CA2083735A1 - N-substituted-1,2,4-triazolone compounds for treatment of cardiovascular disorders - Google Patents

Abstract

2083735 9118888 PCTABS00008 A class of N-substituted-1,2,4-triazolone compounds is described for use in treatment of cardiovascular disorders. Compounds of particular interest are angiotensin II antagonists of formula (I), wherein R1 is selected from 2-oxo-2-(tricyclo[3.3.1.1.3.7]dec-2-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hyroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxyethyl, 2-(2,5-dimethioxy-phenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonyl-butyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl-1-methylethyl, 1-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and 3-acetonitrile; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 1-cyanobutyl, propylthio and butylthio; wherein each of R3 through R11 is hydrido with the proviso that at least one of R5 and R9 must be selected from COOH, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, (a), (b) and (c), wherein each of R42 and R43 is independently selected from chloro, cyano, nitro, trifluoromethyl, methoxycarbonyl and trifluoromethylsulfonyl.
These compounds are particularly useful in treatment or control of hypertension and congestive heart failure.

Description

WO 91/lX$h8 PCT/US91/0 ~ 9 ~_ .

-This is a continuation-in-part of U.S.
Application Ser. No. 07~529,079 filed May 25, 1990.

Non-peptidic N-subs~ituted-1,2,4-triazolone ~ompounds are described for use in treatment of cardiovascular disorders such as hypertension and congestive heart failure. Of particular interest are angiotensin II antagonis~ compounds provided by 1,2,4-triazolones having a biphenylmethyl moiety attached to the nitrogen atom at the four-position of the l,2,4-tria~olone.

The renin-angiotensin system is one of the hormonal mechanisms involved in re~ula~ion of ~ -pressure/volume homeostasis and in expression of hypertension. Activa~ion of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, the primary active species of this system.
This sctapeptide, angiotensin II, is a potent vasocons~rictor agent and also produces other physiological effects such as promoting aldoste~one secretion, promoting sodium and fluid retention, inhibiti~g renin secretion, increasinq sympathetic ner~Qus system activity, increasing ; vasopressin secretion, causing positive cardiac inotropic effect and modulating other hormonal systems.
' , ~revious s~udies ha~e shown that antagonizing angio~ensin II at its receptors is a viable approach tO

- . ~ . ~ - i . .

WO 91/~ 8 PCI'/1)~91/03449 ~ 2 2~ 5 inhibit the renin~an~iotensin system, given the pivotal -ole of this octapeptide which mediates the actions c~ _he renin-angiotensin syst~m ~hrough interaction with varlous ~issue receptors. There are several known angiotensin ~
S antagonists, most of which are peptidic in nature. S~c.
peptidic compounds are of limited use due to their lack oral bioavailability or their short duration of action.
Also, commercially-available peptidic angiotensin II
antagonists te.g., Saralasin) have a significant residual agonLst activity which further limit their therapeut c application. ::

Non-peptidic compounds with an~iotensin II
antagonist properties are known. For example, the sodium salt of 2-n~butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid has specific competitive angiotensin II
antagonist activity as shown in a series of binding experiments, functional assays and in_YLYQ tests lP. C.
Wong et al, ~ ~m~r~l ~r rh.r , 2g~(1), 1-7 (198B)~.
2D Also, the sodium salt of 2-butyl-4-chloro-1-(2-nitrobenzyl)Lmidazole-5-acetic acid has specific competitive angiotensin II antagonisr activity as shown in a series of binding experiments, functional assays and y~yQ tests tA. T. Chiu et al, ~ C~L IE~
2S 1321 (1988)]. A famlly of 1-benzyllmidazole-5-acetate derivatives has bee~ shown to have competitive an~iotensin II antagonist properties [A. T. Chiu et al, ~L_E~L~
; ~ , 2~Q~3), 861-874 ~1989)]. U.S. Patent No.
4,816,463 to ~lankey et al de~cribes a family of 4,5,6,7-30 tetrahydro-1~-imidazo~4,5-c)-tetrahydro-pyridine :~
derivatives useful as an~ihypertensives, some of which are reported to antagonize the bindin~ of labelled angiotPnsin ~; II to rat adsenal receptor preparation and thus cause a significant decrease in mean arterial ~lood pressure in conscious hypertensive rats. EP No. 253,310, published 20 - January 1988, descr~bes a series o~ ara~kyl imiidazolecompounds, including in particular a family of ;~
, :
- ,.

' , ' ' ' . ' . , ,' ~ ' , ,~ , ;. .i .

WO 91/1~ PCT/US91/03449 .: .
Z~ 35 biphenyLmethyl substltuted imidazoles, as antagonists t~
~he angiotensin I: ~eceptor. EP No. 323,841 published ~2 July l989 descrlbes four classes of angiotensin iI
antagonists, namely, biphenyLmethylpyrroles, ~iphenylmethylpyrazoles, biphenylmethyl-l,2,3-t~iazoles a~.d biphenylmethyl 4-substituted-4H-l,2,4-triazoles, includ n~
the compound 3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl~-4H-1,2,4-triazole. U.S. Patent No. 4,880,804 ;~
Carini e~ al describes a family of biphenylmethylbenzlmidazole compounds as angiocensin II
receptor blockers for use in treatment of hyper~ension and congestive heart failure.

There are several other families of known compounds having one or two oxo substituen~s on the eriazole ring. For example, East German Patent No. 160,447 published 3 August 1983 describes a family of l,2,4-triaZolin-5-one compounds, specifically 2,4-dihydro-4,5-bis~phenylmethyl3-3H-l,2,4-triazol-3-one, for use as herbicideg. Belgian Patent No. ~06,146 published 16 October 1972 describes a family of triazolinone compounds, including th~ compound (3-(4-m-chlorophenyl-l-piperazinyl)-propyl)-3,4-diethyl~l,2,4-triazolin-5-one, having tranquilizer, hypotensive and analgesic activities.
Belgian Pa~ent No. 631,842 published 28 February 1963 desc~ibes a family of 1,2,4-triazolones hav~ng hypnotic, tranquilizer, nar~otic, sedative and analgetic activities, -which includes a class o~ 4-N-aralkyl-l,2,4-triazol-5-one compounds~ EP ~7,180 published lS June 1978 describes a family of l,2-disubstituted-4-alkyl-l,2,4-triazolidine-3,5-dione compounds having a wide variety of activities, suc~.
as antiulcer, bronchodilator, antifertility and - cardio~ascular-related activities which includ~
- 35 antihypertensive, antiarrhythmic, platelet aggregation inhibition and smooth muscle activities. EP #283,3lO
published 18 March 1987 describes a family of Nl-WO 91/1~ PCT/US91/034~9 .-- . q , b diarylmethyl-N2-aminoalkyl-diaza-heteroCyCliC derivatives rOr treating cerebral vascular and ischmic diseases and or protecting against anoxia. -~ ' . ;, W~ 91~ P~T/US91~03449 2~ ~S

~ c1ass of biphenylalkyl N-substl_u~e~-l,2,~---~azolone c~m~ounds useful in treating clrcula~ory anc c~-d~ovascuiar disorders is defined by Formuia I:
R1 N--~ R~R4 R~==<R6 N--ECH. ~

R2 Rl1~ Rl R~ R .

wherein m is a number selected from one to four, inclusive;

wherein Rl is selected from polycycloal~yl, polycycloalkylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonyl-methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl,l-naphthalenylmethyl, 2-cyolohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyL, .~ carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-E-ethenyl, 1-benzoyl-~-phenylethyl, 1-oxobutyl, 2-~2,5-dLmethyoxyphenyl~-2-oxoethyl, 2-phenyl-2-~phenylmethoxy)ethyl, 2-~2~s-dimethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, l-benzyoyl-l-methylet~yl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, aralkoxycar~onyl, mercaptocarbonyl, mercaptothiocarbonyl, alkyithiocarbonyl, alkylthiothiocarbonyl, arylthiocarbonyl, i arylthiothiocarbonyl, aralkylthiocarbonyl, .i 30 alkylthiocarbonyL, aralkylsulfinyl, aralkylsulfonyl and radicals of ;he formula :~ s ., .

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

WO 91/1~ PCT/US91/03449 ' :~
X ~12 2 ~ 3 -CN
--Rl3 wnereln each of R12 and Ri3 i5 independently selected _~m .
hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, 5 cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and where~n :
R12 and R13 taken together may ~orm a heterocycllc group having five to seven ring members includLng ~he nitrogen atom of said amino or amido radical and which heterocyclic group may further contain one or more hetero atoms as - ng : :
0 members selec~ed from oxygen, nitrogen and sulfur atoms and which het~rocyclic group may be saturated or partially unsaturated; wherein each of R12 and R13 taken together may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or ~mido radical and which aromatlc heterocyclic group may further contain one or more hetero atoms as r m g atoms selected from oxygen, nitrogen and sulfur atoms, with the proviso . .
that when X is oxygen atom, then R12 and R13 cannot be selected from hydrido and alkyl;
wherein each of ~2 throu~h Rll is independently selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, :
cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aral~yl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycaxbonylalkoxyalkyl, carboxyalkoxyalkyl, aralkoxyal~enyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoalkyl, formyl, aLkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, aralkoxycarbonyl, alkoxyalkyl, alkylcarbonyl, al~ylcarbonylalkyl, alkoxyca~bonyl, alkenyl, ~ycloalkenyl, :~ alkynyl, cyano, nitro, carboxyl, aroyloxyalkyl, - alkylcarbonyioxy, mercaptocarbonyl, mercaptothiocarbonyl, alkoxycarbonyloxy, alkylthio, al~ylthiocarbonyl, alkylcarbonylthio, alkylthiocar~onyloxy, alkylthiocar~onylthio, alkylthiothioc æbonyl, , .

~d Wo 91/1~ PCT/US91/o ~ 9 . 7 alkylthiothiocarbonylthio, arylthio, arylthiocarbonyl, arylcarbonylt~.io, arylthiocarbonyloxy, arylthiocarbonylthio, arylthiothiocaYbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarbonyl, _ aralkylcarbonyl~hio, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, alkylthiocarbonyl, aralkylthiocarbonylthio, mercap~o, al~ylsulfinyl, alkylsulfonyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selec~ed from oxygen, sulfur and ni~rogen aeoms, and amino and amido radicals of the formula -N ~ CN / and -NC R18 R Rl9 wherein X is oxygen atom or sulfur atom;
wherein each of R14, R15, R16, R17, R18 and Rl9 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein R14 and R15 taken together, R16 and R17 taken together and R18 and R19 take~ together may form a heterocy~lic group having five to seven ring members including the nitrogen atom of said amino or amido radical and which heterocyolic group may further contain one or more heeero atoms as ring members selected from oxygen, 25 nitrogen and sulfur atoms and which heterocyclic group may :~
b~ saturated or partially unsaturated; wherein each of R14 and R15 taXen together and each of R16 and R17 taken together may ~orm an aromatic heeerocycLic group having five ring members including the nitrogen atom of said amino or a~ido radical and which aroma~io heterocyclic group may further contain one or more hetero atoms as ring atoms selected from oxygen, nitrogen and sulfur atoms;

wo 91~ PCT/US91/0 ~ 9 ~S~ 3~
and wherein each of R3 through Rl1 may be further independently selected from hydroxy and acidic moieties o-~he fo.-mula -Y A

wherein n is a number selected from zero through three, inclusive, and wherein A is an acidic group seleceed t~
contain at least one acidic hydrogen atom, and the amide, ester and salt deriva~ives of said acidic moie~ies;
wh~rein Y is a spacer ~roup independently selected from cne or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen a~oms;
and wherein any of the foregoing Rl through R19~ Y and A
groups havin~ a substitutable position may be substitu~ed by one or more groups selected from hydroxy, alkyl, alkenyl, alkynyl, aralkyl, hydroxyalkyl, haloal~yl, halo, -oxo, alkoxy, aryloxy, aralkoxy, aralkylthio, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aroyl, cycloalkenyl, cyano, cyanoamino, ni~ro, alkylcarbonyloxy, alkoxycarbonyloxy, aLkylcarbonyl, alkoxycarbonyl, aralkoxy~arbonyl, carboxyl, mer~apeo, mercaptocarbonyl, alkylthio, arylthio, alkylthiocarbonyl, alXylsulfLnyl, . -alkylsulfonyl, haloalkylsul~onyl, aralkylsulfinyl, aralkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroaryl having one or more ring atoms selected from oxygen, sulfur ~ :
and nitrogen atoms, and amino and am~do radicals of the fo2:mula ~0 :

-C-R20 , -N _ z and NC-R

wherein X is oxygen atom or sulfur atom; wherein R20 is selected from Aydrido, alkyl, cycloalkyl, cycloalkylalky 35 aralkyl, aryl, DR25 and . :~

.

:: - . .- ~ .

wo 91~ PCT/~S91/03449 g 2~ 7~5 N

wherein D is selec~ed from oxygen a~om and sulfur a~om 2~.
R25 is selected ~rom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl and aryl; wherein each of R21, R22, R23, R24, R26 and R27 is independentlY selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, alkylsulfinyl, alkylsulfonyl~
arylsulfinyl, arylsulfonyl, haloal~ylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and wherein each cf R21, Ræ~ R23, R24, R26 and R27 is further independen~l~
selected from amino and amido radicals of the formula .
/ R ~ / R3 wherein X is oxygen atom or sulfur ~tom;
wherein each of R2~, R29, R30, ~31 R32 and R33 is independen~ly selec~ed from hydrida, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl, and whe~ei~ each of R21 and R æ taken together and each of R23 and R24 taken together may form a h~terocyclic group having fi~ to seven ring members including the nitrogen atom of said amino or amido radical, which hete~ocyclic group may further contain one or more het~ro atoms as ring members selected from oxygen, nitrogen and sulfur atoms and wnich heterocyclic group may be saturated or partially unsaturated; wherein each of R21 and ~22 taken together and each o~ R26 and R~7 taken togethe~ may form an aromatic heterocyclic group having five ring members including the nitrogen atom of said amino or amido radical and which : ~ : a~omatic heterocyclic group may further contain one o 5.C--:

, - . :

WO 91/1~ PCT/US91/034~9 Z~ 7~5 hecero atoms as rlng atoms selected from oxygen, nitroge~
and sul ur atomsi or a tautomer t~ereof or a pharmaceutically-accep~able salt thereof.

S Compounds of Formula I would be useful n treating a variety of circulatory disorders includiny cardiovascular disorders, such as hypertension, conges;-~e heart failure and arteriosclerosis, and to treat othe-disorders such as glaucoma. These compounds would also oe useful as adjunctive therapies. For example, compounds c Formula I may be used in combination with other drugs, such as a diuretic, to treat hypertension. Also, comDounds o Fonmula I could be used in conjunction with certain surgical procedures. For example, these compounds could oe used to prevent post-an~ioplasty re-stenosis. Compounds o.
Formula I are therapeutically effective in treatment of casdiovascular disorders by acting as antagonists to, or blockers of, ~he angiotensin II (AlI) receptor. Compounds of Formula I would be therapeutically effective in 2D treatment of the above-mentioned circulatory and ~
cardiovascular disorders or would be precursors to, or ~i prodrugs of, therapeutically-effective compounds.

The phrase "acidic group selected to contain at least one acidic hydrogen atom", as used to define the ~YnA
moiety, is intended to embrace chemical groups which, when att~ched to any of the R3 through Rll positions of Fonmula I, confers acidic character to the compound of Formula I.
"As~dic character~ means proton-donor capability, that is, the capacity of th~ compound of Formula I to be a proton donor in the presence of a proton-receiving substance such as water. Typically, the acidic group should be selec~ed to have proton-donor capabili y such that the product compound of Formula I has a PKa in a range from about one ~o about twelve. More typically, the Formula I compound would have a PKa in a range from abou~ two to about seven.
An example of an acidi group containing at least one , j....................................................... . - ....

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

WO 91/1888l~ PCr/US91/0344f9 11 2 ~ $~.7 ~f5 acidic hydrogen a~om ~s carboxyl group (-COOH). Where n s ~ero ~nd ~ is -~OCf~, ~n the ~YnA moiety, such caxboxyl ~roup would be attached directLy tO one of the R3 throu~A
; ~11 positions. The fFormula I co~cound may have one ~YnA
r~ -f moiety a~tached at one of the R3 through Rli positions, cr may have a plurallty of such ~YnA mcfieties attached at ~ore than one of the R3 through Rll positions, up tO a maximum of nine such ~YnA moleties. There are many examples o-acidic groups o~her than carboxyl group, selectable to contain a~ least one acidic hylrogion atom. Such other acidic qroups may be collectively referred tO as "bioisosteres of carboxylic acid" or referred to as "acidic bioisosteres". Specific exa~ples of such acidic ! bioisosteres are described h2reinafter. Compoundsf of Formula I having the -Y~A moiety atta_hed at one of positifns R5, R6, R8 and R9 would be expfected tO have -~
preferred properties, while attachment at R5 or R9 would be more prefferred. Compounds of Formula I may have one ffr more acidic protons and, therefore, may have one or more pXa values. It is preferred, however, that at least one Oc these PKa values of the Formula I compoufnd as conferred by the ~YnA moiety be in a rangfe from acout two to -ff~ffout seven. The ~YnA moie~y may be attached to one of the R3 tfhrough Rll posit ons through any portion of the ~YnA mo;ety --~ 2S which results in a Formula I compound being relatively ; stabfle and also having a latffile or aci~ proton to meet the fore~oing PKa crieeria. For exampfle, where the -Ynf~
acid moiety is tetrazole, the tetrazole is attached at the ring carbon atom.
~0 ~
prefe~red class o~ comFounds consists of those compoun,~s of Formula I whereLn m is one; wherein Rl is 1 sele-cted from polycycloalkyl, polycycloalkylalkyl, 3-i phenylpropyl, 2 oxo-2-phenylethyl, 2-hyi~roxy-2-phenyler.hyl, l,1-dimethylethyloxycar~onyl-methyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cy~lohexylethyl, pentyl, ethoxycarbonylmethoxyethyl . ., ~ , .~ 12 ~ 7 ~3 substituted wi~h phenyl, carboxymethoxyethyl substitu~ed with phenyl, 3,5,5-c imethylhexyl, (2-phenylmethoxy)-i (phenyLmethyl)-_-e~henyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-~2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyi-2-(phenylmethoxy)ethyl, 2-(2,5-dLmethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substitut~d with benzoyl, l-benzyoyl-'-methylethyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl, acetonitrile, cycloalkenyl, cycloalkynyl, mercaptocarbonyl, mercaptothiocarbonyl, alkylthiocarbonyl, arylthiocarbonyl, arylthiothiocarbonyl, aralkylthiocarbonyl, aral~ylsulfonyl and radicals of the formula ~. . -N/
~5 --Rl3 :

wherein X is oxygen atom or sulfur ato~;
wherein each of R12 and R13 is independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, aLkoxyalkyl, aralkyl and aryl, with the proviso that when X i5 oxygen atom, then Rl2 and ~13 cannot be s~lected from hydrido and alkyl;

wherein R2 is selected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carboxy~lkyl, alkoxycarbonylalkoxyalkyl, car~oxyalkoxyalkyl, :
I aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, j 30 cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, - aralkoxy, alkoxyalkyl, alkylca~bonyl, alkoxycar~onyl, ~ .
aryloxyalkyl, aroyloxyalkyl, al~enyl, cyc~oalkenyl, al~ynyl, cycloalkynyl, cyano, car~oxyl, al~lcarbonyloxy, ~ .
alkylthio, alkylthiocarbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkyl~hiocarbonylthio, ....... , ' , Wo 91/1~ PCT/US91/0 ~ 9 $~ S
alkylthiothiocarbonyl, alkylthiothiocarbonylthio, aryl~h_o, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthlocarbonyLthio, arylthiothiocarbonyl, arylthiothiocarbonylthio, aralkylthio, aralkylthiocarb~ny_, - aralkylcarbonylt~io, aralkylthiocarbonyloxy, aralkylthiocarbonylthio, aral~ylthiocarbonyl, aralkylthiocarbonylthio, mercapto, alkylculfonyl, aralkylsulfonyl, arylsulfonyl and heteroaryl having one or more ring atoms seleceed from oxygen, sul ur 10 and nitrogen a~oms;

wherein each of R3 through R11 is independently selec~ed from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, cycloalkylalkyl, alkoxy, aralky , aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, cyano, nitro~ car~oxyl, alkylca~bonyloxy, mercaptocarbonyl, mercaptoehiocar~onyl, al~oxycar~onyloxy, aLkylthio, alkylthiocasbonyl, alkylcarbonylthio, alkylthiocarbonyloxy, alkylthiocarbonylthio, alkylthiothiocarbonyl, arylthio, arylthiocarbonyl, arylcarbonylthio, arylthiocarbonyloxy, arylthiothiocarbonyl, aralkylthio, aralkylthiocarbonyl, aralkylcarbonylthio, a~alkylthiocarbonyloxy, aral~ylthiocar~onylthio, aralkylthisc~bonyl, ar.lkylthiocarbonylthio, me~capeo, alkylsulfonyl, aralkylsul~onyl and arylsulfonyl, and amino and amido ra~ic~ls of the formula - Rl ' -CN ~nd -NC;R

whereLn X is oxygen atom or sulfur atom;
wherein each of R14~ R15, R16, R17, R18 and R19 is independently selected from hydrido, alkyl, cycloalkyl, WO 91/1~ PCT/US91/03449 : 14 ~C~;~7~5 cyano, hydroxyalkyi, cycloalkylalkyl, alkoxyaLkyl, aralky~
and aryl;

and wherein each of R3 through Rll may be fu~ther : 5 independently selected from acidic moie~les cf the for~.~ia ~YnA . ;

wherein n is a number selected from zero through three, inclusive; wherein A is an acidic group select~d from acids containing one or more atoms selected from oxygen, sulfur, -~ .
phosphorus and nitrogen atoms, and wherein said acidic group is selected to con~ain a~ leas~ one acidic hydro~en `' atom, and the amide, ester and salt derivatives of said 15 acidic moie~ies; wherein Y is a spacer group independencly :-selec~ed from one or mare o~ alkyl, cycloalkyl, :
cycloalkylalkyl, alkenyl, alkynyl, aryl, aralkyl and heteroaryl having one or more ring atoms selected from oxygen, sulfur and nitrogen atom~: -.,, and wherein any of the foregoing Rl through Rl9~ Y and A
groups hav m g a substitutabl~ po~ition may be substi~uted by one or more groups selected from hydroxy, alkyl, alkenyl, aral~yl, hydroxyalkyl, halo, haloalkyl, oxo, alkoxy, aryloxy, ar~lkoxy, alkoxyalkyl, alkyloarbonyl, alkoxycar~onyl, carboxyl, cyano, ni~ro, alkylsulf~nyl, 1~ haloalkylsulfonyl, aryl, aralkyl, mercap~ocarbonyl, alkylth~o and alkylthiocarbonyl, and a~lno and am~do . radicals of the formula :.. ; 30 X

-C-RzO, -N~ a.

. .
whe~e~ X is oxygen atom or sulfus atom; wherein Rl9 is ~elected from hydrido, alkyl, cycloalkyl, cycloal~ylalkyl, : 35 aralkyl, aryl, and DR23 and ~ .
- .

