CA2061607C - 1-biphenylimidazole derivatives, their preparation and their therapeutic use - Google Patents

Abstract

Compounds of formula (I):

(see fig. I) wherein R1 is alkyl or alkenyl; R2 and R3 are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl fused to cycloalkyl; R4 is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, totrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl tetrahydrofuryl, a group of formula -SiR a R b R c, in which R a, R b and R c are alkyl or aryl, alkoxymethyl, (alkoxyalkoxy)methyl, haloalkoxymethyl, aralkyl, aryl or alkanoyloxymethoxycarhonyl;
R5 is carboxy or a group of formula -CONR8R9, wherein R8 and R9 are hydrogen atoms or alkyl, or R8 and R9 together form alkylene; R6 is hydrogen, alkyl, alkoxy or halogen; R7 is carboxy or tetrazol-5-yl; and pharmaceutically acceptable salts and esters thereof have hypotensive activity and can be used for the treatment and prophylaxis of hypertension. They may be prepared, inter alia, by reacting a biphenylmethyl compound with an imidazole compound.

Description

DEMANDES OU BREVETS VOLUMINEUX

LA PRI~SENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMPREND PLUS C~'UN TOME.

CECI EST LE TOME / DE ~

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THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE
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M~C FOLIO: 64868/FP-9205 WANGDOC: 1622H

l-BlP~NYLMETHY~IMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE

Background to the Invention The pre~ent invention provides a ~eries of novel l-(biphenylmethyl)~m~zole derivatives havin~ valuable hypotensive activltie~, and which may, therefore, be u~ed in the treatment and prophylaxi~ of hypertension, lncluding di~ease~ o~ the heart and circulatory system We aleo provide methods and composition~ using these compounds, ac well as proces~es for their preparation It i8 known that the renin-angioteneion ~ystem provides one o~ the important mechani~ms ~or maintaining the homeo~ta~ls o~ blood pre~ure in living animal~
When blood pre~sure ic red~ce~ or the sodium ion concentration of the body ~luids ~alls, thls sy~tem i~
activated Ae a re~ult, the enzyme renin and anglotenein converting enzyme (hereina~ter abbreviated, ac ie conventlonal, ae ~ACB~) are activated and act on angioten~lnogen, which i~ irst decomposed by the renln to produce angiotenoln I (hereina~ter abbrevlated as "AI~) Thi~ AI i~ then converted by ACE to angiotensin II thereina~ter abbreviated a~ ~AII~) 9ince AII
~uce~ ~trong contractlonc Or blood vecsels and aacelerat-~ the cecretion o~ aldo~terone, the activation Or the cyctem re~ultc in an elevation o~ blood preeeuro Inhibltoro or ~u~re~cre Or the renln angloten~lon eyetem, ~uch as renln lnhlbitors, ACE
inhlbitorc and A~I~antagonletc, dilate blood ve~els, cauee lower blood proeeure and lmprove the circulatory runctlon, whlch le the bael~ rOr the uee o~ theee agente in the treatment o~ heart dl~ea~ec .

.: , . :., At pre~ent only ACE inhibitor~ are used clinically, although renin inhibitors and AII antagoni~ts are under inve~tigation for such use. Of these, some peptide type AII antagonist~, such as saralasin, have been known for ma~y years, whilst certain non-peptide type antagonist~
have recently been discovered (for example, European Patent Publlcations No. 28 833, 28 834, 245 637, 253 310, 323 841, 324 377, 380 959, 399 732, 399 731 and 400 835 a~d in ~p~nPse Patent Application Kokai No. Sho 57-98270). Of theoe, the clooest prior art i5 believed to be European Patent Publications No. 253 310 and 324 377.

~ uropean Patent Publication No. 253 310 di~clooes a oerieo o~ l-phenyl, l-phenethyl or l-benzyl imidazole derlvativeo whlch are caid to have the abllity to inhiblt the activity of AII. Included in the acope of theoe prior art compounde are a number Or l-blphenyl-methylimidazole derivativeo, which, however, dl~er ~rom the compoundo o~ the preoent inventlon ln the nature o~
the ~ubotltuent at the lmldazole 4- or 5- posltion.

~ uropean Patent Publicatlon No. 324 377 also dl~clococ a cerlee o~ ~uch compoundo. The actlvltiec o~
all o~ the~e prlor art compounde, however, lncludlng thoee o~ Buropean Patent Publicatlone No. 253 310 and 324 377, are not ou~iclent and more potent AII
antagoni~ts aro oought ~or better clinical results.

We have now dlocovered a llmited oerlee o~
l-~blphenylmethyl)lm~a~ole-5-carboxyllc acid dorlvatlvoe having an excellent AII receptor antagonist actlvlty, and whlch aro thererore uoe~ul ao anti~
hyportonoivo drugo and ~or the therapy and prophylaxl~
o~ heart dioeacoo.

' "'' ' ' , 1 6 2 ~

Brief Summary of Invention It i9, therefore, an object of the present invention to provide a series of new l-(biphenylmethyl)imidazole-S-carboxylic acid derivatives.

It 19 a further object of the invention to provide such compound~ having AII inhibitory activity.

Other ob~ects and advantages of the present invention will become apparent as the description proceedc.

Thu~, the pre~ent invention provides compounds of formul~

~ R3 S~2 ~R7 ~4 , , " :' ' ' ~, .

wherein:

Rl represents an alkyl group having from 1 to 6 carbon atoms or an alkenyl group having from 3 to 6 carbon atom~;

R2 and R3 are independently selected from the group consisting of:
hydrogen atoms;
alkyl group~ having from 1 to 6 carbon atoms;
alkenyl groups having from 3 to 6 carbon atoms;
cycloalkyl groups having a total of from 3 to lO
carbon atoms ln one or more saturated carbocyclic ringe;
aralkyl groups in which the alkyl part has from 1 to 6 carbon atoms and the aryl part i~ a~ defined below;
aryl groupc ac defined below; and fu~ed rlng sy~teme in which an aryl group, as defined below, is fu~ed to a cycloalkyl group havlng from 3 to lO carbon atoms;

R4 repr2~0ntc:
a hydrogen atom;
an alkyl group having from 1 to 6 carbon atoms;
an alkanoyl group having from 1 to 6 carbon atoms;
a cubctltuted AlkAnoyl group having from 2 to 6 c~rbon atom~ and cubctituted by at lea~t one cub~tltuent ~elected ~rom the group con~isting of halogen atom~ and alkoxy groupc having rrom 1 to 6 carbon atom~;
an a lke~oyl group having from 3 to 6 carbon atoms;
an arylcarbonyl group ln whlch the aryl part i9 a9 d0~1ned below;
an alkoxycarbonyl group ln whlch the alkyl part ha~
~rom 1 to 6 carbon atome;
a tetrahydropyranyl, tetrahydrothlopyranyl, tetra-hydrothienyl or tetrahydrofuryl group;

a ~ub~tituted tetrahydropyranyl, tetrahydrothio-pyranyl, tetrahydrothienyl or tetrahydrofuryl group which is ub~tituted by at least one sub~tituent selected from the group consisting of halogen atoms and alkoxy groups having from 1 to 6 carbon atoms;
a group of fonmula -SiRaRbRC, in which 1, 2 or 3 of the groups represented by Ra, Rb and Rc are independently selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, and 2, 1 or O of the groups represented by Ra, Rb and Rc are independently selected from the group consisting of aryl groups, as defined below;
alkoxymethyl group~ in which the alkoxy part has from 1 to 6 carbon atoms;
(alkoxyalkoxy)methyl groups in which each alkoxy part ha~ from 1 to 6 carbon atoms;
haloalkoxymethyl groups in whlch the alkoxy part has from 1 to 6 carbon atom~;
aralkyl group~, in whlch an alkyl group havlng ~rom 1 to 6 carbon atom~ ub~tituted by at least one aryl group, a~ de~lned below; or ~lk~noyloxymethoxycarbonyl group~ ln whlch the alkanoyl part ha~ rrOm 1 to 6 carbon atoms;

R5 Le~ca0nt~ a carboxy group or a group Or ~ormula -CONR8R9, whereln R~ and R9 are independently ~elected ~rom the group con~istlng Or hydLog~n atoms, un~ub~tituted alkyl group~ havlng ~rom 1 to 6 carbon atom~, and ~ub~tltuted alkyl group~ whlch have rrom 1 to 6 carbon atomc and whlch are ~ub~tltuted by at least one sub~tltuent ~elected ~rom the group conslYtlng o~ ~ubstltuents ~a), de~lned below, or R8 and R9 together repre~ent an un~ubstltuted alkylene group havlng ~rom 2 to 6 carbon atom~ or a sub~tituted alkylene group whlch hac rrOm 2 to 6 carbon , ' ', , . .' , . . :, , ,, ~ , , ,: . ,:. . - .:.

atoms and which i~ substituted by at least one ~ubstituent ~elected from the group consisting of carboxy group~ and alkoxycarbonyl group~ in which the alkyl part has from 1 to 6 carbon atoms;

R6 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atom~ or a halogen atom;

R7 represents a carboxy group or a tetrazol-5-yl group;

~aid ~ubstituents (a) are selected from the group consisting of:
aryl groups as defined below;
heterocyclic group~ having 5 or 6 ring atoms, of whlch ~rom 1 to 4 are hetero-atom~ selected from the group con~isting of nitrogen, oxygen and sulfur atoms;
halogen atoms;
hydroxy groupc;
alkoxy group~ having ~rom 1 to 6 carbon atoms;
carboxy groupc alkoxycarbonyl g.oupe ln whlch the alkyl part ha3 rrOm l to 6 carbon atomc;
amino groupe; and acylamlno groupe, ln whlch the acyl part i9 an Alkanoyl group havlng rrOm 1 to 6 carbon atoms or an arylcarbonyl group, ln whlch the aryl part i~ as derlned below;

~aid aryl groupc aro aromatlc carbocyclic groupc which havo rrOm 6 to 14 ring atome and whlch are un~ub~tituted or are cub~tltuted by at lea~t one cubctituent ~elected ~rom the 0roup con81~tlng o~ eubctltuent~ (b), de~ined below; and sald cubstltuonto (b) are colocted ~rom the group , I ~ 2 2 20~1607 consisting of nitro groups, cyano groups, halogen atoms, unsubstituted carbocyclic aryl groups having from 6 to 10 ring atoms, alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atomq, carboxy group~, alkoxycarbonyl groups in which the alkoxy part has from 1 to 6 carbon atoms and alkylenedioxy and alkylidene- dioxy groups having from 1 to 3 carbon atomq;
and phArm~ceutically acceptable salt~ and esters thereof.

The invention also provide~ a pharmaceutical compositlon for the treatment or prophylaxls of hypertenslon, which comprisee an effective amount of an anti-hyperteneive agent in ~ 'Yture wlth a ph~rm~ce~ltically acceptable carrier or diluent, wherein the anti-hypertensive agent ie selected from the group consi~ting o~ compounds o~ ~ormula (I) and p~Arm~ceutlcally acceptable salts and ester3 thereof.

The inventlon ~urther provide~ a method for the treatment or prophylaxls o~ hypertenelon ln a mammal, e.g. a human being, which comprleee ~m~n~sterlng an effectlve amount o~ an antl-hyperten~lve agent to said mammal, wherein the antl-hypertenclve agent 19 eelected ~rom the group coneietlng of compounde o~ ~ormula (I) and pharm.~ceutlcally acceptable ealte and e~tere thereof.

The lnvention etill ~urther provldes proce~ec for the preparation o~ compound~ o~ ~ormula (I) and pharr.~coutlcally acceptable ealt~ and estere thereor, whlch are deccribed ln more detall herea~ter.
De~Ail~De~cri~tl~n o~ InV~nti~

In the compound~ o~ the pre~ent invention, where Rl R2 R3 R4 R6 Ra R9 or 8ubetituent . .
, . , ' : ' ' , ' .
'' ., ~ ~ ' .:
~ ' ' '' , :, (b) i9 an alkyl group, this is an alkyl group having from 1 to 6 carbon atom~, and may be a straight or br~nehed chain group having from 1 to 6 carbon atom~;
example~ include the methyl, ethyl, propyl, i~opropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t- pentyl, 2-methylbutyl, 3-methylbutyl, l-ethylpropyl, 4-methyl-pentyl, 3-methylpentyl, 2-methylpentyl, l-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, l,l-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl group~. Rl preferably represents a straight or br~nche~ chain alkyl group conta~ntn~ from 2 to 5 carbon atom~, and more pre~erably a straight chain group, i.e. most preferably an ethyl, propyl or butyl group. Each of R and R , whlch may be the same or different, preferably repre~ents a etraight or brAnche~ chain alkyl group contAln~ng ~rom 1 to 4 carbon atoms, more preferably a methyl, ethyl, propyl, 19GPrO~1 or t-butyl group, and most preferably a methyl or ethyl group when R5 Lsp~e~onts a carboxy group, or an leopropyl or t-butyl group when R5 rapLe~ente a group of formula -CoNR9R9. R4 or R6 preferably represents a etraight or brAn~hed chaln alkyl group contA1n~n~ from 1 to 4 carbon atomo, more prererably a methyl or ethyl group. Where R~ and R9 are alkyl groups, these may be the eame or dlfrerent, and each 19 pre~erably an alkyl group co~t~ln1ng from 1 to 4 carbon atom~, more pro~orably a methyl, ethyl, propyl or butyl group, and moet pre~erably a methyl or ethyl group. In the caee of subetituent (b), when thi~ re~ente an alkyl group, it preferably hae rom 1 to 4 carbon atoms, and the methyl and ethyl grou~ are more preferred.

Where Rl, R2 and R3 ~ d~ent~ an alkenyl group, thl~ may be a stralght or brAnche~ chaln alkenyl group cont~ln~ng ~rom 3 to 6 carbon atom~. Bxample3 o~
~uch group~ lnclude: the l-propenyl, 2-propenyl, ~. , f~

9 20~16~7 1-methyl-2-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, l-butenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, l-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4~hexenyl and 5-hexenyl groups. R1 preferably represents a etraight or br~nche~ chain alkenyl group cont~n~ng 3 or 4 carbon atom~, and more preferably a 1-propenyl or 1-butenyl group. 2ach oS R2 and R3, which may be the same or di~ferent, preferably represente a straight or br~nche~ chaln alkenyl group cont~n~ng 3 or 4 carbon atome, and more preferably a 2-propenyl or 2-butenyl group.

Where R2 or R3 represente a cycloalkyl group, thle hae a total o~ ~rom 3 to 10 carbon atome in one or more eaturated carbocyclic ringe, and the or each rlng pre~erably hae ~rom 3 to 6 c3rbon atoms. Where the group le a multiple ring eystem, thie may be a bridged or ~used rlng ayetem. ~xamplee o~ such groupe include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, no~boL.~rl and adamantyl groupe. 0~ theee, we pr-Ser thoee groupe havlng from 3 to 6 carbon atoms in a alngle rlng, and moet pre~er the cyclopentyl and cyclohexyl groupo.

Altornatlvoly, R2 or R3 may LapLssent an aralkyl group, ln whlch the alkyl part hao ~rom 1 to 6 (more pre~orably ~rom 1 to 4, etill more prererably 1 or 2, and moot pre~erably 1) carbon atome and the aryl part i8 an aromatlc carbocyclic groupe which hao ~rom 6 to 14 ~pro~erably ~rom 6 to 10, and more pre~erably 6 or 10) rlng atomo and which le uneubetltuted or ie eubetltuted - 10 - 20616~7 by at lea~t one ~ubstituent Relected from the group con~i~ting of ~ubstituent~ (b), defined above and exemplified below. Specific examples of alkyl yroups which may form the alkyl part are a~ given above in relation to the alkyl groups which may be repre~ented by R2, and specific examples of the aryl group~ which may form the aryl part are as given below in relation to the aryl group~ which may be repres~nted by ~ . Example~
of ~uch aralkyl groups include the benzyl, 1- and 2-naphthylmethyl, indenylmethyl, phen~nthrenylmethyl, anthracenylmethyl, diphenylmethyl, triphenylmethyl, l-phenylethyl, phenethyl, l-naphthylethyl, 2-naphthyl-ethyl, l-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, l-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, l-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenyl-butyl, l-nAphthylbutyl, 2-n~ph~hylbutyl, 3-n~hthyl-butyl, 4-naphthylbutyl, l-phenylpentyl, 2-phenylpentyl, 3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, l-naphthylpentyl, 2-nArh~hylpentyl, 3-naphthylpentyl, 4-nA~hthylpentyl, 5-naphthylpentyl, l-phenylhexyl, a -phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenyl-hexyl, 6-phenylhexyl, l-~pht~ylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5-na~hthylhexyl and 6-naphthylhexyl groupe. In thoee casee where the ~ralkyl group cont~nP a ~hthyl group, thie may be a 1- or 2- na~hthyl group. 0~ theee aralkyl groups, we pre~er thoee groupe ln which the alkyl part hae rrom 1 to 4 C~rhQn atom~, the benzyl group belng moet prof-rred. ~he~e groupe may be uneubctltuted or they may be eubetltuted by one or more Or ~ubetituents ~b), derin0d abovo and oxempll~led below. Examplee o~ the ~ubotltuted groupo lnclude thooo uneubtltuted groups exempllrled above but in whlch the aryl part le replaced by ono Or the oubetltuted aryl groupe glven below.
~owever, the uneubtltuted groupe are pre~erred.

Where R2 or R3 repL2sente an aryl group, thie 19 ., .. , - ' .

- 11 - 20616~7 an aromatic carbocyclic group which haa from 6 to 14 (preferably from 6 to 10, and more preferably 6 or lo) ring atoms and which is unsubstituted or ia ~ubstituted by at least one ~ubstituent ~elected from the group consisting of aubstituents (b), defined above and exemplified below. Such groups may be unsubtituted or they may be sub~tituted by at least one, and preferably from 1 to 3, of substituents (b), for example:
nitro group~;
cyano groups;

halogen atoma, such aa the fluorine, chlorine, bromine or iodlne atom~, of which the fluorine, chlorine and bromine atom~ are preferred;

unsubatituted carbocyclic aryl group~, e.g. aa exempli~ied below in relation to R2 and R3;

alkyl groupa, aa exemplified above, mo0t pre~erably the methyl group;

alkoxy groupe havlng ~rom 1 to 6, pre~erably ~rom 1 to 4, carbon atom~, auch a~ the methoxy, ethoxy, propoxy, i~opL~G~, butoxy, l~obutoxy, ~ec-butoxy, t butoxy, pentyloxy, neopentyloxy, 2-methylbutoxy, 3-methylbutoxy, 1-ethyl~ro~G~y, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dlmethyl-butoxy, 2,2-dlmethylbutoxy, l,1-dimethyl~utoxy, 1,2-dimethylbutoxy, 1,3-dlmethylbu~oxy, 2,3-dimethyl-butoxy, 2~ethylbutoxy, hexyloxy and isohexyloxy groups, mo~t pre~erably a methoxy or ethoxy group;
.r.
alkoxycarbonyl groupc in which the alkoxy part ha~ ~rom 1 to 6, pre~erably ~rom 1 to 4, carbon atomc, ~uch as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, - 12 - 20~ 7 isopropoxycarbonyl, butoxycarbonyl, i~obutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl group~, of which the methoxycarbonyl and ethoxycarbonyl groups are most preferred;
carboxy group~;

alkylenedioxy and alkyli~ne~1oxy groups having from 1 to 3 carbon atoms, for ~ ~e the methylenedioxy, ethylenedioxy, propylenedioxy, trimethylenedioxy, ethyli~ne~oxy and isopropyli~ene~1oxy group~, of which the methylenedioxy group i~ most preferred.

or these, the alkyl and alkoxy sub~tituents are pre~erred where R2 or R3 represents a substituted aryl group.

Where the group 1Y sub~tituted, the number of substituent0 i~ not critical, and 19 only limited by the number o~ ~ub~titutable pocltions, and po~ibly by ~terlc con~traint~. ~owever, ln practlce, we normally pre~er 1, 2 or 3 ~ub~tituent~.

~ xample~ o~ ~ubctituted and un~ubstituted aryl group~ lnclude the phenyl, ~A~hthyl, phsnAnthrenyl, anthrAcenyl, 2-methylphenyl, 3-methylphenyl, 4-methyl-phenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4 pentylphenyl, 3,5-dlmethylphonyl, 2,5-dlmethylphenyl, 2,6-dimethyl-phenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dlpropyl-4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-p~vpo~yphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentyloxyphenyl and 4-pentyloxyphenyl groupe, o~ which the phenyl, 2-methylphenyl, 3-methyl-phenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl groups are the mo~t pre~erred.

Where R or R3 repre~ent~ a ~used ring sy~tem in which an aryl group i9 fu~ed to a cycloalkyl group having from 3 to 10 carbon atom~, the aryl and cycloalkyl part~ may be as exemplified above, and preferably the aryl part i9 a phenyl or naphthyl group, and the cycloalkyl part has 5 or 6 carbon atom~.
Examples of ~uch fused ring systems include the indanyl, tetrahydronaphthyl and tetrahydroanthryl groups, of which the indanyl and tetrahydronaphthyl groups are preferred R4 can repre~ent an alkanoyl group; such a group may be a straight or br~nche~ chain group and has from 1 to 6 carbon atoms. ~xamples of such groups include the ~ormyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and isovaleryl groups, of which the ~ormyl and acetyl groups are preferred.

Alternatlvely, R4 may be a substituted alkanoyl grou~ ln which the substituent or substituents i9 or are selected ~rom the group conclcting o~ the halogen atoms and the alkoxy groups. Examples o~ such substituted ~1 k~royl groups lnclude the chloroacetyl, dlchloro-acetyl, trichloroacetyl, trl~luoroacetyl and methoxy-acetyl groups, Or which the chloroacetyl and trl~luoro-acetyl groups are prererred.

Where R4 repreoent~ an A lkPnoyl group, this may have ~rom 3 to 6, pre~erably rrOm 3 to 5, carbon atoms, and examplec lnclude the acryloyl, methacryloyl, crotonoyl, 3-methyl-2-butenoyl and 2-methyl-2-butenoyl, e~poclally ~a)-2-mothyl-2-butenoyl, group~.

Where R4 répre~ent~ an arylcarbonyl group, the aryl part may be any o~ tho~e aryl group~ exampll~ied above in relatlon to R2. However, in thl~ case, 1 the group 1~ ~ubctltuted, the ~ubctituents are - , .

2 ~ 7 preferably ~elected from the group consisting of halogen atoms, alkyl groups, alkoxy groups, nitro groups, alkoxycarbonyl groups and unsubstituted aryl group~, more preferably the methyl, methoxy, fluoro and chloro sub~tituents. Examples of the arylcarbonyl groups include the benzoyl, a - naphthoyl, ~-naphthoyl, 3-fluorobenzoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitro-benzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl and 4-phenylbenzoyl groups, of which the benzoyl, 4-toluoyl, and 4-anieoyl groups are preferred.

Where R4 represents an alkoxycarbonyl group, the alkoxy part hae from 1 to 6 c~rhon atoms, i.e. the group ae a whole hae from 2 to 7 carbon atoms, and examples of such groupe include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxyc~rbQ~yl, butoxycarbonyl, leobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl group~, o~ which the methoxy-carbonyl and ethoxycarbonyl y~OUy~ are preferred.

Where R4 reprecente a tetrahydropyranyl, tetra-hydrothlopyranyl, tetrahydrothlenyl or tetrahydro~uryl group, thie may be eubetituted or uneubetltuted. If eubetltuted, the eubetituente are eelected from the group con~lstlng o~ halogen atome and alkoxy groups having ~rom 1 to 6 cArho~ atome, whlch may be any o~
tho~o group~ and atom~ exempll~led abo~e in relation to R4, pre~erably the chloro, bromo and methoxy eubetltuente. Bxam~lee o~ theee eubetltuted and uneubetituted groups lnclude the tetrahydropyran-2-yl, 3-chlorotetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-mothoxytetrahydropyran-2-yl, tetrahydrothlo-pyran~2-yl, 4-mothoxyEetrahydrothlopyran-2-yl, tetra-hydro~uran-2 yl and tetrahydrothlen-2-yl groupe, o~
whlch tho tetrahydropyran-2-yl, 4-methoxytetrahydro-pyran-2-yl, tetrahydrothlopyran-2-yl and 4-methoxytetra-20bl607 hydrothiopyran-2-yl groups are preferred.

Where R4 represent~ a silyl group of formula -SiRaRbRC, in which 1, 2 or 3 of the groups represented by Ra, Rb and Rc are independently ~elected from the group con~isting of alkyl groups having from 1 to 6 carbon atom~, and 2, 1 or 0 of the group~ represented by Ra, Rb and Rc are independently ~elected from the group consisting of aryl groups, as defined above, the alkyl and aryl parts may be any o~ those groups exemplified above in relation to Rl and R2, preferably the methyl, ethyl, t-butyl and phenyl groups. ~xamples of such 5ilyl group~ include the trimethyl~ilyl, triethylsilyl, isopropyldimethyl-5ilyl, t-butyldimethylsilyl, methyldiisopropyl~ilyl, methyldi-t-butylsilyl, trii30propylsilyl, diphenyl-methyl~ilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiieopropyl~ilyl ~ o~p~, o~ which the trimethyl~ilyl, t-butyldimethyl~ilyl and diphenylmethyl-9ilyl groupc are prererred.

Where R4 repre~ents an alkoxymethyl group in which the alkoxy part ha~ ~rom 1 to 6 carbon atom~, the alkoxy part may be any o~ the alkoxy groups exempllfied above ln relatlon to ~ubetltuents (b). Examples of such alkoxymethyl group~ lnclude the methoxymethyl, l,l-dimethyl-l-methoxymethyl, ethoxymethyl, propoxy-methyl, icoproQo~methyl, butoxymethyl and t-butoxy-methyl yro~p~, of whlch the methoxymethyl and ethoxy-methyl yLo~ are pre erred.

Whero R ~e~recentc an ~alkoxyalkoxy~methyl group, each alkoxy part hae ~rom 1 to 6 carbon atoms and may be any o~ the alkoxy groupc exempll~ied above in relation to substltuentc (b). examplee o~ such (alkoxyalkoxy)-methyl group~ lnclude the methoxymethoxymethyl, 2-methoxyethoxymethyl, 2-methox~Lu~o~ymethyl and 20~1607 2-methoxybutoxymethyl groups, of which the 2-methoxy-ethoxymethyl group is preferred.

Where R repre~ents a haloalkoxymethyl group, the alkoxy part has from 1 to 6 carbon atoms and the halogen atoms and alkoxy groups may be any of the atoms and groups exemplified above in relation to substituents (b). Examples of such haloalkoxymethyl groups include the 2,2,2 trichloroethoxymethyl, 2,2,2-tribromoethoxy-methyl, bis(2-chloroethoxy)methyl and bis(2-bromo-ethoxy)methyl group~, of which the 2,2,2-trichloro-ethoxymethyl and bis(2-chloroethoxy)methyl groups are preferred.

Where R4 represent~ an aralkyl group, in which an alkyl group having from 1 to 6, preferably from 1 to 4, carbon atoms i9 sub~tituted by at least one aryl group, the alkyl and aryl part~ may be any of the alkyl and aryl group3 exemplified above in relation to Rl and R2. Examplec o~ ~uch aralkyl groupe include the benzyl, a - naphthylmethyl, ~-n~p~thylmethyl, dlphenylmethyl ~benzhydryl), trityl, ~-naphthyl-diphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 6-phenylhexyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethyl-benzyl, 4-methoxybenzyl, 4-methoxyphenyldlphenylmethyl, 2-nltrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromo-benzyl and 4-cy~nAhenzyl groupe, o~ whlch the benzyl, 4~methylbenzyl, 4-metho~Lanzyl, 4-chlorobenzyl and 4 bromobenzyl groupe are pre~erred.

Whore R4 L~Lecc.-to an Al~noyloxymethoxycarbonyl group, the ~lk~noyl part hac ~rom 1 to 6 carbon atoms and may be any or the alk~noyl groupc exemplirled above in relation to R4. ~xampleo Or cuch A~t~noyloxy-mothoxycarbonyl groupe lnclude the rormyloxymethoxy-carbonyl, acetoxymethoxycarbonyl, proplonyloxymethoxy-c~rho~yl, butyryloxymethoxycarbonyl and plvaloyloxy-20~1607 methoxycarbonyl groups, of which the pivaloyloxymethoxy-carbonyl group is preferred.

R5 represents a carboxy group or a group of formula -CONR8R9. Where it represents a group of formula -CO~R~R9, and R8 or R9 represents an alkyl group, thi~ may be an unsub~tituted alkyl group having from 1 to 6 carbon atom~, such as tho~e ~roups exemplified above, or a ~ub~tituted alkyl group, which has from 1 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consieting of substituents (a), defined above and exemplified below.

Where R8 and R9 together represent an alkylene group, thie has from 2 to 6 carbon atoms and may be ~ub~tituted or uncub~tituted; it may also be a etraight or br~nched chaln group. ~xamples Or the unsubstituted groups include the ethylene, trimethylene, propylene, ethylethylene, tetramethylene, pentamethylene and h~Yamsthylene groupc, o~ which those group~ containing 4 or 5 carbon atoms are pre~erred. In such cases, the group o~ ~ormula -NRaR9 lc a nltrogen-contAin~rg heterocycllc group having ~rom 3 to 7 rlng atoms ~one belng the nitrogen atom), ~or example, when the alkylene group contaln~ 4 or 5 carhon atome, lt 1~ a l-pyrrolldinyl or plperldino group, re~pectlvely. Where ths group io cub~tituted, thore may be one or more ~ubctituente celected rrOm the group consicting o~
carboxy groupc and al~oxycarbonyl groups in which the alkoxy part ha~ ~rom 1 to 6 carbon atoma. Examples Or cuch ~ubctituentc lnclude the carboxy, methoxycarbonyl, ethoxycarbonyl, ~Lo~oxycarbonyl, butoxycarbonyl, i~obutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and hoxyloxycarbonyl groupc, Or whlch the carboxy, methoxyarbonyl and ethoxycarbonyl group~ are pxe~erred.

.. .. .

~ 5 2 2 Where R5 represents a carboxy group, the compound is a carboxylic acid and can, therefore, form esterR, in which the carboxy group represented by R5 is replaced by a group of formula -CooR5a~ in which R5a represents an ester residue (in the case of the carboxylic acid, R5a represents a hydrogen atom). It can also fonm salts, examples of which are as exemplified below in relation to R7. The nature of the ester 90 formed i~ not critical to the invention, except where the ester is to be used for pharmaceutical purposes, in whlch case it should be pharmaceutically acceptable, i.e. it should not have increased, or unacceptably increased, toxicity or reduced, or unacceptably reduced, activity, as compared with the parent acld. ~owever, where the ester i~ to be used for other purpose~, e.g. a~ interm~ tes for the preparation of other, and perhaps more active, compounds, even thls restriction doe~ not apply, and any ecter residue common in the art may be used and may be eelected on the basis of itc functionality and commercial advantage~. However, it i9 well known in the art that certain e~ter re~ldues confer advantages on compound~ lncorporating them, ~or example ea~ier or better ab~orption 1~ vlvo, and, lf desired, euch ester residuee may be used in the present inventlon.
~ xample~ o~ ~uch ester residues include:

alkyl groupe having ~rom 1 to 6 carbon atom~, ~uch a3 thoee exempli~led above in relatlon to Rl;

haloalkyl groups having ~rom l to 6, pre~erably from 1 to 4, carbon atomc, in which the alkyl part may be a~
exempli~led above in relation to Rl, ~or example the ~-r tri~luoromethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoro-ethyl, 2-chloroethyl, 2-~luoroethyl, 2-iodoethyl, ~-fluorobutyl, 3-chloropropyl and 6-io~oh~xyl group~, of " , .

19- 20~16Q7 which the 2,2,2-trichloroethyl and 2-chloroethyl groups are preferred;

hydroxyalkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, in which the alkyl part may be as exemplified above in relation to Rl, for example the 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and 4-hydroxybutyl groups, of which the 2-hydroxyethyl group is preferred;

alkoxyalkyl and alkoxyalkoxyalkyl groups in which the alkoxy and the alkyl parts each have from 1 to 6, preferably from 1 to 4, carbon atoma, and may be as exemplified above in relation to substituents (b) and Rl, reepectively, for example the methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl and 2-methoxyethoxymethyl groups, of whlch the methoxymethyl group is preferred;

ph~nAcyl groups and phPn~cyl groups whlch are sub~tltuted by one or more of substltuents (b), o~ which the unsub~tituted phe~cyl group is preferred;

alkoxycarbonylalkyl groups, such as the methoxy-carbonylmethyl group;

cy~no~lkyl groups having from 1 to 6, preferably from 1 to 4, carbon atoms, in which the alkyl part may be as exempli~led above in relatlon to R1, ~or example the ~cyanoethyl and cyanomethyl groups;

alkylthloalkyl groups ln whlch each alkyl part has ~rom 1 to 6, prererably ~rom 1 to 4, carbon atom~, and may be a~ exempllried above in relation to R1, ~or example the methylthiomothyl and ethylthlomethyl;

arylthioalkyl group~ in which the alkyl part has ~rom 1 to 6, prer~rably ~rom 1 to 4, carbon atom~, and may be ': ' ' ', ', .

r, . .

as exemplified above in relation to Rl, and the aryl part may be a~ defined and exemplified above in relation to R2, for example the phenylthiomethyl group;

alkylsulfonylalkyl group~ in which each alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms, and may be a~ exemplified above in relation to Rl and may be unsubstituted or substituted by one or more halogen atom3, for example the 2-(methanesulfonyl)ethyl or 2-(trifluoromethaneYulfonyl)ethyl groups;

arylsulfonylalkyl groups in which the alkyl part has ~rom 1 to 6, preferably from 1 to 4, carbon atoms, and may be as exemplified above in relation to Rl, and the aryl part may be a~ defined and exemplified above in relation to R2, for example the 2-(benzene~ulfonyl)-ethyl and 2-(2-toluene~ulfonyl)ethyl groups;

aryl group~ such ae tho~e exempli~led above in relation to R2;

aralkyl group~ such a~ those exampll led above in relation to R2, e~peclally the benzyl, ~-methoxy-benzyl, ~-nitrobenzyl and 4-acetoxy-3-methoxybenzyl group~, o~ whlch the benzyl group 1~ pre~erred;

groupc o~ formula -SiRdReR~ (in whlch Rd, Re and ~f are ae de~lned above ln relatlon to Ra, Rb and RC), such as thoeo exempll~led above ln relatlon to R4;

~lkanoyloxyalkyl groupe in whlch each o~ the alkanoyl and the alkyl part~ ha~ from 1 to 6 carbon atoms and may bo ac exemplirled above in relatlon to Rl and R4, re~pectlvely, and pre~erably the Alk~noyl part has ~rom 1 to 5 carbon atom~ and the alkyl part ha~ ~rom 1 to 4 carbon atomc and more pre~erably the alkanoyl part ha~
~rom 2 to 5 carbon atom~ and alkyl part ha~ ~rom 1 to 2 .

, ~

carbon atoms; example~ of ~uch alkanoyloxyalkyl groups include the formyloxymethyl, acetoxymethyl, propionyl-oxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryl-oxymethyl, isovaleryloxymentyl, h~x~noyloxymethyl, l-(formyloxy)ethyl, l-(acetoxy)ethyl, l-(propionyloxy)-ethyl, l-(butyryloxy)ethyl, l-(pivaloyloxy)ethyl, l-(valeryloxy)ethyl, l-(i~ovaleryloxy)ethyl, l-(hex~noyloxy)ethyl, 2-(formyloxy)ethyl, 2-(acetoxy)-ethyl, 2-(propionyloxy)ethyl, 2-(butyryloxy)ethyl, 2-(pivaloyloxy)ethyl, 2-(valeryloxy)ethyl, 2-(isovaleryloxy)ethyl, 2-(hPYAnoyloxy)ethyl, l-(formyl-oxy)propyl, l-(acetoxy)propyl, l-(propionyloxy)propyl, l-(butyryloxy)propyl, l-(pivaloyloxy)propyl, l-(valeryl-oxy)propyl, l-(isovaleryloxy)propyl, l-(hPYanoyloxy)-propyl, l-(acetoxy)butyl, l-(propionyloxy)butyl, l-(butyryloxy)butyl, l-(pivaloyloxy)butyl, l-(acetoxy)-pentyl, l-~propionyloxy)pentyl, l-(butyryloxy)pentyl, l-(pivaloyloxy)pentyl and l-(pivaloyloxy)hexyl groups, preferably the formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, plvaloyloxymethyl, l-(~ormyloxy)ethyl, l-(acetoxy)ethyl, l-(proplonyloxy)-ethyl, l-(butyryloxy)ethyl and l-(pivaloyloxy)ethyl groups, and more pre~erably the acetoxymethyl, proplonyloxymethyl, butyryloxymethyl, plvaloyloxymethyl, l-(acetoxy)ethyl, l-(propionyloxy)ethyl, l-(butyryl-oxy)ethyl and l-(pivaloyloxy)ethyl group~ and most pre~erably the plvaloyloxymethyl and l-(pivaloyloxy)-othyl groups;

cycloalkanoyloxyalkyl group~ ln whlch the cycloalkyl part has 5 or 6 carbon atom~ and the alkyl parte ha~
~rom 1 to 6 carbon atoms, each as exem~ led above in relation to R2; pre~erably the al~yl part ha~ rom 1 to 4 carbon atoms and more prererably 1 or 2 carbon atoms; example~ o~ such cycloalkanoyloxyalkyl groups lnclude the cyclopentanoyloxymethyl, cyclohe~Anoyl-oxymethyl, l-(cyclopentanoyloxy)ethyl, l-~cyclo~exanoyl-, ., , . , ; ~ ' ;
, .
~' ' ' . ' . ,'.:.
.

~ 6 2 2 - 22 - 20~1607 oxy)ethyl, l-(cyclopentanoyloxy)propyl, l-(cyclo-h~xAnoyloxy)propyl, l-(cyclopentanoyloxy)butyl and l-(cyclohPx~noyloxy)butyl, groups, preferably the cyclopentanoyloxymethyl, cyclsh~Anoyloxymethyl, l-(cyclopentanoyloxy)ethyl, and l-(cyclohexanoyloxy)-ethyl groups;

alkoxycarbonyloxyalkyl groups in which each of the alkoxy and the alkyl partY has from 1 to 6 carbon atoms aq exemplified abo~e in relation to eubstituents (b) and Rl, recpectively, and preferably each of the alkoxy and the alkyl parts has from 1 to 4 carbon atoms and more preferably the alkoxy part has from 1 to 4 carbon atoms and alkyl part has from 1 to 2 carbon atoms;
example~ of ~uch alkoxyc~rbonyloxyalkyl group~ include the methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, y-upo~ycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, i~obutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, l-~methoxycarbonyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl, l-~yLopoxycarbonyloxy)ethyl~ opropoxycarbonyloxy)-ethyl, l (butoxycarbonyloxy)ethyl, l-(isobutoxycarbonyl-oxy)ethyl, l-(pentyloxycarbonyloxy)ethyl, l-(hexyloxy-carbonyloxy)ethyl, 2-(methoxycarbonyloxy)ethyl, 2-~ethoxycarbonyloxy)ethyl, 2-~yropûxycarbonyloxy)ethyl, 2 ~i~GyLupu~ycarbonyloxy)ethyl~ 2-(butoxycarbonyloxy)-ethyl, 2-(isobutoxycArbQnyloxy)ethyl, 2-(pentyloxy-carbonyloxy)ethyl, 2-(hexyloxycArbo~yloxy)ethyl, l-~methoxycarbonyloxy)propyl, l-~ethoxycarbonyloxy)-propyl, l-~oQG~carbonyloxy)propyl, l-(l~opropoxy-c~rbo~yloxy)propyl, l-(butoxycarbonyloxy)propyl, l-~lsobutoxycarbonyloxy)propyl, l-~pentyloxycarbonyl-oxy)propyl, l-~hexyloxycarbonyloxy)propyl, l-(methoxy-carbonyloxy)butyl, l-(ethoxycArbonyloxy)butyl, l-~p~u~o~ycarbonyloxy)butyl, l-(lsopropoxycarbonyloxy)-butyl, l-~butoxycarbonyloxy)butyl, l-~lcobutoxycarbonyl~
oxy)butyl, l-(methoxycarbonyloxy)pentyl, l-(ethoxy-- 23 - 20~16Q7 carbonyloxy)pentyl, l-(methoxycarbonyloxy)hexyl and l-(ethoxycarbonyloxy)hexyl group~, preferably th~
methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, .
butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, l-(methoxycarbonyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl, l-(propoxycarbonyloxy)ethyl, l-(isopropoxycarbonyloxy)-ethyl, l-(butoxycarbonyloxy)ethyl, l-(isobutoxycarbonyl-oxy)ethyl, l-(methoxycarbonyloxy)propyl, l-(ethoxy-carbonyloxy)propyl, l-~propoxycarbonyloxy)propyl, l-(isopropoxycarbonyloxy)propyl, l-(butoxycarbonyloxy)-propyl, l-(isobutoxycarbonyloxy)propyl, l-(methoxy-carbonyloxy)butyl, 1-~ethoxycarbonyloxy)butyl, l-~yLoyo~ycarbonyloxy)butyl, l-~i30propoxycarbonyloxy)-butyl, l-~butoxycarbonyloxy)butyl, l-~i~obutoxycarbonyl-oxy)butyl, more preferably methoxyc~rhonyloxymethyl, ethoxycarbonyloxymethyl, p~uy~xycarbonyloxymethyl, i~opropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, icobutoxycarbonyloxymethyl, l-(methoxycarbonyloxy)ethyl, l-(ethoxycarbonyloxy)ethyl, l-(p~yoxycarbonyloxy)ethyl, l-(lcopropoxycarbonyloxy)ethyl, l-(butoxycarbonyloxy)~
ethyl and l-(isobutoxyc~rhonyloxy)ethyl group~ and most pre~erably the methoxycArkonyloxymethyl, ethoxycarbonyl-oxymethyl, icopropoxyc~rhQ~yloxymethyl, l-(methoxy~
carbonyloxy)ethyl, l-(ethoxycarbonyloxy~ethyl and ~ op~opG~ycarbonyloxy)ethyl group~;

cyclo~lkoxycarbonyloxyalkyl group~ in which the cycloalkyl part has S or 6 carbon atoms and the alkyl part~ hac rrom 1 to 6 carbon atom~, each as exemplified above ln relation to R2; pre~erably the alkyl part ha3 ~rom 1 to 4 carbon atome and more pre~erably 1 or 2 carbon atom~; example~ o~ euch cyclo~1koxycarbonyl~
oxyalkyl groupc lnclude the cyclopentoxycarbonyloxy-methyl, cyclohexyloxycarbonyloxymethyl, l-(cyclopentyl-oxycarbonyloxy)ethyl, l-(cyclohexyloxycarbonyloxy)ethyl, l-(cyclopentyloxycarbonyloxy)propyl, l-(cyclohexyloxy-.

- 24 - 2061~7 carbonyloxy)propyl, 1-(cyclopentyloxycarbonyloxy)butyl and l-(cyclohexyloxycarbonyloxy)butyl group~, preferably the cyclopentyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, l-(cyclopentoxycarbonyloxy)ethyl and 1-(cyclohexyloxycarbonyloxy)ethyl group~;

~5-(aryl- or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group~ in which the alkyl part has from 1 to 6 carbon atoms and may be ae exemplified above in relation to Rl and R2, and the aryl part i~ as defined and exemplified above in relation to R2 (and i8 preferably a.~ub~tituted or un~ubstituted phenyl group); preferably the alkyl part has from 1 to 4 carbon atom~ and more preferably 1 or 2 carbon atoms; examples of such ~5-¢aryl- or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group~ include the ~5-phenyl-2-oxo-1,3-dioxolen-4-yl)-methyl, ~5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]-methyl, ~5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]-methyl, ~5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]-methyl, [5-(4-~luorophenyl)-2-oxo-1,3-dioxolen-4-yl]-methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dloxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-d~oxolen-4~yl)methyl and (5-butyl-2-oxo-1,3-~10xolen-4-yl)methyl group~, prererably the (5-phenyl-2-oxo-1,3-dioxolen-4-yllmethyl, (5-methyl-2-oxo-1,3-dloxolen-4-yl)methyl and (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl group~ and more prererably the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group; and phthalldyl group~.

