CA2079343A1 - Substituted pyrazoles, isoxazoles and isothiazoles - Google Patents

Substituted pyrazoles, isoxazoles and isothiazoles

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Publication number
CA2079343A1
CA2079343A1 CA002079343A CA2079343A CA2079343A1 CA 2079343 A1 CA2079343 A1 CA 2079343A1 CA 002079343 A CA002079343 A CA 002079343A CA 2079343 A CA2079343 A CA 2079343A CA 2079343 A1 CA2079343 A1 CA 2079343A1
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Canada
Prior art keywords
methyl
butyl
pyrazole
biphenyl
alkyl
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Abandoned
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CA002079343A
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French (fr)
Inventor
Eric E. Allen
William J. Greenlee
Malcolm Maccoss
Wallace T. Ashton
Stephen De Laszlo
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Merck and Co Inc
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Individual
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Substituted pyrazoles, isoxazoles and isothiazoles of formula (I) are angiotensin II antagonists, and are useful in the treatment of hypertension, ocular hypertension and certain CNS disorders.

Description

,f:~ :.

The compounds of this invention also have central nervous system (CNS) activity. They are useful in the treatment of cognitive dysfunctions including Alzheimer's disease, amnesia and senile dementia. - These compounds also have anxiolytic and antidepressant properties ant are thererore, useful in the relief of symptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental states.
In addition, these compounds exhibit antidopaminergic properties and are thus useful to treat disorders that involve dopamine dysfunction such as schizophrenia.

~ROUND OF T~E INVENTION
Renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and 8eems to be critically involved in hypertension development and maintenance as well as conge8tive heart failure. Angiotensin II (A II), an octapeptide hormone, is produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs, and is the end product of the RAS. A II is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of -his hormone by : .. . ;"

. . , , - ~ ..

WO gl/15479 Pcr/uss1/olss2 ~,~ '7--~
2 ~ 3 -competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lac~ of oral absorption [M. Antonaccio. Clin. Ex~. Hy~ertens. A4, 27-46 (1982); D. H. P. Streeten and G. ~. Anderson, Jr. - ~andbook of Hvpertension, Clinical ~Pharmacology of Antihvpertensive Drugs, ed. A. E.
Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,S76,958; 4,582,847; and 4,880,804; in European Patent Applications 028,834;
245,637; 253,310; 291,969; 323,841; and 324,377; and in articles by A.T. Chiu, ~ 1- tEur- J. Pharm. Exp.
Ih~ , 157, 13-21 (1988)] and by P.C. Wong, ~
~J. Pharm. ~ h~a~. 2~, 1-7(1~88)]. All of the U.S. Patents, European Patent Applications 028,834 and 2S3,310 and the two articles disclose substituted imitazole compounds which are generally bonted through a lower al~yl bridge to a substitutet phenyl. European Patent Application 245,637 discloses terivatives of 4,5,6,7-tetrahydro-2~-imitazo~4,5-~]-pyridine-6-carboxylic acid and analogs thereof as antihypertensive agents.

- . , .
. .

W09ttt5479 PCTt~S9ttO1952 DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention have the general formula (I):

N - K
R6- E--~R3 2)r X
., R2 b~R2R1 (I) wherein:

K is O, S or NR7;

Rl is (a) -Co2R5, (b) -So3R5, (c~ -NHS02(Cl-C4-polyfluoroalkyl), (d) -po(oR5~2, (e) -502-N~-R9, (f~ -CoNHoR5, OH O
( g ) -C--P-oR5, '9 ' 5 W 0 91/15479 PC~r/US91/0195Z

(h) -S02NnI-heteroaryl, (i) -CH2S02NH-heteroaryl, ~ j ) -S02N~I-CO-R23, (k~ -CH2So2NH-Co-R23, ( 1 ) -CoNH-So2R23, (m) -CH2CoNH-So2R23, ( n ) -NHS02N~ICO-R23, (o) -NHCoNHSo2-R23, N-N
P) ~ ,N

N-N
( q) - CHZ 1~N
Rl 1 ( r) CON ~ / ~N
H Rll ( s ) - CONHNHSO2CF3 N-N
( t) N CF3 N_N
( u) ~ NH

(v) ~3 ' "

WO 91/15479 PCl/US91/01952 , . . .
6 ~.~.. ;.... ..

wherein Y is ( 1 ) -Co2R4, (2) -S03R5, (3) -NHso2cF3.
(4~ -Po(oR5)2, (5) -So2NHR9, (6) 1~-tetrazol-5-yl.

O
(x) -P-R23 or oR5 O O
y ) -NHC_p_R23 oR5 wherein heteroaryl i8 an unsubstituted, monosub-stituted or disubstituted r^ive or 8iX membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of 0, N and S and wherein the substituents are members selected from the group coDsisting of -OH, -SH, -Cl-C4-alkyl, -Cl-C4-alkoxy, -CF3, halo, -N02, -C02H, -C02-Cl-C4-alkyl, -NH2, NH(Cl-C4-alkyl), -N(Cl-C4-alkyl)2 and a fused benzo group;

R2a and R2b are independently (a) H, (b) halo, (C) N0 (d) NH2, ~e) Cl-C4-alkylamino, (f) di-(Cl-C4-alkyl)amino (g) So2NHR9, .. .. . . . ~ , .
.~ .
. ~ . , , . . . . .

. ., . ~ , . . . . . ..

wosl/ls47s - PcT/us9l~olss~
~ ~ ~~ 'C V,? . 1 '~; i' . `, (h) CF3, (i) Cl-C4-alkyl, or (j) Cl-C4-alkoxy;

R3a is (a) ~, (b) halo, (c) Cl-C6-alkyl, (d) Cl-C6-alkoxy, or (e) Cl-C6-alkoxy-Cl-C4-alkyl;

R3b iS
(a) H
(b) halo, (C) N02, (d) Cl-C6-alkyl, (e) C2-C6-alkanoyloxy, (f) C3-C6-cycloalkyl, (g) Cl-C6-alkoxy, (h) -N~So2R4, (i) hydrosy-Cl-C4-alkyl, ( j ) aryl-Cl-C4-alkyl, (k) Cl-C4-alkylthio, (1) Cl-C4-alkylsulfinyl, (m) Cl-C4-alkylsulfonyl, (n) N~2, (o) Cl-C4-alkylamino, (p) di(Cl-C4-alkyl)amino, (q) CF3, (r) -S02-N~R9, ( 8 ) aryl or (t) furyl;

. ....................... ~ -- -~, ~

WO 91/15479 P(~r/US91/01952 -- 8 -- f~ J

wherein aryl is phenyl or naphthyl either unsubstituted or subætituted with one, two or three substituents selected from the group consigting of halo, Cl-C4-alkyl, Cl-C4-alkoxy, NO2, CF3, Cl-C4-alkylthio, OH, NH2, -NH(Cl-C4-alkyl), -N(cl-c4-alkyl)2~ -CO2~. -CO2-Cl-C4-alkYl' Cl-C4-polyfluoroalkyl. C3-C6-polyfluorocycloalkyl, and N N
l 11.

H

R4 is H, Cl-C6-alkyl, aryl or -CH2-aryl;

R5 i8 }I, -C~-o-C-R4a, wherein R4a is Cl-C6-alkyl, aryl, or -CH2-aryl;

E is a single bond, -NRl3(CH2)8-, -S(O)x(C~2)8-where x is O to 2 and s is O to S, -CH(OH)-, _o_, --CO--;

R6 i8 Cl-C6-alkyl, C2-Cs-alkenyl or C2-C5-alkynyl each of which can be substituted with a 8ubstituent selected from the group consisting of aryl, C3-C7-cycloalkyl, halo, OH -CF3, -CC13, -NH2, -NH(Cl-C4-alkyl).
-N(Cl-C4-alkyl)2~ -NH-So2R4. -CooR4, -So2NHR9, Cl-C4-alkoxy, or Cl-C4-alkyl-S;

.- --. : . , :, ~ . .

.. . . .

W091/tS479 PCT/US91/o1952 i Z~
_ 9 _ R7 is (a) -H, (b~ Cl-Clo-alkyl;
(c) substituted Cl-C10-alkyl in which one or more substituent(s) is selected from .(1> I, Br, Cl, or F, (2) hydroxy, (3) Cl-C10-alkoxy, (4) Cl-C5-alkoxycarbonyl, (5) Cl-C4-alkylcarbonyloxy, (6) C3-C8-cycloalkyl, (7) aryl, (8) heteroaryl, (9) Cl-ClO-alkyl-S(O)p in which p is O to 2, (10) C3-C8-cycloalkyl-S(O)p, (11) aryl-S(O)p~
(12) 020, (13) carboxy, (14) NR9R9, (15) Cl-C5-alkylaminocarbonyl, (16) di(Cl-C5-alkyl)aminocarbonyl, (17) cyano;
(18) -ocoNR22R23 (19) NR22CoR23 (20) -NR22Co2R23 (21) -N~22coNR22R23 (22) -NR22CON L

- (23) -OCO~_JL wherein L is a single bond, C~2, O, S(O)p or . " ' .

WO91/15479 PCT/US9l/01952 (d) C2-ClO-alkenyl, (e) Cz-ClO-alkynyl, (f) C3-C8-cycloalkyl, (g) substituted C3-C8-cycloalkyl or substituted C3-C8-cycloalkyl-Cl-C4-alkyl having one or more substituents selected from the group:
(1) Cl, Br, F, or I
(2) hydroxy, (3) Cl-C6-alkyl, (4) Cl-C6-alkoxy, (5) Cl-C4-alkylcarbonyloxy, (6) Cl-C5-alkoxycarbonyl, (7) carboxy, (8) oxo, (9) Cl-C5-alkylaminocarbonyl, (10) di(Cl-C5-alkyl)aminocarbonyl, (11) Cl-C4-alkylcarbonyl, and (12) aryl, (h) aryl, or (i) heteroaryl;

R8 is (a) hydrogen, (b) -OH, (c) -N~2, (d) -NH(Cl-C4-alkyl) wherein the alkyl is unsubstituted or substituted with Co2R4, (e) -N(Cl-C4-alkyl)2 wherein one or both of the alkyl groups can be substituted with Co2R4, (f) -NHC02-Cl-C4-alkyl, (g) -NHSOz-aryl, (h) -NHS02-heteroaryl, - - - , :, - ~ . .
- . . . , -~

. ., : ..
. . ~ . . . - .
.

WOgl/15479 PCT/US91/01952 .
~, . ~ . .. ....

(i) -NHS02(Cl-C4-polyfluoroalkyl), ( i ) -C02H, (k) -Co2R5, (1) halo, (m) -CONHS02-aryl, (n) -CONES02-heteroaryl, (o) -CONES02-Cl-C4-alkyl, either unsubstituted or substituted with aryl, -NH2, -NH(Cl-C4-alkyl), -N(Cl-C4-alkyl)2; -0~, -C02H, or CO2(Cl-C4-alkyl), (p) -CONHS02(Cl-C4-polyfluoroalkyl), (q) -CH20H, (r) -CH20CoR4, ( 9 ) -0-Cl-C4-alkyl, (t) -S(O)x-Cl-C4-alkyl, either unsubstituted or substituted with aryl, -N~2, -N~(Cl-C4-alkyl), -N(Cl-C4- alkyl)2, -OH, -C02H, or C02(Cl-C4-alkyl), (u ) -S02NHR21, (v) -CN, (w) tetrazol-5-yl, (x) N-N
-CONnH l ~N
H

(y) -CH2Co2R4;
R9 is H, Cl-C5-alkyl, aryl or -CH2-aryl;
R10 is H, Cl-C4-alkyl;

.

::: !
~: ' ,.: :

WO9t/15479 PCT/US91/01952 "~ . 3 - ~

Rll iS ~I, Cl-C6-alkyl, C2-C4-alkenyl, Cl-C4-alkoxy alkyl, or -CH2-C6~4R20;
R12 is -C~, -NO2, -Co2R4, or -CF3;
3 is H, C2-C4-alkanoyl, Cl-C6-alkyl, allyl, C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, Cl-C8-alkyl, Cl-C8-perfluoroalkyl, C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, Cl-C6-alkyl;
R16 is , H, Cl-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl;
Rl7 iS -NR9R10, -OR10, -NHCONH2, -NHCSNH2, -NH~02 ~ H3 or -NHSO2 ~ ;

R18 and R19 are independently Cl-C4-alkyl or taken together are ~(CH2)q~ where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3;
R21 i8 (a) -CO-aryl, (b) -CO-Cl-C4-alkyl, (c) -COCF3, (d) -CO-heteroaryl, or (e) heteroaryl;
R23 i8 (a) aryl, (b)~ heteroaryl, (c) C3-C7-cycloalkyl, (d) Cl-C6-alkyl either unsubstituted or substituted with aryl, heteroaryl, -O~, -SH, Cl-C4-alkyl, C3-C7-cycloalkyl, -O(Cl-C4-alkyl), , . , . . . .
.; - ~ ..
.
,., ~ . -., ~ ;, . . .
., . . ~ , . ..

?~ - 13 --S(Cl-C4-alkyl),-CF3, halo, -N02, -C02H, C02-Cl-C4-alkyl, -NH2, MHaryl, N(aryl)2, -NH(Cl-C4-alkyl), .A _N(cl-c4-alkyl)2~ ~P03~--PO(OH)(O-Cl-C4-alkyl), or -N(C~2C~2)2L wherein L is 9ingle bond, -C~2-, -O-, -S(O)p, or NR9; and (e) polyfluoro-Cl-C4-alkyl;

X is (a) a carbon-carbon single bond, (b) -CO-, (c) --o--, (d) -S-, (e) -N-, (f) -CON-, (g) -NCO-, (h) -OC~2-, ( i ) -CH20-( j ) -SCH2-, (k) -CH2S-, (1) -N~IC(R9)(R10) (m) -NR9So2_, (n) -So2NR9_, (o) -C(R9)(R10)NH-, ( p ) -C~=C~-, (q) -CF=CF-, (r) -C~=CF-, -: . . .

.: ~ ... : .

W091/15479 PCTtUS91/01952 ~,f ~.~'7 ~ ~
., ' (s) -CF=CH-, (t) -CH2CH2-, (U ) -CF2CF2-, (v) C 1 or j ,CH2 pR14 (w) --C~--, OCORl6 (x) -CH-, (y) -C-, or R180 oR19 : (Z) --C--; ~

Z is O, NR13 or S;
r iE l or 2; and the pharmaceutically acceptable salts thereof.

The terms "alkyl", "alkenyl", "alkynyl: and the like include both the straight chain and branched chain species of these generic terms wherein the number of carbon atoms in the species permit. Unless otherwise notet, the specific names for these generic ~terms,shall mean the straight chain species. For e w mple, the term "butyl" ~hall mean the normal butyl substituent, n-butyl. The term "halo" means Cl, Br, I or F.
, One em~odiment of the compounds of formula (I) are those compounds wherein K 18 -O-.

' . ' ' ' ~
:

,.. , ~,, . , ,, , . ~ . . . -WO 9tt15479 PCr/US91/Ot952 z~

A class of compounds within this embodiment is that wherein:

N--N
Rl i s -COOH ~ NH-so2cF
H

-So2NH-Co-RZ3, -S02N~I-heteroaryl, ~502NH aryl, or -CoNHso2R23, R2a and R2b are E, F, Cl, CF3, Cl-C4-alkyl or Cl-C4-alkoxy;
R3a i~ E, F or Cl;
R3b is E, F, Cl, CF3, Cl-C4-alkyl, Cl-C4-alkoxy, -COOCE3, -COOC2Hs, -S02-cH3~ NH2 -N(Cl-C4-alkyl)2 or -NE-S02C~3;

E is a single bond, -O- or -S-;
R6 is (a) Cl-C5-alkyl either unsubstituted or substituted with a substituent selected f rom the group consisting of Cl, CF3, CC13, -0-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl;
(b) C2-C5-alkenyl or C2-C5-alkynyl;

X is a C-C single bond; and, r lS one.

.. . ;
~ ~. . ...

, ~, ~ ,. . .

WO 91/tS4~9 2i~ PCT/US91/Ot952 , ., ~

In a pre~erred class of this embodiment are those compounds wherein:

E is a single bond or -S-;
r is one, R2a R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -C~3, -C~2CH3, or -C~2-S-c~3;
R8 is -C02RS, -CONHS02aryl, -CON~S02(Cl-C4-alkyl), or CONH-SO2-cyclopropyl, -N~SO2(Cl-C4-polyfluoroalkyl), -S(O)x-(Cl-C4-alkyl)-aryl, -N~SO2aryl, or -NHSO2-heteroaryl;
Rl is -COO~I, -S02NH-heteroaryl, -S02NH-aryl, N--N
l~ ~N -CON~IS02R23 I
H
-N~-S02-CF3, or So2N~CoR23;
R23 is aryl, -N(aryl)2, C3-C7-cycloalkyl, Cl-C6 alkyl, either unsubstituted or substituted with 1) C3-C7 cycloalkyl, 2) polyfluoro, or 3) two aryl groups, and X is a single bond.

Exemplifying this class are the following compounds:

(1) Ethyl 3-butyl-4-~2'-(5-tetrazolyl)biphenyl-4-yl]methyl~isoxazole-5-carboxylate ,. . i ~ . ...

.. - , ~ - ,. i .

.n ~ ~3 (2) 3-Butyl-4-~t2'-(5-tetrazolyl)biphenyl-4-yl]-- methyl]isoxazole-5-carboxylic acid (3) 4-tt2l-(N-Benzoylsulfamoyl)biphenyl-4-yl]
methyl]-3-butylisoxazole-5-carboxylic acid (4) 3-Butyl-4-tt2'-[N-(trifluoroacetyl)sulfamo-yl]biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (5) 3-Butyl-4-t[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid ~6) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (7) 4-~[2~-[N-(Diphenylacetyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisoxazole-5-carboxylic acid (8) 3-Propyl-4-~2'-(5-tetrazolyl)biphenyl-4-yl]
methyl]isoxazole-5-carboxylic acid (9) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propylisoxazole-5-carboxylic acid (10) 4-[[2'-~N-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisoxazole-5-carboxylic acid (11) 3-Propyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid - (12) 5-~N-(Benzenesulfonyl)carbamoyl]-3-butyl-4-~2'-(tetrazol-5-yl)biphenyl-4-yl]methyl~-isoxazole (13) 3-Butyl-4-~2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-isoxazole - .
.. ~ , , .

': -:
. , W091/154~9 PCT/US91/01952 (14) 3-Butyl-5-(pentafluoroethanesulfonamido)-4-[[2~-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (15) 4-~[21-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butyl-5-(trifluoromethanesulfon-amido)isoxazole (16) 3-Butyl-4-t[2'-[N-(cyclopropanecarbonyl)-sulfamoyl~biphenyl-4-yl]methyl-5-(trifluoro-methanesulfonamido?isoxazole (17) 3-Butyl-5-(trifluoromethanesuifonamido)-4-~2'-(trifluoromethanesulfonamido)biphenyl-4-yl]methyl]isoxazole (18) 3-Propyl-4-~[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-isoxazole (19) 5-(Pentafluoroethanesulfonamido)-3-propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (20) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl~-3-propyl-5-(trifluoromethanesulfon-amido)isoxazole (21) 4-[[2~-[N-(Cyclopropanecarbonyl~sulfamoy}]-biphenyl-4-yl]methyl]-3-propyl-5-(trifluoro-methanesulfonamido)isoxazole (22) 3-Butyl-5-(4-chlorobenzylsulfinyl)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (23) 3-Butyl-5-(2-carboxybenzylthio)-4-[~2~-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole - - ,, WO9t/15479 PCT/US91/01962 (24) 3-Butyl-5-tN-(isopropylsulfonyl)carbamoyl]-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-isoxazole (25) 3-Butyl-5-[N-(cyclopropanesulfonyl)car-bamoyl]-4-~C2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isoxazole ~26) 3-Butyl-5-(4-fluorobenzenesulfonamido)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-isoxazole (27) 3-Butyl-5-<3-pyridinesulfonamido)-4-[~2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isoxazole Another embodiment of the compounds of formula (I) is that wherein K is S.

A class of compounds within that embodiment are those compounds wherein N--N
--~ "
Rl i 8 1 -NlI-S02CF3 ~ C2~ ' -So2NH-CoR23, -S02N~-heteroaryl, -S02NH-aryl, or -CoNHSo2R23;

R2a and R2b are H, F, Cl, CF3, Cl-C4-alkyl or Cl-C4-alkoxy;
R3a is ~. F or Cl;

. .
, ..
.

,: ~,, - ~ ' ., ' .

.
wos1/ts479 ~t~ 3 PCT/US91/01952 .~........................... ,~, R3b is H, F, Cl, CF3, Cl-C4-alkyl, C5-C6-cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(Cl-C4-alkyl)2 or -NH-S02CH3;
E is a single bond, -O- or -S-;
R6 is (a) Cl-C5-alkyl either unsubstituted or substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, O CH3~ -OC2H5- -S-CH3, -S-C2Hs or phenyl;
(b) C2-C5-alkenyl or C2-C5-alkynyl;

X is a C-C single bond; and, r i8 one.

In a preferred class of this embodiment are those compounds wherein:

E is a single bond or -S-;
r i8 one, R2a R2b, R3a and R3b are each H;
R6 i8 n-propyl, n-butyl, -CH3, -CH2CH3, or -CH2-S-CH3;
R8 iS -C02R5, -CONHS02aryl, -CONHS02-(Cl-C4-alkyl), -CON~IS02-cyclopropyl, -NRS02(Cl-C4-polyfluoroalkyl), S()x~
:: (Cl-C4-alkyl)aryl, -NHSO2-aryl, or -N~SO2-heteroaryl;
Rl is -COOH, S02NH-heteroaryl, -S02NH-aryl, ' ,::

N-N
~N ~ -CoNHSo2R23 I

H

NH-S02-CF3, or -So2N~CoR23;
R23 is aryl, polyfluoro-Cl-C4 alkyl, C3-C7 cycloalkyl or Cl-C4 alkyl(aryl)2; and X is a single bond.

Exemplifying this class are the following compounds:

(1) Ethyl 3-butyl-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isothiazol~-5-carboxylate (2) 3-Butyl-4-t~2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isothiazole-5-carboxylic acid (3) 4-~t2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butylisothiazole-5-carboxylic acid (4) 3-Butyl-4-tt2'-tN-(trifluoroacetyl)sulfamo-yl]-biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (5) 3-Butyl-4-~t2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (6) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid - . :

. , , ~, . . ~ . . ~ , - :. ,, .. : . .,.. ,.~;,. .. ...

wos1/15479 PCT/~S91/019SZ

~ . .

(7) 4-[[2~-~N-(Diphenylacetyl)sulfamoyl]biphen-yl-4-yl]methyl]-3-propyligothiszole-5-carboxylic acid (8) 3-Propyl-4-~2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isothiazole-5-carboxylic acid (9) 4-~2~-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propylisothiazole-5-carboxylic acid (10) 4-tt2'-tN-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisothiazole-5-carboxylic acid (11) 3-Propyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (12) 5-tN-(Benzene8ulfonyl)carbamoyl]-3-butyl-4 ~t2~-(tetrazol-5-yl)biphenyl-4-yl~methyl]
isothiazole (13) 3-Butyl-4-tt2'-(tetrazol-5-yl)biphenyl-4-yl]methyl~-5-(trifluoromethanesulfonamido)-isothiazole (14) 3-Butyl-5-(pentafluoroethanesulfonamito)-4-t~2'-(tetrazol-S-yl)biphenyl-4-yl]methyl]-isothiazole (15) 4-tt2l-(N-Benzoylsulfamoyl)biphenyl-4-yl]
: methyl~-3-butyl-5-(trifluoromethanesulfon-amido)isothiazole (16) 3-Butyl-4-tt2'-tN-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl-s-(trif methanesulfonamide)isothiazole .

- ~ . ,~ . - . ~, .. .. . ..