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

WO 9~/t~ PCT/US91/0 ~ 9 ; ~

/

-N

wherein ~ is selec~ed f~om oxygen atom and sulfur aeom, and R25 is selected from hydrido, alkyl, cycLoalkyl, cycloalkylalkyl; aral~yl and aryl; wherein each of ~21, R22, R23, R24, R26 a~d R27 is independently s~lected from hydrido, alkyl, cycloaLkyl, cyano, hydroxyalkyl, haloalkyi, cycloalkylalkyl, alkoxyalkyl, alkanoyl, alkoxycarbonyl, c~rboxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

or a tautomer thereof or a pharmaceutically-accep~able salt thereof.
' ~ more preferred class of compounds consists of those compounds of Formula I wherein m is one; wherein R1 is selected from polycycloalkyl, polycycloalXylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 2D l,1-dimethylethyloxycarbonyl-methyl, h~xyl, ethoxycarbonylmethyl, carboxymethyl, 1 naphthalenyLmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with ph~nyl, carboxyme~hoxyethyl substi uted with phenyl, 3,5,5-trlmethyLhexyl, (2-phenylmethoxy)-1-(phenylmethyl~-E-ethe~yl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2~s-di~ethyoxyphenyl~-2-oxoethyl~ 2-phenyl-Z- ~phenyl~thoxy) ethyl, 2- (2, 5-dimethyoxyphe~yl) -2-hydroxyethyl, 2-naph~halenylmethyl, me~hoxycar3~onylbutyl, ethoxyca~bonyle~hyl substituted with benzoyl, l-~enzyoyl-l-30 m~thyle~yl, 1-pentau~oic acid, cyclop~opylmethyl, a~ylalkenyl, ac~tonitrile, cycloallcenyl, mercaptocarbonyl, cyclsalkynyl, aralkylsulfonyl an~ as~ds radicals or the fon~ula - , . . ., ~ .,, ~.. ... . . . . .

WO 91/18B8B Pl:~/US9!/03449 ~ 3 Rl2 -CN
--Rl3 wnerein each of ~12 and R13 is independen~ly seiec~ed cycloalkyl, cyano, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

where~n R2 is selected from hydrido, alkyl~ hydroxyalkyl, ~-halo, haloalkyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, :
2-hydroxy-2-aral~yl, alkoxycarbonylalkyl, carboxyalkyl, al~oxycarbonylalkoxyalkyl, carboxyal~oxyal~yl, aralkoxyalkenyl, aroylalkyl, aral~oxyalkyl, aralkenyl, cyanoalkyl, alkoxy, aralkyl, aryl, aroyl, aryLoxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, alkoxyca~bonyl, aryloxyalkyl, aroyloxyalkyl, al~enyl, cycloalkenyl, alkynyl, cycloalkynyl, car~oxyl, alkylcarbonyloxy, alkylthio, arylthio, aralkylthio, aralkylthiocarbonylthio, alkylsulfonyl, aralkylsulfonyl and arylsulfonyl; :

wherein each of R3 through Rll is m dependently selec~ed from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, al~oxy, aral~yl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, al~oxycarbonyl, alkenyl, eycloalkenyl, alkynyl, cyano, nitro, carboxyl, alkylcarbonyloxy, mereaptoca~bonyl, alkoxycarbonyloxy, alkylthio, arylthio, aralkylthio, meEcapto~ alkylsulfonyl, aralkylsulfonyl and arylsulfonyl, and amino and am~do radicals of the formula Rl ll Rl& 11 R --Rl7 R19 . ;,.. :.. : ... .. .. .. . .. ;-.. - .. .. . . .. . .

wo 91/~888$ PCT/US91/0344s . ~7 7~S
wAerein each of ~i4, R15, Ri6, Rl7, ~18 and Rl~ is ~ndependently selected from hydrido, alkyl, cycloalkyl, _yano, amino, monoal~ylamino, dialkylamino, hydroxyal~yl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl;

and wherein each or ~3 through R11 may be an acidic mole~y :
~urther independen-ly selec~ed from acidic moie~ies or -~.e fon~tula 1 0 ~YnA

whereln n ls a number selected from zero through three, inclusive;
:~ .
wherein ~ is selected from carboxylic acid and bioisosteres : of carboxylic acid selected from 1I D 1~
SH NR~ WH, -5-WH, -~-WH, IP WH, ~ I

~1 20 wherein each W is independently selected from oxygen atom, .~! sulfur atom a~d NR38; wherein each of R34, R35, R36, R37 . and R38 is independently selected from hydrido, alkyl, ~ haloalkyl, haloalkylsulfonyl, haloalkylca~bonyl, cycloalkylr cycloalkylalkyl, aryl and aralkyl; wherein e~ch i 25 of R34, R35, R36 and ~37 may be furthe~ independently ' selected from amino radical of the formula :, ~ R~
R~
~1 .
.~i 30 where m eai^~h of R39 a~d ~40 is independ~nely selected from hydrido, ilkyl, cycloalkyl, hydroxyalkyl, haloalkyl, :
cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and w`nerein ~ :
R39 and R4~ taken together may fo~m a heterocyclic grcup : , :'~3 WO 91J18888 PCI-/US91~034~9 18 ` ;~$~.~735 having five to seven ring members inc~udin~ the nitrogen acom of said amino radical, which he~erocyclic group may further coneain one or mor~ hetero atoms as ring memDers selected from oxygen, nitrogen and sulfur atoms and wh--h heterocyclic group may be saturated or par~ially unsaturated; wherein R39 and ~4~ taken together may form an aromatic heterocyclic group having five rin~ members includins the nitrogen atom of said amlno radical and which aromatic heterocyclic group may further contain one or more hetero a~oms as ring atoms selected from oxygen, nitr~gen and sulfur atoms; wherein each of ~35 and R35 may be further independently selec~ed from hydroxy, alkoxy, alkylthio, aryloxy, arylthio, aralkylthio and aralkoxy; and the amide, ester c~nd salt derivatives of said acidic 15 gro~ps; ;

wherein said bioisostere of carboxylic acid may be further selected from heterocyclic acidic groups consisting of heterocyclic rings of four to ~ ut nine ring members, which heterocyclic ring contains at least one hetero atom selecred from oxygen, sulfur and nitrogen atoms, which heterocyclic rlng m2~ be satu~at~d, fully unsaturated or partially unsaturat~d, cnd which hete~ocyclic rlng may be attached at a single position selecte~ fro~ R3 througA R
or may be actached at any two ad~acent positions selected fr~m R3 through Rll so as to for~ a fused-ring syst~m with ; on~ of the phenyl ring5 of Formula I; c~nd the amide, ester c~nd salt de~ivative~ o~ said heterocyclic acidic groups;

30 wiherein Y is a spacor group independently selected f~o~ one .- :
or more of alkyl, cycloaLkyl, cycloalkylalkyl, alkenyl,~ ~ -, .
I aryl and aralkyl;

. and wherein any of the fore~oing Rl through R19 and R34 ~ ~-3 chrough R40, Y and A groups having a substitutable posi; cr.
may bo substituted by one or more groups selected from hydroxy; alkyl, alkenyl, araLXyl, hydroxyalkyl, halo, ox.o, 1 .

WO 91/1~ PCT/US~1/0 ~ 9 haloalkyl, alkoxy, aryloxy, araLkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, carboxyl, cyano, nitro, alkylsulConyl~ ~aloalkylsulfonyl, aryl, aralkyl, mercaptocarbonyl, alkylthio and al~ylehiocarbonyl, and ; ~ amlno and amldo radicals of the formula _C_R20 , ~N ~ and --C-R~

wherein X is selected from oxygen atom and suL~u- ato~.;
13 whereln R20 is sele~ted from hydrido, aLkyl, cycloalky', cycloalkylalkyl, aral~yl, aryl and DR25 and -N

15 wherein D is selected fro~ oxygen atom and sulfur atom, wherein R25 is selected from hydrido, alkyl, cycloalkyl, ? cycloalkylalkyl, aralkyl and aryl;
., .
wherein each of ~ 1, R22, R23, ~24, R26 and R2~ is 20 independently selected from hydrido, alkyl, cycloalkyl, cyano, hydroxyalkyl, haloalkyl, cycloalkylalkyl, ~ -alkoxyalkyl, alkanoyl, alkoxycar~onyl, car~oxyl, haloalkylsulfinyl, haloalkylsulfonyl, aralkyl and aryl;

ZS or a tautom~r thereo~ or a pha~aceutically-accep~able salt ~:
thereof.

An even more preferred class of compounds ~ consists of those compounds of Formula I wherein m is one;

:~ 30 Rl is selected from polycycloalkyl, polycycloalkylalky;, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, l,1-dimethylethyloxycar~onylme~hyl, hexyl, ethoxycarbonylmethyl, carboxyme~hyl, l-naphthalenylmet~.yl, .

. Z

W ~PCT/US91/03449 ~ "7~,5 - 2-cyclohexyle~hyl, pentyl, ethoxyc2~bonylmethoxyethyl substltuted with phenyl, carboxymethoxyethyl substi~uted wi~h phenyl, 3,5,S-~rimethylhexyl, (2-phenylme~hoxyl-i-(phenylmethyl)-~-ethenyl, l-benzoyl-2-phenylethyl, 1-S oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyi- ~-2-(phenylmethoxy)ethyl, 2-(2,5-dime~hyoxyphenyl)-2-hydroxyethyl, 2-naphthalenyLmethyl, methoxycarbonyLbu~y~, .. .
ethoxycarbonylethyl substituted with benzoyl, l-benzyoyl-'-methylethyl, l-pentanoic acid, cyclopropylmethyl, lD arylalkenyl, acetonitr~le, cycloalkenyl, mercaptocarbonyl, aralkylsulfonyl and radicals of the formula O ~ R
. . .
--Rl3 lS wherein each of R12 and R13 is independently selected from cycloalkyl, cyano, amino, monoal~ylamino, dialkylamino, hydroxyalkyl, cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl; ' ~. .
20 where m each of R2 is selected fr~m hydrido, alkyl, :.:
polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxyca~bonylalkyl, carboxyalkyl, .
alkoxycarbonylalkoxyalkyl, ca~boxyalkoxyalkyl, : aralXoxyalkenyl, aroylalkyl, ar31koxyalkyl, aralkenyl, ;
cyanoalkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, asyl, aroyl, aryloxy, aralkoxy, -' alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, a~yloxyalkyl, a~oyloxyalkyl, alkenyl, cycloalke~yl, alkynyl, carboxyl, - ¦ allcylcar~onyloxy, alkylthio, arylt~io, aralkylthio, ;~ 30 allcylsulfonyl, alkylsulfonyl and arylsulfonyl;
,,j . .
wherein each of R3 through Rll is independently selected from hydrido, hydroxy, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, alkoxy, aralkyl, aryl, aroyl, aryloxy, aralkoxy, alkoxyalkyl, alkylcarbonyl, .i ';
: -1 . . .
- , .

WO 91/1~ PCT/US91/03449 . 21 ~t.itY"5 alkoxycarbonyl, alkenyl, cyoloalkenyl, alkynyl, cyano, nitro, _arboxyl, alkylthio, aralkylthio and mer~apto;

and wherein each of ~3 through Rll may be an acidic ~o~ety ^urther independen~ly selected from acidic moieties of _he formula ~YnA

wherei~ n is a num~er selected from zero through ~hree, inclusive; wherein A is selected from carboxylic acid and bioisosteres or carboxylic acid selected from H W W W
1 34 11 e 11 IS wherein each W is independ~ntly selected from oxygen atom, sulfur atom and NR3~; wherein each of R34, R37 and R38 .5 independently selected fro~ hydrido, alkyl, h.aloalkyl, haloalkylsulfonyl, haloalkylcar~onyl, cyoloalkyl, cycloalkylalkyl, aryl and aral~yl; where m each of ~34 and 2D R37 may be further independently seLected from ami~o radical o~ ~he formula ~39 - R~

whe~cin each o~ ~39 and R40 is independently selected from hydrido, alkyi, cycloalkyl, hyd~oxyaLkyl, haloalkyl, i cycloalkylalkyl, alkoxyalkyl, aralkyl and aryl, and wherein ::
¦ . R39 and R40 ~aken ~ogether may for~ a he~exocyclic group having five to seven ring members including the ni~rogen ato~ of said amino ~adical, which hererocyclic group may i ~usther con~ain one or more hetero atoms as ring members selected fro~ oxygen, nitrogen and sulfur atoms, and wnich heterocyclic group may be satura~ed or pa~tiaLly ' ~ .
.. . .
i .
'I , .
, . . , .. . . ~ . . ... .. . . . . . . . . ... . .. .... . . .. .. . . .... . .... .. ..

WO 91/18%*8 PCT/US91/03449 æ ~,~S~35 unsaturated; wherein ~39 and R40 taken toge~her may for~ an aromatic heterocycllc group having five ring members including the nicrogen atom of said amino radical and whlc;~
aromatic heterocyclic group may further contain one or ~.o-e hetero atoms as -ing a~oms selected from oxygen, nit-oaen and sulfur a~oms; and the amide, ester and salt derivatives of said acidic groups; wherein said bioisostere of carboxylic acid may be fur~her selec~d fzom he~erocyclic acidic groups consistin~ of heterocyclic rings of four tO
0 about nine rin~ members, which ring con~ains at least one hetero atom, selected from oxygen, sulfur and nitrogen ~ .
atoms, which heterocyclic ring may be sa~urated, fully unsaturated or partially unsaturated, and which heterocyclic ring may be attached at a single position ~:
selected from k3 through Rll or may be attached at any two adjacent posiei~ns selected from R3 through Rll so as to form a fused ring syste~ with one of the phenyl:rinqs of ~o~mula I; and ~he amide, ester and salt derivatives of said heterocyclic acidic groups; .

wAerein Y is a spacer group independently selected from one or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, aryl and aralkyl; .

25 wherein each of Rl ~hrough R19, R34 and R37 through R40, and A independ~ntly may be substituted at any substi~u~a~le pos~tiQn with one or more groups selecte~ from alkyl, :
hydroxy, halo, oxo, haloalkyl, alkoxycarbonyl, cyano, nit~o, alXylsulfonyl, haloalkylsulfonyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;

l or a taueo~er thereof or a phar~aceutically-acceptable salt -1 thereof.

A highly p~eferxed class o com~ounds within Formula I consists of those compounds wherein m is one;
wherein Rl is selec~ed from polycycLoalkyl, , . .

., . .

WO 91~l8888 pCT/US91/03449 7 3 ~
polycycloal~ylalkyl, 3-phenylprcpyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-d~me~hylethyloxycarbonyl-.~ethyL, hexyl, ethoxycarbonyimethyl, carboxYmethyl, i-~apht~alenylme~hyl, 2-cyclohexylethyl, pentyl, ; ~ ethoxycarbonylmethoxyethyl substituted with pnenyl, ..
carboxymethoxyethyl substituted with phenyl, 3,5,5-trimQ~hylhexyl, (2-phenylmethoxy)-1-(phenylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-~2,5-dLmethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenyLmethoxy~ethyl~ 2-(2,5-dlmethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonyLbu~yl, ethoxycarbonylethyl substituted with benzoyl, l-benzyoyl- -meehylethyl, 1-pentanoic aci~, cyclopropylme~hyl, arylalkenyl, ac~onitrile, aralkylsulfonyl and amido radicals of the formula 0 ~12 ~13 where m each of ~12 and R13 is independently selected f-om cy~loalkyl, cyano, am~no, hydroxyalkyl, alkoxyalkyl, ! phenalkyl and phenyl;

whe~ein R2 is s~lected from hydrido, alkyl, hydroxyalkyl, halo, haloalkyl, cycloalkyl, polycycloalkyl, polycycloalkylalkyl, aryloxyalkyl, 2-hydroxy-2-aralkyl, alkoxycarbonylalkyl, carhoxyalkyl, alkoxyca~bonylalkoxyalkyl, cax~oxyalkoxyalkyl, aralkoxyalkenyl, aroylalkyl, aralkoxyalkyl, aralkenyl, cyanoaLXyl, alkoxy, aralkyl, aryl, aryloxy, aralkoxy, alkoxyalkyl, alkylc~bonyl, alkoxycarbonyl, aryloxyalkyl, a~oyloxyalkyl, alke~yl, cycloalkenyl, alkynyl, alkylthio, arylthio, aralkylthio and arylsulfonyl; . ~

whereLn each o~ R3 ~hrough ~11 is independently selec~e~ -3 from hyd~ido, hydroxy, alkyl, hydroxyalkyl, halo, .

WO 91/1~ PCT/US91/0 ~ 9 haloalkyl, cycloalkyl, alkoxy, phenalkyl, phenyl, benzoyi, ?henoxy, phenalkyloxy, alkoxyalkyl, alkylcarbonyl, alkoxycar~onyl, alkenyl, cyano, nit-o, carboxyl, alkyl~
and mercapto;

and whe'rein each of R3 through Rll may be an acidic mole~y further independently selected from acidic moieties of ~he formula YnA .
, ~ , wherein n is a number selected from zero through two, incLusive; wherein A is selected from carboxylic acid a.~d bioisosteres of car~oxylic acid selected from H W W W

-OH, -SH, -t~34, -C-WH, -S~ ~~ and -~
W W~ , wherein each W is independently selected fro~ oxygen a~om, sulfur atom and NR38; wherein each ~f R34, R37 and R38 is independently selected fro~ hydrido, alkyl, haloalkyl, haloal~ylsulfonyl, haloalkylcarbonyl, cycloalkyl, phenyl and benzyl; wherein each of R34 and R37 may be further independently selected from amino radical of the formula - R~ ~
':
wherein each of R39 and ~40 is independently s~lected from hydrido, alkyl, cycloalkyl, hyd~oxyalkyl, haloalkyl, alkoxyalkyl, benzyl and phenyl; and thQ amlde, ester and salt de~iYatives of said acadic grcups;

wherein said bioisos~ere of car~oxylic acid may be fu--he-selected from heterocycLic acidic groups co~sisting of heeerocyclic rings of four to about n~ne ring members, ... ~

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

WO 91/18888 PCI'/US91/03449 ~hLch ~lng c~ntalns at least one hetero atom, selected --~~xyqen, sul~ur and r.it-~en atoms, which he~erocyclic -~.
may be satu_at2d, ~ully ~nsaturated or par~ ally ur.saturated, and which he~erocyclic ring may be attzcAed a~
_ a sln~ie posi; on selected ~ om R3 through Rii or may _e attached at any two adjacen~ positions selected from R3 through Rll so as to form a ~used-ring system with one c the phenyl r1ngs of Formula I; and the amide, ester and salt derivatives of said heterocyclic acidic groups;

wherein Y is a spacer group independen~ly selected C_om o~e or more of alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl, phenalkyl and aralkyl; :

15 wherein each of Rl through Rl9, R34 and R37 through R~O, Y
and A and independently may be substituted at any su~sti~utable pos tion with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, halo, oxo, haloalkyl, alkoxycar~onyl, cyano, nitro, al~ylsulfonyl, haloalkylsul~onyl, aryl, aralkyl, alkoxy, aryloxy and aralkoxy;

or a tautomer ehereof or a pharmaceutically-acceptable salt thereof.
2S .
An even more highly preferred class of comæounds consists of those compounds of Formula I wherein m is one; .-wherein Rl is selected from adaman~yl, adamantylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimechylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycar~onyLmethoxyethyl substituted with phenyl, carboxy~ethoxyethyl substituted . with phenyl, 3,5,5-trime~hylhexyl, ~2-phenylmethoxy~
35 ~phenyLmethyl)-E-e~henyl, l-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyi-2-(phenylmethoxy)ethyl, 2-(2,5-dLmethyoxyphenyi)-2-- WO 91J18888 PCr/U~91~U~

Y3~ii hydroxyethyl, 2-naphthalenyLmethyl, methoxycarbonyLbuty~, :
ethoxycarbonylethyl substituted with benzoyl, -benzyoyl- -methyle~hyl, 1-pentanoic acid, cyclopropylmethyl, arylalkenyl and acetonitr~le;
, ~; _ where ~2 is seLected from alkyl, hydroxyalkyl, cycloalkyl, polycycloalkyl, adamantyl, adamantylalkyl, aryloxyalkyl, 2 hydroxy-2-aralkyl, alkoxycar~onylal~yl, carboxyalkyl, alkoxycarbonylalkoxyaLkyl, carboxyalkoxyal~yl, 10 aralkoxyal~enyl, aroylalkyl, aralkoxyalXyl, aralkenyl, ::
cyanoalkyl, haloalkyl, alkoxy, phenalkyl, phenyl, phenoxy, phenalkoxy, alkoxyalkyl, alkylcarbonyl, alkoxycarbonyl, aryloxyalkyl, aroyloxyalkyl, alkenyli cycloalkenyl, i alkynyl~ alkylthio, phenthio and phenalkylthio;

wherein each of ~3 through Rll is independently selected fro~ hydrido, hydroxy, alkyl, hydroxyal~yl, halo, : ~.
haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, alkoxyalkyl, acetyl, al~oxycarbonyl, alkenyl, cyano, nitro, carboxyl, . 20 alkyltihio and mercapto; ~

and wherein each of R3 through Rll may be an acidic moiety .
further independently selected from acid~c moieties consisting o~ C02H, C02CH3, SH, C~2SH, C2H4SH, 203H2, 2S ~HS02CF3, NHS02C6Fs, S03H, CONHNX2, CCWHNHS02CF3, CONHOCH3, C~NWOC2Hs, CON~CF3, OH, CH20i~, C2H40H, OP03H2, 0503H , , ;-~ . .
,~i. - .

~. :
?1~
.

, ' ' ~ ' ' ' ., .` , , !
. " ., ' ` ` : . , . ,. ' ' .
i ' ,. ' ,~ ' ' ' . ' . ': . . -wo 91/18888 P~/US91/03449 27 Z~

~N ( C~3 CH3 OH

¢~OH y~ H

O
O CEl2CH3 --~2C6~s N~ I ~ zO I _fS

N ~ \ ~ NH
N N

wherein each of R41, R42 and R43 is independently selec~ed from H, Cl, CN, N02, CF3, C2Fs, C3F7, CHF2, CH2F, C02CH3, CO2C2~s, SO2CH~, SO2CF3 and SO2C6Fs; wherein Z i5 selected f~om O, S, NR44 and CH2; wherein R44 is selected from hydrido, CH3 and CH2C6Hs; and wherein said acidic moie~y may be a heterocyclic acidic group attached at any two :
adjacent positions of R3 through Rll so as ~o form a fused 10 ring system with one of the phenyl rings of the biphenyl . moiety of ~o~mula I, said biphenyl fused ring system selected from ., ., :' ~

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

WO 91/188~8 PC,~/~ iYI/U~
28 ;~ 35 $1 ~3 s~ ~ ~ S, ~J~6`;H ~o,~ 3o~H

~ d and the esters, amides and salts of said acid~c moie~ies;
or a tautomer thereof or a pharmaceutically-acceptable sal-thereof.

A class of compounds of particular interest consists of thoce compounds o~ Formula I wherein m is one;
wherein Rl ls selected from a a~antyl, adamantylmethyl, adamantylethyl, adaman~ylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dLmethylethyloxycarbonylmethyl, hexyl, ethoxyca~bonylmethyl, carboxymethyl, l-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycar~onylmethoxyethyl IS substituted with phenyl, car~o~ymethoxyethyl substi~uted with phe~yl, 3,5,5-trime~hyLhexyl, (2-phenylmethoxy)-1-(p~enylmethyl)-E-ethenyl, l-benzoyl-2-phenylethyl, ~-oxobutyl, 2-(2,5-dimeehyoxyphenyl~-2-oxoethyl, 2-phenyl-2-(phenylm~hoxy)ethyl, 2-~2,5-dimethyoxyphenyl)-2-2Q hydroxye~hyl, 2-naphthalenyl~ethyl, methoxycarbonyLbutyl, ethoxycarbonyle~hyl sub~titu~ed with benzoyl, ;- ~ zyoyl-i-methylethyl, l-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and acetonitrile; where~n R2 is selected :om h~droxy, methyl, e~hyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, ter~-bu~yl, n-pentyl, isopentyl, WO 91/18888 PCr/~'Sgl/034~9 29 ,,~-- t~l ~ t--;~ J f ~_~

.~eope~tyl, adamantyl~ adamantylmethyL, adamantylethyl, adamantyLpropyl, 3-pAenylpropyl, 2-oxo-2-phenylethyl, 2-~ydroxy-2-phenylethyl, 1,~-dimethylethyloxycarbonylmetA.f', ~exyl, ethoxycarbonylmethyl, carboxymethyl, 1-;S~ apht.halenyime~hyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl su~stituted with phenyl, 3,5,5-trimethylhexyl, ~2-phenyLmethoxy)-1-(phenylme~hyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-~2,5- ~-dLmethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxy)e~hyl, 2-(2,5-dLmethyoxyphenyl)-2-hyoroxyethyl, 2-naphthalenylmethyl, methoxycar~onyLbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benzyoyl- -methylethyl, 1-pen~anoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butyl~hio, 1-oxoethyl, 1-oxopropyl, l-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dLmethoxybutyl, l,l-dimethoxypentyl, hydroxyalkyl, difluoromethyl, l,1-difluoroethyl, 1,1-difluoropropyl, l,l-difluorobutyl and l,1-difluoropentyl;
; wherein at least one of R5, R6, R8 and R9 is an acidic group selected from C02H, S~, P03H2, SO3H, CONXNH2, : CONHNXSO2 OE 3, OH, H I H
N I ~N ~ N - N
~N ' N ~ and ~ ~

;
wherein each of R42 ~nd R43 is independently selected from Cl, CN, N02, CF3, C02CX3 and S02 OE 3;

or a t2uto~er thcreof or a pharmaceutically-acceptable salt thereof. -~ , .
A class of compounds of more particular interes_ consists of those compounds of Formula I wherein m is c~e;
~y,~

q . ,.. , - .