Preferred e~ter re~ldues are, ~or example:
~...
Cl - C4 alkyl group~;

~henyl, naphthyl and eub~tituted phenyl group~ having - 25 - 20~1 607 one or more, preferably from 1 to 3, methyl, ethyl methoxy, ethoxy, fluoro and chloro ~ubstituents, which, in the case of 2 or 3 substituents, may be the same or different;

benzyl, diphenylmethyl and ~- and ~- naphthylmethyl groups, and ~ubstituted benzyl group~ having one or more, preferably from 1 to 3, methyl, ethyl, methoxy, ethoxy, fluoro and chloro substituents, which, in the case of 2 or 3 substituents, may be the same or different;

groupe of formula SiR~eRf in which 1, 2 or 3 of the groups represented by Rd, Re and Rf are independently ~elected from the group consisting of alkyl group~ having from 1 to 4 carbon atoms, and 2, 1 or O are phenyl groups;

alkanoyloxyalkyl group~ in which the alkanoyl group has rrom 1 to 5 carbon atome and the alkyl group ha~ ~rom 1 to 4 carbon atome;
, cyclo~lk~noyloxyalkyl groupe in which the cycloalkyl part hae 5 or 6 carbon atome and the alkyl part has from 1 to 4 c~rbon atome;

alkoxycarbonyloxyalkyl group~ ln whlch each o~ the alkoxy part and the alkyl part hae ~rom 1 to 4 carbon atome;

cycloalkoxycarbonyloxyalkyl groupe ln which the cycloalkyl part hao 5 or 6 carbon atomo and the alkyl part hae ~rom 1 to 4 carbon atomo;

~5-~phenyl or alkyl-)-2-oxo-1,3-dloxolen-4-yllmethyl groupe ln whlch the alkyl part hao ~rom 1 to 4 carbon atome; and ., - 26 - 2061 ~0 7 phthalidyl group~.
More preferred ester residues are, for example, Cl - C4 alkyl groups;
the benzyl group;

alkanoyloxyalkyl groups in which the alkanoyl part ha~
from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

cycloalkanoyloxyalkyl groupe in which the cycloalkyl part has from 5 to 6 carbon atom~ and the alkyl part has 1 or 2 carbon atoms;

alkoxycarbonyloxyalkyl groupe in whlch the alkoxy part hac from 1 to 4 carbon atom~ and alkyl part has 1 or 2 carbon atom~;

cycloalkoxycarbonyloxyalkyl group~ ln whlch the cycloalkyl part hae S or 6 carbon atomc and the alkyl part hae 1 or 2 carbon atom~;

~5~phenyl or alkyl-)-2-oxo-1,3-dloxolen-4-yl]methyl group~ ln whlch the alkyl part ha~ 1 or 2 carbon atoms;
and ~thalidyl group0.

The moot pro~erred eetor reelduee are, ~or example, p~vAloyloxymethyl, ethoxycarbonyloxymethyl, l-~ethoxy-carbonyloxy)ethyl, i~o~u~oxycarbonyloxymethyl, ~ 9U~L o~Gxycarbonyroxy)ethyl, ~S-methyl-2-oxo-1,3-dloxolen-4-yl)methyl and p~th~lldyl groupe.
~xample0 of the groupe and atom~ whlch may ~orm - 27 - 20616~7 sub~tituente (a) include:

aryl groups, ~uch as those exemplified above in relation to R2;

heterocyclic groups having 5 or 6 ring atom~, of which from 1 to 4 are hetero-atom~ selected from the group coneisting of nitrogen, oxygen and sulfur atoms, and as exemplified below;

halogen atoms, alkoxy group~ and alkoxycarbonyl group~, such ae those exemplified in relation to eubstituents ~b);
hydroxy groupe, carboxy group~ and amino groups; and acyl~r~o groups, in whlch the acyl part ie an alkanoyl group havlng ~rom 1 to 6 carbon atom~ or an arylcarbonyl group, in which the aryl part i9 aY de~lned above, o~
whlch the acyl part ie ae exempll~led above ln relatlon to R4, e.g. a benzamldo group, and pre~erably an ~ noylamlno group having from 1 to 4 carbon atoms, and more pre~erably an acetamldo or orr~ o group.

Where 3ubctltuent ~a) ie a heterocyclic group, thie hae 5 or 6 rlng atome, o~ whlch ~rom 1 to 4 are hetero-atoma selected rrOm nitrogen, oxygen and eulfur hetero-atom~. Where there are 4 hetero-atoms, we pre~er that all 4 ehould be nitrogen atom~. Where there are 3 hetero-atome, we prerer that at leaet one (more pre~erably 2) ~houl~ be a nltrogen atom and one or two ehould be nltrogen, o~en or eul~ur atome ~and, where there are two, they may be the ~ame or dir~erent).
Where there are two hetero-atome, these may be the same or dl~erent and they are eelected ~rom nltrogen, oxygen and ~ul~ur atome; however, more pre~erably one ie a nitrogen atom or an oxygen atom and the other 19 a .
,, nitrogen, oxygen or sulfur atom. Examples of such heterocyclic groups include the pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, th; ~ zolyl, triazolyl, tetrazolyl and pyridyl groups (preferably a furyl, thienyl, imidazolyl, oxazolyl or thiazolyl group), preferably a furyl or thienyl group.

Preferably the benzene ring which bears the substituents represented by R6 and R7 is at the 3-or 4- posltlon of the benzyl group to which it attaches, more preferably at the 4-position, i.e. the preferred compounds have the formula (Ia):

R ~o ~.4 7 Rs ~2 ~7 R6 may repreoont a hy~rogon atom, an alkyl group having from 1 to 6 carbon atom~ ~cuch ac those ,. ~' . ' .'' ' ,, exemplified above) or an alkoxy group having from 1 to 6 carbon atom3 or a halogen atom, both of which are as exemplified above in relation to the ~ame groups or atom~ which may be represented by substituents (b).
R6 i~ preferably at the 6-position of the benzene ring.

R7 may represent a carboxy group or a tetrazol-5-yl group. When it represents a carboxy group, or when sub~tituent (a) is a carboxy group, the resulting compounds may form salts or esters. There is no particular restriction on the nature of these salts or esters, provided that, where they are intended for therapeutlc use, they are pharmaceutically acceptable.
Where they are intended for non-therapeutic uses, e.g.
as intermediates in the preparation of other, and po~sibly more active, compounds, even this restriction does not apply. Examples of such salts include: salts with an alkali metal, such as sodlum, potassium or llthlum; salts wlth an alkaline earth metal, such as barlum or calclum; salts wlth another metal, such as magne~lum and alumlnum; organic base salts, such as a salt wlth guAni~l~e, trlethylamlne, dlcyclohexylamine;
and ealt~ wlth a baeic amlno acid, ~uch as lyslne or arglnine. ~xample~ o~ ester group~ may be as exempll~led above ln relation to R5a.

Pre erably R7 repre~ent~ a cArboxy group or a tetrazol-5- yl group, and, where R7 ~Qre30nts a carboxy group, ealtc o~ the~e compound~ are al~o pre~orred. R7 18 pre~erably at the 2- or 3- posltlon o~ the phenyl group, and more pre~erably at the 2-po~ltlon.

The com~oun~ o~ the pre~ent inventlon nece~sarily contaln at lea~t one ba~lc nltrogen atom ln the lmldazole rlng and can there~ore orm acld addltion ealtc. ~xamplee o~ such acid addltlon salts lnclude:

20~1607 addition e~lt9 with inorganic acid~, ~uch a~
hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; and addition salts with organic acids such as maleic acid, fumaric acid, tartaric acid or citric acid.

Preferred claeses of compounds of the present invention are those compounds of formula (I) and salts an estere thereof, in which:

Rl represents an alkyl group having from 2 to 5 carbon atome or an alkenyl group having from 3 to 5 carbon atoms;

R2 and R3 are independently selected from the group conel6ting of:
hydrogen atoms, alkyl group~ having ~rom 1 to 4 carbon atoms, alkenyl group~ havlng rom 3 to 5 carbon atoms, cycloalkyl groupe having 5 or 6 carbon atoms, benzyl, naphthyl and phenyl group~, and ~ub~tituted benzyl and phenyl groups which are eubetltuted by at leaet one eubetltuent selected ~rom the group concieting Or sub~tituente (b'), derlned below;

~ubetltuente ~b') are ~elected rrom the group conslsting o~ methyl, ethyl, methoxy and ethoxy groups and ~luorine and chlorlne atoms;

R4 .op-a~entc:
a hydrogen atom, an alkyl group havlng rrOm 1 to 4 carbon atome, an ~lkAnoyl group havl~g ~rom 1 to 5 carbon atome, a eubetltuted alkanoyl group whlch hac 2 or 3 carbon atomc and which i~ eub~tituted by at leaet one sub~tltuent eelected rrom the group coneleting o~

~ .... .

- 31 - 206~607 fluorine and chlorine atoms and methoxy and ethoxy groups, an alkenoyl group having from 3 to 5 carbon atoms, a naphthoyl group, a benzoyl group, a ~ubstituted benzoyl group which i~ ~ubstituted by at least one sub~tituent selected from the group cons~ting of eubstituents (b~), defined below, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a tetrahydropyranyl, tetrahydrothiopyranyl, tetra-hydrothienyl or tetrahydrofuryl group, a sub~tituted tetrahydropyranyl, tetrahydrothio-pyranyl, tetrahydrothienyl or tetrahydrofuryl group which i9 ~ubstituted by at lea~t one ~ub~tituent selected from the group con~isting of chlorine and bromlne atom~ and methoxy groupe, a group o~ ~ormula -SiRaRbRC, in which 1, 2 or 3 o~ the group~ repre~ented by Ra, Rb and Rc are indep~n~ntly ~elected ~rom the group con~isting o~ alkyl groupe having ~rom 1 to 4 carbon atoms, and 2, 1 or O o~ the groupe rep~esonted by Ra, Rb and Rc are phenyl group~, a methoxymethyl, 2-methoxyethoxymethyl, 2,2,2-tri-chloroethoxymethyl, blet2-chloroethoxy)methyl, ~enzyl, dlphenylmethyl or n~phthylmethyl group or a eubstituted benzyl group which i8 ~ubstituted by at lea~t one ~ubstituent selected ~rom the group con~letlng o~ eub~tltuents ~b'), defined below, or a plvaloyloxymethoxycarbQnyl group;
5a R re~reoont~ a group o~ formula -COOR or a group o~ ormula ~CoNR3R9, in which:

R5a ~e~,c3ente a hydrogen atom, an alkyl group havlng ~rom 1 to 4 carbon atome, 1 6 ~ 2 a phenyl, naphthyl, benzyl, diphenylmethyl or naphthylmethyl group, a substituted phenyl or benzyl group which i9 sub~tituted by at lea~t one substituent selected from the group consisting of substituents (b~), defined below, a group of formula -SiRaRbRC, in which Ra, Rb and Rc are as defined above, an alkanoyloxyalkyl group, in which the alkanoyl part hae from 1 to 5 carbon atoms, and the alkyl part has from 1 to 4 carbon atome, a cyclo~lkAnoyloxyalkyl group, in which the cycloalkanoyl part has 6 or 7 carbon atom~, and the alkyl part has from 1 to 4 carbon atoms, an alkoxycarbonyloxyalkyl group, in wh~ch the alkoxy part has from 1 to 4 carbon atoms, and the alkyl part ha~ f rom 1 to 4 carbon atomo, a cycloAlkoYycarbonyloxyalkyl group, ln which the cycloalkoxy part has S or 6 carbon atoms, and the alkyl part has ~rom 1 to 4 carbon atoms, a ~5~phenyl- or alkyl-)-2 oxo~1,3-dloxolen-4-yll-methyl group ln whlch the alkyl part has ~rom 1 to 4 carbon atomo, or a phthalldyl group;

R8 and R9 are ~nde~e i~ tly selected ~rom the group conoistlng o~:
h~oyen atom~, alkyl groupo havlng ~rom 1 to 4 carbon atom~, and eubstltuted alkyl groupe whlch have ~rom 1 to 4 carbon atomo and whlch are subetltuted by at leaet one oubotltuent oolected ~rom the group conoleting Or oubotltuento ~a'), de~lned below;
or R~ and R9 together repreoent an uneubetltuted alkylene group which hao 4 or 5 carbon atomo or a subotltuted al~ylene group whlch hao 4 or 5 carbon atomo ~nd whlch lo eubotituted by at least one ', , ,. ' , ' ': "' .' ~ . ; " , ., ' ~

2~1607 sub~tituent ~elected from the group consisting of carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups;

substituents (a~) are selected from the group consi~ting of phenyl groups, furyl groups, thienyl groups, fluorine atoms, chlorine atoms, hydroxy groups, methoxy groups, ethoxy groups, carboxy groups and alkoxycarbonyl groups having Erom 2 to 5 carbon atoms;

R6 represente a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group ha~ing from 1 to 4 carbon atom~, a fluorine atom, a chlorine atom or a bromine atom;

R represents a carboxy group or a tetrazol-S-yl group; and the benne~e rlng which bears the substltuents repre~ented by R6 and R7 1~ at the 3- or 4- po~itlon o~ the benzyl group to which lt i~ attAched.

More pre~erred cl~seee o~ compoundc o~ the precent lnvention are tho~e compounde o~ ~ormula ~I) and ~alts an ecterc thereo~, ln which:

Rl Le~eaente an alkyl group having ~rom 2 to 5 carbon atome or an alkenyl group havlng ~rom 3 to 5 carbon atom~;

and R are lrdep~n~e~tly ~elected ~rom the group conoieting o~:
hydrogen atoms, alkyl groupe having ~rom 1 to 4 carbon atom~, alkenyl grou~c having ~rom 3 to 5 carbon atome, cycloalkyl groupe havlng S or 6 carbon atom~, and benzyl and ~henyl groupe;

34 2Q61 ~0 7 R represent~:
a hydrogen atom, a methyl or ethyl group, an alkanoyl group having from 1 to 5 carbon atoms, an alkenoyl group having from 3 to 5 carbon atoms, a benzoyl group, or an alkoxycarbonyl group having from 2 to 5 carbon atoms;

R5 represents a group of formNla -CooR5a or a group of formula -CONR~R9, ln which:

R5a repre~ents a hydrogen atom, an alkyl group havlng from 1 to 4 carbon atoms, a benzyl group, an alkanoyloxyalkyl group, in which the alkanoyl part hae ~rom 1 to 5 carbon atom~, and the alkyl part 1~ a methyl or ethyl group, a cycloalkanoyloxyalkyl group, in which the cycloalkanoyl part ha~ 6 or 7 carbon atomc, and the alkyl part lc a methyl or ethyl group, an alkoxycarbonyloxyalkyl group, ln whlch the alkoxy part ha~ ~rom 1 to 4 carbon atom~, and the alkyl part lc a methyl or ethyl group, a cycloalkoxycarbonyloxyalkyl group, ln which the cycloAlko~y part hac 5 or 6 carbon atom~, and the alkyl part le a methyl or ethyl group, a ~S-(phenyl-, methyl- or ethyl-)-2-oxo-1,3-dloxolen-4-yl~methyl group, or a phthalldyl group;

Ra and R9 are lnde~e-~e.~tly selected ~rom the group con~lctlng o~:
hydrogen atom~, methyl groupc, ethyl groupc, and - 35 20~fiO7 substituted methyl and ethyl group~ which are substituted by at least one sub~tituent selected from the group consisting of carboxy groups, methoxycarbonyl group~ and ethoxycarbonyl groups;
or R8 and R9 together represent an unsubstituted alkylene group which ha~ 4 or 5 carbon atoms or a substituted alkylene group which ha~ 4 or 5 carbon atoms and which i~ substituted by at least one substltuent selected from the group consi~ting of carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups;

R6 represent~ a hydrogen atom, or it represents a methyl group, an ethyl group, a methoxy group, an ethoxy group, a ~luorlne atom or a chlorlne atom on the 6-po~ltion o~ the benzene ring;

R7 repre~ents a carboxy group or a tetrazol-5-yl group at the 2- or 3- position of the benzene rlng; and the benzene rlng which beare the substltuents LepLe~ented by R6 and R7 ie at the 4-position o~ the benzyl group to whlch lt i~ attAc~e~.

Stlll more pre~erred claeees o~ comrolln8~ o~ the ~ro3e..t invention are tho~e compounds o~ ~ormula ~I) and 3alt8 an e~tere thereo~, in which:

Rl .e~e~s~te an alkyl group having ~rom 2 to 5 carbon atoms;

R and R are l~dope~ntly eelected ~rom the group conel~ting o~ hydrogen atom~ and alkyl groupe having erOm 1 to 4 carbon atom~;

R4 repre~ente a hydrogen atom, a methyl group, an ethyl group or an alkanoyl group havlng ~rom 1 to 5 "

- 36 - 2061~07 carbon atoms;

R5 represents a group of formula -CooR5a or a group of formula -CONR8R9, in which:

R5a represents a hydrogen atom, a methyl, ethyl or benzyl group, an alkanoyloxymethyl group, in which the alkanoyl part has from 1 to 5 carbon atome, a l-~alkanoyloxy)ethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, an alkoxycarbonyloxymethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a l-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part ha~ ~rom l to 4 carbon atome, a lS-(phe~yl- or methyl-)-2-oxo-1,3-dioxolen-4-yl~methyl group, or a phthalidyl group;

R and R are indepen~ently eelected ~rom the grou~ coneieting Or hydrogen atome, methyl groupe, ethyl groupe, methoxycarbonylmethyl groupe, ethoxy-cArhonylmethyl groupe and carboxymethyl groupe;
or R~ and R9 together ~cps~cnt a tetra-methylene, pentamethylene, l carboxytetramethylene or l-carboxypentamethylene group;

R6 ~re~snte a hydrogen atom, or lt repreeente a methyl group, an methoxy group, a ~luorine atom or a chlorlne atom at the 6-poeltion o~ the henzene rlng;

R Le~Le~onte a carboxy group or a tetrazol-5-yl group at the 2-~o~ltion o~ the bDnzQne ring; and the benzene ring whlch beare the eubetituente repreeented by R6 and R7 le at the 4~poeitlon Or the ~ . . ... . .

37 - ~2~ 7 benzyl group to which it i9 attached.

Even more preferred cla~es of compounds of the pre~ent invention are tho~e compounds of formula (I) and ~alto an ester~ thereof, in which:

either Rl represents an ethyl, propyl or butyl group;

R2 and R3 are independently selected from the group conoisting of hydrogen atom~ and methyl groups;

R represento a hydrogen atom or a methyl group;

R5 repreoento a group of fo_ lla -COORSa, in which R5a represents a hydrogen atom, a pivaloyloxymethyl g~oup, an ethoxycarbonyloxymethyl group, a l-(ethoxy-carbonyloxy)ethyl group, an ioop~opo~ycarbonyloxymethyl gxoup, a l-(ieopropo~ycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or a phthalidyl group;

R6 lepre~ento a hydrogen atom;

R7 ~epree~nte a carboxy group or a tetrazol-S-yl group at the 2-po~ition Or the b~n~ng ring; and the benzene rlng which beare the oubotltuente Le~eoonted by ~6 and R7 io at the 4-pocition o~ the benzyl group to which it i~ attache~.

R z~re~ento an ethyl, propyl or butyl group;

R repreoentc an ieopropyl group or a t-butyl group;

- 38 - 2~61607 R3 repre~ent~ a hydrogen atom;

R4 represent~ a hydrogen atom or a methyl group;

R5 represent~ a group of formula -CONR8R9, in which R8 and R9 are independently selected from the group consi~ting of hydrogen atoms, methyl groups, methoxycarbonylmethyl, ethoxycarbonylmethyl groups, and carboxymethyl groups;

R6 represents a hydrogen atom;

R7 represent~ a carboxy group or a tetrazol-5-yl group at the 2-position o~ the ben7~ne ring; and the benzene ring which bears the ~ubetituents repre~ented by R6 and R7 i9 at the 4-poeition of the benzyl group to which it i9 attArhe~.

The most pre~erred classeo o~ compounds o~ the present lnvention are thooe compound~ o~ ~ormula (I) and salto an esters thereo~, in which:

Rl repre~eoto an ethyl, propyl or butyl group;

R2 and R3 both re~Leoont methyl groups;

R4 Lo~Looent~ a hydrogen atom or a methyl group;

R5 re~Leo2nto a group o~ ~ormula CooR5a, ln which ~5a reprooont~ a hy~G~en atom, a plvaloyloxymethyl group, an ethoxycarbonyloxymothyl group, a l-(ethoxy-carbonyloxy)ethyl group, an ioop~Gxycarbonyloxymethyl group, a l-~i w~LG~o~carbonyloxy)ethyl group, a ~5-methyl-2-oxo-1,3-dloxolen-4-yl)mothyl group, or a phthalidyl group;

.

39 20~1 ~07 R6 represents a hydrogen atom;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which bears the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it i9 attached.

The compounds of the present invention may contain one or more asymmetric carbon atoms in their molecules, and can thus form optical isomers. Although these are all represented herein by a single molecular formula, the present lnvention lncludes both the individual, isolated isomers and mixtures, including racemates thereof. Where stereoepecific synthesie technigues are employed or optlcally active compounds are employed as 6tarting material~, individual isomers may be prepared directly; on the other hand, if a mlxture o~ isomers is prepared, the lndividual l~omer~ may be obtained by conventional resolution techn~que~.

Specl~ic example~ of lndividual compound~ o~ the present lnvention are ~hown in the followlng rormulae ~I-l), (I-2), ~I-3), (I-4), (I-5) and (I-6):

~ ,, 20~16Q7 N~ oR4 C%3 [~3 (I-l) R6~COOR7a N:::!(C' COOR~

2 ) R~ ~}R7 R ~C

R~

C~2 .,.~. ~
[~coo~

..
,,~ ' ': - , :

N CH~
Rl ~/ 11 COORsa (I-4) <N~ H

R2 ~R3 CON~

S ) N CoOR5a ~ I - 6 ) In these formulae, the m~n;ngs of the various substituent groups are as given in the following Tables 1 to 6, in which Table 1 relate~ to formula (I-1), Table 2 relates to formula (I-2), Table 3 relates to formula (I-3), and ~o on. In the Tables, the following abbreviations are used:

Ac acetyl Boz benzoyl Bu butyl isobutyl ~Bu t-butyl Buc butoxycarbonyl BUC i30butoxycarbonyl Bz benzyl Et ethyl Etc ethoxycarbonyl Fo ~ormyl Fu 2-~uryl ~Hx cyclohexyl Im 4-lmidazolyl Me methyl Mec methoxycarbonyl Mod ~S-methyl-2-oxo-1,3-dioxolen-4-yl)methyl Ph phenyl Phth phthalldyl Plv pivaloyl Pn pentyl ~Pn cyclopentyl ~n isopentyl Pr propyl Pr i80propyl Prc l~opropoxycarbonyl Prn proplonyl Tz tetrazol-5~yl Th 2-thlenyl Table 1 Cpd. R1 R2 R3 R4 R5a R6 R7a No .

1-1 Pr H H H H H
1-2 Bu H H H H H H
1-3 -CH-CH-Et H H H H H H
1-4 Pn H H H H H H
1- 5 Bu H H H Me H H
1-6 Bu H H H Et H H
1-7 Bu H H H Bu H H
1-8 Bu H H H Bz H H
1- 9 Bu H H Me H H H
1-10 Bu H H 2t H H H
1- 11 Bu H H Po H H H
1~12 Elu H H Ac H H H
1-13 Bu H H Boz H H H
1-14 Bu H H Me Et H H
1-15 Bu H H Me PlvOCH2- H H
1-16 Bu H H H H Cl H
1-17 8u H H H Et Cl H
1-13 Bu H H H H OMe H
1-19 Bu H H H Et OMe H
1-20 8u H H H H OEt H
:1~21Bu H H H ~t OEt H
1- 22 BU H H H Mod H H
1~ 23BU H H H EtcOCH2 - H H
1-24 BU H H H 1- ~EtcO) Et H H

1-25 ~U Me H H H H H
1-26 ~U Me H H ~t H H
1~ 27~u Mo H H PlvOCH2 - H H

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

~ 44 ~ 2~6160~
Table 1 (cont . ) Cpd. Rl R2 R3 R4 R5a R6 R7a No .

1- 2 3 Bu Me H H Mod H H
1- 2 9 Bu Me H Ac H H H
1-30 Bu Me H Ac Et H H
1-31 Bu Me Me H H H H
1- 32 3u Me Me H Et H H
1- 3 3 Bu Me Me H Bu H H
1-34 8u Me Me H Me H H
1- 35 Bu Me Me H Pi~rOCH2 - H H
1-36 Bu Me Me H Mod H H
1-37 Bu Me Me Me H H H
1-3a Bu Me Me Me ~t H H
1-39 Bu Me Me Fo H H H
1- 40 3u Me Me Fo Bt H H
1- 41 BU Me Me Ac H H H
1- 42 BU Me Me Ac Bt H H
1- 43 Bu Me Me 30z H H H
1- 44 BU Me Me Boz ~t H H
1- 4 5 au Me Me H H Cl H
1- 4 6 BU Me Me H Et Cl H
1-47 BU Me Me H R OMe H
1-48 BU Me Me H Bt OMe H
1-49 Pr Me Me H H H H
1- 5 Q Pr Me Me H Zt H H
1- 51 Pr Me Me Ac Bt H H
1 52 Pr Me Me H H OMe H
1-53 Pr Me Me H 2t OMe H
1- 54 Pn Me Me H H H H

Table 1 (cont.) Cpd. R1 R2 R3 R4 R5a R6 7a No.

1-55 Pn Me Me H Et H H
1-56 Et Me H H H H H
1-57 Et Me H H Et H H
1-5~ Et Me H H PivOCH2- H H
1-59 Et Me H H Mod H H
1-60 Et Me H H EtcOCH2- H H
1-61 Bt Me H H 1-(EtcO)Et H H .
1-62 Bu Bt H H H H H
1-63 Bu Bt H H Bt H H
1-64 Bu Bt H H H C1 H
1-65 Bu ~t H H Bt Cl H
1-66 Bu ~t H H H OMe H
1-67 Bu Bt H R Bt OMe H
1-68 Bu iPr H H H H H
1-69 Bu iPr H H Bt H H
1-70 Bu lPr H H H Cl H
1-71 Bu iPr H H Bt Cl H
1~72 Bu iPr H H H OMe H
1-73 Bu lPr H H Bt OMe H
1-74 Bu ~Bu H H H H H
1-75 Bu ~Bu H H Bt H H
1-76 Bu ~Bù H H H Cl H
1-77 Bu ~Bu H H Et Cl H
1-78 Bu ~Bu H H H OMe H
1-79 ~u ~9u H H ~t OMe H
1-80 Bu Ph H H H H H
1-81 Bu Ph H H Zt H H

.. . . .
:

Table 1 (cont.) Cpd. Rl R2 R3 R4 R5a R6 R7a No.

1-82 Bu Et Me H H H H
1-83 Bu Et Me H Et H H
1-84 Bu Et Et H H H H
1-85 Bu Et Bt H Et H H .
1-86 au Et Et H H Cl H
1-87 Bu Et Et H Et Cl H
1-88 Bu Et Bt H H OMe H
1-89 Bu Et Et H Et OMe H
1-90 Bu Pr H H H H H
1-91 Bu Pr H H Et H H
1-92 Pr Pr H H H H H
1-93 Pr Pr H H Et H H
1-94 Bu H H H Me H tBu 1-95 Bu H H H Et H ~jBu 1-96 Bu H H H H H ~jBU
1-97 Bu H H H PivOCH2- H ~jBu 1~98 Bu H H H PlvOCH2- H H
1-99 BU H H Me Me H L~u 1-100 Pr H H H ~t H H
1-101 Pr H H H Bu H H
1~102 Pr H H H PlvOCH2- H H
1-103 Pr H H H Mod H H
1-104 Pr H H H H Cl H
~-105 Pr H H H Et Cl H

1-106 Pr H H H H OMe H
1-107 Pr H H H ~t OMe H
1-108 Pr Mo Mb H H Ci H

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

.

47 - 20~1 60 7 Table 1 (cont.) Cpd. R1 R2 R3 R4 R5a R6 R7a No.

1-109 Pr Me Me H Et Cl H
1-110 Pr Me Me H H H Et 1-1 1 1 Pr Me Me H H H Bu 1-112 Pr Me Me H H H PivOCH2-1-113 Bu Me Me H R H Et 1-114 Bu Me Me H H H Bu 1-1 1 5 Bu Me Me H H H P ivOCH2 -1-116 Bu Me Me Mec H H H
1-117 3u Me Me ~tc H H H
1-119 Bu Me Me H Et H tBu 1-119 Pr Me Me H Et H ~,Bu 1-120 Bu Me Me H H F H
1-121 Bu H H Me Me H H
1-122 E3u Me Me H H Cl ~Bu 1-12 3 Bu Me Me H Ft Cl ~Bu 1-124 Bu Me Me H H OMe ~Bu 1-125 Bu Me Me H Et OMe ~Bu 1-12 6 Pr Me Me H H Cl ~Bu 1-12 7 Pr Me Me H Bt Cl ~Bu 1-12~ Pr Me Me H H OMe tBu 1-129 Pr Me Me H Et OMe t~u 1 130 ~t Me Me H 2t H ~E3u 1-131 ~t Me Mo H ~t H H
1-132 Et Me Me H H H H
1-133 Pr Me H H PivOCH2- H H
1-134 Pr Me H H Mod H H
1-135 Pr Me H H FtCOCH2- H H
1-136 Pr Me H H 1- (EtcO) Et H H

, Table 1 (cont.) Cpd. R1 R2 R3 R4 R5a R6 R7a ~.
No.

1-137 Pr Me H H Phth H H
1-133 Et H H H H H H
1-139 Et H H H PivOCH2- H H
1-140 Et H H H Mod H H
1-141 Et H H H EtcOCH2- H H
1-142 Et H H H 1-(EtcO)Et H H
1-143 Et H H H Phth H H

.

. . .

. ' \, , ''' , ' ~ 49 ~ 20 Sl 60 7 Table 2 .

Cpd. Rl R2 R3 R4 R5a R6 R7 No.

2 -1 Pr Me Me H H H 2-Tz 2-2 Bu Me Me H H H 2-Tz 2 - 3 Pn Me Me H H H 2 - Tz 2 - 4 - CHnCH- Et Me Me H H H 2-Tz 2 - 5 Pr Me Me Me H H 2-Tz 2-6 Bu Me Me Me H H 2-Tz 2-7 Pr Me Me H Bt H 2-Tz 2-~ Bu Me Me H ~t H 2-Tz 2-9 Pr Me Me H Me H 2-Tz 2-10 Bu Me Me H Me H 2-Tz 2-11 Pr Me Me Me Me H 2 - Tz 2-12 Bu Me Me Me Me H 2-Tz 2-13 Pr Me Me Me ~t H 2-Tz 2-14 Bu Me Me Me Et H 2 - Tz 2-15 Pr Me Me H PlvOCH2- H 2-Tz 2-16 Bu Me Me H PlvOCH2- H 2-Tz 2-17 Pr Me Me H Mod H 2-Tz 2-18 BU Me Me H Mod H 2-Tz "
2-19 Pr Me Me H EtcOCH2- H 2-Tz 2-20 BU Me Me H EtCOCH2- H 2 - Tz 2-21 Pr Me Me H iPrcocH2- H 2-Tz 2~22 ~u Me Me H lPrCOCH2- H 2-Tz 2-23 Pr Me Me H l-(EtCO)Et H 2-Tz 2-24 ~u Me Me H l-(EtCO)Et H 2-Tz 2-25 Pr Me Me H 1- ~iPrcO) Et H 2-Tz 2-26 3u Me Me H l-(iPrcO)Et H 2-Tz 2-27 Pr Me Me Me EtCOcH2- H 2-Tz 2~ a 8 3u Me Me Me EtCOCH2- H 2 Tz - 50 - 20~1 60 7 Table 2 (cont.) Cpd. R1 R2 R3 R4 R5a R6 R7 No.

2-29 Pr Me Me Me iPrcOCH2- H 2 - Tz 2-30 Bu Me Me Me iPrcOCH2- H 2- Tz 2-31 Pr Me Me Me PlvOCH2- H 2- Tz 2-32 BU Me Me Me PivOCH2- H 2-Tz 2-33 Pr Me Me H H 6-C1 2 -Tz 2-34 Bu Me Me H H 6-C1 2- Tz 2-35 Pr Me Me H H 6-OMe 2-Tz 2-36 Bu Me Me H H 6-OMe 2-Tz 2-37 Pr Me ~t H H H 2- Tz 2-38 Bu Me Bt H H H 2-Tz 2-39 Pr ~t 8t H H H 2-Tz 2-40 BU ~t Bt H H H 2-Tz 2-41 Pr Me Me H Bz H 2-Tz 2 42 Pr Me Me H Bu H 2-Tz 2-43 Bu Me Me H Bz H 2-Tz 2-44 3u Me Me H Bu H 2-Tz 2-45 Pr ~t Pt H ~t H 2-Tz 2-46 Pr Me Me H H H 3 Tz 2-47 Pr Me Me H H H 4-Tz a 48 Pr Me Me H (4-OAc)--(3-OMe)Bz H 2-Tz 2-49 Pr Me Me H Po H 2-Tz 2-50 Pr Me Me H Ac H 2-Tz 2-S1 Pr Me Mo H H 6-C1 3-Tz 2-52 Bu Mo Me H H 6-C1 3-Tz 2 53 Pr Me Mo H H 6-OMe 3-Tz 2-54 Bu Me Me H H 6-OMe 3 Tz 2-SS Pr Me Et H H H 3-Tz .
, .- ; , .. . ~ . -2o6l6~17 Table 2 (cont.) Cpd. R1 R2 R3 R4 R5a R6 R7 No.

2-56 Bu Me Et H H H 3 -Tz 2~57 Pr Et Et H H H 3 -TZ
2-SB Bu Et Et H H H 3 - Tz 2-59 Pr Me Me Me Et H 3 - Tz 2-60 Pr Me Me Me H H 3- Tz 2-61 Bu Me Me Me Et H 3 - Tz 2-62 3u Me Me Me H H 3-Tz 2-63 Pr Et Et H Et H 3 - Tz 2-64 Pr Me Bt Me H H 2-Tz 2-65 Pr Me Me H Phth H 2-Tz 2-66 Pr Me Me Me Mod H 2-Tz 2-67 Bu Me Me Me Mod H 2-Tz 2-6 a Bt Me Me H H H 2- Tz 2-69 Bt Me Me H PlvOCH2- H 2-Tz 2-70 Bt Me Me H EtcOCH2- H 2 Tz 2-71 Bt Mo Me H ~PrcOCH2- H 2-Tz 2-72 Bt Me Me H Bt H 2-Tz 2-73 8t Me Me H Mod H 2-Tz 2 74 Et Me Me H Phth H 2-Tz 2-75 Bt Me Me Me H H 2 Tz 2-76 B~ Me Me Me PivOCH2- H 2-Tz 2 77 Bt Me Mo Me Mod H 2-Tz ' , , ...
... . .

- 52 - 2061 6~ 7 Table 3 Cpd. R1 R2 R3 R4 Rsa No.

3-1 Pr Me Me H PivOCH2-3-2 Pr Me Me H AcOCH2-3-3 Pr Me Me H l-(PivO)Et 3-4 Pr Me Me H 1 (AcO)Et 3-5 Pr Me Me H ~PnCO.OCH2-3-6 Pr Me Me H cHxCO.OCH2-3-7 Pr Me Me H MecOCH2-3-8 Pr Me Me H 1-(MecO)Et 3-9 Pr Me Me H EtcOCH2-3-10 Pr Me Me H 1-~EtcO)Et 3-11 Pr Me Me H 1-(EtcO)-2-MePr 3-12 Pr Me Me H l-~EtcO)Pr 3-13 Pr Me Me H 1PrcOCH2-3-14 Pr Me Me H 1-~iPrcO)Et 3-15 Pr Me Me H 1-~iPrcO)-2-MePr 3-16 Pr Me Me H 1-(1Prc0)Pr 3-17 Pr Me Me H ~PnO.CO.OCH2-3-18 Pr Me Me H ~HxO.CO.0CH2-3-19 Pr Me Me H E3ucOCH2-3-20 Pr Me Me H 1-(PucO)Et 3-21 Pr Me Me H li3ucOCH2-3-22 Pr Me Me H 1-(1~3ucO)Et 3-23 Pr Me Me R 1-(~PnO.CO.O)Et 3-24 Pr Me Me H 1-(~HxO.CO.O)Et 3-25 Pr Me Me H Mod 3-26 Pr Me Me H Phth 3-27 i3u Et Et H PivOCH
3-28 E3u Me Me H AcOCH

2o~l6~7 Table 3 (cont.) Cpd. R1 R2 R3 R4 R5a No.

3-29 Bu Me Me H 1- (PivO) Et 3-30 Bu Me Me H 1-(AcO)Et 3-31 Bu Me Me H cPnCO.OCH2-3-32 Bu Me Me H cHxCO.OCH2-3-33 Bu Me Me H MecOCH2-3-34 Bu Me Me H 1-(MecO)Et 3-35 Bu Me Me H EtcOCH2-3-36 Bu Me Me H 1-(EtcO)Et 3-37 Bu Me Me H 1-(EtcO)-2-MePr 3-39 Bu Me Me H 1-(EtcO)Pr 3 - 3 9 BU Me Me H ~PrcOCH2-3-40 BU Me Me H 1-~iPrcO)Et 3-41 Bu Me Me H ~ PrcO)-2-MePr 3-42 Bu Me Me H l ~1PrcO)Pr 3-43 Bu Me Me H ~PnO.CO.OCH2-3-44 Bu Me Me H ~HxO.CO.OCH2-3-45 BU Me Me H BuCOCH2-3-46 Bu Me Me H 1-~BucO)Et 3-47 Bu Me Me H lBucOCH2-3-4a Bu Me Me H 1-~iBucO)Et 3-49 Bu Me Me H l-~PnO.CO.O)Et 3~50 i3u Me Me H 1-~HxO.CO.O)Et 3-51 Bu Et Et H Mod 3 - 52 Bu Me Me H Phth 3-53 Pr Me Me Me PlvOCH
3-54 Pr Me Me Me AcOCH2-3-55 Pr Me Me Me 1-~PivO)Et 3-56 Pr Me Me Me 1-~AcO)~t 2o~l6~7 Table 3 ( cont . ) Cpd. R1 R2 R3 R4 Rsa No.

3-57 Pr Me Me Me cPnCO.OCH2-3-5~ Pr Me Me Me c~xCO.OCH2-3-59 Pr Me Me Me MecOCH2-3-60 Pr Me Me Me 1-(MecO)Et 3-61 Pr Me Me Me EtcOCH2-3-62 Pr Me Me Me 1-(EtcO)Et 3-63 Pr Me Me Me 1-(EtcO)-2-MePr 3-64 Pr Me Me Me 1-(EtcO)Pr 3-65 Pr Me Me Me iPrcOCH2-3-66 Pr Me Me Me 1-(iPrcO)Et 3-67 Pr Me Me Me 1-(1PrcO)-2-MePr 3-68 Pr Me Me Me 1-(iPrcO)Pr 3-69 Pr Me Me Me ~PnO.CO.OCH2-3-70 Pr Me Me Me QHxO.CO.OCH2-3-71 Pr Me Me Me BucOCH2-3-72 Pr Me Me Me 1-(BucO)Et 3-73 Pr Me Me Me 1BucOCH2-3-74 Pr Me Me Me 1-(1BucO)Et 3-75 Pr Me Me Me 1-~PnO.CO.O)Et 3-76 Pr Me Me Me 1-(QHxO.CO.O)Et 3~77 Pr Me Me Me Mod 3~78 Pr Me Me Me Phth 3-79 ~u Me Me Me PlvOCH2-3- a 0 Bu Me Me Me AcOCH2-3-81 ~3u Me Me Me 1-(PivO)~t 3-82 ~3u Me Me Me l ~AcO)Et 3-83 3 ~ M Me Me QPnCO.OCH2-3-84 Bu Me Me Me QHxCO,OCH2-Table 3 (cont ., 206160 7 Cpd. Rl R2 R3 R4 R5a No .

3-85 3u Me Me Me MecOCH2-3-86 Bu Me Me Me l-(MecO)Et 3-87 Bu Me Me Me EtcOCH2-3-88 Bu Me Me Me l-(EtcO)Et 3-89 Bu Me Me Me l-(EtcO)-2-MePr .
3-90 Bu Me Me Me l-(EtcO)Pr 3-91 Bu Me Me Me iPrcOCH2-3-92 Bu Me Me Me l-(iPrcO)Et 3-93 Bu Me Me Me ~ PrcO)-2-MePr 3-94 Bu Me Me Me ~ PrcO)Pr 3-95 Bu Me Me Me cPnO.CO.OCH2-3-96 Bu Me Me Me gHxO.CO.OCH2-3-97 Bu Me Me Me BucOCH2-3-9a Bu Me Me Me 1-~3ucO)Et 3-99 ~3u Me Me Me iBUCOCH2-3-100 ~u Me Me Me l-(iBucO)Et 3-101 Bu Me Me Me l-(gPnO.CO.O)Et 3-102 Bu Me Me Me l-~gHxO.CO.O)Et 3 103 Bu Me Me Me Mod 3-104 Bu Me Me Me Phth 3 105 Et Me Me H PivOCH2-3-106 3t Me Me H AcOCH2-3-107 Et Me Me H EtcOCH2-3-108 Et Me Mb H l-(~tcO)Bt 3 109 3t Me Me H lPrcOCH2-3-110 Bt Me Me H l-(lPrcO)Et 3-111 Et Me Me H Mod 3-112 Et Me Me H Phth . . ', . ,.' ' " ' ' ~ . ' :, . .
- , . ,~. . :. : .. .. . ..
. .

, --Table 3 (cont.) 2 0 61 6 0 7 Cpd. R1 R2 R3 R4 R5a No.

3-113 Pn Me Me H PivoCH2 -3-114 Pn Me Me H AcOCH2-3-115 Pn Me Me H EtcOCH2-3-116 Pn Me Me H 1-(EtcO)Et 3-117 Pn Me Me H iPrcOCH2-3-118 Pn Me Me H 1-(iPrcO)Et 3-119 Pn Me Me H Mod 3-120 Pn Me Me H Phth 3-121 Pr Me Bt H PlvOCH2-3-122 Pr Me Bt H AcOCH2-3-123 Pr Me Bt H EtcOCH2-3-124 Pr Me Bt H 1-(EtcO)Et 3-125 Pr Me Bt H iPrcOCH2 3-126 Pr Me Et H 1-(iPrcO)Et 3-127 Pr Me Bt H Mod ~
3-123 Pr Me Bt H Phth 3-129 Pr Bt Bt H PlvOCH2-3-130 Pr Bt ~t H AcOCH2-3-131 Pr Bt Bt H EtcOCH2-3-132 Pr Bt Bt H 1-~EtcO)Bt 3-133 Pr Bt Bt H 1PrcOCH2-3-134 Pr ~t Bt H 1-~iPrcO)Et 3-135 Pr Bt Bt H Mod 3-136 Pr ~t Bt H Phth Table 4 2061 6Q 7 Cpd. Rl R2 R4 R5a No .

4-1 Pr H H H
4-2 Pr H H Me 4-3 Pr H H Et 4-4 Pr H H PivOCH2-4-5 Pr H H Mod 4-6 Pr H H EtcOCH2-4-7 Pr H H iPrcOCH2-4-8 Pr H H l-(EtcO)Et 4-9 Pr H H l-(lPrcO)Et 4-10 Pr H H Phth 4-11 Pr H Me H
4-12 Pr H Me Me 4-13 Pr H Me Et 4-14 Pr H Me PivOCH
4-15 Pr H Me Mod 4-16 Pr H Me EtcOCH2-4~17 Pr ~ Me iPrcocH2~
4-18 Pr H Me l-~EtcO)Et 4-19 Pr H Me l-(lPrcO)Et 4-20 Pr H Me Phth 4-21 Pr H Fo H
4~22 Pr H Fo PivOCH2-4-23 Pr H Fo Mod 4-24 Pr H Fo Phth 4~25 P~ H AC H
4 - 2 6 Pr H Ac - PlvOCH2-4-27 Pr H Ac Mod 4-2~ Pr H Ac Phth .' ,': "' .. . . . .
,' ; ' "' , i ' . ' , ., , , , ', :,:
" , .. ::

Table 4 (cont., 206160 7 Cpd. Rl R2 R4 R5a No.

4-29 Pr Me H H
4-30 Pr Me H Et 4-31 Pr Me H PivOCH2-4-32 Pr Me H Mod 4-33 Pr Me H EtcOCH2-4-34 Pr Me H iPrcOCH2-4-35 Pr Me H Phth 4-36 Pr Me Me H
~-37 Pr Me Me Et 4-3~ Pr Me Me PivOCH2-4-39 Pr Me Me Mod 4-40 Pr Me Me Phth 4-41 Pr Et H H
4-42 Pr ~t H Et 4-43 Pr Zt H PlvOCH2-4-44 Pr ~t H Mod 4-45 Pr Bt H Phth 4-46 Bu H H H
4-47 i3u H H Me 4-40 Bu H H Et 4-49 Bu H H PivOCH2 -4-50 Bu H H Mod 4-51 Bu H H EtcOCH2 -4-52 Bu ~ H iPrcOCH2-4-53 8u H H l-~EtcO)Et 4-54 i3u H H l-~PrcO)Et 4 55 Bu H H Ph~h 4-56 Bu H Me H

: . .