WO91/15479 PCT/US91/Ot952 ~ 23 ~

(17) 3-Butyl-5-(trifluoromethane~ulfonamido)-4-t[2'-(trifluoromethanesulfonamido)biphenyl-4-yl]methyl]isothiazole (18~ 3-Propyl-4-~[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido~-isothiazole (19) 5-(Pentafluoroethanesulfonamido)-3-propyl-4-[~2~-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (20) 4-[~2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propyl-S-(trifluoromethanesulfon-amido)isothiazole (21) 4-~t2~-~N-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propyl-5-(trifluoro-methanesulfonamido)isothiazole (22) 3-Butyl-5-(4-chlorobenzylsulfinyl)-4-tt2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (23) 3-Butyl-5-(2-carboxybenzylthio)-4-Ct2'-(tetrazol-S-yl)biphenyl-4-yl]methyl]-isothiazole (24) 3-Butyl-5-tN-(isopropylsulfonyl)carbamoyl]-4-[t2'-(S-tetrazolyl)biphenyl-4-yl]methyl]-isothiazole (25) 3-Butyl-5-[N-(cyclopropanesulfonyl)car-bamoyl]-4-tt2'-(5-tetrazolyl)biphenyl-4-yl]-methyl~isothiazole (26) 3-Butyl-5-(4-fluorobenzenesulfonamido)-h-[t2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-isothiazole ~27) 3-Butyl-5-(3-pyridinesulfonamido)-4-~2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isothia-zole ~, , ., , ~ ~ ' :, ', ': :~: .'` ' :
~: "' ' ." :
': ' . ; ~ ~ ~ ' ., ' ' :
WOs1/1s479 ~ PCT/US91/01952 .. .. ..
. ..

Another embodiment of the novel compounds of formula (I) is that wherein K=NR7.

A class of compounds within this embodiment is that wherein:

N
~,N, Rl i S -COO~, H -N}I-so2cF3, -502NHCoR23, -S02N~-heteroaryl, -S02N~-aryl, or -CoN~So2RZ3;

R2a and R2b are ~, F, Cl, CF3, Cl-C4 alky Cl-C4-alkoxy;
R3a is ~ ~, F or Cl;
R3b is ~. F, Cl, CF3, Cl-C4-alkyl, C5-C6-cycloalkyl, -COOC~3, -COOC2H5, -S02-CH3, NH2, -N(Cl-C4-alkyl)2 or -NH-S02CH3;
E is a single bond, -0- or -S-;
R6 i9 - (a) Cl-Cs-alkyl either unsubstituted or substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -0-CH3~ -OC2H5~ -S-CH3, -S-C2Hs or phenyl;
(b) C2-Cs-alkenyl or C2-C5-alkynyl;
R7 and R8 are as defined above;

.

, . . .. . . . .

~ ~ . . . .
.. .: - . , ~

: `' :

wos1/ls479 PCT/US91/01952 ..

X is a C-C single bond; and, r is one.

In a preferred class of this embodiment are those compounds wherein:

E is a single bond or -S-;
r is one, R2a R2b, R3a ant R3b are each ~;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or -CH2-S-C~3;
Rl is -COOH, -502NH-heteroaryl, -S02NH-aryl, -CoNHSo2R23, -S02N~IS02R23 N--N
~ , ' ~, , H

-N~-S02-CF3, or -502N~CoR23; and R7 i8 H, aryl-Cl-ClO-alkyl, polyfluoro-Cl-C4-alkyl-, heteroaryl, or aryl either : . unsub6tituted or substituted with one or two substituents selected from -Cl, -CF3, -CH3, -OCH3 and -N02;
R8 is -Co2R5, -CONE~502aryl, -CON~S02-: (Cl-C4-alkyl),-CONHS02-cyclopropyl,-NHS02-(Cl-C4- polyfluoroalkyl),-S(O)x-(Cl-~ 4-alkyl~-aryl, or -NHS02-aryl, or N~S02-~: ;; . heteroaryl;
R23 is aryl, -N(aryl)2, C3-C7-cycloalkyl, Cl-C6 alkyl, either unsubstituted or substituted . with l) C3-C7 cycloalkyl, 2) polyfluoro, or : 3) two aryl groups, and ,,, . - -. - -. -,,:, . . :

,. , -, wosl/ls479 PCT/US9l/01952 2 5 ,~

X is a single bond.

Exemplifying this class are the following compounds:

(1) 5-Amino-3-butyl-4-[(2~-carboxybiphen-4-yl)-methyl]-l-phenylpyrazole;
(2) 5-Amino-3-butyl-1-phènyl-4-~(2'-(tetrazol-5-yl)-biphenO40yl)methyl~pyrazole;
(3) 3-Butyl-5-hydroxy-1-phenyl-3-t(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(4) 3-Butyl-5-carboxy-1-phenyl-4-'[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(5) 3-Butyl-5-carbomethoxy-1-phenyl-4-[(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(6) 3-Butyl-5-hydroA~ethyl-l-phenyl-4-t(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(7) 3-Butyl-1-(2-chloro)phenyl-3-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-5-hydroxymethyl-pyrazole;
(8) 1-(2-Chloro)phenyl-5-hydroxymethyl-3-propyl-4-~ ~(2~-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
: . (9) 3-Butyl-5-carbo y -1-(2-chloro)phenyl-4-t(2~-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(10) 3-Butyl-5-carbomethoxy-1-(2-methyl)phenyl-4-~(2l-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(11) 3-Butyl-5-carbomethoxy-1-(2-nitro)phenyl-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(12) 3-Butyl-5-carbomethoxy-1-(2-trifluoromethyl~-phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
(13) 3-Butyl-5-carbomethoxy-1-(2-chloro-4-methoxy)-phenyl-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
~, - , . .. .....

.. , . .. . ~ : - . .

`::
(14) 3-Butyl-5-carbomethoxy-1-propyl-4-~(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
~15) 3-Butyl-5-carbomethoxy-1-isobutyl-4-~(2l-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(16~ 3-Butyl-5-carbomethoxy-1-pentafluoroethyl-4-[(2~-(tetrazol-5-yl)biphen-4-yl)methyl~pyrazole;
(17) 3-Butyl-5-carbomethoxy-1-cyclohexylmethyl-4-t(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(18) 3-Butyl-5-carbomethoxy-1-dimethylaminomethyl-4-~(2l-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(19) 3-Butyl-5-acetamido-1-(2-chloro)phenyl-4-~(2'-(tetrazol-5-yl)biphen-4-yl>methyl]pyrazole;
(20) 3-Butyl-1-(2-chloro)phenyl-4- r ( 2'-(tetrazol-5-yl)biphen-4-yl)methyl]-5-trifluoromethylsulfon-amidopyrazole;
(21) 3-Butyl-1-(2-chloro)phenyl-5-dimethylamino-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(22) 3-Butyl-1-(2-chloro)phenyl-S-propylamino-4-t(2~-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(23) 3-Butyl-1-(2-chloro)phenyl-5-methoxy-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(24) 3-Butyl-1-(2-chloro)phenyl-5-propyloxy-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(25) 3-Butyl-1-(2-chloro)phenyl-5-methylsulfinyl-4-~(2~-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(26) 3-Butyl-1-(2-chloro)phenyl-5-methylsulfonyl-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(27) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-carbo~-4-{(2~-(N-cyclopropanecarbonyl)sulfonamidobiphen -4-yl)methyl]pyrazole;

.' !

W09t/l5479 PCT/US91/01952 (28) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-carbethoxy-4-~(2'-(N-cyclopropanecarbonyl)-sulfonamidobiphen-4-yl~methyl]pyrazole;
(29) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-trifluoromethanesulfonamido-4-[(2'-(N-cyclo-propanecarbonyl)sulfonamidobiphen-4-yl)methyl~-pyrazole;
(30) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-pentafluoromethanesulfonamido-4-t(2'-(N-cyclo-propanecarbonyl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(31) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboxy-4-t(2'-(N-cyclopropanecarbonyl)sulfon-amidobiphen-4-yl)methyl]pyrazole;
(32) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboethoxy-4-t(2'-(N-cyclopropanecarbonyl)-sulfonamitobiphen-4-yl)methyl~pyrazole;
(33) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-tri-fluoromethanesulfonamido-4-t(2'-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;
(34) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-penta-fluoroethanesulfonamidosulfonamido-4-[(2'-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)-methyl]pyrazole;
(35) 3-Butyl-1-(2,6-tichlorophenyl)-5-carboxy-4-t(2l-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)-methyl]pyrazole;
(36) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboetho~
t(2'-(N-cyclopropanecarbonyl)sulfor~amidobiphen-4-yl)-methyl]pyrazole;
(37) 3-Butyl-1-(2,6-dichlorophenyl)-5-trifluoro-methanesulfonamido-4-t(2'-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;

W O 91/15479 P~r/US91/01952 Z~,~: ~ ~ ......
(38) 3-Butyl-1-(2,6-dichlorophenyl)-S-pentafluoro-ethanesulfonamido-4-[(2~-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;
(39) 3-Butyl-l-(trifluoromethyl)phenyl)-S-carboxy-4-~(2~-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(40) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carboethoxy-4-[(2'-~N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(41) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-trifluoromethanesulfonamido-4-~(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(42) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-pentafluoroethanesulfonamito-4-t(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(43) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-carboxy-4-t(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(44) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-carboethoxy-4-t(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(45) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-trifluoromethanesulfonamido-4-~(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyI]-pyrazole;
(46) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-pentafluoroethanesulfonamido-4-t(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(47) 3-Butyl-1-(2,6-(dichlorophenyl)-S-carboxv-4-~(2' -(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(48) 3-Butyl-1-(2,6-(dichlorophenyl)-5-carboethoxy-4-t(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;

.. . ~

W09t/tS479 PcT/US91/019s2 (49) 3-Butyl-1-(2,6-(dichlorophenyl)-5-trifluoro-methanesulfonamido-4-t(2'-(N-butyryl)sulfon-amidobiphen-4-yl)methyl]pyrazole;
(50) 3-Butyl-1-(2,6-(dichlorophenyl)-5-pentafluoro-ethanesulfonamido-4-t(2'-(N-butyryl)sulfon-amidobiphen-4-yl)methyl]pyrazole;
~51) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carboxy--4-t(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
(S2) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carbo-ethoxy-4-t(2~-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(S3) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-tri-fluoromethanesulfonamido-4-t(2'-(tetrazol-5-yl)-biphen-4-yl)methyl]pyrazole;
(54) 3-Butyl-1-(2-(trifluoromet ffl l)phenyl-5-penta-fluoroethanesulfonamido-4-t(2'-(tetrazol-5-yl)-biphen-4-yl)methyl]pyrazole;
(55) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboxy-4-t(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(56) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboethoxy-4-t(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(57) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-trifluoromethanesulfonamido-4-t(Z'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(58) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-pentafluoroethanesulfonamido-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(59) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboxy-4-t(2~-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;

', ' - ' '.~': . , ' ' ' .- ; . .
. - ~:
.. ' , , . ,~1 ~ ' ', '' '' wosl/l5479 PCTtUS91/01952 .:',` ':
~, j ~",~
~' '~ - 31 -(60) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboethoxy-4-t(21-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(61) 3-Butyl-1-(2,6-dichlorophenyl)-S-trifluoro-methanesulfonamido-4-t(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(62) 3-Butyl-i-(2,6-dichlorophenyl)-5-pentafluoro-ethanesulfonamido-4-t(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(63) Ethyl 3-butyl-1-(2,4-dichlorophenyl)-4-[t2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylate (64) 3-Butyl-1-(2,4-dichlorophenyl)-4-[t2l-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acid (65) Ethyl 3-butyl-1-(4-methoxyphenyl)-4-t~2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-lH-pyrazole-5-carboxylate (66) 3-Butyl-1-(4-methoxyphenyl)-4-tt2'-(5-tetrazol-yl)biphenyl-4-yl]methyl]-lH-pyrazole-5-carbox-ylic acid (67) Ethyl 3-butyl-1-(2-nitrophenyl)-4-~t2~-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylate (68) 3-Butyl-l-(2-nitrophenyl)-4-tt2l-(s-tetrazolyl) biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acit (69) Ethyl 3-butyl-1-(4-methoxy-2-nitrophenyl)-4-tt2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-lH-pyrazole-5-carboxylate (70) 3-Butyl-1-(4-methoxy-2-nitrophenyl)-4-[[2~-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-S-carboxylic acid .
: :
;

"

WO 91/15479 PCr/uS91/Otg52 t' ~ ?,~
: !', <71) 3-Butyl-1-(2-pyridyl)-4-[~2~-(5-tetrazolyl)bi-phenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acid (72) 1-Benzyl-3-butyl-4-[t2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-S-carboxylic acid (73) Ethyl 1-(2-chlorophenyl)-3-propyl-4-~2~-(5-tetrazolyl)biphenyl-4-yl]methyl~ -pyrazole-5-carboxylate (74) 1-(2-Chlorophenyl)-3-propyl-4-~[2'-(5-tetrazol-yl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carbox-ylic acid (75) 1-(2,6-Dichlorophenyl)-3-propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acid (76) Ethyl 3-propyl-4-~t2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-[2-(trifluoromethyl)phenyl]-1~-pyrazole-5-carboxylate (77) 3-Propyl-4-~[2'-(5-tetrazolyl)biphenyl-4-yl~-methyl]-l-t2-(trifluoromethyl)phenyl]-l~-pyra-zole-5-carboxylic acid (78) Ethyl 3-Propyl-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-(trifluoroethyl)-1~-pyra-zole-5-carboxylate (79) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]-l-(2,2,2-(trifluoroethyl)-1~-pyrazole-5-carboxylic acid (80) Ethyl 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-l~-pyrazole-5-carboxylate (81) 3-Propyl-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]-l~-pyrazole-5-carboxylic acid (82) 3-Butyl-1-(2-chlorophenyl)-4-[[2'-~N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-lH-pyrazole-5-carboxylic acid - ~ ,, . ,; . . .

WO 91/15479 PCI`/US91/0195 (83) 3-Butyl-1-(2,6-dichlorophenyl)-4-~[2~-~N-isobut-yrylsulfamoyl]biphenyl-4-yl]methyl]-1~-pyrazole-S-carboylic acid (84) 3-8utyl-4-~ r 2'-[N-(3-cyclopentylpropionyl)sul-famoyl]biphenyl-4-yl]methyl]-1-[2-(trifluoro-methyl)phenyl]-l~-pyrazole-5-carboylic acid (85) 3-Butyl-4-Ct2'-[N-(diphenylacetyl)sulfamoyl]bi-phenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acid (86) 4-~[2~-[N-(N,N-diphenylcarbamoyl)sulfamoyl]bi-phenyl-4-yl]methyl]-3-propyl-l~I-pyrazole-S-carboxylic acid ~87) 4-~[2l-[N-(Diphenylacetyl)sulfamoyl]biphenyl-4-yl]methyl]-3-propyl-1~-pyrazole-5-carboylic acid (88) 4-~t2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-1-(2-chlorophenyl)-3-propyl-1}~-pyrazole-5-carboylic acid (89) 1-(2,6-Dichlorophenyl)-3-propyl-4-t~2'-(tri-fluoromethanesulfonamido)biphenyl-4-yl]methyl]-l~I-pyrazole-5-carboxylic acid (90) 3-Butyl-4-[t2'-~N-(pyrimidin-2-yl)sulfamoyl]bi-phenyl-4-yl]methyl]-1-[2-(trifluoromethyl)-phenyl]-l~I-pyrazole-5-carboylic acid (91) 4-~2'-tN-(4-Nitrophenyl)sulfamoyl]biphenyl-4-yl]methyl]-3-propyl-1-(2,2,2-trifluoroethyl)-1~-pyrazole-5-carboxylic acid (92) 4-~2'-~N-(Diphenylacetyl)sulfamoyl]biphenvl-8-yl]methyl]-3-ethyl-1~1-pyrazole-5-carboxylic acid (93) 3-Butyl-4-~(2'-carboybiphenyl-4-yl)methyl]-1-(2,6-dichlorophenyl)-l~I-pyrazole-5-carboylic acid -, . . . . . .
,. . . .
, -:

WO 91/15479 PCl'/US91/01952 - 2~
. ) .

(94~ 4-[~2'-tN-(Benzenesulfonyl)carbamoyl]biphenyl-4-yl]methyl]-3-butyl-1-(2-chlorophenyl)-1~-pyrazole-5-carboxylic acid (95) 5-[N-(Benzenesulfonyl)carbamoyl]-3-butyl-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoroethyl)-l~-pyrazole (96) 3-Butyl-4-~2~-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-5-(trifluoromethanesulfonamido)-1-~2-(trifluoromethyl)phenyl]-l~-pyrazole (97) 3-Butyl-1-(2-chlorophenyl)-5-(pentafluoro-ethanesulfonamido)-4-~t2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl]-1~-pyrazole (98) 3-Butyl-5-(pentafluoroethanesulfonamido)-4-~[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1-t2-(tri-fluoromethyl)phenyl]-l~-pyrazole (99) 4-~2'-[N-(Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butyl-1-~2-(chlorophenyl)-5-(tri-fluoromethanesulfonamido)-l~-pyrazole (100) 4-~2~-(N-Benzoylsulfamoyl)biphenyl-4-yl]methyl]
-3-butyl-5-(trifluoromethanesulfonamito)-1-~2-(trifluoromethyl)phenyl]-l~-pyrazole (101) 3-Butyl-1-(2-chlorophenyl)-4-[t2'-[N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-l~-pyrazole (102) 3-Butyl-1-(2-chlorophenyl)-4-~[2'-[N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-. (pentafluoroethanesulfonamido)-l~-pyrazole (103) 3-Butyl-4-t~2'-~N-(cyclopropanecarbonyl)sulfamo-yl]biphenyl-4-yl]methyl]-5-(trifluoromethane-sulfonamido)-1-[2-(trifluoromethyl)phenyl]-1~-pyrazole , -- .:

WO91/15479 PCT/US91/n19S2 , _.

2; ~

(104) 1-(2-Chlorophenyl)-3-propyl-4-[~2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethane-sulfonamido)-l~-pyrazole (105) 3-propyl-4-t[2~-(tetrazol-5-yl)biphenyl-4-yl]
methyl]-5-(trifluoromethanesulfonamido)-1-[2-(trifluoromethyl)phenyl-l~-pyrazole (106) 4-tt2l-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-1-(2-chlorophenyl)-3-propyl-5-(tri-fluoromethanesulfonamido)-l~-pyrazole (107) 4-tt2l-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propyl-5-(trifluoromethanesulfon-amido)-l-t2-(trifluoromethyl)phenyl]-1~-pyrazole (108) 1-(2-Chlorophenyl)-4-tt2'-tN-(cyclopropane-carbonyl)sulfamonyl]biphenyl-4-yl]methyl]-3-propyl-5-(trifluoromethanesulfonamido)-1~-pyrazole (109) 4-tt2l-tN-(cyclopropanecarbonyl)sulfamoyl]bi phenyl-4-yl]methyl]-3-propyl-5 (trifluoro-methanesulfonamido)-l-t2-(trifluoromethyl)-phenyl]-l~-pyrazole (110) 1-(2-Chlorophenyl)-4-tt2'-~N-(cyclopropane-carbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-(pentafluoroethanesulfonamido)-3-propyl~
pyrazole (111) 1-(2-Chlorophenyl)-5-(pentafluoroethanesulfon-amido)-3-propyl-4-tt2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl]-1~-pyrazole (112) 3-Butyl-1-(2-chlorophenyl)-5-(trifluoromethane-sulfonamido)-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]-lH-pyrazole.

..
, . :
. ., ~ ~. .
- ~

~ !

(113) 3-Butyl-5-tN-(isopropylsulfonyl)carbamoyl]-4-[C2'-(s-tetrazolyl)biphenyl-4-yl~methyl]_ 1-(2,2,2-trifluoromethyl)- U-pYrazole (114) 3-Butyl-5-~N-(cyclopropane 8U lfonyl)carbamoyl]-4-C[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoromethyl)-1~-pyrazole (115) 3-Butyl-5-(4-fluorobenzenesulfonamide)-4-tt2'-(5-tetrazolyl)biphenyl-4-yl~methyl]-1-(2,2,2-trifluoromethyl)-l~-pyrazole (116) 3-Butyl-5-~3-pyritinesulfonamide)-4-C[2l-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoromethyl)-l~-pyrazole ,. . . ' ~ ' ' . , - .

~ .

.

Several methods for preparing the compounds of this invention are illustrated in the ensuing Schemes.
ABBREVIATIONS USED IN SCHEMES AND EXAMPLES
Reagents:
NBS N-bromosuccinimide AIBN 2,2'-azobis(isobutyronitrile) DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone Ac~O acetic anhydride TE~ or Et3N triethylamine DMAP 4-dimethylaminopyridine P~h3 triphenylphosphine TFA trifluoroacetic acid TMS-Cl trimethylsilyl chloride Im imidazole AcSK ~otassium thioacetate p-TsOH p-toluenesulfonic acid DBU l,8-diazabicyclot5.4.0]undec -7-ene Solvents:
DMF dimethylformamide HOAc (AcOH) acetic acid EtOAc (EtAc) ethyl acetate Hex hexane THF tetrahydrofuran DMSO dimethylsulfoxide MeOH methanol iPrOH isopropanol EtO~ ethanol Q~h~ .
rt room temperature TBDMS t-butyldimethylsilyl OTf OS02CF3 OTs OSO-(4-methyl)phenyl OMs S2c~3 Ph phenyl FAB-MS (FABMS) Fast atom bombardment mass spectroscopy NOE Nuclear Overhauser Effect SiO~ silica gel tri~yl triphenylmethyl LG leaving group TLC thin layer chromatography MPLC medium pressure liquid chromatography MPM (4-methoxyphenyl~methyl ~, ~

- , W09t/t5479 ~. ! ~, ,1 ~ PCT/US91/01952 . --Pyrazoles substituted in the 1,3,4,5-positions and isothiazoles substituted in the 3,4,5-positions may be prepared as shown in Schemes 1 through 6.
Scheme 1 shows how the dianion of ethyl hydrogen malonate can be acylated with an R6 acyl chloride then acidified to give the a-unsubstituted-~-ketoester shown.l The ~-ketoester is then alkylated with sidechain 1 using sodium hydride in DMSO (or other suitable base in a suitable solvent) to give a-substituted-~-ketoester ~. Condensation of the ~-ketoester ~ with an R7 hydrazine as shown in Scheme 2 results in the formatidn of pyrazole ~.
Similarly, condensation of ~-ketoester ~ with hydroxylamine as shown in Scheme 3 results in the formation of isoxazole 4.
Scheme 4 provides a route to the useful intermediate ~-ketonitrile 5. Cyanoacetic acid can be condensed with an R6 acyl chloride to give the R6 a-unsubstituted-~-ketonitrile.2 This can then be a-alkylated using NaH in DMSO (or other suitable base and solvent) and the appropriate sidechain electrophile to afford ~. ~etonitrile ~ will afford 5-aminopyrazole 6 when condensed with an R7 hydrazine .
(Scheme 5). Likewise, 5-aminoisoxazole 7 results from the condensation of ketonitrile ~ with hydroxylamine (Scheme 6).
One examplè of the assembl~ of an isothiazole is shown in Schemes 7. 8, and 9. Lithium acetylide displacement of the leaving group of compound 1 would give intermediate 8. This material - . -, .. - .

~ 39 -can be deprotonated with butyllithium, LDA, or other suitable baæe and added to ethyl chloroformate to give the ethyl propiolate derivative 2. Scheme 8 provides a route to the precursor of the unstable nitrile N-sulfide. Contensation of an R6 amide with chlorocarbonylsulfenyl chloride will give the oxathiazolone 11. Heating this material in the presence of the substituted propiolic ester 2 will give a mixture Of t3~2]-diPolar cycloaddition products which may then be separated.3 Scheme 10 gives an alternate preparation of an isosazole via [3+2]-dipolar cycloaddition.
Deprotonation of intermediate 8 as before followed by attition of formaltehyte and subseguent protection (illustrated here with the methoxyphenylmethyl (MPM) group) will give substitutet propargyl alcohol 1~.
Alternatively, 1~ could be preparet from 1 ant the anion of O-protected propargyl alcohol, or from the retuction ant protection of the propiolate ester 2.
Attition of an R6 nitrile oxite to the alkyne 13 will give a mixture of protucts with one component being isoxazole 1~. Separation of isomers followet by Raney Nickel retuction ant intoduction of the sulfur using P2S5 with or without an oxitant will give the corresponting isothiazole 1~-4 The latent alcohol may be deprotectet with DDQ.5 Oxidation would give the corresponting carbo~ylic acid. Alternatively, the R6 nitrile oxite coult be atded directly to the propiolate ester 9.
The ~-ketonitrile 5 can be converted to the n-amino-,n-unsaturatet nitrile 1~ upon treatment of with concentratet ammonium hytroxide (Scheme 11).

. . .
. . - . ,, ~. .

. .

:

Wo91/l547g ~ ~ PCT/US91/01952 .....