WO 91/18888 ~ / U~44Y

wherein Rl is selec~ed from 2-oxo-2-(t-icyclo[3.3.1.1.3 7]dec-2-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenyle~hyl, 2-hydroxy-2-phenylethyl, ;,1-methylethyloxycarDonylm~thyl, hexyl, ~ e~hoxycarbonylmerhyl, carboxymethyl, 1-naphthalenylmetr.~_, 2-cyclohexylethyl, pentyl, ethoxycarbonylmechoxyethyl :~
substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trlmethylhexyl, (2-phenylmethoxy)~
(phenyLmethyl)-E-ethenyl, 1-benzoyl-2-phenylethyl, : 10 1-oxobutyl, 2-~2,S-dimethyoxyphenyl)-2-oxoethyl, 2-phenvl-2-~phenylmethoxy)eehyl, 2-~2,5-dLmethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substi~uted with benzoyl, l-benzyoyi- -methylethyl, 1-pen~anoic acid,`cyclopropylmethyl, 3-phenyi-2E-propenyl and l-cyanobutyl; wherein R2 is selected f-om ethyl, n-propyl, isopropyl, n-bu~yl, sec-butyl, isobutyl, 4-methyLbutyl, tert-butyl, n-pentyl, neopentyl, l-cyanobutyl, propylthio and butylthio; wherein at leas~
one of R5, R6, R8 and R9 is an acidic group selected from 2D C02H, SH, P03H2, S03H, CONHNH2, CONHNHS02CF3, OH, ~ _ ~ /N ~ N- ~

whe~ein each of R42 and R43 is independently sel~cted from Cl, CN, N02, CF3, C02C~3 and S02 OE 3;

or a tauto~er thereof or a pharmaceutically-acceptable salt --thereo~. :
,, , A class of compounds of even more parti~la-interest consis~s of those compo~nds of For3ula I wherein m is one; wherein Rl is selected ~rom 2-oxo-2-(tr~cyclo~3.3.1.1.3-7]dec-2-yl)ethyL, 3-phe~ylpropyl, 2-oxo-2-phenyle~hyl, 2-hydroxy-2-phenylethyl, 1,1-WO 91/1~$ PC~/US91/0~9 : 31 ~m.e~hylethyloxycar~onylme~hyl, hexyl, -thoxycarDonyimethyl, carbo~ymethyl, l-naphthalenylme~
2-oyc'ohexylethyl, pentyl, ethoxycarbonyLmethoxyethyl s w st~uted wit~ phenyl, carboxymethoxyethyl su~st~;uted pr.enyl, 3,5,~-t-~me~hylhexyl, (2-pAenyl~met~.~xy)---(phenyLmechyl)-_-ethenyl, l-benzoyl-2-phenyle~hyl, l-oxobutyl, 2-(2,5-dLmethyoxyphenyl)-2-oxoethyl, 2-phenyi-2-(phenylmethoxy)ethyl, 2-~2,5-dimethyoxyphenyl)-2-hy~roxyethyl, 2-naphthalenyLmethyl, methoxycarbonyLbutyi, 0 ethoxycarbonylethyl subs~ituted with benzoyl, l-benzyoyl-'-methylethyl, l-pentanoic acid, cyclopropylmethyl, 3-phenyl-2E-propenyl and 1-cyanobutyl; whereLn R2 is selected --c~
ethyl, n-prapyl, isopropyl, n-butyl, sec-butyl, isobut~ , - 4-methyIbutyl, n-pentyl, l-cyanobutyl, propylthio and bu~ylthio; wherein each of R3, R4, R6, R7, R8, RlO and R-~
is hydrido; wherein one of R5 and R9 is hydrido and the other of R5 and R9 is an acidic group seLected From C02H
and N- N
N

or a tautomer thereo~ oz a pharmaceu~ically-acceptable sal~
thereof.

~5 ~ f~mily of speci~ic compounds of particular interest within Formula I consists of compounds, and the~
pharmaceutically-acceptable salts, o~ the g~o~p of ~ compounds consisting o~:
-~ 4'-[~1,3-dibutyl-4,5-dihydro-5-oxo-lH-1,2,4-triazol-4-yllmerhyl][l,l'-biphenyl]-2-carboxylic acid;
S-butyl-2,4-dihyd~o-2-t2-oxo-2-(tricyclo[3.3.1.1.37]dec-2-, yl)ethyl]-4-[2'-~lH-tetrazol-5-yl3[1,1'-biphenyl] 4'- ylmathyl]-3H-1,2,4-triazol-3-one;

WO 9 1 / 1 888~ u~

~, -butyl-2,4~dihydro-2-(3-pAenylpropyl)-4-[2'-(l ~ ~ ~ ~c ~-yl)tl,l'-biphenylj-4-ylme~hyl~-3H-1,2,4-t~iazol-3-one;
~-bu~yi-2,4-dihydro-~-(2-oxo-2-phenylethyl)-4-~2'-(lH-:etrazol-S-yl)[l,1'-biphenyl]-4-ylmethyl~-3H-1,2,4-er-azo!-5 3-one;
~-butyl-2,4-dihydro-2-(2-hydroxy-2-phenyle~hyl)-4-[2'-( .i-te~razol-5-yl)[1,1'-biphenyl~-4-ylmethyl]-3H-1,2,4-t-l~z^!-3-one;
1,1 dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH-.~trazol-5-yl)[1,1'-biphenyl~-4-ylmethyl]-lH-1,2,~-;r~.azole-l-acetate;
5-butyl-2,4-dihydro-2-hexyl-4-[2'-(lH-tetrazol-5-yl)[
biphenyl]-4-ylmethyl]-3H-1,2, 4-tr~azol-3-one;
! ethyl 3-bu~yl-4,5-dihydro-5-oxo-4-[2'-~lH-te~razol-5-yl~[l,l'-biphenyl~-4-ylmethyl]-1~-1,2,4-triazole-1-acetate;
3-butyl-4,5-dihydro-5-oxo-4-[2'-~lH-tetrazol-5-yl)tl,!'-biphenyll-4-yLmethyl~-lH-1,2,4-triazole-1-acetic acid;
5-butyl-2,4-dihydro-2-(1-naphthalenylmethyl)-4-[2'-(lH-tetrazol-5-yl)ll,1'-biphenyl]-4-yLmethyl~-3~-1,2,4-triazol-3-one;
S-butyl-2-~2-~yclohexylethyl)-2,4-dihyd~o-4~ E2 ' - ~lH-~ tetrazol-S-yl)[1,1'-biphenyl~-4-ylmethyl]-3H-1,2,4-triazol-- 3-one;
5-butyl-2,4-dihyd~o-2-pentyl-4-[2'~ te~razol-5-yl)[~
2S biphenyl]~4-ylmethyl]-3~-1,2,4-triazol-3-one; :
ethyl ~2-[3-butyl 4,5-dihydro-5-oxo-4-[2'-(lH-tetrazol~
yl~[l,1'-biphenyl]-4-ylmethyl]-lH-1,2,4-triazol-l-yl]-}-ph~nylethoxy~acetate;
[2-l3-butyl-4,5-dihydro-5-oxo-q-[2'-(1~-tet~azol-5-i 30 yl~[l,l'-biphenyl]-4-ylmethyl]-lH-1,2,4-triazol-1-yl~- -:l phenylethoxy]acetic acid;
. S-butyl-2,4-dihydro-4-~2'~ -tetrazol-5-yl)[1,1'-, ~iphenyl]-4-ylmethyll-2-(3,5,5-trimethylhexyl)-3H-1,2,4-triazol-3-one;
5-butyl-2,4-d~hydro-2-[2-phenyl-2-tphenylmethoxy)-l- -(phenylmethyl)-~ethenyl~-4-~2'-(lH-tetrazol-S-yL)[1,1 ~iphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
.
.

,,~ - . - .

: . :

WO 91/1~#~ PCT/US91/03449 2-(1-benzoyl-2-phenyle~hyl)-5-butyl-2,4-dihyaro- ~
et-azol-~-yl)[l,1'-~iphenyi]-4-yimethyl]-3H-1,2,4-t~lazoi-3-one;
_-Dutyl-2,4-dihyoro-2-(1-oxobutyl)-4-[2'-(lH-te~-azol-~-l,''-biphenyl]-4-ylmethyl]-3~-1,2,4-tr azol-3-one;
;-butyl-2,4-dihydro-2-~2-(2,5-dime~hyoxyphenyl)-2-oxoe~hyl]-4-[2'-(lH-ee~razol-5-yl)[l,l'-biphenyl]-4-ylmethyl]-3H-1,2,~-triazol-3-one;
5-bueyl-2~4-dihydro-2-l2-phenyl-2-~phenylmethoxy)ethyl]-4-[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl~-4-ylmethyl]-3H-i,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-[2-(2,5~dimethyoxyphenyl)-2-hydroxye~hyl]-4-[2'-(1~-t~trazol-5-yL)~,1'-b1phenyl]-4-ylmethyl]-3H-1,2,4-tria201-3-one; ~ : .
5-butyl-2,4-dihydro-2-~2-naphthalenylmethyl)-4-[2'-(lH- ~:
tetrazol-5-yl)[1,1'-biphenyl]-4-yLmethyl]-3H-1,2,4-tr~azol-3-one;
methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-~lH-tetrazol-5-yl)[l,1'-biphenyl]-4-yLmethyll-1~-1,2,4-triazole-1-pentanoate;
ethyl ~-henzoyl-3-butyl-4,5-dihydro-5-oxo-4-[2'-(lH- ;~
tetrazol-5-yl)[l,l'-biphenyl]-4-ylmethyl]-lH-1,2,4-t~iazole-l-propanoa~e; ~ .
2-(1-benzyoyl-1-me~hylethyl)-5-butyl-2,4-dihydro-4-[2'-(lH-~etrazol-5-yl)[l,l'-biphenyl]-4-yLmethyl]-3H-1,2,4-trlazol-3-one; ;
3-butyl-4,5-dihydro-5-oxo-4-[2'-~lH-tetra201-5-yl)[1,1'-biphenyl~-4-ylmethyl]-lH-1,2,4-triazole-1-pentanoic acid;
5-~utyl-2-(cyclopropylmethyl~-2,4-dihydro-4-[2'-~lH- ~
tetrazol-5-yl)[1,1'-biphenyll-4-ylmethyl]-3~-1,2,4-triazol- :- :
3-one;
5-butyl-2,4-dihydro-2-(3-phenyl-2E-propenyl)-4-[2'-(lH-tet~azol-5 yl)~ iphenyl~-4-ylmethyl]-3H-1,2,4-tri3zol-~i 3-one; and 1-butyl-4,5-dihydro-5-oxo-~-propyl-4-[2'-~lH-tetrazol~
yl)[1,1'-~iphenyl~-4-ylmethyl]-lH-1,2,4-triazole-3-acetonitrile.

" .

~ -2~
, ~35 ~ -e ~e-m. "~ydri~o" cen.o~es a s~~.~'e ~ rocer.
z~cm (:~). -b s ~yd- co g~ou? may ~e â~-rhe~'~ 3r ex~-..T e~
t~ an o:~cen a_cm ~ ~orm a hydrcxyl sroU?; or, zs ænc_:-.e~
e:~ample, or.e ~.yd-~c~ ~rouo may ~e ae.zchec to â ca-bon _- ^3 S tO _orm a C- g~cup; or, as æn.cthe~ examDle, ~o hvc-groups may be attached co â car-~on atom to .o-m a -CX2-group. ~ne~e the t^rm "alkyl" is used, ~-t:ner alone or ~ithin othe- terms such as "haloalkyl" and "hydro~yalkyi", the term "alkyl" embraces linear or branched radicals having one to twenty carbon atoms or, prefer2bly, or.e to twelve carbon atoms. More prefer-ed alkyl r~lcals are "lower alkyl" radicals havi~g one to te~
carbon atoms. Most preferred are lower alkyl radicals having one to five carbon atoms. The term 15 "cycloalkyl" e~braces cyclic radicals having three ~o ten ring carbon atoms, prererably three to six carbon acoms, such as cyclopropyl, cyclobutyl, cyclopenryl and cyclohe~yl. The term "polycycloalkyl" denotes a radical ~
^~ ~ having t~o or more cycloalkyl rings; for example, two - `
: - 20 cycloalkyl rings may share a single atom to form a spiro-ring sys~em, such as a dicyclohe~yl-spiro ring system; or an alkylene group of one or more methylene radicals may ~
bridge 2 cycloalkyl ring to form, for exam~le, an adam2r.Tyl -- group. Prererred polycycloal~yl groups contained 10 to 2~-~arbon atoms. The te~ "haloal~yl" e.~braces radicals whe~ein any one or more of the alkyl carbon atcms is substituted with one or more halo groups, preferably selected 'rom bromo, chloro and fluoro. Specifically ~ embraced by the term "haloal~yl" are monohaloalkyl, :-~ 30 ~ihalcalky} and polyhaloalkyl grou~s. A monohaloalkyL
.1 group, for example, may have either a bromo, a chloro, or a 7 fluoro atom within the group. Dihaloalkyl and polyhaloalkyl groups may be substituted with tWO or more of - the same halo groups, or may have a combination of ~5 different halo groups. A dihaloalkyl group, for e~ample, may ha~e two fluoro atoms, such as difluoromethyl and difluorobutyl groups, or two chloro atoms, sucn as a 5UBs~ JTE s~lE'r ~ '7 _~c~ cm~e_~.y~ C-~?, or cne 1uoro atom anc-cr.e chlor~
2_0m, such cS a ~'ucro-chl~_cme~hyl srou?. _~er.ples CL G
olynzloalkyi are trifluoromethyl, 1,1-dirluoroerhyl, 2,2,2-r-ifluorcerhyl, pe~_luoroethyl and 2,2,3,3-S te~-zfluoroprcpyl croups. The tenmi "dirluoroalkyl"
embr2ces alkyl c-~uos having two fluoro 2toms s~bs~it~_r~d on any one or two or the alkyl group carbon atoms. The terms "alkylol" ~nd "hyoroxyalkyl" e.~brace linear or brancned al~yl groups having one to ten car~on atoms any one or whicn may be substitu~ed with one or more hydroxyl groups. The term "alkenyL" emDraces linear or branched radicals having t~o to twenty carbon atoms, :prereraDly three to . ten car~on atoms, and contalnlng a~ least one carbsn-carbon double bond, which carbon-car~on double ~ond may have either ~ls or ~n~ geome~ry within the al~enyl moiety. The term "alkynyl" embraces linear or branched radicals having ~wo to twenty carbon atoms, preferably ;wo to ten carbon atoms, and con~ainir.g a.
least one carbon-carbon trlple bond. The term ~0 "cycloalkenyl" embraces cyclic radicals having thres to ten ring carbon atoms including one or more double bonds involving adjacent ring carbons. The terms "alkoxy"
and "alkoxyalkyl" embrace linear or branched oxy-containing radicals each having alkyl portions of one to te~
carbon atoms, such 2S methoxy group. The tenm "alkoxyalkyl" also embraces all~yl radicals havins two or more al~oxy groups attached to the alkyl radical, that is, ~- 'to form monoalkoxyalkyl and dialkoxyalkyl groups. The ~ `
"alkoxy" or "al~oxyalkyl" radicals may be rurther suostl-~-I30 tuted with one or more ha~o atoms, such as fluoro, chloro or bromo, to provide haloalkoxy or haloalkoxyal~yl grou?s.
The term "alkylthio" e.~br~ces radicals containing a linear - ~or branched alkyl group, of one to ten carbon atoms attached to a divalent sulfur atom, such as a methythio ~5 group. Prererred aryl groups are those consisting or one, two, or three benzene rings. The term "aryl" e~braces aromatic radicals such as phenyl, naphthyl and biphenyl.
. .
. - ` Sl;B5~1T~1 ~ 5t~e~ET ~ ` `

wo gl/l~ PCT/US91/0 ~ 9 36 ;~ 35 The term ~aralkyl" embraces aryl-substltuted alkyl -ac -~Ls such as benzyl, diphenylmethyl, triphenylmethyl, ?heny -ethyl, phenylbutyl and diphenylethyl. The terms "benz;'~' and "?henylmethyl" are i~terchangeable. The cerms "aryloxy" and "arylt.~io" denote radical respect~vely, ~ y groups having an oxygen or sulfur a~om through which t~.e radical is attached to a nucleus, examples of which are phenoxy and phenylthio. The terms "sulfinyl" and "sulfonyl", whether used alone or linked to other terms, denotes respec~ively divalen~ radicals SO and SO2. ~.~e term ~'aralkoxy~, alone or within another term, embraces a.
aryl group attached ~o an alkoxy group ~o form, for example, benzyloxy. The ~erm ~'acyl" whether used alone, or within a term such as acyloxy, denotes a radical provlded by the residue after removal of hydroxyl from an organic acid, exdmples of such radical being acetyl and benzoyl.
"Lower alkanoyl" is an example of a more prefered sub-class of acyl. The term "amido" denotes a radical consisting o~
nitrogen atom attached to a carbonyl group, which radical may be fur~her substituted in th~ mdnner described he_ein.
~he amido radical can be attached to the nucleus of a compound of the invention through the car~onyl moiety or through the nitrogen atom of the amido radical. The term "alkenylal~yl" denotes a radical having a double-bond unsatura~ion site bet~een two carbons, and which radical may consist of only two carbons or may be further subst -tuted with alkyl groups which may optionally contain additional double-bond unsaturation. The term ~he~eroaryl"
embraces aromatic ring systems containing one or two he~ero atoms selected from oxygen, nitrogen and sulfur in a ring system having five or six ring mem~ers, examples of which are thienyl, fu~anyl, pyridinyl, thi`azolyl, pyr~midyl and - isoxazolyl. Such heteroaryl may be attached as a substituent through a carbon atom of the heteroaryl ring system, or may be attaChed through a carbon atom of a moiety cubstituted on a heteroaryl ring-m~mber carbon a:om, fo~ example, through the methylena substituenc o~

Wo 91/1~ PCT/US91/0344s 2~ '7~i midazolemethyl molety. Also, such heteroaryl may be at.ached throu~n a ~ ~.g ~it-ogen a~om as lon~ as ~roma~ c y of the heteroaryl moiety is preserved afte-attaG~ment. For any of the foregoing def ned -adicals, ?refer-ed radicals are those containing r_om one to aDc~:
ten carbon atoms.
- .
Specific examples of alkyl groups are methyl, ~ .
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, ~ert-bu yl, n-pen~yl, isopentyl, methylbutyl, dimethylr.~
and neopentyl. Typical alkenyl and alkynyl groups may have sne unsaturated bond, such as an allyl group, or may have plurallty of unsaturated bonds, with such plurality of bonds either adjacent, such as allene-cype structures, cr in conjugation, or separated by several saturated carbons.

Compounds of Formula I have been found to inhibit ~he action of angiotensin II in mammals.
Angiotensin II is a potent vasoconstrictor and parcicipates 20 in the formztion of aldost~rone which regulateq sodium and - ~:
-: water balance in mammals. ~hus, compounds of Formula I are ; therapeutically useful in methods for treating hypertension by ad~inistering to a hypertensive pa~ient a therapeutically-effective amount of a compound af Formula I. Th~ phrase "hypertensive patient" means, in this context, a mammalian subject su~fering from or a~flicted by the effects of hyper~ension or susceptible tO
a h~pertensive condition if not treated to prevent or cont~ol such hyperte~sion. :
Also included in the fzmily of compounds of : Formula I are op~ical isomeric fo 3 including :
.i diastereoisomers. Further included in t~.is inventicn are - ~ .
... r~gioisomers of the comDounds of Formula I, e.g., compou~.ds having the biphenylalkyl moiety exchanged with the Ri substituent on the t:iazole ring nitrogen a~oms shown in Formula I. Also included in this invention are ~he , :' :

WO 91/1~ PCT/U591/03449 38 ~ ~ 5 ~harmaceutically-acceptable salts of the Formtlla I
c~mpounds. ~he ~erm ~phar~aceutically-acceptable salts~
embraces sal~s c~mmonly used to form alkali me~al salts an~
,o form ad~ition salts of free acids or ree bases. ~e nature of the salt is not critical, provlded that ~c ~s pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula :
may be prepared from an inorganic acid or from an organi_ acid. Examples of su~h ~norganic acids are hydrochlor-_, hydrobromlc, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphaeic, heterocyclic, carboxylic and sulfonic classes of organi-acids, example of which are formic, acetic, propionic, 5 succinic, ~lycolic, gluconic, lactic, malic, tartaric, -citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, ~mbonic (pamoic), methansulfonic, eehane~ulfonic, 2-hydroxyetha~esulfonic, pantoehenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosuLfonic, stearic, algenic, ~-h~droxybutyric, malonic, galactaric and galactu~onic acid. Suitable phanmaceutically-acceptable base addit on salts of compcunds of Formula I include metallic salts made from aluminium, calciu~, lithiu~, magnesium, potassium, sodiu~ and zinc or organic salts made from N,N'-diben2yleehylen~dia~ine, chloroprocaine, choline, diethanolam1ne, eehylenedlamine, meglumine (N-methylgluca-mine) and procaine. All of these salts may be prepared by conventional m~ans from the corresponding oompound of For~ula I by react~ng, for example, the appropriate acid o~
base with the com$ound of Formula I.

WO 91/1~ PCT/US91/03449 Z~t.~7~5 ~n~ral $y~thQtie Proc~dure .he compounds of the invention can be syn~hesized according to the follo~ing procedures cf -~
Schemes _-VI, wherein each of the R substituents are as defined for Formula I above, except ~here fur~her noted.

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

~ ~ .
~ .

:~:
"~ : , .... ..

WO 9 1 / 1 8888 t'~ Y I / U~W~

;~S~7~5 SCHEME I

S

~C:02Et R2M9X ,ll ~ CO2Et S C_N 4 ~ R2 7, ', .

- N-zNHRI ~

~Rl . .

R~N~O

H

j .
.1 ' .`

,:

- - ' :: . . ' ' .' .' ' . . ' . . : : ' ' ', ' , , . . . , ~ .,: , . , WO 91/18888 PCT/VS~1/0 ~ 9 41 ~ ~5 Synthetio Sc~. me ~ shows the orepara~ion o ',2,4-t-~azolone 1 -cm ~so~hiocyanate 2 vla N-ethoxyc~rDonyi ~~.ioamide ~ according tO the general ~rocedu-e out1 ned by Pa~aaopoulos, ~. P. and George, 3., e~ ~ 32~3 ('976). In the fi-st step, N-ethoxycarbonyl ~hioamide ~ can be prepared f_om ethoxycarbonyl isothiocyanate 2 and the corresponding organometallic 4 . The N-ethoxycarbonyl thioamide ~ can ~e converted to triazolone l by the action of the 0 corresponding hydrazines ~ as described in ehe refe~ence given ~bove.

, ,~
' ., ... '. , '',' .. . ' ' , ',, , .. ~ , . . ..