.

Table 4 (cont.) 2061607 Cpd. R1 R2 R4 R5a No.

4-57 Bu H Me Me 4-58 Bu H Me Et 4-59 Bu H Me PivOCH2-4-60 Bu H Me Mod 4-61 Bu H Me EtcOCH2-4-62 Bu H Me iPrcOCH2-4-63 Bu H Me 1-~EtcO)Et 4-64 Bu H Me 1-(iPrcO)Et 4~65 Bu H Me Phth 4-66 Bu H Fo H
4-67 Bu H Fo PivOCH2-4~6 a Bu H Fo Mod 4-69 Bu H Fo Phth 4-70 Bu H Ac H
4-71 Bu H Ac PlvOCH2-4-72 Bu H Ac Mod 4-73 Bu H Ac Phth 4-74 Bu Me H H
4-75 Bu Me H Bt 4-76 Bu Me H P1vOCH2-4~77 Bu Me H Mod 4-7a Bu Me H BtcOCH2-4-79 3u Me H iPrcOCH2-4 a o au Me H Phth 4~81 Bu Me Me H
4-82 Bu Me Me Me 4-83 3u Me Me PivOCH
4~84 Bu Me Me Mod ', ' , - 60 - 2~61607 Table 4 (cont.) Cpd. R1 R2 R4 R5a No.

4-85 Bu Me Me Phth 4-86 Bu Et H H
4-87 Bu Et H Me 4-88 Bu Et H PivOCH2-4-89 Bu Bt H Mod 4-90 Bu Et H Phth 4-91 Et H H H
4-92 Et H Et H
4-93 Et H Et PivOCH2-4-94 Et H Et Mod 4-95 Et H Et Phth 4-96 Pn H H H
4-97 Pn H H Et 4-9B Pn H H PlvOCH2-4-99 Pn H H Mod 4-100 Pn H H Phth 4-101 Pr iPr H H
4-102 Pr ipr H PivOCH2-4-103 Pr iPr H Mod 4- ln4 Pr ~Bu H H
4 -105 Pr ~Bu H PivOCH2-4-106 Pr ~Bu H Mod 4-107 ~t Me H H
4-lOB ~t Me H Bt 4~109 Bt Mo H PivOCH2-4-110 Zt Me H Mod 4~111 Bt Me H Phth .

Table 4 (cont., 206160 7 Cpd. R1 R2 R4 R5a No .

4-112 Et H H PivOCH2-4-113 Et H H Mod 4-114 Et Me H PivOCH2-4-115 Et Me H Mod Ta~le 5 206160 7 Cpd. R1 R2 R3 R4 R7 R~ R9 No.

5-1 Pr H H H COOH H H
5-2 Pr Me H H COOH H H
5-3 Pr Et H H COOH H H
5-4 Pr Pr H H COOH H H
5-5 Pr iPr H H COOH H H
5-6 Pr tBu H H COOH H H
5-7 Pr Me Me H COOH H H
5-~ Pr Me Et H COOH H H
5~9 Pr H H Me COOH H H
5-10 Pr H H Et COOH H H
5-11 Pr Me H Me COOH H H
5-12 Pr Et H Me COOH H H
5-13 Pr iPr H Me COOH H H
5-14 Pr ~3u H Me COOH H H
5-15 Pr H H Po COOH H H
5-16 Pr Me H Fo COOH H H
5-17 Pr 8t H Po COOH H H
5-18 Pr lPr H ~o COON H H
5-19 Pr ~Bu H Po COOH H H
5-20 Pr H H Ac COOH H H
5- a 1 Pr Me H Ac COOH H H
5 ~ 22 Pr 8t H Ac COOH H H
5-23 Pr ~Pr H Ac COOH H H
5-24 Pr ~Bu H Ac COOH H H
5~25 Pr H H R COOH H Me 5-26 Pr H H H COOH H
5 - 2 7 Pr H H H COOH H Pr 5~2 a Pr H H H COOH H 1 Table 5 (cont.) 2061607 Cpd. Rl R2 R3 R4 R7 Ra R9 No .

5 - 2 9 Pr H H H COOH H ~u 5 - 3 0 Pr H H H COOH H Pn 5 - 31 Pr H H H COOH Me Me 5 - 32 Pr H H H Tz H H
5 - 3 3 Pr Me H H Tz H H
5 - 34 Pr Et H H Tz H H
5 - 3 5 Pr Pr H H Tz H H
5 - 3 6 Pr iPr H H Tz H H
5 - 3 7 Pr ~;Bu H H Tz H H
5 - 3 8 Pr Me Me H Tz H H
5- 39 Pr Me Bt H Tz H H
5 - 4 0 Pr H H Me Tz H H
5 - 41 Pr H H Bt Tz H H
5 - 42 Pr Me H Me Tz H H
5-43 Pr Et H Me Tz H H
5 - 44 Pr ~,Pr H Me Tz H H
5 - 4 5 Pr ~Bu H Me Tz H H
5 - 4 6 Pr H H Fo Tz H H
5 - 47 Pr Me H Fo Tz H H
5-4~ Pr Bt H Fo Tz H H
5 - 49 Pr lPr H Fo Tz H H
5- 50 Pr S,Bu H Fo Tz H H
5 - 51 Pr H H Ac Tz H H
5 - 52 Pr Me H Ac Tz H H
5 - 53 Pr ~t H AC Tz H H
5 - 54 Pr lPr H Ac Tz H H
5 - 5 5 Pr ~EIu H Ac Tz H H
5 - 56 Pr H H H Tz H Me ' .;
.~

Table 5 (cont ) 2061 60 7 Cpd. Rl R2 R3 R4 R7 R8 R9 No.

5-57 Pr H H H Tz H Et 5-58 Pr H H H Tz H Pr 5-59 Pr H H H Tz H iPr 5-60 Pr H H H Tz H iBU
5-61 Pr H H H Tz H iPn 5-62 Pr H H H Tz Me Me 5-63 Bu H H H COOH H H
5-64 Bu Me H H COOH H H
5-65 Bu Et H H COOH H H
5-66 Bu Pr H H COOH H H
5-67 3u iPr H H COOH H H
5-68 Bu ~Bu H H COOH H H
5-69 Bu Me Me H COOH H H
5-70 au Me ~t H COOH H H
5-71 Bu H H Me COOH H H
5-72 BU H H Et COOH H H
5-73 BU Me H Me COOH H H
5-74 Bu ~t H Me COOH ~ H
5-75 BU iPr H Me COOH H H
5-76 Bu ~Bu H Me COOH H H
5- 77 BU H H Po COOH H H
5-7~ ~U Me H Fo COOH H H
5-79 Bu 3t H Po COOH H H
5 - ~0 BU i~r H Fo COOH H H
5~1 BU ~BU H Fo COOH H H
5 a2 BU H H AC COOH H H
5~8 3 BU Mo H AC COOH H H
5-84 BU ~t H AC COOH H H

- 65 - 20~1607 Table 5 (cont.) Cpd. R1 R2 R3 R4R7 R8 R9 No.

5-85 Bu iPr H Ac COOH H H
5-86 Bu ~Bu H Ac COOH H H
5-B7 Bu H H H COOH H Me 5-88 Bu H H H COOH H Et 5-89 Bu H H H COOH H Pr 5-90 Bu H H H COOH H iPr 5-91 3u H H H COOH H iBU
5-92 Bu H H H COOH H iPn 5-93 Bu H H H COOH Me Me 5-94 Bu H H HTz H H
5- 9 5 3u Me H HTz H H
5 - 9 6 Bu Et H HTz H H
5 - 9 7 Bu Pr H HTz H H
S - 9 B BU iPr H HTz H H
5-99 BU ~Bu H H Tz H H
5-100 Bu Me Me HTz H H
5-101 Bu Me Bt H Tz H H
5-102 au H H Me Tz H H
5-103 3u H H Bt Tz H H
5-104 Bu Me H Me Tz H H
S-105 Elu Bt H Me Tz H H
S~106 E3u iPr H Me Tz H H
5-107 Bu ~Bu H Me Tz H H
5-108 3U H H Fo Tz H H
5-109 au Me H Fo Tz H H
5-110 BU 2t H ~o Tz H H
S-111 ~u iPr H Fo TZ H H
5-112 ~U ~3u H Po Tz H H

.

Table 5 (cont.) 20~1607 Cpd. Rl R2 R3 R4 R7 R8 R9 No.

5-113 Bu H H Ac Tz H H
5-114 Bu Me H Ac Tz H H
5-115 Bu Et H AC Tz H H
5-116 Bu iPr H Ac Tz H H
5-117 Bu tBu H Ac Tz H H
5-118 Bu H H H Tz H Me 5-119 Bu H H H Tz H Et 5-120 Bu H H H Tz H Pr 5-121 Bu H H H Tz H lPr 5-122 Bu H H H Tz H iBU
5-123 Bu H H H Tz H ~Pn 5-124 Bu H H H Tz Me Me 5-125 Bu H H H COOH H CH2COOH
5-126 3u H H H COOH H CH2COOEt 5-127 8u H H H COOH H l-~HOOC)Et 5-128 Bu H H H COOH H l-(Etc)Et 5-129 Bu H H H COOH H 2-(HOOC)Et 5-130 9u H H H COOH H 2-(Etc)Et 5-131 Bu H H H COOH H ~-(HOOC)Bz ' 5-132 Bu H H H COOH H l-(HOOC)-2-(Ph)Et 5 133 Bu H H H COOH H l-(HOOC)-2-(Fu)Et 5 134 BU H H H COOR H l-(HOOC)-2-(Th)Et 5-135 Bu H H H COOH H l-(HOOC)-2-(Im)Et S-136 au H H H COOH H . l-(HOOC)-2-(HO)Et 5-~37 Bu H H H COOH H l-(HOOC) 2-(MeO)Et 5-133 BU M~ H H COOH H CH2COOH
5-139 ~u Me H H COOH H CH2COO~t 5-140 Bu Me H H COOH H l-(HOOC)Et Table 5 (cont.~ 2U61~07 Cpd. R1 R2 R3 R4 R7 R8 R9 No. ..

5-141 Bu Me H H COOH H 1-(Etc)Et 5-142 Bu Me H H COOH H 2-(HOOC)Et 5-143 Bu Me H H COOH H 2-(Etc)Et 5-144 Bu Me H H COOH H ~-(HOOC)-Bz 5-145 Bu Me H H COOH H 1-(HOOC)-2-(Ph)Et 5-146 Bu Me H H COOH H 1-(HOOC)-2- (FU) Et 5-147 Bu Me H H COOH H l-(HOOC)-2-(Th)Et 5-148 Bu Me H H COOH H 1-(HOOC)-2-(Im)Et 5-149 Bu Me H H COOH H 1-(HOOC)-2-(HO)Et 5-150 Bu Me H H COOH H l-(HOOC)-2-(MeO)Et 5-151 Bu iPr H H COOH H CH2C0OH
5-152 Bu 1Pr H H COOH H CH2COOEt 5-153 Bu lPr H H COOH H 1-(HOOC)Et 5-154 Bu iPr H H COOH H 1-(EtC)Et 5-155 8u iPr H H COOH H 2-(HOOC)Et 5-156 Bu iPr H H COOH H 2-(Etc)Et 5-157 au iPr H H COOH H ~-(HOOC)-~z 5-158 Bu 1Pr H H COOH H 1-(HOOC)-2-(Ph)Et 5-159 Bu iPr H H COOH H 1-(HOOC)~2-(Fu)Et 5-160 au iPr H H COOH H 1-(HOOC)-2-(~h)Et 5-161 Bu ~Pr H H COOH H 1-(HOOC)-2-(Im)Et 5-162 ~u iPr H H COOH H 1-(HOOC)-2-(HO)Et 5-163 Bu iPr H H COOH H 1-(HOOC)-2-(MeO)Et 5-164 au ~au H H COOH H CH2COOH
5~165 au ~Bu H H COOH H CH2COOEt 5~166 BU ~BU H H COOH H 1-~HOOC)Et 5-167 au ~Bu H H COOH H 1-(Etc)Et 5-168 Bu ~Bu H H COOH H 2-(HOOC)Et ~' ' ' ' . ' , , ' 20~1607 Table 5 (cont.) Cpd, Rl R2 R3 R4 R7 R8 R9 No.

5-169 Bu ~3u H H COOH H 2-(Etc)Et 5-170 Bu tBu H H COOH H a- (HOOC)-Bz 5-171 Bu tBu H H COOH H 1-(HOOC)-2-(Ph)Et 5-172 3u tBu H H COOH H 1-(HOOC)-2-(Fu)Et 5-173 Bu ~8u H H COOH H 1-(HOOC)-2-(Th)Et 5-174 Bu ~3u H H COOH H 1-(HOOC)-2-(Im)Et 5-175 Bu ~Bu H H COOH H 1-(HOOC)-2-(HO)Et 5-176 Bu ~Bu H H COOH H 1-(HOOC)-2-(MeO)Et 5-177 Bu H H H TZ H CH2COOH
5-178 Bu H H H Tz H CH2COOEt 5-179 Bu H H H Tz H 1-(HOOC)Et 5-180 Bu H H H Tz H 1- (Etc)Et 5-191 Bu H H H Tz H 2-(HOOC)Et 5-la2 Bu H H H Tz H 2-(Etc)Et 5-183 3u H H H Tz H a-(HOOC)-Bz 5-184 Bu H H H TZ H 1- (HOOC)-2 (Ph)Et 5-185 Bu H H H Tz H 1-~HOOC)-2-~Fu)Et 5-186 Bu H H H Tz H 1-~HOOC)-2-~Th)Et 5 1~7 Bu H H H Tz H l-(HOOC)-2-(Im)Et 5-188 Bu H H H Tz H 1-~HOOC)-2-(HO)Et 5-189 au H H H Tz H 1-(HOOC)-2-(MeO)Et 5 190 Bu Me H H Tz H CH2COOH
s 191 au Me H H Tz H CH2COOEt 5-192 Bu M~ H H Tz H l (HOOC)Et 5-193 Bu Mo H H Tz H 1-~Etc)Et 5-194 Bu Me H H Tz H 2-~HOOC)Et 5-195 ~u Me H H Tz H 2-~Etc)~t 5-196 3u Me H H Tz H ~-~HOOC)-Bz .,- . , ,, ... ' :,~ ' ' ,~ , .
: ~ .
~ . .

Table 5 (cont.) Cpd, Rl R2 R3 R4 R7 R8 R9 No .

5-1g7 ~u Me H H Tz H 1-(HOOC) 2-(Ph)Et 5-198 Bu Me H H Tz H 1-(HOOC)-2-(Fu)Et 5-199 Bu Me H H Tz H 1-(HOOC)-2-(Th)Et 5-200 Bu Me H H Tz H 1-(HOOC)-2-(Im)Et 5-201 Bu Me H H Tz H l-(HOOC)-2-(HO)Et 5-202 Bu Me H H Tz H 1-(HOOC)-2-(MeO)Et 5-203 Bu iPr H H Tz H CH2COOH
5-204 Bu iPr H H Tz H CH2COOEt 5-205 Bu iPr H H Tz H 1-(HOOC)Et 5-206 Bu iPr H H Tz H 1-(Etc)Et 5-207 Bu iPr H H Tz H 2-(HOOC)Et 5-208 ~u iPr H H Tz H 2-(Etc)Et 5-209 au iPr H H Tz H ~-~HOOC)-Bz 5-210 Bu iPr H H Tz H l-(HOOC)-2-(Ph)Et 5-211 Bu iPr H H Tz H 1-(HOOC)~2-(Fu)Et 5-212 Bu iPr H H Tz H 1-(HOOC)-2-(Th)Et 5-213 Bu iPr H H Tz H 1-~HOOC)-2-(Im)Et 5-214 Bu iPr H H Tz H 1-(HOOC)-2-(HO)Et 5-215 Bu iPr H H Tz H l-(HOOC)-2-(MeO)Et 5-216 Bu ~Bu H H Tz H CH2COOH
5-217 ~u S3u H H Tz H CH2COOEt 5~21~ Bu ~Bu H H Tz H 1-(HOOC)Et 5-219 Bu ~Bu H H Tz H 1-~Etc)Et 5-220 Bu ~Bu H H Tz H 2~tHOOC)Et 5~221 Bu ~Bu H H Tz H 2-(Etc)Et 5 222 Bu ~Bu H H Tz H ~-(HOOC) -az 5-223 Bu ~Bu H H Tz H l-(HOOC)-2-(Ph)Et 5-224 Bu ~3u H H Tz H 1-(HOOC)-2-(Fu)Et Table 5 (cont.) Cpd R1 R2 R3 R4 R7 R8 R9 No.

5-225 Bu ~Bu R H Tz H 1-(HOOC)-2-(Th)Et 5-226 Bu S~u H H Tz H 1-(HOOC)-2-(Im)Et 5-227 3u tBu H H Tz H 1-(HOOC)-2-(HO)Et 5-228 Bu ~Bu H H Tz H 1-(HOOC)-2-(MeO)Et 5-229 Pr H H H COOH H CH2COOH
5-230 Pr H H H COOH H CH2COOEt 5-231 Pr H H H COOH H 1-(HOOC)Et 5-232 Pr H H H COOH H 1-(Etc)Et 5-233 Pr H H H COOH H 2-(HOOC)Et 5-234 Pr H H H COOH H 2-(Etc)Et 5-235 Pr H H H COOH H ~-(HOOC)-3z 5-236 Pr H H H COOH H 1-(HOOC)-2-(Ph)Et 5-237 Pr H H H COOH H 1-(HOOC)-2-(Fu)Et 5-238 Pr H H H COOH H l-(HOOC)-2-(Th)Et 5-239 Pr H H H COOH H 1-(HOOC)-2-(Im)Et 5-240 Pr H H H COOH H l (HOOC)-2-(HO)Et 5-241 Pr H H H COOH H 1-(HOOC)-2-(MeO)Et 5-242 Pr Me H H COOH H CH2COOH
5-243 Pr Me H H COOH H CH2COOEt 5 244 Pr Me H H COOH H 1-~HOOC)Et 5-245 Pr Me H H COOH H 1-(Ftc)Bt 5 246 Pr Me H H COOH H 2-~HOOC)Et 5-247 Pr Me H H COOH H 2-(Etc)Bt 5 248 Pr Me H H COOH H ~-(HOOC)-Bz 5-249 Pr MQ H H COOH H 1-(HOOC)-2-(Ph)Et 5-250 Pr Me H H COOH H 1-(~OOC)-2-(Fu)Et 5 251 Pr M H H COOH H 1-(HOOC~ 2-(Th)Et 5-252 Pr Me H H COOH H 1-(HOOC)-2-(Im)Et ~. , .. .

Table 5 (cont.) 2~16Q7 Cpd, Rl R2 R3 R4 R7 R8 R
No.

5-253 Pr Me H H COOH H l-(HOOC)-2-(HO)Et 5-254 Pr Me H H COOH H l-(HOOC)-2-(MeO)Et 5-255 Pr iPr H H COOH H CH2COOH
5-256 Pr iPr H H COOH H CH2COOEt 5-257 Pr iPr H H COOH H l-(HOOC)Et 5-258 Pr iPr H H COOH H l-(Etc)Et 5-259 Pr iPr H H COOH H 2-(HOOC)Et 5-260 Pr iPr H H COOH H 2-(Etc)Et 5-261 Pr iPr H H COOH H CH2(ph)cooH
5-262 Pr iPr H H COOH H l-(HOOC)-2-(Ph)Et 5-263 Pr iPr H H COOH H l-(HOOC)-2-(Fu)Et 5-264 Pr iPr H H COOH H l-~HOOC)-2-(Th)Et 5-265 Pr iPr H H COOH H l-(HOOC)-2-(Im)Et 5-266 Pr iPr H H COOH H l-(HOOC)-2-~HO)Et 5-267 Pr iPr H H COOH H l-~HOOC)-2-~MeO)Et 5-268 Pr ~Bu H H COOR H CH2C0OH
5-269 Pr ~Pu H H COOH H CH2COOEt 5-270 Pr ~u H H COOH H l-(HOOC)Et 5-271 Pr ~Bu H H COOH H l-(Etc)Et 5-272 Pr ~au H H COOH H 2-(HOOC)Et 5-273 Pr ~3u H H COOH H 2-(Etc)Bt 5-274 Pr ~Bu H H COOH H ~-(HOOC)-Pz 5-275 Pr ~u H H COOH H l-(HOOC)-2-(Ph)Et 5-276 Pr ~Bu H H COOH H l-(HOOC)-2-(Fu)Et 5-277 Pr ~BU H H COOR H l-(HOOC)-2~(Th)Et 5-27a Pr ~u H H COOH H l-(HOOC)-2-(Im)Et 5~279 Pr ~Bu H H COOH H l-(HOOC)-2-(HO)~t 5-2~0 Pr ~BU H H COOH H l-(HOOC~-2-(MeO)Et -. ' ' ' ,' , :,.

,~ :
- ' ' ' ~ ' :
, :, , . ' ' . ' ':, - 72 - 20~1607 Table 5 (cont.) Cpd, R1 R2 R3 R4 R7 R8 R9 No.

5-281 Pr H H H Tz H CH2COOH
5-2~2 Pr H H H Tz H CH2COOEt 5-283 Pr H H H Tz H 1-(HOOC)Et 5-284 Pr H H H Tz H 1-(Etc)Et 5-285 Pr H H H Tz H 2-(HOOC)Et 5-2~6 Pr H H H Tz H 2- (Etc)Et 5-287 Pr H H H Tz H ~-(HOOC) -BZ
5-2~8 Pr H H H Tz H 1-(HOOC)-2-(Ph)Et 5-2~9 Pr H H H Tz H 1-(HOOC)-2-(Fu)Et 5-290 Pr H H H Tz H 1-(HOOC)-2-(Th)Et 5-291 Pr H H H Tz H 1-(HOOC)-2-(Im)Et 5-292 Pr H H H Tz H 1-(HOOC)-2-(HO)Et 5-293 Pr H H H Tz H 1-(HOOC)-2-(MeO)Et 5-294 Pr Me H H Tz H CH2COOH
5-295 Pr Me H H Tz H CH2COOEt 5 296 Pr Me H H Tz H 1-(HOOC)Et 5-297 Pr Me H H Tz H 1-(Etc)Et 5-298 Pr Me H H Tz H 2-(HOOC)Et 5-299 Pr Me H H Tz H 2-(Etc)Et 5-300 Pr Me H H Tz H ~-(HOOC)-Bz 5-301 Pr Me H H Tz H 1-(HOOC)-2-(Ph)Et 5-302 Pr Me H H Tz H 1-(HOOC)-2-(Fu)Et 5-303 Pr Me H H Tz ~ 1-(HOOC)~2-(Th)Et ,.
5-304 Pr Me H H Tz H 1-(HOOC)-2-(Im)Et 5-305 Pr Mo H H Tz H l-(HOOC)-2-(HO)Et 5-306 Pr Me H H Tz H l ~HOOC)-2-(MeO)Et 5-307 Pr iPr H H Tz H CH2COOH
5-308 Pr iPr H H TZ H CH2COOEt - 73 ~ 20S1~07 Table 5 (cont.) . .

Cpd R1 R2 R3 R4 R7 R8 R9 No.

5-309 Pr iPr H H Tz H 1-(HOOC)Et 5-310 Pr iPr H H Tz H 1-(Etc)Et 5-311 Pr iPr H H Tz H 2-(HOOC)Et 5-312 Pr iPr H H Tz H 2-(Etc)Et 5-313 Pr iPr H H Tz H ~-(HOOC)-Bz 5-314 Pr iPr H H Tz H 1-(HOOC)-2-(Ph)Et 5-315 Pr ~Pr H H Tz H 1-(HOOC)-2-(Fu)Et 5~316 Pr iPr H H Tz H 1-(HOOC)-2-(Th)Et 5-317 Pr iPr H H Tz H 1-(HOOC)-2-(Im)Et 5-318 Pr iPr H H Tz H 1-(HOOC)-2-(HO)Et 5-319 Pr iPr H H Tz H 1-(HOOC)-2-(MeO)Et 5-320 Pr ~Bu H H Tz H CH2COOH
5-321 Pr ~Bu H H Tz H CH2COOEt 5-322 Pr ~u H H Tz H l-~HOOC)Et 5-323 Pr ~Bu H H Tz H 1-~Etc)Et 5-324 Pr ~Bu H H Tz H 2-(HOOC)Et S-325 Pr s3u H H Tz H 2-~Etc)Et S-326 Pr ~Bu H H Tz H ~-~HOOC)-Bz 5-327 Pr ~Bu H H Tz H l-(HOOC)-2-(Ph)Et 5-32a Pr ~Bu H H Tz H 1-(HOOC)-2-(Fu)Et 5-3ag Pr ~Bu H H Tz H 1-~HOOC)-2-~Th)Et 5-330 Pr ~3U H H Tz H 1-(HOOC)-2-(Im)~t S-331 Pr ~3U H H Tz H 1-~HOOC)-2-~HO)Et 5-332 Pr ~u H H Tz H 1-(HOOC)-2-~MeO)Et 5-333 Bu iPr iPr H COOH H H
5-334 Bu H H H COOH -~CH2)3CH~COOH)-5~335 Bu H H H COOH -~CH2)3CH~COOMe)-5-336 Pr H H H -COOCH2--OPlv H H

.
.

, .
. .

2061~û7 Table 5 (cont.) Cpd. Rl R2 R3 R4 R7 R8 R9 No.

5-337 Pr Me H H -COOCH20Piv H H
5-338 Pr Me Me H -COOCH20Piv H H
5-339 Pr H H H -COOMod H H
5-340 Pr Me H H -COOMod H H
5-341 Pr Me Me H -COOMod H H
5-342 Bu H H H -COOCH20Piv H H
5-343 Bu Me H H -COOCH20Piv H H
5-344 Bu Me Me H -COOCH20Piv H H
5-345 Bu H H H -COOMod H H
S-346 Bu Me H H -COOMod H H
5-3~7 Bu Me Me H -COOllod H H
5-349 Et iPr H H Tz H H
5-349 Et iPr H H COOH H H
5-350 ~t ~Bu H H Tz H H
5-351 ~t ~Bu H H COOH H H

.

20~1607 Tabl e 6 Cpd. R1 R2 R3 R4 R5a R6 R7 No .

6-1 Pr Me Me H H H 2-Tz 6-2 Pr Me Me H H 6-Cl 2-Tz 6-3 Bu Me Me H H 6-C1 2-Tz 6-4 Pr Me Me H H 6-OMe 2-Tz 6-5 3u Me Me H H 6-OMe 2-Tz 6-6 Pr Me Et H H H 2- Tz 6-7 Bu Me Et H H H 2-Tz 6-3 Pr Et Et H H H 2-Tz 6-9 Bu Et Et H H H 2-Tz 6-10 Pr Me Me Me Et H 2-Tz 6-11 Pr Me Me Me H H 2-Tz 6-12 Bu Me Me Me Et H 2-Tz 6-13 3u Me Me Me H H 2-Tz 6-14 Pr Bt Et H Et H 2-Tz 6-15 Et Me Me H H H 2-Tz 6-16 Et Me Me H Et H 2-Tz 6-17 Et Me Me H iPrcOCH2- H 2-Tz 6~13 ~t Me Me H PlvOCH2- H 2-Tz 6-19 ~t Me Me H Mod H 2-Tz 6-20 Et Me Me H Phth H 2-Tz , - 76 - 20616~7 Of the compounds li~ted above, the following are preferred, that i~ to say Compounds No. 1-1, 1-2, 1-3, 1-9, 1-11, 1-12, 1-15, 1-22, 1-23, 1-24, 1-25, 1-27, 1-28, 1-31, 1-35, 1-36, 1-37, 1-39, 1-41, 1-49, 1-54, 1-56, 1-58, 1-59, 1-60, 1-61, 1-62, 1-82, 1-84, 1-98, 1-102, 1-103, 1-132, 1-133, 1-134, 1-138, 1-139, 1-140, 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-37, 2-38, 2-39, 2-40, 2-49, 2-50, 2-64, 2-65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, 3-13, 3-14, 3-25, 3-26, 3-27, 3-35, 3-36, 3-39, 3-40, 3-51, 3-52, 3-53, 3-61, 3-65, 3-77, 3-78, 3-79, 3-87, 3-91, 3-103, 3-104, 3-105, 3-107, 3-109, 3-111, 3-112, 3-121, 3-127, 3-128, 3-129, 3-135, 3-136, 4-1, 4-4, 4-5, 4-6, 4-7, 4-a, 4-9, 4-10, 4-11, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-21, 4-22, 4-23, 4-25, 4-26, 4-27, 4-29, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-38, 4-39, 4-41, 4-43, 4-44, 4-46, 4-49, 4-50, 4-51, 4-52, 4-53, 4-54, 4-55, 4-56, 4-59, 4-60, 4-61, 4-62, 4-63, 4-64, 4-65, 4-66, 4-67, 4-68, 4-70, 4-71, 4-72, 4-74, 4-76, 4-77, 4-78, 4-79, 4-80, 4-81, 4-83, 4-84, 4-a5, 4-91, 4-96, 4-98, 4-99, 4-107, 4-109, 4-110, 4-112, 4-113, 4-114, 4-115, 5-1, 5-2, 5-3, 5-5, 5-6, 5-13, 5-14, 5-la, 5-19, 5-23, 5-24, 5-32, 5-33, 5-34, 5-36, 5-37, 5-44, 5-45, 5-49, 5-50, 5-54, 5-55, 5-63, 5-64, 5-65, 5-67, 5-68, 5-75, 5-76, 5-80, 5-81, 5-85, 5-a6, 5-94, 5-95, 5-9b, 5-98, 5-99, 5-106, 5-107, 5-111, 5-112, 5-116, 5-1~7, 5 125, 5-138, 5-151, 5-164, 5-177, 5-190, 5-203, 5-216, 5-229, 5-242, 5-255, 5-268, 5-281, 5-294, 5-307, 5-320, 5-348, 5-349, 5 350 and 5-351, o~ whlch Compounds ~o. 1-22, 1-25, 1 27, 1 28, 1-31, 1-35, 1-36, 1-37, 1-49, 1-54, 1-56, 1-58, 1-59, 1-132, 1-133, 1-134, 2-1, 2-2, 2-3, 2-5, 2-6, 2-15, ~-16, 2-17, 2 18, 2-19, 2-20, 2 21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-2B, 2-29, 2-30, 2-31, 2-32, 2 65, 2-66, 2-67, 2-68, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, .... : . :, 20616~7 3-13, 3-14, 3-25, 3-26, 3-35, 3-39, 3-40, 3-52, 3-53, 3-61, 3-65, 3-77, 3-78, 3-79, 3-87, 3-91, 3-103, 3-104, 3-105, 3-107, 3-109, 3-111, 3-112, 4-4, 4-5, 4-6, 4-7, 4-11, 4-14, 4-15, 4-16, 4-17, 4-20, 4-29, 4-31, 4-32, 4-33, 4-34, 4-35, 4-36, 4-38, 4-39, 4-41, 4-43, 4-44, 4-46, 4-49, 4-50, 4-51, 4-52, 4-55, 4-56, 4-59, 4-60, 4-61, 4-62, g-65, 4-74, 4-76, 4-77, 4-78, 4-79, 4-80, 4-81, 4-83, 4-84, 4-91, 4-96, 4-107, 4-109, 4-110, 4-114, 4-115, 5-5, 5-6, 5-13, 5-14, 5-32, 5-36, S-37, 5-44, 5-45, 5-63, 5-67, 5-68, 5-75, 5-76, 5-80, 5-81, 5-94, 5-98, 5-9g, 5-106, S-107, S-348, 5-349, 5-350 and 5-351 are more preferred, and Compounds No. 1-2B, 1-31, 1-35, 1-36, 1-49, 1-56, 1-58, l-S9, 1-132, 1-133, 1-134, 2-1, 2-2, ~-3, 2-S, 2-6, 2-lS, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22, 2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-65, 2-66, 2-67, 2-63, 2-69, 2-70, 2-71, 2-73, 2-74, 2-75, 2-76, 2-77, 3-1, 3-9, 3-10, 3-13, 3-14, 3-25, 3-26, 3-53, 3-61, 3-65, 3-77, 3-7a, 4-29, 4-31, 4-32, 5-36 and 5-37 are etill more pre~erred. The moct preferred compounde are Compound~
No.:

1-31. 2-~3utyl-1-~2'-caLboAybiphenyl-4-yl)methyl]-4-~1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid;

1-35. Pivaloyloxymethyl 2-butyl-1-~(2'-carboxyblphenyl-4-yl) methyl]-4-~l-hydroxy-1-methylethyl)imidazole-5-carboxylate;

1-36. ~5-Mothyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-~ 2'-carboxybiphenyl-4-yl)methyl]-4-~1-hydroxy-1-methylethyl)~ A zcle-5-carboxylate;

1-49. 1-~2'-Carboxybiphenyl-4-yl)methyl]-4-~1-hydroxy-1-methylethyl)-2-propyllm~zole-5-carboxyllc acid;

1-132. 1-~2'-Carboxyblphenyl-4-yl)methyl]-2-ethyl-4-.

(l-hydroxy-l-methylethyl)imidazole-5-carboxylic acid;

2-1. 4-(1-Hydroxy-l-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

2-2. 2-Butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

2-15. Pivaloyloxymethyl 4~ hydroxy-1-methylethyl)-2-propyl-l-(4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

2-16. Pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methyl-ethyl)-l-{4-[2-(tetrazol-5-yl)phenyl]phenyl~methyl-imldazole-5-carboxylate;

2-17. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-l~methylethyl)-2-propyl-1-(4-[2-(tetrazol-5-yl)phenyl]phenyl)methyl~ m~ ~ 701e-5-carboxylate;

2-18. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydraxy-1-methylethyl)-1-~4-~2-(tetrazol-5-yl)-phenyl~phenyl)methylimldazole-5-carboxylate;

2-19. Zthoxycarbonyloxymethyl 4-(1-hydroxy-1-methyl-othyl)-2-p~opyl-1-~4-12-(tetrazol-S-yl)phenyl]phenyl~-m~thylimldazole-5-car~oxylate;

2-21. Ico~L~o~carbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-~2-(tetrazol-5-yl)phenyl]-phenyl)methyllmldazole-S-carboxylate;

2-23. l-(~thoxyc~r~o~yloxy)ethyl 4-(1-hydroxy l-methyl-ethyl)-2-propyl-1-l4-~2-(tetrazol-S-yl)phenyl]phenyl~-methylimldazole-5-carboxylate;

, .

~ 79 2~160~
2-2s. l-(Isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

2-69. Pivaloyloxymethyl 2-ethyl-4-~1-hydroxy-1-methyl-ethyl)-1-~4-[2-(tetrazol-5-yl)phenyl]phenyl~methyl-imidazole-S-carboxylate;

2-73. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethyl-4~ hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)-phenyl]phenyl~methyl~ m~ ole-S-carboxylate;

3-1. Pivaloyloxymethyl 1-[(2'-carboxybiphenyl-4-yl)-methyl~-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

3-25. (S-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-~2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-l-methylethyl)-2-propyl~ m~ d~zole-5-carboxylate;

3-26. Phthalidyl 1-~2'-carboxyblphenyl-4-yl)methyl]-4 ~1-hydroxy~l-methylethyl)-2-prowllmidazole-5-carboxylate;

4-29. 4-~1-Hydroxyethyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyl]phenyl~methylimidazole-5-carboxylic acid;

4-31. Pivaloyloxymethyl 4-~1-hydroxyethyl)-2-propyl-1-~4-[2-~tetrazol-5-yl)phenyl~phenyl~methylimidazole-5-carboxylate: and 4-32. ~5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-~1-hydroxyethyl)-2-propyl-1-~4-~2-~tetrazol-5-yl)phenyl]-phenyl)methylimldazole-5-carboxylate;

and p~arr~ceutically acceptable saltc thereo~.

.

. .

20l~1~07 The compounds of the present invention can be prepared by a variety of methods well known in the art for the preparation of compounds of this type.

' ~' ' "' . '",'"' ', ' .
.
. , . , :. . , , . , ' ' ; ' ' ~
-For example, in general terms, the compounds may be prepared by reacting a compound of formula ( II ):

\~
/N~¢ Re ( ) H
in which:

Rl is as defined above and Rd represents a group of formula - ¢-R3 wherein R2, R3 and R4 are as defined above, or Rd represents a group of formula -COORf wherein Rf represents a carboxy-protecting group, Rd represents a ~roup of formula -COR2, wherein R2 i8 as defined above, or Rd represents a cyano group; and Re represents a cyano group, a carboxy group or a group o~
formula -COORf, wherein Rf is as defined above, with a compound o~ formula ~III):

~2 ~ (m) R6 R~

.

. . . . .
, . .

~ ~n6l607 in which: R6 is as defined above; R7a represents a protected carboxy group, a cyano group, a protected tetrazol-5-yl group, a carbamoyl group or an alkylcarbamoyl group; and x represents a halogen atom;

to give a compound of formula (IV):

Rl"~'~ Rd N~~Re ~ CH2 \

R6 R~
wherein Rd, Re, R1, R6 and R7a are as defined above; and in any order, removing protecting groups, and, if necessary, converting said group Rd to a group of formula - C-~3 oR4 wherein R2, R3 and R4 are as defined above, and, i~ nece~s~ry, converting said group Re to a group R5, convertins said ~roup R7~ to a group R7, or alkylating or acylatin~ a hydroxy ~roup in R4, to give a compound of ormula ~I); and optionally salifyin~ or esterifying the product :; . . ' ~ .

Preferably, Re represents a protected carboxy group, when R7a represents a protected carboxy group, a cyano group, a protected tetrazolyl group, a carbamoyl group or an alkylcarbamoyl group, and Re represents a cyano group when R7a represents a protected carboxy group or a protected tetrazolyl group.

- 84 - 20~1 607 In more detail, the compounds of the present invention may be prepared as described below in Reaction Schemes A to F.

Reaction Scheme A:

In this Reaction Scheme, a compound of formula (I) is prepared by reacting an imidazole-5-carboxylic acid or ester thereof of formula (V) with a biphenylmethyl halide of formula ~III), and then, if desired, removing protecting groups, converting the group of formula ~CoOR5a to any other group represented by R5, converting the group represented by R7a to any other group represented by R7 and/or alkylating or acylating a hydroxy group in R4, as shown below:

_ 85 - 20~ 7 Reaction Scheme A: .

R COOR5 ~ XC~ \RS
(V~
(III) Rl~ Rl~3 Step A2 (Ia) (I) . . :, ~~' - 86 - ~ 7 In the above reaction scheme, Rl, R2, R3, R4 Rs R5a R6 R7 R7a and X are as defined above, and R5a preferably represent~ a group other than a hydrogen atom.
7a Where R represents a protected carboxy group, the protecting group may be any of the e~ter residues illu~trated above in relation to R5a. Alternatively, R7a may be a carbamoyl group or a substituted carbamoyl group of formula -CONHR, where R represent~ a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, for example any of tho~e illustrated above in relation to Rl. Examples of such carbamoyl groups which may be represented by R7a include the c~rb yl, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, t-pentylcarbamoyl and hexylcarbamoyl groups, of which the carbamoyl, t-butylcarbamoyl and t-pentylcarbamoyl grcup~ are prererred. Where R7a represent3 a protected tetrazolyl group, the protecting group may be any protectlng group commonly used to protect tetrazolyl groupc ln conventional compound~ o~ thi~ type. Examples of ~ultable protectlng groupe lnclude the aralkyl groups de~ined and exempll~led above ln relation to R2, but lc pre~erably a benzyl, dlphenylmethyl ~benzhydryl) or trlphenylmethyl ~trityl group), moet prererably a trityl group.

X .e~ocont~ a halogen atom, pre~erably a chlorlne, bromlne or lodtne atom).

In Step Al o~ thie Reactlon Scheme, a compound o~
~ormula (Ia) ic prepared by reacting an imldazole-5-carboxylats compound Or rormula ~V) wlth a blphenyl-mothyl compound o~ ~ormula (III). The reactlon normally and pre~erably takeo place in an lnert ~olvent and prererably ln the preeence o~ a ba~o.

.
' The reaction i9 normally and preferably effected in the pre~ence of a ~olvent. There is no particular restriction on the nature of the ~olvent to be employed, provided that it has no adver~e effect on the reaction or on the reagents involved and that it can di~solve the reagents, at least to some extent. Example~ of suitable solvents include: hydrocarbons, preferably aromatic hydrocarbons, such as benzene or toluene; ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or t-butanol; amides, such as ~,~-dimethylacetamide, _,N-dimethylformamide or N-methyl-2-pyrroli~inone; ketones, such a~ acetone or methyl ethyl ketone; nitriles, such as acetonitrile; and sulroY~es, such as dimethyl sulfoxide. Of the~e, we pre~er the ~m~eg, ketones, nitrilee and sulfoxides.

The nature o~ the baee employed ln the reaction i9 llkewlee not critical, and any base capable o~ reacting wlth the acid H-X can be used in this reactlon.
Prererred example~ o~ ba~e~ which may be used include:
alkali metal carbonatee, euch as sodlum carbonate or potacslum carbonate; alkali metal hydridee, ~uch as sodium hydride, potaceium hydride or lithium hydrlde;
alkali metal a~koY~ee, euch ae eodium methoY~de, sodium ethnY~de, pota~eium t-butox~e or lithium met~oY~de; and alkali metal blcarbonatee, euch a~ eodium bicarbonate or potacoium blcarbonate. or these, we pre er the alkall motal cArbonAtee, alkali motal hydrides or alkali metal a1 koY~ dee, The reaction can take place over a wide range o~
temporaturee, and the preciee reaction temperature is not critlcal to the inventlon. In general, we ~ind lt convonient to carry out the reaction at a temperature o~
~rom ~10~C to 100~C, more pre~erably ~rom 0~C to aooc.
Tho tlme requlred ~or tho reactlon may aleo vary wldely, de~o~lrg on many ~actore, notably the reaction - 88 - 20 61 6~7 temperature and the nature of the reagents and solvent employed. However, provided that the reaction i9 e~fected under the preferred condition~ outlined above, a period of from 30 minute~ to 24 hours, more preferably from 1 to 16 hour~, will usually suffice.

After completion of the reaction, the de~ired compound of formula (Ia) can be recovered from the reaction mixture by conventional means. For example, one ~ultable recovery procedure compri~es: removing the eolvent by di~tillation under reduced pre~sure; mixing the re~idue with water; extracted the re31due with a water-lmmisclble solvent, ~uch a~ ethyl acetate; drying the extract over, for example, anhydrous sodium sulfate;
and ~reeing the product rrOm the solvent by di~tillation. The re~ult~ng product can, i~ necessary, be puri~ied by conventional meane, ~or example, by recry~tallization, or the various chromatography technlgue~, notably preparative thin layer chromatography or column chromatography.

5tep A2 may compri~o any one or (ir ap~ropLiate) more o the ~ollowing reactione:

~i) removing the carboxy-protecting groupc either eoloctlvoly or non-eolectively ~rom the group o~ ~ormula ~CooR5A and/or the group R7a, to convert it or them to a froo carboxy group ac Lepre~0~te~ by R5 or R7;

~il) eeteri~ying any euch rree carboxy group to provlde ~n e~ter o~ the group, ~or exam~le ae llluetrated above 1~ rol~tlon to R5;

~1ii) converting ~uch a rreo carboxy group repre~ented by RS to A group o~ ~onmula -CONR~R9;

llv) removing the tetrazolyl-protectlng group;

20~1~07 (v) converting a cyano group represented by R7a to a tetrazolyl group;

(vi) converting a m~no~lkylcarbamoyl group or a carbamoyl group repre~ented by R7a first to a cyano group and then to a tetrazolyl group;

(vil) where R4 represents a tri-substituted 9ilyl group, an aralkyl group, an aliphatic acyl group, an alkoxymethyl group, an alkoxyalkoxymethyl group, a halo~lko~ymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrothienyl group, a tetrahydro~uryl group or a eubstituted tetrahydro-pyranyl, tetrahydrothiopyranyl, tetrahydrothlenyl or tetrahydro~uryl group havlng a halogen or alkoxy eubotltuent, all o~ which can be regarded as hydroxy-protectlng group~, remov~ng the protectlng group to produce a compound in whlch R4 repreeent~ a hydrogen atom; and (vlli) whoro R4 r~proao~t~ a hydroxy group, alkylatlng or acylatlng thle group.

(1) R~mQVA1 0~ rArhn~Y~PrOteCtir~q gr0~1Da:

~ ho naturo o~ the roaction omployed to remove the carboxy-protocting group will, o~ couree, ~epend on the natur- of th- group to be removed and are well ~nown ln tho rl-ld Or organlc eyntheole.