Alternatively, the ~-enol triflate6 or phosphate7 could be treated with ammonia to give 16. Conversion of this material to the 5-aminoi~othiazole 17 could be achieved using the methods described by Adams and Slack.8 The 5-aminoisothiazole 1~ can be a final product (after any required deprotection) or may be used as an intermediate to the carboxy derivative 1~. Diazotization of 17 and conversion to the bromide followed by heating with CuCN and hydrolysis would give the carboxy derivative 1~ Diazotization Of 1~ followed by reduction with hypophosphorous acid would give the 5-hydridoisothiazole.9 Scheme 12 provides a route for the preparation of acyl sulfonamides 2Q. The carboxylic acid can be activated by conversion to the acid chlorite by various methods including treatment with refluxing thionyl chloride or preferably with oxalyl chloride ant a catalytic amount of DMF at low temperature.10 Activation by conversion to the acyl imidazole can be achieved upon treatment of acid 12 with carbonyldiimidazole. N,N-Diphenylcarbamoyl anhytride intermediates may be prepared as activated carbonyls.ll Trèatment of the activated carbonyls with a}kaIi metal salts of alkyl or aryl sulfonamides or with the sulfonamide and DBU will give the expected acyl sulfOnamide 2Q-12 Scheme 13 provides a route to the isomeric acyl sulfonamides ~. The commerically available bromobenzenesulfonyl chloride ~1 may be converted to the corresponding sulfonamide upon treatment with ammonia or ammonium carbonate. Protection with the triphenylmethyl group gives sulfonamide 2~. Palladium . ~ ' .

.: . .

Z.,, ~

catalyzed cross-coupling of 23 with the aryltrimethyltin derivative 24 gives the biaryl 2S.13 Treatment of this material with N-bromosuccinimide and catalytic AIBN in refluxing CC14 will give the alkylating agent 26. The bromide 26 may now be used as the alkylating agent 1 shown in previous schemes to give intermediate 27.
Deprotection and acylation will give the acyl sulfonamide ~.
A useful pathway for the synthesis of compounds of Formula I wherein K=NR7 and R3=Co2~ or Co2R4 is illustrated in Scheme 14. In this case, the side chain attached to C4 of the pyrazole ring is ~2'-(5-tetrazolyl)biphenyl-4-yl]methyl. Reaction of the appropriate methyl ketone ~2 with diethyl oxalate (30) in the presence of sodium ethoxide yields the 2,4-diketo ester ~1-14 Treatment of ~1 with methoxyamine hydrochlorite in the presence of 3A
molecular sieves (methot baset on that of Mukaiyama, 5) selectively gives the 2-methoxime derivative ~. Reaction of 32 with 4-bromomethyl-2~-cyanobiphenyl (~)16 affords the tesired alkylatet protuct 34. When 34 is heatet with the appropriate hydrazine hydrochloride 35, preferably at about 100-110C in acetic acid, optionally containing a cosolvent such as 2-methoxyethanol, the pyrazolecarbosylate ~ is formed. This ring formation is highly regioselective in the case of arylhytrazine hydrochlorides and at least cert~in alkylhydrazine hydrochlorites. The cyano group of 36 is ne~t converted to the tetrazole ~ upon heating with trimethyltin azide in toluenel7, the free .
, wost/ts479 PCT/US91/01952 Z~ , ~ J' _~3 tetrazole being obtained upon treatment with silica gel. Saponification of 37, typically by warming in a mixture of aqueous sodium hydroxite and methanol followed by acidification, provides the pyrazolecarboxylic acid ~. The isoxazole analog of 38 (K=0 in Formula I) may be prepared analogously by substituting hydroxylamine hytrochloride for ~ in Scheme 14.
A similar sequence to pyrazolecarboxylate6 in which the tetrazole group of 37 or 38 is replaced by acylsulfonamite is shown in Scheme 15. Alkylation of ~ (from Scheme 14) with the t-butyl sulfonamide intermediate 39 (see Scheme 17) yields 40, which reacts with the hydrazine salt ~ to give the pyrazole 41. The free sulfonamide 42 is obtained by deprotection of ~1 with trifluoroacetic acid in the presence of anisole. Acylation of the sulfonamide, for e~ample, wit~ an acid chloride 43 in pyridine (see also Scheme 13), yields the acylsulfonamide 44, which may then be saponified to 45. Alternative acylation conditions may be employed. The use of an N-acylimidazole derivative (generated from the acid with l,l~-carbonyldiimidazole) in the presence of DBU
(1,8-diazabicyclot5.4.0]undec-7-ene) in 'r~- is also an effective method. In some cases the acid chloride in Scheme 15 may be replaced by an acid anhydride, as in the case of trifluoroacetic anhydride. It should be noted that for 44 (R23=CF3~, the trif}uoroacetyl-sulfonamide may be hydrolyzed during the saponifi-cation step, in which case reacylation at the free acid stage yields 4S (R23=CF3).

- . - . . ~ . , . . , - .. :: . . . - . .
.; . .
- . . : . ~. -. ~ - . . . -.
. . .

wosl/1s479 PCT/US91/01952 /s ~
2 ,~ ~
_ 43 -Scheme 16 also shows a similar route leading to pyrazolecarbosylates in which the tetrazole group of 37 or 38 is replaced by trifluoromethanesulfon-amide. Alkylation of ~ (from Scheme 14) with the nitrobiphenyl species 46 (see Scheme 17) gives 47, which is carried on to the pyrazole derivative 48.
Xydrogenation of the nitro group of 48 in the presence of a catalyst such as platinum oxide yields the amine 49. Treatment of 49 with trifluoromethanesulfonyl chloride or trifluoro-methanesulfonic anhydride gives, depending on the conditions, either the mono(trifluoromethanesulfonyl) derivative ~Q or the bis(trifluoromethanesulfonyl) derivative ~1 as the major or exclusive product. The sulfonylation may be carried out in pyridine or, alternatively, in methylene chloride in the presence of a base such as 2,6-di-t-butyl-4-methylpyridine.
Under the saponificatiOn condition8, both 50 and ~1 are converted to the target pyrazolecarbosylic acid 52.
The synthesis of the intermediate alkylating agents ~2 (see Scheme 15) and 46 (see Scheme 16) are shown in Scheme 17. Reaction of 2-bromobenzene-sulfonyl chloride (~1) with an escess of t-butylamine yields the ~-butylsulfonamide ~. The trimethylstannyl derivative 2~ is prepared from ~-tolylmagnesium bromide (54) by treatment with trimethyltin chloride at -35C to room temperature.
Cross-coupling of 24 with 53 catalyzed by bis(triphenylphosphine)palladium(II) chloride in DMF
at about 90-C affords the biphenyl derivative 55.

, . . .. . .
. .
~: . ., ; :
.
., ~ ... : - ,. .: ;.. , : . .
: :- .. -- :~ : . . :
: . .: . .- . . -~:
- . . . . . .. .
. .

WO 91/15479 PCl'/US91/01952 The bromomethyl species ~2 is obtained by heating 55 with N-bromosuccinimide (NBS) in carbon tetrachloride in the presence of an initiator such as 2,2~-azobis(isobutyronitrile) (AIBN). Similarly, palladium(II)-catalyzed cross-coupling of 24 with 2-bromonitrobenzene (56) yields the biphenyl product ~1, which is brominatet as above to give 46.
Schemes 18-21 illustrate transformations of the R8 group. Scheme 13, for example, shows the synthesis of a trifluoromethanesulfonamido group at R8. In this illustration, com~ound 58 is a compound of formula I wherein R8 is NH2 and Rl is tetrazol-5-yl. Reaction of ~ with trityl chloride in the presence of triethylamine gives the trityl-protected tetrazole derivative 59. Treatment Of ~2 with trifluoromethanesulfonic anhydride in the presence of 2,4,6-collidine provides the sulfonamide 60. Finally, ~Q is deprotected with methanolic ~Cl (or, alternatively, with aqueous acetic acid) to give 61. Other R8 polyfluoroalkanesulfonamides, as well as aryl or heteroaryl sulfonamides and the like, may be prepared in similar fashion. It is often convenient to use a sulfonyl chloride as the sulfonylating reagent, especially in the presence of DMAP and triethylamine. The scheme can also be modified for Rl groups other then tetrazole, with use of suitable protection ant deprotection as necessary.
In Scheme 19, 62 (a compound of formula I
wherein R8 is C02~) undergoes initial treatment with carbonyl~diimidazole (CDI) to give an N-acylimidazole intermediate which, without isolution, is reacted with a sulfonamide in the presence of DBU to give the . .. ,. ~
.: -.~ . . . ~- . .
- - . : ; ' .

Wo91/15~79 PCT/US91/01952 acylsulfonamide of type 63 (wherein R is aryl, heteroaryl, al~yl, or perfluoroalkyl). As in Scheme 18, it may be necessary to protect the Rl group prior to these reactions and to deprotect it afterwards.
Scheme 20 shows a route to a reversed acylsulfonamide grouping at R8. Compound 64 (a compound of formula I wherein R8 is NH2) may be diazotized either under agueous conditions with nitrous acid or under nonaqueous conditions with an alkyl nitrite such as t-butyl nitritel8 and reacted `Ln ~ with sulfur dioxide in the presence of cupric chloride in acetic acid to give the sulfonyl chloride 65. Treatment of ~ with ammonia yields the sulfonamide 66, which can be acylated with an acid chloride in pyridine or an acylimidazole derivative in the presence of DBU. The product thus obtained i8 the acylsulfonamide of structure 67, wherein R is aryl, heteroaryl, alkyl, or perfluoroalkyl. The earlier comments about protection and deprotection of Rl also apply.
The synthesis of some other sulfur-linked side chains at R8 is shown in Scheme 21. The amino heterocycle 64 i8 converted to the chloro heterocycle 68 by use of nitrosyl chloride in chloroforml8.
Compound 68 is heated with a thiol in the presence of a base, such as potassium carbonate, N,N-diisopropyl-ethylamine, or DBU, to give the.thioether 69.
Alternatively, 69 may be obtained directly from 64 hy nonaqueous diazotization with t-butyl nitrite in the presence of a disulfide. Compound 69 can then be oxidized to either the sulfoxide 70 or the sulfone 71 using a reagent such as 30% hydrogen peroxide ,. - . . ;. . - ~ . , :.- :
,. . . .
. : . . ,.,.; ; ; ~, .
.. , -;, --.... ,: . : - ~ . .

W O 91/15479 PC~r/US91/Ot952 2- . r`i i ~

(aqueous~ in acetic acid or an organic peracid. The choice of reagent, stoichiometry, temperature, and reaction time govern whether 70 or 71 is the major or exclusive product. In this scheme R is alkyl, aryl, or aralkyl.
A route to a carbamoylphosphinic acid Rl group is illustrated in the pyrazolecarboxylic acid series in Scheme 22. The amino intermediate 49 may be converted to the isocyanate ~ upon heating with phosgene in an inert solvent. Reaction of 72 with phenylphosphinic acid 73 in the presence of tri-ethylamine, according to the method of Fox and Baileyl9, gives the carbamoylphosphinic acid derivative 74. Finally, saponification of the ester affords the pyrazolecarboxylic acid 75. This method may be extended to the use of ring substituted phenylphosphinic acids and may be modified for the preparation of other compounds of formula I outside the pyrazolecarboxylate series.
The incorporation of an aryl- or alkyl-phosphinoyl group of Rl is illustrated in the pyrazolecarboxylic acid series in Scheme 23. The nitrobiphenyl intermediate is readily reduced to the amine 76 using either stanous chloride reduction or catalytic hydrogenation. The amine ~ upon diazoti-zation with nitrous acit ant treatment with cuprous bromide yields the bromobiphenyl derivative 77. The bromomethyl derivative 78 is obtainet from 77 by standard NBS bromination conditions as described in previous schemes. Employing the methods of Scheme 14, 7R is converted to the pyrazolecarboxylate terivative 79. Next, 79 undergoes pallatium-.
.

.. ' . ~ .. "

wosl/ts47s PCT/US91/01952 ;: .

,~, ,~, ; . :0 . ...
catalyzed cross-coupling-with a monoethyl arene- or alkanephosphonite 80, using the conditions of xU,20~2l to give the disubstituted phosphinate ester 81. The phosphonite intermediate 80 may be obtained by reaction of a Grignard reagent R23MgBr with diethyl chlorophoæphite followed by partial hydrolysis.21 Finally, both the carboxylate ester and the phosphinate ester22 of 81 may be saponified by heating with sodium hydroxide in aqueous methanol to give 82. Again, this pathway can be modified for the preparation of other compounds of formula I
outside the pyrazolecarboxylate series.
Although the reaction schemes described herein are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of formula I may render the molecule incom-patible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagents, solvent, temperature, and time, should be chosen so that they are consigtent with the nature of the functionality present in the molecule.

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3 D.K. Buffel, B.P. Simons, J.A. Deceuninck, G.J.
Hoornaert, J. OrE. Chem. (1984~ 49 2165.

. ~ , . . . .
., . , ; . . .

.

.:

4 D.N. McGregor, U. Corbin, J.E. Swigor, L.C.
Cheney, Tetrahedron (1969) ~ 389.
Y. Oikawa, T. Yoshioka, O. Yonemitsu, Tet. Lett.
(1982) ~ 885.
K. Horita, T. Yoshioka, T. Tanaka, Y. Oikawa, O. Yonemitsu, Tetrahedron (1986) 42 3021.
6 E. Piers, ~.L.A. Tse, Tet. Lett. (1984) ~ 3155-.
7 M. Alderdice, F.W. Sum, L. Weiler, Or~. Syn.
(1984) ~ 14.
8 A. Adams, R. Slack, J. Chem. Soc. (1959) 3061.
9 See reference #8. The methods of J.R. Beck, ~ al pro~ide an excellent opportunity for the introduc-tion of 5-cyano groups and, indirectly, 5-carbox-amides, esters, and carboxylates. J.R. Beck, et ~1. J. ~et. Chem., ~, 955 (1988).
A.W. Burgstahaler, L.O. Weigel, C.G. Shaefer, Synthesis (1976) 767.
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(1985) 837.

. .
- , . . . . .
,.. - ~ : ; ~ ., - ~ ~ ,,, ~. .. : ., .

W091/tS479 PCT/US91/Ot952 ..

}6 D.J. Carini, J.J.V. Duncia, European Patent Application EP 253,310.
17 P.E. Aldrich, M.E. Pierce, J.J.V. Duncia, European Patent Application EP 291,969.
18 J.R. Beck, R.P. Gajewski, M.P. Lynch, F.L.
Wright, J. ~eterocycl. ~hg~. (1987) 24 267.
19 R.B. Fox, W.J. Bailey, J. Ore. Chem. (1960) 25 1447.
Y. Xu, Z. Li, J. Xia, H, Guo, Y. Huang, ~y~thesis (1983) 377.
21 Y. Xu, ~, Wei, J. Xia, ~Lie~igs_A~n. ~hem. (1988) 1139.
22 P. Favs, Chem. Ber. (1970) 103 2428.

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- : ~

WO 91/15479 PCI'/US91/01952 ~C~EM~ 1 ~COOEt BuLi O
COOH R6COCl R6J~OOEt NaH, DMSO
LG R~OOEt ( CH2) r(lH2) r R3b~_ R3b_~R3Q

~R1 ~R
R

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, . . .
- : .
-.
.~ . , . .

WO 91/15479 PCI`/US91/01952 ~' O N--N
R~COC)Et R6 ~--OH

(CH2)r H2N-NH-R7 (CH2)r R ~R3a R3b_~}R3a R2 b _g~ R2 b_g~
R2a R2 .. .. , ~

.. . . . . . .
. . . .

Z~

~IEMl~ 3 O N--O
R6~COOEt R6 ~--OH
(CH2)r H2NOH (CH2)r R ~}R30 R3b_~}R3a X X
R2b~ R2b~
R2~ R20 .. . - : -: ~ -: ~ . .... . .

,..... . ,.,, ` : ~ . .: ~ ' WO 9l/ls479 PCI/US91/01952 SC~ 4 fC" ~, J . ~ . ., .~ . d ~CN BuLi O
COOH R6CCCl R6~N

NaX D~;O
o LG R~N
(CH2)r (CHz)r R3 b~~R3 El R3 b--~}R3 a X X
R2b ~ R2b ~
R2a R2a .,: . : , ,.-WO 91/15479 PCI`/1JS91/01952 ?~

SCHE~IE 5 o N--N
R6~CN H2 N- NH- R7 R --~H2 ( CH2) r ( CH2) r _~ R3b~_R3a X X

R2 b~ R2 b_~
R2~ R2a ,"`~

., ; . .

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WO 91/15479 PCl/US9t/01952 '-:

'j_. . - .SCHEME 6 O N--O
R6~C H2 N- OH R6 ~2 (CH2)r (CH2)r _~_ R3b_~R3 X X

{~ R2b ~
R2~ R2a .

- SC~IEME 7 LG ~H
~CH2)r (CHz)r R3b~R3A Li-- b--3 _ ~ R3b~R3,, X H2N~NH2 X
Ra b~ R2 b~
R2~1 R2a ,COOEt BuLi( CH2) r THFR3 b~R3 a Cl /~OEt1 R
R2 b~
R

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SC~IEME 8 o N--S
R --< ClSCOC ~ R6 ~o~O

SC~IlEME 9 ~ N--S
11 + 9 R~--(j~OOEt -C2 (CH2)r ~R3 X

R2b~
R2a .. . . . .

WO 91~15479 o,~ ?~PCI /US91/01952 , ~

/~ 1 ) /~--OMPM
( CH2) r BULi ( CH2) r R3b_~ CH20 R3b~R3 X MPM~r X

R2 b~R1 R2 A

+ - N--R6 ~N ~ R6 ~MPM

( CH2) r R2 b~

R2a . ~

.. ~ . . ~
, wo 91/15479 PC~/US91/01952 H~M~; 10 (~ont'd) N~
R6 ~,OMPM
14 1 )Ra-Ni (CH2)r 2) P2Ss R3b~_R3a tol R2 a .
~ ~ , - :

PCI~/US91 /01 952 ,.:..

$~;~Il~;ME 11 R ~ R ~C

2)r ~CH2)r X X

R2il RZ

,. .

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WO 91/15479 P~/USg1/o19s2 . . .

SC~IEME 11 (C0NT'D~

N~
R6 ~NH2 (CH2)r 16 1 ) H2S R3b~ R3a R2 b{~
R2 a 1 ) HONO N~
H~r R6~00H

2 ) CuCN (lH2) r 3)KOH, H20,R3b~3_R3 hea t R~

:

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WO 91/1S479 PCl`lUS91/01952 ~' ` '.

SC~;ME 12 N--K N--K
R~sl~--R8 R~
(CH2)r1 ) ~activatlon (CHz)r R3b~ or ~}R3a OOHR23So2NHz~ DE~UX ONHso2R23 R2~_Ç~c2b R2b_~

M is Na or Li * Activation of the carboxylic acid can include:
1 ) SOC12, 2) carbonyldiimidazole 3) (COC1)2. ~
4) N(N,N-diphenylcarbamoyl)pyridinium chloride/aq. NaOH.

' ' Wo 9tttS479 Pcr/ussl/0l9s2 Br Br 2Cl NH3 ~5O2NH2 or ~ NH4) 2CO3 Br ~52 NHCPh3 Ph3CC1 Et3N 23 ~3 NBS

2 4 S ~ 3 ~,S 02 NHCPh3 ( Ph3 P) 4 Pd 2 5 catalys t Br 32NHCPh3 . . , :.. . .. . . . . : . ~ .
, . .: - , .:
- .
... ~. . .. . . . ~ . ~ ,. :

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WQ 91/15479 PCr/US91/01952 2 . . ~ ~g . . .

SC~ ; 13 (COI!T

N--K
R6 ~3 ~2NHCPh3 1 ) AcOH/H2O N--K
" ~ ~
2) R23COCl or R6~--R~
R23Co- irridazole or ~ SozN}~CoR23 ot her acylat ing agent ~3 WO 91/15479 PCr/US91/01952 .SCHEME 14 R~ J~H ~ ol~) N OEt RJUl~co~Et ~ONII,' N~l R~ J~~Ee ~N
3A n~l. 32 ~lov -, ~eOH -- ~

R~J~O~Et K~CO" DMF
R NW~, HCl 3~ JICOH, A

R~ Et 1 ) ~g SnN"
~ a~ lllc~ 9--l ~N 1 ) N~O~
R~_~Et M~OH-H~O, ~,~N~ 2) HCl ,R7 O,H

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' ' " : ` , , - . . .

WO 91/15479 2~ i~ ~ 9 ~3 PCl'/US91/01952 , . .

R~ J~CO~Et ~ D~F
~2 ~502NH~3u- t O NO~
Ra~J~OzEt ~2 AcO~

N--N
Ro~CO2Et CFlCO2H, ~2N~u- t ~nls ole ,R7 ~32 2 pyrldlne ,:-' ~ i; . :
.
~:

WO 91/tS479 PCI/US91/01952 '.:r~

SC~EME 15 CONT ' D

N--N N--N
R~CO2Et 1 )NaOE~ R~CO2H
M~OH- H20 NH~OR 2 ) HCl ~2NHCOR23 SC~E~E 16 _~r O NOM~

R7NHNH~ HCl ~R
R~C02Et H2, PCO2 Et OAc AcO~ ~ ~;

N--N
R~CO2Et ~ NH2 .,: , .
' ' ~

.

WO91/15479 ~ 1~ PCl/US91/01952 : ,`

SC~ 16 CONT ' D

R7 ,R7 CF3SO~Cl or lN--N ~N
( CF3S0~) ,0 R--~CO~Et ~Ind/or R~CO~Et pyr~dln~, 0-20C ~O~CF, ~S02CF3)~

1 ) N~O~ ~OH- H20 /

- N--N
R~CO~H
~O,CF3 - : . ~ - ;. ;.: :
~-' ' ,' ,'~ .~.
':' ', ., ' '; '~ ` ' .' , ~: - . . -: ..

WO 91~tS479 PCI/US91/01952 , SC~ ;ME 17 9r 9r ~:O2Cl ~ SO~ u-t W t-~uNH, I~J
CHCl3 Zl 53 CH~
c~3 M~7SnCl, TB ICH3 J~ ~ 53, Pd( Ph,P),Cl:, ~
-35--20C~ DMF. 90C ~SC~NHBu-t 54 M~Br sn~3 NeS, AI~N
CCl,. i~
~80~NH9u- t Z4~ Pd(Ph3P)~Cl~ l~ NPS, AI3N
DMF, 110C 57 ¢~ ~,N~, CCl~, :

':' ' ~ ' ' ' ` ' ' ' ,. . -, WO 91/15479 PCrtUS91/019~2 2 .
.

N--K N--X
R~ R ~12 CCH2), Ph3CCl, Et3N (ClH2), (CF3S0~)20 R3b~}R3. CH2Cl2 R3b~_R3, 2, 4, 6-collidlne, CPh3 N--K N--K
Ro--~NHSO2CF3 Rol~j~NBO~CF3 ( CHl), . HCl/~30H~ CH2) r R3b~_R3~ R3b~--R~' R~b~ph3 R2 .. , .- .
: . ,. ~ .. .: - . : ;. :
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-:.
- : . , ~ :

WO 91/15479 PCl/US91/01952 ~d SC~EME 19 N--K N--K
R6~CO2H R6~CONHSO2R
( CH2) r 1 ) CDI ~ CH2) r R3b{~R3~ 2 ) RSO2NH2, D~U R3b~R3 R2~1 R2~l NOTE: R1 ITay be protected prior to these react ions and depro t ec t ed s ubs equent ly .' " ,` "
. ",.
, - . .

N - K N-K
R6 ~ Hz R6 ~ O2C
(CHz)r t-3uONO or HONO(CHz)r NH~
R3b ~ R3A SOz,CuClz,AcOH R

X X

RZ. RZ.

N-K N-K
R6 - ~9o2NH2 R~SOzNHCOR
( CH2) r RCOCl, pyridine (CH2) r R3b ~ R3~ or RCO-I~ D3U R3b ~ R3 R2. R2b,_g~

NOTE R1 nay be protected prior to these reactions and deprotected 9 ubsequently ,: . .

,:: : : . .~ -.:; , W O 91/15479 PC~r~US91/01952 2 ~ 4 ~ 73 -$CHEME 21 N - K N-K N-K
R6 ~NH2 R6--~: R6 _~: R
( lH2)r NOCl ClH2)rRSH. base(CHa)r R3b ~ R3~CHCl3R3b ~ R3~ ~ R3b ~ R3 X X X

R2. R2. R2.
64 6~ 69 ¦ t-BuONO, RSSR t N--K R~_~R

H202~AcOH ( CH2) r and/or (CHa) r or R' C03H R3b~R3~ R3b~R3 X X
RZb_~1 R
RZ~ R2 NOTE: Rl ITay be protected prior to thsse react ions and deprot sct ed s ubs equent ly . - : : .................. ...

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WO 9t/tS479 2 ~ ~ ,,? ~3 PCl'/US91/0t952 , . ~ .
r:.`~ `., ..

