. A derivative according to claim 1 which is selected from the derivatives of the formulae

8. A method of preparing the derivatives of formula (I) according to any one of claims l to 7, which comprises reacting a hydrazine of the formula H2N-NH-R2, R2 being as defined above, with a keto-ester of formula (V) or a diketone of formula (VI):

Formula (V) Formula (VI) in which R1, R' and q are as defined above, R10 is a lower alkyl, preferably ethyl or methyl, and V is a functional group selected from NO2; COOR12, R11 being a lower alkyl radical or benzyl;

R12 being a lower alkyl radical or benzyl;

R12 being as defined above; and ; ; R12 being as defined above, or reacting hydrazine hydrate with a diketone of for-mula (VI) as mentioned above, this being followed by alkylation in the presence of DBU (1,8-diazabicyclo [5.4.0]undec-7-ene) with halogenated derivatives of the formula Z-R2, in which R2 is as defined above and Z is a bromine, chlorine or iodine atom.

9. A method according to claim 8, wherein the keto-ester of formula (V) mentioned above is obtained:
- by benzylation of an alkyl 3-oxoalkanoate of formula (II):

Formula (II) in which R1 and R10 are as defined above, with a compound of formula (IV):

Formula (IV) in which W is a halogen atom, preferably chlorine or bromine, and V is as defined above:
- or by condensation of an aldehyde of formula (VII):

Formula (VII) in which V is as defined above, with said alkyl 3-oxoalkanoate of formula (II), followed by catalytic hydrogenation.

10. A method according to claim 8, wherein the diketone of formula (VI) mentioned above is obtained:
- by benzylation of a 1,3-diketone of formula (III):

Formula (III) in which R1, R' and q are as defined above, with a com-pound of formula (IV):

Formula (IV) in which W is a halogen atom, preferably chlorine or bromine, and V is as defined above;
- or by condensation of an aldehyde of formula (VII):

Formula (VII) in which V is as defined above, with said 1,3-diketone of formula (III), followed by catalytic hydrogenation.

11. A synthesis intermediate for the preparation of the derivatives of formula (I) according to any one of claims 1 to 7, useful especially for carrying out the method according to claim 8, said intermediate having formula (V) or (VI):

Formula (V) Formula (VI) in which R1, R10, V, q and R' are as defined above.

12. A synthesis intermediate for the preparation of derivatives of formula (I) according to any one of claims 1 to 7, useful especially for carrying out the method according to claim 8, said intermediate having formula (IX), (XI) or (XII):

Formula (IX) Formula (XI) Formula (XII) in which R1, R2, R3, V, q and R' are as defined above.

13. A pharmaceutical composition which comprises a pharmaceutically effective amount of at least one com-pound of formula (I) according to any one of claims 1 to 7, or one of its pharmaceutically acceptable addi-tion salts, in association with a pharmaceutically acceptable excipient, vehicle or carrier.

14. A pharmaceutical composition with antagonistic activity towards angiotensin II receptors, which com-prises a pharmaceutically effective amount of at least one compound of formula (I) according to any one of claims 1 to 7, or one of its pharmaceutically accep-table addition salts, in association with a pharmaceu-tically acceptable excipient, vehicle or carrier.

15. A method of preparing a pharmaceutical composition, which comprises incorporating a pharmaceutically effec-tive amount of at least one compound of formula (I) according to any one of claims 1 to 7, or one of its pharmaceutically acceptable addition salts, into a pharmaceutically acceptable excipient, vehicle or carrier.

16. A method according to claim 15, wherein the phar-maceutical composition is formulated as gelatin cap-sules or tablets containing from 1 to 400 mg of active ingredient, or as injectable preparations containing from 0.01 to 50 mg of active ingredient.