Por ox4mplo, whero tho carboxy-protoctlng group le an aralkyl group, rOr oxamplo a bonzyl or ~-nltrobenzyl group, tho protoctlng group may bo removod by catalytlc roduction, ln the pc~o~nce Or hydrogon, which may be undor ~tmo~phorlc pro~euro or euporatmo~pherlc preeeure, ~or ~xampl- up to 5 atmoephoree preceure. The reactlon normally ant pro~erably takeo place ln an lnert ~olvent go- 20~1~07 (preferably an alcohol, such as methanol or ethanol, or a carboxylic acid, such as acetic acid) and in the presence of a catalyst. Any catalyst commonly used for catalytic hydrogenation or reduction may equally be employed here, preferably palladium-on-charcoal or platinum oxide.

Where the carboxy-protecting group is a t-butyl or diphenylmethyl group, it may be removed by reacting the protected compound with an acid (preferably a mineral acid, such as hydrogen chloride or sulfuric acid, or an organic acid, such as trifluoroacetic acid, methane-sulfonic acid or ~-toluenesulfonic acid) in an inert solvent (preferably an alcohol, such as methanol or ethanol; an ether, auch as tetrahydrofuran or dioxane;
water; or a mixture of water and one or more of the above organic 301vent~).

Where the carboxy-protecting group i~ a ~ilyl group, thi~ may b~ a group o~ formula -SlRaRbRC, in which Ra, Rb and Rc are ac de~ined above. In this ca~e, the protecting group may be removed by reacting the protected compound wlth an acid (pre~erably a mineral acid, cuch a~ hydrogen chlorlde, or an organic acld, euch as acetic acid, trirluoroacetic acid, methane-sul~onlc acld or ~-toluene~ul~o~lc acld) or with a rluorlne ~alt, such a~ tetrabutylammonium ~luoride. The reactlon normally and pre~erably takee place in an inert eolvent (pre~erably an ether, such as tetrahydro~uran or dioxane; an alcohol, ~uch ac methanol or ethanol; an amldo, cuch ac ~ dtmethylrormamide or ~,~ dimethyl-acetamlde~ water; or a mlxture o~ water and one or more o~ the above organlc solventc).

Where the carboxy-protecting group 1~ an e~ter recldue, the protecting group may be removed by hydrolysie ueing a baee ~pre~erably an alkali metal , 91- 20616~7 hydroxide, such a~ lithium hydroxide, sodium hydroxide or potassium hydroxide, or an alkali metal carbonate, such as sodium carbonate or potassium carbonate) in an inert ~olvent (preferably an alcohol, such as methanol or ethanol; an ether, such as tetrahydrofuran or dioxane; water; or a mixture of water and one or more of the abo~e organic ~olvent~). Where R4 represents an acyl group, it is .- ved simultaneously in the course of this reaction.

The reaction can take place over a wide range of temperatures, and the preci3e reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from 0~C to 100~C, more preferably from about room temperature to 60~C. The time reguired for the reaction may also vary widely, depen~ng on many factors, notably the reaction temperature and the nature of the reagents and ~olvent employed. However, provided that the reaction 1~ ef~ected under the pre~erred condltions outlined above, a perlod o~ from 30 minute~ to 24 hours, more preferably ~rom 1 to 16 hours, wlll u~ually suffice.

A~ter completion of the reaction, the deslred compound may be recovered by conventional means, the nature o~ which will ~epen~ on the nature of the reaction. For example, where the deprotection i9 carried out by catalytic reduction, the desired product can bo ~ccv~ered by riltering oS~ the catalyst and by di~tilling o~ the solvent. Where the deprotection is carrled out uclng an acid, the de~lred product can be rocovered by collecting the precl~ltate in the reaction cy~tem by ~lltration or by concentration o~ the reactlon mixure. Where the deprotection i~ carried out by alkallne hydrolyci~, the declred product can be recovered by di~tilling O~r the solvent and then neutralizing the recldue with an aqueous acld, arter which the precipitate in the aqueous solvent may be collected by filtration; alternatively, it may be recovered by neutralizing the aqueous layer obtained by extracting the reaction mixture with a water-immiscible organic ~olvent (such as ethyl acetate or diethyl ether), extracting the neutralized solution with a water-immiscible organic solvent (~uch as ethyl acetate), and then distilling off the solvent. The reaction product may, if nece~sary, be further purlfied by conventional means, for ~Y~mrle by recrystallization or the variou~ chromatography techniques, notably preparative thin layer chromatography or column chromatography.

Each o~ the protecting groups represented by R5a and R7a can be selectively eliminated by appropriate choice of the protecting groups and the specific reaction conditione employed to remove them.

terl~icati~n Where a compound cont~n~nq one or more ~ree carboxy group~ 1~ produce~, thi~ group or the~e groups may be esteri~ied, by methods well known in organlc chemistry.
For exam~le, the reactlon may be carrled out by reacting the co~e~pond1n~ carboxylic acid wlth a compound of rormula, R5b-Y [in which R5b may represent any o~
the group~ defined above for RSa other than a hydrogen atom, and Y ~e~a30nt~ a halogen atom, such a~ a chlorine, bromlne or lodine atom, a group o~ ~ormula ~oSo3R5b ~ln which R5b ie ae de~ined above) or a ~ul~onyloxy group, ~uch a~ a methanecul~onyloxy or a- toluene~ul~onyloxy group~. The reac~lon ic carried out ln the y~dc~nce o~ a baee, ~or example: an organic amlne, cuch ac trlethylamlne, pyrldine or ~-methyl-morphollne; an alkall metal carbonate, such as sodium car~onate or potaecium carbonate; or an alkall metal - 93 ~ 2061607 hydrogencarbonate, such a~ sodium hydrogencarbonate or potas~ium hydrogencarbonate. It is also normally and preferably carried out in an inert solvent (preferably an amide, such as N,N-dimethylformamide or N,N-dimethylacetamide; a halogenated hydrocarbon, preferably a halogenated aliphatic hydrocarbon, such as methylene chloride; a ketone, such as acetone or methyl ethyl ketone; or an ether, such as tetrahydrofuran or dioxane). Where the deRired ester group i9 an alkyl group, the reaction i8 carried out by reacting the carboxylic acid with the corresponding dialkyl sulfate.

The reaction can take place over a wide range of temperatureo, and the precioe reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of ~rom 0~C to 120~C, more pre~erably ~rom 20~C to 80~C.
The time required for the reaction may also vary widely, depen~1ng on many ~actor~, notably the reaction temperature and the nature o~ the reagents and solvent employed, However, provided that the reaction i8 e~ected under the pre~erred condltlon~ outlined above, a period o~ ~rom 30 m~nl)tec to 24 hours, more pre~erably rom 1 to 16 hourc, will ucually 9U ~ice.

Where a c~nho~y-protecting group ie a Cl - C6 alkyl group, the eoterirication reaction may be carried out by reacting the cG~seb~ondlng carboxyllc acid with a Cl C6 alcohol, ouch a~ methanol, ethanol, propanol or hsx~nol, ln the pree~nce o~ an acid catalyot, such as hydrogen chlorldo or ~ulrurlc acid, ln an i.nert oolvent ~or exam~le: one o~ tho Cl - C6 alcohols wh~ch may bo ueed ao tho otarting material dew rlbed above; a halogenated hydrocarbon, ~uch ae methylene chloride; or an ether, ~uch a~ tetrahydro~uran or dioxane) at a temporature o~ ~rom 0~C to 100~C ~or a perlod o~ ~rom 1 to 24 hours, or by reactlng the correopon~ng carboxylic ,; , . ..

o~ ~ ~

20~1607 acid with a halogenating agent (e.g. pho~phorus pentachloride, thionyl chloride or oxalyl chloride) in an inert solvent (for example: a halogenated hydrocarbon, ~uch a~ methylene chloride; an ether, such ae tetrahydrofuran or dioxane; or an aromatic hydrocarbon, such ae benzene or toluene) at a temperature of about room temperature for a period of from 30 minutee to 5 hours to yield the corresponding acyl halide, which ie then reacted with the correeponding alcohol in an inert solvent (e.g. benzene or methylene chloride) in the presence of a base (for example triethylemlne; in case of the t-butyl e~ter, potassium t-butoxide is used as the preferred base) at a temperature of about room temperature for a period of ~rom 30 mlnutee to 10 hour~ The desired compound can be recovered by conventional meane, for example, by a simllar method to that described in Step Al.
( lii) Formatl~n 0~ A r~rh~moyl gro-V

Co,.veL3ion o~ a carboxy group represented by R5 to a group of ~ormula -CONR8R9, in which Ra and R9 are ae defined above, may be carried out uslng well known methode, ~or example by reacting the carboxyllc acid compound, in which the group a7 i5 protected, with a compound o~ formula (VI):

R R NH ~VI) whereln Ra and R9 are ae de~lned above).

Thlc react~on conBl~te o~ the ~ormatlon o~ a peptide bond and le gonorally well known ln organlc eynthetic chemietry. It may be carrled out ln an lnert solvent ~pre~orably a halogenated hydrocarbon, more pre~erably a halogenated allphatlc hydrocarbon, such ac methylene chlorldo or chloro~orm; an eeter, euch ae ethyl acetate;

, an ether, such a~ tetrahydrofuran or dioxane; or an amide, such as N,N-dimethylacetamide or N,N-dimethyl-~ormamide) in the presence of a condensing agent.

Example~ of co~n~ing agent~ which may be used in this reaction include: carbodiimides, such as N,N-dicyclohexylcarbodiimide or 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride; pho~phoryl compounds, such as diphenylphosphoryl azide or diethylpho~phoryl cyanide; carbonyldiimidazole; and triphenylphosphine-diethyl azodicarboxylate. Of these, we prefer the carbodiimides and diphenylphoephoryl azide. Where a pho~phoryl compound i~ u~ed, the reaction i~ pre~erably carried out in the presence of a tertiary amine, such as triethyl~m~nq or ~-methyl-morpholine Alternatively, the reaction in this ~tep can be accompliAhed by reacting the cArho~ylic acid with a lower alkyl chloroformate, ~uch ao ethyl chloro~ormate or l~obutyl chloro~ormate, in the pre~ence of a tertiary amlne, Auch aA triethylamlne or ~-methylmorpholine, to produce a mlxed acid anhydrlde, or by reacting the carboxylic acld with ~-hyd~u~y~ccinlmide, ~-hydroxy-benzotriazole or ~-nitroph~nol or the like in the ~L~Ee-~o o~ a carbodllmlde, such as ~ dicyclohexyl-c~rbodilmlde, to produce the co~reGyQ~d~n~ actlve ester, an~ ~ubsequently reacting the mixed acld anhydride or the active ester wlth the amine compound o~ ~ormula (VI).

AJ a ~urther alternative, the reaction in thi~ 3tep can be carried out by reactlng tho carboxylic acid wlth a halogenatlng agent, cuch a~ phocphorus pentAchloride, oxalyl chloride or thlonyl chlorlde, ln an inert ~olvent (~or example: a halogenated hydrocarbon, such a3 methylone chlorido; an ether, ~uch a~ tetrahydro~uran or dloxane1 or an aromatlc hydrocarbon, such as benzene or - 96 - 20616~7 toluene) to give the corresponding acyl halide, and then reacting the acyl halide with the amine compound of formula (VI).

All of these reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -20~C to 100~C, more preferably from -5~C to 50~C. The time required for the reaction may aleo vary widely, depending on many factors, notably the reactlon temperature and the nature of the reagents and solvent employed However, provided that the reaction 18 effected under the preferred conditions outllned above, a perlod of from 30 mlnute~ to 24 hours, more pre~erably from 1 to 16 hours, wlll usually suffice.

After completlon o~ the reactlon, the reaction product can be recovered ~rom the reactlon mlxture by conventional means. For example, insoluble materlal~ ln the reaction sy~tem are ~iltered off; a water-immisclble organic solvent, ~uch a~ ethyl acetate, and water are added to the ~lltrate; the organic solvent layer i8 ~eparated and drled over a drylng agent, ~uch as anhydrou~ magne~lum sulfate; and then the 301vent 18 dlstllled o~ to leave the de~lred product. The reaction product may, 1~ nece~Ary, be ~urther purifled by conventional mean~, ~or example by recry~tallizatlon or th~ varleus chromatogr~h~ technlgues, notably preparative thln layer chromatography or column chromatography.

~lv) R~mov~l o~ tstr~Lyl-protect~ng grol~

Thi~ may b~ accompll~hsd by reactlng the protected compound wlth an acld. The reaction is normally and pre~orably e Sec~ed in an inert solvent.

,.

The reaction i9 normally and preferably effected in the presence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it ha~ no adverse effect on the reac~ion or on the reagent~ involved and that it can dissolve the reagents, at least to some extent. Examples of 3uitable solvents include: water; an organic acid, such as acetic acid; an ether, such as tetrahydrofuran or dioxane; an alcohol, ~uch a~ methanol, ethanol or t-butanol; a ketone, ~uch a~ acetone or methyl ethyl ketone; or a mixture of any two or more of these ~olvents. Of these, we prefer water, an organic acid, an alcohol or a mixture thereof.

There i~ no particular limitation upon the nature of the acld u~ed in the reaction, provided that it can normally ~unctlon as a Broneted acid. Preferred examples Or such acids include: organic acid~, such as acetic acld, ~ormic acid, oxalic acid, methane~ulronic acld, ~-tolueneculfonic acld or trlfluoroacetic acid;
and inorganic acidc, such a~ hydrochloric acid, hydrobromic acid, sul~uric acid or phosphoric acid. 0 thece, we pre~er acetlc acid, rormlc acld, trifluoro-acetlc acld or hydrochlorlc acld.

The reactlon can take place over a wlde range of temporatureo, and the preclse reactlon temperature i9 not crltical to the lnvention. In general, we ~lnd it conven~ent to carry out tho reactlon at a temperature o~
~rom -10~C to 120~C, more preierably ~rom 0~C to 100~C.
Tho tlmo regulred ~or tho roactlon may al90 vary wldely, ~o~c ~ny on many ~actorc, notably the reactlon temporaturo and the nature o~ the reagontc and ~olvent employed. Howevor, provided that the reaction ic oi~octed under tho prererred condltlonc outllned above, a perlod o~ ~rom ~rom 0.5 to 24 hour~, more pre~erably rrom 1 to 16 hourc, will ucually su~lce.

~ 6 2 2 After completion of the reaction, the desired product of thi~ reaction can be recovered from the reaction mixture by con~entional means. For example, after distilling off the eolvent, the residue is dissolved in water and a water-immiscible organic solvent. The organic layer contAln;ng the desired compound ie separated and dried over anhydrous magnesium sulfate. After distilling off the solvent, the desired compound can be obtAine~. The reaction product may, if neceeeary, be further purified by conventional means, for example by recryetallization or the various chromatography techniques, notably preparative thin layer chromatography or column chromatography.

~V) ~nver9inn 0~ A CyAnn qroup to ~ tetrazolyl grouD

In thie etep, a cyano group ie converted to a tetrazolyl group by reacting the cyano compound wlth an alkali metal azlde.

The reaction ie normally and preferably e~fected in the preeence o~ a solvent. There ie no particular re~triction on the nature o~ the eolvent to be employed, ~rovlded that it ha~ no adveree e~ect on the reaction or on the reayente involved and that lt can diseolve the reagonte, at leaet to eome extent. Examplee o~ ~uitable ~olventc include: am~es, cuch as N,~-dimethylformAm~e or ~ dimethylacetamlde; etherc, such as dioxane or 1,2~dlmethoxyethane; and eul~ox~dee, euch ae dlmethyl eul~oxide.

~ xamplec Or sultable alkali metal azidee include lithium azide, ~odium azide and potaeelum azlde, o~
whlch sodium azldo lc pre~e~red. There i9 no particular re~trlctlon on the amount ot alkall metal azide eployed, but we generally pre~er to u~e ~rom 1 to 5 equlvalente, more pre~erably ~rom 1 to 3 equivalent~, o~ the alkall . . : . .

, .
, ~

1 6 ~ 2 2061~07 metal azide per equivalent of the cyano compound.

We also prefer to carry out the reaction in the presence of an ~m~n~um halide, ~or example ~mm~nlum fluoride, ~mm~n~um chloride or ~mm~nium bromide, of which ~mmoni um chloride i9 preferred. There is no particular restriction on the amount of Ammontum halide employed, but we generally prefer to use from 0.5 to 2 equivalent~, more pre$erably from 1 to 1.2 equivalents, of the ammonium halide per equivalent of the cyano compound.

The reaction can take place over a wide range of temperature~, and the preci~e reaction temperature i9 not critical to the lnvention. In general, we find it convenient to carry out the reaction at a temperature of from 70 to 150~C, more preferably ~rom 80 to 120~C. The tlme required ~or the reaction may also vary widely, dependin~ on many factors, notably the reaction temperature and the nature o~ the reagent~ and solvent employed, However, provlded that the reaction 1~
e~ected under the pre erred conditlons outllned above, a perlod o~ ~rom 10 hour~ to 7 dayc, more pre erably ~rom 1 to 5 days, will usually su~lce.

Alternatively, the cyano group may be converted to a tetrazolyl group by reacting the cyano compound with a trialkyltin azide or triaryltin azide, and then treating the ro~ulting tin compound with an acid, a ba~e or an alkali metal ~luorlde.

The reactlon o the cyano compound wlth the trialkyltln azlde or trlaryltin azide i8 normally and prererably e~rected ln the preeence o~ a solvent. There i~ no ~articular re~triction on the nature o~ the ~olvent to be employed, provided that it hae no adver~e e~ect on the reaction or on the reagents involved and - lOO- 20616~7 that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include:
hydrocarbons, which may be aliphatic or aromatic hydrocarbons, ~uch as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such a~
1,2-dichloroethane or chloroform; ethers, such a~
dioxane or 1,2-dimethoxyethane; amides, such as N,~-dimethylformamide or N,N-dimethylacetamide; and esters, ~uch as ethyl acetate or butyl acetate.

Although there i9 no particular limitation on the nature of the trialkyltin or triaryl tin azide, and any such compound commonly ueed in reactions of this type may equally be employed here, we generally prefer to u~e: a trialkyltin azide in which each of the alkyl group~ ~which may be thè same or dl~ferent, although they are pre~erably the same) have from 1 to 4 carbon atom~, ~or example trimethyltin azide, triethyltin azide or trlbutyltln azlde; or a trlaryltin azide in which each o~ the aryl group~ (which may be the same or di~erent, although they are preferably the ~ame) is a~
de~lned above ln relation to the aryl group~ which may be represented by R2, pre~erably a phenyl or cubstltuted phenyl group, ~or example triphenyltin azide or tritolyltin azide. The amount o~ the trialkyltin azlde or triaryltln azide employed i~ not critical, although an amount o~ ~rom 1 to 3 equivalents per equivalent o~ cyano compound i~ pre~erred, and rom 1 to 2 equlvalont~ 1~ more pre~erred.

lOl - 20~1 6~ 7 M~C FOLIO: 64868/FP-9205 WANGDOC: 1623H

The reaction of the cyano compound with the trialkyltin azide or triaryltin azide can take place over a wide range of temperatures, and the precise reaction temperature iq not critical to the invention.
In general, we ~ind it convenient to carry out the reaction at a temperature of from 60 to 150~C, more preferably from 80 to 120~C. The time required for the reaction may also vary widely, depPnd;ng on many factor~, notably the reaction temperature and the nature o~ the reagents and solvent employed. However, provided that the reaction ia effected under the preferred condltlons outllned above, a perlod of from 8 hours to 7 day~, more preferably from 1 to 5 day~, wlll usually ~uf~ice.

The tin-cont~ln~ng compound produced by this reaction i~ then treated with an acid, a base or an alkali metal ~luorlde, to convert it to the de~ired tetrazolyl compound. Any acid, bace or alkali me~al ~luoride commonly u~ed for thle type o~ reaction may be u0ed, and example~ Or euitable compound~ lnclude: acid~, e~pecially mlneral acide, ~uch as hydrochloric acid or eul~uric acld; bacee, eepecially inorganic base~, ~uch a~ alkall metal carbonate~ and hydrogencarbonates (~or oxamplo sodium carbonate, potas~ium carbonate, ~odium h~ goncarbonate or potaseium hydrogencarbonate) or alkali metal hydroY~e~ (~or example sodium hydroxide or potaceium hydroxido); and alkall metal rluorldes, 3uch ae lithium ~luoride, sodium ~luoride or pota~ium ~luorlde.

Tho roactlon le normally and pre~erably er~ected in tho y~¢nce o~ a ~olvent. There 1~ no partlcular roctrlctlon on the nature o~ the ~olvent to be employed, provldod that it hae no advereo e~roct on the reaction ., ', .
, : .

or on the reagents involved and that it can di~Rolve the reagent~, at least to some extent. Examples of suitable solvent~ include those listed above for the reaction of the cyano compound with the trialkyltin azide or triaryltin azide and other solventR, such a~ alcohols (for example methanol or ethanol), water or aqueous alcohol~. The reaction can take place over a wide range of temperatures, and the precise reaction temperature i9 not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from 0~C to 100~C, preferably about room temperature.
The time required for the reaction may al~o vary wldely, ~ep~n~ng on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction i9 ef~ected under the preferred conditions outlined above, a period of ~rom 30 minutes to 3 days, more preferably from 1 hour to 24 hours, wlll usually suffice.

A ~urther alternative method of converting a cyano group to a tetrazolyl group ie to react the cyano compound with a trialkyltin halide or trlaryltln hallde, in the plesence o~ an alkali metal azide, and then treating the resulting tln compound wlth an acid, a base or an alkall metal ~luorlde.

The reaction o~ the cyano compound wlth the trlalkyltln hallde or triaryltln hallde ln the presence o~ an alkall metal azlde i8 normally and pre~erably e~rected in the preeence o~ a eolvent. There io no partlcular reotrlctlon on the nature o~ the oolvent to be omployed, provlded that lt hao no adverse e~ ect on tho reaction or on the reagente involved and that lt can ~ooolvo the reagento, at leaot to oome extent.
~YAm~lee o~ sultable ~olvente lnclude: hydrocarbon~, which may be allphatic or aromatic hydrocarbons, ~uch as bonzene, toluene, xylene or heptane; halogenated ' .

. ' 2061607 hydrocarbon3, especially halogenated aliphatic hydrocarbon3, such a~ 1,2-dichloroethane or chloroform;
ethers, such as dioxane or 1,2-dimethoxyethane; ketones, such a~ acetone or methyl ethyl ketone; amides, such as N,N-dimethylformamide or N,N-dimethylacetamide; and e3ters, such a~ ethyl acetate or butyl acetate.

Although there is no particular limitation on the nature of the trialkyltin or triaryl tin halide, and any such compound commonly used in reaction~ of this type may equally be employed here, we generally prefer to use: a trlalkyltin halide in which each of the alkyl group~ (which may be the same or different, although they are preferably the same) have from 1 to 4 carbon atom~, for example trlmethyltln chloride, trimethyltin bromlde, trlethyltln chlorlde or trlbutyltln chloride;
or a trlaryltin hallde in which each of the aryl group~
~which may be the eame or different, al~hough they are preferably the ~ame) 1~ a~ deflned above ln relation to the aryl group~ whlch may be ~pLe~en~ed by R2, pre~erably a phenyl or sub~tltuted phenyl group, ~or example triphenyltln chloride or tritolyltin chloride.
The amount o~ the trialkyltln hallde or trlaryltln hallde employed i9 not critlcal, although an amount of rom 1 to 3 eguivalentc per equivalent o~ cyano compound ie pre~erred, and from 1 to 2 equivalent~ i~ more pre~erred.

There lc no particular reetriction on the alkall metal azlde whlch 1~ aleo employed in thi~ reaction.
~xample~ includo lithium azlde, codlum azlde and potaccium ~zide, of which codium azide i~ pre erred.
The amount of the alkali metal azide employed 19 not crltlcal, although an amount of ~rom 1 to 3 equivalent3 per ~guivalent of cyano compound ic preferred, and from 1 to 2 oquivalent~ i9 more pre~erred.

, . . , . :

The reaction of the cyano compound with the trialkyltin halide or triaryltin halide in the presence of an alkali metal azide can take place over a wide range of temperature~, and thP precise reaction temperature i~ not critical to the invention. In general, we find it con~enient to carry out the reaction at a temperature of from 60 to 150~C, more preferably from 30 to 120~C. The time required for the reaction may also vary widely, dep~n~;n~ on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from ~ hours to 7 days, more preferably from 1 to 5 day~, will u~ually 3uffice.

The tin-conta~n~n~ compoun~ produced by thi~
reaction i~ then treated with an acid, a base or an alkali metal fluoride, to convert it to the desired tetrazolyl compound. The reaction i9 e~entlally the came as the reaction Or the tin cont~1n~ng compound ~pro~uced ~y reacting the cyano compound wlth a trlalkyltin azide or triaryltin azide) with an acid, a bace or an alkali metal ~luoride, and may be carried out w lng the s_me colventc and reaction condltlons.

(vl) ~nnvercl~n o~ An Al~ylrArb~moyl grou~ or ga~8Loyl ~rou~ to A

To conve,L an alkylcarbamoyl group to a cyano group, the alkylcarbamoyl compound i~ reacted with a halogen compound capable o~ acting a~ a halogenatlng agent, pre~erably chlorlnating agent, ~or example oxalyl chlorlde, phocphorw oxychloride or eul~onyl chlorlde.
There i~ no particular rectrlctlon on the amount o~
halogsn compound employed, although we generally ~ind it conv~nient to u~e ~rom 1 to 3 e~uivalents, more pre~erably ~rom 1 to 2 equivalent~, per equi~alent o~

~ 6 2 3 ~ - 105 - 20~1 60 7 the c~rb~moyl compound.

The reaction i8 normally and preferably effected in the presence of a ~olvent. There is no particular restriction on the nature of the solvent to be employed, provided that it ha3 no adverse effect on the reaction or on the reagent~ involved and that it can dissolve the reagents, at least to ~ome extent. Example3 of suitable ~olvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as ben~ene, tolllene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as dioxane, tetrahydrofuran or diethyl ether; and esters, such as ethyl acetate or butyl acetate.

The reaction can take place over a wide range of temperature3, and the precise reactlon temperature is not crltical to the lnvention. In general, we flnd lt convenlent to carry out the reaction at a temperature o~
rom -10 to 100~C, more preferably from 0 to 50CC. The tlme re~uired ~or the reaction may also vary widely, dep9nflt n~ on many factor~, notably the reactlon tèmperature and the nature o~ the reagent~ and ~olvent employed. Howover, provlded that the reactlon ie e~ected under the pre~erred conditionc outlined above, a period o~ ~rom 10 minute~ to 16 hours, more preferably ~rom 30 minutes to 6 hour~, w~ll u~ually su~fice.

To convert a carbamoyl group to a cyano group, the carbamoyl compound i~ reacted wlth a dehydratlng agent, ~or exam~le acetlc anhydrlde, tri~luoroacetic anhydrlde, methane~ul~onic anhydride, tri~luoromethanesul~onic anhydrido, oxalyl chloride or ~ulfonyl chlorlde, in the precence o~ an organic amlne, ~or example trlethylamlne, pyridlne or ~-methylmorpholine.

" -' .. .. ..

The reaction i9 normally and preferably effected in the presence of a ~olvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverqe effect on the reaction or on the reagents involved and that it can dissolve the reagents, at lea~t to some extent. Example~ of suitable solvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbons, such as benzene, toluene, xylene or heptane; halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as dioxane, tetrahydrofuran or diethyl ether; and esters, such ~9 ethyl acetate or butyl acetate.

The reaction can take place over a wide range of temperaturee, and the precise reaction temperature i8 not crltlcal to the invention. In general, we ~ind it convenlent to carry out the reaction at a temperature of rom -10 to 100~C, more pre~erably ~rom 0 to 50~C. The time required ~or the reaction may al~o vary widely, depen~tng on many ~actor~, notably the reactlon temperature and the nature o~ the reagents and ~olvent employed. However, provlded that the reaction i8 e~ected under the pre~erred conditlone outlined above, a perlod o~ from 10 minutee to 16 hour~, more preferably ~rom 30 minutec to 6 hour~, wlll usually suffice.

The deeired product Or the~e reaction~ can be recov~r-d ~rom the reaction mixture by conventional meane, rOr ex~mple by neutralizing the mixture with a weak ba0e, euch a~ ~odium hydrcsencarbonate and then workin~ up the product ln a eimilar manner to that doecrlbed in 8tep Al o~ Reaction Scheme A.

The cyano compound thus obtalned may then be converted to the co~Lee~G~d~ng tetrazolyl compound, u~lng any o~ the reactione deecribed above.

- 107 - ~0616~7 (vii) Remo~ing hydroxy-protectinq qroups Where R4 repre~ents a tri-sub~tituted 9iIyl group, an aralkyl group, an acyl group, an alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrothienyl group, a tetrahydrofuryl group or a sub~ituted tetra~-y~.o~yranyl, tetrahydro-thiopyranyl, tetrahydrothienyl or tetrahydrofuryl group, all of which can be regarded as hydroxy-protecting group~, the protecting group i8 removed, to produce a compound in which R4 repre~ents a hydrogen atom. The nature of the reaction employed to L~.~.JV~ the protecting group, will, o~ course, ~epen~ on the nature of the protectlng group, a~ i~ well known in the art, and any o~ the many well known reaction~ u~ed for deprotecting compounds of thl~ type may egually be used here.

Where the hydroxy-protect~ng group 1~ a s~lyl group, lt can normally be removed by treatlng the protected compound with a compound c~pahle of ~ormlng a fluorine anlon, such as tetrabutylammonium ~luoride. The reactlon 1~ normally and prererably efrected ln the presence o~ a eolvent. There lc no particular rectrlctlon on the nature o~ the colvent to be employed, provlded that lt ha~ no adverse effect on the reaction or on the reagents involved and that it can di~3elve the reagent~, at lea~t to ~ome extent. ~xamples of ~uitable ~olvent~ lnclude ethers, such as tetrahydrofuran or ~ ~ Oyane .

The reactlon can take place over a wide range of temperatures, and the precl~e reactlon temperature i9 not crltlcal to the lnventlon. In general, we find lt convenlent to carry out the reactlon at about room temperature. The tlme re~ulred ~or the reaction may also vary wldely, depen~ on many factorc, notably the ' .; ' .' ,. . ~ , .
' '' . ;' ,"' '"' '. " '.',':'". ''"'"
, ', , ,~ , , ;',' ;, ' 20~1607 reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction i~ effected under the preferred condition~ outlined above, a period of from 10 to 18 hour~ will usually suffice.

Where the hydroxy-protecting group i9 an aralkyl group, deprotection can normally be accompli~hed by catalytic reduction at a temperature of from 0~C to 80~C, more preferably from 10~C to 60~C, in a ~olvent in the preeence of hydrogen and of a catalyst.

The reactlon ie normally and preferably effected in the preeence of a solvent. There le no partlcular reetriction on the nature of the solvent to be employed, provided that it hae no adveree erfect on the react~on or on the reagente involved and that it can dis301ve the reagents, at least to oome extent. Examples of suitable eolvente include: alcohols, euch ae methanol, ethanol or i~opropanol; ethere, such ae diethyl ether, tetrahydro~uran or ~ox~ne; aromatlc hydrocarbons, such ae toluene, benzene or xylene; aliphatlc hydrocarbons, euch a~ h~Y~ne or cyclohsYene; esters, such ae ethyl acetate or propyl acetate; fatty aclds, such a~ acetic acld; or a mlxture o water and any one or more of the a~ovo organlc eolvent~.

There lo no particular llmltatlon upon the nature of tho catalyst ueed, and any catalyet commonly used for catalytlc reductlon may aleo be ueed here. Preferred oxamplos oS ouch catalyeto lncludo palladlum on charcoal, Ranoy nlckol, platlnum oxlde, platinum black, rhodium on alumlnum oxide, a complex oS triphenyl-phoophino and rhodlum chlorldo and palladlum on barium eul~ate.

The hydrogen presoure ueed le not critlcal to the . .

reaction and may vary over a wide range, although the reaction i9 normally carried out at a pressure of from to 3 time~ atmospheric pres~ure.

The reaction can take place over a wide range of temperatures, and the precise reaction temperature i9 not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from 0~C to 100~C, more preferably from 10~C to 50~C.
The tlme required for the reaction may al~o vary widely, depen~n~ on many factors, notably the reaction temperature and the nature of the reagents, catalyst and solvent employed. However, provided that the reaction la e~ected under the preferred conditiona outlined above, a period of from 5 mlnutec to 24 hours, more pre~erably from 30 minute~ to 16 hours, will usually au~ice.

Where the hydroxy-protecting group i~ an aliphatic acyl group, an aromatic acyl group or an alkoxycarbonyl group, it can be removed by treating the protected compound with a bace.

~ here ie no particular limitatlon upon the nature of tho baae uaed, provlded that lt doea not affect other parts o~ the compound. Pre~erred examplec o~ such base~
include: metal alko~ea, eapecially alkall metal AlkoY~ l auch a~ codium met~sx~d~; alkali metal cArbor~t~R, such as codium carbonate or potaccium cArbo~te; alkali metal hydro~o~, ~uch ac ~odium hydroxide or potaa~ium h~d~o~lde; and ammonia, which i3 pre~er~bly ln the ~orm o~ agueoua ammonia or a concentrate~ aolution o~ ammonia in methanol.

The reaction ia normally and pre~erably e~ected in ~he preaence o~ a aolvent. There la no particular re~triction on the nature o~ the colvent to be employed, ' ' ' " .

provided that it has no adver~e effect on the reaction or on the reagent~ involved and that it can dissolve the reagents, at least to ~ome extent. Examples of suitable solvents include: water; organic solvent~, such as alcohols (e.g. methanol, ethanol or propanol) or ethers (e.g. tetrahydrofuran or dioxane); or a mixture of water and one or more of these organic solvent~.

The reaction can take place over a wide range of temperaturee, and the precise reaction temperature i9 not critical to the invention. In general, we find it convenient to carry out the reactlon at a temperature of ~rom 0~C to 150~C, more preferably from 0~C to ~0~C.
The time required for the reaction may also vary widely, depending on many factor~, notably the reaction temperature and the nature Or the reagentc and solvent employed. However, provided that the reaction 19 e~ected under the preferred conditlon~ outlined above, a period of ~rom 1 to 20 hour~, more preferably from 1 to 16 hourc, wlll u~ually cu rice.

Where the hydroxy-protecting group i~ an alkoxy methyl group, an alkoxyalkoxymethyl group, a haloalkoxy-methyl group, a tetral~d~ ranyl group, a tetrahydro-thlopyranyl group, a tetrahydro~uranyl group, a tetrahydrothienyl group, or a eubctituted tetrahydro-pyranyl, tetrahydrothlopyranyl, tetrahydrofuranyl or tetrahydrothienyl group having at least one halogen or al~oxy ~ub~t~tuent, it can normally be removed by treating the protected compound wlth an acid.

There i0 no ~artlcular limitation upon the nature of the acid u0ed, and any ~ron~ted acid may be u~ed in this reaction. Preferred example~ of ~uch acldo include:
inorganlc acidc, especially mineral acid0, ~uch a~
hydrochlorlc acld or 0ul~uric acid; and organlc acids, lncludlng both carboxyllc acld~ and sul~onlc aclds, such 111 20616~7 - -as acetic acid or ~-toluenesulfonic acid. Strongly acidic cation ~xch~nge resinC, ~uch as Dowex 50W (trade mark) can also be used.

The reaction i9 normally and preferably effected in the preeence of a solvent. There is no particular restriction on the nature of the ~olvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can dissolve the reagents, at least to some extent. Examples of suitable solvents include: alcohols, such as methanol or ethanol;
ethere, such ae tetrahydrofuran or dioxane; organic acids, euch as formic acid or acetic acid; and mixtures o~ water and one or more of the~e solvents.

The reaction can take place over a wide range of temperatures, and the preclee reactlon temperature i8 not crltical to the invention. In general, we Find it convenient to carry out the reactlon at a temperature of trom 0~C to 50~C. The tlme reqylred ~or the reaction may also vary widely, depen~n~ on many ~actors, notably the reactlon temperature and the nature o~ the reagents and eolvent employed. However, provided that the reaction i9 e~ ected under the pre~erred conditions outllned above, a period o~ from 10 mlnute~ to la hours wlll u~ually eu~ice.

A~ter completlon o~ any o~ the above reactlons, the de-lred compound o~ the lnventlon can be recovered ~rom the reactlon m~xture by conventlonal mean~ depending on tho naturo o~ tho reactlon and the reaction medium. An examplo o~ one ~uch technlque comprl~es: neutrallzlng the roaction mlxture approprla~ely; removlng any incolublo matorlal whlch may exlet ln the mlxture, ~or examplo by rlltratlon; ~dd~ng a water-lmmleclble organlc eolvent; w~ehi~ wlth water; and ~lnally dlstllllng o~
the eolvent. The resultlng product can, i~ necessary, . .
, , -.

be purified by conventional mean~, for example, by recrystallization, or by the various chromatography technique~, notably preparative thin layer chromatography or column chromato~raphy.

Under the conditions used for removing the hydroxy-protecting group, ~imultaneous deprotection of a protected carboxy group may take place occasionally.

(vlil) ~1 ~ylatinn ~n~ acylation of ~ydroxy grou~s Al~ylation of a hydroxy group may be carried out by reacting the hydroxy compound with an alkyl halide in whlch the alkyl group has rrom l to 6 carbon atoms, preferably methyl iodide, ethyl iodide, ethyl bromide, propyl iodide, propyl bromide or butyl lodlde, or a dialkyl eul~ate ~in which each alkyl group has ~rom 1 to 6 carbon atome and may be the eame or dif~erent, althou~h they are pre~erably the eame), euch as dimethyl 0ul~ate or diethyl eulfate.

The reaction i8 normally and pre~erably e~fected in the p~e~e~ce o~ a eolvent. There le no particular re~trictlon on the nature of the eolvent to be employed, provlded that lt hae no adveree e~$ect on the reactlon or on the reagente lnvolved and that it can diseolve the roagent~, at leaet to eome ~Ytont~ ~xamplee of eultable ~olvent~ include: amides, ouch as ~ dimethyl~ormamide, dimethylacetamlde or ~-methylpyrroli~no~e; ketones, euch ae acetone or mothyl othyl ketone; or eul~oY~des, euch a~ dimethyl ~ulroxide.

Th- re~ction ie o~rocted in the preeence of a base, the naturo Or whlch i~ not crltlcal, provlded that it doee not damAge the roagent~ or productc. Pre~orred oxlmplee o~ bacoe which may bo u~ed lnclude alkall metal hydrlde~, ~uch ae eodium hydrido, potaecium hydride or , - 113 - 20616~7 lithium hydride. The reaction can take place over a wide range of temperature~, and the precise reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from ooC to 120~C, more preferably from 20~C to 80~C. The time required for the reaction may al~o vary widely, depPn~;n~ on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reactlon i3 e~fected under the preferred conditions outllned above/ a period of from 30 minutes to 24 hours, more preferably from 1 to 16 hours, will usually suffice.

Acylation of a hydroxy group may al~o be carried out by well known methods cc - ly u~ed in organic synthetic chemistry For example, lt can be carrled out by reacting the hydroxy compound with: an al~anoyl halide, cont~n~ng ~rom 2 to 6 carbon atom~, such a~ acetyl ehlorlde, proplonyl ehlor~de, butyryl bromide, valeryl chlorlde or hsY~noyl chlorlde; a carboxyllc acid anhydrlde, in which the group derived ~rom the or each carboxylle acid eontain~ from ~ to 6, pre~erably from 2 to 6, carbon atome, such ae a mlxed anhydrlde o~ formic acld and acetic acld, acetlc anhydrlde, proplonlc anhydride, valerle anhydrlde or ~eYanolc anhydride; an alkoxyearbonyl hallde, ln whieh the alkoxy group eontaln~ ~rom 1 to 6 earbon atomc, ~ueh a~
methoxyeArho~yl chlorlde, methoxyearbonyl bromide, ethoxyearbonyl chloride, ~,uQo~yearbonyl chlorlde, butoxyc~rb~nyl ehlorlde or hexyloxycarbonyl chlorde; an arylearbonyl hallde, eueh ae benzoyl chloride, benzoyl bromlde or "a~thoyl ehloride; a halo- or alkoxy-kAnoyl halide eont~tn~n~ rom 2 to 6 carbon atoms,~ueh a~ ehloroaeetyl ehlorlde, dlehloroacetyl chlorlde, trlehloroaeetyl ehloride or methoxyacetyl chloride; or an Alkenoyl ehloride cont~lntn~ ~rom 3 to 6 carbon atom~, eueh a~ aeryloyl ehlorlde, methacryloyl chloride, ,~

.~
,, 20~1607 crotonoyl chloride, 3-methyl-2-butenoyl chloride or 2-methyl-2-butenoyl chloride.

The reaction is normally and preferably effected in the pre~ence of a solvent. There i9 no particular re~triction on the nature of the 301vent to be employed, provided that it has no adverse effect on the reaction or on the reagent3 involved and that it can dissolve the reagents, at least to some extent. Example~ of suitable ~olvent~ include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chlorlde or chloroform; esters, such as ethyl acetate;
and ethere, such as tetrahydroSuran or dioxane. The reactlon i~ effected in the pre~ence of a base, pre~erably an organic tert~ary A~n9e, ~uch as triethylamlne, pyridine, diethylisopropylamlne or 4~dimethylamlnopyridine. The reactlon can take place over a wlde range o~ temperatures, and the prec~e reaction temperature i~ not critical to the lnvention.
$n general, we ~lnd lt convenient to carry out the reaction at a temperature o~ from -10~C to 120~C, more prererably rrom 0~C to ~0~C. The tlme required ~or the reactlon may al~o vary wldely, ~9p9nA~ng on many ~actor~, notably the reactlon temperature and the nature oS the roagent~ and ~olvent employed. However, provlded that tho reactlon i~ e~ected under the pre~erred condltion~ outllned above, a perlod o~ from 30 minutes to 24 hour~, more pre~erably ~rom 1 to 16 hours, wlll u~ually ~u~lce.

A~ter completlon o~ elther o~ the above reactlons, the de~lr-d product can b- rocovered ~rom the reactlon mlxture by convontlonal mean~. For example, a recovery method i~ carried out ac already de~crlbed ~or rocovorlng tho product o~ 8tep Al.

- 11S - 20~1607 Reaction Scheme B:

Compounds of formula (Ia) in which R4 represents a hydrogen atom, that i9 to say compounds of formula (Ib), may also be prepared as shown in the following Reaction Scheme B:

Reaction Scheme B:

H COORSa + XCH3 ~ Step ~31 (VII) ( III ) N~ y~H
H2 cooR5a l H2 CoOR5a Step B2 , ~

R~\R7a R3~R7a (VIII ) ~ Ib) '' ,''' '' ~ ~

2 0 ~ 7 In the above formulae, Rl, R2, R3, R5a, R6, R7a and x are as defined above, and RSa preferably represents a group other than a hydrogen atom.

In Step Bl, an imidazole-5-carboxylate compound of formula (VII) i~ reacted with a biphenylmethyl compound of formula (III), to give a compound of formula (VIII).
Thi~ reaction i8 e~sentially the same as that of Step Al in Reaction Scheme A, and may be carried out using the same reagents and reaction conditions.

In Step 32, a compound of formula ~Ib) i9 prepared by reacting a compound of formula (VIII) with a reducing agent or w~th a Grignard reagent of formula, R3a-Mg-X
(in which R3a represent~ any of the group~ defined above for R3 other than a hydrogen atom, and X is as defined above).

~ xamplee o~ the reducing agents which may be used include: alkylaluminum hydridee, euch ae dii~obutyl-alumlnum hytrlde; and metal, especlally alkall metal, borohydridee, euch a~ sodlum borohydride or Yodlum cy~nohorohydride. 0 theee, we prerer diisobutyl-alumlnum hydrlde and ~odlum borohydrlde.

The reaction o~ the compound o~ rormula (VIII) wlth the reduclng agent 1~ normally and preferably conducted ln an inert eolvent. There le no particular restriction on the nature o~ the eolvent to be employed, provlded that lt hae no adveree ef~ect on the reactlon or on the reagente involved and that lt can dlseolve the reagent~, at leaet to eome extent. Examplee of sultable solvents lnclude: hydrocarbone, eepeclally aromatlc hydrocarbon~, euch ae toluene or h~x~ne; ethere, such as tetrahydrofuran or dloxa~e; alcohole, ~uch a~ methanol or ethanol; water; and mlxturee o~ water wlth any one or more of the above organlc eolvente. Preferred ~olvent~

~ . . . .

~ 6 2 3 206160~

vary depending upon the nature of the reducing agent used. For example, where the reducing agent i~ an alkylalllm;nllm hydride, hydrocarbons or ethers are preferred; alternatively, where it ie an alkali metal borohydride, alcohols, water or mixtures of water with an alcohol are preferred.