WO 9t/1888~ PCl[/US91/03449 42 ;~ J~-s 5 SCHEME~

I H3 CH2Br ¢ NBS, AI~N ¢~

~3~Rs ~Rs ,~ .

`.1 : .
.. i .
. Il ' .
, :. , .~.~ .
~,'', -~. . ' ' .

~; :

WO 91/1888B PCT/US91/O~i9 ~ 43 ~ '7~S
Syn~he~c Scheme ;I shows .he preparatlon cf _.~e ai~ylat~ng agent ~ from the corresponding precursor ~. ;Jnen ~ eauals C~2C~.3, ' was purcnased C-om Ch~mo Dynamics .~c.

.". ' ' '''' '' .' .

~i .
1 ~

' :
::
.~ . . .

wo 91~18888 ~ YI/u~w~

21~J~5 NaOH/HCI

~ 2 3 4 Socl2 ~CN

7 P~5 = CO2CH3 9 Me3SnN3 : ~ .

CH

1. HOAc~H
2. Pll~CCI, Et3N

SnMe 3 7 Rs = CN"CPh3 8 ;::

WO 91/1$~ PCT/US91/03449 q5 Syn~hetic Scheme III shows the preparation o_ the alkylating agen~ precursor 1 where R~ equal CN4C(C6HS)3 '_om the corresponding methyl ester 1 (R5 = C02C~3). I~
step l, ~he methyl ester is converted to the corresponai ng S acid (R5 = CO2H) by the action of sodium hydroxide/hydrochloric acid. In step 2, the acld is converted to the corresponding acid chloride (R5 = COCl) by the action of oxalyl chloride. In step 3, the acid chloride is con~er~ed to the corresponding prim2ry amide tR5 = C0NH2) by the action of ammonium. I~ step 4, the amide is converted to the corresponding ~itrile 2 by the action of thionyl chloride at reflux. The nitrile 2 is reacted with trimethyltin azide in toluene at reflux to give the corresponding trimethyltin protec~ed tetrazole 8;
deprotection with acetic acid/wa~er and reprotection with triphenylmethyl chloride/triethylamine gives the N-trityl tetrazole 7 ~5 = CN4C(C6~5)3)-1 ':

, :
., . :.

.
.. ~ . . .:

' "~
~' ",.
ii . . . . .

Wo 91/18888 PCr/US91/03449 SCHEME IV

Rt ~1 N--N KOC(t:~3)3 N--N
R ~N DMF R 2~ N~O
~3 CH*r R ~1 NN~bRo I ~J Rs CH2 ¦

TFA
~¦~CO2H ~ 5 - C02C(CH3)3 ~J \ ,R~ ~ :
N--N
ii 12 R 2 N
l , ...
I R5 = CN4CP~3 CH2 Z N--N'Rl HOAc ~ ! -R2 N Ri s CN
. : CH2 M03SnN
~ ~ '; ' . ~ N-N~ 1 1 Ol1H

. ' .
N.B.: R~ may a~so b~ hydrido for ~ompound 1 and ~, -.. . . .
: ~ .
, . .

", ; ~ i , , WO 91/1~ P~T/US91/03449 47 ~ ~ ~1J7~5 Syn~hetic Scheme IV shows the csupling reac~ n or the l,2,4-t-iazoione l with the appropria~e alkylat-ng _eagent ~; and subsequient c~nversion to the compounds of ~e invention. In the first step, l is treated with a base, S such as potassium t-butoxide, to genera~e the corresponcir.g anion lQ. Anion ~Q is reacted with an alkylating agent _ ;o give coupled produc~ ll. The trisubstituted 1,2,4-triazolone 11 can be subsequently converted to the corresponding acid 1~ or tetrazole 11 by treatmeint with one 0 of the appropriate reagents as shown in Scheme IV.

Alternatively, the compounds of the inven~ion can be synthesized according to the following procedures c Schemei V and VI.

... ' .-. , . ,', , : , W~ 118888 ~ ~W~49 ~8 SCHF~YIE V

,r, ¢~
b--R5 6 17 ~-~5 _ CN or 1:02C~CH3)3 :

H~, PdlC

~NH CH~IH2 C~ OCI2 ¢~

- br 2~ N H N H

.~; . .

... .

,~., -.
., ` :

WO 91 tl X~ PCT/US91/03449 I
49 2~ 3S

Syntheti_ Scheme v shows the preparation of semicarbaz~de 1~ from bromide 6. Semicarbazide 1~ can be p-epared f-om aminomethylbiphenyl ~ and the corresponding hydrazide ~ which can be obtained by treating its ester recursor wi~h hydrazine. Amine 1~ can be prepared by :'?
hydrogenation of the corresponding azide 12 ~hich can be obtained from i~s bromide precursor h by treatment with sodium azide.

,, : ~:

.
' .' ' '' ' ', ' ' :. :
. .
~::
~j!

, l .
. ...
:"' : -:

; ' ~ .

Ja~ . . .

- WO 91/18888 PCr/US91/0344Y
so ~ 5 SCHE~ME Vl NaOMe, CH30H
- ~- C t1 2 , ~ reflux b, Rs Rs _ CN or CO2C(CH~)3 KOC(CH3)3 l DMF

N--,N,~ R 1 X R2 1 N ~ O . .

S:H2 ~ 20 CH2 ::
b--Ri b--R5 :
-I ~

':

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

WO 91~18888 PCr/US91/0344~ , ~35 Synthet-c Scheme VI shows ~he cycliza~ion o~
tO 1~ and the subsequent alkylation to 11. In the f rst step, triazolone 1~ can be prepared by dehydration of semicarbazide 1~ in alcohol with a base catalyst, such as :
sodium methoxide. Then triazolone 1~ is treated with a base, such as potassium t-butoxide, to generate the corresponding anion 1~. Anion 12 is reacted with an alkylating agent 2Q tO give alkylated product lL which may be converted to the corresponding acid 12 or tetrazole 0 by treatment with one of the appropriate reagents as shown in Scheme IV.

':

! ~

,....................................... :
., . ':

W~ 1/18888 PCT/~S9l/03449 52 ~ 5 The rollowing Examples 1-30 are de~ailed descriptions of the methods of preparation or compounds o_ - -ormula I. These detailed prepara~ions faLl wlthin the scope of, and serve to exemDlify, the a~ove desc-ibed General Synthetic D_ocedures whic~ form part of the invention. These ~xamples are presented for illustrative purposes only and are not intended as a restr~ction on ~h.e scope of the invention. All parts are by weight unless otherwise indicated.
, .

.

' ' ' ' .:
.
'7 -- ` - ' : -, ' .
' ~' ' ' '" ~ ' i l . ~ . "~,i'.' ':

WO 91/1~ PCT/US~1/0 ~ 9 ~3 : ~:

Ex~MoeL~ #l N-N - .
N ~ O
l~H

' ' , -.

S ~ ' _ r ~ . 3-~i h~tyl -4 . 5-dihyd~o-5-o~ ?. 4-~ ; a~o l -4 -~ .
S~eD t ~re~aratlon of ?~ r~lvllb _ A mixture of 52 g ~0.23 mol) of methyl 2-(Fr tolyl)benzoate ~Chemo Dynamics Inc.) and 100 mL (0.25 mol) of 2.5 N aqueous sodium hydroxide solution in 100 mL o~ methanol was stirred at room temperature for about 6 h, then at reflux for about 6 h. The resulting - 15 solution was concentrated i~_~=~9 to half of its original volume. The aqueous solution was acidified with 3 N hydrochloric acid to about p~ 3 and extracted with-methylene chloride. The extracts were dried ~MgSO4~ and concentrated ;n ~ac~o to ~ive 48.7 g (99%) of 2-(p-tolyl)benzoic acid as a white solid: lH MMR
~CDC13) ~ 2.40~s, 3H), 7.00-8.05~m, 8H), 10.4-11.4(broad ~
. ~ s, lE~. -`.

.

WO 91/lX~ PCT/VS91/0344s : 54 St~p~ 2- ?~ rari~ ~c t~-~tuty~ 2~ tQlvll~en~

To 48 g (0.226 mol) of 2-(p-tolyl)benzoic acld from step 1 and 5 mL of conce~trated sulfuric acid in 100 mL of anhydrous ether cooled in a dry ice-ace~one bath was transferred 100 mL of 2-methylpropene. The resulting mixture was agitated on a Parr apparatus a~
room temperature for about 15 h, and the excess of 2-methylpropene was allowed to evaporate at room temperature. The ethereal solution was neutralized wi~h 2.5 N aqueous sodium hydroxide solution, and extracted wi~h three 200 mL-portions of ether. The combined extracts were dried (MgSOq~ and concentra~ed i n vac~o to give 57.2 g ~94%) of tert-butyl 2-(p-tolyl)benzoate as a solid: lH MMR (CDCl3) ~ 1.29(s, 9H~, 2.40(s, 3H), 7.21~s, 4H), 7.25-7.55(m, 3H), 7.7-7.8~m, 1~).
' ' Ste~ 3- Pr~a~iQn Qf 4-~=~h5r'L~
bYC~C ~ ~L~ CI~

To a mixture of 57 g ~0.213 mol) of tert-bu~yl 2-(p-tolyl)benzoate from step 2 in 1.7 L of carbon tetrachloride ae about 65~C was added 36.4 g (0.204 mol) of N-bromosuccinLmide (NBS) and 0O82 g (5 mmol) of azobisisobutyronitrile (AIBN) in one portion. The resulting solution was stirred ~t reflux for about 6 h followed by addition of another 1.7 g (9.6 mmol~ of N-bromosuccinlmide and 0.1 g (0.6 mmol) of AIBN. The 3Q mixture was stirred at reflux for additional 13 h, a~d concentrated ; n vac~n, The residue was dissolved in ethyl acetate-hexane ~1:3) and filtered through a pad of - silica gel, eluted with ethyl acetate-hexane (1:3) to give 79 g (quan~itative) of a sa~ple which contained ~;
:

wo 9t/l$~ PcT/US9l/o ~ 9 i .

-;

~' ~ostly desired product, 4-bromomethyl-2'- ter~ -~utoxycarbonyl~iphenyl, ~it~ a small amoun~ or dibrominated product and starting material. No fur.her ~ .
surification, however, was attempted and the mlxture was used directly i~ subsequent reactions: 1H NMR (CDC13) 1.26~s, 9~), 4.56~s, 2H), 7.2-7.9~m, 8H).

Ste~) 4 3~e~a~ f 4-a~
10 ~

The mixture of 11.0 g (0.032 mol) of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl from step 3 and 4.6 g ~0.071 mol) of sodium azide in 42 mL of dLmethyl~ormamide and 4.2 mL of water was seirred at room temperature for about 24 h and concentrated i~
y3~Q. The residue was extracted with ethyl acetate, and the combined extracts were washed with water, dried ~MgSO4) and concentrated l~_Ya~ to give 10 g ~, 20 (quantitative) of 4-azidomethyl-2'-tert-butoxycarbonyl biphenyl as a yellow oil: lH NMR (CDCl3) ~ 1.26(s, 9~), ., 4.38~s, 2H~, 7.2-7.9(m, 8H).

~

~A suspension of 10 g (32 mmol) of the - azidQ~ethylbiphenyl from step 4 and 0.6 g of 10%
: 30 . pall~dium on carbon in 39 mL of absolute ethanol was agitated on a Parr apparatus under a hydrogen atmosphere at 40 psi for about 20 h. me mlxture was filtered i through a pad o~ celite and concentrated i~ 8 to '~ . give 9.2 g (quantitative) of 4-aminome~hyl-2'-tert-, .

.. . . .
G'.l . . ' ..

- WO 91/1~ PCT/US91/03449 s6 7~ 35 ~utoxycarbonylblphenyl as a yellow oil: lH NMR (CDCl3) 1.28(s, 9H), 1.71(broad s, 2H), 3.92(s, 2H), 7.2-7.9(m, 8H).

~i~Qhenvl 1 -2-carhoxyl ~te To 6.4 mL of lM (6.4 mmol) phosgene in toluene and S mL of toluene at 0C was added dropwise solution of 1.0 g (3.53 mmol) of 4-amlnomethyl-2'-tert-butoxycarbonylbiphenyl-in S ml of methylene chloride alonq with dropwise addition of 1.5 mL (18.5 mmol~ of pyridine. The resulting mlx~ure was stirred at 0 C for abou~ 30 min, at room temperature for about 1.5 h, and the excess of phosgsne was removed under a stream o~
nitrogen. To the mixture was added 800 mg (6.9 mmol) of valeric acid hydrazide (Lancaster Synthesis), 1.0 mL
~12.3 mmol) of pyridine and 2 mL of ether, and the .! resulting mixture was stirred at room temperature for about 2.5 h. The reaction mixture was concentrated 1 vac~o, and the residue was chromatographed over silica gel (eluted with isopropanol-hexane, 1:5) to give 780 mg (52%) of semicar~azide as a white solid: lH NMR (CDCl3) 0.86(t, ~ ~ 7.2 Hz, 3H), 1.28~s, 9H), 1.20-1.40~m, 2~), 1.56~qu mtet, ~ - 7.2 Hz, 2H), 2.20~t, ~ = 7.5 Hz, 2H), 4.38(d, ~ - 6 Hz, 2H), 6.27(broad t, lH1, 7.2-7.5(m, 7Hl, 7.76~dd, ~ = 7.5, 1.0 Hz, lH~, 7.95-8.05~m, lH), 8.85~broad s, lH); 13C NMR ~CDCl3) ~ 13.7, 22.3, 27.4, 2~.7, 33.~, 43.7, 127.0, 128.8, 129.7, 130.7, 132.7, - 127.7, 140.7, 141.7, 15&.3, 167.9, 173Ø

~ ~, '~ '` ''~ .

.. - ' .
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'. ~

WO 91~ PCT/US91/03449 ~7 .735 St~p 7 ~ pa~2t~ o t~ utyl 4 ' - ! (3-huty~ a, ~-dihvd~o-~-oxn-~ 2.4-t-~a~ol-4-yl~merhyl1 r~ h~nyll-2=~

To 500 mg (1.18 mmol) of the semicarbazide from step 6 in lO mL of methanol and 5 mL of toluene was added 126 mg (2.33 mmol) of sodium methoxide and the resulting mixture was stirred under vigorous reflux for about 48 h with a moisture trap (molecular sieve, 3A) attached between a condenser and the reaction vessel.
The mlx~ure was acidified with acetic acid and concentrated ~ he residue was dissolved in chloroform and washed with water, saturated sodium bicarbonate and brine. The ex~ract was dried ~MgSO4) and concentrated i~_yaSyg- The residue was chromatographed over silioa gei (eluted with ethyl acetate-hexane, 2:1) to give 480 mg (90%) of 3-butyl-1,2,4-triazolone as an oil: lH NMR (CDC13) ~ O.90~t, ~ =

7.2 Hz, 3Hl, 1.24(s, 9H), 1.30-1.45(m, 2~), 1.62(quintet, ~ = 7.8 Hz, 2H), 2.43(t, ~ = 7.5 Hz, 2~), 4.87(s, 2H), 7.2-7.55(m, 7H), 7.78(dd, ~ = 7.5, 1.2 Hz, lH).

.
To 226 mg (0.555 mmol) of the 3-butyl-1,2,4-39 triazolone from step 7 in 5 mL of N,N-dimethylfonm2mlde at about 5C was added 0.66 mL (0.66 mmol) of 1 M
potassium teIt-butoxide in tetr hydrofuran. The resulting solution was stirred at about S C for 20 min, followed by addition of 200 ~L ~1.76 mmol) of 1-, .,--~ . . .
.

' wo 91/1~#~ PCT/US91/03449 sa ~ '735 iodobutane. The mixture was stirred at room t~mpera~u.e for 30 min, quenched wich acetic acid and concen~-ated i~ vac~Q. The residue was chroma~ographed (elu~ed wit~.
ethyl ace~ate-hexane, 1:2) to glve 210 mg (82%) of dibutyl-1,2,4-triazolone as an oil: lH N~R (CDCl3) ~ 0.8-l.O~m, 6H), 1.24(s, 9H), 1.24-1.45(m, 4H), 1.50-1.68(m, 2H), 1.68-1.80(m, 2H), 2~41~t, ~ = 7.5 Hz, 2H), 3.80(t, = 7.2 ~z, 2~), 4.86(s, 2H), 7.20-7.34[m (with s at 7.28), 5H], 7.35-7.55~m, 2H), 7.78~dd, ~ = 7.5, 1.2 Hz, lH); 13C NMR (CDCl3) ~ 14.2, 20.3, 22.8, 26.3, 28.1, 28.5, 31.4, 45.0, 45.6, 127.4, 127.8, 129.7, 130.2, 131.0, 131.2, 133.4, 135.5, 141.8, 142.2, 146.~, 154.6, 168.3; mass spec~rum (FAB) m/e (relative intensity) ~ :
470(40), 414(100).
, ~ .
0~0-~ .2~a-t~iazQl-4-yl~m~thYll r~ h~nyl] -~-To 165 mg (0.356 mmol) oS the tert-~utyl es~er from step 8 in 2 mL o chloroform was added 1 mL (13 ! mmol) of tri~luoroacetic acid ~TFA). The resulting solution was stirred at room temperature for about lS h, and concentrated iCLY~s~. The residue ~as chromatographed over silica gel (ethyl acetate-methanol-acetic acid, 85:10:5) to give 152 mg lquan~itative) of product compound of example 1 as a solid: lH NMR (CDCl3).
0.75-l.O~m, 6H), 1.2-1.4~m, 4H), 1.52~qulntet, ~ = 7.8 Hz, 2H), 1.69(~u~ntet, ~ - 7.5 Hz, 20 , 2.37(t, ~ = 7.S
Hz, 2H), 3.78~t, ~ - 6.9 Hz, 20 , 4.85(s, 2H), 7.12~d, i 7.8 ~z, 2H), 7.2-7.32lm~ 4H), 7.37(t, ~ = 7.2 Hz, 1~), 7.SOlt, ~ 8 7.5 Hz, lH), 7.88~d, ~ = 7.5 Hz, lH);
3CMMR ~CDCl3) ~ 14.11, 14.13, 20.2, 22.6, 26.1, 28.4, :' . ,: .

wo 91/18888 PCr/US91/0344ig ~5 31.2, 45.0, 45.7, '27.', 127.8, 129.6, 130.7, 131.0, :31.4, '32.2, 135.0, 141.5, 1~2.9, 147.4, 154.C, ~2.C;
mass spect-um (FAB~ m/e (relative intensity) 408 (33), 390 (20), 211 (100 .
.~

.
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WO 9t/l~ PCT/US91/0 ~ 9 EX~ # 2 N--N--~
~O N = N
N.

: .
~, hi~he-~v~ 1 -a I-~fLl~~ , ?~4-~ 70~
.

~ -To 95 mL of 2 M (0.190 mol~ butyLmagnesium chloride in tetrahydrofuran and 55 mL of anhydrous ethe~
at about -60C (chloroform-dry ice~ was added dropwise 24.4 g (0.162 mol~ of ethoxycarbonyl isothiocyanate in 205 mL of anhydrous ether over a period of 2 h. The resulting mixture was stirred cold for about 3 h and allowed to slowly warm to room temperature. The solven~
was decanted and the solid was washed with four S0 mL-portions of ether. The solid was partitioned ~etween 200 mL of ether and 200 mL of saturated ammonium chloride. The aqueous layer was extracted with two S0 mL-portions of e~her and the combi~ed extracts were driied (~gSO4) and concentrated iD~ 3~. The ~ed oily residue was distilled under reduced pressure to give 18 g (58S) of N-ethoxycarbonyl thiovaleramide as a yellow oil: bp 86 C~ 1.5 torr; lH ~ [CDC13) ~ O.90~t, ~ = 7.5 Hz, 3H), 1.20-1.5~m, SH), 1.65 -l.B(m, 2H), 3.20(t, ~ = -7.5 Hz, 2H), 4.2(~, ~ = 7.2 Hz, 2H~, 9.2~broad s, lH).

,' , , ilJ'- ~
, WO 91tl~ PCT/~'S91/0 ~ 9 ~3S

~t~o ~ ?-~7a~ a;~qn Q~ ~-hucyl -2, 4-dihyd.~ -', 2, 4-~ o~

To 567 mg ~3 mmol) of N-ethoxycarbonyl ~hiovaleramide in 6 mL of absolute ethanol at room temperature was added 190 mL (6 mmol) of 98% hydrazine in 1.5 mL of ethanol. The resulting solution was stirred at abou~ 84C for 30 min, and concentrated i~ .
Yas~Q. The resulting solid was rinsed with ether-hexane, and collected by filtration tO give 320 mg (76%) of 5-butyl-triazol-3-one as a whi~e solid~ MR
; (CDC13) ~ 0.85~t, ~ = 7.8 Hz, 3H), 1.2-1.4(m, 2H), 1.55(quintet, ~ = 7.8 Hz, 2H), 2.0-3.0[ m (with t at 2.42, ~ = 7.8 HZ), 3H], 9.6-ll(broad s, lH~.

A 542.5 g ~2.4 mol) sample of methyl 2-(p-i tolyl)benzoate ~Chemo Dyni~mlcs Inc.) was dissolved in 5.5 L of e~hanol and tr~ated with 3 L (7.5 mol~ of 2.~ N
sodium hydroxide. The reaction was stirred overnight at 25 ambient temperature and treated with an additional 480 : :
mL (6.0 mol) of sodium hydroxide; stirring was continued ~or an a ~ional 24 h and the ethanol removed i~_Y~syQ.
The remainlng solutio~ was cooled in ice and acidified to pH 1 with hydrochloric acid which caused the product ., 30 tO precipitate; filtration and drying ~lLyaeuo gave 510 j g (100%) of crude 2-~p-tolyl)benzoic acid: mp 145.0-147.5~C; NMR ~CDC13) 8 2.40(s, 30 , 7.17-7.28~m, 4H), - 7.35-7.45(m, 2Hl, 7.51-7.59(m, lHl, 7.90-7.97~m, lH).
The crude acid was ~uspended in 1 L of toluen and .
i ' ~

:
WO 91/1$~ PCT/US91/03449 slowly treated with 400 g (3.15 mol) of oxalyl chloride under ni~-ogen. The resulting solution was allowed to s~ir at ambien~ tempera~ure ror 4.5 h and concentrated ~ acUQ to remove excess oxalyl chloride. The residue . .~, .
was redissolved in 2 L o~ toluene and trea~ed with 92.8 g (5.46 mol) of anhiydrous ammonia. The reaction was filtered and the filtrate concentrated L~-~aay~
producing 424 g (84%) of crude 2-(p-tolyl)benzamiide: mp 12~-130C; NMR (CDCl3) ~ 2.40(s, 3H), 5.28(br s, iH), i0 ~.77(br s, l~), 7.21-7.53(m, 7H), 7.76-7.83~m, lH). The crude amide was t~eated with 1420 mL (19.5 mol) of thionyl chloride a~ reflux for 3.5 h. The reac~ion was filtered and ~hionyl chloride removed Ln~y~-c~o. ~he residue was dissolved in 800 mL of toluene and 15 reconcentrated ,; n vacu~ . On standing overnight, the ~ -residue crystallized. The crystals were collected and washed with hexane to give 296 g t64%) of 2-(p-tolyl)benzonitrile: mp 50.5-52.0C; NMR ~CDCl3) ~
2.42(s, 30 , 7.22-7.34(m, 2Hl, 7.37-7.52tm, 3H), 7.58-20 7.66~m, lH), 7.72-7.78~m, lH). A 2~6 g (1.48 mol) sample of the crude nitrile was dissolved in 1630 mL of ~ -toluene ar.d treated with 377 g ~1.8 mol) of trimethyltin -azide at reflux for 24 h. The reaction was cooled; -filtration gave 600 g of crude N-trimiethylstannyl~5-~2- ~
25 (4'-methylbiphen-2-yl]te~razole: mp 271-272C (dec.); ~ -NMR ~D~SO-d6) ~ 0.36~br t, ~ o 34 Hz, 9H), 2.24(s, 3H), 6.89-7.06~m, 4H), 7.35-7.55~m, 4Hi). The crude N-trlmethyls~annyl tetrazole was suspended in 4270 mL of toluene and 287 mL of a~hiydrous tetrahydrofuran (THF) `
30 and treated with 63.4 g (173 mol) of anhydrous hydrogen chloride at ambient temperature under nitrogen with ~I stirring. The reaction was allowed to stand overnight and filt~red; recrvstallization from toluene gave 217 g ~62%) of 5-~2-~4'methyLbiphen-2-yl)]tetrazole as a .