SC~IEME 22 ,R7 R7 ~1 R~ CO~E:tcocl~R~)--CO~Et H
T ~ ¦ Et3N
~ ~

,R ~OH- }~O R H

o 2~
ON ~ OH

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, ~

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WO 9t/tS479 PCr/US91/Ot952 ~~; 23 SnC12/H~1 ~J HONO, Cul3r ~ CCl~
~NOz ~N~2 ~Br R~ O
,~r N--N H

by m3thods of SchelTe 14 ~ Qd(PPh3)~" Et3N

7~ 79 ,R7 ,R7 N 02Et 1 ) N~OR MeOH-H20 R ~CO2H
3R 2) HICl ~R~23 31 ~2 The compounds of this invention form salts with various inorganic and organic acids and bases uhich are also within the scope of the invention.
Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine salts, N-methyl-D-glucamine salts, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared;
e.g., ~Cl, ~Br, ~2S04, H3P04, methanesulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free acit or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed Ln vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
Angiotensin II (AII) is a powerful arterial vasoconstrictor, and it exerts its action by interacting with specific receptors pre~ent on cell membranes. The compounts described in the present invention act as competitive antagonists of AII at the receptors. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established.

. :-.
- .
- . ~

~ .

2,r ~'~ 3 77 Receptor binding assay using rabbit aortae membrane p~eparation:
Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5mM
Tris-0.25M Sucrose, p~ 7.4 buffer (50 ml), homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4C.
The pellet thus obtained was resuspended in 30 ml of 50mM Tris-5 mM MgC12 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/ml Bacitracin, and the suspension was used for lO0 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 ml) there was added l25I-SarlIle8-angiotensin II ~obtained from New England Nuclear] (lO ~l; 20,000 cpm) with or without the test sample, and the mixture was incubated at 37-C for 90 minutes. The mixture was then diluted with ice-cold 50mM Tris-0.9% NaCl, p~ 7.4 (4 ml) and filtered through a glass fiber filter (GF/B Whatman 2.4~1 diameter). The filter was soaked in scintillation cocktail (lO ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist, which gives 50Z
displacement of the total specifically bound l25I-SarlIle8-angiotensin II, was presented as a measure of the efficacy of such compounds as AII
antagonists.

- - .- . ...
.. . .. : - .

., - , ..
- ~;,; . ' .

,*. " . .. .

Wo91~tS479 PCT/US91/01952 ~::' ,' Z,~ ,'^' ~, '` ,~? ~

Receptor assay using Bovine adrenal cortex preparation Bovine adrenal cortex was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 assay tubes) was suspended in Tris.HCl (50mM), pH 7.7 buffer and homogenized. The homogenate was centrifuget at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer ~Na2~P04 (lOmM)-NaCl (120mM)-disodium EDTA (5mM) containing phenylmethane-sulfonyl fluoride (PMSF)(O.lmM)]. (For screening of compounds generally duplicates of tubes are used).
To the membrane preparation (0.5 ml) there was added 3~-angiotensin II (50 mM) (10 ~1), with or without the test sample, and the mixture was incubated at 37-C for 1 hour. The mixture was then diluted with Tris buffer (4 ml) ant filtered through a glass fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 ml) and counted for radioactivity using Packard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist, which gives 50%
displacement of the total specifically bound 3H-angiotensin II, was presented as a measure of the efficacy of such compounds as AII antagonists.
Using the methodology described above, representative compounds of the invention were evaluated and were found to exhibit an activity of at least IC50 ~ 50~M, thereby demonstrating and confirming the utility of the compounds of the invention as effective AII antagonists.

, . ' ` '~ . . ', ' ~' .
~: ' : , .:

WO9t/15479 PCT/US91/01952 The potential antihypertensive effects of the compounds described in the present invention may be evaluated using the methodology described below:

Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohexital (Bre~ital; 50 mg/kg i.p.). The trachea was cannulated with PE 205 tubing. A stainless steel pithing rod (1.5 mm thick, 150 mm long) waæ inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a ~arvard Rodent Ventilator (rate - 60 strokes per minute, volume - l.l cc per lO0 grams body weight>. The right carotid artery was ligated, both left and right vagal nerves were cut, the left carotid artery was cannulated with PE 50 tubing for drug atministration, and body temperature was maintained at 37-C by a thermostatically controlled heating pad which received input from a rectal temperature probe. Atropine (l mg/kg i.v.) was then administered and 15 minutes later propranolol (l mg/kg i.v.). Thirty minutes later antagonists of formula I were administered intravenously or orally. Angiotensin II was then typically given at 5, lO, 15, 30, 45 and 60 minute intervalæ and every half-hour thereafter for as long as the test compound showed activity. The change in the mea~ arterial blood pressure was recorted for each angiotensin II challenge and the percent inhibition of the angiotensin II response was calculated.

. , , . . ~. , - - ~ -WO91~tS479 PCT/US91/01952 Thus, the compounds of the invention are useful in treating hypertension. They are also of value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders such as migraine, Raynaud~s disease, luminal hyperplasia and to minimize the atherosclerotic process. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.
The compounts of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables ant the like as well as topical ocular formulations in the form of solutions, ointments, inserts, gels, and the like.
Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about O.l~ to 15% by weight, preferably 0.5% to 2% by weight, of a compound of this invention.
In the management of hypertension and the clinical conditions noted above the compounds of this invention may be utilized in compositions such as tablets, capsules or eligirs for oral adminis-.
. . ~ . .

. , ~ ... . .. , .

WO9t/1547s PCT/US91/01952 ^.~ ~.~ ~ - 81 -tration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient, depending upon the nature and severity of disease, the patient' 8 weight, special diets then being followed by a patient, concurrent medication and other factors, which those skilled in the art will recognize, the dosage range will generally be about 1 to 1000 mg. per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg. per patient per day; more preferably about 2.5 to 75 mg. per patient per day.
The compounts of this invention can also be administered in combination with other antihyper-tensives such as diuretics, angiotensin converting enzyme inhibitors, calcium channel blockers or ~-blockers. For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, , reserpine, sodium nitroprussite, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipir~, nisoldipine, nitrendipine, and the like, as well as admixtures and combinations thereof.
Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin II antagonists of this invention effective clinically in the 2.5-2S0 milligrams per tay range can be effectively combined at levels at the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hytrochlorothiazide (15-200 mg) chloro-`thiazid~ (125-2000 mg), ethacrynic acid (15-200 mg),amilorite (5-20 mg), furosemide (S-80 mg), propranolol (20-480 mg), timolol maleate (5-60 0g.~.
methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (S-60 mg).
In addition, triple drug combinations of hydrochloro-thiazide (15-200.mg) plus amiloride (5-20 mg) plu8 .. . .. ..
' , WOgl/1s47s PCT/US91/01952 ~ ~, .. ..., . ~

angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients. Naturally, these dose ranges can be atjusted on a unit basis as necessary to permit divided daily dosage ant, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.
Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg. of compound or mixture of compounds of Formula I or a phy~iologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is ~uch that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the like; a lubricant such as magnesium - .

. . .

stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseet oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioxidants and the like can be incorporated as required.
The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.

COGNITIVE FUNCTION ASSAY

The efficacy of these compounds to enhanc~
cognitive function can be demonstrated in a rat passive avoidance assay in which cholinomimetics such as physostigmine and nootropic agents are known to be active. In this assay, rats are trained to inhibit :~ ' ' ' , - , ,' ' , ' ~ ' WO 91tlS479 PCI-/USg1/Ot952 2 ..~
their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they receive a brief electric shock to the feet. The test animals are pretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hours later, the rats are returned to the illuminated chamber.
Upon return to the illuminated chamber, normal young rats who have been subjected to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been esposed to the apparatus but who have not received a shock. Rats treated with scopolamine before training to not show this hesitation when tested 24 hours later. Efficacious test compounds can overcome the disruptive effect on learning which scopolamine produces. Typically, compounds of this invention should be efficacious in this pas~ive avoidance assay in the dose range of from about 0.1 mg/kg to about 100 mg/kg.

ANXIOLYTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a .

W O 91J1S479 P{~r/US91/01952 2~ J ~j clinically useful anxiolytic which is active in this assay. In the CER protocol, male Sprague-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly ~five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed LlDlL2D2L3 sequence. During both periods (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever presses also elicit mild footshock (0.8 mA, 0.5 sec) on an independent shock presentation schedule of VI 20 seconds. Lever pressing is suppressed during t~e dark periods reflecting the formation of a conditioned emotional response (CER).
Drug testing in this paradigm is carried out under extinction conditions. During extinction, animals learn that responding for food in the dark is no longer punished by shock. Therefore, re8ponse rates gradually increase in the dark periods and animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.1 mg/kg to about 100 mg/kg.

wos1/1s~79 PCT/US91/01952 , - 2~ 87 -DEPRESSION ASSAY

The antidepressant activity of the compounds of this invention can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a use suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation.
Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity cote and to measure latency, duration and frequency of immobile periods.
Compounds of this invention should be efficacious in this test procedure in the range of from about O.l mg/kg to about lOO mg/kg.

SC~IZOPERENIA ASSAY

The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-induced stereotypy model. A clinically useful antipsychotic drug that is used as a positive control in this assay is haloperidol. The assay method is based upon the observation that stimulati~n of the dopaminergic system in rats, produces stereo-typed motor behavior. There is a strong correlation between the effectiveness of classical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior , .

wosl/ls479 PCT/US91/01952 ; .

induced by apomorphine, with and without pretreatment with test compounts, is recorded uæing a keypad linked to a microcomputer. Compounds of the inven-tion should be efficacious in this assay in the range of from about O.l mg/kg to about lO0 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspen-sions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient~s weight, special diets then being followed by a patient, concurrent medication, and other factors which those skillet in the art will recognize, the dosage range will generally be about 5 to 6000 mg.
per patient per day which can be administered in single or multiple doses. Preferably, the dosage range will be about lO to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.
In order to obtain maximal enhancement of cognitive function, the compounds of this invention may be combined with other cognition-enhancing agents. These include acetylcholinesterase inhibitors such as heptylphysostigmine and tetrahydroacridine (T~A; tacrine), muscarinic agonists such as .-.. . . . ..

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oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers and as nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other anxiolytic agents such as alprazolam, lorazepam, diazepam, and buspirone.
In orter to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepressants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine osidase inhibitors such as tranylcypromine.
In order to obtain maximal antipsychotic activity, the compounts of this invention may be comDined with other antipsychotic agents such as promethazine, fluphenazine ant haloperitol.
The following examples illustrate the preparation of the compounds of formula (I) and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.
Al} reàctions as appropriate were carriet out under an atmosphere of try nitrogen under standard conditions for tbose skilled in the art.

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wosl/ls47s PcT/US91/01952 ' 90 ~` ~^

5-AMINO-3-BUTYL-4-~(2'-(TLTRAZOL-~-YL)BIPEEN-4-YL)-METHYLlISOXAZOLE

A: 2-Cyano-4'-methylbi~henyl To a solution of p-bromotoluene (30 g) in dry ether (lSO ml) at -78C, a solution of t-BuLi in pentane (1.7M) (210 ml) was adted slowly over a period of 1.5 hr, using a dropping funnel. The bath was then removed and the mixture was stirred at room temperature for an additional 2 hr. The contents of the flask was then added slowly (using a cannula) at room temperature to a premixed solution of ZnC12 in ether (lM) (180 ml) and dry T~F (360 ml). The mixture was stirred for 2h at that temperature and then the slurry was added (using a cannula) to a solution of 2-bromobenzonitrile (21.3 g) and NiClz(Ph3P)2 (2.1 g) in dry 1~ (300 ml). The mi~ture, after stirring at room temperature overnight (18 h), was poured slowly under stirring into ice-cold lN HCl (1500 ml). The organic layer was separated, and the aqueous phase was extracted with ether (3 X
300 ml). The combined organic layer was washed with water, brine and then dried over MgS04. Removal of the solvent gave the crude product as a semisolid mass (34 g). The material was purified on a silica-gel flash column using ethyl acetate-hexane (1:12) to give the desired nitrile as a low-melting solid (28 g, 88%). lH NMR (CDC13): 2.42 (s, 3H), 7.2-7.8 (m, 8H); FAB-MS: m/e 194 (M++l).

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B: ~rimethylstannvl azide To a concentrated solution of NaN3 (1.2 ~g, 18.5 moles) in water (3 L), a solution of trimethyltin chloride (600 g, 3 moles) in dioxane (400 ml) was added in three portions under vigorous stirring. A precipitate formed instantaneously. The mixture, after stirring overnight at room temperature, was filtered. The residue was washed with water and dried under suction and then Ln vacuo over P205. ~ield 541 g (88%), mp 120-122C.

C: 5-r2-(4'-Methylbiphenyl)ltetrazole To a solution of 2-cyano-4'-methylbiphenyl (Step A) (390 g, 2.02 moles) in toluene (2.3 L) was added trimethyltin azide (Step B) (525 g, 2.55 moles) at r.t. The mixture was reflu~ed for 24 h, cooled to r.t., filtered, washed with toluene and sucked dry in a funnel. The precipitate was resu~pended in toluene (3.5 L) and TaF (250 mL) was added. Anhydrous HCl was bubbled in at a moderate rate at r.t. to give a clear solution (45 min). M dition of ~Cl gas was continued for another 20 min. with stirring whereupon a white precipitate formed. The reaction mixture was stirred over night. The solid product was filtered, washed with toluene followed with ether and then dried under vacuum. This produced 250 g (53% yield of the tetrazole. m.p. 152-154C; lH-NMR (CDC13):2.40 (s, 3H), 7.19 (td, 1~), 7.55 (m, 2H), 8.25 (dd, lH~

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D: N-Triphenylmethyl-5-t2-(4'-methylbiphenyl)]-tetrazole To a cloudy solution of 5-[2-(4'-methylbi-phenyl)]tetrazole (Step C) (250 g, 1.06 mole) in CH2C12 (4 L) was added triphenylmethylchloride (310 g 1.11 mole) at r . t. The reaction mixture was stirred and triethylamine (190 mL, 138 g, 1.36 mole) was added portionwise. After addition, the mixture was stirred at reflux for 90 min. The' solution was cooled to r.t., washed with water (2xlL)and dried over MgS04, filtered through a silica gel plug and concentrated on the rotovap to a solid. This was crystallized from toluene to give the product as an off-white solid (425 g, 84%); m.p. 166-168 C; l~_NMR
(CDC13): 2.28 (s, 3H), 6.9-7.05 (m, lOH), 7.2-7.5 (m, 12~), 7.9 (dd, 1~).

E: N-Triphenylmethyl-5-~2-(4'-bromomethylbiphenyl)]
tetrazole To a solution of N-triphenylmethyl-5-~2-(4~-methylbiphenyl)J tetrazole (Step D) (425 g, 0.89 moles) in CC14 (4.0 L) were added N-bromsuccinimide (159 g, 0.89 mole) and dibenzoyl peroxide (22 g, 0.089 moles). The mixture was refluxed for 2 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give a thick oil. The addition of ether (2.0 L) to this oil resulted in a clear solution.
Crystallization, followed by filtration, gave a white solid (367 g, 74Z). m.p. 137-139.5C; lH-NMR (CDC13):
4.38 (s, 2~), 6.9-8.0 (m, 23H).

. ~., , ' ~. ' .~ ,, ~ ~, ' F: 3-Oxohe~tanenitrile To a mechanically stirred solution of 14.3 g MgS04-dried cyanoacetic acid and -100 mg 1,10-phenanthroline in 500 mL T~ at -78C was added 60 mL 2.5 M n-butyllithium in hexanes <~one half of the totalj. The indicator color persisted at this point. The solution was warmed to -5 to +5C after which the indicator color disappeared. Another 55 mL
2.5 M n-butyllithium in hexanes was added until the indicator color again persisted. The mixture was cooled to -78C then 10.0 mL valeryl chloride was added over 3 minutes. After 10 minutes the now yellow solution was allowed to warm to room temperature and stir for 1 hour. The mixture was poured into a solution of 50 mL concentrated HCl in 300 mL water. The mixture was extracted 3 times with ether. The combinet organic material was washed twice with saturated Na~C03 solution then once with brine. The washes were back extracted with ether and the back extracts were washed with brine. The back extracts were combined with the other organic material and then were dried over MgS04. The organic material was stripped of solvent Ln vacuo and was then distilled at -1 Torr with the title compound distilling at 87-91C. The title compound was isolated as a clear oil, 6.32 g, 60% yield. To this material there was added 1% by weight B~T to prevent polymerization. The material was also refrigerate~
to prevent polymerization. Rf 0.18 in 20%
EtOAc/hexane, visualized by ninhydrin stain;

WO 91/tS479 PCl'/US91/01952 _ 94 -lH-NMR (300 MHz, CDC13): ~ 3.46 (s, 2~), 2.62 (3 line m, 2~), 1.61 (m, 2H), 1.35 (m, 2H), 0.92 (t, J=7.3Hz, 3~); 13C-NMR (75.4 MHz, CDC13): ~ 197.6, 113.8, 41.9, 31.9, 25.3, 22.0, 13.7.

G: 2-[(2'-(N-Triphenylmethyl-tetrazol-5-yl)biphen-4-yl~methvll-3-oxohe,,Dtanenitrile To a solution of 225 mg of ethyl 3-oxo-heptanenitrile (Step F) in 10 mL of DMSO was added 144 mg of 601 Na~ in oil. After two minutes, 500 mg of N-triphenylmethyl-5-t2-(4'-bromomethylbiphenyl)~-tetrazole (Step E) was added all at once to the solution. After 20 minutes the solution was poured into brine and extracted 3 times with ether. The organic material was dried over MgSO4, stripped of solvent ~n vacuo, and MPLC'd in 15% EtOAc/hexane.
The title compound was isolated as a white foam, 125 mg, 23Z yielt. Rf 0.23 in 20% EtOAc/hexane, visualized by W and ammonium molybdate/ceric sulfate stain; l~_NMR (300 MHz, CDC13): 8 7.93 (m, l~), 7.47 (10 line m, 2H), 7.40-7.20 (m, 10H), 7.04 (m, 4~), 6.90 (m, 6H), 3.44 (X of ABX, lH), 3.03 (AB of ABX, JAB=138 ~Z- JAg=8-6 ~Z, Jgx=5-3 Hz, ~v=43.s ~z, 2H), 2.59 (sym. 12 line m, 2~), 1.55 (m, 2H), 1.28 (m, 2H), 0.88 (t, J=7.3 Hz, 3~

H: 5-Amino-3-butyl-4-~(2'-(N-triphenylmethyl-tetra-zol-5-vl~biDhen-4-vl~methvllisoxazole A solution of 60 mg of Z-[~2'-(N-triphenyl-methyl-tetrazol-5-yl)biphen-4-yl)methyl]-3-oxoheptane-nitrile (Step G), 17 mg of hydrosylamine hydrochloride, and 100 ~L of pyridine in 3 mL of W091/15479 PcT/usg1/0l9s2 ethanol was heated to reflux for two hours. The mixture was cooled to room temperature and was stripped of solvent in vacuo. The crude material was MPLC'd in concentrated NH40H/EtOAc/hexane to give the title compound.

I: 5-Amino-3-butyl-4-[(2~-(tetrazol-5-yl)biphen-4-yl3methyl~isoxazole The title compound may be obtained by stirring 5-amino-3-butyl-4-t(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]isoxazole (Step H) in methanol with e2cess concentrated HCl at room temperature. After l5 minutes, an indicator quantity of phenolphthalein is added followed by 10% NaO~
until pink. Acetic acid is addet to p~ 5 ant the mixture is stripped of most of its solvent Ln vacuo.
The remainder is partitionet between brine and ether or methylene chloride. The aqueous layer is extracted twice more. The combined organic material is dried over MgS04 or Na2S04, 8tripped of solvent Ln vacuo, then column chromatographed to give the title compound.

5-AMINO-3-BUTYL-l-(2'-C~LOROPHENYL)-4-t(2'-TETRAZOL-5-YL3BIPHEN-4-YL~MET~YLlPYRAZOLE
A mixture of 61 mg 2-t(2'-~N-triphenyl-methyltetrazol-5-yl)biphen-4-yl)methyl]-3-oxoheptane-nitrile, (Example l, Step G) 20 mg o-chlorophenyl-hydrazine, and lO mg NaOAc in 5 mL xylenes was heated to reflux for one hour. The volatile materials were :

WO 91/15479 PCI-/US91/01gS2 ~,~ ?

removed in vacuo. The crude material was redissolved in methanol and 20 drops concentrated HCl was added.
After 30 minutes phenolphthalein was added and 10%
NaO~ was added until pink. The mixture was reacidified with about 500 ~L acetic acid. Most of the volatiles were removed in vacuo. Brine was added and the mixture was extracted three times with ether. The combined organic material was dried over MgS04, stripped of solvent Ln Ya~gQ~ and MPLC~d in 1/55/44 acetic acid/ethyl acetate/hesane to give 11 mg of the title compound. Rf 0.17 in 1/60/39 acetic acid/ethyl acetate/he~ane; lH-NMR (300 MHz, CDC13):
7.87 (d, lH), 7.70-6.98 (m, llH), 3.74 (s, 2H), 2.18 (3 line m, 2~), 1.53 (m, 2~), 1.31 (m, 2H), 0.88 (t, 3H).

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3-BUTYL-1-(2-CHLOROP~ENYL)-4-~t2'-(5-TETRAZOLYL]-BIPHENYL-4-YLlMET~YLl-lH-PYRAZOLE-5-CARBOXYLIC ACID

A: 3-Butyl-5-chloro-1-(2'chlorophenyl~-4-[(2'(n-tri-phenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]-~yrazole A solution of 5-amino-3-butyl-1-(2'-chloro-phenyl)-4-t(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)methyl]pyrazole (Example 2) in CC14 is diazotized according to the procedure in Japanese Patent 1,100,570 to give the title compound.

B: 3-Butyl-l-(2-chlorophenyl)-4-[r2'-(5-tetrazolyl]-biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylic acid A solution of 5-chloro-3-butyl-1-(2'-chlorophenyl)-4-t(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methylpyrazole (Step A) and sodium cyanide in DMSO is heated. The resulting solution nitrile pyrazole tiluted with brine and extracted with ether. The crude product may be hydrolyzed with 50% H2S04 with warming to give the title compound.

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ETHYL 3-BUTYL-l-PHENYL-4-[t2'-(5-TETRAZOLYL)BI-P~ENYL-4-YLlMET~YLl-lH-PYRAZOL~-5-GARBOXYLATE

A: ~thvl 2-methoxvimino-4-oxooctanoate A mixture of 7.00 g (35 mmole) of ethyl 2,4-dioxooctanoate ~K. Seki, J. Isegawa, M. Fukuda, and M. Ohki, Chem. Pharm. Bull., 32 1568 (1984)], 3.07 g (36.75 mmole) of methoxyamine hydrochloride, 35 g of 3A molecular sieves, and 35 ml of dry EtOH was stirred vigorously at room temperature in a stoppered flask. After 21.5 hours, the mixture was filtered, and the filter cake was washed with EtOH. The combined filtrate and washings were concentrated ~n vacuo at < 35C. The residue was partitioned between 100 ml of Et20 and 100 ml of saturated aqueous NaHC03 solution. The Et20 layer was washed with 2 x 100 ml of H20, then filtered to remove some insoluble solid, and re-separated. The Et20 phase was dried over MgS04, filtered, and concentrated in vacuo at < 30C
to give a reddish-orange residual oil. This material was chromatographed twice on silica gel (gradient elution, first with 3-7.5% and then 3-10% EtOAc in hexane) to yield, after vacuum-drying at room temperature, 4.14 g (52%) of very pale yellow reæidual oil, homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz lH NMR (CDCl3): ~ (ppm) 0.88 (t. 3H!.
1.2-1.35 (m, 5H), 1.54 (m, 2H), 2.45 (t, 2H), 3.68 (s, 2H), 4.03 (s, 3H), 4.31 (q, 2H). FAB-MS: m/e 230 ~M+H)+.

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WOgl/15479 PCT/US91/01952 ~ ~; ~ . ~ ., , ~ s., _ 99 _ Analysis (Cll~lgN04) Calcd: C, 5~.62; H, 8.35; N, 6.11 Found: C, 57.65; H, 8.05; N, 6.05 Note: In a similar preparation, the higher Rf contaminant (removed by column chromatography) was isolated in 8% yield and identified as ethyl 2,4-bis(methoxyimino)octanoate, which by NMR appeared to exist as a pair of syn- and anti-isomers.
300 MHz lH NMR (CDC13~: ~ (ppm) 0.89 (apparent dt, 3H), 1.2-1.35 (m, 5H), 1.45 (m, 2H), 2.18,2.26 (t, total 2H), 3.34 (apparent d, 2H), 3.74 (apparent d, 3H), 4.04 (apparent d, 3H). 4.32 (apparent dq, 2~).
FAB-MS: 259 (M+R)+.