The reaction can take place over a wide range of temperature~, and the precise reaction temperature i9 not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -30~C to 80~C, more prefera~ly from -20~C to 20~C, when the reduclng agent i~ an alkylalllm~nllm hydride, or at a temperature o~ ~rom -30~C to 80~C, more preferably ~rom 0~C to 50~C, when it i~ an alkali metal borohydrlde. The time required for the reaction may also vary widely, depen~n~ on many factors, notably the reaction temperature and the nature o~ the reagents and eolvent employed However, provlded that the reaction ie et~ected under the pre~erred conditiono outllned above, a period o~ ~rom 30 minute~ to 24 hour~, more preterably from 1 to 16 hours, will usually suttice.

The reaction ot the compound o~ tormula ~VIII) with a Grlgnard reagent le normally and pre~erably eftected ln the ~reoence o~ a eolvent. There i9 no particular rectriction on the nature o~ the oolvent to be employed, provldod that lt hac no adverce e~ect on the reaction or on the reagente lnvolved and that it can dlo301ve the reagente, at loaot to eome e~t~nt. Examplee o~ suitable colventc lnclude: hydrocarbono, whlch may be allphatic or aromatic, 8uch ae ha~ne or toluene; halogenated hydrocarbono, eopeclally halogenated allphatic hydrocarbonc, ~uch ao methylene chlorlde or 1,2-dichloroethane; and ethero, cuch ao tetrahydro~uran or dlothyl ether, o~ which the ethor~ and halogenated hydrocarbone are preterred.

- . . , , , ~ .. .

The reaction can take place over a wide range of temperaturee, and the precise reaction temperature i9 not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from -50~C to 100~C, more preferably from -10~C to 50~C. The time required for the reaction may also vary wide].y, depending on many factors, notably the reaction temperature and the nature of the reagents and ~olvent employed. However, provided that the reaction is e~ected under the preferred conditions outlined above, a period o~ from 30 minutee to 24 hours, more preferably from 1 to 16 hours, will usually suffice.

A~ter completion of any of the above the reactions, the deeired compounde of each reaction can be recovered ~rom the reaction mlxture by conventlonal mean~. For ~xample, the reaction mixture le mixed wlth water or with an agueoue eolutlon o~ ammonium chlorlde and etlrred at room temperature, after whlch lt ie extracted wlth a water-lmmlecible eolvent, such ae ethyl acetate.
The extract i9 w-~be~ with water and drled over a drying agent, such ae anhydroue magneeium eul~ate, and then the eolvent le dletilled o~ neceecary, the product can be ~urther purl~led by conventlonal meane, ~or example, by recryetalllzation, or by the varioue chromatography techn~ues, notably preparative thin layer chromato~LaQhy or column chromatography.

~art~ nn 9~hem~ C:

Compounde o~ ~ormula ~Ia) in which R2, R3 and R all L3~Leoent hydrogen atom~, that le to say com~ounde o~ ~ormula ~Ic), and com~ounde o~ tormula ~VIII), whlch are lntermedlatee in reaction qcheme B, can be prepared ae ~hown in Reaction 9cheme C:

20~1607 RP;lrti~n St~h~mP C

R7a Rl N CoOR5a ~R6 ~ + XCH2 Step Cl H CoOR5a (IX) ~III) RI~COOR; \~ ~ 2 $~ StepC2 ~ $~

R6 R7a ~R7a ~X) (VIII) Step C3 R~CH20H N ~

~H COOR~a I H CoOR5a Ste~ CS

R~\R7~ R~R7a ~Ic) ~VIIla~

,~ ' ~; ' . . .
.

~. , . . : ' ., . ;', ' In the above formulae, Rl, R2, R5a, R6, R7a and X are as defined above, and R5a preferably represents a group other than a hydrogen atom.

In Step Cl of this reaction scheme, an imidazole-5-carboxylate compound of formula (IX) is reacted with a biphenylmethyl compound of formula (III), to give a compound of formula (X). This reaction i9 eg9entially the same as that described above in Step Al of Reaction Scheme A, and may be carried out using the same reagents and reaction conditions.

In Step C2 o~ this reaction scheme, the dicarboxylate compound of fonmula ~X) obt~ine~ a~ shown ~n Step Cl i~ reacted with about one equivalent of a Grignard reagent of ~ormula R2aMgX (ln which X is as de~ined above and R2a represents any of the group~
de~ined above for R2 other than a hydrogen atom) and/or with about one equivalent o~ a reducing agent to glve the compound o~ ~ormula ~VIII). These reactlons are e~aentially the ~ame a~ tho~e described above ln 8tep ~2 o~ Reactlon 8cheme B, and may be carried out using the same reagent~ and reaction conditions.

In gtep C3 o~ this reaction scheme, the compound of ~ormula ~X~ 1~ reacted with two or more molar egulvalent~ o~ the reduclng agent to glve the compound Or ~ormula ~Ic). The reaction i9 e~entially the ~ame a~ that de~cribed above in 9tep 32 o~ Reaction Scheme B, and may be carrled out u~lng the ~ame reagents and reaction condltion~.

In Step C4, the hydroxymethyl compound o~ ~ormula ~Ic) 18 ~xldlzed to convert the hydroxymethyl group to a ~ormyl group and prepare a compound o~ ~ormula ~VIIIa).

The oxidlzation reaction may be carried out by : ,.: ,,, , ,................. , :,... . . ..
~ ~ ' . 1 .; , , .

,, 20~1607 reacting the hydroxymethyl compound with an oxidizing agent, such as magnesium oxide or ~ilver oxide.

The reaction is normally and preferably effected in the presence of a solvent. There is no particular reetriction on the nature of the solvent to be employed, provided that it hae no adveree effect on the reaction ;~
or on the reagents involved and that it can dissolve the reagents, at leaet to eome extent. Examples of suitable eolvents include: hydrocarbons, which may be aliphatic or aromatic hydrocarbone, euch ae benzene, toluene, xylene or heptane; halogenated hydrocarbons, eepecially halogenated allphatic hydroc~rbonq, such as methylene chloride or chloroform; ethere, such ae diethyl ether, tetrahydro~uran or dioxane; eeter~, such a~ ethyl acetate or butyl acetate; and ketones, such ae acetone or methyl ethyl ketone.

The reactlon can take place over a wlde range of temperaturec, and the preclse reactlon temperature ie not critlcal to the invention. In general, we find it con~enient to carry out the reaction at a temperature of from 0 to 100~C, more pre~erably from 10 to 60~C. The time reguired ~or the reactlon may aleo vary widely, ~epen~n~ on many ~actore, notably the reactlon temperature and the nature Or the reagents and eolvent employed. However, provided that the reactlon ie e~octed unter the pre~erred conditlone outlined above, a perlod of ~rom 30 m~nute~ to 24 houre, more preferably from 1 to 16 hourc, wlll ucually eufflce.

Alternatiw ly, the reaction of 9tep C4 may be carried out by reacting the hydroxymethyl compound of formula ~Ic~ with dimethyl cul~oxide and wlth a dehydrating agent in the p~ce~ce of an organic amlne.
9uitablo dehydratlng agente lnclude, for example, eulfur trloxlde-dloxane complex, oxalyl chloride and 2061~07 trifluoroacetic anhydride. Suitable organic amines include, for example, triethylamine and pyridine.

The reaction i~ normally and preferably effected in the pre~ence of a solvent. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reactlon or on the reagents involved and that it can dissolve the reagents, at least to ~ome extent. Examples of suitable ~olvents include: halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons, such as methylene chloride or chloroform; ethers, such as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate or butyl acetate; and sulfoxides, ~uch as dimethyl sulfoxlde.

The reaction can take place over a wide range of temperature~, and the preci~e reaction temperature is not critlcal to the invention. In general, we find it convenient to carry out the reaction at a temperature of rrom -60~C to 60~C, more preferably ~rom -50~C to 30~C.
The tlme required for the reaction may also vary widely, depe~d~ng on many Sactors, notably the reaction temperature and the nature o~ the reagent~ and solvent employed. However, provided that the reaction i9 efrected under the pre~erred conditions outlined above, a period of from 10 minute~ to 8 hour~, more preferably ~rom 30 minutes to 5 houre, will usually su~ice.

A~ter completion of any o~ the above reactions, the de~ired product o~ the reaction can be recovered ~rom the reaction mixture by conventional means. For exam~le, the reaction mixture ie mixed wlth water and with a water-immiccible colvent, ~uch ac ethyl acetate.
The organlc layer ic ~eparated, w~9d wlth water and dried over a drylng agent, cuch a~ anhydrou~ magne~ium ~ul~ate; the solvent ic then removed by di~tillatlon, ''' ' ' " , ' '' . ' ' ' ,.

. . . ', ' ~

normally under reduced pre~sure. If necessary, the product can be further purified by conventional means, for example, by recrystallization, or by the various chromatography techniques, notably preparative thin layer chromatography or column chromatography.

The re~ulting compound of formula (VIII) may then, if desired, be allowed to react with a Grignard reagent of formula R3aMgX (in which R3a and X are a~ defined above) according to the method described above in Step BZ of Reaction Scheme B, to give the corresponding compound having a group of formula -CR2(R3a)-oH (in whlch R2 and R3a are as described above) at the 4-po~itlon of the ;~A~O1Y1 ring - not shown in the reactlon scheme.

~tinn S~he~e D:

In thi~ reaction ~cheme, a cyano compound o~ formula (XII) i~ ~irst prepared, and then thl~ i~ con~erted to a com~ound o~ ~ormula ~I):

.

- 125 - 206~607 Reaction Scheme D:
\~ ¦~R ~R6b H,N CN XCH2 Step Dl (XI) ~ IIIa) RI~RR43 ~R5 [~ Step D2 ~ ~R7 (XII ) ~I) ' , :, - .
' In the above form~ e, Rl, R2, R3, R , R5, R6, R7 and X are as defined above, and R7b represent~ a protected carboxy group or a protected tetrazolyl group, both of which may be as previously exemplified in relation to R7a.

In Step Dl of this reaction scheme, an imidazole-5-carbonitrile compound of formula (XI) is reacted with a biphenylmethyl compound of formula (IIIa), tc give a compound of fonmula (XII). This reaction i~ essentially the same a3 that described above in Step Al of Reaction Scheme A, and may be carried out using the same reagents and reaction conditions.

In Step D2, the resulting compound of formula (XII) may be sub~ected to any one or (in appropriate cases) more of the following reaction~:

(lx) converting the cyano group at the 5-position of the im~Azole ring to a carboxy group;

~x) convertlng the cyano group at the 5-position of the zole ring to a carbamoyl group;

~xi~ removing any carboxy protecting group~;

~xil) e~teri~ying the carboxy group at the 5-position o~ the imldazole ring or on the biphenyl group;

txiii) converting the carboxy group at the 5-position o~ the imidazole ring to a group o~ ~ormula -CONR8R9;

~xlv) removing the tetrazolyl-protecting group;

~xv) where R4 repre~ent~ a tri-~ubetituted cilyl group, an aralkyl group, an aralkyloxycarbonyl group, an aliphatic acyl group, an alkoxymethyl group, an alkoxy-''':;
.. ..

....
, ~ :

,~
- 127 - 2061~07 alkoxymethyl group, a haloalkoxymethyl group, a tetra-hydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrothienyl group, a tetrahydrofuryl group or a sub~tituted tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl or tetrahydrofuryl group having at least one halogen or alkoxy substituent, all of which can be regarded as hydroxy-protecting groups, removing the protecting group to produce a compound in which R4 represents a hydrogen atom; and (xvi) where R4 repre~ents a hydroxy group, alkylating or acylating thi~ group.

( 1Y) Conver~lnn of ~ cy~nn group to A carboxy grou~

The conversion i~ effected by hydrolysls of the cyano group ln the compound of formula (XII) via a carbamoyl group. Thi8 reactlon 19 well known in chemlcal eynthe~is generally, and may be carrled out using any reagent known for thi~ purpose. For example, alkali metal hydroY~ss, ~uch a~ sodium hydroxide, potae~ium hydroxide or lithium hydroxide.

The reaction i~ normally and pre~erably effected in the prqs~nce o a eolvent. There 1~ no particular rostrlctlon on the nature o~ the solvent to be employed, provldod that it has no adverse ef~ect on the reaction or on the reagent~ involved and that it can di~301ve the reagonto, at leaot to some sYt~nt. Bxample~ Or suitable solvent~ include: water; alcohols, such as methanol or othanol; ethor~, ~uch ae tetrahydrofuran or dloxane; or A mlxture ot any two or more o~ theoe oolvento; an aqueouo solvent is prererred.

The reaction can take place over a wide range o~
temperatures, and the preci~e reaction temperature i5 not critical to the invention. In general, we ~lnd lt ..

convenient to carry out the reaction at a temperature of from 0~C to 120~C, more preferably from 20~C to 100~C.
The time required for the reaction may aleo vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed However, pro~ided that the reaction is effected under the preferred conditions outlined above, a period of from 30 minutes to 24 hours, more preferably from 1 to 16 hours, will usually ~uffice.

After completion of the reaction, the desired p~oduct can be recovered from the reaction mixture by conventlonal means. For example, one suitable recovery procedure comprises: neutralizing the reaction mixture by ~A~ ng a mineral acid, such a~ hydrochloric acid; if the desired product of formula (I) preclpitates, it can then be recovered by filtration; alternatlvely, after neutralizing the reaction mixture, the solvent is di~tllled o~f and the reeultlng resldue ls purlfled by column chromatography to give the de~ired product;
alternatlvely, the residue i~ mixed wlth water and wlth a water-lmmlocible eolvent, ouch as ethyl acetate, and the resulting mlxture 18 extracted wlth an organic solvent, a~ter which the extract io dried over a drying agent, such a~ anhydrouo magneelum sul~ate, and freed ~rom the ~olvent to glve the desired product. If ~eceo~ry, the product can be ~urther puri~led by convontional mean~, ~or example, by recry~talllzation, or by the variouo chromatography technlgue~, notably preparative thin layer chromatography or column chromatography.

In thi~ reaction, where the startlng material 1~ a compound, ln which R4 repreeent~ an acyl group and/or R7b L~La~ont~ an e~ter group o~ a primary or secondary alcohol ~such a~ methanol, ethanol or lcopropanol), the acyl group o~ R4 and the ester , : , - ~ .. , residue of R7b are simultaneously removed.

(x) Conversion of a cyano group to a carbamoyl ~roup In this reaction, a cyano group in the compound of formula (XII) i9 converted to a carbamoyl group.

The product of thi~ reaction is an intermP~;~te of the previous reaction (ix). Therefore the reaction is carried out under milder conditions than those employed in reaction (ix).

The reaction i9 carried out by treating the compound o~ ~ormula (XII) with an alkali, for example: an alkali metal hydroxidej ~uch a~ lithlum hydroxide, sodium hydroxide or pota~ium hydroxide; or an alkali metal carbonate, such a~ sodium carbonate or potae~ium carbonate. The reactlon 19 normally and pre~erably e~rected in the pre~ence o~ a ~olvent. There 1~ no particular re6trlctlon on the nature o~ the solvent to be employed, provlded that lt ha~ no adverse e~ect on the reaction or on the reagents lnvolved and that it can dic~olve the reagente, at lea~t to some extent.
Examplec Or ~uitable colvent~ lnclude: water; a mlxture Or water and an alcohol, ~uch ac methanol or ethanol; or a mixture Or water and an ether, ~uch as tetrahydrofuran or ~oYAne.

Tho reaction can take place over a wlde range o~
temperaturee, and the preci~e reactlon temperature i~
not critical to tho inventlon. In general, we ~ind lt cGn~enlent to carry out the reactlon at a temperature o~
rrom 0~C to 100~C, more prererably rrom 10~C to 80~C.
The time ro~ulret rOr the reaction may al~o vary wldely, deFe"~n~ on many ~actoro, notably the reactlon temperature and the nature Or the reagent~ and solvent employed. However, provlded that the reaction 1~

:

. , . .. ~,' - 130 - 2~sl 60 7 effected under the preferred conditions outlined above, a period of ~rom 0.5 to 24 hours, more preferably from 1 to 8 hours, will usually suffice. The reaction can be accelerated by ~1 ng a catalytic amount of hydrogen perioxide.

After completion of the reaction, the reaction product can be recovered from the reaction mixture by conventional meano. For example, one ~uitable recovery procedure comprise~: neutralizing the reaction mixture with a mineral acid, such as hydrochloric acid;
dl~till~ng off the solvent under reduced pre~sure;
~ ng water to the re~idue; extracting the mixture with a water-immlscible ~olvent, such as ethyl acetate;
drylng the organic extract solution over a drying agent, ouch a~ anhydrouo magnecium ~ul~ate; and distilling off the eolvent. I~ ~ecessAry, the product can be further purl~ied by conventional meanA, ~or example, by recrystallization, or by the various chromatography technique~, notably preparative thln layer chromatography or column chromatography.

(Y~ mQv~ rArh~y~rotect~ng grou~

Thio io the ~ame reaction a~ io lnvolved ln reaction (1) o~ 9te~ A2 o~ Reaction Scheme A, and may be carried out w lng the same reagentc and reaction conditions.

( Y~ R~teri I~ irA t inn Thio lo the oamo reactlon ae lo lnvolved in reactlon ~11) o~ Stop A2, and may be carrled out uolng the oame reagent~ and re~ctlon conditione.

. .

.
.

- 131 - 2061 ~ 7 (xiii) Conversion of a carboxy group to a group of formula -CONR8R9 This is the same reaction as is involved in reaction (iii) of Step A2, and may be carried out using the same reagents and reaction conditions.

(xiv) Removal of tetxazolyl-~rotecting group~

Thlg i9 the same reaction as i9 involved in reaction (lv) of Step A2, and may be carried out using the same reagentc and reaction condition~.

(xv) R~movinq ~ydroxy-protectin~ groups Thi~ i9 the same reaction as i3 involved in reaction (vii) of Step A2, and may be carried out using the same reagent~ and reaction conditions.

(xvi) Alkyl~tinn ~n~ ~r~l~tinn o~ ~y~ro~y ~rou~

Thi~ 1~ the same reactlon ac i9 involved in reaction ~vili) of Step A2, and may be carried out using the same reagent~ and reaction conditlons.

pQa~tlnn s~-hem~ B:

In thi~ reactlon ~cheme, a compound of fQrmula (XII) in whlch R4 1~ hydrogen, that i9 to ~ay a compound of ~ormula ~XV), lc prepared from the correepondlng compound o~ ~ormula ~XIII) havlng a ketonlc ~-C~O)R2l group at the 4-po~ltlon Or the imidazole rlng.

'~ - 132 - 2061 6 û 7 rti~n Srh~~ E:

'1'~ XCH2~ Step El (XIII) (IIIa) R)~R7b R6~R7b ~XIV) ~XV) .
,~ , ' ' ' '~' ,' " ' ' ,' , . . .............. ..

-, ,~ : . .:

- 133 - 2~6 In the above formulae, Rl, R2, R3, R6, R7b and x are as defined above.

In Step El of this reaction ~cheme, an imidazole-5-carboxylate compound of formula (XIII) ie reacted with a biphenylmethyl compound of formula (IIIa), to give a compound of formula (XIV). This reaction is e~sentially the ~ame ac that described above in Step Al of Reaction Scheme A, and may be carried out using the same reagents and reaction condltlons.

The re~ultlng compound of formula (XIV) i~ then reacted in Step E2 with a reducing agent or with a Grlgnard reagent of formula, R3a-Mg-X tin which R3a and X are a~ defined above). Thi~ reactlon i9 essentlally the ~ame a~ that de~cribed above in Step 92 o~ Reactlon Scheme 3, and may be carried out using the eame reagents and reaction conditions. The re~ulting product may then be recovered and, if desired, further purified, as described in Step 92.

.tl~n 8~heme F:

Certain 5-cyano~ zole derivative~, ror u~e as lntermedlates ln the foregolng reaction schemes may be prepared a~ illu~trated in the followlng Reaction Scheme F:

- 134 - 2061 6~7 Reaction Scheme F: ' F~ CN ~ Step Fl H CN
~XVI ) ( I I Ia ) R~ CN Step F2 . R \~N~R~

[~A7b ~'R7b ~XIV) ~I J

Step P3 R~ CH20H N ~ . .

CH2 Step F4 f~2 ' ~

R~ R7b R~R7b ~XVIII) ~XIVaJ

- ~ ' . ~,.

In the above formulae, ~1, R2, ~6, R7b and X
are as defined above.

In Step Fl of this reaction scheme, an imidazole-5-carboxylate compound of formula ~XVI) is reacted with a biphenylmethyl compound of formula (IIIa), to give a compound of formula (XVII). This reaction is essentially the same as that described above in Step Al of Reaction Scheme A, and may be carried out using the same reagents and reaction conditions.

Steps F2, F3 and F4 are es~entially the same a~
Steps C2, C3 and C4, re~pectively, of Reaction Scheme C, and may be carrled out using the same reagents and reaction conditions. The resulting product may then ~e recu~eL-~d and, if desired, further purlfied, a~
de~cribed in Reaction Scheme C.

The preparation o~ certain o~ the starting materials u~ed in the above reaction ~chemes i9 shown in React~on Schem~ G and H:

li . , , ,.,", ~ .=""~ ," .r, .,,. ,., .. , ~, ; .,, j;, ~ ", ,~,;, ~ . .. .; :rr .. . . .

.' , .

2061 6~7 Reaction Scheme G:

RlC (OR ~) 3 + H2N~<NH2 Step Gl NC CN
(XIX ) (XX) N CN N COOH
R ~ ~ Step G2 R~
/N CN ~ COOH
H H
(XVI ) (XXI ) Step G3 ~ ~ 3~ Step G4 H~N -CooR5a (IX ~

R~ o N CoOR5a H

(Va) .
~:

_ 137 -20616~7 Reaction Scheme H:

N~CN Step Hl ~N3CCN
H
(XVIa ) Step H2 R~ R2Step H3 Rll/
(XIIIa ) _<N j~< Step H4 R ~ 3~<OH
~N CN
Rll (XXII ) (XIa ) ~<R3 Step H5 ~ /N~COORSa (Va) : ' , ' '', . - ~ , '' Reaction Scheme H (cont):

/ R2 Step H6 1 ~/ ~ R2 Rll N COOH
Rll (XIIIa) (XXIII) Step H7 , Rl ~ / ~ R2 Step H8 p CO( R5a Rll (VlIa) R2\ R3 Rl ~/ ~ OH
N COORSa H

(Va) , . ' '. , '' ~ ' ' ' ' ..
~' , ''''' ~' ' '"' '" ' ' ;

In the above f orm~ e ~ R , R , R3 and R
are a~ defined above. Rl~ represents an alkyl group cont~inlng from l to 6 carbon atoms, such as those illustrated above in respect of Rl, and i9 preferably an alkyl group having from l to 4 carbon atoms, and more prefera~ly a methyl or ethyl group. Rll represents a hydrogen atom or a ;ml~7olyl-protecting group, for example an aralkyl group, such as a trityl group, a diphenylmethyl group or a benzyl group, or a Cl - C4 alkoxymethyl group, such as a methoxymethyl, ethoxy-methyl, pLu~y~ethyl or butoxymethyl group, preferably a trityl group, a benzyl group, a methoxymethyl group or an ethoxymethyl group, more prefera~ly a trityl group.

~tl~n 9rho~e G:

In thi~ reaction scheme G, a compound of formula (V) ln which R4 represents a h~d.oyen atom, that is a compound o ~ormula (Va), ~IX1 or (XVI) ~which are etarting materials ln Reaction Scheme~ A, C or F, re~pectlvely) ic prepared. The compound o~ formula ~Va) may then, lr de~ired, be protected, e.g. by alkylation, acylation, ~ormation o~ a tetrahydropyranyloxy, tetrahydrothlopyranyloxy, tetrahydrothienyloxy or totrahydro~uryloxy group, a ~ub~tituted tetrahydro-pyranyloxy, tetrahydrothlopyranyloxy, tetrahydro-thlenyloxy or tetrahydro~uryloxy group or a group o ~ormula -SiRaRbRC, in whlch Ra, Rb and Rc ar- ae de~ined above. The the~e reactions other than ~ormatlon o~ an o~tionally cub~tituted tetrahydro-pyranyloxy, totrahydrothlopyranyloxy, totrahydrothlenyl-oxy or tetrahydro~uryloxy group may be carried out a3 doecrlbed ln reaction (vill) o~ Step A2 Or Reaction 8chome A, to give the co.re~o~ng compound in which R4 L~pLccont~ any o~ tho groupa L~ra~ented by R4 othor than a hydrogon atom.

, :

Formation of a tetrahydropyranyloxy, tetrahydro-thiopyranyloxy, tetrahydrothienyloxy or tetrahydro-furyloxy group or a sub~tituted tetrahydropyranyloxy, tetrahydrothiopyranyloxy, tetrahydrothienyloxy or tetrahydrofuryloxy group may be carried out by reacting a compound of formula (V) in which R4 represents a hydrogen atom with dihydropyran, dihydrothiopyran, dihydrothiophene or dihydrofuran or a substituted dlhydropyran, dihydrothiopyran, dihydrothiophene or dlhydrofuran having at leaYt one halogen or Cl - C6 alkoxy sub~tituent in the presence of an acid (~uch as ~-toluene~ulfonic acid) in an inert solvent (for example a halogenated hydroc~rbon, ~uch a~ methylene chloride) at about room temperature for from 1 to 24 hours.

In Step Gl, a compound of formula (XVI) is prepared by reacting an ortho ester compound of formula (XIX) wlth dlamlnomaleonltrlle Or formula (XX). The reaction i~ normally and pre~erably e~ected in the presence of a colvent. There i~ no particular restriction on the nature o~ the solvent to be employed, provlded that it hae no adverce e~fect on the reaction or on the reagents involved and that it can dls~olve the reagent~, at least to ~ome sYtent. ~xamples o~ ~uitable ~olvent~ include:
aromatlc hydrocarbon~, ~uch a~ b~n7enel toluene or xylene; halogenated hydrocarbon~, especially halogenated allphatlc hydrocarbone, ~uch a~ 1,2-dlchloroethane or c~rbQn tetrachlorlde; ether~, ~uch as tetrahydrofuran or ~10Y~ne; and nltrile~, ~uch as acetonltrile.

The reaction can take place over a wide range of temperature~, and the precice roaction temperature i3 not critical to the inventlon. In general, we ~ind it convenlent to carry out the reaction at a temperature Or from 50~C to 180~C, more prererably rrOm ~0~C to 150~C.
The time required rOr the reaction may also vary wldely, dep~ing on many ~actor~, notably the reaction ,- 2o6l6o7 temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the preferred conditions outlined above, a period of from 1 to 24 houre, more preferably from 2 to 10 hour~, will u~ually ~uffice.

The reaction product of formula (XVI) can be recovered by collecting the crystals deposited in the reaction ~ystem or by distilling off the solvent. The product can, if nece~sary, be further purified by conventional means, $or example, by recrystallization, or by the various chromatography techniques, notably preparative thin layer chromatography or column chromatography.

Step G2 consi~t~ o~ preparing an imidazole-4,5-dlcarboxy}ic acid compoùnd of formula (XXI) by hydrolyzing the compound o~ ~ormula ~XVI) prepared in Step Gl. This reaction may be carrled out by heating the compound Or ronmula (XVI) under re~lux wlth an aqyeou~ mineral acld, such as agyeous hydrochloric acid, sul~urlc acid or nltrlc acid, ~or a perlod of from 1 to 24 houre (pre~erably from 3 to ~6 hourc). The product Or ~ormula ~XXI) can be recovered by collecting the cryctals depo~ited in the reaction mixture upon cooling, by ~lltratlon or by dlctllling o~ the ~olvent.

8tep G3, an optlonal ctep, conclets o~ preparlng a dieeter compound o~ ~ormula ~IX) by protectlng the carboxy group o~ the ~m~ ole-4,5-dlcarboxyllc acld compound o~ ~ormula ~XXI) prepared in 8tep G2. Thl~
roaction may bo carried out by reactlng the compound ~XXI~ with a compound o~ ~ormula R5b-Y, ln whlch RSb and Y ar~ ac de~lned above.

The reaction 1~ normally and pre~erably e ~ected ln the precence o~ a ~olvent. There ic no ~articular , , . , . , , , , . " , , :

~ 6 2 3 ,- 20616o7 re~triction on the nature of the ~olvent to be employed, provided that it has no adverse effect on the reaction or on the reagents involved and that it can di3solve the reagents, at lea~t to some extent. Examples of suitable solvent~ include: hydrocarbons, e~pecially aromatic hydrocarbon~, ~uch as benzene or toluene; halogenated hydrocarbon~, e~pecially halogenated aliphatic hydrocarbon~, such a~ methylene chloride or chloroform;
ethers, such as tetrahydrofuran or dioxane; alcohols, such as methanol, ethanol or t-butanol; amides, such as ~,N-dimethylacetamide, N,~-dimethylformamide or N-methyl-2-pyrrolid~nQne; ketones, such a~ acetone or methyl ethyl ketone; nitriles, such as acetonitrile; and ~ulfloY~des, such a~ dimethyl ~ulfoxide. Of these, we prefer the nltr~les, halogenated hydrocarbons or amides.

We alco pre~er that the reaction ~hould be carried out ln the pre~ence o~ a base, the nature of which i9 not critical, provided that it doe~ not affect any other partc o~ the reagent~. Pre$erred example~ o~ ba~es which may be uced include: organic A~ne9, such a~
triethylamine, ~ diicoyropylethyl~m~ns or N-methylmorphollne.

The reaction can take place over a wide range ofl temperaturee, and the preci~e reaction temperature is not crltical to the invention, although the pre~erred temperature may variee depen~ng upon the nature of the etarting material, tho solvent and the base. In general, we flind lt conven~ent to carry out the reactlon at a temporature o~ ~rom -10~C to 100~C, more pre$erably ~rom 0~C to 80~C. The tlmo required $or the reactlon may alco vary wldely, dopen~ on many flactor~, notably the reactlon temperature and the nature o~ the reagent~
and colvont employed. However, provided that the reactlon is o~octed under the pro$erred conditlon~
outlinod above, a poriod o~ ~rom 0.5 to 24 hour~, more . . .
, . , . , . " ., , - 2o6l~7 preferably from 1 to 16 hours, will usually suffice.

After completion of the reaction, the desired compound can be recovered from the reaction mixture by conventional mean~. For example, after distilling off the solvent, the residue is mixed with water; the mixture i~ extracted with a water-immiscible organic ~olvent, euch as ethyl acetate; the extract is dried over a drying agent, such as anhydrous magnesium sulfate; and the solvent i9 distilled off. ~he product can, if nece~sary, be further purified by conventional means, for example, by recrystallization, or by the various chromatography technique~, notably preparative thin layer chromatography or column chromatography.

Alternatively, the dic~rhoxylic acid compound o~
~ormula (XXI) may be e~terified, to give the diester of ~ormula ~}X). The reaction employed ~or thi~ will, as lc well known ln the art, ~epenA on the nature of the ester recldue RSb.

~ or example, where the group repre~ented by R5b i9 a Cl - C6 alkyl group or an aralkyl group, such ae a benzyl group, the compound of formula ~IX) can be prepared by reacting the cGLLecpo~ng dicarboxylic acid wlth a Cl - C6 alcohol, ~uch a~ methanol, ethanol, pro~nol or h9x~nol, or an aralkyl alcohol, such as a benzyl alcohol, in the precence o~ an acid cataly~t, ~uch a~ hydLG~cn chlorlde or ~ul~urlc acid in an inert ~olvont ~or example: one o~ the Cl - C6 alcohols whlch may bo w ed ac the ~tartlng materlal de~cribed above; a halogenated hydrocarbon, cuch ac methylene chlorldo~ or an ether, ~uch ac tetrahydro~uran or dloxane) at a t~mperature of ~rom 0~C to 100~C, pre~orably ~rom 20~C to aooc, ~or a perlod o~ ~rom 1 hour to 3 day~, pre~erably ~rom 16 to 24 hourc; or by tr0atlng the COLLe~O~ g dlcarboxylic acid with a -- 2o6l6~7 halogenating agent (e.g. phosphoru~ pentachloride, thionyl chloride or oxalyl chloride) in an inert sol~ent (for example: a halogenated hydrocarbon, ~uch as methylene chloride; an ether, ~uch a~ tetrahydrofuran or dioxane; or an aromatic hydrocarbon, such as benzene or toluene) at about room temperature for a period of from 30 minutes to 5 hours, preferably from 1 to 3 hours, to give the corresponding acyl halide and then reacting thi~ acyl halide with the correspon~ng alcohol (when the t-butyl e~ter is prepared, it is de~irable to use potas~ium t-butoxide in place of the alcohol) in an inert ~olvent ~e.g. benzene or methylene chloride) in the pre~ence of a base (e.g. triethyl~m~e) at about room temperature for a period of from 30 minutes to 10 hours.

The de~ired compound can be recovered from the reaction mixture by conventional means. For example, a~ter di~tilling of~ the ~olvent, the residue i3 dls~olved in water and a water-immlsclble organlc solvent, ~uch a~ ethyl acetate, and the resulting solution 1~ neutralized wlth ~odlum hydrogencarbonate;
the organic layer i8 then separated and dried over a drying agent, such as anhydrous magne~lum sul~ate; the solvent i~ then distilled o~ to leave the de~ired protuct. The product can, i~ neces~ary, be further puri~ied by conventional means, ~or PY~ple, by recryctallization, or by the variou~ chromatography techn~ue~, notably preparative thin layer chromatography or column chromatography.

In 8top G4, a compound o~ rormula (Va) i~ prepared by roacting a diecter compound o~ ~ormula (IX) with a Grlgnard reagent o~ ~ormula R2 ~gX and/or R3aMgX (in whlch R2a, Q3a and X are a~ de~ined above).

The reactlon 1~ essentially the ~ame as that described above in Step B2 of Reaction Scheme B, and may be carried out u~ing the same reagent~ and reaction conditions.

Reaction Scheme H:

These reactions prepare compound~ of formulae (XIIIa), (XIa) and (VIIa), in each of which Rll i3 a hydrogen atom, that i~ to say compounds of formulae (XIII), ~XI) and IVII)~ and a compound of formula (Va), which are atarting material3 used in ~eaction Schemes E, D, A and B, re~pectively.

In Step Hl, which i~ an optional ~tep, a compound of ~ormula (XVIa) ie prepared by reacting a dinitrile compound of ~ormula (XVI) with a compound of fonmula Rlla~X (in which X ie ae de~ined above and Rlla Lep-e~onte any o~ the groupe de~ined above ~or Rll other than a hydrogen atom) in the preeence of a ba~e.

Examplea o aultable baeeA include: alkall metal hydridee, euch ae lithlum hydride or sodium hydrlde;
alkall metal carbonatea, euch ae eodlum carbonate or potaacium cArbonate; and alkali metal A~koY~ee, such a~
eodlum me~hoYl~e, eodium ethoY~de or potasalum t-bntox~e.

The reactlon la normally and pre~erably e~ected in tho ~rwe~ce o~ a eolvent. There ia no particular reatrlctlon on the nature o~ the eolvent to be employed, provlded that lt hae no advoreo e~ect on the reactlon or on tho roagenta involved and that it can dissolve the reagonta, at leaat to aome extent. Ex~mplee of eultable ~olvonte include: halogenated hydrocarbons, 9uch ae mothylene chloride or chloro~orm; ethere, auch ae tetrahydro~uran or di9x~ne; amlde~, euch aa - 146 - 20~1 60 7 dimethylformamide or dimethylacetamide; and ketones, such as acetone or methyl ethyl ketone. The reaction can take place over a wide range of temperature~, and the preci~e reaction temperature is not critical to the invention. In general, we find it convenient to carry out the reaction at a temperature of from 0~C to 120~C, more preferably from 20~C to 80~C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature o~ the reagents and sol~ent employed. However, provided that the reaction is effected under the preferred condition3 outlined above, a period of from 1 to 24 hour~, more preferably from 3 to 8 hour~, will u~ually euf f~ice, After completlon of the reactlon, the desired compound can be recovered from the reaction mixture by conventional means. For example, one sultable recovery procedure comprleee: A~ ng water to the reaction mlxture; extracting the mixture with a water-mlscible organic solvent, euch a~ ethyl acetate; weeh~ng the extract wlth water and drylng lt over a drylng agent, euch ae anhydrous magneclum sul~ate; and ~inally dietllllng o~ the eolvent. The product can, 1~
nocee~ry, be ~urther purlrled by conventional mean~, ~or example, by recryctallizatlon, or by the varlous chromatoy~h~ tec~nl~uee, notably preparative thin layer chromatography or column chromatography.

In 9tep H2, a compound o~ ~ormula ~XIIIa) i~
prepared by reactlng a dinitrile compound o~ ~ormula ~XVIa) with a Grl~nard reagent o~ ~ormula R2aMgX, in which R2~ and X aro a0 de~lned above, or with a reduclng agent. ~hi~ reactlon 1~ e~entially the ~ame a~ that de~cribed above in Step B2 o~ Reaction Scheme ~, and may be carried oue ueing the eame reagente and reactlon conditione.

,.' ., ' ' ', :. ~
~" ' : ,. ..... ..
, An imidazolyl-protecting group of a compound of formula (XIIIa) may optionally be removed by treating the compound of fonmula (XIIIa) in a conventional m~nner, depending on the nature of the protecting group, to give the compound of formula (XIII).

For example, when the protecting group i9 a trityl group or an alkoxymethyl group, it may be removed by reacting the protected compound with an acid.

~ xamples of ~uitable acids include: lnorganic acids, euch a~ hydrochloric acid or sulfuric acid; and organic acld~, such as acet~c acid, formic acid, trifluoroacetic acid, methanesulfonic acid or ~-toluene~ulfonic acid.

The reaction i~ normally and preferably effected in the pre~ence o~ a solvent. There i9 no particular restriction on the nature of the solvent to be employed, provided that lt has no adverse e~ect on the reaction or on the reagents involved and that lt can dls~olve the reagent~, at least to some P~tent. Examples o~ sultable ~olvents lnclude: ethers, ~uch as tetrahydro~uran or ~oY~ne; alcohols, such as methanol or ethanol; aclds, ~uch ae acetic acid; water; or a mixture o~ any two or more o~ the above ~olvent~.

The reactlon can take place over a wlde range o~
temperaturee, and the preci~e reaction temperature i~
not crltlcal to the invention. In general, we ~lnd it convonient to carry out the reactlon at a temperature of ~rom 0~C to 120~C, more pre~erably ~rom 10~C to lOO~C.
Tho tlm~ re~uired ~or the roaction may also vary widely, depen~r~ on many ~actor~, notably the reactlon temperature and the nature o~ the reagents and solven~
employed. However, provlded that the reaction is e~ected under the pre~erred conditionc outllned above, a period o~ ~rom 30 minute~ to 24 hour~, more pre~erably - 148 - 2~61 6~ 7 from 1 to 16 hours, will usually suffice.
.
After completion of the reaction, the de~ired compound can be recovered from the reaction mixture by conventional means. For example, one suitable recovery procedure compri~e~: evaporating the solvent and purifying the product by recrystallization or chromatography; or neutralizing the reaction mixture with a weak base (such a3 sodium hydrogencarbonate), extracting with a water-immiscible organic solvent, ~uch a~ ethyl acetate, and evaporating off the solvent. The product can, if necessary, be further purified by conventlonal mean~, for ? ~ le, by recrystallization, or by the varlou~ chromatography techniques, notably preparative thin layer chromatography or column chromatography.

When the ~m~ olyl-protecting group i9 an aralkyl group, ~uch a~ a benzyl or dlphenylmethyl group, it can be removed by catalytic hydrogenation. The reactlon i9 es~entlally the ~ame ae that deocrlbed above in reaction (1) o~ 8tep A2 o~ Reaction Scheme A, in which the carboxy-protecting group i8 an an aralkyl group, and may be carrled out uclng the oame reagent~ and reactlon conditlon~.

In Step H3, the reeultlng carbonyl compound o~
~ormula (XIIIa) i9 then reacted wlth a Grlgnard reagent o~ formula R3 ~gX, ln which R3a and X are a~ de~ined above, or with a reducing agent, to glve the compound of ~ormula ~XIa). Thio reaction ie e~oentlally the same as that deccrlbed above ln Step B2 o~ Reactlon qcheme ~, and may be carrled out w lng the ~amo reagents and roactlon condltlon~.

I~ declred, the im~azolyl-protecting group o~ the compound o~ ~ormula ~XIa) can be removed by e~sentially the same reaction a~ that optional reaction de~cribed above as Step H2 of Reaction Scheme H, which may be carried out using the same reagents and reaction conditions.

In Step H4, a carboxylic acid compound of formula (XXII) is prepared by hydrolyzing the rem~;n;ng cyano group at the 5-position of the imidazole ring. The reaction may be carried out using an alkali metal hydroxide, such a~ sodium hydroxide, pota~sium hydroxide or lithium hydroxide, in an inert solvent (preferably water; an alcohol, ~uch as methanol or ethanol; an ether, such as tetrahydrofuran or dloxane; or a mixture o~ any two or more of the above solvents). The reaction can take place over a wide range of temperatures, and the preciee reaction temperature i~ not critical to the inventlon. In general, we ~ind it convenient to carry out the reaction at a temperature of ~rom 0~C to 120~C, more prererably from 20~C to 100~C. The time requlred ~or the reaction may alco vary widely, dep~n~ng on many ~actor~, notably the reac~ion temperature and the nature oE the reagent~ and colvent employed. However, provided that the roaction lc effected under the pre~erred conditlons outllned above, a period oE ~rom 0.5 to 24 houro, more ~reEerably from 1 to 16 hours, will u~ually eu~lce. A~ter completion o~ the reaction, the reactlon produc~ can be recovered by conventional meanc. For example, the reactlon mixture i9 neutralized by adding a mlnoral acid, ~uch ae h~dLochlorlc acid; iE the desired compound o~ ~ormula ~XXII) ~ppeA~e as a preclpitate in the reaction modium, it can be collected by ~lltration.
Alternatlvely, the de~irod compound can be recovered a~
~ollow~: a~tor neutrallzlng the reaction mlxture, the colvent i~ di~tilled oE~ and the re~idue i9 ~ub~ected to col = chromatography; altornatively, the resldue may be mlxed wlth wator and a water-lmmleclble organlc solvent and extracted with the organic solvent, aEter whlch the - 150 - 20~16Q7 extract i9 dried over a drying agent, such as anhydrous magne~ium sulfate, and the solvent i~ distilled off to leave the desired product. The product can, if necessary, be further purified by conventional means, for example, by recrystallization, or by the various chromatography techniques, notably preparative thin layer chromatography or column chromatography.

In Step H5, an optional step, a compound of formula (Va) is prepared by esterification of the carboxylic acid compound of formula (XXII), optionally followed by deprotection o~ the im~n~Zolyl group. This e~terl~lcatlon reaction 19 essentially the same as that de~crlbed above in reactlon (li) of Step A2 of Reaction Scheme A, and the optional deprotectlon i9 essentially the ~ame as Step H2 of Reaction Scheme H, and each may be carried out uslng the ~ame reagents and reaction condition~.

In 8tep H6, a compound o~ ~ormula (XXIII) 19 prepared by hydrolyslng a compound o ~ormula (XIIIa).
Thie reactlon ie e~eentially the same as that described above ln Step ~4 o~ Reaction Scheme H, and may be carrled out u~ing the came reagent~ and reaction conditlonc.

In 8te~ H7, a compound o~ rormula (VIIa) i9 prepared by ecterlrlcatlon o~ the compound o~ ~ormula ~XXIII).
Thi~ reactlon i9 aeeentlally the same a~ that de~crlbed above ln Step H5 o~ Reactlon Scheme H, and may be carrled out u~lng the same reagente and reactlon condltlonc.

I~ de~ired, the lm~Azolyl-protecting group o~ the compound o~ ~ormula ~VIIa) can be removed by es~entially the ~me reactlon ac that optional react1on deecrlbed above a~ Step H2 o~ ~eaction gcheme H, whlch may be ' ~ ~ ~ 3 - 151 - 2061~7 carried out using the same rea~ents and reaction conditions.

In Step H8, a compound of formula (Va) is prepared by reacting a compound of formula (VIIa) with a Grignard reagent and/or a reducing agent, and then optionally deprotecting the imidazolyl group. This reaction is e~sentially the same as that described above in Step B2 of Reaction Scheme B, and the optional deprotection i~
essentially the same as Step H2 of Reaction Scheme H, and each may be carried out using the same reagents and reaction condltlons.