!

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

WO sl/~#~ PCT/US91/0 ~ 9 ; 63 ~ ~ 3~73~

solid: m~ 149-iS2C; NMR (DMSO-d6) ~2.28(s, 3H), 6.94-7.02(m, 2H), ~.08-7.15(m, 2~), 7.50-7.59(m, 2H), 7.62-7.72(m, 2H). A 200 g (0.85 mol) sample of the tetrazole was suspended in 3.3 L of dichloromethane a~d t_eated S with 262 g (0.91 mol) of triphenylmethyl chloride and 191 mL (1.0 mol) of anhydrous triethylamine. The reaction was s~irred at reflux for 3 h under nitrogen, washed with warer, dried (M~S04), and concentra~ed ~YR. ~ecrystallization gave 338 g (83%) of N-triphenylmethyl-5-[2-(4'-methylbiPhen-2-yl)]tetraZole as a colorless solid: mp 170-173C; NMR ~CDC13) ~ 2.27(s, 3H), 6.86-6.96(m, 8H~, 6.98-7.04(m, 2H), 7.09-7.52(m, 12H), 7.86-1.94(m, lH). The N-triphenylmethyl tetrazole was dissolved in 4260 mL of carbon tetrachloride ~nd treated with 126.4 g ~0.71 mol) of N-bromosuccinLmide (NBS) and 11.9 g (49 mmol) of benzoyl peroxide at reflux for ~.S h. The reaction was filtexed and the solvent removed i~_Y~S~Q- Recrystallization from toluene gave 277 g ~59%) of N-triphenylmethyl-S-~2-~4'-bromomethyl~iphen-2-yl)~tetrazole as a colorless solid:
mp 140-142C; MMR (CDC13) ~ 4.39ts, 2H), 6.85-6.95(m, 7H), 7.06-7.15~m, 4H), 7.22 7.43~m, 9H), 7.45-7.55~m, 2H), 7.94-8.01~m, lH). NMR indicated that this material was only 85~ pure; it conta med 7% of corresponding dlbromo- compound (~ 6.50) and 8% of starting material (~
2.27); however, no further attempts at purification were made and this mixture was used in all subsequent alkylation reactions.

~ "'.
-.

.
:' ' `

W~ PCT/US91/0 ~ 9 ~ D 4- ~r~r~ f~ r,l-2.4-d;hv~-r~7-!1-; vllmethvLl-~H-1~2.4-t~
' :
To 247 mg (1.75 mmol) of the 5-butyl-triazol-3-one from st~p 2 in 17 mL of N,N-dimethylformi~mide was added dropwise 1.8 mL ~1.8 mmol) of 1 M potassium tert-bu~oxide in tetri~hydrofuri~n. The result m g light brown solution was stlrred at room temperature for 10 min, followed by addition of 952 mg (1.7 mmol) of N-triphenylmethyl-5-~2-~4'-bromomethylbiphen-2-yl~tetrazole from step 3 in two portions, 30 min apart.
The resulting solution was stirred at room temperature for about 1 h, quenched with 160 mL of acetic acid and concentrated LDL~3cY~. The residue was chromatographed (eluted with isopropianol-hexiane, 1:7) to give 290 mg ~2~%) of N-substituted triazolone as a solid: lH NMR
(CDC13) ~ 0.85(t, ~ 3 7.3 Hz, 3H), 1.28(septet, ~ = 7.5 Hz, 2H), 1.53(quintet, ~ - 7.7 Hz, 2H), 2.29(t, ~ - 7.3 Hz, 2H), 4.71~s, 2H), 6.90~d, ~ ~ ~.2 Hz, 6H~, 7.01~d, ,1 . .
= 8.3 Hz, 2H), 7.12~d, ~ - 8.2 Hz, 2H) " .2-7.4(m, lOH)f 7.4-7.55~m, 2H), 7.9-~.O~m, lH), 9.0~s, 1~); mass spec~rum (FAB) m/e (relative intensity) 624(22), 568~4), 388~30), 382~18), 339~10~).
.~ ' ~

.~ --~ .. ..
To 240 mg tO.389 mmol) of the N-substituted triazolone from step 4 in 4.5 mL of N,N-; dimethylformamide was added 460 ~L ~0.46 mmol) of 1 M
potassium tert-~utoxide in tetrahydrofuran. The .
- '.

.
~' '' ' . . .
l . ' ' , ' .~ . .

WO 91/1~ PCT/US9l/0 ~ 9 .
~ 7~5 ~esultlng solut on was stirred at _oom tempera~ure for 10 min, foll~wed by addition of 150 ~L (1.32 mmol) of '-iodobutane. The mixture was stirred at room cempera~ure for about 1 h, quenched with ace~ic acid and S concentrated L~ C~. The residue was filtered througn a pad of silica gel (eluted with ethyl acetate-hexane, 1:3) to give 255 mg (97%) of N,N'-disubstituted tria~olone as an oil: 1 H NMR (CDC13 ) ~ O . 84 (t, ~ = 7 . 3 Hz, 3H), 0 . 96 ~t, ~1 = 7 . 4 Hz, 3H), 1.27 (septe~, ~ = 7. 3 10 Hz, 2H), 1.38(septer, ~ = 7.7 Hz, 2H), 1.50(quintet, ~ =
7.9 Hz, 2H), 1.75(quintet, ~ = 7 . 5 Hz, 2H), 2 . 28 (t, ~ =

8.0 Hz, 2H), 3.80~t, ~ = 7.3 Hz, 2H), 4.70(s, 2~), 6.87-6.96(m, 6H), 7.01(d, ~ = 8 . 3 Hz, 2~), 7.11 (d, J = 8 . 3 : Hz, 2H), 7 . 20-7 . 40(m, lOH), 7.40-~.53~m, 2H), 7.88-7.95(m, lH); mass spectrum (FAB) m/e (rela~ive intensity) 680~20), 624(4), 444~2S), 410(20), 395~100), 381tl5).

.
.
20 ~
ll~te~ra7nl~ yl~ rl, ~-htpheryl 1 ~ '-yl 1m~thyl l-~H-1 2,4--rr;;~ 7,r~ 0~

A solution of 245 mg (0.364 mmol) of the N,N'-disubstituted triazolone from step 5 in 4 mL of acetic acid and 0~4 mL of water was stirr~d at room temperature for a~out 17 h and concentrated ;n va~uo. T~e oily residue was dissolved in saturated sodium bicarbonate and washed with three 5 mL-portions of ether-hexane.
The aqueous layer was acidified to about pH 3 whith 3 N
hydrochloric acid and extracted with chloroform and ethyl acetate. The combined extracts were dried (MgS04) and concentrated i~ U:8~ to give 150 mg (quantitative) of the product compound of example 2 as a solid: lH NMR
~' ~''', ~1 --' . ' .

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

WO 91/18888 PCr/U~iYI/U~

2~ 3~ : ~
(CDCl3) ~ 0.85~t, ~ - 7.1 Hz, 6H), 1.15-1~42~m, 4H), 1-L.42-1.70[m (wlth two ~uintet at 1.50 and 1.61, ~ = 7.4 and 7.3 Hz), 4H], 2.34(t, l = 7.5 Hz, 2H), 3.64(t, ~ =
7.2 Hz, 2H), 4.69(s, 2H), 7.06(q, ~ = 8.1 Hz, 4H), 7.27(broad s, lH), 7.41(d, ~ = 7.5 Hz, lH), 7.45-7.65(m, 2H), 7.82(d, ~ = 7.2 Hz, lH); mas~ spectrum (FAB) m/e ; (relative intensity) 432(40), 207(100~, 178(25); HRMS.
calcd for M+H: 432.2512. Found: 432.2510.
:', ': ' ,- ..,, ..~ .

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,7.1 ' ~ ' WO 91/18888 PCr/US91/03449 C-ene-al ~-ocedur~ ~h* ~e~ct; on of ~~i zz~l~n~ wi th To a solution of 0.4-O.S mmol of 5-butyl-2,4-dihydro-4-[2'-(~-triphenylmethyl-lH-tetrazol-S-yl)[l,1'-biphenyl]-4-yimethyl]-3H-1,2,4-triazol-3-one (prepared i.~
example 2, step 4~ in 4-5 mL of N,N-dimechylformamide was added dropwise 1.2 eqivalent of potassium tert-butoxide (1.0 M in tetrahydrofuran), and the resulting yellow solution was stirred at room temperature for 10 min. To the mixture was added l.S eqivalent of an appropriate alkylating reagent dropwise ~or in portions, if solid).
The resulting solution was stirred at room temperature f~r 1-5 h, and concentrated in va~o. The crude product could be purified by silica gel chromatography, eluting with ! 20 ethyl acetateJhexane, tO give pure al~ylated product. In most cases, the crude mix~ure was pure enough, and was used directly for deprotection in step 2.

t~ a7~lone i The alkylated product obtained from s~ep 1 was dissolved in 12 mL of glacial acetic acid and 1.2 mL of water. The resulting solution was stirred at room t~mperature for 20 h, and concentrated n va~uo. The solid residue was stirred with 5 mL of saturated sodium ,q ~`i bicarbonate and 10 mL of ether for 10 min. The ethereal solution was removed and the aqueous layer was washed twice ' ~ with fresh e~her. The resulting aqueous layer was .

~ .

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acldified with 3 N hydrochlor~c acid tO about pH 3, and ex~-acted with three 10 mL-portions of chloroform. The :
c~mbined extracts were dried (M~S04) and concent-ated ~3 ~acuo. The resuLting oil or foam solidified upon standing :-S to ~ive the desired tetrazolyLbiphenyl 2,5-disubstituted-triazolone. ~
.. .. . ..

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C ~619/1 ~ 3 ~ :

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N- N--j~\~

[~1 N- N' S

9=d~hy ro-2-~2-oxo-2-(t-;cvclo r3 . 3 .1 . i .~ ~
'Jl) Pthy~ 2~ -tet-azol-s-y~ -bi~h~n~yL
~l~ethVl1_3~-1,2, ~-t~l 2701 -3-on~
: .
Following the General Drocedure for reacting ~
triazolone with an alkylating asent (described above~, 300 mg (0.486 mmol) of 5~butyl-2,.4-d1:~ydro-4-[2'-(1~
triphenylmethyl-lH-tetrazol-5-yl)~1,1'-biphenyl]-4-yLmethyl~-3H-1,2,4-triazol-3-one in 4.5 mL or N,N- . .
dimethylformamide was reacted with 0.574 mmol of potassium tert-butoxide in tetrahydrofur2n znd 150 mg (0.584 mmol) or 1-adamantyl brom~methyl ~etone. The al~ylated product was deprotected following General ~roceduxe s~ep 2 and the resulting solid was recrystallized from ethyl acetate~hexane to give 180 mg (67%) of the desired product compound as a white solid: 1H NMR (~MSO-d6) ~ 0.77(t, ~ -7.25 Hz, 3H), I.22(m, 2H), 1.38(ouintet, ~ = 7.25 Kz, 2H), 1.67(br s, 60 , 1.80(br s, 6H), 1.98(br s, 3a), 2.37(t~
7.25 Hz, 2H), ~.76(br s, 2H), 4.81(br s, 2H), 6.87(d, ~ = -. .
`'' S~ t--~T '~
~ ~ .. - . .

''' : '.' . ' .~ '' ' ','' ' . .. ,, ' ' ~' ;' ~ , 1., . " . . . `.

WO 91/18888 PC~/IJ~;~I/U344~
.
~J~ 3S

8.0; Hz, 2H), 7.14(d, ~ = 8.06 Hz, 2H), 7.48-7.60(m, 2H), 7.60-7.72 (m,2~); MS (FAB) m/e (relative intenslty) 552 (35), 207 (100), 178 (40); ~ . calcd for M+H: 552.3087.
Found: 552.3108.
S

C-2619/l 71 ~3~ S

EXA*~ 4 N-N "-~^`Ph O

~ N- N'H

S
~-butv1-2 4-~lhvdrQ 2~ henvlorc~vl)-4- r2~ r~-~e~-~7 5-vl ) r ~ -bi~henvll-4-vlmethyll-3~ 2~4-triazol-3-on~

Following ~he General P-ocedure for reac~ ng 2 triazolone with an alkylating agent ~desc ibed above), 300 mg (0.486 mmol) or 5-butyl-2,4-dihydro-4-[2'-(1-triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,~-triazoL-3-one in 4.5 mL or N,N-dimethylform2mide was reac~ed ~ith 0.574 ~mol or pot2ss~um ~ert-butoxide in tetrzhydrorur2n and 89 ~L (0.583 mmol) of l-bromo-3-~r.enylpropane. The alky ated produc~ was c~protected ~ollowing General Procedure step 2 to give 218 m~ t90%) of the desired product compound as a white solid:
lH NMR (CDC13) S0.82(t, ~ = 7.25 Yz, 3Y.), 1.27(septet, ~ =
7.25 Kz, 2K), 1.50(quintet, J = 7.2S ~z, 2H), 2.01(ouin~et, = 7.25 Hz, 2H), 2.31~t, ~ = 7.66 Hz, 2~), 2.59~t, ~ =
7.65 Hz, 2H), 3.75~t, J = 6.B5 Yz, 2H), 4.71~br s, 2~), 6.95-7.30~m, 9H), 7.30-7.60~m, 3K), 7.68(d, ~ = 7.Z5 Yz, lH); MS (FAB) m/e (relative intensity) 494 (32), 207 (100), 2S 178 (45); ~RMS. calcd for M+H: 494.2268. Found: 494.2678.

-lTUTE: S31EET
.~ .
.` . :

C~o~ "

72 2~ 735 ~L~ :
-` Ph N-N~
,~ O ,.

N- N~ H

N *

. S
5-'2utvl -2, a-d; h~,rd~-2- (2-~xo-2-~henyl ethyl ) -a- r2 ' ~
t~tr270l -5-~11 r~ oheny7 1 -~-ylmethyl 1 -3E~-1, 2, 4-~ 27~l -3-one ; 10 Following the General Procedure ror reac.ing a triazolone with an alkylating agent (descri~ed above), SaO
mg (0.972 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1-tripAenylmethyl-lH-tetrazol-5-yl)~1,1'-biphenyl~-4-yLmethyi]-3H-1,2,4-tri2zol-3-one in 9 mL or N,~
lS dimethylfor.~æmide was reacted with 1.14 mmol of ~otass um tert-butoxice in tetrahydroruran and 215 mg (1.08 mmol) o_ 2 bromoacetophenone. A portion of the alkylated produc~
. (220 mg, 0.299 mmol) was deprotected following tAe C~neral Procedure steD 2 to give 127 mg (86~) of the desired product compound as a white solid: 1~ N~R (CDC13) ~ 0.80(t, = 7.25 Hz, 3H), 1.27(seocet, ~ = 7.7 Hz, 2H), 1.51(quintet, ~ = 7.26 Hz, 2H), 2.36~t, ~ = 7.66 Hz, 2H), 4.74tbr s, 2H), 5.17~br s, 2H), 7oo2tbr s, 4H), 7.30-7.65(m, 6H), 7.79(d, ~ = 7.Z5 Hz, lH), 7.86(d, J = 7.25-Hz, 2H); ~S ~F.aB) m/e (relative intensity~ 494 tl7), 451 (3), , ~ '~r5T~e: ~EET
,~^ . , .~ .

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

WO 91/18888 PCr/US91/03449 376 ~8), 207 (lO0); .~MS. calcd for M+H: 494.2304. Founc:
4 54 . 2300 .

' ''.
.

`

- - r : 6l9/1 !

?~ ~ ?J q~ ~ S
74 -~

~oe~,~ ' .
~ Ph .
N- N
~~ N ~ .

C~12 . .

f~ N- N

. ~ N " N :
~.' '~ ' ' .
- .:
5-~utyl-2 a-di~yd~-2-~2-h~drQxy-2-~henylethvl)-a-~2'-(1H-t~t~2~ ??~1-5-~ L) ~ -b ~hen~11- a--Jl~erhyl~ 2 a -t~i2~01-I To 2 soLution or 400 mg (0 544 mmol) or trityl .~? 10 tetrazolylbiphenyl ketone from example 5 in 4 mL of methanol and 2 ml of tetrahydrofuran at 0C was added 25 mg I (0.66} mmol) or sodium borohydride in portions. The resulting solution was stirred at 0 C for 2 h, and quenched with saturated ammonium chloride. Volatiles were 15 renoved ;~ V~C'10 . The aqueous layQr was extracted with chLoroform, dried (MgSO4) and concentrated ' ?1 V2CUO to give ~l 380 mg (95%) of the desired alcohol. Following the Geleral "r i Procedure step 2, 200 mg (0.271 mmol) of the alcohol ~, obtained from procedure described above was deprotec~ed, ~, 20- and the resulting solid was recrystallized to give 102 m~ -(16%) of the ~esired product compound as a white solid: lH
?~MR ~DMS0-d6) ~ 0.77~t, ~ = 7.25 Hz, 3H), 1.10-1.28tm, 2H), 1.28-1.45~m, 2H), 2.34~t, ~ = 7.65 Hz, 2H), 3.73(dd, ~ =
13.7, 6.0 Hz, lH), 3.85~dd, ~ = 13.7, 7.7 Hz, lH), 4.74(br s, 2H), 4.88~a, ~ = 6 Hz, lH), 5.54~d, ~ = 4.8 Hz, lH~, , -~sl ' ~~' 5UB5TITUT?~ S?~lEET-WO 91/18888 PCr~VS91/03449 ;2 ~ 3S

6.97(d, i - 8.1 H.z, 2H), 7.04(d, .1 = 8.4 Hz, 2H), 7.10-7 . 40 (m, SH), 7 . 45-7 . 60 (m, 2H), 7 . 60-7 . 70 ~m, 2H) i MS (FAB) m/e kelative intensity) 496 (5), 478 (12), 435 (3), Z07 (100); .~RMS. calcd for ~H: 496.2461. Found: 496.2S01.
'i 5 :, ~

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

C-~6 19/1 ~$~ 5 , 76 ::

~ ' ~
. .
N--N rO~ . :.
~ ~o O
N - :

N--N~H

L~1-dimethvle~hyl 3-butyl-4 S-dihvdro-S-oxo a-r2'-(lH=
tetra~ol-5-vl)r~ bi~he~y~ v~ethv~ H-l 2 9=
triazole-l-ace_ate , . .
Following the General ~rocedure for reacting a t~iazolone with an alkylating agent ~described above), 450 mg ~0.728 mmol) of S-butyl-2,4-dihydro-4-[2'-~1-tri~henylmethyl-lH-t~trazol-S-yl)~l,1'-biphenyl]-4-ylmethyL]-3H-1,2,4-triazol-3-one in 8 mL or N,N-dimethyLform2mide was reacted with 0.87 mmol or po~assium lS tent-butoxIde in tetrahydrof~r2n and 141 ~L (0.87 mmol) or ~ert-butyl bromoace~ate. A portion or the alkylat~d - product ~240 mg, 0.328 mmol) was de~rotected following GeneraL Procedure step 2 to give 161 mg ~78%) or the `~
desired product compound as a white solid: lH NMR (CDCl3) . 20 0.88(t, ~ = 7.25 Hz, 3H), 1.35~m, 2H), 1.59(quintet, ;r= -~
- 7.25 Hz, 2H), 2.43~t, ~ z 7.25 Hz, 2H), 4.43(s, 2H), ; 4.78~s, 2H), 7.18~AB-quartet, ~ = 8.5 Hz, 4H), 7.41~d, ~ =
~; 7.7 Hz, 1~, 7.48-7.65~m, 2H), 8.02(dd, ~ = 7.7, 1.2 Hz, lH); MS ~FAL) m/e trelative intensity) 496 (39), 440 (60), . . .

~UB5~ 5tlEET `~
~ .
.,.~ . ~

WO 91/18~8 PCI/US91/03449 77 ~i2~ ~` .3 ~';~ ~ ~i 412 (45~ , 397 (25), 235 (22~ , 207 (100), lg2 (40), 178 ~60); HRMS. calcd for M+H: 490.2567. Found: 490.2598.

" :

; ' ' , .

.?;~ : ~
'.,.
':'~ . , :
`,'";;',~
' .
' . . .
~"
.," ~ ` '~'.

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

~ ` ~
- C-26i9/l EXAM~E ~8 `~ ~ N-N~
~, ,~0 .:

CH2 , [~1 N--N'H
~N"N

5 5-hlltv1-2 a~ ydro-2-he~yl-a-r2~ H-rQt~2zQl-s-vl)r ~;~he~y~ -v~ merhyl 1 -8~-1 . 2, ~-trl a~ol-3-one : .:
Following the General Procedure for reacti~g ~
tr~azolone wl~h en alkylating agent ~esc_ibed above), 250 mg ~0.486 mmol) or S-butyl-2,4-dihydro-4-~2'-(1-triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl]-9-ylmethyl]-3Y.-1,2,4-triazol-3-one in 4 mL of N,N-dLmethylformami~e was reacted with 0.58 mmol o~ potassium tert-outoxide in tetrahydrofurzn and 745 ~L ~0.98 ~mol) of lS l-iodohexane. The alkylated produc- was deprotected following Ge.~eraL Procedure step 2 and the resulting solid was recrystallized to give 127 mg (57%) of the cesired product compound as a white solid: lH NMR (DMSO-d6) ~0.7-O.9~m, 6H~, 1.15-1.32(m, 8H), 1.41(q, J = 7.25 Hz, 2H), 1.5-1.7(m, 2H), 2.37(t, J = 7.26 Hz, 2~), 3.64(t, ~ = 6.85 :, .
. Hz, 2H), 4.79(s, 2H), 7.05(d, ~ = 8.06 Hz, 2H), 7.10(d, ~ =
8.06 Hz, 2H), 7.45-7.60(m, 2H), 7.60-7.70(m, 2H); HRMS. ~-calcd for M+H: 460.2825. Found: 460.2820.

~ ' ~ ' ' . ., ~ sTlTuT~ SHE~ T - :

C-~6 19/1 - --79 ~z~ ~S

E~ .

N-N ~CO2Et ~N--O
~ ''.