B: Ethyl 3-~(2'-cyanobiphenyl-4-yl)methyl]-2-methoxvimino-4-oxooctanoate A mixture of 4.08 g (17.8 mmole) of ethyl 2-methoxyimino-4-oxooctanoate (from Step A), 5.70 g (17.8 mmole, based on 85% purity) of 4-bromomethyl-2'-cyanobiphenyl (EP 253,310), 2.95 g (21.4 mmole) of freshly pulverized anhydrous K2C03, and 5Q ml of dry DMF was 8tirred vigorously at room temperature under N2. After 24 hours, the mixture was partititoned between 1 L. of EtOAc and 1 L. of 0.2 N HCl. The EtOAc phase was washed with 3 x 1 L of H20, then dried over MgS04, filtered, and concentrated in vacuo. The viscous residual oil was dissolved in CH2C12 and evaporated onto silica gel (just enough to give a free-flowing powder). This was added as a slurry in hexane to the top of a column of silica gel (74 x 6 cm) packed in hexane. Gradient elution with :. ~.... . .
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Wo91/15479 PCTtUS91/01952 '' 2~

5-10% EtOAc in hexane yielded 4.56 g (61%) of colorless residual gum, suitable for use but containing a trace of higher Rf impurity by TLC in 4:1 hexane-EtOAc.
400 MHz lH NMR (CDC13): ~ (ppm) O.86 (t, 3~), 1.5-1.3 (m, 5~. including t at 1.23), 1.53 (m, 2H), 2.31 ~t, 2H), 2.98 (dd, lH), 3.42 (dd, 1~), 3.98 (s, 3~).
4.15-4.3 (m, 3H), 7.23 (d, 2H), 7.35-7.5 (m, 4H), 7.60 (m, lH), 7.72 (d, lH). FAB-MS: m/e 421 (M+H)+.

After prolonged standing at room temperature, the remaining material had partially crystallized and was intuced to crystallize fully upon trituration with petroleum ether. The material was collected on a filter and washed with some additional petroleum ether. After vacuum drying at room temperature, there was obtained 3.76 g (projected yield 56%) of white crystals, mp 62-63-C., homogeneous by TLC in 4:1 hexane-EtOAc.
AnalysiS (C25~28N204) Calcd: C, 71.40; H, 6.71; N, 6.66 Found: C, 71.38; ~, 6.64; N, 6.60 C: Ethyl 3-Butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-1-phenvl-l~-pyrazole-5-carbo2ylate A mixture of 210 mg (0.5 mmole) of ethyl 3-t(2l-cyanobiphenyl-4-yl)methyl]-2-methogyimino-4-oxooctanoate (from Step B), 219 mg (1.5 mmole) of phenylhydrazine hydrochloride. 4 ml of glacial acetic acid, and 2 ml of 2-methoxyethanol was stirred under N2 at 105C for 40 hours. After combination with two similar 0.025 mmole-scale reactions, the mixture was .. ~ -O

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concentrated in vacuo at < 50C. The residue was partitioned between 20 ml of EtOAc and 20 ml of 0.2 _ HCl. The EtOAc phase was washed with 20 ml of H2O, then dried over MgSO4, filtered, and concentrated Ln vacuo. The residual oil was dissolved in CH2C12 and evaporated onto silica gel (just enough to give a free flowing powder). This was added as a slurry in hexane to a column of silica gel (40 x 2.4 cm) packed in hexane. Elution with 95:5 hexane-EtOAc followed by 90:10 hexane-EtOAc yielded (after vacuum-drying) 169 mg (66Z) of golden-yellow residual gum, homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz 1~ NMR (CDC13): ~ (ppm) 0.86 (t, 3H), 1.03 (t, 3~, 1.33 (m, 2H), 1.57 (m, 2H), 2.61 (t, 2H), 4.12 (q, 2H), 4.17 (s, 2H). 7.29 (d, 2H), 7.35-7.5 (m, 9H), 7.60 (dd, lH), 7.73 (d, lH). FAB-MS: m/e 464 (M+H)+.
AnalySiS (C30H29N3O2) Calct: C, 77.73; ~, 6.31; N, 9.06 Found: C, 77.49; H, 6.09; N, 8.81 .

D: Ethyl 3-Butyl-l-phenyl-4-~(2'-(5-tetrazolyl)-bi~henvl-4-vllmethvll-lH-~vrazole-5-carboxylate To 116 mg (0.25 mmole) of ethyl 3-butyl-4-t(2'-cyanobiphenyl-4-yl)methyl]-1-phenyl-la pyrazole-5-carboxylate (from Step C) were added 180 mg (0.875 mmole) of trimethyltin azite (Example 1, Step B) and 1.2 ml of dry toluene. The mixture was stirred at reflux under N2 for 39 hours, then coole~.
and concentrated in vacuo. The residual gum was treated with 1.2 g of silica gel and 3.6 ml of dry MeO~. The mixture was stirred overnight in a . ::
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wost/1s479 PCT/-JS91/01952 stoppered flask and then concentrated in vacuo at <
30-C. The residual powder was added as a slurry in CH2Cl2 to the top of a column of silica gel (24 x 2.3 cm) packed in CH2C12. Gradient elution with 1-4%
MeOH in CH2C12 afforded (after vacuum-drying at 50OC.) 95.9 mg (76%) of pale yellow, stiff foam, mp - >60C. (gradual); homogeneous by TLC in 19:1 CEI2C12-MeOH .
400 MHz lH NMR (CDC13): ~ (ppm) 0.88 (t, 3~), 0.99 (t, 3H, 1.35 (m, 2H), 1.59 (m, 2H), 2.58 (t, 2H), 4.09 (q, 2H), 4.15 (s, 2H). 7.14 (d, 2H), 7.24 (d, 2H), 7.3-7.6 (m, 8H), 8.17 (d, lH) FAB-MS: m/e 507 (M+H)+.
Analysi8 (C30H30N602) Calcd: C, 7I.12; H, 5.97; N, 16.59 Found: C, 70.96; H, 5.99; N, 16.50 EXAMPT.~ 5 3-BUTYL-l-PHENYL-4-[[2'-(5-TETRAZ0LYL)BIPHENYL-4-YL]-.2~_=5-CARBOXYLIC ACID
A solution of 70.6 mg (0.139 ole) of ethyl 3-butyl-1-phenyl-4-tt2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carboxylate (from Example 4) in 1.1 ml of MeOH was treated with 0.55 ml (1.4 mmole) of 2.5 _ NaOH. The resulting solution was stirred unter N2 in an oil bath at 60-C for 21 hours. The cooled solution was filtered. diluted with 10 ml of H20, and acidified to pH < 2 by gradual addition of 2 N HCl, resulting in precipitation.
After a few minutes, the precipitate was collected on a filter and washed thoroughly with dilute HCl (pH

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WO91/1s47s PCT/US91/01952 ..

~ 103 -2). The solid was sucked dry overnight on the filter and then dried in vacuo (< 1 mm) at 75C for several hours to yield 62.3 mg (92Z) of white powder, mp >
115C (gradual; preliminary softening); homogeneous by TLC in 9:1 CH2C12-MeOH. 400 MHz lH NMR (DMSO-d6):
(ppm) 0.79 (t, 3H), 1.24 (m, 2H), 1.41 (m, 2H), 2.45 (t, 2H), 4.05 (s, 2H), 6.99 (d, 2H), 7.12 (d, 2H), 7.35-7.7 (m, 9H), FAB-MS: m/e 479 (M+H)+.
AnalysiS (c28H26N6o2-o 6~20) Calcd: C, 68.72; H, 5.60; N, 17.18 Found: C, 68.67; H, 5!64; N, 17.17 ETHYL 3-BUTYL-1-(2-CHLOROPHENYL)-4-[[2'-(5-TETRA-ZOLYL)BIPHENYL-4-YLlMETHYLl-lH-PYRAZOLE-5-CARBOXYLATE

A: Ethyl 3-butyl-4-t(2~-cyanobiphenyl-4-yl)meth (2-chlorophenyl)-1~-pyrazole-5-carboxylate Reaction of ethyl 3-[(2'-cyanobiphenyl-4-yl)methyl]-2-methoxyimino-4-oxooctanoate (Example 4, Step B) with 2-chlorophenylhydrazine hydrochloride accorting to the procedure of Esample 4, Step C, gave a 73% yield of the title compound as a yellow-orange gum; nearl~ homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz lH NMR (CDC13): ~ (ppm) 0.85 (t, 3H), 1.32 (m, 2H), 1.58 (m, 2H), 2.61 (t, 2H), 4.11 (br q, 2H), 4.23 (s, 2H). 7.28 (d. 2H~, 7.35-7 ~
(m, 8H), 7.61 (dd, lH), 7.73 (d, lH). FAB-MS: m/e 498 (M+H)+.

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wo91/1s47s - PCT/US91/01952 "

Analysis (c3oH28clN3o2-o 1C~2C12) Calcd: C, 71.37; H, 5.61; N, 8.30 Found: C, 71.31; H, 5.45; N, 8.10 B: Ethyl 3-butyl-1-(2-chlorophenyl)-4-[[2'-(5-tetra-zolyl)biphenyl-4-yl]methyl]-1~-pyrazole-5-carbox-ylate The product from Step A was converted to the title compound by the procedure of Example 4, Step D, in 65% yield as a pale yellow, stiff foam, mp >70C. (gradual); homogeneous by TLC in 9:1 CH2C12-MeOH. 400 M~z 1~ NMR (CDC13): ~ (ppm) 0.87 (t, 3H), 0.96 (t, 3H), 1.34 (m, 2H), 1.60 (m, 2H), 2.61 (t, 2H), 4.08 (br q, 3H), 4.22 (s, 2H), 7.16 (d, 2H), 7.25 (d, 2H), 7.3-7.6 (m, 7H), 8.21 (d, lH). FAB-MS:
m/e 498 (M+H)+.
AnalySiS (C30H29clN6O2) Calcd: C, 66.59; ~, 5.40; N, 15.53 Found: C, 66.38; H, 5.56; N, 15.31 ~n~L~

3-BUTYL-1-(2-CHLOROPHENYL)-4-t~2'-(5-TETRAZOLYL)-BIPHENYL-4-YLlMETHYLl-lH-PYRAZOLE-5-CARBOXYLIC ACID
By the method of Example 5, ethyl 3-butyl-1-(2-chlorophenyl)-4-tt2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-lE-pyrazole-5-carboxylate (Example 6) was converted in 96% yield to the title compound as a nearly white solid, mp > 125C (gradual; preliminar~
softening); homogeneous by TLC in 9:1 CH2C12-MeOH.
400 M~z lH NMR (DMSO-d6): ~ (ppm) 0.78 (t, 3U), 1.22 .. . . . , .-~ ... .
., , ~ , , , ; ., .. ~: ; ., , ; ; , ~ :,,, -:. ,. : -.
: : :,.,, . ,., . i . , ,. . ...

W O 91/15479 PC~r/US91/Ot952 , ., . . .`. i . ~
f~ 105 -(m, 2H), 1.42 (m, 2H), 2.45 (t, 2H), 4.11 (s, 2H), 7.01 (d, 2H), 7.10 (d, 2H), 7.4-7.7 (m, 8H). FAB-MS:
m/e 513 (M+H)+.
AnalySiS (C28H25clN602-o 5H20) Calcd: C, 64.42; H, 5.02; N, 16.10 Found: C, 64.50; H, 5.19; N, 15.91 ~XA~L~ 8 .

ETHYL 3-BUTYL-1-(2-METHYLPHENYL)-4-~2'-(5-TETRA-ZOLYL)BIP~ENYL-4-YLlMET~YLl-lH-PYRAZOLE~5-CARBOXYLATE

A: Ethyl 3-butyl-4-~(2'-cyanobiphenyl-4-yl]methyl]-1-(2-methylphenyl)-lH-~yrazole-5-carbosylate Reaction of ethyl 3-~(2'-cyanobiphenyl-4-yl)-methyl]-2-methosyimino-4-osooctanoate (Esample 4, Step B) with Q-methylphenylhydrazine hydrochloride according to the procedure of Esample 4, Step C, yielded 70Z of the title compound as a light orange gum; homogeneous by TLC in 4:1 hesane-EtOAc.
400 M~z lH NMR (CDC13): ~ (ppm) 0.85 (t, 3H), 0.96 (t, 3H), 1.32 (m, 2H), 1.58 (m, 2H), 2.03 (æ, 3H), 2.62 (t, 2H), 4.05 (q, 2H), 4.21 (æ, 2H), 7.2-7.5 (m, 10H), 7.61 (dd, lH), 7.73 (d, lH) FAB-MS: m/e 478 (M+H)I.
AnalySiS (C31H31N3O2) Calcd: C, 77.96; H, 6.54; N, 8.80 Found: C, 77.67; H, 6.55; N, 8.57 .
. . .

wo st/ts47s ~ ~ ~.3 Pcrtuss1/01ss2 B: Ethyl 3-butyl-1-(2-methylphenyl)-4-~[2'-(5-tetra-zolyl)biphenyl-4-yl~methyl]-1~-pyrazole-5-carboxylate ~ y the proceture of Example 5, Step D, the product from Step A (above) was converted in 69%
yield to the title compound as a nearly colorlegs glass, mp >60-C (gradual); homogeneous by TLC in 9:1 CH2C12-MeO~. 400 MHz lH NMR (CDC13): ~ (ppm) O.88, 0.91 (overlapping t, each 3H), 1.34 (m, 2H), 1.60 (m, 2H), 2.00 (s, 3H), 2.60 (t, 2H), 4.03 (q, 2H), 4.20 (s, 2H), 7.1-7.6 (m, llH), 8.17 (d, lH) FAB-MS: m/e 521 (M+H)+.
Analysis (C3lH32N602-o 1 C~2C12) Calcd: C, 70.59; H, 6.13; N, 15.89 Found: C, 70.27; H, 6.16; N, 15.86 3-BUTYL-1-(2-MET~YLP~ENYE)-4-~2'-(5-TETRAZOLYL)-BIpHENyL-4-yLlMEI~r~ RAzQ~ -cARBoxyLI~ AC}D
Ethyl 3-butyl-1-(2-chlorophenyl)-4-~2'-; (5-tetrazolyl)biphenyl-4-yl]methyl]-1~-pyrazole-~5-carbo y late (Example 8) was saponified according to the procedure of Example 5 to give a 91% yield of the title compound as a white powder, mp >125C.
(gradual; preliminary softening); homogeneous by TLC
in 9:1 CH2C12-MeOH. 400 MHz lH NMR (DMSO-d6): ~
(ppm) 0.78, (t, 3H), 1.22 (m, 2H). 1.42 (m, 2H). 1 '-'4 (s, 3H), 2.45 (t, 2H), 4.10 (s. 2H), 7 00 (d, 2H), 7.10 (d, 2H), 7.2-7.4 (m, 4H), 7.5-7.7 (m, 4H).
~; FAB-MS: m/e 493 (M+H)+.

.

.

WO 91/lS479 PCTIUS91/01952 .,: .

.. ~....... 3 -- 107 ~ .J.. ~
Analysis (C29H28N602-0.6 H2O) Calcd: C, 69.19; H, 5.85; N, 16.70 Found: C, 69.35; H, 5.62; N, 16.37 ~XA~LE 10 ETHYL 3-BUTYL-1-(2,6-DICULOROP~ENYL~-4-[[2~-(S-TETRAZOLYL)BIPHENYL-4-YL~METHYL]-l~-PYRAZOLE-S-CARBOXYLATE

A: Ethyl 3-butyl-4-~(2'-cyanobiphenyl-4-yl)methyl]-1-(2.6-dichloro~henvl)-1~-~vrazole-S-carboxvlate Ethyl 3-~(2-cyanobiphenyl-4-yl)methyl]-2-methoxyimino-4-oxooctanoate (Example 4, Step ~) was reacted with 2,6-dichlorophenylhydrazine hydrochloride according to the procedure of Example 4, Step C, to give a 74% yield of the title compound as a light orange gum; homogeneous by TLC in 4:1 hexane-EtOAc. 400 M~z 1~ NMR (CDC13): ~ (ppm) 0.84 (t, 3H), 1.00 (t, 3H), 1.31 (m, 2~), 1.56 (m, 2~), 2.62 (t, 2H), 4.10 (q, 2H), 4.26 (s, 2U), 7.2-7.5 (m, 9U), 7.61 (dd, lH), 7~.74 (d, lU). FAB-MS: m/e 532 ~M+H)+.
Analysi8 (C30H27C12N3O2) Calct: C, 67.67; U, 5.11; N, 7.89 Found: C, 67.38; H, 5.10; N, 7.81 B: Ethyl 3-Butyl-1-(2,6-dichlorophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-lH-pyrazole-S-carboxvlate Reaction of the product from Step A with trimethyltin azide according to the method of Example ,. ..

. ., ~-, . ~ , ~ .
.. .. ,,,~ ~ -. . ~. .

WO91/15479 ~ ~ ~ ~,1~ PCT/US91/01952 .. ..

4, Step D, provided a 51% yield of the title compound as a very pale yellow-tan, stiff foam, mp >
80C (gradual); homogeneous by TLC in 9:1 C~2C12-MeOH.
200 MHz lH NMR (CDC13): ~ (ppm) 0.89, (t, 3H), 1.00 (t, 3H), 1.36 (m, Z~), 1.63 (m, 2~), 2.66 (t, 2H), 4.12 (q, 2~), 4.28 (s, 2H), 7.15-7.6 (m, 10~), 8.26 (d, lH), FAB-MS: m/e 575 (M+H)+.
AnalySiS (C30H28cl2N602) Calcd: C, 62.61; H, 4.90; N, 14.61 Found: C, 62.51; H, 4.94; N, 14.34 3-BUTYL-1-(2,6-DICHLOROPEENYL)-4-t[2'-(5-TETRA-ZOLYL)BIPE~ENYL-4-YL]METHYL]-lEl-pyRAzoLE-5-cARBogyLIc ACID
Saponification of ethyl 3-butyl-1-(2,6-bi-phenyl-4-yl]methyl]- U-PYrazole-5-carbosYlate according to the procedure of Esample S gave an 87%
yield of the title compound as a white powder, mp >130-C (gradual; preliminary softening); homogeneous by TLC in 9:1 CH2C12-MeOH. 400 M~z 1~ NMR (DMS0-d6):
(ppm) 0.77, (t, 3H), 1.21 (m, 2H), 1.41 (m, 2H), 2.46 (t, 2H), 4.14 (s, 2H), 7.00 (d, 2H), 7.08 (d, 2H), 7.5-7.7 (m, 7H), FAB-MS: m/e 547 (M+H)+.
Analy8iS (C28H24cl2N602-o 4~20) Calcd: C, 60.63; H, 4.51; N, 15.15 Found: C, 60.92; H, 4.52; N, 14.76 ,, , .,. ~ - , . .
.;; ;.,.- : ... , ., ~.. ; :, .. : - -. ~ . " ; . ~ ,. , ., ~ . .. . . ..

WO9t/15479 PCT/US91/01952 , ETHYL 3-BUTYL-4-tt2'-(5-TETRAZOLYL)BIPHENYL-4-YL]METHYL]-1-~2-~TRIFLUOROMETHYL)PHENYL]-lH-A: Ethyl 3-butyl-4-~(2'-cyanobiphenyl-4-yl-methyl]-1-(2-(trifluoromethyl)phenyl~-lH-pyrazole-5-carboxylate Reaction of ethy} 3-~(2'-cyanobiphenyl-4-yl)methyl]-2-methoxyimino-4-oxooctanoate (Example 4, Step B) with 2-(trifluoromethyl)phenylhydrazine hydrochloride according to the method of Example 4, Step C, afforded a 48% yield of the title compound as a light orange gum; homogeneous by TLC in 4:1 hexane-EtOAc. 400M~z lH NMR (CDC13): ~ (ppm) 0.84, (t, 3H), 0.94 (t, 3H), 1.30 (m, 2H), 1.55 (m, 2H), 2.60 (t, 2H), 4.05 (q, 2H), 4.23 (8, 2H), 7.26 (d, 2H), 7.4-7.8 (m, 10H) FAB-MS: m/e 532 (M+H)+.
Analysi 9 ( C31H28F3N32) Calcd: C, 70.04; H, 5.31; N, 7.91 Found: C, 70.30; ~, 5.21; N, 7.77 B: Ethyl 3-butyl-4-tt2'-(5-tetrazolyl)biphenyl-4-yl-methyl]-l-t2-(trifluoromethyl)phenyl]-l~I-pyrazole-5-carboxvlate The product from Step A was reacted with trimethyltin azide according to the procedure of Example 4, Step D, to give a 66% ~ield of the title compount as a golden-tan glass, mp ~80OC (gradual);
homogeneous by TLC in 9:1 CH2C12-MeOH. 400MHz ,, . ,. , .. . - ; - -.
- . ~ . , .

~ , .. . ...

WO 91/15479 PCl'tUS91/01g52 lH NMR (CDC13): ~ (ppm) 0.86,0.90 (overlapping t, each 3H), 1.32 (m, 2H), 1.58 (m, 2H), 2.62 (t, 2H), 4.04 (q, 2H), 4.23 (s, 2~), 7.17 (d, 2~), 7.25 ~d, 2H), 7.39 (d, lH), 7.45 (d, lH), 7.5-7.7 (m, 4H), 7.75 (d, lH), 8.2S (d, lH). FAB-MS: m/e 575 (M+H)+.
Analysi8 (C31~29F3N6O2) Calcd: C, 64.80; H, 5.09; N, 14.63 Found: C, 64.62; ~, 4.89; N, 14.43 EXAMP~-F 13 3-BUTYL-4-~t2'-<5-TETRAZOLYL)BIP~ENYL-4-YL]-MET~YL~ 2-(TRIFLUOROMETHYL)PHEN~L]-l~-The title compound was prepared from ethyl 3-butyl-4-~2'-(5-tetrazolyl)biphenyl-4-yl~methyl~-1-(2-(trifluoromethyl)phenyl~- U-pyrazole-5-carboxylate (Example 12) by use of the procedure of Example 5. This material was obtained in 90% yield as a white powder, mp > 125-C (gradual; preliminary softening); homogeneous by TLC in 9:1 CH2C12-MeOH.
400 M~z lH NMR (DMSO-t6): ~ (ppm) 0.76 (t, 3H), 1.19 (m, 2~), 1.39 (m, 2H), 2.43 (t, 2H), 4.12 (8, 2~), 6.99 (d, 2H), 7.08 (d, 2~), 7.5-7.8 (m, 7~), 7.86 (d, lH), FAB-MS: m/e 547 (M+H)+.
Analy8i8 (Cz9H25F3N602) Calcd: C, 63.73; H, 4.61; N, 15.38 Found: C, 63.47; H, 4.33; N, 15.09 . ~

. . .. . , . .~, . . . . . ..

.. . ..

WO 91/15'179 PCI~/US91/OlgS2 - 111 - .
," o ETHYL 3-BUTYL-4-[t2'-(S-T~TRAZOLYL)BIP~NYL-4-YL]-MET~YLl-l~-PYRAZOLE-5-CARBOXYLATE

A: Ethyl 3-Butyl-4-t(2'-cyanobiphenyl-4-yl)methyl]-1U-~yrazole-5-carbox~late The title compound was prepared by reaction of ethyl 3-butyl-4-t(2'-cyanobiphenyl-4-yl)methyl]-2-metho~yimino-4-osooctanoate (Example 4, Step B) with hydrazine hydrochloride under the conditions described in E~ample 4, Step C, except that only 2 equivalents of hydrazine hydrochloride were used.
Purification was achieved by column chromatography on silica gel using a gradient of 5-2S% EtOAc in hexane to give a 59% yield of the title compound as a light yellow, stiff gum; homogeneous by TLC in 2:1 hexane-EtOAc. 400 M~z lU NffR (CDC13): 8 (ppm) 0.85 (t, 3~), 1.30 (t overlapping m, total 5~), 1.54 (m, 2~), 2.61 (t, 2~), 4.16 (8, 2~), 4.33 (g, 2~), 5.3 (br 8, lU), 7.23 (d, 2R), 7.35-7.5 (m, 4H), 7.60 (dd, lR), 7.72 (d, lR). FAB-MS: m/e 388 (M+R)+.
Analy8i8 (C24~25N302) Calcd: C, 74.39; ~, 6.50; N, 10.84.
Found: C, 74.38; ~, 6.57; N, 10.68.