The compounds of the present lnvention can form salts. There 18 no partlcular restriction on the nature of these salts, provided that, where they are intended ~or therapeutic use, they are phAr~Aceutically acceptable. Where they are intended for non-therapeutic uses, e.g. as lntermediates in the preparation of other, and posslbly more active, compounds, even this restriction does not apply. The compounds of the present invention can rOrm salts with bases. Examples of such ~alts lnclude: salts with an alkall metal, such a~ codlum, pota~ium or lithlum; salts with an alkaline earth metal, such as barium or calclum; salts with another metal, such as magnesium or al~lmln~lm; organic base ealt~, cuch a~ a ~alt with dicyclohexylamlne, g~1An~ne or trlethylAm~ne; and salts with a basic amino acid, such ae lyslne or arginine. Also, the compound of the present invention contAln~ a ba~ic group ln lt~
molecule a~d can therefore ~orm acid addltlon salts.
~A~rles o~ 5uch acid addition saltc include: salts wlth mineral acids, eepecially hydrohalic aclds ~such ae hydrofluoric acid, hydrobromic acld, hydroiodic acid or hydrochloric acid), nitric acid, carbonic acid, sulfurlc acid or phosphoric acid; salts with lower alkylsulfonic acld~, ~uch as methane~ulfonlc acld, trlfluoromethane-.. . . .

I ~ 2 3 - 152 - 206~ ~D 7 sulfonic acid or ethanesulfonic acid; salt~ with aryl~ulfonic acids, ~uch as benzenesulfonic acid or ~-toluene~ulfonic acid; salts with organic carboxylic acids, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; and ~alts with amino acids, such as glutamic acid or aspartic acid. The compounds of the present invention can be converted to a pharmaceutically acceptable salt by treatment with an acid or a base by conventional means, as is well known in the art.

The compounds of the present invention exhibit an excellent inhibitory effect against the elevation of blood pre~0ure induced by angioten~in II and are therefore extremely useful for prevention or treatment of circulatory diseases a3 a hypotensive drug or a therapeutic drug for heart disease~.

Their blological activity was determ~ned by the ~ollowing experiment.

EvAl1~atinn o ATI receptor blo~k~n~ ~ctivity by tl~n o~ pre~or resDnn~e to ~giot~n~

The blologlcal activlty o~ each compound wa3 a~ee~ced by determlnlng the dose requlred to inhlbit the pre~cor re~ponce to intravenou~ angiotensin II by fifty percent (ID50) in rat~. Male Wlster-Imamichi rats, each weighlng 300 to 400 g, were anesthe~lzed by intraperltoneal ln~ectlon o~ lO0 mg/Xg o~ sodium thlobutabarbltal ~Inactln (trade name)~ and two cannulae were lncerted: one lnto the ~emoral artery for measuring blood pre~eure and the other lnto the remoral veln for ln~ecting drug~. Fi~ty ng/kg o~ angioten~ion II were lntravenou~ly adm~nl3tered at intervals o~ about lO
mlnute~, and the elevatlon o~ blood pressure (normally about 50 mmHg) wa~ ob~erved. A~ter con~tant pres~or ' - 153 - 2~61607 responses to angiotensin II were obtained, a test compound was intravenously ~m;nistered~ Two minutes later, angiotension II was again injected, and the inhibitory effect of the test compound was estimated.
The percent inhibitions of the pres~or response to angiotensin II by progreYsive increase of the test compound was used to calculate the value of ID50.
Angiotensin II was used in this test dissolved in 0.5 bovine serum albumin (~3SA) and the test compounds were dissolved in 100% dimethyl sulfoxide (DMS0). Table 7 show~ the ID50 values thus det~r~ned~

In addition to the compounds of the invention (which are identifled hereafter by the number of the one of the following Examples which illustrates their preparation), we also carried out the same experiment using a prior art compound (identified in the Table a3 "compound A"), whlch 1~ 2-~4-(2-butyl-5-chloro-4-chloromethylimidazol-l-ylmethyl)phenyl]benzoic acid, which i~ disclosed in Example 118 of European Patent Publlcatlon No. 253 310.

. - , , . - ., , - 154 - 2~61 ~0 7 Table 7 Test compound ID50 (mg/kg, i.v.) (Compound of Example No.) 0.22 0.066 11 0.25 17 0.056 19 0.008 22 0.017 23 0.043 24 0.014 36 0.0062 39 0.010 41 0.0063 44 0.0082 0.19 46 O.lB
48 0.064 0.22 0.23 59 0.066 0.134 69 0.019 74 0.036 0.11 76 0.022 A 3.3 The compound8 o~ the pre8ent lnventlon can be a~m~ tered, ~or sYA~ple, orally ln the ~orm o~
tablet8, cap9ule~, granule~, powder~, syrup~ or the . .

: !

.

2061~07 like, or parenterally by injection, suppository or the like. These pharmaceutical preparations can be produced in the conventional m~nne~ using the adjuvants generally known in the art, such as excipients, binders, disintegrating agents, lubricant~, stabilizers, corrigents and the like. Although the dosage may vary depending upon the symptoms and age of the patient, the nature and severity of the disease or d~sorder and the route and manner of ~m; nistration, in the case of oral ;n;stration to an adult human patient, the compounds of the present invention may normally be ~m;n~stered at a total daily dose of from 1 to 1000 mg, preferably from 5 to 300 mg, either in a single dose, or in divided dosee, for example two or three times a day; in the ca~e of intravenou~ in~ection, a dose of from 0.1 to 100 mg, preferably from 0.5 to 30 mg, may be ~m;n~stered be~ween one and three times a day.

The inventlon i9 further lllustrated by the following Examplec, whlch demonstrate the preparation of various of the compounds o~ the invention. The preparation o~ certain starting materials used in these Examples i3 shown in the subsequent Preparations.

, . . ~ , .
.

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

20~1607 M&C FOLIO: 64868/FP-9205 WANGDOC: 1620H

Methyl 1-~(2~-t-butoxycarbonylbiphenyl- 4-Y1) methY11-2-butyl- 4 -hydroxymethylimidazole-5-carboxylate (Compound NQ. 1-94~

l(a) D~mPthyl l-t(2'-t-buto~ycarbonylbi~henyl-4-yl)-m~yll-2-butylimidazole-4.5-dicarboxylate A ~odium methoxide solution prepared from ~.69 g of sodium and 40 ml of methanol was added to a solution of 7.2 g of dimethyl 2-butylimidazole-4,5-dicarboxylate (prepared ac de~cribed in Preparatlon 4~ in 40 ml of methanol, and the resulting mixture was concentrated by evaporation under reduced pressure. The resulting resldue wae mlxed wlth ben7ene, and the mlxture was concentrated by distillation under reduced preesure.
After thlc operation had been repeated three tlme~, the 801id thu~ obt~e~ wa~ dis~olved in 72 ml of ~,~-dimethylacetAm~e. A solution o~ 10.41 g of t-butyl 41-bromomethylbiphenyl-2-carboxylate in 100 ml of dimethylacetAm~e was then added dropwlse to the re~ultlng solutlon. The reactlon mixture wae then stlrred at room temperature for 1 hour and at 50 - 55~C
for 2 hours. At the end of thi~ time, it wa~ mixed with ethyl acetate and water, and the ethyl acetate layer wa~
~e~arated, and dried over anhydrous magnesium sulfate;
the solvent was then removed by distillation under reduced ~ressure. The resldue was puri~ied by column chromatography through slllca gel, uslng a 1 : 1 by volume mlxture of ethyl acetate and hs~ne as the eluent, to give 15.1 g o~ the title compound as a gum.

Nuclear Magnetlc Re~onance Spectrum ~CDCe3) ~ ppm:
0.90 ~3H, triplet, J ~ 7 Hz);

. .
' , . ~ 2 o 1 . 26 ~9H, triplet);
~ 2.0 (4H, multiplet);
2.70 ~2H, triplet, J = 7 Hz);
3 . 81 ~3H, singlet);
3 . 90 ~3H, ~inglet);
5.47 (2H, singlet);
6.95 - 7.85 (~H, multiplet).

ll~L Methyl 1-~(2~-t-butoxycaxbonylbi~henyl-4-yl) methyll-2-butyl-~-hydroxymethyl~ mi dazole-5-carboxylate 42 ml of dli~obutylal~m~ nl~m hydride (as a 1.5 M
~olution ln in toluene) were added dropwise at a temperature between -20~C and -15~C to a solution of 16.0 g o~ dimethyl 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-4,5-dicarboxylate [prepared as described in etep ~a) above] in 200 ml of tetrahydrofuran, and the re~ulting mixture was allowed to ~tand at 0 - 5~C for 16 hours. At the end of thi~
time, the reaction mixture wa~ mixed with an aqueous solution of A -, ~um chloride and ethyl acetate and wa~
then 3tlrred ~or 1 hour. After this, precipitate~ were removed by ~iltration The ethyl acetate layer wa3 then ~eparated and dried over anhydrou~ magnesium sulfate, and the solvent was removed by di~tillation under reduced pressure. The residue was then purified by column chromatography through silica gel, using ethyl acetate ac the eluent, to give 12.0 g of the title compound as cryctals, melting at 99~C.

Nuclear Magnetic Reconance 9pectrum ~CDC43) ~ ppm:
0.90 (3H, triplet, J . 7 Hz);
1.20 i9H, cinglet);
1.1 - 2.0 ~4H, multiplet);
2.69 ~2H, triplet, J . 7 Hz);
3.55 ~lH, broad ~inglet);

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

, 20~1~07 3.78 (3H, singlet);
4.84 (2H, doublet, J = 5 Hz);
5.60 (2H, singlet);
6.35 - 7.9 (8H, multiplet).

Et~yl 1-[(2'-t-butoxycarbonylbiphenyl- 4-yl) methyll-2-butyl-4-hydr~...ethylimidazole-5-carboxylate (C~Co~n~ No. 1-95) ~1~1 Die~yl l-r(2'-t-buto~carbo~ylbi~henyl-4-yl)-met~yll-2-butyl~AA7~1e-4.5-dicarboxylate Following a procedure eimilar to that deecr~bed in Example l(a), but using 8.0 g of dlethyl 2-butyl-lmldazole-4,5-dicarboxylate (prepared ae deecribed in Preparatlon 3) and 10.41 g of t-butyl 4'-bromo-methylblphenyl-2-carboxylate, 15.4 g o~ the title compound were obt~i~e~ as a gum.

Nuclear Magnetlc ReeonAncq 9pectrum (CDC~3) ~ ppm:
0.90 (~H, triplet, J . 7 Hz);
1.1 - 2.0 (4H, multiplet);
1.24 ~9H, ~lnglet);
1.26 ~3H, trlplet, J . 7 Hz);
1.39 (3H, trlplet, J . 7 Hz);
2.72 ~2H, trlplet, J - 7 Hz);
4.28 ~2H, quartet, J ~ 7 Hz);
4.40 (2H, quartet, J . 7 Hz);
5.S0 ~2H, singlet);
7.0 ~ 7.9 ~8H, multlplet).

. .. . , ~
., .

- 159 - 20S1~07 2 (b) Ethyl 1- ~ ( 2 ' - t-butoxycarbonylbiphenyl- 4 -yl ) -methyll-2-butyl-4-hydroxymethylimidazole-5-carboxylate Following a procedure ~imilar to that de~cribed in Example l(b), but u~ing 1.50 g of diethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl~ml~A2ole-4,5-dicarboxylate [prepared as described in ~tep (a) above]
and 3.9 ml of diisobutylalllm~nl~m hydride (as a 1.5 M
~olution in toluene), 1.1 g of the title compound was obtA~ne~ as a gum.

Nuclear Magnetic Resonance Spectrum (CDCR3) ~ ppm:
0.90 (3H, triplet, J ~ 7 Hz);
1.24 (9H, singlet);
1.30 ~3~, triplet, ~ - 7 Hz);
1.1 - 2.0 ~4~, multiplet);
2.68 ~2H, triplet, J . 7 Hz);
3.60 ~lH, broad singlet);
4.24 (2H, quartet, ~ . 7 Hz);
4.a4 ~2H, cinglet);
5.57 ~2H, singlet);
6.9 - 7.85 ~8H, multiplet).

~C Z~h~PT .12 3 Met~yl 2-butyl~ 2~-carh~ybleh~yl-4-yl)methyll-4-ro~ymet~ m~ ~IA 7ole - 5-~!A rbo~ylAte (Com~o~n~ No. 1-5) A ~olution o~ 0.36 g Or methyl 1-~(2'-t-butoxy-carbonylbiphenyl~4-yl)methyll-2-butyl-4-hydroxymethyl-imldazole-5-carboxylate ~preFared a~ described in ~xample 1) ln 4 ml Or a 4 N solution Or hydrogen chloride ln dloxane was allowed to stand at room temperature ~or 4 hourc. At the end o~ thi~ time, the reaction mixture wa~ concentrated by evaporation under - 160 - 20~1~07 reduced pressure, and the residue was triturated with ethyl acetate, to give crystals, which were collected by filtration to give 0.35 g of the title compound in the form of its hydrochloride, melting at 192-195~C (with decomposition).

Nuclear Magnetic Re~onance Spectrum (h~x~euterated dimethyl ~ulfoxide) ~ ppm:
0.81 (3H, triplet, J - 7 Hz);
1.22 - 1 35 ~2H, multiplet);
1.43 - 1.56 ~2H, multiplet);
3.00 (2H, triplet, J ' 7 Hz);
3.82 (3H, ~inglet);
4.~1 ~2H, ~inglet);
5. 77 (2H, singlet);
7 .18 - 7 . 75 (8~, mNltiplet).

RYI~MPT.1;! 4 21-t-Buto~rArhn~ylh~?h~yl-4-yl)mel~ -2-butyl-4-~y~roxyme~yli~ 7~1 e-5-~A rbo~yl i C ~ cid (Co~o~nA No. 1-96~

A solutlon Or 2 . 01 g 0~ lithium hydroxtde monohydrate ln 97 ml o~ water wa~ added to a ~olution of 4.78 g 0~ methyl 1-1(2'-t-butoxycarbonylbiphenyl-4-yl)-methyl]- 2 -butyl-4-hydroxymethylimidazole-5-carboxylate ~prepared a~ deccrlbed in ~xample 1) in 48 ml of dtox~ne, and the reculting mlxture was stirred at room tem~erature ~or 13 hours. At the end o~ thl~ time, the reaction mixture wa~ ~reed rrom dioxane by di~tillatlon under re~ucefl precsure, and 47.6 ml of 1 N aqueou~
hydrochloric acid were added to the aqueous residue.
The cry~tals which precipltated were collected by ~iltration and then w-~he~ wlth water and with diethyl ether, in that order, to give 4.26 g Or the tltle compound, melting at la7~C ~with decompocition).

.' ! ' .. , ~ - 161 - ~1 Go7 Nuclear Magnetic Resonance spectrum (CDCQ3) ~ ppm:
0.85 (3H, triplet, J = 7 Hz);
1 . 24 (9H, singlet);
1 . 1 - 1 . 9 (4H, multiplet);
2 . 80 (2H, triplet, J = 7 Hz);
5 . 05 (2H, ~inglet);
5 . 93 (2H, ~inglet);
7 . 0 - 7. 85 (8H, multiplet).

EX~MPLE 5 2 - ~utyl-1-~(2'-carboxybi~h~yl- 4 - yl )methyll-4-y~ylim~A7~le-5-carboxyliC acid ~Com~olln~l No. 1-2) A solutlon of 0.12 g of 1-[~2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimldazole-5-car~oxylic acid (prepared a~ described in Example 4) in 2 ml of a 4 N solution of hydrogen chloride in dioxane wa6 allowed to stand at room temperature for 5 hours and then the solvent wac removed by distlllation under re~uce~ pressure. The re~ulting residue was triturated ln ethyl acetate, to glve 0.11 g of the title compound in the ~orm of it~ hydrochloride, melting at 130 - 140CC (with ~o~tening).

Nuclear Magnetic Re~onance Spectrum (hPx~euterated dimethyl oulfoxide) ~ ppm:
0.80 ~3H, triplet, J . 7 Hz);
1.2 - 1.33 ~2H, multiplet);
1.4 - 1.53 ~2H, multiplet);
2.9a ~2H, trlplet, J . 7 Hz);
4.84 ~2H, slnglet);
5.81 ~2H, clnglet);
7.17 ~ 7.74 ~8H, multlplet).

, , ,: ' ~ ~ z o 2 0 ~ 7 - 1~2 -Pivaloyloxymethyl 1-~(2l-t-butoxycarbonylbiphenyl-4-yl)methyll-2-butyl-4-hydroxymethylimidazole-5-carboxylate (Com~ound No, 1- 9 7 ) 350 mg of pota~ium carbonate were added to a ~olut~on of 552 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylic acid (prepared as de~cribed in Example 4) and 220 mg of pivaloyloxymethyl chloride in 7 ml of N,~-dlmethylacetamide, and the resulting mixture was ~tirred at room temperature for S hours. At the end of thi~ time, the reaction mixture wa~ mixed with ethyl acetate and water, and the ethyl acetate layer was ceparated and dried over anhydrous magnesium ~ulfate;
the solvent was then removed by dl~tillatlon under reduced pre~ure. The reculting residue was purlfied by column chromatography through silica gel, using ethyl acetate as the eluent, to glve 0 62 g of the tltle compound ac a ~yrup.

Nuclear Magnetic Re~o~Ance Spectrum (CDCQ3) 6 ppm:
0.91 (3H, triplet, J - 7 Hz);
1.18 (3H, ~inglet);
1.21 (9H, cinglet);
1.1 - 2.0 (4H, multiplet);
2.72 (2H, triplet, J ~ 7 Hz);
3.35 (lH, broad);
4.a5 ~2H, doublet, J . 5 Hz);
5.61 (2H, ~inglet);
5,90 (2H, slnglet);
6.95 ~ 7.9 (BH, multiplet).

s . - .

, ~,. . . .

- 163 - 2~61607 Pivaloyloxymethyl 2-butyl-1-1(2'-carboxybiphenyl-4-yl)methyll-4-hydroxymethylimidazole-5-carboxylate (Compound No. 1-98) A ~olution of 0.62 g of pivaloyloxymethyl 1-[(2'-t-butoxycarbonylblphenyl-4-yl)methyl]-2-butyl-4-hydroxy-methylimidazole-5-carboxylate (prepared as described in Example 6) in 10 ml of a 4 N solution of hydrogen chloride in dioxane was allowed to stand at room temperature for 4 hours, after which it was concentrated by evaporation under reduced pressure. The syrupy reYidue was stlrred in diethyl ether, and then the ~olvent was removed by decantation and the residue was dried i~ vacuo, to give 0.46 g of the hydrochloride of the title compound a~ a powder.

Nuclear Magnetic Re~onance Spectrum (CDC~3) ~ ppm:
0.85 ~3H, triplet, J ~ 7 Hz);
1.19 (9H, ~inglet);
1.25 - 1.45 (2H, multiplet);
1.65 - 1.80 (2H, multiplet);
2.99 (2H, triplet, J . 7 Hz);
5.01 (2H, ~inglet);
5.70 (2H, ~inglet);
5.89 ~2H, ~inglet);
7.05 - 7.9'7 (8H, multiplet).

~ pr.~ 8 Met~yl l-l(2~-t-buto~y~Arbo~ylbiphe~yl-4-yl)met~yll-2-butyl-4-(metho~yme~hyl~im~A7~1e-5-rArbo~ylAte lSQ~ 'n~ No. 1-99) 0.057 g o~ sodlum hydride (as a 55~ w/w disper~lon in mineral oil) was added to a ~olution of 0.478 g of .
.
, , - ~ , , .

1 6 2 ~

20~16~7 methyl 1-~(2'-t-butoxycarbonylbiphenyl- 4 - yl )methyl]-2-butyl-4-hydroxymethylimidazole-s-carboxylate (prepared as described in Example 1) in 5 ml of N,N-dimethyl-acetamide, and the resulting mixture was stirred at room temperature for 30 minute~. At the end of this time, 0.125 ml of iodomethane were added, and the reaction mixture wa~ ~tirred at 50~C for 3 hours. The reaction mixture was then mixed with ethyl acetate and water.
~he ethyl acetate layer was separated and dried over anhydrous ~gne~ium sulfate; the solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through eilica gel, u~ing a 1 : 1 by volume mixture of ethyl acetate and methylene chloride as the eluent, to give 0.30 g of the title compound as a gum.

Nuclear Magnetic Reso~Ance Spectrum (CDC~3) ~ ppm:
0.90 (3H, triplet, J . 7 Hz);
1.24 ~9H, singlet);
1.1 - 2.0 (4H, multiplet);
2.71 (2H, triplet, J . 7 HZ);
3.46 (3H, singlet);
3.80 (3H, ~inglet);
4.68 (2H, Binglet);
5.60 (2H, 3inglet):
6.9 - 7.9 (8~, multiplet).

P!X I~IPT.P'. 9 ~eth~yl 2-hut~yl-1-~( 2 ' - rA rbo~ybiah~r~yl - 4 - yl ) met ~yl l - 4 -(mQtho~ymgth~yl)imt~zole-5-~rbo~ylAte ~Qmpol~n~ No. 1-121) A ~olution o~ 0.30 g o methyl 1-~2 ' - t-butoxy-carbonylblphenyl-4 yl)methyll-2-butyl-4-~methoxymethyl)-~mldazole-5-carboxylate ~prepared a6 deBcrlbed in Example 3) in 3 ml o~ a 4 N ~olution o~ hydrogen I ~ 2 0 chloride in dioxane was allowed to stand at room temperature for 5 hours, after which the solvent was removed by distillation under reduced pressure. The syrupy residue was triturated in diethyl ether and collected by filtration, to give 0.26 g of the title compound in the form of it~ hydrochloride, melting at 106 - 110~C (with softening).

Nuclear Magnetic Resonance Spectrum ~h~x~euterated dimethyl sulfoxide) ~ ppm:
0.81 (3H, triplet, J , 7 Hz);
1 2 - 1.35 (2H, mNltiplet);
1.45 - 1.6 (2H, multiplet);
2.97 (2H, triplet, J - 7 Hz);
3.39 (3H, singlet~;
3.82 (3H, singlet);
4.72 (2H, singlet);
5.75 (2H, singlet);
7.16-7.74 (BH, multiplet).

T.R 10 2-Butyl-l-r(2~-~Ar~oxybi~h~yl-4-yl)met~yll-4-y~ro~y-l-m~th~yl)e~yll~m~fl~7~1e-5-~Arboxylic acid (Compo~n~ No. 1-31) lO~a) l-r(2'-t-~uto~yrArbo~ylbiDh~yl-4-yl)met~yll-2-butyl-5-cy~nn-4-r(1-~ydro~y-l-m~t~yl)ethyll-~ m~ fl:~ 7~-1e 48 mg o~ sodium hydride (a~ a 55~ w/w dispersion in mineral oll) were added, at room temperature and under - an atmo~phere o~ nitrogen, whilet stirrlng, to a ~olution o~ 207 mg o~ 2-butyl-5-cyano-4-[(1-hydroxy-1-me~hyl)ethyl]~m~A~zole ~prepared ae de~cribed in - Preparatlon 7) ln 10 ml o~ -dlmethylacetamlde, and the resulting mixture was ~tirred ~or 30 mlnutes; at the . . .
. ~ .

I o 2 0 ' - 166 - ~6~5~7 end of thi3 time, 347 mg of t-butyl 4~-bromomethyl-biphenyl-2-carboxylate were added. The reaction mixture was then stirred at room temperature for 2 hours, after which it was poured into a mixture of ice and ~odium chloride and extracted with ethyl acetate. The extract wa~ dried over anhydrous magne~ium sulfate and concentrated by evaporation under reduced pressure, to give an oily crude product. This was purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of h~x~ne and ethyl acetate as the eluent, to g~ve 462 mg of the title compound.

Nuclear Magnetic Re~o~nce Spectrum (CDCQ3) ~ ppm:
0.90 ~3H, triplet, J - 7 Hz);
1.1 - 2.1 (4H, multiplet);
1.21 (9H, singlet);
1.61 ~6~, singlet);
2.70 ~2H, trlplet, J . 7 Hz);
3.40 ~1~, singlet);
5.22 (2H, ~ingletJ;
7.0-~.0 ~8H, multiplet).

~lQl~L 2-Butyl-1-~2'-carbo~ybi~hP~yl-4-yl)methyll-5-cyAn~-4- ~ ~dro7~y- l-met~url) e~,yll im~ ~zole A solution o~ 462 mg o~ (2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-5-cyano-4-~(1-hydroxy-1-methyl)ethyl~m~zole ~prepared aa deecribed ~n step ~a) above] ln 10 ml o~ a 4 N ~olutlon o~ hydrogen chloride in dioxane wa~ allowed to stand overnight at room temperature. At the end o thlc time, the reaction mixture wac concentrated by evaporation under reduced prec~ure, and the concentrate was dissolved in methylene chlorlde. The precipitate which depoaited was collected by ~iltration and drled, to glve 457 mg o~ the hydrochlorlde o~ the title compound a~ a colorlesc powder, meltlng at 209 - 210~C.

. .
, , ~ i' ., ., . , : , , . D ~ U

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.85 (3H, triplet, J = 7 Hz);
1.0 - 1.8 (4H, multiplet);
1.58 (6H, ~inglet);
3.00 (2H, triplet, J = 7 Hz);
5.51 (2H, singlet);
7.1 - 8.0 (8H, multiplet).

lQ(c) 2-Butyl-l- r (2'-carbo~ybi~henyl-4-yl)methyll-4-r(l-hydxoxy-l-methyl)ethyllimidazole-5-carboxylic acid A solution of 314 mg of 2-butyl-1-[(2'-carboxy-biphenyl-4-yl)methyl~-5-cyano-4-~(1-hydroxy-1-methyl)-ethyl]imidazole hydro~hloride ~prepared a~ de~cribed in step ~b) above] in an aqueou~ solution of 460 mg of sodium hydroxide in 5 ml of water was stirred in an oil bath kept at 100~C for S hours. At the end of thi~
time, the reaction mixture was cooled, and its pH was ad~usted to a value of 3 to 4 by the addition of 1 N
aqueouc hy~rochloric acid. The colorle~s precipitate whlch depo~lted wa~ collected by filtration, w?qhe~ wlth water and drled over anhydrous magnesium sulfate, to glve 244 mg o~ the title compound, meltlng at 139 141~C.

Nuclear Magnetlc Re~onance Spectrum (heY~deuterated dimethyl sul~oxide~ ~ ppm:
o.a6 (3H, triplet, J . 7 Hz);
1.0 - 1.9 ~4H, multiplet);
1.60 ~6H, ~inglet);
2.66 (2H, trlplet, ~ . 7 Hz);
5.70 ~2H, clnglet);
6.9 ~ 7.9 ~H, multlplet).

.. . .

, , .

I ~ 2 ~
20~1 60 7 2-Butyl~ (2~-carboxybiphenyl-4-yl)methyll-4-tl-hydroxyethyl)imidazole-5-carboxylic acid (Compound No. 1-25) ll(a) 4-Acetyl-1-~(2'-t-butoxycarbonylbi~henyl-4-yl)-met~yll-2-butyl-5-cyanoimidazole 0.87 g of potassium carbonate and 2.4 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate were added to a eolution of 1.2 g of 4-acetyl-2-butyl-5-cyanoimidazole ~prepared ae descri~ed in Preparation 5) in 12 ml of ~,~-dimethylacetamide, and the resulting mixture was stlrred at room temperature for 3 hours. At the end of thic time, the reaction mixture was diluted with 100 ml of ethyl acetate and w-sbe~ with a saturated aqueous eolution of ~odlum chloride. The aqueous layer was once agaln extracted with 50 ml of ethyl acetate, and the comblned extracts were weehe~ with a saturated aqueous ~olutlon of sodlum chloride. The ~olvent was removed by distillation under reduced pre~sure, and the re3ulting re~idue wae purified by column chromatography through eillca gel, ueing a 3 : 1 by volume mlxture of h~ne and ethyl acetate a~ the eluent, to give 1.31 g of the title compound.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.93 ~3H, trlplet, J - 7 Hz);
1.1 ~ 2.1 ~4H, multiple~);
1.23 (9H, ~lnglet);
2. sa ~3H, ~lnglet);
2.75 (2H, triplet, J - 7 Hz);
5.32 (2H, slnglet);
7.0 3.0 ~H, multiplet).
, . , .
. , . ' , , . . . .

ll(b) 4-Acetyl-2-butyl-1-[(2'-carboxybiphenyl-4-yl)-methyll-5-cyanoimidazole A solution of 1.3 g of 4-acetyl-1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-5-cyanoimidazole [prepared as de~cribed in step (a) above] in 30 ml of a 4 N ~olution of hydrogen chloride in dioxane was allowed to ~tand overnight at room temperature, after which it wa~ concentrated by evaporation under reduced pressure.
The concentrate was purified by column chromatography through silica gel, u~ing a 10 : 1 by volume mixture of methylene chloride and methanol as the eluent, to give a colorless amorphous solid. The solid was triturated in ha~ne/ collected by filtration and dried, to give 1.1 g of the title compound, melting at abo~e 55~C (with so~tening).

Nuclear Magnetic Re~onance Spectrum (CDC~3) 6 ppm:
0.84 (3H, triplet, J - 7 Hz);
1.0 - 2.0 (4H, multiplet);
2.54 ~3H, slnglet);
2.66 ~2H, triplet, J . 7 Hz);
5.17 ~2H, singlet);
6.3 - 7.0 ~8H, multiplet).

ll(c) 2-Butyl-1-~(2~- rA rbo~yh~h~yl-4-yl~me~yll-5-cy21n~-4- (l-4ytlro~yet~yl) ~m~7.nle 68 mg o~ sodi~un borohydride were added to a solution o~ 719 mg o~ 4-acetyl-2-butyl-1-1~2'-c~rbo~ybiphenyl-4-yl)methyl]-5-cyanoi~ zole ~prepared ac deecribed in ~tep ~b) above~ ln a mlxture o~ 20 ml o leopropanol and 10 ml o~ ethanol, and the reeultlng mlxture wa~ ~tirred at room temperature ~or 3 houre. At the end o~ thls time, the pH o~ the reactlon mixture wa~ ad~u3ted to a value o~ 3 by the addition o~ 1 N aqueoue hydrochlorlc acld, a ter whlch the ~olvent was di~tilled o~ under "~

~ ~ 2 ~

- 170 - 206~7 reduced pre~sure. The resulting residue was mixed with methylene chloride and water, and the methylene chloride layer was separated. The aqueous layer was extracted three times with methylene chloride, and the combined extract~ were dried and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature. The solid which then deposited was collected by filtration and dried, to give 398 mg of the title compound as a colorless powder, melting at 200 - 201~C.

Nuclear Magnetic Resonance Spectrum ~hexAdeuterated dlmethyl ~ulfoxide) ~ ppm:
0.88 (3H, trlplet, J - 7 Hz);
1.0 - 2.0 ~4H, multipletl;
1.54 ~3H, doublet, J ~ 7 Hz);
2.68 (2H, triplet, J - 7 ~z);
4.91 ~lH, quartet, J . 7 Hz);
5.21 (2H, singlet);
7.0 - 8.0 ~8~, multiplet).

ll~d) 2~utyl-~ 2'-r~rboxy~i~h~yl-4-yl)m~t~yll-4-(l-hy~ro~ye~yl)im~A7~1e-5-~rbo~ylic aci~

A mixture of 300 mg of 2-butyl-1-~2'-carboxy-biphenyl-4-yl)methyl]-S-cyano-4-~1-hydroxyethyl)imidazole ~prepared ac de~cribed in ~tep (c) above] and 3 ml of a 1 N aqueoue eolutlon of sodium hydroxide wac stirred ln an oil bath kept at 80~C for 3 hour~. At the end of thl0 ~ime, the reaction mlxture wa~ cooled and then wea~ly acidifled with hydrochloric acid; lt wae then ex~racted ~our times, each tlme with 30 ml of methylene chlor~de. The combined extracts were dried and concentrated to drynese by evaporation under reduced pre~ure, to give an amorphoue solid. Thic ~olld wa~
puri~ied by column chromatography through sillca gel, .

i .
. , ~

~ 6 2 0 ~ - 171 - 20~1607 using mixtures of methylene chloride and methanol ranging from 10 : 1 to 3 : 1 by volume as the eluent. A
solid obtained from the eluate was triturated in diethyl ether. The resulting powder was collected by filtration and dried, to give 72.3 mg of the title compound a~ a colorle~s powder, melting at 168 - 170~C (with softening above 140~C). .

Nuclear Magnetic Resonance Spectrum th~A~euterated dimethyl ~ulfoxide) ~ ppm:
0.84 (3H, triplet, J , 7 Hz);
1 0 - 2 0 (4H, multiplet);
1 52 (3H, doublet, J . 7 Hz);
2.3 - 2.~ (2H, overlapped with a peak of dimethyl ~ul~oxide);
4.93 ~lH, guartet, J - 7 Hz);
5.60 ~2H, broad ~inglet);
6 8 - 7 8 (8H, multiplet).

P!X l~MDT. IZ 12 2-~tyl-1-~(2'-~A~bo~ybiphP~yl-4-yl)met~yll-4-Y~roxyb~n7~l)im~zole-5-~rbo~ylic ~cid (Com.~o~n~ No 1-80) 12(a) 4-~n7~yl-l-~(2'-t-buto~y~rbo~ylbiDhP~yl-4-yl~-me~yll-2-hutyl-5-cyAn~m~7.01e Followlng a procedure ~imilar to that described in Example ll~a), but using 1 27 g Or 4-benzoyl-2-butyl-5-cyanolm~Azole ~prepared as described in Preparation 6~, 1 74 g o~ t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 0 63 o~ potacsium carbonate and 20 ml of ~,~-dlmethylacetamlde, and then purl~ylng the product by column chromatography through sllica gel, u~lng a 2 : 1 by volume mixture o~ heY~ne and ethyl acetate ac the eluent, 2.1 g o~ the tltle compound were obtained.

', ~', ' ',~, ' , - 172 - 2~ B~ ~0 7 Nuclear Magnetic Resonance Spectrum (C~CQ3) ~ ppm:
0.93 (3H, triplet, J = 7 Hz);
1.0 - 2.1 (4H, multiplet);
1.23 (9H, singlet);
2.79 (2H, triplet, J = 7 Hz);
5.38 (2H, singlet);
7.1 - 8.0 (llH, multiplet);

8.3 - 8.7 (2H, multiplet).

12~b) 1-r(2'-t-Buto~ycarbo~ylbi~henyl-4-yl)methyll-2-butyl-5-cyano-4-(Y-hydroxybenzyl)imidazole 50.5 mg of sodium borohydride were added to a solution of 691 mg of 4-benzoyl-1-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-5-cyanoimidazole [prepared as described in step (a) above] in 10 ml of ethanol, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then neutralized with aqueou~ hydrochloric acid, after which it wa~ mixed wlth ethyl acetate and with a saturated aqueous solution o~ sodlum chloride. The ethyl acetate layer wa~
~eparated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The re6idue wac purified by column chromatography through ~illca gel, uelng a 1 : 1 by volume mlxture of he~ne and ethyl acetate as the eluent, to glve 589 mg of the tltle compound a~ a colorle~ amorphous solid.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.89 ~3H, triplet, J - 7 Hz);
1.0 ~ 2.0 ~4H, multiplet);
2.68 (2H, triplet, J . 7 Hz);
5.18 ~2H, ~inglet);
5.89 ~lH, slnglet);
7.0 - ~.0 ~13H, multiplet).
i 1 6 ~ o 12(c) 2-Butyl-1-~(2/-carboxybiphenyl-4-yl)methyl]-s-cyano-4-( a -hydroxybenzyl)imidazole A solution of 589 mg of 1-[(2~-t-butoxycarbonyl-biphenyl-4-yl)methyl]-2-butyl-5-cyano-4-(~-hydroxy-benzyl)lm;~Azole ~prepared as described in step (b) above] in 20 ml of a 4 N solution of hydrogen chloride in dioxane wa~ allowed to stand at room temperature overnight and then concentrated by evaporation under reduced pressure. The re~idue was triturated in hexane and collected by filtration to give 493 mg of the hydrochloride of the title compound a~ a colorless powder, melting at 95 - 97~C (with softening).

Nuclear Magnetic Resonance Spectrum (h~Y~deuterated dimethyl sul~oxide) ~ ppm:
o . ~a ~3H, trlplet, J - 7 Hz);
1.0 - 2.0 (4~, multiplet);
3.00 (2H, trlplet, J . 7 Hz);
5.47 ~2H, slnglet);
6.09 (lH, singlet);
7.0 - 8.0 (13H, multlplet).

~2~L 2-3utyl~ (2'-~A rho~ybivhe~yl~4-yl)met~yll-4-(u~by~roxybPn7~1)1~t~zole-5-r~rboxylic acid A mixture of 450 mg o~ 2-butyl-1-l(2'-carboxy-biphenyl~4-yl)methyl]-5-cyano-4-( a - hydroxybenzyl)-lm~A~zole hydrochloride ~prepared ae deecrlbed in step (c) above~ and 20 ml of a 1 N aqueoue ~olution of sodium hydroxide was stirred in an oil bath kept at 100~C for 7 houre. At the end o~ this tlme, the reaction mixture wae cooled, and ite pH was ad~usted to a value of 3 to 4 by the addition o~ hydrochloric acid. The resultlng colorleee precipitate wa~ collected by ~iltratlon, waehed with water and dried to give 331 mg of the title I compound as a colorlee~ powder, melting at 192 - 194~C.

.

.
', . ' ' ' ~, .
- ' ~ ~ 2 o - 174 - 2061 ~Q 7 Nuclear Magnetic Resonance spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0 . 80 (3H, triplet, J = 7 Hz);
1. 0 - 2 . 0 (4H, multiplet);
2 . 69 (2H, triplet, J = 7 Hz);
5.69 (2H, singlet);
6.32 (lH, singlet);
6.9 - 7.9 (13H, multiplet).

Et~yl 1-r(2'-t-buto~ycarbonylbi~henyl-4-yl)met~yll-2-butyl-4-(1-~y~ro~y-1-met~ylet~yl)~m~dazole-5-carboxylate (Compound No. 1-118) Followlng a procedure sim~lAr to that described in Example l(a), but using 0.92 g of ethyl 2-butyl-4-(1-hydroxy-l-methylethyl)~ m~ ~A zole-5-carboxylate (prepared as described ln Preparatlon 8) and 1.28 g of t-butyl 4'-b~c othylbiphenyl-2-carboxylate, 1.23 g of the title compound were obtAine~ as crystal~, melting at 92 - 93~C.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.90 ~3H, trlplet, J - 7 Hz);
1.23 (3H, triplet, J . 7 Hz);
1.26 ~gH, einglet);
1.2 - 2.05 (4H, multlplet);
1.65 ~6H, slnglet);
2.69 ~2H, triplet, J . 7 Hz);
4.24 ~2H, quartet, J ~ 7 Hz);
5.52 ~2H, ~lnglet);
5.73 ~lR, slnglet);
6.3a ~ 7.9 ~8H, multiplet).

'. . :

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

- 175 - 20 ~ 7 Ethyl 2-butyl-1-[(2~-carboxybiphenyl-4-yl)methyll-4-(l-hydroxy-l-methylethyl)imidazole-5-carboxylate (Compound No. 1-32) Following a procedure similar to that described in Ex_mple 7, but using 0.50 g of ethyl 1-[(2~-t-butoxy-carbonylbiph~nyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as described in Ex_mple 13) and a 4 N solution of hydrogen chloride in dioxane, 0.45 g of the hydrochloride of the title compound was obt~ne~ a~ an amorphous powder, melting at above 80~C (with softening).

Nuclear Magnetic Resonance Spectrum (hPYA~euterated dimethyl ~ul~oxlde) ~ ppm:
0.82 (3H, triplet, J ~ 7 Hz);
1.14 (3H, triplet, J . 7 Hz);
1.2 - 1.35 (2H, multiplet);
1.41 - l.SS (2H, multiplet);
1.60 (6H, singlet);
3.00 (2H, trlplet, J - 7 Hz);
4.21 (2H, quartet, J . 7 Hz);
5.63 (2H, singlet);
7.14 - 7.75 (8H, multiplet).

S!X Z~MP! .P! 15 Et~yl 1-~(2'-t-buto~y~Arbn~ylbi~ha~yl-4-yl)methyll-4-( l - ~yflro~y~ t~yle~yl)-2-propyllm~AzQle-5-~Arboxyl~te (com~olln~ No. 1-119) Followl~g a procedure ~lmilar to that descrlbed in ~xample l(a), but uslng 0.845 g o~ ethyl 4-(1-hydroxy-l-methylethyl)-2-propyllmidazole-S-carboxylate ~prepared as descrlbed in Preparation 9) and 1.22 g of t-butyl ~- , : , ;, - . :. . :

~, ,, .

. ~ 2 o - 176 - 2 ~61 ~0 7 4'-bromomethylbiphenyl-2-carboxylate, 1.31 g of the title compound were obtained a~ a gum. This compound was allowed to stand at room temperature, which caused it to crystallize. It was then recryRtallized from a mixture of dii30propyl ether and hPxAne, to give pure title compound, melting at 90 - 91~C.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.97 (3H, triplet, J , 7 Hz);
1.23 (3H, triplet, J = 7 Hz);
1.25 (9H, singlet);
1.60 (6H, singlet);
1.82 (2H, sextet, J - 7 Hz);
2,67 (2H, triplet, J . 7 Hz);
4.24 (2H, quartet, J ~ 7 Hz);
5.51 (2H, cinglet);
5.72 (lH, singlet);
6.~7 - 7.85 (8H, multiplet).

~MPT-~ 16 ~yl 1-~(2~-rArbo~ybiDhe~yl-4-yl)~t~yll-4-(l-~y~roxy-l-methyle~-~yl)-2-Dropylim~Azole-5-rA rbo~y~ A te (C~o~ n~ No. 1-50) Following a procedure similar to that described in ~xample 7, but u~ing 0.80 g o~ ethyl 1-~(2'-t-butoxy-carbonylblphenyl-4-yl)methyl]-4-(1-hydroxy-1-methyl-ethyl)-2-propyl~ m~ ~A zole-5-carboxylate (prepared as described ln Example 15) and a 4 N solutlon of hydrogen chlorlde ln dioxane, 0.67 g o~ the hydrochloride of the tltle compound was obt~ined as an amorphous powder.

Nuclear Magnetic Resonance Spectrum (h~A~euterated dlmethyl ~ul~oxide) ~ ppm:
0.88 ~3H, triplet, J . 7 Hz);
1.14 (3H, trlplet, ~ . 7 Hz);

1.50 - 1.65 (2H, multiplet);
1.60 (6H, singlet);
3.00 (2H, triplet, J = 7 Hz);
4.20 ~2H, quartet, J = 7 Hz );
5.63 ~2H, singlet);
7.13 - 7.75 (8H, multiplet).

ExAM~LE 17 1-~(2'-Carboxybiphenyl-4-yl)methyl~-4-(1-hydroxy-l-met~ylethyl)-2-pxoDylimidazole-5-carboxylic acid tC~ound No. 1-49) A solution of 0.20 g of ethyl 1-[(2'-carboxy biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propyllmidazole-S-carboxylate hydrochloride (prepared as described in Example 16) in an aqueou~ ~olutlon of ~4 mg of lithium hydroxide monohydrate in 5 ml of water was stirred at room temperature for 6 hours. At the end of thic time, 2 ml of 1 N aqueouc hydrochloric acid were added dropwise to the reactlon mixture, and the resulting precipitate wac collected by filtration, to give 0.17 g of the title compound, melting at 176 - 179~C (with decompo~ition).

Nuclear Magnetlc Resonance Spectrum (hP~A~euterated dimethyl ~ulfoxide) ~ ppm:
0.88 (3H, triplet, J . 7 Hz);
1.5 ~ 1.65 ~2H, multiplet);
1.56 ~6H, singlet);
2.66 (2H, triplet, J . 7 Hz);
5.69 (2~, singlet);
7.03 ~ 7.72 ~8H, multlplet).

-, ., ' ' : , ' - 178 - 2061 5~ 7 Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-~2-(tetrazol-5-yl)phenyllphenyl}methylimidazole-s-carboxylate (Compound No . 2 - 7 ) 18(a) Ethyl 4-(1-hydroxy-1-metbylethyl)-2-propyl-1-~4-~2-(trityltetrazol-5-yl)~henyllphenyllmethyl-~ m~ dazole-5-carboxylate 48 mg of ~odium hydride (as a 55% w/w dispersion in mineral oll) were added to a solution of 0.26 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of N,~-dimethylfor~mi~e, and the resulting mixture wae stirred at room temperature for 30 minutes. A
solution of 0.72 g of 4-[2-(trityltetrazol-5-yl)phenyl]-benzyl bromide in 5 ml of ~,~-dimethylformamide was then added, and the reactlon mixture was ~tirred at room temperature for 2 hours and then at 60~C for 4 hours.
At the end o~ this time, it wa3 dissolved in ethyl acetate and the ~olution wa~ w?~he~ three times with water. The ~olution was then dried over anhydrous ~odium ~ul~ate, after which it was freed from the ~olvent by di~tlllatlon. The resldue wa~ puri~ied by column chromatography through silica gel, using a 1 : 1 by volume mixture Or he~ne and ethyl acetate as the eluent, to glve 0.62 g o~ the title compound a~ an amorphou~ solid. This wae crystallized ~rom diisopropyl e~her, to give the title compound as crystals, melting at 167 - 16a~C (wlth decompositlon).