N--N
~ N ' ethyl ~- utyl-q 5-dihy~o-~-o~n-a-L~-L~-t~r-~7o~
vl~r~ -Qi ~r.en.v~ v ~e~.yl1-~Y-1~ 2~-tr~2701~ 2ce~2~e Following the General ~rocedure for reacting 2 triazolone with an al~ylating agent (described ~bove), 500 ms (0.81 mmol) or 5-butyl-2,4-dihydro-4-~2'-(1-triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl~-4- ~.
ylmethyl]-3H.-1,2,4-triazol-3-one in 7 mL of N,N-dimethylfor~amide was reacted with 1.06 mmol of potassium tert-butoxide in tetrahydrcfuran and 147 ~L (1.33 mmol) o ethyl bromoacetate. The alkylated product was deprotected following General-Procedure step 2 to give 336 mg (90%) or ~he desired product comDound as a white solid: lH NMR
~DMSO-d6) ~ 0.77~t, ~ = 7.65 Hz, 3H), 1.10-1.30[m ~with t a~ 1.17, ~ = 6.85 Hz), 5H], 1.41~ouintet, ~ = 7.25 Hz, 2~
20 2.39(t, ~ = 7.65 Hz, 2H), 4.12~a, ~ = 6.9 Hz, 2H), 4.55(s, 2H), 4.83~s, 2H), 7.06(d, ~ = 8.06 Hz, 2H), 7.12~d, ~ =
8.46 Hz, 2H~, 7.45-7.75tm, 4H); MS (FAB) m~e ~relative intensity) 462 (85),.446 ~10), 235 tl5), 207 (100), 192 (18); HRMS. calcd for M+H: 462.2254. . Found: 462.2277.
2S . :

: ~:

r~ 5~ E:ET ~ -c~l9ll :

~o ~,,~,$,~t735 :

~L~

-' N-N ~CO2H
~0 [~

~-butvl-~ S-dihydro-5-oxo-4 r2~ u-t~tr2z~-s-v~
~;~he~yl~ ~et~v~ .2.a-r~;27ole-l-~ce~;~ 2c~d A mix~ure or 170 mg ~0.368 mmol) of ethyl es~er rom ex2mple 9 in 3.4 mL of tetrahydrofuran and 3.4 mL of 2 N aqueous lithium hydroxi~e was stirred at room temperature -; for Z h. Volatlles were r~moved :U~ 3l~. The aoueous ., ~
layer W2S wzshed with three 4 mL-portions of ether, and acidified with 3 N hydrochloric acid to about p~ 3. The mixture was Liltered, and the solid was washed with water.
The solid was dried in vacuo to give lO0 mg (63~) of the desired product compound. The filtrate was e.Ytrzcted with ch~loroform, dried ~MgSO4), concentrated in y2cuo and trlturated with ether to give additional 50 mg (31~) of ~he desired product compound as a white solid: 1~ NMR ~DMS0-d6) 20 ~ 0.78~t, j~ = 7.25 Hz, 3H), 1.17-1.32(m, 2H), 1.32-l.SO~m, 2Hj, 2.39~t, ~ = 7.26 Hz, 2Hj, 4.43~s, 2H), 4.82(s, 2H), 7.06~d, ~ = 8.06 Hz, 2H), 7.13~d, ~ = 8.06 ~, 2H), 7.45-7~.60(m, 2~), 7.58-7.7~m, 2H); MS ~F~B) m/e (relative intensity) 440 (2S), 4Z9 (12); ERM5. calcd for M+H:
2S 434.1941. Found: 434.1977.
:: .

,. ~ . .

51JBSTITUT ~HEET

619/1 ..

7~5 ~ .
.~ ~,?, ~ ., .
[~,1 N - N ' H

5 5-~utvl-2,4-dihv~ o-2~h~h~L~nvlmLethyl)-q-r2'-(lH-te1_r2~0~ -5-vl) r 1, l ' -biphe~yl 1 -a-yl n~rhyl 1-3~2-~ 2 a-t r; 2ZOl ~
3-one Fcllowing the General Procedure for reacting a 10 triazolone with an ~lkylating agent (described above), 250 ";
mg (0.405 mmol) of 5-butyl-2,4-dihydro-4-~2'-(1-triphenylmethyl-lH-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3Y.-1,2,4-triazol-3-one in 4 mL of N,N- `
dLmethylfonmamide was reacted with 0.5 mmol of potassium ! 15 teEt-butoxide in tetrahydrofuran and 134 mg (0.606 mmol) or 1-(bromomethyl) naphthalene. The al~ylated product was deprotected following General ~rocedure step 2 to give 159 mg (76%) of the desired product comDound as a white solid: ~-H NMR (DMSO-d6) 8 0.73(t, ~ = 7.25 Hz, 3H), lO1-1.25(m, 20 2H), 1.25-1.4(m, 2H3, 2.34~t, ~ = 7.66 Hz, 2H), 4.84(s, 2H~, 5.31(s, 2H), 7.05(d, ~ = ~.46 Hz, ZH), 7.12~d, ~ =
7.06 H2, 2H3, 7.36~d, ~ = 6.45 Hz, lH)~ 7.40-7.65(m, 7H), :~ ' ' '. ` '' 5U~3~iTl~U~E ~i~EET

C ~ol9/1 -- ,~
...

82 ~u ~

7.80-~.0(.-., 2.~:), 8.18-8.3(m, lH); Y~MS. calc- o- M+r::
516.2512. ~ound: 516.2534.

EXAMPLE~
~ . .
N - N--[~ N_N-H ;

5-buty~ (2-c~,~clohexyL~ 2,~4-dihydro-q- ~2'~
tetrazol-S-vl) rl~-bl'~)henvll-4-~vlm_~d~
3-on~ ~

Following the G2neral Procedure for reacting a triazolone with zn alkylating agent (described above), 250 15 mg ~0.405 mmol) of 5-butyl-2,4-dihydro-4-[2'- (1-~i ~ triphenylmëthyl-lH-tetrazol-S-yl) [1,1'-biphenyl]-4-ylmethyl]-3E-1,2,4-triazol-3-one in 3 mL of N,N-dirnethylformamide was reacted with 0.53 mmol of potassium tert-butoxide in tetrahydrofuran and 100 mg (0.523 mmol) o~
. 20 2-cycIohexyl ethylbromide. me al3cylated product was deprotected following General Procedure step 2 to give 16;
mg (84%) of the desired product compound as a white solid:
H NklR ~DMS0-d6) ~ 0 77(t, ~ = 7.25 Hz, 3H), 0.8-0.95(m, 2H), 1.0-1.3~m, 6H), 1.3-1.8(m, 9H), 2.37(t, ~1 = 7.65 Hz, 2EI), 3.67 (t, ,I = 7.26 Hz, 2H), 4.79 (5, 2H), 7.07 (d, !1 =
~ : ~

-- -- r c ~619/1 .~ - .
a3 ~ 3~3 8.46 :-z, 2~), 7.10(d, ~ = 8.46 Hz, 2H), 7.~5-7.60(m, 2~
7.60-7.70(m, 2~); r.~S. calcd for M+~:: 4~6.2981. -ound:
~86.301~.

~a~ :, N- N~
O

f~ N N~H - ~::
[~ N~ N :~

5-~ut~Jl-2 ~-d;hvdro~ ~tvl-~- r2~ tetr~7ol-s-yl~ r~
- b;~enyll -a-~lmetl~yl 1 -3H-1 ~ 2 ~ a-tr- a~ol-3-one Following the General Procedure for reactlng z triazo~one with an alkylatin~ agent (described above), 250 m~ ~0.41 mmol) of 5-butyl-2,4-dihydro-4-[2'-~1-triphenylmethyl-lH-tetrazol-5-yl)~1,1'-bipnenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N-dimethylformamide was reacted with 0.53 mmol of potassium ~ert-butoxide in tetrahydrofuran and 70 mg ~0.354 ~mol) or - 1-iodopetane. The alkylated product was deprotected following General Procedure step 2 to give 110 mg (60%) o, -,~ the desired product compound as a white solid: lH NMR
~DMSO-d6) ~ 0.7-O.9~m, 6H), 1.13-1.32~m, 6~), 1.41~quintet, ~ = 7.2 Hz, 2X), 1.61~quintet, ~ - 6.g Hz, 2H), 2.37(t, J =
..... -.. .
.: '-. .
SUBSTITIJ ~ E
,'"~

PCr/US9 1 /03449 84 ~ S

7.7 Hz, 2H), 3.64~t, ~ = 6.8 Hz, 2H~, 4. 79~s, 2H), 7.05(d v = 8.46 H2, 2H), 7.11(d, ~1 = 8.46 Hz, 2}~), 7.45-7.6(m, 6.2666. Found; 446.Z705 d :

.~ .
j ; :
~,` ` . .
. ..

~ .
" .r s! - ' ' C-26 19/l - _ .
_ ' ~ t~3 S

:

N- N~O , CO2E~
= O Ph C~2 :

[:~1 N- N' H ~: -~ NsN

S ethvl r2~ utvl-4~s-dihydLro-s-oxo-4-r2~ H-tet~a2Ql-5 vl)rl 1'-bi~henYll-4-vlmeth~7l-l~ ~ 2 4-trla701-l-vll-l-oxvlacetate To a solution of 160 mg (0.217 mmol) of hydroxyphenethyl tri~yltetrazolylbiphenyl triazolone obtained from example 6 in 4 mL of dry tetrahydrofuran was ! added 18 mg (0.45 mmol) of sodium hydride ~60% in oil) in one portion, and the resulting suspension was stirred at room temDerature for 10 min. After gas evolution was 15 complete, 76 ~L ~0.866 mmol) of ethyl bromoacetate was added. The resulting solution was sti-red at room te.~perature ~or 4 h, and cuenched witn sat ammonium chioride. The mixture was concentrated in vacuo, dissolved in chloroform and washed with water. The aueous layer was -extracted with three 10 mL-portions of chloroform, and the combined extracts were dried ~gS04) and concentrated ~
S~Q to give the crude alkylated product. Following the General ~rocedure s~ep 2 the alkylated product was deprotected to give lOS mg (~3%) of the desired product 25 compound as a white solid: lH NMR (DMS0-d6) ~ 0.75(t, ~ =

~ ~ , ;~ .. . ~ .
UE35T~TU~ ii~ J

WO 91/1888l3 PCr/US91/U344 7.66 Hz, 3H), 1.06-1.46[m ~with t at 1.12, ~ = 7.25 Hz), 7H], 2.31(t, ,T = 7.65 Hz, 2EI), 3.70-4.20(m, 5E~),- 4.73(s, 2H), 4 . 82 ~d, J = 6. 9 Hz, lH), 6 . 91 (d, ~1 = 8 . 05 Hz, 2H), 6.9S-7.20~m (with d at 7.01, ~ = 8.06 Hz), 3H~, 7.20-7 . 40 (m, SH), 7 . 45-7 . 7S (m, 4H); MS (FAB) m~e (relative intensity) 582 (lO), 478 (18), 235 (15), 207 ~100), 192 (48), 178 ~28); HRMS. calcd for M+H: 582.2829. Found:
582 . 2832 .
,..

"''-;
.'~, .1 . .

.. j .
' 'I
':' ' . - , ~;, ,'''~
'' 1 ~- t . lr~3 .
~ 3 . . .

. :

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

WO 91tl~ PCT~US91/0 ~ 9 87 ~ 7~ S

. .

N- N~O CO2H
, ~~~ ,~ O Ph .:
[O] H
~ N-N' [~ N' , phenyl.etho~yl~~ic acid A mixture of 80 mg (0.138 mmol) of ester from , 10 example 14 in 1.~ mL of tetrahydrofuran and 1.7 mL of 2 N
il lithium hydroxide was stirred at room temperature ~or 3 h.
Volatiles were removed iD_Y3~YQ~ and the aqueous solution was washed with three portions of ether. The resulting aqueous solution was acidified with 3 N hydrochloric acid, :~
ex~racted with chloroform, dried (MgSO4) and concentra~ed l~L~ U~. The solid residue was recrystallized from ethyl ace~ate/hexane to give 72 mg ~94%) of th~ desired product compound as a white solid: lH NMR t~MSO-d6) ~ 0.75(t, ~ = -7.26 Hz, 3~), 1.08-1.48~m, 4H1, 2.30(t, ~ = 8.05 ~z, 2H), 20 3.70-4.15(m, 4H), 4.65-4.90~m (with s at 4.71), 3H~, 6.88(d, ~ - 8.06 Hz, 2H), 6.95-7.18[m (with d at 7.01, ~
8.46 Hz), 3~1, 7.20-7.40(m, SH), 7.45-7.75(m, 4H); MS (FAB) m/e (relative intensity) 554 (8), 478 (12), 450 (S), 235 ;i (10), 207 ~100~, 19~ (30), 178 (25); HR~S. calcd for M+H: :
¦ 25 SS4.2516. Found: 554.2536.
:, .~. ' '''' ,, ' . ,;

~q~3~ 3~:;
~8 i, N-N ^J~
,~0 ': .

C~2 N-N' ~ N' S-b~tv1-2 a-~ih~Vd~-4- [2'-(1U-tetr2zol-S-vl~1 1'-bi~he~yll-4-vlm~thv1l-2-~3 ~ 5-~r;~ethvlheYyl)-3~ 2 a-t rl2 ~ c1 1--3--o~

Following the General Procedure for r-acting a 1~ triazolone with an alkylating agent ~descr bed above), 250 mg (0.405 mmal) or S-butyl-2,4-dihyoro-4-[2'-(1-triphenylmethyl-1~-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one ~n 2.5 mL or N,N-dimethylform2mlde was re2cted with 0.43 mmol or 2o~asslum lS tert-butoxid~~in tetrahydrofuran and 100 m~ (0.483 mmol) o_ 3,5,5-trime~hyl-1-bromohexane. The alkylated product was ~eprotected rollowing General Procedur2 step 2 to give 176 mg (87%)- or the desired product comDound as a whit~ solid:
lH NMR (CDCl3) ~ 0.70-0.95~m, lSH), 1.02(dd, ~ = 13.2, 5.7 1 20 Hz, lH)~ 1.16(dd, ~ ~ 13.2t 2.8 Hz, lH), 1.29(septet, ~ =
7.25 Hz, 2H), 1.35-1.6tm, 4H), 1.60-1.77(m, lH), 2.36~t, ~
= 8.06 Hz, 2H), 3.55-3.75~m, 2~), 4.68~br s, 2H), 7.07 ~A3 quartet, ~ = 7.7 Hz, 4H), 7.40td, ~ = 7.7 Hz, lH), 7.49~t, = 7.25 ~z, lH), 7.57~t, ~ = 7.26 ~z, lH), 7.a6(d, ~ =

SLIB5TITUT 5.~ T
.

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

WO 91/~ 8 PCT/US91/03449 89 ~ 3~

7.25 Hz, lH~; MS (FAB) m/e ~relative in~ensity) 502 (28), 444 (5), ~03 (3), 235 (5), 207 (100), 192 (20), 178 (20);
r:RMS. calcd for M+H: 502.3294. Found: 502.3295.

':

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

9ll ~3~JLE 17 1 r N- N~f O~_,Ph y ,~ O Ph [~ N- N' 5-butvl-~ 4-dihvdro-2-r2-~he~vl-2-(~he~y~ h~oxv) t~henvlmethvl~- ~ethenvll-4-~2'-(~ ~ -a~ol-5-v bl~ne~vll -4-vlmethv1 1 -3H-1, 2, ~-tr1~zQl~-one ~' To a solu~ion or 100 mg (0.136 mu~ol) or pnenacyl 10 trityltet~azolylbiphenyl triazolone f-cm example S ln l.S
J mL of cry te~rahydrofuran was added 10 mg (0.25 mmol) of sodium hydride (60% in oil) and the resulting suspension was stirred at room temperature for S min. After gas evolution was complete, 30 ~L (0.25 m~ol) of benzyl bromi~e ~5 was added.- The resultins mixture was st rred at room t~perature for 20 h, quenched with a~onium c~.loride, evaporated and worked up with wate- æ~d chloroform. The crude was chromatographed over silica gel, eluting with ethyl acetate/hexane, to gi~e 70 mg (56%) of the trityl 20 protect~d desired product compound as an oil: lH N~R
DCl3) ~ 0.74(t, ~ = 7.25 Hz, 3H), l.lO(septet, ~ = 7.7 . ~ Hz, 2H), 1.37~quintet, ~ = 7.65 Hz, 2:0 , 2.12(t, ~ = 7.25 Hz, 2H), 3.85(s, 2~), 4.63(s, 2X), 4.74(s, 2X), 6.73(d, ~ =

- , .
: . .
- : SLJE3STITUIT~ S-~EET

.... . .. .. ~ .. . . -. . -.. .

WOgl/18888 PCT/VS91~0 ~ 9 9~ 73~

8.06 Hz, 2H), 6.80-7.00(m, 8H), 7.08-7.60 lm, 27H), 7.93(~
= 2.0 Hz, lH).

Following the General Procedure step 2, 70 mg (0.076 mmol) of the alkylated product was depro~ected, and the resulting oil was recrystallized from ethyl acetate/etherihexane to give 46 mg (90%) of the desired product compound as a white solid: lH NMR (CDC13) ~ C.78 (t, ~ = 7.25 Hz, 3H), 1.18(septet, ~ = 7.25 Hz, 2H), 10 1.41(quintet, J = 7.7 Hz, 2H), 2.24(t, ~ = 7.7 Hz, 2H), 3.67(s, 2H), 4.SO(s, 2H), 4.55 (s, 2H), 6.69~d, ~ = 8.06 Hz, 2H), 6.91~d, J = 8.46 Hz, 2H), 7.00-7.20~m, 9H), 7.37(br s, 5H), 7.45(td, ~ = 7.65, 1.2 Hz, lH), 7.55~td, ~ -= 7.65, 1.2 Hz, 1~), 7.85~td, ~ = 7.66, 1.21 Hz, lH); MS
15 (FAB~ m/e (relative intensity) 674 (15), 582 (8), 554 (3), 325 (S), 297 (20), 235 ~8), 207 ~100), 192 (50), 178 (40);
HRMS. calcd for M+H 674.3243. Found: 674.3302. : -i :

'~

:
,, -. :

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

..2619 `'.
~ 3~.~'73~:2 g2 EX3~
. rPh N-N~
~Y ~ O O
1 ~2 [~ N- N

2~ be~7ovl-2-~he~vlethvl)-i-~utv1~2.~ hvdro-4-r2~-tlU.-t~trazol-~-vl)r~ hen.v1l-4-vl~et~ -3H-~~2~4-t iazcl=
3-one To a solution or 0.24 mL (0.36 mmol) of lithium diisopropylamice ~1.5 M in tetrahydro-uran, Ald~ich) at -20C was added a solution or 105 mg ~0.143 mmol) of phenacyl tri~yltetrazolyLbipneny~ triazolone from examQle S
in 2.5 mL of dry tetrahydrofuran via cannula. The resulting solution was stirred cold '3_ 10 min. To the :~
lS sDlution was-added 25 ~L ~0.21 mmol) o- benzyl bromice, and :. the resulting solution was stirred at ~oom temper~ture ror -2 h. The reaction was quenched with a~monium chloride, evaporated, and worked up with water znd methylene chLoride. The crude was chromatograp;~ed over silica gel, .~ 20 eluting with ethyl acetate/hexane, to give 106 mg (90%) or the trityl protected desired product. Following the . General ~rocedure step 2 the alkylated product was :
deprotected to give 60 mg ~80%~ of the desired product compound as a white solid: lH NMR tCDC13) ~ 0.75(t, ~ = 7.05 SU~351'1TUT5~ ET
~i . . .

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

-WO 91/~8B88 PCT/~S91/0 ~ 9 '~ 93 Hz, 3H), 1.00-i.45(m, 4H), i.83-2.00~m, lH), 2.00-2.20(m, lH), 3.36(dd, ~ = 13.3, 4.4 Hz, lH), 3.85(t, ~ = 12.9 Hz, lH), 4.99ldd, J = 10.9, 3.6 Hz, lH~, 5.11~AB quartet, ~ =
17.7 Hz, 2H), 7.0-7.7(m, 14H), 7.90(d, J = 7.26 Hz, 4H); MS
^ 5 ~FAB) m/e ~relative intensity) 584 ~15), 325 (60), 260 (100), 207 ~10); ~RMS. calcd for M+H: 584.2774. Found:
5~4.2794.

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

.`,, ' ~' .
`l , .

.

- - .~,, .

.~6i9/~ ~c 3 5 Y l 9 ,,. O

N N~
O

[~; N--N' S 5-' tyl-2~4-dihvdro-~-oxobutvl)-4- r 2 ~ er-~ 7~1-5-vl)r~ -b~Dnenv~l-4-vlmet~vll-3H-l~2~4-~rl27ol-3-~ne . Following the General Procedure .~o~ rezcting a triazolone witn an 21kylating agent (described above), 150 ; 10 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-~2'-(1-triphenylmethyl-lH-~etrazol-5-yl)[l,l'-~iphenyl]-4-ylmethyl]-3H-1,2,4-t A 2zol-3-one in l.S mL of N,N-dimethylformamide was reacted with 0.26 mmol of potassium :
t rt-~utoxide ln tetranydroruran and 60 ~L (0.367 mmol) or lS b~tyric anhydL-ide. The acylated pro~ct was deDro~ect~d following General ~rocedure steD 2, the c-uce product was recrystallized from ethyl acetate/nexzne to give 92 mg (85~) or the desired product compound as a wnlte solid~
NMR (CDC13A ~0.89~t, ~ = 7.1 Hz, 3H), l.OO(t, ~ = 7.26 Hz, 3~), 1.30-1~45(m, 2H), 1.55-1.70(m, 2Y.), 1.77(q, ~ = 7.3 Hz, 2HI, 2.48~t, ~ = 7.6 Hz, 2H), 2.92(t, ~ - 7.26 Hz, 2~), 4.84(s, 2H), 7.18-7.32(m, 4H), 7.35-7.45(m, lH), 7.45-7.65(m, 2H), 8.05-8.15~m, lH);. M5 (FAB) m/e (relative intensity) 468 (33), 446 (45), 376 ~100), 235 (45), 207 ~ :

~ ' .
. . ~ 'A
SUBSTIT~JT~ ET

~6 19/1 ~J ~ J ~
c~5 (100), '92 ~42); .~S. calcd for M~: 446.2304. ~ounc:
.6.235'.

O :

OMe N- N ~
~: 00 OMe C~2 ......
~ . ., N-N~H
s 5-butvl-2,4-dihvdrQ-2-r2-(2,S-dimQt~.voxv~he~vl)-2-o~oethy1l-a- r2~ -te~xzzQl-s-vl)r~ he~yll-a 10 vl~etkvll ~ 3~ æ~4-~ri zzo l - 3-Following the General Procedure ror reacting z triazolone w~th an alkyIating agent (desc_~ed ~bove), 600 ~ mg tO.g71 mmol) of 5-butyl-2,4-dihy~ro-4-~2'-(1-: 15 triphenylmethyl-1~-tetrazol-5-yl)[l,l'-~ipnenyl]-4-ylmethyl]-3~-1,2,4-triazol-3-one in 6 mL or N,N-dimethylformamide was reacted with 1.17 mmol of potassium ~.
tert-~utoxide in tetrahydrofuran and 310 mg ~1.20 mmol) of 2,5-dimethoxyphenacyl bromide. The c~ude product was 20 recrystallized from ethyl acetate/ether/hexane to give 750 mg (97~) of the trityl protected desired product. Following General Procedure step 2, 200 mg of the alkylated product was deprotected, and the crude proouct was recrystallized - ~U~iTlT;~lTt: ~;r~ T

. ! .
. _ ... ._ .. _.. , ..... _ _ . _ .. _ .. . _ .~ ' ' ' ', " ', ' '~ ' ,' ' ,' . ' . , ', ' . '` ' ' . . ,, ; ' ;'` ' ' ' ' ~

: WO 91~18888 PCI/USg1/03449 .
96 Z~,~

to givf~ 110 mg (79%) of the desired product compound as a white solid: lH MMR (CDC13) ~0.35(t, ~ = 7.65 Hz, 3H~, 1.32(septet, ~ = 7.65 Hz, 2H), 1.5a(qu mtet, J - 7.65 Hz, ~; 2H)/ 2.41(t, ~ = 8.06 Hz, 2H), 3.75(s, 3H), 3.90~s, 3H), 4.82(s, 2H), 5.15(s, 2H), 6.92(d, ~ = 9.27 Hz, lHJ, 7.09(dd, ~ - 8.87, 3.2 Hz, lH), 7015(d, ~T = 8.06 Hz, 2H), 7.21(d, ~ = 8.06 Hz, 2H), 7.33-7.6(m, 4H), 7.92(dd, ~T =
8.06, 1.2 Hz, lO ; MS (FAB) m/e (relative intensity~ 576 (13), 554 (38~, 207 (100), 165 (63); XRMS. calcd for M+H:
S54.2516. Found: 554.2567.

~i .