B: Ethyi 3-Butyl-4-~t2'-(5-tetrazolyl)biphenyl-4-yl]-e~o~ L=c~ -s-carboxvlate The product from Step A was reacted with trimethyltin azide according to the procedure of E~ample 5, Step D, but in the column chromatography the solvent gradient was increased to a masimum of ... . - - . , - . . . .

. . . . . .

;. - ; . -:: - ~`~ - - , ~. ,, , , ,:

WO 9t/15~79 Pcl/US9l/o1952 7.5% MeO~ in C~2C12. The title compound was obtained in 49% yield as a cream-colored, stiff foam, mp>100 (gradual); nearly homogeneous by TLC in 9:1 CH2C12-MeOH. 400 M~z lH NMR (DMSO-d6): ~ (ppm) 0.79 (t, 3H), 1.1-1.3 (m, 5H), 1.40 (m, 2~), Z.4-2.55 (m, 2~, overlapping residual DMSO peak), 3.98 ~s, 2~), 4.18 (br m, 2~), 6.94 (t, 2H), 7.01 (d, 2~), 7.45-7.65 (m, 4H). FAB-MS: m/e 431 (M~H)+.
Analy9ig (C24~26N62 0-05 H2O 0.15 CH2C
Calcd: C, 65.30; ~, 5.99; N, 18.92.
Found: C, 65.67; H, 6.07; N, 18.59.

3-BUTYL-4-~2'-(5-TETRAZOLYL)BIP~EN~L-4-YL]METHYL]-l~-PYRAZOLE-5-CARBOXILIC ACID
Saponification of ethyl 3-butyl-4-[~2'-(5-tetrazolyl)biphenyl-4-yl] methyl]-l~-pyrazole-5-carboxylate (Example 14) accorting to the procedure of Example 5 furnished the title compound in 93%
yield as a cream-colored powder, mp 205.5-207 C.
dec.; homogeneous by TLC in 9:1 C~2C12-MeO~.
400 MHz 1~ NMR (DMSO-d6): ~ (ppm) 0.78 (t, 3~), 1.18 (m, 2H), 1.39 (m, 2H), 2.43 (t, 2H), 4.00 (s, 2~), 6.94 (d, 2H), 7.03 (d, 2H), 7.45-7.7 (m, 4H). FAB-MS:
m/e 403 (M+H)+.
Analy8i8 (C22H22N602 0 95 ~2) Calcd: C, 62.98; H, 5.74; N, 20.03.
Found: C, 63.34; H, 5.59; N, 19.67.

.. .. , . ~.. . .
., , . ~, , "
':
, ' 1 .

WO91/15479 PcT/ussl/ol9s2 ,.

E,XAMPLE 16 ETHYL 3-Bul~L-4-t~2'-(5-TETRAZOLYL)BIPHENYL-4-YL]MFTHYL~ (2,2,2-TRIFLUOROETHYL)-l~-PYRAZOLE-5-CARB0XYLATE, A: Ethyl 3-Butyl-4-~(2'-cyanobiphenyl-4-yl)methyl]-1-(2.2.2-trifluoroethyl)-lH-~yrazole-5-carhoxvlate A suspension of 210 mg (0.5 mmole) of ethyl 3-~(2~-cyanobiphenyl-4-yl)methyl~-2-methoxyimino-4-oxooctanoate (Example 4, Step B) in 2.0 ml of glacial acetic acid was treated with 189 ~l (245 mg, 1.5 mmole) of 70% trifluoroethylhydrazine (aqueous), followed by 125 ~1 (1.5 "ole) of concentrated (12N) hytrochloric acid. The misture was stirred under N2 in an oil bath at 105- C. for 23 hours. The resulting solution was cooled and concentrated Ln vacuo. The residue was partitioned between 20 ml of EtOAc and 20 ml of 0.2 ~ ~Cl. I'he EtOAc phase was washed with 20 ml f ~2~ then dried over MgSO4, filtered, and concentrated in vacuo. The residue was dissolved in C~2C12 and evaporated onto 2.0 g. of silica gel. The resulting try powder was added as a slurry in hexane to the top of a column of silica gel (34 x 2.3 cm) packed in hexane. Elution with 95:5 hexane-EtOAc yielded 85.9 mg (37%) of the title compound as a nearly colorless, viscous oil;
homogeneous by TLC in 4:1 hexane-EtOAc. 400 MHz lH
NMR (CDC13): ~ (ppm) 0.84 (t. 3H). 1.21 (t, 3H), 1.29 (m, 2H), 1.52 (m, 2H), 2.54 (t, 2H), 4.13 (s, 2H), 4.27 (q, 2H), 5.23 (q, 2H), 7.16 (d, 2H), 7.35-7.5 (m, 4H), 7.60 (dd, lH), 7.73 (d, lH). FAB-MS: m/e 470 (M+H)+.

.
.
,..... .. . .
.
,,,. ~ .

WOgl/15479 PCT/US91/01952 AnalySiS (C26H26F3N32) Calct: C, 66.51; ~, 5.58; N, 8.95.
Found: C, 66.28; H, 5.67; N, 8.67.

B: Ethyl 3-Butyl-4-~t2'-(5-tetrazolyl)biphenyl-4-yl]-1-(2.2.2-trifluoroeth~l)-lH-pyrazole-5-carboxYlate The product from Step A was reacted with tri-methyltin azide according to the procedure of Example 4, Step D, to give a 65% yield of the title compound as a colorless glass, mp > 45C (gradual);
homogeneous by TLC in 9:1 CH2C12-MeOH. 400 M~z lH
NMR (CDC13): ~ (ppm) 0.86 (t, 3H), 1.26 (t, 3H), 1,31, (m, 2H), 1.54 (m, 2~), 2.55 (t, 2H), 4.13 (s, 2H), 4.31 (g, 2H), 5.21 (q, 2H), 7.15 (m, 4H), 7.37 (d, 1~), 7.5-7.6 (m, 2H), 8.21 (d, lH). FAB-MS: m/e 513 (MIH)+.
AnalysiS (C26H27F3N6O2) Calcd: C, 60.93; H, 5.31; N, 16.40.
Found: C, 60.64; H, 5.45; N, 16.16.

~3~L~Z
/i 3-BUTYL-4-~2'-(5-TETRAZOLYL)BIPHENYL-4-YL]METHYL-l-(2,2,2-TRIFLUOROE'T~L)-l~-PYRAZOLE-5-CARBOXYLIC
ACID
Ethyl 3-butyl-4-t(2l-cyanobiphenyl-4-yl) methyl]-l-(2,2,2-trifluoroethyl)-1~-pyrazole-5-carboxylate (Example 16) was saponified according to the procedure of Example 5 to give an 88% yield of the title compound as a white powder, mp >95C
(gradualj; homogeneous by TLC in 9:1 CH2C12-MeOH.
400 M~z lH NMR (DMSO-d6): ~ (ppm~ 0.77 (t, 3H), 1.19 . . .
..... .. ~,.,. , , ,: ,, , :
W091/15479 PCT/US9ltO1952 .

f~ 115 -~m, 2~`, 1.37 (m, 2H), 2.40 (t, 2H), 4.04 (s, 2H), 5.36 (q, 2H), 6.99 (ABq, 4H), 7.45-7.7 (m, 4H).
FAB-MS: m/e 485 (M+H)+.
Analy8iS (c24H23F3N6o2-o 6H2o) Calcd: C, 58.20; H, 4.92; N, 16.97.
Found: C, 58.33; ~, 4.77; N, 16.75.

El~rL 4-[~2'-(N-BENZOYLSULEAM~YL)BIPEENYL-4-YL]-METHYL]-3-n-BUTYL-1-(2-CHLOROPEENYL)-l~-PYRAZOLE-5-CARBOXYLATE

A: 2-Bromo-N-(tert-butyl~benzenesulfonamide To a stirred solution of 2-bromobenzene-sulfonyl chloride (Lancaster Synthesis) (2.21 g, 8.65 mmol) in chloroform (40 ml) under nitrogen at room temperature was added tert-butylamine (Aldrich) (2.30 ml, 21.9 mmol). The orange solution was stirred at room temperature for 12 hours, then the mixture evaporated to dryness. Elash chromatograFhy (silica gel, 15Z ethyl acetate-hexane) afforded the title compound, (2.12 g, 84%) as a white solid; lH NMR (300 MHz, CDC13) ~ 8.18 (t, J = 8.5 Hz, lH), 7.73 (d, J =
8.5 Hz, lH), 7.50-7.35 (m, 2H), 5.11 (s, lH), 1.20 ~8, 9~)-B: ~-Tolyltrimethvltin p-Tolylmagnesium bromide solution (Aldrich) (l.OM solution in diethyl ether) (53 ml, 0.0530 mol) was added tropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in tetrahydrofuran (50 ml) under nitrogen ' ~ ,, , ' ' 2. . ~

at -10C. The suspension was allowed to warm slowly to room temperature over 3 hours then saturated ammonium chloride solution (lO ml) was added followed by sufficient water to dissolve the precipitate. The solution was extracted three times with diethyl ether-hexane (l:l). The combined organic phase was washed with brine, dried (magnesium sulfate) ant the solvents removed Ln vacuo. Vacuum distillation of the residue afforded a colorless liquid (39-40C, O.l mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin (7.30 g, 82Z) as a colorless liquid; lH NMR (300 M~z, CDCl3) ~ 7.40 (d, J = 7.7 Hz, 2~), 7.19 (d, J = 7.7 Hz, 2~), 2.34 (s, 3H), 0.30 (8, 9H).

C: 2'-(N-t-Butylsulfamoyl)-4-methylbiphenyl 2-Bromo-N-(tert-butyl)benzene8ulfonamide (from Step A) (l.00 g, 3.92 mmol), p-tolyl-trimethyltin (from Step B) (1.95 g, 6.67 mmol), bi~(triphenylphosphine)palladium(II) chloride (Aldrich) (165 mg, 0.235 mmol) ant di~ethylformamite (25 ml) were heated with stirring under nitrogen at 90-C for S hours. The black suspension was cooled to -room temperature, then filtered through a pad of Celite which was washed with tetrahydrofuran. The colorlesæ filtrate was evaporated to dryness, then chromatographed (silica gel, 10% ethyl acetate-hexane) to give the title compound (0.88 g, 74%) as a white solid; lH NMR (300 M~z, CDCl3) ~ 8.16 (d, J = 7.9 Hz, lH), 7.60-7.37 (m, 4H), 7.36-7.24 (m, 3~), 3.57 (8, 1~), 2.42 (8, 3~), 0.99 (8, 9~).

" . ,, -. ~ . . ~ , , ,' ,. ! ~ . "
' ' ' ' '.' ' ' '~ . ' D: [2'-(N-t-Butylsulfamoyl)biphenyl-4-yl]methyl bromide N-Bromosuccinimide (387 mg, 2.17 mmol), ~,a'-azobiæ(isobutyronitrile) (catalytic), 2'-(N-t-butylsulfamoyl)-4-methylbiphenyl (from Step C) (550 mg, 1.81 mmol) and carbon tetrachloride (50 ml) were heated with stirring at reflux for 3 hour. After cooling to room temperature the mixture waæ filtered and the filtrate evaporated to dryness. Flash chromatography (silica gel, initially 10 and then 20%
ethyl acetate-hexane) afforded the title compound [699 mg, 77% pure (the remainder of the material was the corresponding dibromo derivative), 97% yield] as a white solid; lH NMR (300 MHz, CDC13) ~ 8.17 (dd, J
= 7.5, 1.6 Hz, lH), 7.68-7.45 (m, 6H), 7.31 (dd, J =
7.5, 1.6 ~z, lH), 4.55 (s, 2H), 3.52 (s, 1~), 1.00 (s, 9H).

E: Ethyl 3-tr2~-(N-t-Butylsulfamoyl)biphenyl-4-yl]-methyl1-2-metho y imino-4-oxooctanoate A mixture of 50 mg (0.218 mM) of ethyl 2-methoxyimino-4-oxooctanoate (Example 4, Step A), 83 mg (0.2l8 mM) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (Step D), 36 mg (0.262 mM) of freshly pulverized anhydrous potassium carbonate, and 0.6 mL of dry DMF was stirred vigorously for 24 hours at room temperature at which time the starting material was all consumed tTLC (5:1 hexane/EtOAc)~.
The mixture was partitioned between lOmL of EtOAc and 10 mL of 0.2N ~Cl. The EtOAc layer was then washed with 3 X 10 mL H20~ 1 X 5 mL brine, and dried briefly over anhydrous sodium sulfate. The filtrate, WO g1/15479 PCr/US91/OlgS2 2~
;

obtained from filtration over sintered glass, was concentrated to dryness and the resulting residue was flash chromatographed over 20 mL silica gel (column packed using hexane, sample introduced as a solution in CH2C12) eluting with 20/1 hexanelethyl acetate, to give 83 mg (71%) of the desired product as an oil, homogeneous by TLC. Rf=0.35 in 5:1 hexane/EtOAc.
lH NMR (200 MHz, CDC13, ppm) = ~ 0.88 (t, J=7.2 Hz, 3H), 1.00 (s, 9H), 1.31 (m, 5H), 1.52 (m, 2H), 2.32 (t, J=7.0 Hz, 2~), 3.03 (m, lH), 3.40 (m, lH), 3.61 (8, lH), 4.04 (s, 3H), 4.25 (m, 3H), 7.16-7.52 (m, 7~), 8.15 (m, lH) Mass spectrum: FAB (m/~) 531 (M+l)+

F: Ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-lH-pyrazole-5-carboxylate A mi~ture of 95 mg (0.179 mM) of ethyl 3-~2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl~-1-(2-chlorophenyl)-lH-pyrazole-5-carboxylate (Step E~, 96 mg (0.538 mM) of 2-chlorophenylhydrazine hydrochloride, 1 ml glacial acetic acid, and 0.5 mL
2-methoxyethanol was heated at 105C for 20 hours.
After cooling to room temperature, volatiles were evaporated and the residue was co-evaporated with toluene 3x and then flash chromatographed over 40 mL
silica gel, eluting with 0.5% MeOH/CH2C12 to give 74 mg of desired material as colorless oil, homogeneous on TLC. TLC: Rf=0.35 in 2% MeO~/CH2C12.
lH NMR (400 MHz, CDC13, ppm) ~ O.88 (t, J=7.4 Hz.
3H), 0.98 (t, Jz7.1 Hz, 3H), 1.31 (m, 2H), 1.57 (m, 2H), 2.61 (t, J=8.3 Hz, 2H), 4.08 (m, 2H), 4.08 (m, 2H), 4.13 (s, br, 2H), 4.23 (s, 2H), 7.24-7.58 (m, llH), 8.12 (m, lH). Mass spectrum: FAB (m/e) 552 (Mil)+.

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G: Ethyl 4-[~2~-(N-benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-n-butyl-1-(2-chlorophenyl)-1~-pyrazole-5-carboxvlate A solution of 51 mg (0.093 mM) ethyl 3-n-butyl-1-(2-chlorophenyl)-4-~(2'-sulfamoyl-biphenyl-4-yl)methyl]-1~-pyrazole-5-carboxylate (Step F), 140 mg (1.0 mM) of benzoyl chloride, and 1 mL dry pyridine was stirred vigorously under N2 at room temperature for 36 hours. After 4 hr, a yellow-orange salt fell out of solution. The reaction mixture was partitioned between 4mL aqueous saturated ~H2PO4 and 5 mL EtOAc. The aqueous layer was extracted further using 2 x 5 mL EtOAc, and the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, solvents were evaporated and the residue was coevaporated with toluene 3x before being loaded on a flash column (lSmL SiO2) and eluted with 0.5-1.0-2.0%
MeOH/CH2Cl2 to give 35 mg of a clear glass (57%) homogeneous on TLC: Rf=0.4 (5% MeOH/CH2C12) lH NMR (400 MHz, CDC13, ppm) ~ 0.87 (t, J=7.3 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H), 1.33 (m, 2H), 1.58 (m, 2H), 2.S8 (t, J=8.0 Hz, 3H), 4.08 (m, 2H), 4.15 (s, 2H), 7.03-7.64 (m, lSH), 8.08 (m, lH), 8.36(m, lH) Mass spectrum: FAB (m/~) 6S6 (M+l)+

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W O 91/t54~9 ~^. J. ~ PC~r/US91/01952 4-~t2'-(N-BENZOYLSULFAMOYL)BIPHENYL-4-YL]METHYL]-3-n-BUTYL-1-(2-CHLOROPHENYL)-l~-PYRAZOLE-5-CARBOXYLIC
ACID
A solution of 24 mg (0.0366 mM) ethyl 4-~2~-(N-benzoylsulfamoyl)biphenyl-4-yl]methyl]-3-n-butyl-l-(2-chlorophenyl)-lH-pyrazole-5-carboxylate (Example 18), 146 ~L of a 2.5N NaOH solution (0.366 mM), ant 300 ~L methanol was stirred at 60C for 2h.
After filtration, the volatiles were evaporated under reduced pressure and the residue acidified with lN
HCltMeOH solution (SOO ~L) to pH -1.5. After the volatiles were evaporated, the residue was triturated with chloroform and filtered. The residue obtained after evaporation of the volatiles was pumped overnight to give 21 mg off-white solid (91%), homogeneous by TLC Rf=0.3 (10% MeOH/CH2C12).
lH NMR (400 MHz, CDC13, ppm) ~ 0.87 (t, J=7.4 Hz, 3H), 1.34 (m, 2H), 1.60 (m, 2H), 2.60 (t, Jz8.0 Hz, 2H), 4.11 (s, 2H) 7.03-7.63 (m, 15H), 8.36-8.41 (m, 2H) Mass spectrum: FAB (m/~): 628 (M+l)+
Analy8is (C34H30ClN30sS-l.l H20) Calc'd = C, 63.02; H, 5.00; N, 6.48 Fount = C, 62.75; H, 4.67; N, 6.54 3-n-BUTYL-1-(2-CHLOROPHENYL)-4-[2'-[N-(TRIFLUORO-ACETYL)SULFAMOYL]BIPHENYL-4-YL]METHYL]-l~-PYRAZOLE-5-CARBO~YLIC ACID.

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A: Ethyl 3-n-butyl-1-(2-chlorophenyl)-4-t[N-(tri-fluoroacetyl)sulfamoyl]biphenyl-4-yl~methyl]-lH-pyrazole-5-carboxylate A ~olution of 74 mg ~0.134 mM) ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[(2'-sulfamoyl-biphenyl-4-yl)methyl]-1~-pyrazole-5-carboxylate (Example 18, Step F), 281 mg (1.34 mM) trifluoro-acetic anhydride, and 1.3 mL dry pyridine was vigorously stirred at room temperature for 24 h. The resulting brown solution was partitioned between 3 mL
saturated aqueous K~2P04 and 3 mL ethyl acetate. The aqueous layer was further extracted with 2 g 3 mL
EtOAc, and the combined organic layers were washed with brine and dried over anhydrous Na2S04. ~fter filtration, volatiles were evaporated and the residue was flash chromatographed over 15 mL silica gel using gradient elution (2-10% MeOH/CH2C12) to give 26 mg of the desired product in its K+ salt form as indicated by MS (FAB). The material was acidified with 1 mL lN
aq HCl and extracted with 2 x 1 mL CH2C12. The combined organic layers were dried over Na2S04 and filtered. Solvents were evaporated to give 17 mg of the desired compound as a glassy solid.
TLC: Rf=0.4 (10% MeO~/CH2C12~
1~ NMR (400 MHz, CDC13, ppm) ~ 0.78 (m, 6~), 1.29 (m, 2H~, 1.55 (m, 2H), 2.56 (t, J=7.6 ~z, 2E~, 3.97 (m, 2H~, 4.09 (s, 2H~, 7.05-7.60 (m, llH~, 8.13 (m, lH~
Mass spectrum: FAB (_/e):648 (M+l)+

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WO 91/15479 PCI'/US91/01952 2~

B: 3-n-Butyl-1-(2-chlorophenyl)-4-[(2'-sulfamoyl-biphenyl-4-yl)methyl]-1~-pyrazole-5-carboxylic acid A solution of 17 mg (0.026 mM) of ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[N-(trifluoroacetyl)-sulfamoyl]biphenyl-4-yl]methyl]-l~-pyrazole-5-carboxylate (Step A), 104 ~L of 2.5 N aq NaOH
solution, and 200 ~L of MeOH was stirred at 60C for 2 h. After filtration volatiles were evaporated, and the residue was acidified to pH 1.5 using lN
HCl/MeOH. Volatiles were again evaporated and the residue was flash chromatographed over 10 mL silica gel eluting with 2-5-10% MeOH/C~2C12, to give 11 mg of a gum, NMR and MS consistent with the title compound; TLC Rf=0.1 (10% MeOH/CH2C12).
1~ NMR (400 MHz, CDC13, ppm) ~ O.84 (t, J=7.4 ~z, 3H), 1.30 (m, 2H), 1.55 (m, 2~), 2.59 (t, J=7.8 Hz, 2H~, 4.20 (8, 4~), 7.22-7.58 (m, 11~), 8.10 (m, lH) Mass spectrum: FAB (m/e): 524 (M+l)+

C: 3-n-Butyl-1-(2-chlorophenyl)-4-[[2'-~N-(trifluoro-acetyl)sulfamoyl]biphenyl-4-yl]methyl]-l~-pyra-zole-5-carboxvlic acid A solution of 9.3 mg (0.0178 mM) 3-n-butyl-l-(2-chlorophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)-methyl]-l~-pyrazole-5-carboxylic acid (Step B), 0.2 mL dry pyridine, and 37 mg (0.178 mM) trifluoroacetic anhydride was stirred at room temperature for 24 hr.
The resulting mixture was partitioned between 1 mL
sat. aq. KH2P04 and 2mL ethyl acetate. The aqueous layer was further extracted with 2 mL EtOAc, and the combined organic layers were washed with brine and .. .. .
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WO 91/1S479 PCr/US91/01952 r~
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dried over anhydrous Na2S04. After filtration, the volatiles were removed and the residue was flash chromatographed over 10 mL silica gel, eluting with 2-lOZ MeO~/C~2C12 to give 9.3 mg single spot material as an off white solid. This material was mainly the potassium salt of the desired product, as shown by MS
(FAB). Therefore, it was acsdified using 1 mL lN aq HCl and extracted with 2xl mL CH2Clz, and dried using Na2S04. After filtration, volatiles were evaporated to give 5.3 mg of off-white foam. TLC:Rf = 0.3 (10%
MeOH/CH2C12) 1~ NMR (400 M~z, CD30D, ppm) ~ O.88 (t, J=7.3 ~z, 3H), 1.33 (m, 2t), 1.54 (m,2H), 2.61 (t, J=7.6 ~z, 2H), 4.24 (s, 2H), 7.15-7.57 (m, llH), 8.14 (m, 2~).
Mass spectrum: FAB (m/~): 620 (M+l)+

F~.~

3-n-BUTYL-1-(2-CHLOROPHENYL)-4-t(2'-~N-(TRIFLUORO-METHANESULFONYL)AMINO]BIPHENYL-4-YL]METHYL]-l~-A: 4-Methvl-2'-nitrobiyhenyl Under N2, a clean, dry flask was charged with p-tolyltrimethyltin (Example 18, Step B) (5.61 g, 0.022 mol), 2-bromonitrobenzene (4.04 g, 0.020 mol), anhytrous DMF (40 mL), and palladium(II) bis(triphenylphosphine)dichloride (140 mg. O.2 mmol m heated at 110C and stirred for 4 h when TLC (4:1 hexanetEtOAc) indicated disappearance of starting materials. The nearly black reaction mixture was cooled to room temperature, poured into a solution -. , . . ; ~ .
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made from 100 mL lN KOH and 100 mL sat. NaCl, and extracted with 3 x 150 mL EtOAc. The combined organic layers were washed with 100 mL lN KOH and 100 mL sat. NaCl, and then dried over anhydrous Na2S04.
After filtration, the amber solution was evaporated to dryness and then flash chromatographed over 900 mL
SiO2, eluting with 2.5% EtOAc-hexane to give 4.109 g (96%) of the title compound as a light orange liquid, homogeneous on TLC (4/1 hex-EtOAc).
H NMR ~400 M~z, CDC13, ppm) ~: 2.38 (s, 3H), 7.21 (m, 4H), 7.43 (m, 2H), 7.58 (m, lH), 7.80 (dd, J=8.09, 1.34 ~z, 1~).
Mass spectrum:El (m/e):213 (M+) B: (2'-Nitrobiphenyl-4-yl~methyl bromide 4-Methyl-2'-nitrobiphenyl (Step A) (2.173 g, 10.2 mmol) was disæolved in CC14 (100 mL) and heated to reflux with stirring . To this was added a bromine solution tprepared by diluting 11.2 ml (11.2 mmole) of commercial 1.0 M solution in CC14 to a final volume of 40 mL with CC14] dropwise while a 100 W lamp was used to irradiate the refluxing reaction mixture. After completion of addition, the solution was cooled to room temperature, volatiles were removed, and the residue was flash chromatographed over 700 mL SiO2, eluting with 1.5-4.0-10.0%
EtOAc/hesane, to afford 2.68 g (90%) of the title compound, 85% pure as indicated by NMR (the remaind~r being the dibrominated material), but homogeneous on TLC (4/1 hex-EtOAc).