Nuclear Magnetic Re~onance Spectrum (CDC~3) ~ ppm:
O.~B (3~, triplet, J . 7 Hz);
l.OB (3H, triplet, J ~ 7 Hz);
1.5 - 1.8 (2H, multiplet);
1.64 (6H, singlet);

, - 179 - 20~1 6Q 7 2.52 (2H, triplet, J = 8 Hz);
4 . 12 (2H, quartet, J = 7 Hz);
5 . 38 (2H, singlet);
5.7a (lH, ~inglet);
6.7 - 7.6 (22H, multiplet);
7.8 - 8.1 (lH, multiplet).

18(b) Ethyl 4-(1-hydroxy-1-methylethyl)-2-~ropyl-1-~4-~2-(tetrazol-5-yl)~henyll~henyl}methylimidazole-5-~rbo~ylate A ~olution of 0.50 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-~2-(trityltetrazol-S-yl)phenyl~phenyl}methylimidazole-5-carboxylate lprepared a3 degcribed in Example l~(a)] dissolved in 5 ml of a 4 N solution of hydro~en chloride in dioxane wa~ allowed to stand overnight at room temperature, after which the reaction mixture was concentrated by evaporation under reduced pres~ure. The resulting re~idue was trlturated wlth dllsopropyl ether and then washed wlth diisopropyl ether, to give 0.34 g o~ the hydrochloride o~ the tltle compound, meltlng at 100 - 103~C.

Nuclear Magnetlc Re~onance Spectrum (CD30D) ~ ppm:
0.97 ~3H, trlplet, J . 7 Hz);
1.24 (3H, trlplet, J ~ 7 Hz);
1.50 - 1.65 (2H, multiplet);
1.70 (6H, singlet);
3.00 (2H, trlplet, J - B Hz);
4.30 (2H, quartet, J - 7 Hz);
5.70 (2H, slnglet);
6.9 ~ 7.8 ~8H, multlplet).

,:

. . ~ . , - 18Q - 2~61~o7 4~ Hydroxy-1-methylethyl)-2-propyl-1-{4-~2-(tetrazol-5-yl)phenyllphenyl}methylimidazole-s-carboxylic acid (Compound No. 2-1) 3.65 ml of a 1 N aqueou~ solution of ~odium hydroxide were added to a solution of 0.31 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyl~phenyl}methylimidazole-5-carboxylate hydrochloride ~prepared as described in Example la(b)]
in 6 ml of methanol, and the re~ulting mixture was allowed to stand overnight at room temperature. At the end of thi~ time, the reaction mixture was concentrated by evaporation under reduced pressure to remo~e the methanol. The concentrate was diluted with water and it~ pH wa~ ad~u~ted to a value of 3 by the addition of dilute hydrochloric acid, a~ter which it wa3 extracted with ethyl acetate. The organic extract was dried over anhydrou~ ~odium ~ul~ate and then concentrated by evaporation under re~uce~ pre~ure. The resulting residue was triturated with diisopropyl ether, to give 0.15 g o~ the title compound, melting at 166 - 169~C.

Nuclear Magnetlc Resonance Spectrum ~h~A~euterated dimethyl sul~oxide) ~ ppm:
0.85 ~3H, triplet, J . 7.5 Hz);
1.54 ~6H, ~lnglet);
1.4 - 1.6 (2H, multiplet);
2.58 ~2H, triplet, J . 8 Hz);
5.64 (2H, singlet);
6.94 ~2~, doublet, J ~ 8.5 Hz);
7.06 ~2H, doublet, J . 8.5 Hz);
7.5 - 7.7 ~4H, mult~plet).

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

": ,, - .. ...
.
, , , . : , , , Pivaloyloxymethyl 4-(1-hydroxy-l-methylethyl)-2-propyl-1-{4- r 2-(tetrazol-5-yl)phenyllphenyl~methyl-; ml ~ zole-5-carbo~ylate (Compound No. 2-15) 20(a) Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-~ro~yl-1-{~-~2-(trityltetrazol-5-yl)~henyll-~hP~yl}methylimidazole-5-carboxylate 5.30 ml of a 1 N aqueous solution of sodium hydroxide, followed by 5 ml of tetrahydrofuran, were added to a ~olution of 0.76 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-12-(trityltetrazol-5-yl)-phenyl]phenyl~methylimidazole-5-carboxylate ~prepared as descrlbed in Example 18(a)] in 30 ml of methanol, and the resultlng mixture wac ~tirred at room temperature for ~ hours. The reaction mixture wa~ then concentrated by evaporation under reduced pres~ure to remove the methanol and tetrahydrofura~. Water wa~ added to the concentrate, and the pH of the mixture was ad~u3ted to a value of 4 by the addition of dilute hydrochloric acid, whllst ice-cooling. The mixture wa~ then extracted with ethyl acetate. The extract was dried over anhydrous sodlum ~ul~ate and concentrated by evaporation to drynees. The recldue wac diesolved ln 10 ml of dimethylacetamlde, and 0.23 g of potassium carbonate and 0.13 ml o~ pivaloyloxymethyl chloride were added to the resulting colutlon. The mlxture wa~ then stirred at 50~C ~or 4 hourc, a~ter whlch 0.06 ml of pivaloyloxy-methyl chloride wae added, and the mixture was ~tlrred for a ~urther 2 hourc. The reaction mixture was then dlluted wlth ethyl acetate, and washed three tlmes wlth water. The organic layer wae ceparated, dried over anhydrouc sodium sul~ate and concentrated by evaporation under reduced preccure. The concentrate was purifled by column chromatography through sillca gel, using a 1 : 1 .. .
, .~ . . . .
.

- 182 - 2061~7 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.23 g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCe3) ~ ppm:
0.~6 (3H, triplet, J = 7 HZ);
1.12 (9H, singlet);
1.62 (6H, singlet);
1.4 - 1.9 (2H, multiplet);
2.51 (2H, triplet, J - 7 Hz);
5.37 (lH, broad singlet);
5.40 (2H, single~);
5.72 (2H, singlet);
6.6 - 8.1 (23H, multiplet).

2g(b) Plv~loyloxymethyl 4-(1-hydro~y-1-met~ylethyl)-2-~roDyl-1-~4-~2-(tetr~7nl-s-yl)~hP~yllgh~yl~-me~ylim~Azole-5-~Arboxylate 5 ml o~ a 4 N solution of hydrogen chlorlde in dloxane were added to 0.20 g o~ pivaloyloxymethyl 4-~1-hydroxy-1-methylethyl)-2-propyl-1-(4-~2-(trltyl-~etrazol-5-yl)phenyllphenyl~methylimldazole-5-carboxylate ~prepared a~ descrlbed in ExampLe 20~a)], and the recultlng mixture was allowed to ~tand at room temperature overnight. At the end of thls tlme, the reactlon mlxture wa~ concentrated to dryness by evaporatlon under reduced pre~ure. The re~ulting resldue wa~ trlturated wlth dlisopropyl ether to induce cry~tallizatlon and give 0.13 g of the hydrochlorlde of the tltle compound ac crystalc, melting at 104 - 107~C.

Nuclear Magnetic ~esonance 9pectrum ~hexadeuterated dimethyl 9Ul ~oxide) 6 ppm:
o . a4 ~3H, trlplet, J - 7.5 ~z);
1.09 ~9H, clnglet);
1.35 - 1.50 ~2H, multiplet);

', , ' ' . '~' ' ~, ' ~ ~ 2 o 1~3 2061~07 1.56 (6H, singlet);
2.88 (2H, triplet, J = 8 Hz);
5.58 (2H, singlet);
5.~5 (2H, singlet);
7.05 (2H, doublet, J = 8.5 Hz);
7.10 (2H, doublet, J = 8.5 Hz);
7.5 - 7.7 (4H, multiplet).

2-Butyl-4-(1-ethyl-1-hy~ro~y~ropyl)-1-~4-~2-(tetrazol-5-yl)~h~yll~h~yl~m~t~yl~m~ ole-5-carboxylic acid (Compolln~ No. 2-40) 21(a) R~yl 2-butyl-4-(1-ethyl-1-~y~ro~ypro~yl)-1-(4-~2-(trityltetrA~ol-S-yl)~h~yll~hP~yl~-me~yl lml ~A 7nle - 5-rArboxylAte Followlng a procedure similar to that de~cribed in Example 18(a), but using 0.75 9 of ethyl 2-butyl-4-(1-e~hyl-l-hydroxypropyl)~ m~ ~A zole-S-carboxylate (prepared as described in Preparation 13), 0.12 g o~ sodlum hydrlde (ae a 55% w/w dl~persion in mlneral oll) and 1.51 g o~ 4-~2-~trityltetrazol-5-yl)phenyl]benzyl bromide, there were obtA~ne~ 1.05 g of the title compound as an amorphou~ ~olid.

Nuclear Magnetic Re~onance Spectrum (CDCi3) ~ ppm:
0.83 (6H, triplet, J - 7.5 Hz);
0.85 (3H, triplet, ~ . 6 Hz);
1.11 ~3H, triplet, J . 7 Hz);
1.23 - 1.32 ~2H, multiplet);
1.56 ~ 1.65 ~2H, multlplet);
l.B0 - 1.89 ~2H, multiplet);
2.03 ~ 2.14 ~2H, multiplet);
2.55 (2Hj triplet, J ~ 8 Hz);
4.12 (2H, quartet, J - 7.5 Hz);

206~7 5.37 (2H, singlet)i 5.64 (lH, broad singlet);
6.70 (2H, doublet, J = 8.5 Hz);
6.9 - 7.0 (6H, multiplet);
7.10 (2H, doublet, J = 8.5 Hz);
7,2 - 7.4 (lOH, multiplet);
7.4 - 7.5 (2H, multiplet);
7.~5 - 7.90 (lH, multiplet).

21(b) 2-Butyl-4-(1-ethyl-1-hydroxy~ropyl)-1-~4-~2-(tetrazol-5-yl)l~henyllDhenyl}methylimidazole-s-carboxylic acid 1.71 ml of 1 N aqueous hydrochlor~c acid were added to a solution of 0.65 g of ethyl 2-butyl-4-(1-ethyl-1-hydroxypropyl)-l-(4-t2-(trityltetrazol-5-yl)phenyl]-phenyl~methyllmldazole-5-cArbo~ylate [prepared as deecribed ln etep (a) above] in 10 ml of methanol, and the resulting mixture wae allowed to stand overnight at room temperature. At the end o~ this time, the eolvent was removed by dietillatlon under reduced pressure, and the concentrate wae agaln dleeolved ln 10 ml o~
methanol. The reeultlng ~olution wae mlxed wlth 4.2B ml o~ a 1 N aqueoue solution o~ eodium hydroxide and then allowed to atand overnight at room temperature. The reaction mlxture wae then conc~ntrated by evaporation under reduce~ preseure to remove the methanol. The pH
o~ the concentrate wae ad~ueted to a value of 3 by the addltio~ Oe dllute aqueouc hydrochloric acld, and the cryetale whlch precipitated were collected by ~lltration. The cryetale thue obtained were euspended in dll~opropyl ether and then again collected by ~iltratlon and dried to give 0.35 g o the title compound, melting at 181 - la3~C.

-, 20616~7 Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.74 (6H, triplet, J = 7.5 Ez);
0.79 (3H, triplet, J = 7.5 Hz);
1 . 1 - 1 . 3 (2H, multiplet);
1.40 - 1.55 (2H, multiplet);
1 . 67 - 1 . 80 (2H, multiplet);
1.90 - 2.05 (2~, multiplet);
2.59 (2H, triplet, J - 7.5 Hz);
5.67 (2H, singlet);
6.~8 (2~, doublet, J - 8.5 Hz);
7.05 (2H, doublet, J ~ 8.5 Hz);
7.5 - 7.7 (4H, multiplet).

F.~y~PT.~ 22 2-~utyl-4~ y~roxy-1-me~ylet~yl)-1-{4-~2-(tetrazol-5-yl)~h~yllphP~yl~me~-~ylim~701e-5-~-~rboxylic acid (Compo~n~ No. 2-2) 22(a) Et~yl 2-hutyl-4-(1-~yAro~y-l-rm~ylet~yl)~ 4-~2-(trltyltetr~7nl-5-yl~hP~yll~h~yl~met~yl-~ zole-S-~rboxylAte Followlng a procedure similar to that deecribed in ~xample lB~a), but uelng 0.26 g o~ ethyl 2-butyl-4-(1-hydroxy-l-methylethyl)~ m~ ~ zole-5-carboxylate (prepared a~ deecribed in Preparation 8), 45.5 mg of sodium hydride ~a~ a 55~ w/w dlspexslon ln mineral oll) and 0.63 g o 4-~2-~trltyltetrazol-5-yl)phenyl]benzyl bromide, 0.28 g o~ the title compound were obtained a~
an oil.

Nuclear Magnotic Reeonance Spectrum (CDC~3) ~ ppm:
0.85 (3H, trlplet, J ~ 7 ~z);
1.09 (3H, trlplet, J . 7 Hz);
1.64 ~6H, einglet);

.

: -~. 2 ~ 7 1.3 ~ (4H, multiplet);
2.56 (2H, triplet, J = 8 Hz);
4.14 (2H, quartet, J = 7 Hz);
5 . 38 (2H, singlet);
5.78 (lH, ~inglet);
6.6 - 7.6 (22H, muitiplet);
7.7 - 8.1 (lH, multiplet).

2~b) 2-Butyl-4-(1-hydroxy-1-methylethyl)-1-~4-~2-(tetrazol-5-yl)Dhenyllphen,yl~met}~ylimidazole-S-carboxylic acid Following a procedure similar to that described in Example 21(b), 78 mg of the title compound, melting at 138 - 141~C, were obt~ne~ by treating 0.28 g of ethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityl-tetrazol-5-yl)phenyl~phenyl~methylimidazole-5-carboxylate ~prepared a~ descrlbed in step (a) above]
wlth 0.42 ml of 1 N aqueou~ hydrochloric acid and then treatlng the product with 1.70 ml o~ a 1 N aqueous solutlon o~ ~odlum hydroxlde.

Nuclear Magnetic Reson~nce Spectrum (hPY~euterated dlmethyl ~ul~oxlde) ~ ppm:
0.81 (3H, trlplet, J - 7.5 Hz);
1.15 - 1.35 (2H, multlplet);
1.4 - 1.6 (2H, multlplet);
1.53 (6H, slnglet);
2.5~ ~2H, trlplet, J . 8.5 Hz);
5.64 ~2H, slnglet);
6.94 ~2H, doublet, J . 8.5 Hz);
7.06 ~2H, doublet, J ~ 8.5 ~z);
7.15 - 7.70 ~4H, multiplet).

.
, : 6 ~ o ~ - 187 - 2 0~1 ~0 7 2-Butyl-4-(1-hydroxy-1-methylpropyl)-1-~4-[2-(tetrazol-S-yl)phenyllphenyllmethylimidazole-5-carboxylic acid (Compound No. 2-38) 23(a) 2-Butyl-5-cyano-4-(1-hydroxy-1-methyl~ropyl)-1-~4-t2-(trityltetrazol-5-yl~phenyllphenyl}
met~ylimidazole Following a procedure similar to that described in Example 18(a), but u~ing 465 mg of 2-butyl-5-cyano-4-(l-hydroxy-l-methylpropyl)~m;~zole ~prepared as de3cribed in Preparation 19), 92 mg of sodium hydride (as a 55~ w/w di~persion in mineral oil) and 1.11 g of ~-~2-~trityltetrazol-5-yl)phenyl]benzyl bromide, 1.00 g of the title compound was obtA~ne~ as a gum.

Nuclear Magnetic Resonance Spectrum ~CDCe3) ~ ppm:
O.B6 ~3H, trlplet, J . 7.5 Hz);
0.87 (3H, triplet, J . 7 Hz);
1.21 - 1.34 ~2H, multlplet);
1.54 - 1.66 ~2H, multlplet);
1.60 ~3H, ~inglet);
1.~2 - 1.97 ~2H, multiplet);
2.51 ~2H, trlplet, J . 7.5 Hz);
3.22 ~lH, singlet);
5.04 ~2H, singlet);
6.87 - 7.52 ~22H, multiplet);
7.93 - 7.96 ~lH, multiplet).

2-R--~yl-5-~yAnn~ -h~ro~y-l-~t~ylpropyl)-l-(4-~2-~tetrAzol-S-yl)9he~yll~h~yl ~ m~thyl -~ m~ ~A ~ole A mlxture o~ 1.00 g o~ 2-butyl-5-cyano-4-(1-hydroxy-l-methylpropyl)-l-(g-~2-~trltyltetrazol-5-yl)phenyl]-2061~7 phenyl}methylimidazole [prepared a~ described in step (a) above] and 25 ml of 20% v/v aqueou~ acetic acid was stirred at 60~C for 2 hour~, and then the solvent was removed by di~tillation under reduced pres~ure. The residual water and acetic acid were removed as a toluene azeotrope by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, uQing mixtures of methanol and methylene chloride ranging from 1 : 9 to 1 : 4 by volume as the eluent, to give 0.65 g of the title compound as a glasa.

Nuclear Magnetic Re~onance Spectrum (CDC~3) ~ ppm:
0.83 (3H, triplet, J . 7 Hz);
0.~8 (3H, triplet, J . 7 Hz);
1.23 - 1.37 (2~, multiplet);
1.57 (3H, singlet);
1.55 - 1.70 (2H, multiplet);
1.82 - 1.89 (2H, multiplet);
2.64 (2H, trlplet, J . 7 Hz);
5.12 ~2H, ein~let);
6.9 - 7.1 (4H, multiplet);
7.29 - 7.60 (3H, multlplet);
7.~7 ~lH, doublet, J - 7.5 Hz).

23(c) 2-Bu~yl-4 ~1-h~y~ro~y-1-methylpropyl)-1-(4-~2~
(tetr~701-5-yl)Qh~ ~llphPrl~yl)met}~ylim~Azole-S-r~ rhn~yl iC A C i ~1 A m~xture o 360 mg o~ 2-butyl-5-cyano-4-(1-hydroxy~
l-methylpropyl)-1-l4-12 (tetrazol-5 yl)phenyl~-phenyl~methyllm~zole lprepared ae deecribed in step (b) above], 266 mg o~ lithlum hydroxide monohydrate and 3.6 ml o~ water wae stirred ln an oll bath kept at 115~C
~or 16 houre. At the end o~ thie tlme, the reactlon mixture wae cooled and 6.4 ml o~ 1 N aqueoue hydrochlorlc acld were added to the mlxture, whllst ~ . , , , - .

2061~07 ice-cooling. The crystal~ which precipitated were collected by filtration, to give 302 mg of the title compound, melting at 152 - 154~C.

Nuclear Magnetic Resonance Spectrum (h~ euterated dimethyl sulfoxide) ~ ppm:
0.79 ~3H, triplet, J - 7 Hz~i 0.~2 (3H, triplet, J = 7 Hz);
1.20 - 1.34 (2H, mNltiplet);
1.44 - 1.55 (2H, multiplet);
1.55 (3H, singlet);
1.71 - 1.95 (2H, multiplet);
2.62 (2H, triplet, J ~ 7.5 Hz);
5.6~ ~2H, A3-quartet, ~-0.10 ppm, J - 17 Hz);
6.86 - 7.10 ~4H, multiplet);
7.53 - 7.72 (4H, multiplet).

~PT.R 24 4-(1-~y~ro~y-1-met.~yl~ro~yl)-2-propyl-1-~4-~2-(tetr~ 7~1 ' 5 ' yl )ph~yll~h~ylLme~ylim~ 7nl e-5-r~r~Yylic A~ cQm~olln~ No. 2-37~

24(a~ 5-Cy~nn-4-(1-~y~ro~y-1-me~yl~ro~yl)-2-pro~yl-1-~4-~2-(tri~yltetr~7nl-5-yl)~h~yl1~hP~yl~-~o~.~yllm~ le Following a procedure slmllar to that descrlbed ln le l~a), but u~lng 3~0 mg of 5-cyano-4-~1-hydroxy-l-mothylpropyl)-2-propyl~ zole ~prepared a~ described ln Preparatlon 20), a8 mg o sodium hydrlde ~a~ a 55 w/w dl~persion in mlneral oil) and 1.07 g o~ 4-~2-~trityltetrazol-5-yl)phenyl]benzyl bromlde, 0.97 g of the titlo compound were ob~tne~ ac an amorphous solld.

Nuclear Magnetlc Re00nance Spectrum ~CDC~3) ~ ppm:
0.86 ~3H, trlplet, J . 8 Hz);

' :, - lgO - 20S1 ~7 0.87 (3H, triplet, J = 7.5 Hz);
1.60 (3H, singlet);
1.60 - 1.75 (2H, multiplet);
1.80 - 2.00 (2H, multiplet);
2.48 (2H, triplet, J - ~ Hz);
5.04 (2H, singlet);
6.88 (2H, doublet, J , 8.5 Hz);
6.9 - 7.0 (4H, multiplet);
7.14 (2H~ doublet, J - 8.5 Hz);
7.2 - 7.4 (14H~ multiplet);
7.45 - 7.55 (lH, multiplet).

24(b) 5-CyAnn-4-(l-hydroxy-l-met~ylDropyl)-2-pro~yl-1-~4~ ~2-(tetrazol-5-yl)~h~yll~h~yl~methyl-~m~ zole Following a procedure similar to that deecribed in Example 23(b), 0.32 g of the title compound were obt3ined a~ crystals, melting at 141 - 145~C, by treating 0.51 g o~ 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-~ropyl-l-(4-~2-~trityltetrazol-5-yl)phenyl~phenyl}-methylimidazole ~prepared a~ deecrlbed in etep (a) above] with 75~ v/v aqueoue acetlc acld.

Nuclear Magnetlc Reeonance Spectrum (CD30D) 6 ppm:
0.~4 (3H, trlplet, J - 8 Hz);
0.90 (3H, trlplet, J - a.5 Hz);
1.52 (3H, ~inglet);
1.5 - 1.7 (2H, multlplet);
1.75 ~ 1.90 (2H, multiplet);
2.65 (2H, triplet, J . a Hz);
5.27 (2H, einglet);
7.03 ~2H, doublet, ~ ~ a . s Hz);
7.14 (2H, doublet, J - ~.5 Hz);
7.45 - 7.63 (4H, multlplet).

' .

, . .

2 0~ 7 24(c) 4~ Hydroxy-l-methylpropyl)-2-propyl-1-~4-[2-(tetrazol-5-yl~phenyllphenyl}methylimidazole-5-carboxylic acid Following a procedure similar to that described in Example 23(c), 0.14 g of the title compound were obt~;ned ae a powder, melting at 174 - 177~C, by treating 0.19 g of 5-cyano-4-(1-hydroxy-1-methylpropyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-im~dAzole ~prepared as de~cribed i~ etep (b) above] with 0.15 g o. lithium hydroxide monohydrate.

Nuclear Mag~etic Reeonance Spectrum (CD30D) ~ ppm:
0.88 ~3H, triplet, J ~ 7.5 Hz);
0.94 (3H, triplet, J . 7.5 Hz);
1.50 - 1.65 (2H, multlplet);
1.63 (3H, singlet);
1.85 - 2.05 (2~, multiplet);
2.76 (2H, triplet, J . 7.5 Hz);
5.80 (2H, AB-quartet, ~0.14 ppm, J ~ 16.5 ~z);
7.01 (2H, doublet, J . 8.5 Hz);
7.11 (2H, doublet, J . 8.5 Hz);
7.48 - 7.75 (4H, multiplet).

RX'Z~MPT~P! 25 Plv~loylo~me~yl 1-~(2'-rArhnYybiphP~yl-4-yl)met~yll-4-(1-~y~ro~y-l-me~h~ylet~yl)-2-pro~yllm~dazole-5-~Arho~ylAte (Compo~n~ No. 3-1) ,2S ~4) E~th~l 1- ~ ~2' -t-butox~y~Arbt ~lbl~?h~-~yl-4-yl) -m~yll-4-(1-hy~rox~y-1-met~ylet~yl)-2-prQDyl-~ m~ ~ 7ole-s-~rbox~yl A te 3.00 g o~ potaeelum t-butoxide were added, whilet lce-coollng, to a eolutlon o~ 6 g o~ ethyl 4-(1-hydroxy-l-methylethyl)-2-propyllmidazole-5-carboxylate (prepared - 192 - 20~1~07 as described in Preparation 9) in 40 ml of N,N-dimethyl-acetamide, and the resulting mixture was stirred for 10 minutes, after which a solution of 9.00 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate in 40 ml of N,N-dimethylacetamide was added. After the reaction mixture had been stirred at room temperature for 1 hour and then at 50~C for 2 hour~, it was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure, after which the re3idue was purified by column chromatography through ~ilica gel, using a 1 : 1 by volume mixture of he~ne and ethyl acetate as the eluent, to give 11.6 g o~ the title compound as a solid, softening at above 85~C.

Nuclear Magnetic Re~onAnce Spectrum (CDC~3) ~ ppm:
0.97 (3H, triplet, J ~ 7 Hz);
1.23 (3H, triplet, J ~ 7 Hz);
1.25 (9H, singlet);
1.60 (6H, singlet);
1.82 (2~, sextet, J . 7 Hz);
2.67 (2H, triplet, J ~ 7 Hz);
4.24 ~2H, quartet, J - 7 Hz);
5.51 (2H, ~lnglet);
5.72 ~lH, singlet);
6.87 - 7.85 ~H, multiplet).

1-~(2'-t-Buto~ycarb~ylblph~yl-~-yl)met~yll-4-(l-hyAroxy-l-mech~ylethyl~-2-proDyl~m~d~~ole~5-rA rhn~ c A c lrl A eolutlon o~ 4.8 g o llthlum hydroxide monohydrateln 100 ml o~ water was added to a solution o~ 11.6 g of ethyl 1-[~2'-t-butoxycarbonylblphenyl-4 yl)methyll-4-(l-hydroxy-l-methylethyl)-2-propyllmldazole-5-carboxylate lprepared a~ descrlbed ln ctep (a) above] ln 60 ml o~

, :- , .
; . , .

- 206~6~7 dioxane, and the resulting mixture was stirred at room temperature for 16 hours. The dioxane was removed by distillation under reduced pressure, and then the concentrate was mixed with ice-water and with ethyl acetate, after which 114 ml of 1 N aqu~ou~ hydrochloric acid were added. The ethyl acetate layer was separated, dried o~er anhydrous ma~nesium sulfate and freed from the solvent by dlstillation under reduced pressure. The crystalline residue was triturated in dii~opropyl ether and collected by filtration to give 9.09 g of the title compound, melting at 155 - 157~C.

Nuclear Ma~netic Re~onance Spectrum (CDCQ3) ~ ppm:
0.85 (3H, triplet, J - 7.5 Hz);
1.23 (9H, einglet);
1.53 - 1.6S (2H, multiplet);
1 65 ~6H, slnglet);
2.91 (3H, triplet, J . 7.5 ~z);
5.90 (2H, singlet);
7.09 (2H, doublet, J ~ 8 Hz);
7.21 - 7.48 (5H, multiplet);
7.75 ~lH, doublet, J ~ 9 Hz).

25(c) PlvAloylo~yme~-~yl 1-~(2'-t-butoxycarbn~ylbi~h~yl-4-yl)me~yll-4-(1-~ydro~y-1-methyle~yl)-2-Dro~yl-lm~ ~A zole-5- r~ rboxylate 2.13 ml o~ chloromethyl plvalate and 3.99 g of pota~lum carbonate were added to a ~olution of 6 g of 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4~
hydroxy-l-methylethyl)-2-propylimidazole-5-carboxyllc acld ~prepared as deccribed ln step (b) above~ ln 70 ml o ~,~-dlmethylacetamide, and the resultlng mixture was otlrred at room temperature ~or 1 hour and then at 50~C
~or 2 hours. At the end o~ this time, the reactlon mixture wac mixed with ethyl acetate and water. The ethyl acetate layer wa~ separated and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of ethyl acetate and h~ne as the eluent, to give 6.80 g of the title compound as crystals, melting at 106 - 107~C.

Nuclear Magnetic Resonance Spectrum ~CDC~3) ~ ppm:
1.07 (3H, triplet, ~ , 7 Hz);
1.25 (9H, singlet);
1.32 ~9H, singlet);
1.71 ~6~, singlet);
1.79 - 1.90 (2H, multiplet);
2.75 (2H, triplet, J ~ ~ Hz);
5.50 (1~, slnglet);
5.59 (2H, ~inglet);
5.92 (2H, singlet);
7.05 (2H, doublet, J - a Hz);
7.34 - 7.56 (5H, multlplet);
7.~5 ~lH, doublet, J . 7 Hz).

25(d) PivAloylo~y~ yl 1- r ( 2~-~A rbo~ybi~h~yl-4-yl)-me~yll-4-(l-hydro~y-1-~4thylethyl)-2-propyl-im~ A~ 7nle 5.rArho~ylAte A mixture o~ 6.6 g of pivaloyloxymethyl 1-[~2~-t-butoxycarbonylbiphenyl-4-yl)methyl~-4-(1-hydroxy-1-methylethyl)-2-propyli~ ~A zole 5-carboxylate [prepared as described ln step ~c) above] and 57 ml of a 4 N
~olution o~ hydrogen chloride in dioxane wae stirred at room tem~erature ~or 4 houre. At the end o~ this time, tho reaction mixture wa~ concentrated by evaporation under reduced prescure, and the re~ldue wac triturated wlth ethyl acetate to crystalllze it, givlng 6.52 g o~
the ti~le compound as the hydrochloride, melting at 170 - 173~C.

,~

- 19S - 20616~7 Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.87 (3H, triplet, J = 7 Hz);
1.10 (9H, singlet);
1.45 - 1.60 (2H, multiplet);
1.58 (6H, singlet);
2.96 (2H, triplet, J = 7.5 Hz);
5.65 ~2H, singlet);
5.87 (2H, singlet);
7.17 (2H, doublet, J ~ 8 Hz);
7.33 (2H, doublet, J ~ 8 Hz);
7.43 - 7.60 (3H, multiplet);
7.74 (lH, doublet, ~ ~ 8 Hz).

EXAMPT ~R 2 6 ~ro9o~ A rb~lox5rmet~ ( 2 ' - r~ rbo~ybi~henyl - 4 -yl)~t~yll-4-(1-hydro~y-1-m~ylet.~yl)-2-~rQ~yl-~m~ ole-5-carbo~yl~te (~7o~n~ No. 3 13) 26(a) Isopro~o~y~Arh~ylQxyme~yl 1-~(2'-t-buto~yrArbonyl-bi~h~yl-4-yl)methyll-4-(1-~y~roxy-l-met~ylethyl)-2-~ro~yl~m~A7~1e-5-rArbo~yl~te Following a procedure simllar to that described in ~xample 25~c), 0.58 g o~ the title compound wa~ obtained ae cryctale, melting at B5 - 87~C, by stirrlng a mlxture compri~ing 0.50 g o~ 2'-t-butoxycarbonylblphenyl-4-yl)methyl]-4-~1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxyllc acid ~prepared ae deecribed in Example 25(b)], 0.19 g o~ isopropoxycarbonyloxymethyl chlorlde and 0.33 g o~ potas~lum carbonate ln 6 ml o~
~,~-dlmethylacetamlde at room temperature ~or 3 hours.

Nuclear Magnetlc Reaonance 8pectrum (CDCQ3) 6 ppm:
0.99 (3H, trlplet, ~ ~ 7 Hz1;
1.23 ~9H, elnglet);

., , , ;

1.29 (6H, doublet, J = 6 Hz);
1.63 (6H, singlet);
1.70 - 1.85 (2H, multiplet);
2.68 (2H, triplet, J = 8 Hz);
4.89 (lH, quintet, J = 6 Hz);
5.38 (lH, singlet);
5.51 (2H, singlet);
5.82 (2H, singlet);
6 97 (2H, doublet, J , 8 Hz);
7.26 - 7.48 (5H, multiplet);
7.77 (lH, doublet, J ~ 8 Hz).

26(b) I~opro,~oxycarbonyloxymethyl 1-~(2'-carboxybi~henyl-4-yl~me'r~yll 4~ ydroxy-1-me'~ylethyl~-2-~ropyl-im'l ~1A ~ole-S-r;~rbo~yl A te Following a procedure similar to that described in ~xample 25~d), 0.36 g of the hydrochloride o~ the title compound wae obt~ne~1 as an amorphoue powder, melting at 153 - 155~C, by treating 0.46 g o~ lsopropoxycarbonyl-oxymethyl 1-~2'-t-butoxycarbonylblphenyl-4-yl)methyl]-4-~1-hydroxy-1-methylethyl)-2-propylimidazole-5--carboxylate lprepared ae deccribed ln step ~a) above]
wlth a 4 N eolution of' hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (C~CQ3) ~ ppm:
0.98 ~3H, triplet, J ~. 7 Hz);
1.29 ~6H, doublet, J . 6 Hz);
1.50 - 1.65 ~2H, multlplet);
1.76 ~6R, einglet);
3.13 ~2H, trlplet, J . 7 Hz);
4.90 ~lH, ~ulntet, J . 6 Hz);
5.55 ~2H, elnglet);
5.82 ~2H, elnglet);
7.02 ~2R, doublet, J . 6.5 Hz);
7.21 ~ 7.57 ~5H, multiplet);
7.96 ~lH, doublet, ~ - 8 Hz).

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

.

Ethoxycarbonyloxymethyl 1-~(2'-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (Compound No. 3-9) 27 (a) Ethoxycarbonyloxymethyl 1-~(2~-t-butoxycarbonyl-bi~he~yl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate Following a procedure similar to that de~cribed in Example 25(c), 0 69 g of the title compound was obtained as an oil from 0.55 g of 1-[(2'-t-butoxycarbonyl-blphenyl-4-yl~methyl]-4-(1-hydroxy-1-methylethyl) -2-propylimidazole-5-carboxylic acid [prepared a~ described in Example 25(b)], O.30 g oS ethoxycarbonyloxymethyl chlorlde and 0.50 g of potas~ium carbonate.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.99 (3H, triplet, J . 7 Hz);
1.23 (9H, singlet);
1.29 ~3H, triplet, J . 7 Hz);
1.64 (6H, singlet);
1.74 - 1.85 (2H, multiplet);
2.69 ~2H, triplet, J ~ 7.5 Hz);
4.21 (2H, quartet, J . 7 Hz);
5.39 (lH, singlet);
5.52 (2H, singlet);
5.83 ~2H, slnglet);
6.97 ~2H, doublet, J . 8 Hz);
7.26 - 7.51 ~5H, multlplet);
7.77 ~lH, doublet, J - 6.5 Hz).

, ", 27(b) Ethoxycarbonyloxymethyl 1- r (2'-carboxybiphenyl- 4 -yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate Following a procedure ~imilar to that described in Example 25(d), 0.48 g of the hydrochloride of the title compound was obtA-ne~ as an amorphous powder, softening at above 70~C, by treating 0.69 g of ethoxycarbonyl-oxymethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as descrlbed in step (a) above]
with a 4 N ~olution of hydrogen chloride in dioxane.

Nuclear Magnetic Reso~Ance Spectrum (h~A~euterated dlmethyl ~ulfoxide) ~ ppm:
0 88 (3H, triplet, J . 7 Hz);
1.19 ~3H, triplet, J . 7 Hz);
1.5 - 1.65 ~2H, multiplet);
1.59 (6H, Yinglet);
2.95 (2H, triplet, J . 7.5 Hz);
4.15 ~2H, quar~et, J ~ 7 Hz);
5.64 (2H, singlet);
5.84 (2H, singlet);
7.18 (2H, doublet, J . 8 Hz);
7.32 - 7.61 (5H, multiplet);
7.74 (lH, doublet, J - 7 Hz).

' : .

2061 6~7 l-(I~opropoxycarbonyloxy)ethyl 1-~(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-l-methylethyl)-2-propyl-;m;~ole-5-carboxylate (Compound No . 3 -14) 28(a) 1~ opro~oxycarbonyloxy)ethyl 1-~(2'-t-butoxy-carbonylbi~henyl-4-yl)methyll-4-(1-hydroxy-1-met~ylethyl)- 2 -~ro~ylimidazole-5-carboxylate Following a procedure B;m11 ~r to that described in Example 25~c), 0.60 g of the title compound was obt~-ne~
as a gum by stirring 0.50 g of 1-[(2~-t-butoxycarbonyl-biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimldazole-5-carboxylic acid ~prepared as described in Example 25(b)] and 0.21 g o~ yLu~u~carbonyl-oxy)ethyl chloride with a solution of 0.40 g of potassium carbonate in 6 ml o~ -dimethylacetamide at 60~C ~or 16 hours.

Nuclear Magnetic ~e~on~nce Spectrum ~CDCQ3) ~ ppm:
0.97 ~3H, trlplet, J . 7.5 Hz);
1.26 ~9H, singlet);
1.27 ~6H, doublet Or doublets, J - 4.5 & 6 Hz);
1.42 ~3H, doublet, J . 5.5 Hz);
1.64 ~6H, doublet, J - 3 Hz);
1.75 - 1. ao ~2H, multlplet);
2.65 ~2H, doublet, J . 7.5 Hz);
4.86 ~lH, quintet, J . 6 Hz);
5.50 ~2H, slnglet);
6.90 ~lH, quartet, J - 5.5 Hz);
6.97 ~2H, doublet, J . 8.5 Hz);
7.26 ~ 7.50 ~5H, multiplet);
7.78 ~lH, doublet, J . 8 Hz).

i ~ 2 ~) - 200 - 20~1 6Q 7 2~(b) l-(Isopropoxycarbonyloxy)ethyl 1-~(2/-carboxy-biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate Following a procedure ~imilar to that de~cribed in Example 25(d), 0.41 g of the hydrochloride of the title compound, melting at 94 - 96~C, wa~ obtalned as an amorphous powder by treating 0.60 g of l-(isopropoxy-carbonyloxy)ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)-methyl~-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described ln step (a) above]
with a 4 N ~olution of hydrogen chloride in dioxane.

Nuclear Magnetic Re~onance Spectrum ~CDC~3) ~ ppm:
0.94 (3H, triplet, J - 7 Hz);
1.27 (6H, doublet of doublets, J ~ 6.5 & 11 Hz);
1.47 (3H, doublet, J - 5.5 Hz);
1 50 - 1.65 (2H, multiplet);
1.76 (6H, doublet, J - 8.5 Hz);
3.08 (2~, broad triplet, J ~ 8 Hz);
4.86 (lH, ~eptet, J . 6 Hz);
5.56 (2H, ~lnglet);
6.87 ~lH, quartet, J . 5.5 Hz);
7.04 ~2H, doublet, J . 7.5 Hz);
7.27 - 7.65 ~5H, multlplet);
7.97 ~lH, doublet, J - 8 Hz).

,.: . ... .

, .,' ~ ~ , ' .. . ~ , 20616~7 (5-Methyl-2-oxo-1.3-dioxolen-4-yl)methyl 1-[(2~-carboxybi~henyl-4-yl)methyll-4-(1-hydroxy-1-methyl-ethyl)-2-propylimidazole-s-carboxylate (Com~ound No . 3-25) 29(a) (5-Methyl-2-oxo-1.3-dioxolen-4-yl~methyl 1-~(2'-t-butoxycarbonylbi~he~yl-4-yl)methyll-4-(1-hydroxy-l-met~ylethyl)-2-pro~ylimidazole-5-carboxylate Following a procedure similar to that described in Example 25(c), 0.65 g of the title compound was obtained as a gum from 0.50 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4~ hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylic acid [prepared ae described in Example 25(b)~, 0.27 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide and 0.3 g of potaesium carbonate in 6 ml of ~,~-dimethylacetamide.

Nuclear Ma~netic ResonAnce Spectrum (CDCQ3) ~ ppm:
0.99 (3H, triplet, J ~ 6.5 Hz);
1.28 (9H, singlet);
1.64 ~6H, elnglet);
1.55 - 1.90 (2H, multiplet);
2.07 (3H, singlet);
2.70 ~2H, trlplet, J . 7 Hz);
4.90 (2H, singlet);
5.47 ~2H, singlet);
5.51 (lH, einglet);
6.91 (2H, doublet, J ~ 8.5 Hz);
7.2 - 7.9 (6H, multiplet).

'~

l o ~ o 29(b) (5-Methyl-2-oxo-1.3-dioxolen-4-yl)methyl 1-~(2~-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate Following a procedure similar to that described in Example 25(d), 0.54 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at 90 - 93~C, by treating 0.65 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate ~prepared as described ln ~tep (a) above~ with a 4 N ~olution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (h~Adeuterated dimethyl ~ulfoxide) ~ ppm:
0.88 (3H, triplet, J . 7.5 Hz);
l.S - 1.7 ~2H, multiplet);
1.59 (6H, slnglet);
2.11 (3H, ~inglet);
3.00 (2H, triplet, J . 7.5 Hz~;
5.13 (2H, singlet);
5.63 (2H, ~inglet);
7.13 (2H, doublet, J ~ 8 Hz);
7.26 - 7.75 (6H, multlplet).

~!X'Z~MPJ.~ 3 0 PlvAloyloxymeth~yl 1-~(2'-~Arbo~ybiDhe~yl-4-yl)methyll-4-(l-hvvAro~y l~methylethyl)~2~Dro~ylimidazole-5 r.ArbO~ylAte (cm~llnA No. 3-1) PivAloyloxy~thyl 1~(2~-t-butoxyrArbo~Ylbi~he~Yl 4-yl)met~yll-4-(1-hydro~y-l-met~ylet~yl)-2-~roDyl 1 m~ ~ Zole-5-~A rbo~ylA te Following a procedure 31milar to that de~cribed ln - 203 - 2061 ~ 7 Example 25(a), 0.81 g of the title compound was obtained from 500 mg of pivaloyloxymethyl 4-(1-hydroxy-1-methyl-ethyl)-2-propylimidazole-5-carboxylate [prepared as described in Preparation 22!ii)] and 560 mg of t-butyl 4'-bromomethylbiphe~yl-2-carboxylate. The melting point and Nuclear Magnetic Resonance Spectrum of the product were identical with those of the compound obtained as described in Example 25(c).

30(b) Pivaloyloxymet~yl 1- r ~2'-earboxybiphe~yl-4-yl)-met~yll-4-(1-~ydroxy-1-methylethyl)-2-pro~yl-; m~ ole-5-carboxylate Following a proeedure similar to that de~eribed in Example 25(d), 0.45 g of the hydroehloride of the title compound was obtained a~ cry~tals from 0.5 g of pivaloyloxymethyl 1-l(2'-t-butoxycarbonylbiphenyl-4-yl)-methyl]-~-~1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate ~prepared a~ described in ~tep (a) above].
The melting point and Nuclear Magnetic Reeonance Speetrum Oe the produet were identieal with those of the eompound prepared a~ deeerlbed ln Example 25(d).

M~T.lZ 3 1 Plvaloylo~ymeth~yl 2-butyl-1-~(2'- r~ rbo~yblphe~yl - 4 -yl)m~yll-4-(1-~y~ro~y-1-met~yleth~yl)im~dazole-5-rArbo~ylAte (Compo-ln~ No. 3-27) 31(a) Methyl 1-~(2'-t-butoxyrArbn~ylbi~h~yl-4-yl)-met~yll-2-butyl-4-(1-~y~ro~y-1-me~yle~yl)-~m~lAzole.5-~Arbo~,ylAte Following a procedure similar to that deccribed ln Example 25(a), 3.54 g o~ the title eompound were obtained a~ a cyrup ~rom 2.00 g o~ methyl 2-butyl-4-~1-hydroxy~1-methylethyl)imidazole-5-carboxylate (prepared ' '' . .

.
. ~

2061~7 a~ descri~ d in Preparation 21) and 3.03 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.92 (3H, triplet, J = 7.5 Hz);
1.25 (9H, singlet);
1.33 - 1.46 (2H, multiplet);
1.64 (6H, singlet);
1.68-1.78 (2H, multiplet);
2.70 (2H, triplet, J , 8 Hz);
3.78 (3H, singlet);
s.50 (2H, singlet);
5.70 (lH, ~inglet);
6.97 (2H, doublet, J ~ 8.5 Hz);
7.26 - 7.33 (3H, multiplet);
7.37 - 7.54 (2H, multiplet);
7.76 - 7.B1 (lH, multiplet).

31(b) 1-~(2'- t - 3uto~yrA rbo~ylhi~h~yl - 4 - yl )met~yll-2-butyl-4-(1-by~ro~y-1-~t~yle~yl)~m~zole-5-rA rbo~yl ic A ~

Followlng a procedure clmilar to that described inExample 25(b), 2.46 ~ o~ the title compound were obtained as cryetale, melting at 158 - 159~C, by hydrolyzing 3.31 g o~ methyl 1-~(2'-t-butoxycarbonyl-biphenyl 4-yl)methyl~-2-butyl-4-(1-hydroxy-1-methyl-ethyl)imidazole-5-carboxylate ~prepared as deecribed in ~tep ~a) above] with 1.37 ~ o~ lithlum hydroxide monohydrate.