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

: ~61911 ' 97 2~ ~S

0~ Ph N- N~

~':',."':,-N N'H
~ N

5-butv~ -dl~vdr~-2-r2-~he.~vl-2-(~he~lvlme-hQxy)e~hvl1-4-f2'- (lE~-tetrazol-~-vl) rl~l l-bi~henvll-4-vlTne~hvl l-3~ 2~- , tr~ 2701 - 3-o~

To a solution of 14~ mg (0.210 mmol) of crude tr~tyl tetrazolylbiphenyl phenylhydroxyethyl tr-azolone from e~ample 6 in 4 mL of dry tetranydroruran W25 added ~8 ~i~ mg (0.201 mmol) of sodium hydride (60~ in oil), and the resulting suspension was stirred at room temperature for 5 min. After gas evolution was complete, 50 ~L (0.42 mmol) of benzyl bromide was added. The resulting mi~ture was stirred at room te~perature for 1 h, ~uenched with ammonium chLoride, and concentrated in va~l~. The r~sidue was worked up with water and methylene chLori~e to sive 200 mg o~ the crude al~ylated product. Following the General ~rocedure step 2 the al~ylated product was deprotected to give 120 mg (quantitative) of the desired product compound - as a white solid: lH NMR (DMSO-d6~ ~ 0.75~t, ~ = 7.25 Hz, 3K), 1.10-1.38(m, 2H), 1.35(quintet, ~ = 7.66 Xz, 2X), 2.34(t, ~ = 7.65 Hz, 2X), 3.77(dd, ~ = 14.1, 5.44 Hz, lX), 4.03(dd, ~ - 13.7, 8.46 Hz, lH), 4.21(d, ~ = 12.1 Hz, lH), '.

;UE~ IT~ E 5~ ET `~
; ,', :` ~
~: 26l9/l ~8 4.39(d, ~ = 12.1 ~ ,), d. iO-4.82~ (-~it:~ s c- ~.7O), 4:-1, 8.99(~r s, ~;-), 7.~ 0-7.d3 (m, lOr), 7.43-7.72 (~, ~' );
S (F`~B) m~e (-e~ctive inte~sity) 586, 478 (18), 243 (iOO), 207 (88); E~;~S . Cc~ C_ for ~f+~l 586 .2930 . ~ounc: sa5 .2''79.

OMe 1 :

N-N~
~=O OH OMe I
~2 .

~ N ' : ' .
10 S~butvl-2 4-diLhvdro-2- r2-/2.~-dimethvoxv~heny1)-~-hyd~Q~4f~r~ll--d--r 2 ~ L~ZQl--S--vl ~ r ~ bi~n~vl1--~--- To a solution of 250 mg ~0 314 mmol) o- trl~yl protected biphenyl dimethoxyphenacyl tr~a2010ne from example 21 in 3 mL of methanol and 6 mL or tetræhydrofuran at 0C was added 16 mg ~0.423 mmol) or sodium borohydride in one portion. The resulting solution was stirred cold for `~ 1 h, quen~hed with ammonium chloride, and evaporated. The residue was chromatographed over silica gel, eluting with - ethyl acetate/methylene chloride, 3:1, to give 246 mg ~98%~
of the trityl protected desired product. Following the General Proced~re step 2, 71 mg (0.089 mmol) of the : : .
' ~ IT~3~r t;~ Er -.... :, : .: , - . ,, : : . ,, :. : .. , ,.. .. . . . : .:

WO 91/1~ PCT/US91/0 ~ 9 al~ylated produc~ was deprotec~ed to give 50 mg ~-~
(quantitative) of the desired product comDound as a ~hite solid: !H MMR ~CDC13) ~O.88~t, ~ = 7.4 Hz, 3H), 1.25-1.42(m, 2H), 1.50-1.63~m, 2H), 2.42(t, ~ = 7.4 Hz, 2H), 3.67(s, 3H), 3.81(s, 3H), 4.0-4.25(m, 2H), 4.76(s, 2H), 5.13-5.25(m, lH), 6.70-6.83tm, 2H), 6.92-7.00(m, lH), 7.05-7.20~m, 4H), 7.35-7.43lm, lH), 7.45-7.65(m, 2H), 7.96-8.08(m, lH); MS (FAB) m/e (relative intensity) 578 (35), 538 (90), 510 (3), 495 (6), 235 (12), 207 (100), 192 ~30), :
10 178 (30); HRMS. calcd for ~+H: 556.2672. Foun~: 5;6.2691.

., :- .

,........................................................................ :' .
'.' ' , . .

i~ .
. ~ .

,. ~ .

: ~

,;,~ ,. . .

26 l9/1 00 ~S~ 5 ~3~ ' --N~) N--N'H

[~ N ~
. '" .
~-~ut~l -2 ~-d~ d-0-2-L2-~ h~nyl~e-~vl)-a-~2 t~ ~ zoL 5-vL)~l ~'-b;~h~ vlmerhvl 1-~ 1, 2, a-rr~ ~7Q~,-Followlng the Ganeral Procedure ror ~ctiag 2 triazolone with an al~ylating agent (descriDed ~bove), lS0mg (o.2a3 mmol) of 5-~utyl-2,4-dihydro-4~[2'-(1-triphenylmethyl-l.i-tetrazol-S-yl)[l,l~-~ipnenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one in 3 mL OL N,N-d~methylformamide was reacted with 0.3 mmol OL potassium 15 tert-~utoxide in tetxahydrofuran and 81 mg ~0.367 mmol) or 2-tbromomethyl) naphthalene. The al~ylated product was deprotected following C~neral Procedu_e st=p 2 and the crude product was recrystallized to give 125 mg tcuantit2tive) of the desired product compound 25 a white 20- solid: 1~ N~R (CDC13) ~O.81tt, ~ = 7.25 Hz, 3Y.), .~ 1.27tseptet, ~ = 7.25 Hz, 2~), 1.50(cuinte~, ~ = 8.06 Hz, 2H), 2.34(t, ~ = 7.25 Hz, 2H), 4.6gts, 2H), 5.04ts, 2H), 6~95-7.10(m, 40 , 1.30-7.60(m, 7H), 7.55-7.8(m, SH); MS
tFAB) m~e ~rela~i~e intensity) 516 (25), 326 (30), 242 ~" ~, , ' :., . ~
.;j ~- 5U ;~IT~ S~EET

: 261911 ---. . .

(2s), ~7 (loo)t 192 (30), 178 (35), 141 (iOC); ~ S.
c~ -c- ~.+~: 516.2512. ~ound: 516.2455.

E~a~9æ~E~
,~,.
N-N~CO2C~13 =0 CH2, N_N ~ H
~ N ' ; methvl ~-~u~vl-4 5-dihvdro-5-oxo-4-L2'-(lY-tetra7~1-5_ 10 vl)rl~ll-blo~e~vll-a-vlmethvll-1H-l~2 ~-tric701e-L-oentanoate Following the General Procedure for reacting z triazolone with an alkvlating agent (descri~ed cDove), 150 15 mg ~0.243 ~mol) of 5-bu~yl-2,4-dihydro-4-~2'-(1-triphenylmethyl-lH-tetrazol-5-yl)~l,1'-biphenyl~-4-y~methyII-3H-i,2,4-triazol-3-one in 3 mL o~ N,N-dimethylformamide was reacted with 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and SZ ~L ~0.36 ~mol) o~
methyl 5-bromovalerate. The alkylated product was deprotected following General Procedure step 2 to give 115 mg (97%) o~ the desired product comDound as a white solid:
H NMR ~CDCI3) ~0.8~tt, ~ = 7.3 Hz, 3H), 1.35(septét, ~
~-~ 7.5 Hz, 2H), 1.50-1.68(m, 4H), 1.75(cuintet, ~ = 8.04 Hz, 25 2H), 2.32(t, ~ = 7.5 Hz, 2H), 2.42~t, ~ = 8.0 Hz, 2H), :
r~ 3 E~

WO 91/188~
102 ~ 5 3.62(s, 3H), 3.761t, 1 = 6.8 Hz, 2H~, 4.78~s, 2H), 7.17(d, i = 7.96 Hz, 2H), 7.22(d, ~ = 8.5 Hz, 2H), 7.42~dd, ~ =
7.4, 1.5 Hz, lH), 7.50-7.68(m, 2H), 8.02(dd, ~ = 7.7, 1.2 - Hz, lH); ~S (,P~3) m/e ~relative intensity) 490 (20), 430 5 (8), 235 (8), 207 (100), 192 (30), 178 (50); ~RMS. calc-; for M+H: 490.2567. Found: 490.2570.

'' ' ' .

' ~ :
', : ~
, ,:
;. . .. ..
... .
..

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

C '619/1 2~ r~ 35 , 7 E~P~ X2.~
. rCO Et N- N~Ph ,~ O O

N- N'H
~ , N

S e~hvl B-ben.zovl-3-~utvl-a.S-dlhydro-5-oxo-4-r2'-(1H_ t~tr~7ol-s-vl~r~ -blphenyll-4-vlme~hv~ a tr~a7ele~ ro~2noate ,,~ .

I To a solution or 0.56 mL (o.8a mmol) of lithium -~ 10 diisopropylamide (1.5 M in tetrahydro~uran, Aldrich) at -'' !
78C was added a solution of 348 mg (0.473 mmol) of phenacyl trityltetrazolylbiphenyl triazolone from exa~ple 5 ~
in 2 mL of dry tetrahydrofuran via cannula. The resulting -solution was stirred cold for 10 min. To the solution was added 63 ~ (0.568 mmol) of ethyl bromoacet~te, and the ~1 ~ résulting solution was stirred cold ~20r 15 min, then slowly warmed to -30C over a 30-min period. The reaction was quenched with 1 N hydrochloric acid, stirred to room i temperature, and worked up with water and methylene chloride. The crude was chromatograpned over silica gel, eluting with ethyl acetate/hexane, to give 82 mg (21~) or the trityl protected desired product. Eollowing the ;~ General Procedure step 2 th~ aIkylated product was deprotected, and the crude product was chromatographed over : SUE~St-lTl.lTE S~ ET

:

WO 91/l~

silica gel (eluted with isopropanol-hexane-acetic acid, 65:32:3) ~o give 30 mg ~55~ of the desired produc~
compound as a white solid: lH NMR (DMSO d6) ~0.66(t, ~ =
7.3 Hz, 3H), 0.86 (quintet, ~ = 7.0 Hz, 2H), 1.05(septet, J
S = 7.2 Hz, 2H), 1.15(t, ~ = 6.73 Hz, 3H), 2.27(t, J = 7.2 Hz, 2H~, 2.95(dd, ~ = 16.3, 6.9 Hz, lH), 3.14(dd, J = 16.3, 7.2 Hz, lH), 9.05~q, J = 6.8 Hz, 2H), 4.79(s, 2H), 6.00(t, = 7.3 Hz, lH), 6.84(d, ~ = 8.2 Hz, 2H), 6.99(d, ~ = 8.0 Hz, 2H), 7.15-7.40(m, 3H), 7.40-7.80~m, 9H), 7.88~d, ~ =
10 8.0 Hz, 2H); HRMS. calcd for M+H: 58002672. Found:
580.2~14 ' ~''.

..

.:

'' . :. : : ' ' ' , - , , EXAMPLE #26 2-(1-benzyoyl-1-methylethyl)-5-butyl-2,4-dihydro-4-(2'-(1H-tetrazol-5-yl)(1,1'-biphenyl1-4-ylmethyl1-3H-1,2,4-triazol-3-one Following the General Procedure for reacting a triazolone with an alkylating agent (described above), 100 mg (0.162 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl) [1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one in 2 mL of N,N-dimethylformamide was reacted with 0.2 mmol of potassium tert-butoxide in tetrahydrofuran and 41 uL (0.24 mmol) of 2-bromo isobutyrophenone. To the reaction mixture was added 15 mg (0.38 mmol) of sodium hydride (60% in oil), and the resulting mixture was stirred at for 2 h. The mixture was concentrated in vacuo and chromatographed over silica gel (eluting with ethyl acetate-hexane) to give 30 mg (24%) of the trityl protected product: 1H NMR (CDCl3) .delta. 0.84(t, J
= 7.31 Hz, 3H0, 1.18-1.32(m, 2H), 1.47(quintet, J = 7.46 Hz, 2H), 1.90(s, 6H), 2.29(t, J = 7.7 Hz, 2H), 4.55(s, 2H), 6.59(d, J = 8.2 Hz, 2H), 6.89(d, J = 7.7 Hz, 6H), 6.97(d, J

w o 91/18~ YI/u~
~6 ~ 735 = 8.08 Hz, 2~, 7.'5-7.48(m, 12~), 7.48-7.55(m, 3H), 7.78(d, ~ = 7.2 Hz, 2~), 7.90-7.98(m, lH).

The al~ylated product was deprote~ed 'ollowina S the General Procedure s~ep 2 and the crude produc~ was recrystallized to give 16 mg (80%) of the desired produc-compound as a white solid: lH MMR ~CDC13) ~ 0.85(t, ~ = 7.25 Hz, 3H), 1.30(septet, ~ = 7.6 Hz, 2H), 1.52(quintet, ~ =
7.25 Hz, 2H), 1.7~(s, 6~), 2.39(t, ~ = 8.05 ~z, 2H), 10 4.50(S, 2H), 6.55(d, ~ = 8.06 ~z, 2H), 6.87(d, T = 8.06 Y.z, 2H), 7.15-7.30(m, 2H), 7.30-7.42~m, 2X), 7.4i-7.70~m, 9H), 7.85-7.95~m, lH); MS (FAB) m/e (relative intensity) 544 (20), 522 (20), 416 (5), 235 (5), 207 (100), 192 (45), '78 : (30); HRMS. calcd for M+H: 522.2617. Found: 522.2658.

.:

., I

` ' ' ~ .

. ~ .
~ ' .

'`1 .
,,- :' :. . ~'.',.

- .: .
, ,.

.,.,.,~
i:

:.

~6l9ll ~`
107 ~ ~ ~ ~ 7 ~ 5 E~A~PLE__~27 N-N/--~C02 ,~0 C~2 [~ N--N'H

~-butyl_~ S-dlhvdrn-~oxo-~-r2~ tet a~ol-5-vl)r~
~i~henyll-4-ylmethv~ H-l 2 4-tr~2znle~ en.t2noic ~c~d A mixture of 80 mg (0.163 mmol) of ester from example 24 in 3 mL of tetrahydrofuran and 3 mL ~r 2 U
lithium hydroxide was stirred at room temper2ture for 2 h.
~olatiles were removed in v2CUQ~ and the aoueous solution was washed with three portions of ethe-. The resulting aqueous solution was acidified with 3 ~ hydrochloric acid, extracted with chloroform, dried (MgSO4) and concentrated . 15 1DL~ . The solid residue was recrystall'zed from ethyl acetate/hexa~e to give 74 mg (94~1 or the desired produc~
co~pound as a white solid: 1~ NMR (DMSO-d6) ~ 0.78~t, ~ =
.7.25 Hz, 3~l, 1.10 1.53(m, 6H), 1.63tcuintet, J = 8.06 Hz, 2H)`, 2.22~t, ~ = 7.25 Hz, 2H), 2.37(t, ~ = 7.66 Hz, 2X), 3.65~t, ~ = 6.85 Hz, 2H), 4.79(s, 2H), 7.06(d, ~ = 8.46 Hz, 2H), 7.12~d, ~ = 8.06 Hz, 2H), 7.45-7.72(m, 4X), 11.7--~ 12.3~br s, lH); HRMS. calcd for ~H: 476.2410. Found 476.2411 :~

.
C ~ ~ B5TIl~UT SI~E~;

,. E_ .
~N--N~ :

[~ ) N--N ' [~ N"N ~ :

S-~utyl-2-~cv~lo~rc~vlmethvl)-2.d-dLhYd~o-~-r2~
t~tr2~ol-~-Vl~2 r~ bi~henvl~a-vlme~h~ H-~ 2 ~ 2YOl-Following the General Procedure for react~ng a triazolone with an alkylating agent (descrioed aoove), 200 ~ mg (0.324 mmol) or 5-butyl-2,4-dihydro-4-[2'-(1-; triphenylmethyl-iH-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one in 4 mL of N,N-dimethylformamide was reacted at 0C with 0.39 mmol of potassium tert-butoxide in tetrahydroruran and 47 ~L (0.48 mmol) of bro~omethyl cyclopropane for 1.5 h and at room ~ t~mperature for 2 h. The alkylated product was deprotected -- following General Procedure step 2 to give 131 mg (94%) or ;- the desired product compound as a white solid: 1H NMR
(DMSO-d6) 8 0.28(q, ~ = 4.8 ~z, 2Hj, 0.44(q, ~r = 5.6 Hz, 2H), 0.79~t, ~ = 7.25 Hz, 3H), 1.00-1.08(m, lH), 1.24tseptet, ~ = 7.65 Hz, 2H), 1.42(quintet, ~ = 7.25 Hz, r~ 2H), 2.39~t, ~ - 7.25 Hz, 2H), 3.S4-~d, ~ = 6.9 Hz, 2H), 4.79~s, 2H), 7.06~d, ~ - 8.05 Ez, 2H), 7.12(d, ~ = 8.06 Hz, ., ; ' ` ' .~;l3R.C:~` i Ir~Jr~--S~ T
~ , c-26 1911 ~rJ ~ ~J'~ F '~

2~), 7.45-7.75(m, ~ ~MS. calcd for ~+~ 30.2355.
Fo~nd: a30.2395.
i~c~.s ~a2~2 N- N ~ Ph ,~ O
GH

~) H .

[~ N ' :
,. :

5-butvl-2 4-d~hvd~o-2-t3-ohenyl-2~-~re?e~v'!-4-~2'-(lY.-~.j 10 tetr2zol-~i-yl) rl~ l l-b;~henyLl-a-ylraet~y~ ?~4-tr;a :. ~-one Followins the General Procedure for reacting a triazolone with an al~ylating agent (desc lDed ab~ve), 150 . 15 mg (0.243 mmol) of 5-butyl-2,4-dihydro-4-[2'-(1-triphenylmethyl-lH-tetrazol-5-yl)~l,l'-bipnenylJ-4-y~methyl]-3H-1,2,4-triazol-3-one in 3 mL of N,N-dimethylformamide was reacted ~ith 0.3 mmol of potassium tert-butoxide in tetrahydrofuran and 72 mg (0.366 mmol) of cinnamyl bromide. The al~ylated product was deprotected . following General ~rocedure step 2 and the crude product was:chromatographed over silica gel, eluting with ~i ~ : isopropanol/hexanelacetic acid, to give 60 mg (50%) of the ~:!'` desired product compound as a whit~ solid: lH NMR (DMSO-d6) ~ 0.78~t, ~ = 7.25 Hz, 3~), 1.24(septet, ~ = 7.66 Hz,. 2H),.
, .

5UE~5SIT~T~: S.~ T
.
,,;,i ~ - , .

WO 91/1~888 PCr/US9l/03449 1.42 ~quintet, ,~ = 7.65 Hz, 2H), 2.40 (t, ~ = 7.65 E~z, 2E~
4.46(d, ~1 = 5.24 Hz, 2H), 4.82(s, 2H), 6.31(c~t, ,~ = 16.1, 5.6 Hz, lH), 6.49(d, ~ = 16.1 Hz, lH), 7.07 (d, ~ = 8.06 . z, 2H), 7.15(d, ~ = 8.06 Hz, 2H), 7.20-7.75(m, 9H)i MS ~FAB) m/e (relative lntensity) 492 (38), 464 (3) 376 (3), 243 (12), 2G7 (87), 178 (20), 117 tlOO); HRMS. calcd for M+l;.:
492.2512. Eound: 492.2542.

: ~, .. .

, ~

'1 . - . ' ', :: ' .
- .

i'l ' ', :

C ~619/1 .
3 ~35 ~a~.~Q

N-N~~
--~ N ~C O
,,, CH2 , ..
N J~

N"
~`
.
5 l-hutyl~ d;hvdro-5-o~Q-~-~ro~vl-a- ~2 ~ ff-tetrA7Q~=
vl) rl,l'-b;phenvli-a-yt~ethvl~ 7-1,2~-t~i2zol~ 3-Step ~smi~of 2 . 5-d ~utvl -2, 4-d; hlvd- o-a- ~2 ' _ , 10 ~ tet~azol-~-yl) r~ -b~ -y~ 2~ 4-. ~ .
"
A solution or 2.0 g ~2.97 mmol) or trityl tetrazolylbiphenyl dibutyl triazolone (prepared in e~ampie 2, step 5), 0.63 g (3.56 mmol) or N-~romosuccinimide, and 60 mg ~0.~6 ~mol) of azoisooutyronitr le in 200 mL or ; degassed carbon tetrachloride was St' rred at 65C for l h, cooLed and concentrated ;~ vacuo. Th~ residue was chromatographed to give 1.35 g (61~) of bromobutyl triazolone: lH NMR (CDCl3) ~ 0.72(t, ~ = 7.65 Hz, 3H), 0.94(t, ~ - 7.25 ~z, 3H), 1.10-1.45~m, 3H), 1.75(quintet, ~ -- = 7.66 ~z, 2~), l.gS-2.20(m, 2~), 3.83(t, ~ = 7.25 Hz, 2H), 4.34(t, ~ - 6.85 Hz, lH), 4.65~d, ~ = 15.7 Hz, lH), 5.12(d, , ~ 16.1 Hz, lO , 6.85-6.95~m, 6H), 7.01(d, ~ = 8.46 Hz, . .
Sl~35TIl-UTE 5~:F~ ;

W~ /18888 PCT/US91/03449 112 ,~

lH) ~ 7.10(d, J = 8.05 Hz, 2H), 7.20-7.40(m, ;0~), 7.40-7.~3(m, 2H), 7.~5-7.g5(m, lH).

5 ~ ~:

A mixture of 226 mg tO.3 mmDl) of the brominared product from step 1, 38 mg (0.776 mmol) or sodium cyanide, and 0.3 mL of water in 4.5 mL of N,N-dlmerhylformamide was stlrred at room temperature for 23 h.
The resulting mixture was concentrated in vac~o and ::
chromatographed over silica gel (eluting with ethyl acetate/hexane) ~o ~ive 178 mg (85%) of cyanobutyl triazolone as a white solid: lH NMR (CDC13) ~0.75(t, ~ =
; 7.25 Hz, 3~), 0.94~t, ~ = 7.26 Hz, 3H), 1.15-1.5(~, 4H), 1.55-1.85(m, 4H~, 3.34(dd, ~ z 8.86, 6.05 Hz, lH), 3.82(t, . ~.
;.:
I ~ = 7.26 Hz, 2H), 4.73(d, ~ = 15.7 Hz, lH), 4.99(d, ~ - :
-.I 15.7 Hz, lH), 6.85-6.9B~m, 6H), 7.02~d, ~ = 8.46 Hz, 2H~, 7.11~d, ~ - 8.06 Hz, 2H~, 7.20-7.40~m, lOH), 7.4-7.55~m, 2H), 7.85-7.95~m, 1~). -Following the General Procedure step 2, 80 mg ~0.114 mmol) ; -of the cyanobutyl triazolone was deprotected and chroma~ographed (eluting with isopropanol/hexanefacetic aciO to g~ve 48 mg 592%) of the desired product compound - as a white solid: lH NMR ~DMSO-d6) ~ 0.74~t, ~ = 7.3 Hz, 3~), 0.89tt, ~ = 7.4 Hz, 3H), 1.29(quintet, ~ = 7.3 Hz, ~i 4H), 1.40-1.73(m, 4H), 3.73(t, ~ ~ 6.96 Hz, 2H), 4.44~dd, - 7.9, 5.7 Hz, lH), 4.91~A3 quartet, ~ 3 16.4 Hz, 2H), 7.10~d, ~ ~ 8.0 Hz, 2H~, 7.18(d, ~ - 8.1 Hz, ZH), 7.45-1l 7.78(m, 4H); MS (FAB) m~e (relative intensity~ 457 (18), ! 4~9 (5~, 235 ~10), 207 ~50~, 192 (8~, 149 (25), 147 (100):
HRMS. calcd for M~H: 457.2464. Fou~d: 457.2521.
. ~ .
': ' ... . , ~ : .. , , ;,, ,, ., ., . . , . . . :. -Wo 91/18888 PCI/IJS91/03449 ~ 73~;

Compounds of Formula I were tes~ed for abili~y to bind to the smooth muscle angiotensin II receptor using a rat uterine membrane preparation. Angiotensin (AII) was purchased from Peninsula Labs. 125I-angiotensin II ~specific activity of 2200 Ci~mmol) was purchased from Du Pont-New England Nuclear. Other chemicals were obtained from Siyma Chemical Co. This assay was carried out according to the method of Douglas et al ~L9s~i3~1Qgy, lQ~, 120-124 (1980)~. Rat uterine membranes were prepared from fresh tissue. All procedures were carried out at 4C. Uteri were stripped of fat and homogenized in phosphate-buffered saline at p~
7.4 containing 5 mM EDTA. The homogenate was centrifuged at 1500 x g for 20 min., and ~he supernatant was:
recentrifuged at 100,000 x g for 60 min. Th~ pellet was resuspended in buffer consisting of 2 mM EDTA and 50 mM
Tris-HCl ~pH 7.5) to a final protein concentration of 4 mg~ml. Assay tubes were charged with 0.25 ml of a solution containing 5 mM MgC12, 2 mM EDTA, 0.5% bovine serum albumin, 50 mM Tris-HCl, pH 7.5 and 125I-AII
(approxlmately 105 cpm) in the absence or in the presence of unlabelled ligand. The reaction was initiated by the a ~;tion of membrane protein and the mixture was incubated at 25C for 60 min. The incubation was terminated wi~h ice-cold 50 mM Tris-HCl (pH 7.5) and the mixture was filtered to separate membrane-bound labelled peptide from ~he free ligand. The incubation ~ube and filter were washed with ice-cold buffer. Filters were assayed for radioactivity in a Micromedic gamma counter.
Nonspecific binding was de~ined as binding in the presence of 10 ~M of unlabellad AII. Specific binding - , :
~, -`91/18888 PCT/US91/03449 ~$~ d5 was calculated as to~al binding minus nonspec~_ic bindlng. The recep~or binding affinity of an AII
antagonist compound was indicated by the concentration i~ (IC50) of the tested AII antagonist which gives 50%
displacement of the total specifically bound 125I-AII
from the high af.inity AII receptor. Binding data were analyzed by a nonlinear least-squares curve fitting program. Results are reported in Table I.