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WO91/tS479 PCT/US91/01952 2 . . .;:: . 3 1~ NMR (400 M~z, CDC13, ppm) ~ 4.52 (s, 2H), 7.29 (m, 2H), 7.48 (m, 4H), 7.61 (m, lH), 7~85 (dd, J=8.05, 1.26 Hz, lH). Mass spectrum: FAB (m/e): 292 (M+l)+

C: Ethyl 2-methoxyimino-3-t(2'-nitrobiphenyl-4-vl)methvll-4-oxooctanoate A mixture of 650 mg (2.84 mM) of ethyl 2-methoxyimino-4-oxooctanoate (Example 4, Step A), 829 mg (2.84 mM) of (2'-nitrobiphenyl-4-yl)methyl bromide (from Step B), 470 mg (3.41 mM) of freshly pulverized anhydrous potassium carbonate, and 9 mL of dry DMF, was stirred vigorously under nitrogen at room temperature for 16 hours. The resulting mixture was partitioned between 90 mL 0.2N HCl and 90 mL EtOAc.
The aqueous layer was further extracted with 30 mL
EtOAc and the combined organic layers were washed with water and brine before being dried over anhydrous Na2SO4. After filtration, the volatiles were removed to give a crude product mixture which was flash chromatographed over 300 mL silica gel, eluting with 2011 to 10/1 hexane/ethyl acetate, to afford 940 mg (75%) of a colorle~s oil, homogeneous on TLC. TLC: Rf=0.3 (4/1 hex/EtOAc).
lH NMR (400 MHz, CDC13, ppm): ~ 0.86 (t, J=7.3 ~z, 3H), 1.25 (m, 5H), 1.53 (m, 2H), 2.31 (m, 2H), 2.96 (m, lH), 3.40 (m, lH), 3.98 (s, 3H), 4.24 (m, 2H), 7.16-7.81 (m, 8H). Mass spectrum (m/~) 441 (M+l)+.
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Wo91/15479 PCT/US91/01952 2~

D: Ethyl 3-n-butyl-1-(2-chlorophenyl)-4-[(2'-nitrobiphenyl-4-yl)methyl]-1~-pyrazole-5-carboxylate A mixture of 381 mg (0.866 mM) of ethyl 2-methoxyimino-3-[(2'-nitrobiphenyl-4-yl)methyl]-4-oxooctanoate (Step C), 465 mg (2.60 mM) of 2-chloro-phenylhydrazine hydrochloride, 4.4 mL glacial acetic acid and 2.2 mL 2-methoxyethanol was heated with vigorous stirring at 105C for 24 hours. After cooling to room temperature, volatiles were evaporated and the residue was coevaporated with toluene 3X before being flash chromatographed over 120 mL silica gel, eluting with 15/1 hexane/ethyl acetate, to give 274 mg (62%) of a yellow oil, homogeneous on TLC. TLC: Rf=0.45 (4/1 hexane/ethyl acetate).
1~ NMR (400 MHz, CDC13, ppm): ~ 0.85 (t, J=7.4 ~z, 3H), 0.99 (t, J=7.1 Hz, 3H), 1.31 (m, 2H), 1.55 (m, 2~), 2.60 (m, 2H), 4.09 (m, 2H), 4.21 (s, 2H), 7.21-7.82 (m, 12H). Mass spectrum: FAB (m/e) 518 ~M+l)+.

~: Ethyl 4-~(2~-aminobiphenyl-4-yl)methyl]-3-n-butyl-l-(2-chlorophenyl)-1~-pyrazole-5-carboxylate A mixture of 42 mg (0.081 mM) of ethyl 3-n-butyl-l-(2-chlorophenyl)-4-t(2'-nitrobiphenyl-4-yl)-methyl]-l~-pyrazole-5-carboxylate (Step D), 4.5 m~ ef platinum oxide, and 2 mL ethyl acetate was hydrogenatet under a H2-balloon at room temperature for 30 minutes. The catalyst was removed by filtering over a pad of Celite, the filtrate was .

, . ~ ~ . - . . ~

WO91/tS479 PCT/US91/01952 .r ~ 127 -pumped to tryness, and then flash chromatographed over 10 mL silica gel using 15/1->10/1 hexane/ethyl acetate to give 33 mg (33%) of a yellow oil, homogeneous on TLC. TLC:Rf-0.35 (4/1 hexane/EtOAc).
H NMR (400 MHz, CDC13, ppm): ~ O.84 (m, 3H), 0.99 (mj 3H), 1.32 (m, 2H), 1.56 (m, 2H), 2.60 (t, J=7.7 Hz, 2H), 4.11 (m, 2H), 4.19 (s, 2H), 6.84-7.47 (m, 12H). Mass spectrum: FAB (~/e) 488 (M+l)+.

F: Ethyl 4-~[21-~N,N-bis(trifluoromethanesul-fonyl)amino]biphenyl-4-yl]methyl]-3-n-butyl-1-!2-chlorophen~l)-lH-pyrazolo-5-carboxylate A mixture of 30 mg (0.062 mM) of ethyl 4-[(2'-aminobiphenyl-4-yl)methyl]-3-n-butyl-1-(2-chlorophenyl)-l~-pyrazole-5-carboxylate (Step E), 175 mg (0.62 mM) of trifluoromethanesulfonic anhydride, and 0.6 mL anhydrous pyridine was stirred at room temperature, under N2, for 6 hours. The dark red reaction mixture was treated with 2 mL lN HCl, 2 mL
saturated aqueous KH2PO4 and extracted with 2 x 4 mL
EtOAc. The combined organic layers were washed with brine ant dried over anhydrous Na2SO4. After filtration, volatiles were evaporated and the residue was coevaporated 3x with toluene before being flash chromatographed over 15 mL of silica gel, eluting with 20/1 hexane/ethyl acetate to give 20 mg of a hard gum, homogeneous by TLC.
lH NMR (200 MHz, CDC13, ppm): ~ O.88 (t. J=7.2 Hz.
3H), 1.03 (t, J=7.2 Hz, 3H), 1.33 ~m, 2H), 1.58 (m, 2H), 2.62 (t, J=7.6 Hz, 2H), 4.10 (m, 2H), 4.25 (s, 2H), 7.23-7.61 (m, 12H).
Mass spectrum:FAB (m/e) 751 (M+l)+

wog1/1s47s PCTtUS91/01952 2~

G: 3-n-Butyl-1-(2-chlorophenyl~-4-[[2'-~N-(tri-fluoromethanesulfonyl)amino]biphenyl-4-yl]-methyll-lH-~yrazole-5-carboxylic acid A solution of 20 mg (0.027 mM) of ethyl 4-~2'-~N,N-bis(trifluoromethanesulfonyl~amino]biphenyl-4-yl]methyl]-3-n-butyl-1-(2-chlorophenyl)-1~-pyrazole-5-carboxylate (Step F), 104 ~L of 2.5N NaO~, and 200 ~L MeO~ was stirred at room temperature for 4 hours.
Volatiles were evaporated and the residue was acidified using 1 mL 2N ~Cl and extracted with 2 x 1 mL CH2C12. Combined C~2C12 layers were dried over anhydrous Na2S04. After filtration, solvents were removed to give an off white solid, single spot by TLC. TLC:Rf=0.15 (10% MeOH/CH2C12).
1~ NMR (200 MHz, CDC13, ppm): ~ O.86 ~t, J=7.3 Hz, 3H), 1.32 (m, 2H), 1.58 (m, 2H), 2.61 (t, J=7.6 9z, 2~), 4.25 (8, 2~), 6.74 (9, 1~), 7.19-7.64 (m, 12~).
Mass spectrum:FAB (m/e) 592 (M+l)+

3-BUTYL-1-(2-C~LOROP~ENYL)-S-(TRIFLUOROMET~ANESULFON-AMIDO)-4-~(2'-TETRAZOL-5-YL)BIP9ENYL-4-YL]MET~YL~-~YRAZOLE

A: 5-Amino-3-Butyl-1-(2-chlorophenyl)-4-t(2'-(N(2)-(triphenylmethyl)tetrazol-5-yl)biphen-4-vl)methvll~yrazole To a solution of 408.5 mg (0.838 mmol) 5-amino-3-butyl-1-(2 ! -chlorophenyl)-4-~(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole (Example 2) in 10 mL
CH2C12 were added O.292 mL (2.10 mmol) triethylamine . . ~ . .. . ~......... . ..

wosl/ls479 PCT/US91/01952 and 234 mg (2.10 mmol) chlorotriphenylmethane. After four hours, the mixture was poured into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgS04, stripped of solvent in vacuo, then was medium pressure chromatographed on silica gel using 30%
EtOAc/hexane to give 327.1 mg of title compound, 54~
yield. Rf 0.16 in 30% EtOAc/hexane, visualized by W
and ammonium molybdate/ceric sulfate stain;
H NMR (300 NHz, CDC13): 8 7.90 (m, lH), 7.53-7.14 (m, 17H), 7.05 (4 line me, 4H), 6.91 (m, SH), 3.67 (s, 2H), 3.02 (br s, 2~), 2.54 (3 line m, 2~), 1.63 (m, 2H), 1.36 (6 line m, 2~), 0.89 (3 line m, 3E).

B: 3-Butyl-1-(2-chlorophenyl)-5-(trifluoro methanesulfonamido)-4-t(2'-(N(2)-(tri-phenylmethyl)tetrazol-5-yl)biphen-4-yl)-methyllpvrazole To a solution of 217 mg (0.299 mmol) 5-amino-3-butyl-1-(2'-(N-triphenylmethyl-tetrazol-5-yl)biphen-4-yl)methyl]pyrazole and 0.295 mL (2.23 mmol) 2,4,6-collidine in 5 mL C~2C12 was added 0.201 mL trifluoromethanesulfonic anhydrite. After 1 hour, the mixture was poured into brine and extracted 3 times with ether. The combined organic material was washed with brine, dried over MgS04, stripped of solvent Ln vacuo, then was medium pressure chromato-graphed on silica gel using 15Z EtOAc/hexane to gi~
title compound. Rf 0.54 in 35% EtOAc/hexane, visualized by W and ammonium molybdate/ceric sulfate stain;

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lH NMR (300 MHz, CDC13): ~ 7.90 (m, lH), 7.78 (m, lH), 7.49 (m, 5H), 7.40-7.21 (m, llH), 7.05 (4 line m, 4H), 6.95 (m, 5Hj, 3.81 (benzylic CH2, AB, J=15.7 Hz, a~-16.0 Hz, 2H), 2.81 (m, 2H), 1.65 (m, 2H), 1.30 (m, 2H), 0.85 (3 line m, 3H).

C: 3-Butyl-l-(2-chlorophenyl)-5-(trifluoro methanesulfonamido)-4-~(2'-(tetrazol-5-vl~bi~hen-4-vl)methyll~yrazole To a solution of the trityl protected title compound in 10 mL methanol was added 10 drops concentrated HCl. After 30 minutes, an indicator quantity of phenolphthalein was added and the mixture was basified with 10% NaOH then reacidified with HOAc. Ether and brine were addet and the mixture extracted 3 times with ether. The combined organic material was dried over MgS04, stripped of solvent Ln vacuo, then was medium pressure chromatographet on silica gel using 1/50/49 AcOH/EtOAc/hexane. The title compound was obtained in pure form after being ~PLC'd using the following contitions: Rainin DynamaxD C-18 column, 25 x 2.14 cm w/Guard Column;
gradient of acetonitrile in water 5 to 100% over 60 minutes at 5 mL/minute; Rf 0.23 in 1/65/34 AcOH/EtOAc/
hexane, visualized by W and ammonium molybdate/ceric sulfate stain;
lH NMR (300 MHz, CD30D): ~ 7.71-7.43 (3 overlapping m, 8H), 7.12 (4 line m, 4H), 3.90 (s, 2H). 2.39 (3 line m, 2H), 1.46 (m, 2H), 1.27 (m, 2H), 0.85 (3 line m, 3H); MS (FAB) m/e 616 (M+l).

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~XAMPLE 23 Typical Pharmaceutical Compositions Containing a Compound of the Invention A: Dry Filled Capsules Containing 50 mg of Active Ingredient Per Capsule In~redient Amount ~er ca~sule (mg) 3-butyl-1-(2-chlorophenyl)- 50 4-[[2l-(5-tetrazolyl)-biphenyl-4-yl]methyl-1~-pyrazole-5-carboxylic acid Lactose 149 Magnesium stearate Capsule (size No. 1) 200 The 3-butyl-1-(2'-chlorophenyl)-4-~[2'-(5-tetrazolyl)biphenyl-4-yl]methyl-1~-pyrazole-5-carboxylic acid can be reduced to a No. 60 powder and the lactose and magnesium stearate can then be passed through a No. 60 blotting cloth onto the powder. The combined ingredients can then be mixed for about 10 minutes and filled into a No. 1 dry gelatin capsule.

B: Tablet A typical tablet would contain 3-butyl-1-(2-chlorophenyl)-4-[~2'-(5-tetrazolyl)biphenyl-4-Y!.l-methyl-lH-pyrazole-5-carboxylic acid (25 mg), pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

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wosl/1s479 PCT/US91/01952 C: Combination Tablet A typical combination tablet would contain, for example, 3-butyl-1-(2-chlorophenyl)-4-~[2'-~5-tetrazolyl)biphenyl-4-ylJ-methyl-l~-pyrazole-5-carboxylic acid, a diuretic such as hydrochloro-thiazide and consist of hydrochlorothiazide (50 mg) pregelatinized starch USP (82 mg), microcrystalline cellulose (82 mg) and magnesium stearate (1 mg).

D: Suppository Typical suppository formulations for rectal administration can contain 3-butyl-1-(2-chloro-phenyl)-4-~2'-(5-tetrazolyl)biphenyl-4-yl~-methyl-l~-pyrazole-S-carboxylic acid, (0.08-1.0 mg), disodium calcium edetate (0.25-0.5 mg), and polyethylene glycol (775-1600 mg). Other suppository formulations can be made by substituting, for example, butylated hydroxytoluene (0.04-0.08 mg) for the disodium calcium edetate and a hydrogenated vegetable oil (675-1400 mg) such as Suppocire L, Wecobee FS, Wecobee M, Witepsols, and the like, for the polyethylene glycol. Further, these suppository formulations can also include another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme and/or a calcium channel blocker in pharmaceutically effective amounts as described, for example, in C
above.

- ~ , , . ~ ~ . .

;

WOs1/t5479 PCT/US91/01952 2~ 133 -E: Injection A typical injectible formulation would contain 3-butyl-1-(2-chlorophenyl)-4-[[2'-~5-tetra-zolyl)biphenyl-4-yl]-methyl-1~-pyrazole-5-carboxylic acid, sodium phosphate dibasic anhydrous (11.4 mg), benzyl alcohol (0.01 ml) and wate~ for injection ~1.0 ml). Such an injectible formulation can also include a pharmaceutically effective amount of another active ingredient such as another antihypertensive and/or a diuretic and/or an angiotensin converting enzyme inhibitor and/or a calcium channel blocker.

.:
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.
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Claims (18)

WHAT IS CLAIMED IS:
1. A compound having the formula:

(I) or a pharmaceutically acceptable salt thereof wherein:
K is O, S' or NR7;

R1 is (a) -CO2R5, (b) -SO3R5, (c) -NHSO2(C1-C4-polyfluoroalkyl), (d) -PO(OR5)2, (e) -SO2-NH-R9, (f) -CONHOR5, (g) , (h) -SO2NH-heteroaryl, (i) -CH2SO2NH-heteroaryl, (j) -SO2NH-CO-R23, (k) -CH2SO2NH-CO-R23, (1) -CONH-SO2R23, (m) -CH2CONH-SO2R23, (n) -NHSO2NHCO-R23, (o) -NHCONHSO2-R23, (P) (q) (r) (s) - CONHNHSO2CF3 , (t) (U) (V) wherein Y is (1) -CO2R4, (2) -SO3R5, (3) -NHSO2CF3, (4) -PO(OR5)2, (5) -SO2NHR9, (6) 1H-tetrazol-5-yl.

(W) , or (X) ;

wherein heteroaryl is an unsubstituted, monosub-stituted or disubstituted five or six membered aromatic ring comprising from 1 to 3 heteroatoms selected from the group consisting of O, N and S and wherein the substituents are members selected from the group consisting of -OH, -SH, -C1-C4-alkyl, -C1-C4-alkoxy, -CF3, halo, -NO2, -CO2H, -CO2-C1-C4-alkyl, -NH2, NH(C1-C4-alkyl), -N(C1-C4-alkyl)2 and a fused benzo group;

R2a and R2b are independently (a) H, (b) halo, (c) NO2, (d) NH2, (e) C1-C4-alkylamino, (f) di-(C1-C4-alkyl)amino (g) SO2NHR9, (h) CF3, (i) C1-C4-alkyl, or (j) C1-C4-alkoxy;

R3a is (a) H, (b) halo, (c) C1-C6-alkyl, (d) C1-C6-alkoxy, or (e) C1-C6-alkoxy-C1-C4-alkyl;

R3b is (a) H, (b) halo, (C) NO2, (d) C1-C6-alkyl, (e) C2-C6-alkanoyloxy, (f) C3-C6-cycloalkyl, (g) C1-C6-alkoxy, (h) -NESO2R4, (i) hydroxy-C1-C4-alkyl, (j) aryl-Cl-C4-alkyl, (k) C1-C4-alkylthio, (1) C1-C4-alkylsulfinyl, (m) C1-C4-alkylsulfonyl, (n) NH2, (o) C1-C4-alkylamino, (p) di(C1-C4-alkyl)amino, (q) CF3, (r) -SO2-NHR9, (s) aryl or (t) furyl;

wherein aryl is phenyl or naphthyl either unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo, C1-C4-alkyl, C1-C4-alkoxy, NO2, CF3, C1-C4-alkylthio, OH, NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -CO2H, -CO2-C1-C4-alkyl, C1-C4-polyfluoroalkyl. C3-C6-polyfluorocycloalkyl, and R4 is H, C1-C6-alkyl, aryl or -CH2-aryl;
R5 is H, , wherein R4a is C1-C6-alkyl, aryl, or -CH2-aryl;

E is a single bond, -NR13(CH2)s-, -S(O)x(CH2)s-where x is 0 to 2 and 8 is 0 to 5, -CH(OH)-, -O-, -CO-;

R6 is C1-C6-alkyl, C2-C5-alkenyl or C2-C5-alkynyl each of which can be substituted with a substituent selected from the group consisting of aryl, C3-C7-cycloalkyl, halo, -OH, -CF3, -CCl3, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -NH-SO2R4, -COOR4, -SO2NHR9, C1-C4-alkoxy, or C1-C4-alkyl-5;

R7 is (a) -H, (b) C1-C10-alkyl;
(c) substituted C1-C10-alkyl in which one or more substituent(s) is selected from (1) I, Br, Cl, or F, (2) hydroxy, (3) C1-C10-alkoxy, (4) C1-C5-alkoxycarbonyl, (5) C1-C4-alkylcarbonyloxy, (6) C3-C8-cycloalkyl, (7) aryl, (8) heteroaryl, (9) C1-C10-alkyl-S(O)p in which p is 0 to 2, (10) C3-C8-cycloalkyl-S(O)p, (11) aryl-S(O)p, (12) oxo, (13) carboxy, (14) NR9R9, (15) C1-C5-alkylaminocarbonyl, (16) di(C1-C5-alkyl)aminocarbonyl, (17) cyano;
(18) -OCONR22R23 (19) NR22COR23 (20) -NR22CO2R23 (21) -NR22CONR22R23 (22) (23) wherein L is a single bond, CH2, O, S(O)p or (d) C2-C10-alkenyl, (e) C2-C10-alkynyl, (f) C3-C8-cycloalkyl, (g) substituted C3-C8-cycloalkyl or substituted C3-C8-cycloalkyl-C1-C4-alkyl having one or more substituents selected from the group:
(l) Cl, Br, F, or I
(2) hydroxy, (3) C1-C6-alkyl, (4) C1-C6-alkoxy, (5) C1-C4-alkylcarbonyloxy, (6) C1-C5-alkoxycarbonyl, (7) carboxy, (8) oxo, (9) C1-C5-alkylaminocarbonyl, (10) di(C1-C5-alkyl)aminocarbonyl, (11) C1-C4-alkylcarbonyl, and (12) aryl, (h) aryl, or (i) heteroaryl;

R8 is (a) hydrogen, (b) -OH, (c) -NH2, (d) -NH(C1-C4-alkyl) wherein the alkyl is unsubstituted or substituted with CO2R4, (e) -N(C1-C4-alkyl)2 wherein one or both of the alkyl groups can be substituted with CO2R4, (f) -NHCO2-C1-C4-alkyl, (g) -NHSO2-aryl, (h) -NHSO2-heteroaryl (i) -NHSO2(C1-C4-polyfluoroalkyl), (j) -CO2H, (k) -CO2R5, (l) halo, (m) -CONHSO2-aryl, (n) -CONHSO2-heteroaryl, (o) -CONHSO2-C1-C4-alkyl, either unsubstituted or substituted with aryl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2; -OH, -CO2H, or CO2(C1-C4-alkyl), (p) -CONHSO2(C1-C4-polyfluoroalkyl), (q) -CH2OH, (r) -CH2OCOR4, (s) -O-C1-C4-alkyl, (t) -S(O)x-C1-C4-alkyl, either unsubstituted or substituted with aryl, -NH2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -OH, -CO2H, or CO2(C1-C4-alkyl), (u) -SO2NHR21, (v) -CN, (w) tetrazol-5-yl, (x) , (y) -CH2CO2R4;
R9 is H, C1-C5-alkyl, aryl or -CH2-aryl;
R10 is H, C1-C4-alkyl;
R11 is H, C1-C6-alkyl, C2-C4-alkenyl, C1-C4-alkoxy alkyl, or -CH2-C6H4R20;

R12 is -CN, -NO2, -CO2R4, or -CF3;
R13 is H, C2-C4-alkanoyl, C1-C6-alkyl, allyl, C3-C6-cycloalkyl, phenyl or benzyl;
R14 is H, C1-C8-alkyl, C1-C8-perfluoroalkyl, C3-C6-cycloalkyl, phenyl or benzyl;
R15 is H, C1-C6-alkyl;
R16 is H, C1-C6-alkyl, C3-C6-cycloalkyl, phenyl or benzyl;
Rl7 is -NR9R10, -OR10, --NHCONH2, -NHCSNH2, or ;

R18 and R19 are independently C1-C4-alkyl or taken together are -(CH2)q- where q is 2 or 3;
R20 is H, -NO2, -NH2, -OH or -OCH3;
R21 is (a) -CO-aryl, (b) -CO-C1-C4-alkyl, (c) -COCF3, (d) -CO-heteroaryl, or (e) heteroaryl;
R23 is (a) aryl, (b) heteroaryl, (c) C3-C7-cycloalkyl, (d) C1-C6-alkyl either unsubstituted or substituted with aryl, heteroaryl, -OH, -SH, C1-C4-alkyl, C3-C7-cycloalkyl, -O(C1-C4-alkyl), -S(C1-C4-alkyl),-CF3, halo, -NO2, -CO2H, CO2-C1-C4-alkyl, -NH2, NHaryl, N(aryl)2, -NH(C1-C4-alkyl), -N(C1-C4-alkyl)2, -PO3H--PO(OH)(O-C1-C4-alkyl), or -N(CH2CH2)2L wherein L is single bond, -CH2-, -O-, -S(O)p, or NR9; and (e) polyfluoro-C1-C4-alkyl;

X is (a) a carbon-carbon single bond, (b) -CO-, (c) -O-, (d) -S-, (e) , (f) , (g) , (h) -OCH2-, (i) -CH2O-(j) -SCH2-, (k) -CH2S-, (l) -NHC(R9)(R10), (m) -NR9SO2-, (n) -SO2NR9-, (o) -C(R9)(R10)NH-, (p) -CH=CH-, (g) -CF=CF-, (r) -CH=CF-, (s) -CF=CH-, (t) -CH2CH2-, (u) -CF2CF2-, (v) or (w) , (x) , (y) , or (z) ;