~
~ .

! Compounds of Formula I were tested for antagonis~ activi~y in rabbit aortic rings. Male New Zealand white rabbi~s t2-2.5 kg) were sacrificed using an overdose of pentobarbital and exsanguinated via the carotid arteries. The thoracic aorta was removed, ~ -cleaned of adherent fat and connective tissue and then cut into 3-mm ring segments. The endothelium wac removed from the rings by gently sliding a rolled-up piece of 1 filter paper into the vessel lumen. The rings were then ; moun~ed in a water-jacketed tissue bath, maintained at 37C, hetween moveable ~nd fixed ends of a stainless steel wire with the moveable end attached to an FT03 Grass transducer coupled to a Model 7D Grass Polygraph for recordLng isometric force responses. The bath was filled with 20 ml of oxygenated (95% oxygen/5% carbon dioxide) ~r~bs solution of the following composition ~mM): 130 NaCl, 15 NaH~03, 15 KCl, 1.2 NaH2P04, 1.2 -,~ 30 MgS04, 2.5 CaC12, and 11.4 glucose. The preparations were equilibrated for one hour before approxima~ely one gram of passive tension was placed on the rings.
'i Angiotensin II concen~ration-response curves were then :, recorded ~3 X 10-i to 1 X 10-5 M). Each concentration of AII was allowed to elicit its maximal contraction, and .
.:

., .

WO 91/l8888 PCT/US91/03449 ^pl~5 ~hen AII was washed out repeatedly for 30 minutes ~efore -echallensing wlth a higher concentration of AII. Aort~ --ings were exposed to the tes~ antagonis~ at 10-5 M for _ minutes before challenging with AII. Adjacent segmen~s of ,he same aorta r-ng were used for all concentra~lon-response curves in the presence or absence of the test antagonist. The effectiveness of the test compound was expressed in terms of PA2 values and were calcl~lated according to H.O. Schild [~ J. PhaIm3s~l~
10 Chemoth~L~, ~ 9-206 (1947)~. The PA2 value is the concentrati~n of the antagonist whlch increases the ECso value for AII by a factor of two. ~ach tes~ antagonis~
was evaluated in aorta rings from two rabbits. Resul~s are reported in Table I.
i 15 ~ .

Male Sprague-Dawley rats weighing 225-300 grams were anesthetized with Inactin ~100 mg/kg, i.p.) and catheters were Lmplanted into the trachea, femoral ~-i artery, femoral vein and duodenum. Arterial pressure was recorded from the femoral artery catheter on a Gould chart recorder (Gould, Cleveland, OH). The femoral vein ¦ catheter was used for injections of angiotensin II, mecamylamln~ and atropine. The tracheal catheter allows j for airway patency, and the duodenal catheter was used for intraduodenal (i.d.) administration of test compounds. After surgery, the rats were allowed to equilibrate for 30 minutes. Mecamylamine (3 mg/kg, 0.3 ml~kg) and atropine (400 ug/kg, 0.3 ml/kg) were then given i.v. to produce ganglion blockade. These ~i compounds were admlnistered every 90 minutes throughout the test procedure. Angiotensin II was given in bolus !

;. ` -, . .

WO 91/18888 PCT/USgltO ~ 9 116 ~3 ~ 35 does i.v. ~30 ng/kg in saline with 0.5% bovine serum albumun, 0.1 ml/kg) every 10 mlnutes three tlmes or unt~I
;~e inc-ease in arterial pressure produced was within 3 mmHg for two consecutive AII injections. The last ~wo AII injections were averaged and were taken as the control AII pressor response. Ten minutes after the fin~l control AII injection, the tes~ compound ~dissolved i~ sodium bicarbonate) was administered i.d. at a dose of 30 mg~kg in a volume of 0.2 ml. Angiotensin II
injections were then given 5, 10, 20, 30, 45, 60, 75, 90, and 120 minutes after administration of the test compound and response of arterial pressure was monitored. The response to AII was calculated as percent of the control response and then the percent inhibition is calculated as 100 minus the percent control response. Duration of action of a test compound was defined as the time from peak percent inhibition to 50% of peak. One compound at one dose was tested in each rat. Eaeh test compound was tested in twO rats and the values for the two rats were averaged. Results are reported in Table I.

Assay n Tn Vl vn Int~4~s~rl~ P~e~r ~ssay Re5pon~e fQr ~lL~15~ . ,' ' .
Male Sprague-Dawley rats weighing 225-300 grams ; were anesthetized with methohexi~al (30 mg/kg, i.p.) and catheters were implanted into the femoral artery and vein.
The catheters were tunneled subcutaneously to exit I dorsally, posterior to the head and between the scapulae.
; 30 The catheters were filled with heparin (1000 units/ml of 3 saline). The rats were returned to their cage and allowed i regular rat chow and water ~d l; hitl~, Ater full I r~covery from surgery (3-4 days), rats were placed in Lucite holders and the arterial 11nQ was connected to a 35 pressure transducer. Arterial pressure was recorded on a Gould poly~raph (mmHg). Angiotensin II was administered ' , ' ':

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

WO 91~18888 PCT/US91/0 ~ 9 as a 30 ns/kg bolus vla the venous catheter delLvered in a 50 ~1 volume with a 0.2 ml saline flush. The pressor ~esponse in mm Hg was measured by th~ difference from pre-injection arterial pressure to the maximum pressure achieved. The AII lnjection was repeated every lO minu~es until three consecutive injections yielded responses within 4 mmHg of each other. These three responses were then averaged and represented the control response to AI_.
The test compound was suspended in 0.5% methylcellulose in water and was adminis~ered by gavage. The volume administered was 2 ml/kg body weight. The standard dose was 3 mg/kg. Angiotensin II bolus injections were given at 30, 45, 60, 75, 120, lS0, and 180 min~tes after gavage.
The pressor response to AII was measured at each time 15 point. The rats were then returned to their cage for --future testing. A minimum of 3 days was allowed between tests. Percent inhibition was calculated for each time point following gavage by the following formula: [(Control Response - Response at time point)JControl Responsel X
lO0. Results are shown in Table I.

::j . . .

,j .
. i -., .

'' .' "':

., .

,, .
.~ :

' ' ' ' ' ' ' "' :, ' ' '': ',: .: ;' "" ' ' - ':' ' ' : ' ', ' ' ,: ' ' . .; " ~ '~ :, ' . , ' . . . . ' ,.

W O 91/18888 P ~ /US9~/03449 118 ~ 3 5 In~i~Q ar~ T `
Act ~ vi ty o~ C~n~ound~; of Fo~;~u 1.~, T

Test Compound 1Assay A 2Assay B 3Assays C and D
Example # IC50 P~2 Inhibition Dura~ion n~ ? (m.~

1~ 101 7.0 93 60-100 2~ 4.9 9.2 100 >200 2 50 >180 ` ! 3 25 8.1 NT NT
,i g 18 8.0 40 180 . , 7.9 8.5 20 180 6 3.6 8.3 15 . >180 16 7.1 20 30 8 8.7 8.9 NT NT
9 9 7.8 NT NT
91 7.8 NT NT

11 50 7 . ~ Nr NT
-~ 12 18 7.9 NT NT
i~ 13 5.6 9.0 Nr NT
14 180 8.3 NT NT
8.6 40 >180 16 35 7.9 Nr NT

~;, 18 5,800 NT NT NT
19 66 8.2 NT Nr . 21 8.0 NT N
~j 21 280 7 . 7 M N
.~ : æ 22 8.1 N~ M

! ~ ~ ~ 2 3 2 8 0 6 . 5 M ~
. 1~ 24 4.4 9.4 Nr NT
36 7.8 NT
~:

WO 91/18g88 PCT/US9~/0 ~ 9 J 7~

~est Compound lAssay A 2Assay B 3Assays C and D
ExamDle # IC50 PA2 Inhibition Duratlon (nM~ ) (mi~. ) :. 5 26 43 7 . 7 Nr NT
27 12 8 . O NI NT
28 15 8 . O Nr NT
29 290 6. 6 NI NI
48 7.7 ~ Nr NT = NOT TESTED ;
lAssay A: Angiotensln II Binding Activity 2Assay B: In Y~ Vascular Smooth Muscle Response ~ :
3Assay C: 1~ ~iYQ Intraduodenal Pressor Response for compounds of Examples #l* and #2~.
A55ay n Tn V;vo Intragastric Pressor Response : for Compounds of Example #2-30.

:
, ''.' ":

. :
. I .
'i, .1 .

: . ' , -:
~ ~ .

WO 9l/18888 PCT/US91/03449 Also embraced within this invention is a c!ass of pharmaceutical compositions comprising one o- more compounds of Formula I in association with one or more ! non-toxic, pharmaceutically acceptable carriers and/or S diluents and/or adjuvants (collectively refe-red to herein as ~'carrier~ materials) and, if desired, other active ingredients. The compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition ;
adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds of the present invention required to prevent or arrest th~ progress of the medical condition are readily ascertained by one of ordinary skill in the art. The compounds and composition may, for example, be administered intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. ~xamples of such dosage units are tabLets or capsules. These may with advantage contain an amount of active ingredient from about 1 to 250 mg, preferably from about 25 to 150 mg. A suitable daily dose for a mammal may vary widely depending on the condition of ~he patient and other factors. However, a dose o~ from about 0.1 to 30 3000 mg~g body wei~ht, particularly from about 1 to 100 mg/kg body weight, may be appropriate.
., .
The active ingredient may also be administered by injection as a composition wherein, for example, - 35 saline9 dextrose or water may be used as a suitable .
. .

- .
.~

WO g1/1~ PCT/US91/03449 car-ier. A sui.able daily dose is from abou~ 0.1 to 100 mg/kg body weight injected per day ln multiple doses depending on the disease being treated. A preferred daily dose would be from about 1 to 30 mg~kg body weight.
Compounds indicated for prophylactic therapy will preferably be administered in a daily dose generally in a range from about 0.1 mg to about lO0 mg per kilogram of body weight per day. A more preferred dosage will be a range from about 1 mg to about 100 mg per kilogram of body weight. Most preferred is a dosage in a range from about 1 to about 50 mg per kilogram of body weight per day. A suitable dose can be administered, in multiple sub-doses per day. These sub-doses may be administered in unit dosage forms. Typically, a dose or sub-dose may contain from about l mg to about 100 mg of actlve compound per unit dosage form. A more preferred dosage will contain from about 2 mg to about 50 mg of active compound per unit dosage form. Mos~ preferred is a dosage form containing from about 3 mg to about 25 mg of active compound per unit dose.
.. . .. .
... ..
~ The dosage regimen for treating a disease - ' condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, includinq the type, age, weight, sex and medical condition of the patient, the severity of the disease, the route of administration, and the particular compound employed, and thus may vary widely.

' 30 For therapeutic purposes, the compounds of - I this invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of ~, adm~nistration. If administered De~ gs, the compou~ds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl :' :
. ~, . ~ .

WO 91/18888 122 P(~/US91/03449 ~$~b'73~
esters, talc, stearic acid, magnesi~m stearate, magnesium oxide, sodium and calci~m salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
Such capsules or tablets may con~ain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral adminlstration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the fonmulations for oral lS administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, andior various buffers. Other ad~uvants and modes of administration are well and widely known in the pharmaceutical art.

Although this invention has ~een described with respect to specific embodiments, the details of these embodiments are not to be construed as limutations.

.

.

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"
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Claims (23)

Claims:

1. A compound of Formula I:

(I) wherein m is one; wherein R1 is selected from adamantyl, adamantylalkyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthlenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarnoyylmethoxyethyl,substituted with phenyl, carboxymethyethyl substituted with phenyl, 3,5,5-trimethylhexyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyloxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxy)ethyl, 2-(2,5-dimethyloxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benz oyl-1-methylethyl, pentanoic acid, cyclopropylmethyl, and acetonitrile;
wherein R2 is selected from C1-C20-alkyl, C1-C20-hydroxy-alkyl, C3-C10-cycloalkyl, C10-C20-polycycloalkyl, adamantyl, adamantyl-C1-C20-alkyl, aryloxy-C1-C20-alkyl, 2-hydroxy-2-ar-C1-C20-alkyl, alkoxycarbonyl-C1-C20-alkyl, carboxy-C1-C20-alkyl, aroyl-C1-C20-alkyl, aralkoxy-C1-C20-alkyl, C1-C20-cyanoalkyl, C1-C20-haloalkyl C1-C1- alkoxy, phen-C1-C20-alkyl, phenyl, phenoxy, phenalkoxy, C1-C10 alkoxy-alkyl, C1-C20-alkylcarbonyl, alkoxycarbonyl, aryloxy-C1-C20-alkyl, aroyloxy-C1-C20-alkyl, C1-C20-alkenyl, C1-C20-cycloalkenyl, C1-C20-alkynyl, C1-C20-alkylthio, phenthio and phen-C1-C20-alkylthio;

wherein each of R3 through R11 is independently selected from hydrido, hydroxy, C1-C20-alkyl, C1-C20-hydroxyalkyl, halo, C1-C20-haloalkyl, alkoxy, phenyl, benzoyl, phenoxy, C1-C20-alkoxyalkyl, acetyl, alkoxycarbonyl, C1-C20 kenyl, cyano, nitro, carboxyl, C1-C20-alkylthio and mercapto;

and wherein each or R3 through R11 may be an acidic moiety further independently selected from acidic moieties consisting or CO2H, CO2CH3, SH, CH2SH, C2H4SH, PO3H2, NHSO2CF3, NHSO2C6F5, SO3H, CONHNH2, CONHNHSO2CF3, CONHOCH3, CONHOC2H5, CONHCF.3, OH, CH2OH, C2H4OH, OPO3H2, OSO3H, , , , , , , , , , , and wherein each of R41, R42 and R43 is independently selected from H, Cl, CN, NO2, CF3, C2F5, C3F7, CHF2, CO2CH3, CO2C2H5, SO2CH3, SO2CF3 and SO2C6F5; wherein Z is selected from O, S, NR44 and CH2; wherein R44 is selected from hydrido, CH3 and CH2C6H5; and wherein said acidic moiety may be a heterocyclic acidic group attached at any two adjacent positions of R3 through R11 so as to form a fused ring system with one of the phenyl rings of the biphenyl moiety of Formula I, said biphenyl fused ring system selected from , , , , , , and and the esters, amides and salts of said acidic moieties;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

2. Compound of Claim 1 wherein m is one;
wherein R1 is selected from adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylathyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxothyl, 2-phenyl-2-(phenylmethoxy)ethyl,2-(2,5-dimethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benz?oyl-1-methylethyl, pentanoic acid, cyclopropylmethyl, and acetonitrile; wherein R2 is selected from hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, adamantyl, adamantylmethyl, adamantylethyl, adamantylpropyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxymethyl, substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxy)ethyl, 2-(2,5-dimethoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, 1-cyanobutyl, ethoxycarbonylethyl substituted with beenzoyl, 1-benz?oyl-1-methylethyl, pentanoic acid, cyclopropylmethyl, acetonitrile, phenyl, benzyl, phenethyl, cyclohexyl, cyclohexylmethyl, propylthio, butylthio, 1-oxoethyl, 1-oxopropyl, 1-oxobutyl, 1-oxopentyl, 1,1-dimethoxypropyl, 1,1-dimethoxybutyl, 1,1-dimethoxypentyl, hydroxyalkyl, difluoromethyl, 1,1-difluoroethyl, 1,1-difluoropropyl, 1,1-diflourobutyl and 1,1-difluoropentyl;
wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNHSO2CF3, OH, , and wherein each of R42 and R43 is independently selected from Cl, CN, NO2, CF3, CO2CH3 and SO2CF3, and wherein each of the remaining of R3 through R11 is hydrido;
or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

3. A compound of the formula I

(I) wherein m is one;
wherein R1 is selected from 2-oxo-2-(tricyclo[3.3.1.1.3.7]dec-1-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethlethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cycloexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethethyl substituted with phenyl, 3,5,5-trimethlhexyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxy)ethyl, 2-(2,5-dimethoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benz oyl-1-methylethyl, pentanoic acid, cyclopropylmethyl, and 1-cyanobutyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, tert-butyl, n-pentyl, neopentyl, 1-cyanobutyl, propylthio and butylthio;
wherein at least one of R5, R6, R8 and R9 is an acidic group selected from CO2H, SH, PO3H2, SO3H, CONHNH2, CONHNSO2CF3, OH, , and wherein each of R42 and R43 is independently selected from C1, CN, NO2, CF3, CO2CH3 and SO2CF3, and wherein each of the remaining of R3 through R11 is hydrido;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

4. Compound of Claim 3 wherein m is one;
wherein R1 is selected from 2-oxo-2-(tricyclo[3.3.1.1.3.7]dec-1-yl)ethyl, 3-phenylpropyl, 2-oxo-2-phenylethyl, 2-hydroxy-2-phenylethyl, 1,1-dimethylethyloxycarbonylmethyl, hexyl, ethoxycarbonylmethyl, carboxymethyl, 1-naphthalenylmethyl, 2-cyclohexylethyl, pentyl, ethoxycarbonylmethoxyethyl substituted with phenyl, carboxymethoxyethyl substituted with phenyl, 3,5,5-trimethylhexyl, 1-benzoyl-2-phenylethyl, 1-oxobutyl, 2-(2,5-dimethyoxyphenyl)-2-oxoethyl, 2-phenyl-2-(phenylmethoxy)ethyl, 2-(2,5-dimethyoxyphenyl)-2-hydroxyethyl, 2-naphthalenylmethyl, methoxycarbonylbutyl, ethoxycarbonylethyl substituted with benzoyl, 1-benz?oyl-1-methylethyl, pentanoic acid, cyclopropylmethyl, and 1-cyanobutyl; wherein R2 is selected from ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 4-methylbutyl, n-pentyl, 1-cyanobutyl, propylthio and butylthio;
wherein R1 may be further selected as n-butyl when R2 is selected as 1-cyanobutyl; wherein each of R3, R4, R6, R7, R8, R10 and R11 is hydrido; wherein one of R5 and R9 is hydrido and the other or R5 and R9 is an acidic group selected from CO2H and ;

or a tautomer thereof or a pharmaceutically-acceptable salt thereof.

5. Compound of Claim 4 selected from compounds, and their pharmaceutically-acceptable salts, or the group consisting of 4'-[(1,3-dibutyl-4,5-dihydro-5-oxo-1H-1,2,4-triazol-4-yl)methyl][1,1'-biphenyl]-2-carboxylic acid;
5-butyl-2,4-dihydro-2-[2-oxo-2-(tricyclo[3.3.1.1.3.7]dec-1-yl)ethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4'-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4 dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;
5-butyl-2,4-dihydro-2-hexyl-9-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-acetate;
3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-aceric acid;
5-butyl-2,4 dihydro-2-(1-naphthalenylmethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-pentyl-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
ethyl [2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1-phenylethoxy]acetate;

[2-[3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-yl]-1-phenylethoxy]acetic acid;
5-butyl-2,9-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-2-(3,5,5-trimethylhexyl)-3H-1,2,4-triazol-3-one;

2-(1-benzoyl-2-phenylethyl)-5-butyl-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-(1-oxobutyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxphenyl)-2-oxoethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triaxol-3-one;
5-butyl-2,4-dihydro-2-[2-phenyl-2-(phenylmethoxy)ethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-[2-(2,5-dimethyoxyphenyl)-2-hydroxyethyl]-4-[2'-(1H-tetrazol-5-yl)[1,1'-'biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
5-butyl-2,4-dihydro-2-(2-naphthalenylmethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-bipheny1]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
methyl 3-butyl-4,5-dihydro-5-oxo-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoate;
ethyl b-benzoyl-3 butyl-4,5-dihydro-5-oxo-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-propanoate;
2-(1-benzyoyl-1-methylethyl)-5-butyl-2,4-dihydro-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;
3-butyl-4,5-dihydro-5-oxo-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid;

5-butyl-2-(cyclopropylmethyl)-2,4-dinyoro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one;

?and 1-butyl-4,5-dihydro-5-oxo-4-propyl-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-acetonitrile.

6. Compound of Claim 5 which is 5-butyl-2,4-dihydro-2-pentyl-4-(2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

7. Compound of Claim 5 which is 5-butyl-2,4-dihydro-2-hexyl-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

8. Compound oî Claim 5 which is 5-butyl-2-(2-cyclohexylethyl)-2,4-dihydro-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yimethyl]-3H-1,2,4-triazol-3-one.

9. Compound of Claim 5 which is 5-butyl-2-(cyclopropylmethyl)-2,4-dihyoro-4-[2'-(1H-tetrazol-5-yl)(1,1'-biphentl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

10. Compound of Claim 5 which is 1,1-dimethylethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H,2,4-triazol-1-acetate.

11. Compound of Claim 5 which is ethyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H1,2,4-triazol-1-acetate.

12. Compound of Claim 5 which is methyl 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-triazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazol-1-pentanoate.

13. Compound of Claim 5 which is 3-butyl-4,5-dihydro-5-oxo-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-1-pentanoic acid.

14. Compound of Claim 5 which is 5-butyl-2,4-dihydro-2-(3-phenylpropyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

15. Compound of Claim 5 which is 5-butyl-2,4-dihydro-2-(2-oxo-2-phenylethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

16. Compound of Claim 5 which is 5-butyl-2,4-dihydro-2-(2-hydroxy-2-phenylethyl)-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-3H-1,2,4-triazol-3-one.

17. A compound of the formula which is 1-butyl-4,5-dihydro-5-oxo-.alpha.-propyl-4-[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-acetonitrile.

18. A pharmaceutical composition comprising a thera-peutical-effective amount of an angiotensin II antagonist compound and a pharmaceutically acceptable carrier or diluent said antagonist compound selected from a family of compounds according to any of Claims 1 to 5.

19. Use of a compound according to any of Claims 1 to 5 for preparing a medicament for treating a circulatory dis order in a subject.

20. Use according to Claim 29 wherein said circulatory disorder is a cardiovascular disorder.

21. Use according to Claim 20 wherein said cardio-vascular disorder is hypertension.

22. Use according to Claim 20 wherein said cardio-vascular disorder is congestive heart failure.

23. Use of a compound according to any of Claims 1 to 5 for preparing a medicament for treating glaucoma.