Z is 0, NR13 or S;
r is 1 or 2; and
2. The compound of Claim 1 where K is 0.
3. The compound of Claim 2 wherein:

R1 is, -COOH , -NH-SO2CF3, -SO2NH-CO-R23, -SO2NH-heteroaryl, -SO2NH-aryl or -CONHSO2R23 R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or C1-C4-alkoxy;

R3a is H, F or Cl;
R3b is H, F, Cl, CF3. C1-C4-alkYl, C1-C4-alkoxy, -COOCH3. -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;

E is a single bond, -O- or -S-;
R6 is (a) C1-C5-alkyl either unsubstituted or substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl;
(b) C2-C5-alkenyl or C2-C5-alkynyl;

X is a C-C single bond; and, r is one.
4. The compound of Claim 3 wherein:

E is a single bond or -S-;
r is one, R2a, R2b, R3a and R3b are each H;

R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or -CH2-S-CH3;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2-(C1-C4-alkyl), -CONHSO2-cyclopropyl, -HNSO2(C1-C4- polyfluoroalkyl), -S(O)x-(C1-C4- alkyl)-aryl, -NHSO2-aryl or -NHSO2-heteroaryl;

R1 is -COOH, SO2NH-heteroaryl, -SO2NH-aryl , -NH-SO2-CF3, or -SO2NHCOR23;
R23 is aryl, -N(aryl)2, C3-C7-cycloalkyl, C1-C6 alkyl, either unsubstituted or substituted with 1) C3-C7 cycloalkyl, 2) polyfluoro, or 3) two aryl groups, and X is a single bond.
5. The compound of Claim 4 which is a member of the group:

(1) Ethyl 3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isoxazole-5-carboxylate (2) 3-Butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isoxazole-5-carboxylic acid (3) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butylisoxazole-5-carboxylic acid (4) 3-Butyl-4-[[2'-[N-(trifluoroacetyl)sulfamo yl]biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (5) 3-Butyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (6) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (7) 4-[[2'-[N-(Diphenylacetyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisoxazole-5-carboxylic acid (8) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (9) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propylisoxazole-5-carboxylic acid (10) 4-[[2'-[N-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisoxazole-5-carboxylic acid (11) 3-Propyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isoxazole-5-carboxylic acid (12) 5-[N-(Benzenesulfonyl)carbamoyl]-3-butyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (13) 3-Butyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-isoxazole (14) 3-Butyl-5-(pentafluoroethanesulfonamido)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (15) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butyl-5-(trifluoromethanesulfon-amido)isoxazole (16) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl-5-(trifluoro-methanesulfonamido)isoxazole (17) 3-Butyl-5-(trifluoromethanesulfonamido)-4-[[2'-(trifluoromethanesulfonamido)biphenyl-4-yl]methyl]isoxazole (18) 3-Propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-isoxazole (19) 5-(Pentafluoroethanesulfonamido)-3-propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (20) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propyl-5-(trifluoromethanesulfon-amido)isoxazole (21) 4-[[2'-(N-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propyl-5-(trifluoro-methanesulfonamido)isoxazole (22) 3-Butyl-5-(4-chlorobenzylsulfinyl)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (23) 3-Butyl-5-(2-carboxybenzylthio)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isoxazole (24) 3-Butyl-5-[N-(isopropylsulfonyl)carbamoyl]-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-isoxazole (25) 3-Butyl-5-[N-(cyclopropanesulfonyl)car-bamoyl]-4-[[2'-(tetrazolyl)biphenyl-4-yl]-methyl]isoxazole (26) 3-Butyl-5-(4-fluorobenzenesulfonamido)-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-isoxazole (27) 3-Butyl-5-(3-pyridinesulfonamido)-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-isoxazole
6. The compound of Claim 1 wherein K is S.
7. The compound of Claim 6 wherein:

R1 is, , -NH-SO2CF3, CO2H

-SO2NHCOR23, -SO2NH-heteroaryl, -SO2NH-aryl or -CONHSO2R23;

R2a and R2b are H, F, Cl, CF3, C1-C4-alkyl or C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C5-C6-cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-;

R6 is (a) C1-C5-alkyl either unsubstituted or substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2H5, -S-CH3, -S-C2H5 or phenyl;
(b) C2-C5-alkenyl or C2-C5-alkynyl;

X is a C-C single bond; and, r is one.
8. The compound of Claim 7 wherein:

E is a single bond or -S-;
r is one, R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or -CH2-S-CH3;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2-(C1-C4-alkyl), -CONHSO2-cyclopropyl, -NHSO2(C1-C4- polyfluoroalkyl) (S(O)x-(C1-C4- alkyl)aryl, -NHSO2-aryl or -NHSO2-heteroaryl;

R1 is, -COOH, -SO2NH-heteroaryl, -SO2NH-aryl , NH-SO2-CF3, or -SO2NHCOR23;
R23 is aryl, polyfluoro-C1-C4 alkyl, C3-C7 cycloalkyl or C1-C4 alkyl(aryl)2; and X is a single bond.
9. The compound of Claim 8 which is:

(1) Ethyl 3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]isothiazole-5-carboxylate (2) 3-Butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isothiazole-5-carboxylic acid (3) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butylisothiazole-5-carboxylic acid (4) 3-Butyl-4-[[2'-[N-(trifluoroacetyl)sulfamo-yl]-biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (5) 3-Butyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (6) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (7) 4-[[2'-[N-(Diphenylacetyl)sulfamoyl]biphen-yl-4-yl]methyl]-3-propylisothiazole-5-carboxylic acid (8) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]isothiazole-5-carboxylic acid (9) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]
methyl]-3-propylisothiazole-5-carboxylic acid (10) 4-[[2'-[N-(cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propylisothiazole-5-carboxylic acid (11) 3-Propyl-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]isothiazole-5-carboxylic acid (12) 5-[N-(Benzenesulfonyl)carbamoyl]-3-butyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (13) 3-Butyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamid??-isothiazole (14) 3-Butyl-5-(pentafluoroethanesulfonamide)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (15) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butyl-5-(trifluoromethanesulfon-amido)isothiazole (16) 3-Butyl-4-[[2'-[N-(cyclopropanecarbonyl)-sulfamoyl]biphenyl-4-yl]methyl-5-(trifluoro-methanesulfonamide)isothiazole (17) 3-Butyl-5-(trifluoromethanesulfonamido)-4-[[2'-(trifluoromethanesulfonamido)biphenyl-4-yl]methyl]isothiazole (18) 3-Propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-isothiazole (19) 5-(Pentafluoroethanesulfonamido)-3-propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (20) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propyl-5-(trifluoromethanesulfon-amido)isothiazole (21) 4-[[2'-[N-(Cyclopropanecarbonyl)sulfamoyl]-biphenyl-4-yl]methyl]-3-propyl-5-(trifluoro-methanesulfonamido)isothiazole (22) 3-Butyl-5-(4-chlorobenzylsulfinyl)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (23) 3-Butyl-5-(2-carboxybenzylthio)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-isothiazole (24) 3-Butyl-5-[N-(isopropylsulfonyl)carbamoyl]-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-isothiazole (25) 3-Butyl-5-[N-(cyclopropanesulfonyl)carba-moyl]-4-[[2'-(tetrazolyl)biphenyl-4-yl]-methyl]-isothiazole (26) 3-Butyl-5-(4-fluorobenzenesulfonamido)-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-iso-thiazole (27) 3-Butyl-5-(3-pyridinesulfonamido)-4-[[2'-(tetrazolyl)biphenyl-4-yl]methyl]-iso-thiazole
10. The compound 1 wherein K is NR7.
11. The compound of Claim 10 wherein:

R1 is -COOH, , -NH-SO2CF3, -SO2NHCOR23, -SO2NH heteroaryl, -SO2NH-aryl, -CONHSO2R23;

R2a and R2b are H, F, Cl, CF3, C1-C4 alky C1-C4-alkoxy;
R3a is H, F or Cl;
R3b is H, F, Cl, CF3, C1-C4-alkyl, C5-C6-cycloalkyl, -COOCH3, -COOC2H5, -SO2-CH3, NH2, -N(C1-C4-alkyl)2 or -NH-SO2CH3;
E is a single bond, -O- or -S-;
R6 is (a) C1-C5-alkyl either unsubstituted or substituted with a substituent selected from the group consisting of Cl, CF3, CCl3, -O-CH3, -OC2H5- -S-CH3, -S-C2H5 or phenyl;
(b) C2-C5-alkenyl or C2-C5-alkynyl;
R7 and R8 are as defined above;

X is a C-C single bond; and, r is one.
12. The compound of Claim 11 wherein E is a single bond or -S-;
r is one, R2a, R2b, R3a and R3b are each H;
R6 is n-propyl, n-butyl, -CH3, -CH2CH3, or -CH2-S-CH3;
R1 is -COOH, -SO2NH-heteroaryl, -SO2NH-aryl -CONHSO2R23, -SO2NHSO2R23 , -NH-SO2-CF3, -SO2NHCOR23, and R7 is H, aryl-C1-C10-alkyl, polyfluoro-C1-C4-alkyl, heteroaryl, or aryl either unsubstituted or substituted with one or two substituents selected from -Cl, -CF3, -CH3, -OCH3 and -NO2;
R8 is -CO2R5, -CONHSO2aryl, -CONHSO2-(C1-C4-alkyl), -CONHSO2-cyclopropyl, -NHSO2(C1-C4 polyfluoroalkyl), -S(O)x-(C1-C4-alkyl)-aryl -NHSO2-aryl or -NHSO2-heteroaryl;
R23 is aryl, -N(aryl)2, C3-C7-cycloalkyl, C1-C6 alkyl, either unsubstituted or substituted with 1) C3-C7 cycloalkyl, 2) polyfluoro, or 3) two aryl groups, and X is a single bond.
13. The compound of Claim 12 which is a member of the group selected from:

(1) 5-Amino-3-butyl-4-[(2'-carboxybiphen-4-yl)-methyl]-1-phenylpyrazole:
(2) 5-Amino-3-butyl-1-phenyl-4-[(2'-(tetrazol-5-yl)-biphenO4Oyl)methyl]pyrazole;

(3) 3-Butyl-5-hydroxy-1-phenyl-3-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(4) 3-Butyl-5-carboxy-1-phenyl-4-'[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(5) 3-Butyl-5-carbomethoxy-1-phenyl-4-[(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(6) 3-Butyl-5-hydroxymethyl-1-phenyl-4-[(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(7) 3-Butyl-1-(2-chloro)phenyl-3-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-5-hydroxymethyl-pyrazole;
(8) 1-(2-Chloro)phenyl-5-hydroxymethyl-3-propyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(9) 3-Butyl-5-carboxy-1-(2-chloro)phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(10) 3-Butyl-5-carbomethoxy-1-(2-methyl)phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(11) 3-Butyl-5-carbomethoxy-1-(2-nitro)phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(12) 3-Butyl-5-carbomethoxy-1-(2-trifluoromethyl)-phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
(13) 3-Butyl-5-carbomethoxy-1-(2-chloro-4-methoxy)-phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
(14) 3-Butyl-5-carbomethoxy-1-propyl-4-[(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(15) 3-Butyl-5-carbomethoxy-1-isobutyl-4-[(2'-(tetra-zol-5-yl)biphen-4-yl)methyl]pyrazole;
(16) 3-Butyl-5-carbomethoxy-1-pentafluoroethyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(17) 3-Butyl-5-carbomethoxy-1-cyclohexylmethyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;

(18) 3-Butyl-5-carbomethoxy-1-dimethylaminomethyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(19) 3-Butyl-5-acetamido-1-(2-chloro)phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(20) 3-Butyl-1-(2-chloro)phenyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-5-trifluoromethylsulfon-amidopyrazole;
(21) 3-Butyl-1-(2-chloro)phenyl-5-dimethylamino-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(22) 3-Butyl-1-(2-chloro)phenyl-5-propylamino-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(23) 3-Butyl-1-(2-chloro)phenyl-5-methoxy-4-[(2'-(tetrazol-5-yl)biphen-4-y?)methyl]pyrazole;
(24) 3-Butyl-1-(2-chloro)phenyl-5-propyloxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(25) 3-Butyl-1-(2-chloro)phenyl-5-methylsulfinyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(26) 3-Butyl-1-(2-chloro)phenyl-5-methylsulfonyl-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(27) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-carboxy-4-[(2'-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;
(28) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-carbethoxy-4-[(2'-(N-cyclopropanecarbonyl)-sulfonamidobiphen-4-yl)methyl]pyrazole;
(29) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-trifluoromethanesulfonamido-4-[(2'-(N-cyclo-propanecarbonyl)sulfonamidobiphen-4-yl)methyl]-pyrazole;

(30) 3-Butyl-1-(2-(trifluoromethyl)phenyl)-5-pentafluoromethanesulfonamido-4-[(2'-(N-cyclo-propanecarbonyl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(31) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboxy-4-[(2'-(N-cyclopropanecarbonyl)sulfon-amidobiphen-4-yl)methyl]pyrazole;
(32) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboethoxy-4-[(2'-(N-cyclopropanecarbonyl)-sulfonamidobiphen-4-yl)methyl]pyrazole;
(33) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-tri-fluoromethanesulfonamido-4-[(2'-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;
(34) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-penta-fluoroethanesulfonamidosulfonamido-4-[(2'-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)-methyl]pyrazole;
(35) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboxy-4-[(2'-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)-methyl]pyrazole;
(36) 3-Butyl-1-(2,6-tichlorophenyl)-5-carboethoxy-4-[(2'-(N-cyclopropanecarbonyl)sulfonamidobiphen-4-yl)-methyl]pyrazole;
(37) 3-Butyl-1-(2,6-dichlorophenyl)-5-trifluoro-methanesulfonamido-4-[(2'-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-yl)methyl]pyrazole;
(38) 3-Butyl-1-(2,6-dichlorophenyl)-5-pentafluoro-ethanesulfonamido-4-[(2'-(N-cyclopropane-carbonyl)sulfonamidobiphen-4-vl)methyl]pyrazole;
(39) 3-Butyl-1-(trifluoromethyl)phenyl)-5-carboxy-4-[(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;

(40) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carboethoxy-4-[(2'-(N-butyryl)sulfonamidobiphen-4 -yl)methyl]-pyrazole;
(41) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-trifluoromethanesulfonamido-4-[(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(42) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-pentafluoroethanesulfonamido-4-t(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(43) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-carboxy-4-[(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(44) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-carboethoxy-4-[(2'-(N-butyryl)suifonamidobiphen-4 -yl)methyl]-pyrazole;
(4S) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-trifluoromethanesulfonamido-4-[(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(46) 3-Propyl-1-(2-(trifluoromethyl)phenyl-5-pentafluoroethanesulfonamido-4-[(2'-(N-butyryl)-sulfonamidobiphen-4-yl)methyl]-pyrazole;
(47) 3-Butyl-1-(2,6-(dichlorophenyl)-5-carboxy-4-[(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(48) 3-Butyl-1-(2,6-(dichlorophenyl)-5-carboethoxy-4-[(2'-(N-butyryl)sulfonamidobiphen-4-yl)methyl]-pyrazole;
(49) 3-Butyl-1-(2,6-(dichlorophenyl)-5-trifluoro-methanesulfonamido-4-[(2'-(N-butyryl)sulfon-amidobiphen-4-yl)methyl]pyrazole;
(50) 3-Butyl-1-(2,6-(dichlorophenyl)-5-pentafluoro-ethanesulfonamito-4-[(2'-(N-butyryl)sulfon-amidobiphen-4-yl)methyl]pyrazole;

(51) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carboxy--4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]-pyrazole;
(52) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-carbo-ethoxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(53) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-tri-fluoromethanesulfonamido-4-[(2'-(tetrazol-5-yl)-biphen-4-yl)methyl]pyrazole;
(54) 3-Butyl-1-(2-(trifluoromethyl)phenyl-5-penta-fluoroethanesulfonamido-4-[(2'-(tetrazol-5-yl)-biphen-4-yl)methyl]pyrazole;
(55) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(56) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-carboethoxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)-methyl]pyrazole;
(57) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-trifluoromethanesulfonamido-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(58) 3-Propyl-1-(2-(trifluoromethyl)phenyl)-5-pentafluoroethanesulfonamido-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(59) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(60) 3-Butyl-1-(2,6-dichlorophenyl)-5-carboethoxy-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(61) 3-Butyl-1-(2,6-dichlorophenyl)-5-trifluoro-methanesulfonamido-4-[(2'-(tetrazol-5-yl)biphen-4 -yl)methyl]pyrazole;

(62) 3-Butyl-1-(2,6-dichlorophenyl)-5-pentafluoro-ethanesulfonamido-4-[(2'-(tetrazol-5-yl)biphen-4-yl)methyl]pyrazole;
(63) Ethyl 3-butyl-1-(2,4-dichlorophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (64) 3-Butyl-1-(2,4-dichlorophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (65) Ethyl 3-butyl-1-(4-methoxyphenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (66) 3-Butyl-1-(4-methoxyphenyl)-4-[[2'-(5-tetrazol-yl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carbox-ylic acid (67) Ethyl 3-butyl-1-(2-nitrophenyl)-4-[[2' -(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (68) 3-Butyl-1-(2-nitrophenyl)-4-[[2'-(5-tetrazol-yl)-biphenyl-4-yl]methyl]-1H-pyrazole-5-carbox-ylic acid (69) Ethyl 3-butyl-1-(4-methoxy-2-nitrophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (70) 3-Butyl-1-(4-methoxy-2-nitrophenyl)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (71) 3-Butyl-1-(2-pyridyl)-4-[[2'-(5-tetrazolyl)bi-phenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (72) 1-Benzyl-3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (73) Ethyl 1-(2-chlorophenyl)-3-propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (74) 1-(2-Chlorophenyl)-3-propyl-4-[[2'-(5-tetrazol-yl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carbox-ylic acid (75) 1-(2,6-Dichlorophenyl)-3-propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-ca rboxylic acid (76) Ethyl 3-propyl-4-[[2'-(5-tetrazolyl)biphenyl-4 yl]methyl]-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate (77) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]-1-[2-(trifluoromethyl)phenyl]-1H-pyra-zole-5-carboxylic acid (78) Ethyl 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-(trifluoroethyl)-1H-pyra-zole-5-carboxylate (79) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]-1-(2,2,2-(trifluoroethyl)-1H-pyrazole -5-carboxylic acit (80) Ethyl 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylate (81) 3-Propyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]-methyl]-1H-pyrazole-5-carboxylic acid (82) 3-Butyl-1-(2-chlorophenyl)-4-[[2'-[N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (83) 3-Butyl-1-(2,6-dichlorophenyl)-4-[[2'-[N-iso-butyrylsulfamoyl]biphenyl-4-yl]methyl]-1H-pyra-zole-5-carboxylic acid (84) 3-Butyl-4-[[2'-[N-(3-cyclopentylpropionyl)sul-famoyl]biphenyl-4-yl]methyl]-1-[2-(trifluoro-methyl)phenyl]-1H-pyrazole-5-carboxylic acid (85) 3-Butyl-4-[[2'-[N-(diphenylacetyl)sulfamoyl]bi-phenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (86) 4-[[2'-[N-(N,N-diphenylcarbamoyl)sulfamoyl]bi-phenyl-4-yl]methyl]-3-propyl-1H-pyrazole-5-carboxylic acid (87) 4-[[2'-[N-(Diphenylacetyl)sulfamoyl]biphenyl-4-yl]methyl]-3-propyl-1H-pyrazole-5-carboxylic acid (88) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]
methyl]-1-(2-chlorophenyl)-3-propyl-1H-pyrazole-5-carboxylic acid (89) 1-(2,6-Dichlorophenyl)-3-propyl-4-[[2'-(tri-fluoromethanesulfonamido)biphenyl-4-yl]methyl]-1H-pyrazole-5-carboxylic acid (90) 3-Butyl-4-[[2'-[N-(pyrimidin-2-yl)sulfamoyl]bi-phenyl-4-yl]methyl]-1-[2-(trifluoromethyl)-phenyl]-1H-pyrazole-5-carboxylic acid (91) 4-[[2'-[N-(4-Nitrophenyl)sulfamoyl]biphenyl-4-yl]methyl]-3-propyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (92) 4-[[2'-[N-(Diphenylacetyl)sulfamoyl]biphenyl-4-yl]methyl]-3-ethyl-1H-pyrazole-5-carboxylic acid (93) 3-Butyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-1-(2,6-dichlorophenyl)-1H-pyrazole-5-carboxylic acid (94) 4-[[2'-[N-(Benzenesulfonyl)carbamoyl]biphenyl-4-yl]methyl]-3-butyl-1-(2-chlorophenyl)-1H-pyra-zole-5-carboxylic acid (95) 5-[N-(Benzenesulfonyl)carbamoyl]-3-butyl-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole (96) 3-Butyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-5-(trifluoromethanesulfonamido)-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole (97) 3-Butyl-1-(2-chlorophenyl)-5-(pentafluoro-ethanesulfonamido)-4-[[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl]-1H-pyrazole (98) 3-Butyl-5-(pentafluoroethanesulfonamido)-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1-[2-(tri-fluoromethyl)phenyl]-1H-pyrazole (99) 4-[[2'-[N-(Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-butyl-1-[2-(chlorophenyl)-5-(tri-fluoromethanesulfonamido)1H-pyrazole (100) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]methyl]
-3-butyl-5-(trifluoromethanesulfonamido)-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole (101) 3-Butyl-1-(2-chlorophenyl)-4-[[2'-[N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-(trifluoromethanesulfonamido)-1H-pyrazole (102) 3-Butyl-1-(2-chlorophenyl)-4-[[2'-[N-(cyclopro-panecarbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-(pentafluoroethanesulfonamido)-1H-pyrazole (103) 3-Butyl-4-[[2'-[N(cyclopropanecarbonyl)sulfamo-yl]biphenyl-4-yl]methyl]-5-(trifluoromethane-sulfonamido)-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole (104) 1-(2-Chlorophenyl)-3-propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5-(trifluoromethane-sulfonamido)-1H-pyrazole (105) 3-Propyl-4-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-methyl]-5-(trifluoromethanesulfonamido)-1-[2-(trifluoromethyl)phenyl-1H-pyrazole (106) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-1-(2-chlorophenyl)-3-propyl-5-(tri-fluoromethanesulfonamido)-1H-pyrazole (107) 4-[[2'-(N-Benzoylsulfamoyl)biphenyl-4-yl]-methyl]-3-propyl-5-(trifluoromethanesulfon-amido)-1-[2-(trifluoromethyl)phenyl]-1H-pyrazole (108) 1-(2-Chlorophenyl)-4-[[2'-[N-(cyclopropane-carbonyl)sulfamonyl]biphenyl-4-yl]methyl]-3-propyl-5-(trifluoromethanesulfonamido)-1H-pyrazole (109) 4-[[2'-[N-(Cyclopropanecarbonyl)sulfamoyl]bi-phenyl-4-yl]methyl]-3-propyl-5-(trifluoro-methanesulfonamido)-1-[2-(trifluoromethyl)-phenyl]-1H-pyrazole (110) 1-(2-Chlorophenyl)-4-[[2'-[N-(cyclopropane-carbonyl)sulfamoyl]biphenyl-4-yl]methyl]-5-(pentafluoroethanesulfonamido)-3-propyl-1H-pyrazole (111) 1-(2-Chlorophenyl)-5-(pentafluoroethanesulfon-amido)-3-propyl-4-[[2'-(tetrazol-5-yl)-biphenyl-4-yl]methyl]-1H-pyrazole (112) 3-Butyl-1-(2-chlorophenyl)-5-(trifluoromethane-sulfonamido)-4-[[2'-(trifluoromethanesulfon-amido)biphenyl-4-yl]methyl]-1H-pyrazole.

(113) 3-Butyl-5-[N-(isopropylsulfonyl)carbamoyl]-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole (114) 3-Butyl-5-[N-(cyclopropanesulfonyl)carbamoyl]-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole (115) 3-Butyl-5-(pyridinesulfonamido)-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazole
14. A pharmaceutical composition useful in the treatment of hypertension which comprises a therapeutically acceptable carrier and a pharmaceutically effective amount of a compound of Claim 1.
15. The composition of Claim 11 which includes in addition another antihypertensive agent selected from a diuretic or a .beta.-blocker or an angiotensin converting enzyme inhibitor or a calcium channel blocker which is a member selected from the group consisting of: amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamide tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, as well as admixtures and combinations thereof.
16. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Claim 1.
17. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.
18. A method of treating ocular hypertension comprising administering to a patient in need of such treatment therapeutically effective amount of a compound of Claim 1.
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