Nuclear Magnetlc Resonance Spectrum ~CDCe3) ~ ppm:
0.84 ~3H, trlplet, J ~ 7.5 Hz);
1.23 ~9H, ~in~let);
1.25 - 1.38 (2H, multlplet);
1.52 1.65 ~2H, multiplet);
1.68 (6H, s~nglet);

.

- 20s 2061 6~ 7 2.83 (2H, triplet, J = 6 . 5 Hz);
5.81 (2H, singlet);
7.07 (2H, doublet, J = 8.0 Hz);
7.22 - 7.2~ (3H, multiplet);
7.34 - 7.50 (2H, multiplet);
7.74 - 7.78 (lH, multiplet).

31(c) Pivaloyloxymethyl 1-~(2~-t-butoxycarbonylbiphenyl-4-yl)m~thyll-2-butyl-4-(1-hydroxy-1-methylethyl~-~ m~ dazole-5-carboXYlate Following a procedure similar to that described in Example 25(c), 0.48 g o~ the title compound was obtained a~ a ~yrup by e~terlfying 0.40 g of 1-[(2'-t-butoxy-carbonylblphenyl-4-yl)methyl]-2-butyl-4-(l-hydroxy-l-methylethyl)imidazole-5-carboxylic acid ~prepared as described ln step (b) above] wlth chloromethyl pi~alate and potas61um carbonate, Nuclear Magnetic Reeonance Spectrum (CDC~3) ~ ppm:
0.92 (3H, trlplet, J - 7.5 Hz);
1.17 ~9H, elnglet);
1.24 (9H, slnglet);
1.32 - 1.47 (2H, multlplet);
1.63 ~6H, einglet);
1.66 - 1.79 (2H, multiplet);
2.69 (2H, trlplet, J . B Hz);
5.41 ~lH, elnglet);
5.51 ~2H, einglet);
5.83 (2H, ~lnglet);
6.97 ~2H, doublet, J ~ 8 Hz);
7.25 ~ 7.28 (3H, multiplet);
7.3B - 7.51 (2H, multlplet);
7.75 - 7.79 (lH, multlplet).

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

- 206 - 20S~7 31(d) Pivaloyloxymethyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate Following a procedure similar to that described in Example 25(d), 0,45 g of the hydrochloride of the title compound was obtained as an amorphous solid, melting at 139 - 144~C (~oftening at 127~C), by treating 0.48 g of pivaloyloxymethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)-methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-S-carboxylate ~prepared as described in step (c) above]
with a 4 N solution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (hP~deuterated dimethyl sulfoxlde) ~ ppm:
0.80 (3H, triplet, J . 7.5 Hz);
1.10 (9H, singlet);
1.21 - 1.35 (2H, multiplet);
1.39 - 1.50 ~2H, multiplet);
1.58 (6H, singlet);
2.96 ~2H, trlplet, J - 7.5 Hz);
5.64 ~2H, singlet);
5.B9 ~2H, ~inglet);
7.17 ~2H, doublet, J - 8.5 Hz);
7.32 - 7.34 ~3H, multiplet);
7,43 - 7.49 ~lH, multiplet);
7.55 - 7.61 ~lH, multiplet);
7.73 ~ 7.75 ~lH, multiplet).

2061 ~G7 Isopropoxycarbonyloxymethyl 2-butyl-1-[(2'-carboxy-biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-imidazole-5-carboxylate (Compound No. 3-39) 32(a) Iso~ropoxycarbonyloxymethyl 1-~(2'-t-butoxy-carbn~ylbi~henyl-4-yl)methyll-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate Following a procedure similar to that de~cribed in Example 25(c), 0.46 g of the title compound was obtained as cry~tale, melting at 91 - 93~C, from 0.40 g of 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid [prepared as described in Example 31(b)], O.15 g of isopropoxycarbonyloxymethyl chlorlde and 0.31 g of potassium carbonate.

Nuclear Magnetic Resonance Spectrum (CDCt3) b ppm:
0.92 (3H, triplet, J . 7.5 Hz);
1.23 (9H, ~inglet);
1.29 (6H, doublet, J - 6 Hz);
1.35 - 1.45 (2H, multiplet);
1.63 ~6H, singlet);
1.65 - l.B0 (2H, multiplet);
2.71 ~2H, triplet, J - 7.5 Hz);
4.90 ~lH, septet, J . 6 Hz);
5.39 ~lH, ~inglet);
5.51 ~2H, singlet);
5.82 ~2H, slnglet);
6.98 ~2H, doublet, J . a Hz);
7.25 - 7.30 ~3H, multlplet);
7.35 ~ 7.52 ~2H, multiplet);
7.75 7.~0 ~lH, multiplet).

.

~~ - 20~ - 20616~7 32(b) Isopropoxycarbonyloxymethyl 2-butyl-1-~(2~-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate Following a procedure similar to that described in Example 25(d), 0.39 g of the hydrochloride of the title compound was obt~ine~ as crystals, melting at 154 - 156~C, by treating 0.40 g of isopropoxycarbonyl-oxymethyl l-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate ~prepared as described in step (a) above] with a 4 N
solution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (he~A~euterated dimethyl ~ulfoxide) ~ ppm:
0.81 (3H, triplet, J . 7.5 Hz);
1.21 (6H, doublet, J ~ 6.5 Hz);
1.23 - 1.36 (2H, multiplet);
1.38 ~ 1.52 (2H, multlplet);
1.59 (6H, singlet);
2.98 (2H, triplet, J . 6.5 Hz);
4.79 (lH, septet, J . 6.5 Hz);
5.65 (2H, ~inglet);
5.B5 (2H, slnglet);
7.1a (2H, doublet, J . 8 Hz);
7.30 ~ 7.38 (3H, multlplet);
7.42 - 7.62 ~2H, multlplet);
7.74 (lH, doublet, J . 7.5 Hz).

,-, ~ ~ ~ o 20~1607 (s-Methyl-2-oxo-1.3-dioxolen-4-yl)methyl 2-butyl-l-~(2~-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (Compound No. 3-51) 33(a) (5-Met~yl-2-oxo-1.3-dioxolen-4-yl~methyl 1-~(2~-t-butoxycarbonylbiphe~yl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-met~ylethyl)imidazole-5-carboxylate Following a procedure similar to that described in Example 25~c), 0.43 g o~ the title compound was obtained a~ cry~tals, melting at 156 - 157~C, from 0.40 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(l-hydroxy-l-methylethyl)im~d~ole-5-carboxylic acid ~prepared ae described in ~xample 31(b)], 0.22 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide and 0.26 g o~ potas~ium carbonate in 5 ml of N,~-dimethyl-acetamide.

Nuclear Magnetic Reso~nce Spectrum (CDC~3) ~ ppm:
0.92 (3H, triplet, J ~ 7.5 Hz):
1.27 (9H, singlet);
1.30 - 1.45 (2H, multiplet);
1.62 (6H, singlet);
1.65 - 1.80 (2H, multiplet);
2.07 (3H, 6inglet);
2.70 (2H, trlplet, J . 7.5 Hz);
4.89 (2H, single~);
5.46 (2H, singlet);
5.55 ~lH, cinglet);
6.91 ~2H, double~, J ~ 8.5 Hz);
7.26 - 7.50 (SH, multiplet);
7.76 (lH, doublet, J ~ 6.5 Hz).

b . 6 2 0 ' - 210 - 20~ 7 33(bl (5-Methyl-2-oxo-1.3-dioxolen-4-yl)methyl 2-butyl-1-~(2'-carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-1-methylethyl)imidazol~-5-carboxylate Following a procedure similar to that described in Example 25(d), 0.26 g of the hydrochloride of the title compound was obt~-~e~ a~ a powder, melting at above 70~C
(~oftening), by treating 0.32 g of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate [prepared as described in step (a) abo~e]
wlth a 4 N colution of hydrogen chloride in dioxane.

Nuclear Magnetic Re~onance Spectrum (h~ euterated dimethyl sulfoxide) ~ ppm:
0.82 (3H, triplet, J ~ 7 Hz);
1.20 - 1.40 (2H, multiplet);
1.40 - 1.60 (2H, multiplet);
1.59 (6H, slnglet);
2.12 ~3H, slnglet);
2.9~ ~2H, trlplet, J - 7.5 Hz);
5.14 ~2H, singlet);
5.63 ~2H, slnglet);
7.13 ~2H, doublet, J - 7.5 Hz);
7.30 - 7.60 ~5H, multiplet);
7.74 ~lH, doublet, J . 7.5 Hz).

: ', . ' ' ' .~ . .

Phthalidyl 1-~(2 ' -carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate (Compound No 3 - 2 6 ) 34(a) Phthalidyl 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate Following a procedure similar to that described in Example 25(c), 0.62 g of the title compound was obtained as crystals, melting at 144~C, from O.S0 g of 1-[(2'-t-butoxycarbonylbiphenyl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-S-carboxylic acid ~prepared as described in Example 25~b)], 0.25 g of 3-bromophthalide and 0.3 g of pota~sium carbonate in 6 ml of ~,~-dimethylacetAm~e.

Nuclear Magnetic Re30nance Spectrum (CDCQ3) 6 ppm:
0.97 (3H, triplet, J . 7.5 Hz);
1.25 (9H, singlet);
1.62 (6H, ~nglet);
1.75 (2H, ~extet, J ~ 7.5 Hz);
2.66 (2H, triplet, J - 6.5 Hz);
5.38 ~2H, A3-quartet, ~ . 0.10 ppm, J ~ 17 Hz);
5.42 (lH, cinglet);
6.69 ~2H, doublet, J . 7.5 Hz);
f 7.15 ~2H, doublet, J - 7.5 Hz);
7.28 - 7.89 (9H, multiplet).

PhthAl ~ (2' -rArbol~ybiDhenyl-4-yl)methyll -4~ y~ro~y-1-methylethyl)-2-~ropyl~ m~ ~A zole-5-~.A rho~yl A te Following a procedure similar to that de~cribed ln ~xample 25(d), 0.37 g o~ the hydrochloride o~ the title ' ",- : ' . ' ' ' , ' !: ' .
,. . ~ ' ~

- 212 2061~7 compound was obtained as an amorphous powder, melting at 142 - 144~C, by treating 0.45 g of phthalidyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-l-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in step (a) above] with a 4 N
solution of hydrogen chloride in dioxane.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.92 ~3H, triplet, J = 7.5 Hz);
l.S0 - 1.70 (2H, multiplet);
1.59 (6H, singlet);
3.00 ~2H, triplet, J = 7.5 Hz);
5.65 ~2H, singlet);
7 01 (2H, doublet, J - 8 Hz);
7.27 (2H, doublet, J . 8 Hz);
7.36 ~ 7.9~ (9H, multiplet).

P~ pT~R 35 ~t~yl 4-~y~ro~ymet~yl-2-~ro~yl~ 4-~2-~tetrazol-5-yl)~h~r~yllph~ met~,ylim~Azole-5-carbo~ylate (Cn~o~n~ No. 4-3) 35(a) ~le~yl 2-propyl-1-(4-12-~trityltetrazol-S-yl)-~hP~yllDh~yl~methyl~m~Azole-4 5-dicarboxylate 0.441 g o~ potassium t-butoxide was added to a ~olution o~ 1.00 g of diethyl 2-propylimidazole-4,S-dicarboxylate ~prepared as de~cribed in Preparation 12) ln 15 ml o~ -dimethylacetAm~e, and the resulting mixture wa~ ~tirred at room temperature ~or 30 minutes.
A solution o~ 2.19 g o~ 4-~2-(trityltetrazol-5-yl)-phenyl~benzyl bromide in 15 ml o~ N,~-dimethylacetamide wa~ then added dropwise to the reaction mixture at room temperature, and the reactlon mlxture was stirred at room tem~-rature ~or 3 hour~ At th- end o~ thls time, , , :
:, :
:

- 213 - 20616~7 it was diluted with water and then extracting with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of h~ne and ethyl acetate as the eluent, to give 2.24 g of the title compound a~ an amorphou~ solid.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.88 (3H, triplet, J - 7.5 Hz);
1.20 (3H, triplet, J , 7.5 Hz);
1.39 (3H, triplet, J . 7.5 Hz);
1.59 (6H, singlet);
1.61 - 1.72 (2H, multiplet);
2.55 (2H, triplet, J . 7.5 Hz);
4.20 (2H, quartet, J ~ 7.5 Hz):
4.39 (2H, quartet, J . 7.5 Hz);
5.30 ~2H, slnglet);
6.7~ (2H, doublet, J - 8 Hz);
6.92 - 7.52 ~20~, multlplet);
7.90 ~lH, doublet, J - 7.5 Hz).

35(b) Etbyl 4-~ydro~ymathyl-2-prQDyl-1-~4-[2~trltyl-tetrA7nl-5-yl)phA~yllphP~yl~m~yllm~701e-5-O~yl~te 10 ml of a 1.5 M solution of dii~obutylall-m~ntlm hydrlde in toluene were added dropwise at -20~C under an atmosphere of nitrogen to a eolution of 4.27 g of diethyl 2-propyl-1-(4-~2-~trltyltetrazol-5-yl)phenyl]
phenyl~methylimidazole-4,5-dicarboxylate ~prepared as de~cribed in step (a) above] in S0 ml of ~etrahydro~uran. The resulting mlxture wa~ allowed to ctand at 0~C for 16 hours and then mlxed with ethyl acetate and with a saturated aqueou~ colution of onium chloride; lt was then stlrred at room .. . .

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

- 214 - 20~ 7 temperature for 1 hour. The resulting precipitate was filtered off, and the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The crystalline residue was washed with diisopropyl ether, to give 4.03 g of the title compound, melting at 135 - 138~C.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.94 ~6H, triplet, J , 7.5 Hz);
1.29 (3H, triplet, J - 7 Hz);
1.67 - 1.77 (2H, mNltiplet);
2.56 (2H, triplet, J = 7.5 Hz);
3.43 (lH, broad triplet, J ~ 4 Hz);
4.25 (2H, quartet, J , 7 Hz);
4.91 (2H, doublet, J , 4 Hz);
5.49 ~2H, singlet);
6.~2 ~2H, doublet, J . 7.5 Hz);
6.98 - 7.57 (20H, multiplet);
7.94 ~lH, doublet, J ~ 7 ~z).

~SL ~t~yl 4-hy~roxy~ethyl-2-propyl-1-~4-~2-(tetrazol-5-yl)l~hPr~ hPr~yl)methyl~m~9Azole-5-~Arboxylate A solution of 0.28 g o~ ethyl 4-hydroxymethyl-2-~ropyl-~4-~2-~trityltetrazol-5-yl)phenyllphenyl~-methylimidazole-5-carboxylate [prepared as described in ctep ~b) above~ in 4 ml of 75~ v/v aqueous acetic acid was stlrred at 60~C for 2 houre. The reaction mixture wa~ then concentrated by evaporation under reduced pressure, and the residue was di~solved ln toluene. The re~ultlng solutlon wa~ again concentrated by evaporatlon under reduced preseure, to remove as much water and ace~lc acld as po~cible. The residue wa~ then purl~ied by column chromatography through sllica gel, uslng 9 : 1 and 4 : 1 by volume mlxture~ o~ methylene chloride and methanol a~ the eluent, to give 0.20 g of the tltle .

..

. ' ~
, I ~ 2 ~

~ - 215 - 2061~7 compound as an amorphous sol id.

Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.80 (3H, triplet, J = 7.5 Hz);
1.20 (3H, triplet, J = 7.5 Hz);
1.45 - 1.65 (2H, multiplet);
2.44 (2H, triplet, J = 7.5 Hz);
4.20 (ZH, quart~t, J = 7.s Hz);
4,58 (2H, singlet);
5.43 ~2H, ~inglet);
6.7~ ~2H, doublet, J - 7.5 Hz);
6 98 (2H, doublet, J - 7.5 Hz);
7.38 - 7.60 (3H, multiplet);
7.79 (lH, doublet, J a 7.5 Hz).

EXAMPL~ 36 4-~y~roxy~th~yl-2-propyl-1-~4-~2-(tetrazol-5-yl)~h~yll~hP~yl~met~yl~m~A701e-5-carbo~yllc acid ~Com~o~ n~ No . 4 -1 ) A mlxture of 0.20 g of ethyl 4-hydroxymethyl-2-~propyl-1-l4-12-(tetrazol-5-yl)phenyl]phenyl)methyl-~ m~ ~ zole-5-carboxylate ~prepared as described in Example 35~c)~ and 0.10 g o~ llthium hydroxide monohydrate ln 3 ml o~ water was stirred at room temperature rOr 3 houre, after which it wa~ allowed to ~tand for 16 hour~ at the ~ame temperature. The reaction mlxture was then mlxed wlth 2.3B ml of 1 N
aqueou~ hydrochlorlc acld and the resulting precipitate wa~ collected by ~iltration, to give 150 mg of the title compound, meltlng at 233~C (wlth decompo~ition).

Nuclear Magnetlc Resonance Spectrum (he~deuterated dlmethyl cul~oxlde) h ppm:
- 0.~9 (3H, trlplet, J . 7.5 Hz);
1.59 (2H, cextet, J ~ 7.5 Hz);

; , "
. , . ~

~ - 2 6 - 20616Q7 2.58 (2H, triplet, J = 7.5 Hz);
4.64 (2H, singlet);
5.62 (2H, singlet);
6.98 (2H, doublet, J = 8 Hz);
7.08 (2H, doublet, J = 8 Hz);
7.3g - 7.69 (4H, multiplet).

Plvaloyloxymethyl 4-hydroxymethyl- 2-~ro~yl~ 4-~2-(tetrazol-5-yl)phenyll~he~yl}methylimidazole-5-carbo~ylate (Compound No. 4-4) 37(a) 4-~y~roxymetbyl-2-propyl-1-(4-~2-(trityltetrazol-5-yl)ph~yllphenyl~methylimidazole-5-carboxylic A ~olution of 0 66 g of lithium hydroxide monohydrate in 20 ml of water was added to a solution of 1.22 g o~ ethyl 4-hydroxymethyl-2-propyl-1-~4-[2-~trityltetrazol-5-yl)phenyl]phenyl~methylimidazole-5-carboxylate lprePared as described in Example 35~b)] in 5 ml o~ dioxane, and the resulting mixture was stirred at 80~C or 5 hours At the end of this time, the reaction mixture was freed from dioxane by distillation under reduced pressure, and the aqueous residue was mixed with ice and with ethyl acetate; 15.7 ml of 1 N
aqueous hydrochlorlc acid were then added. The title compound ~reclpitated, and was collected by filtration and wa~hed wlth water. The ethyl acetate layer was then separated ~rom the eiltrate and dried over anhydrous magne~ium ~ul~ate, and the solvent was removed by dl~tlllatlon under reduced pressure. The resulting re~idue wa~ wa~hed wlth die~hyl ether, to glve more o~
the title compound a~ a powder. The two portions of the tltle compound were combined and together weighed 0.98 g, and thls was immedlately used in the subsequ6nt :.
:.

. , . . ~ ., ., .

~ - 217 - 2061~7 esterification reaction without further purification or characterisation.

37(b) Pi~aloyloxymethyl 4-hydroxymethyl-2-propyl-1-~4-~2-(trityltetrazol-s-yl)phenyl]phenyl~methyl-imidazole-5-carboxylate 0.30 g of potassium carbonate and 0.24 g of plvaloyloxymethyl chlor~de were added to a solution of 0.98 g of 4-hydroxymethyl-2-propyl-1-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid ~prepared as de~cribed in ~tep (a) above] in 10 ml of N,~-dimethylacetamlde, and the resulting mixture was stirred at room temperature for 6 hours. At the end of this time, the reaction mixture wa~ mixed with ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magne~ium culfate, and then the solvent was removed by dlctlllation under reduced pressure. The re~ultlng residue wac purified by column chromatography through ~lllca gel, u~ing a 2 : 1 by volume mixture o~ ethyl acetate and hexAne ac the eluent, to give 0.91 g o~ the tltle compound ac a gum.

, Nuclear Magnetic Reeonance Spectrum (CDCQ3) ~ ppm:
0.89 (3H, triplet, J . 7.5 Hz);
1.18 ~9H, clnglet);
1.70 ~lH, sextet, J . 7.5 Hz);
2.52 ~2H, triplet, J - 8 Hz);
3.35 ~lH, broad einglet);
.83 ~2H, singlet);
5.~2 ~2H, cinglet);
5.80 (2H, singlet);
-. 6.76 ~2~, doublet, J , 8 Hz);
~ 6.92 ~ 7.51 (20H, multiplet);
-, 7.90 ~lH, doublet, J . 7.5 ~z).
-. . . .

.
.
- , , ~ - 218 - 2~61~7 37(c) Pi~aloyloxymethyl 4-hydroxymethyl-2-pro~yl-1-{4-12-(tetrazol-5-yl)phenyllphenyl}methylimidazole-s-carboxylate Following a procedure similar to that described in Example 35(c), 0.91 g of pivaloyloxymethyl 4-hydroxy-methyl-2-propyl~ 4-[2-(trityltetrazol-5-yl)phenyl]-phenyl}methylimidazole [prepared as described in step (b) above] was detritylated by treatment with 75~ v/v aqueous acetic acid, to give 0.42 g of the title compound as a powder, melting at above 60~C (with ~oftening).

Nuclear Magnetic Reso~Ance Spectrum (CDCQ3) ~ ppm:
0.94 (3H, triplet, J ~ 7.5 Hz);
1 1.14 (9H, singlet);
1.72 ~2H, ~extet, J ~ 7.5 Hz);
; 2.61 (2H, triplet, J - 7.5 Hz);
2.90 (2H, broad singlet);
4.77 ~2H, singlet);
5.49 ~2H, elnglet);
5.84 ~2H, singlet);
6.94 ~2H, doublet, J - 8 Hz);
~ 7.15 ~2H, doublet, J . 8 Hz);
7.26 7.61 (3H, multiplet);
8.07 ~lH, doublet, J . 7.5 Hz).

E~a~PT.~ 3~

~ Met~yl 2-bu~yl-4-h~y~ro~ymeth~yl~ 4-l2-(tetrAzol-5-g yl~he~,yllpher~,yl~meth~yl~m~ A7nle-5 ~ArhoxylAte (~o~o--n~ No. 4-47) 3~a) ~im~th~yl 2-bu~yl-1-[4-12-(trltyltetrA~1-5-yl)-phe~yll~hP~yl )met~yl~ml~zole-4.5-~ArbnYlyl~te Followlng a procedure eimilar to that deecrlbed ln .

- 219 - 20616~7 Example 35(a), but using 0.50 g of dimethyl 2-butyl-imidazole-4,5-dicarboxylate (prepared as described in Preparation 4) and 1.17 g of 4-~2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.51 g of the title compound was obt~;ne~ as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.85 (3H, triplet, J , 7.5 Hz);
1.20 - 1.80 (4H, multiplet);
2.59 (2H, triplet, J ~ 8.0 Hz);
3.73 (3H, singlet);
3.92 (3H, singlet);
5.30 (2H, einglet);
6.6 - 7.6 (22H, multiplet);
7.8 ~ 8.0 (lH, multiplet).

~8(b~ Met~yl 2-butyl-4-~y~ro~y~ yl-1-{4-[2-~trityl-tetr~701-5-yl)~hPr~yllphP~l~met~yli~ zole-5-carbo~ylAte Following a procedure eimilar to that described in Example 35~b), 0.51 g of dimethyl 2-butyl-1-~4-[2-(trityltetrazol-5-yl)phenyl]phenyl~methyllmldazole-4,5-dicarboxylate ~prepared ae deecribed in etep ta) above]
wae reduced u~ing 0.99 ml o~ a 1.5 M eolution of diicobutylal~ um hydride in toluene, to gi~e 0.44 g of the tltle compound ae an o~l.

- Nuclear Magnetlc Reeonance Spectrum ~CDCQ3) ~ ppm:
0.86 (3H, ~riple~, J . 7.5 Hz);
1.23 ~ 1.36 ~2H, multiplet);
,- 1.58 ~ 1.70 ~2H, multiplet);
1.80 ~ 1.95 ~lH, multiplet);
2.54 ~2~, trlplet, J . 9.0 Hz);
3.72 ~3H, elnglet);
.85 ~2H, doublet, J . 6.0 Hz);
5.~3 (2H, elnqlet);

.

: , ' ; , - 220 - 2061'6'07 6.77 (2H, doublet, J = 8.5 Hz);
6.92 - 6.95 (4H, multiplet);
7.08 (2H, doublet, J = 8.5 Hz);
7.22 - 7.51 (14H, multiplet);
7.87 - 7.90 (lH, multiplet).

38(c) Methyl 2-butyl-4-hydroxymethyl-1-{4-~2-tetrazol-5-yl)~henyllphenyl}methylimidazole-5-carboxylate A ~olution of 0.44 g of methyl 2-butyl-4-hydroxy-methyl-1-{4-~2-~trityltetrazol-5-yl)phenyl]phenyl}-methyl~ m~ ~A 701e-5-carboxylate [prepared as described in step (b) above~ in 10 ml of methanol and 0.70 ml of 1 N
aqueou~ hydrochloric acid was allowed to stand overnight at room temperature. At the end of this time, the reaction mlxture was concentrated to dryness by dictlllation under re~uce~ pre~ure, and the residue was triturated with diethyl ether to give 0.30 g of the hydrochloride of the title compound as a solid.

Nuclear Magnetlc Resonance 8pectrum (hex~euterated dimethyl sul~oxide) ~ ppm:
0.31 ~3H, triplet, J ~ 7.5 Hz);
1.19 - 1.32 ~2H, mult$plet);
1.33 - 1.51 (2H, multiplet);
2.95 ~2H, triplet, J - 7.5 Hz);
4.80 (2H, singlet);
5.71 (2H, singlet);
- 7.20 - 7.75 ~8H, multiplet).

EXA~VT.~ 39 ~' ; 2-~u~yl-4-ky~ro~ymet~yl-l-~4-~2-(tetrA~01-5-yl)-~hP~yllphe~yl~methylim.~Azole-5-~Arbo~ylic Acid : ~ ~C~Do~-n~ No. 4-46) ~ Following a procedure ~imilar to that descrlbed in ,' ., ~ . .

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

- 2~

Example 36, but using 0.30 g of methyl 2-butyl-4-hydroxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}-methylimidazole-5-carboxylate [prepared as de~cribed in Example 38(c)] and 2.50 ml of a 1 N aqueou~ solution of sodium hydroxide, 95 mg of the title compound were obt~;ne~ ae cry~tals, melting at 215 - 217~C.

Nuclear Magnetic ~esonance Spectrum (he~euterated dimethyl sulfoxide~ 6 ppm:
0.82 ~3H, triplet, J ~ 7.5 Hz);
1.27 (2H, multiplet);
~ 1.52 l2-~, mult plet);
2.56 ~2H, triplet, J , ~.5 Hz);
; 4,60 (2H, singlet);
5.5~ ~2H, ainglet);
6.94 ~2H, doublet, J . a.s Hz);
7.06 ~2H, doublet, J ~ 8.5 Hz);
7.50 - 7.70 ~4H, multiplet).
, F!xz~hlDT~R 40 - ~t~yl 4 (1-~y~ro~yethyl)-2-propyl-1-(4-~2-~tetrazol-5-yl)ph~11~7h~ meth~yl~m~Azole-5-rArbo~;ylAt~
* (Cn~ n~ No. 4-30) 40~a) ~yl 4~on~yl~l~pro~yl-l-~4-~2-~trityltetrazol~
5-yl)ph~yllphP~yl)~thyl~ m~ ~A zole-5-carboxylate 6 g o~ activated man~ne~e dioxide were added to a colutlon o~ 2 g o ethyl 4-hydroxymethyl-2-propyl-1-t4 12-~trltyltetrazol 5-yl)phenyl~phenyl)methyl-m~ ~A zole-5-carboxylate lprepared as de~crlbed in ~xample 35(b)~ ln 40 ml o methylene chloride, and the re~ultlng mlxture was stirred at room temperature ~or 2.5 hours. At the end o~ this tlme, the m-n~Anese . dloxlde wa~ ~lltered o-~ and the ~lltrate was ~ concentrated by evaporatlon under reduced pres~ure. The ' ' ' ' ' ' ".
~' ~ ' ' , ' ' ' , , - . . . .. .

..
, ~, ' ' , 20~1607 resulting re~idue was purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of ethyl acetate and h~Y~ne as the eluent, to give 1.45 g of the title compound as crystals, melting at 177 - l7soc (with decomposition).

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.88 (3H, triplet, J = 7.5 Hz);
1.29 (3H, triplet, J - 7 ~z);
1.74 (2H, sextet, J , 7.5 Hz);
2.57 (2H, triplet, J , 7.5 Hz);
4.29 (2H, quartet, J - 7 Hz);
5.49 (2H, singlet);
6.76 (2H, doublet, J D 8.5 Hz);
6 92 - 7.88 (20H, multiplet);
7.90 (lH, doublet, J ~ 7.5 Hz);
10.42 (lH, singlet).

~0 (b) Et~yl 4~ hy~roxyet4yl)-2-propyl-1-~4-[2-(trityltetr~7~1-5-yl)Dhe~yll~h~yllmet~yl-~ m1 ~A ZQle-5-~A rboxylA te 4.0 ml o~ a 1 M solution of methylmagnesium bromide in tetrahydro~uran were added dropwiee at -10~C to a eolutlon of 1.2 g of ethyl 4-~ormyl-2-propyl-1-~ 2-(trityltetrazol-5-yl)phenyl]phenyl~methyllmldazole-5-carboxylate [prepared as deecribed ln step (a) above] in 5 ml o~ tetrahydro~uran, and the resultlng mixture was stlrred at a temperature between -10~C and 0~C for 3 hours. At the end o~ this tlme, the reaction mlxture wae mixed with ethyl acetate and wlth an aqueous eolution o~ ammonlum chloride, and the mlxture was atlrred at room temperature ~or 20 mlnutes. The ethyl ace~a~e layer was then eeparated and dried over anhydroue magneeium sul~ate. The solvent was removed by di~tlllation under reduced pre3sure, and the resldue was purl~led by column chromatogra~hy through dllica gel, ':
, , : ~ , ,'~ , : ,, using 1 : 4 and 1 : 2 by volume mixtures of ethyl acetate and methylene chloride as the eluent, to give 1.23 g of the title compound as a viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.87 (3H, triplet, J - 7.5 Hz);
1.22 (3H, triplet, J = 7 Hz);
1.54 (3H, doublet, J = 7 Hz);
1.68 (2H, sextet, J = 7.5 Hz);
2 50 (2H, trlplet, J , 7.5 Hz);
3.82 (lH, doublet, J - 8 Hz);
4.18 (2H, quartet, J = 7 Hz);
5.23 (lH, quintet, J . 7 Hz);
5.42 (2H, singlet);
6.76 (2H, doublet, J ~ ~3 Hz);
6.93 - 7.52 (20H, multiplet);
7.8~ (lH, doublet, J . 7.5 Hz).
.
40(c) Et~Yl 4-(1-by~ro~yet~yl)-2-prQpyl-1-~4-~2-', (tetr~7ol-5-yl)~?hPrurllQh~ mq~ m~lA7ole S-carbo~yl~te ,, ~
Following a procedure cimilar to that described ln Example 35~c), 1.23 g o~ ethyl 4-(l-hydroxyethyl)-2-propyl-l-lg-[2-~trityltetrazol-5-yl)phenyl]phenyl}-methylimidazole-5-carboxylate ~prepared as described in step (b) above] were treated with 75% v/v agueou~ acetlc acld, to give 0.82 g of the title compound a~ an -~ amorphoue eolid.

Nucl0ar Magnetic Re~onance 9pectrum (C~CQ3) ~ ppm:
0.85 ~3H, triplet, J - 7.5 Hz);
1.2~ ~3H, triplet, J ~ 7 Hz);
1.~2 ~3H, doublet, J ~ 6 Hz);
~- 1.59 (2H, ~extet, J . 7.5 Hz);
2.50 ~2H, triplet, J ~ 7 Hz);
.22 ~2H, ~uartet, J ~ 7 Hz);

.

.
, ~ : , , ' ,'.

, ~ , .: . .

20~1~07 5.13 - 5.20 (lH, multiplet);
5.44 (2H, AB-quartet, ~ = 0.12 ppm, J = 16.5 Hz);
6.78 (2H, doublet, J = 8 Hz);
6.99 (2H, doublet, J = 8 Hz);
7.38 - 7.59 (3H, multiplet);
7.76 (lH, doublet, J - 7.5 HZ).

4-(1-~ydroxyethyl)-2-propyl-1-{4-~2-(tetrazol-5-Yl)phP~yllDhenyl~met~ylimidazole-5-carboxylic acid (C~o1~n~ No. 4-29) Following a procedure similar to that described in Example 36, 0.~2 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate ~prepared as described ln Example 40(c)]
was hydrolyzed using 0.43 g of lithium hydroxide monohydrate, to glve 0.50 g of the title compound as a powder, melting at 193 - 201~C.

Nuclear Magnetic Resonance Spectrum (h~Adeuterated dimethyl sul$oxide) ~ ppm:
0.~6 (3H, triplet, J - 7.5 Hz);
1.39 (3H, doublet, J - 6.5 Hz);
1.55 (2H, eextet, J - 7.5 Hz);
~ 2.5~ (2H, triplet, J - a Hz);
.- 5.21 (lH, quartet, J - 6.5 Hz);
5.61 (2H, singlet);
6.95 - 7.0~ (4H, multiplet);
7. 51 ~ 7.70 ~4H, multlplet).

: .
;'.
"

,. ... . - , . . .
.

~ ~ 2 ~

Ethyl 4-(1-hydroxyethyl)- 2 -propyl-l-{ 4 - [2 - tetrazol-5-yl)phenyllphenyl~methylimidazole-5-carboxylate (Compound No . 4 - 3 0 ) 42(a) Ethyl 4-(1-hydroxyethyl)-2-Rro~yl-1-{4-[2-(trityltetrazol-5-yl)phenyll~henyl}met~yl-~ m~ dazole-5-carboxylate Followlng a procedure 3imilar to that described in ~xample 35(a), but using 113 mg of ethyl 4-(1-hydroxy-ethyl)-2-propylimldazole-5-carboxylate [prepared as described in Preparation 23(iii)], 280 mg of 4-~2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 60 mg of pota~ium t-butoxide, 255 mg of the title compound were obt~ine~ ae a viccou~ oil. The Nuclear Magnetic Resonance Spectrum o~ this compound wa~
identical with that of the compound obtained as deccribed in Example 40(b).

42(b~ Ethyl 4-(1-hy~ro~yetbyl)-2-pro~yl-1-{4 ~2-(tetrAzol-5-yl) ph~yl 1 ~hP~yl I m~thyl ~ m~ dazole-5. r~ rhn~yl A te Following a procedure eimilar to that described ln xample 35(c), 255 mg of ethyl 4-(1-hydroxyethyl)-2-propyl~ 4-~2 ~trityltetrazol-5-yl)phenyl]phenyl)~
methylim1flAzole-S-carboxylate ~prepared as described in step ~a) above] was de~rltylated by treatment with 75 v/v aqueouc acetic acld, to give 170 mg of the title compound a~ an amorphous ~olid. The Nuclear Magnetic Reeonance Spectrum Or thie compound wa~ identlcal with that o~ the compound obtalned ae deccribed in Example 40~c).

,, EthYl 2-butyl-4-(1-hydroxyethyl) -1-~4- [2- (tetrazol-5-yl)phenyl]phenyl~methylimidazole-5-carboxylate (Compound No . 4 - 7 5) 43(a) Ethyl 2-butyl-4-(1-hydroxyethyl)-1-{4-[2-(trityl-tetrazol-5-yl)phenvll~henyl~methylimidazole-5-carboxylate Following a procedure similar to that described in Example 35(a), but using 400 mg of ethyl 2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxylate ~prepared as described in Preparation 24(iii)], 1.00 g of 4-~2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 197 mg of potassium t-butoxide, 0.94 g of the title compound waq obtained as a viscous oil.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
~ 0.87 (3H, triplet, J - 7.5 Hz);
1.24 (3H, triplet, J ~ 7 Hz);
1.25 - 1.38 ~2H, multiplet);
1.55 (3H, doublet, J . 6.5 Hz);
1.60 - 1.72 (2H, multiplet);
2.54 (2H, triplet, J . 8 Hz);
~ 3.84 (lH, doublet, J . 6.5 Hz);
4.20 (4H, quartet, J ~ 7 Hz);
; 5.25 ~lH, quintet, J - 6.5 Hz);
~ 5.44 ~2H, ~inglet);
- 6.73 ~2H, doublet, J w 8 Hz);
6.94 - 7.54 ~20H, multiplet);
7.90 ~lH, doublet, J . 7.5 Hz).

' .

:. . ~ ', . ' - , 20~1~û7 43tb) Ethyl 2-butyl-4-(1-hydroxyethyl)-1-{4-[2-(tetrazol-5-yl)phenyllphenyl~methylimidazole-5-carboxylate Following a procedure ~imilar to that described in Example 40(c), 0.84 g of ethyl 2-butyl-4-(1-hydroxy-ethyl)-1-~4-[2-(trityltetrazol-5-yl)phenyl]phenyl}-methylimidazole-5-carboxylate [prepared a~ described in step (a) above] was treated with 75~ v/v aqueous acetic acid, to give 0.54 g of the title compound a~ an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.78 (3H, triplet, J . 7.5 Hz);
1.15 - 1.30 (2~, multiplet);
1.19 ~3H, triplet, J - 7 Hz);
:1.35 ~3H, doublet, J . 6.5 Hz);
1.44 - 1.60 ~2H, multiplet);
2.49 ~2H, triplet, J . ~ Hz);
4.17 ~2H, quartet, J . 7 Hz);
5.09 ~1~, quartet, J . 6.5 Hz);
5.35 & 5.45 ~each lH, A~-quartet, J ~ 16.5 Hz);
6.~9 ~2H, doublet, J . 8 Hz);
~i 6.96 ~2H, doublet, J - 8 Hz);
- 7.30 - 7.50 ~3H, multiplet);
7.65 ~lH, doublet, J ~ 7.5 Hz).

~x~PLE 44 -~2-Butyl-4~ ydro~yet~yl)-1-~4-~2-(tetrAzol-5-; yl)~henyllphe~yl)met~yllmidazole-5-rArboxylic acld . (Compound No. 4-74) -Followlng a procedure similar to that de~cribed in :~~xample 36, 0.54 g o~ ethyl 2-butyl-4-(1-hydroxyethyl)-4~ tetra~ol-S-yl)phenyllphenyl~methyllmidazole-S-carboxylate ~prepared a~ described in Example 43~b)~
, , . . . . .

I ~ 2 0 was hydrolyzed, using 245 mg of lithium hydroxide monohydrate, to give 0.43 g of the title compound as a powder, melting at 214 - 217~C.

Nuclear Magnetic Re~onance Spectrum (h~fleuterated dimethyl ~ulfoxide) ~ ppm:
0.82 (3H, triplet, J = 7.5 Hz);
1.27 (2H, sextet, J = 7.5 Hz);
1.37 ~3H, doublet, J = 6.5 Hz);
1.50 (2H, quintet, J = 7.5 Hz);
2.58 (2H, triplet, J - 8 Hz);
5.20 (lH, quartet, J ~ 6.5 Hz);
5.61 (2H, ~inglet);
6.96 (2H, doublet, J , ~ Hz);
7.06 (2H, doublet, J ~ 8 Hz);
7.50 - 7.66 (4H, multiplet).

~XZ~MPJ.F 4 5 ;2-Butyl-1-~(2'-~ rbo~ybi~hP~yl -4-yl)~yll-4-(1-~ytl ro~ye t}~yl ) ~ m~ 7 ~1 - 5-~ A rb~ Am~de ; (C~n~n~ No. 5-64) , I
45(a) 4-Acetyl-l-t(2'-t-buto~y~Arhn~ylblch~yl-4-yl)-- methyll-2-butyl~ml~zole-5-carb~n~trile .
0.192 g Or sodium hydride (as a 55~ w/w dicpersion in mineral oil) wa~ added to a solutlon of 0.~43 g of ~-acetyl-2-butyl~ m~ ~ zole-5-carbonitrlle ~prepared a~
de~cribed ln Preparation 24~ in 17 ml o~
dlmethylacetamlde, and the recultlng mixture was ~lrred at room temperature for 20 minute~. 1.6~ g of E-bu~yl ~ bromomethyl)blphenyl-2-carboxylate wa~ then added, and the re~ulting mixture waa stirred at 55~C for 2.5 hour~. At the end of ~hl~ time, an aqueou~ ~olution o~ ~odium chlorlde wa~ added to the mixture, whlch was ~hen extracted with ethyl acetate. The extract was . .

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

l ~ ~ o - 229 - 20616~7 washed with water and dried over anhydrous magnesium ~ulfate, and then the solvent was removed by distillation under reduced pressure. The resulting oily residue was purified by column chromatography through ~ilica gel, using 4 : 1 and 2 : 1 by volume mixtures of heY~ne and ethyl acetate as the eluent, to afford 1.14 g of the title compound as a viscous oll.

Nuclear Magnetic Resonance Spectrum (CDC~3) ~ ppm:
0.93 ~3H, triplet, J , 7 Hz);
1.23 (9H, singlet);
1.3 - 2.1 (4H, multiple~);
2.58 ~3H, einglet);
2.75 ~2H, triplet, J ~ 7 Hz);
5.32 ~2H, einglet);
7.0 - ~.0 ~8H, multiplet).

~S(b) 1-~(2~-t-Butoxy~rbn~ylbi~hp~yl-4-yl)met~yll-2-butyl-4-(l-hy~roxYet~yl)~m~A701e-5-~Arbonitrlle 0.09~ g o~ eodlum borohydride wae added to a eolutlon o~ 1.18 g o~ 4-acetyl-1-[~2'-t-butoxycarbonyl-biphenyl-4-yl~methyl~-2-butylimidazole-5-carbonitrile ~prepared ae deecribed in etep ~a) above] in 30 ml of ethanol, and the reeulting mixture was etirred at room temperature rOr 1 hour. The exceee sodium borohydride wae decompoeed by ~di~ acetone, and then the reaction mixture wae concentrated by evaporation under reduced pre8eure. The reeidue wae diluted with an aqueoue eolution o~ eodium chlorlde and extracted with ethyl aceta~e. The extract wae dried and concentrated by evaporation under reduced preéeure. The oily reeidue w~0 purl~led by column chromatography through silica gel, u~ing a 3 : 2 by volume mixture o~ ethyl acetate and hexa~e ae ~he eluent, to a~ord 1.~8 g o~ the title compound ae a viecoue oil.

';~

!

. .
.... .

~ ~ 2 0 20~1607 Nuclear Magnetic Resonance spectrum (CDCQ3) ~ ppm:
0.92 (3H, triplet, J = 7.5 Hz);
1.25 (9H, singlet);
1. 3 - 1. 5 (2H, multiplet);
1.60 (3H, doublet, J = 6.5 Hz);
1.6 - 1.8 (2H, multiplet);
2.6 - 2.8 (2H, multiplet);
f 5.00 (lH, ~uartet, J , 6.5 Hz);
- 5.22 ~2H, singlet);
- 7.1 - 7.9 (8H, multiplet).

45(c) 1-~(2'-t-~uto~ycarbonylbi~henyl-4-yl)methyll -2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxamide , - 12 ml o~ a 1 N aqueous eolution of eodium hydroxide were added to a eolution of 0.52 g of 1-[(2'-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4~(1-hydroxyethyl)-zole-5-carbonitrile [prepared ae described in step (b) above] in 3 ml of ethanol, and the resulting mixture wae heated under reflux ~or 3 hours. At the end of this - tlme, the reaction mixture wa~ neutralized by the -- addition o~ dilute aqueoue hydrochloric acid and ~extracted with ethyl acetate. The extract wae washed wlth water and dried over anhydroue magneeium sulfate.
The eolvent was then removed by distillation under reduced preesure. The resulting resldue was purlfied by column chromatography through silica gel, using a 4 : 1 by volume mlxture o~ ethyl acetate and heYA~e, followed by ethyl acetate alone, a~ the eluent, to afford 0.14 g o~ the title compound ae an amorphoue eolld.

Nuclear Magnetic Re~onance Spectrum (CDCe3) ~ ppm:
0.90 ~3H, trlplet, J - 7.5 H~);
1.23 ~9H, elnglet);
1.2 - 1.5 ~2H, multlplet);
1.6 - 1.8 ~2H, multiplet);
1.66 ~3H, doublet, J ~ 6.5 Hz);

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

- 231 - 2061g~7 2.63 (2H, triplet, J = 8 Hz);
5.11 (lH, quartet, J = 6.5 Hz);
5.59 ~ 5.74 (each lH, AB-quartet, J = 16 Hz);
7.0 - 7.9 (8H, multiplet).

45(d) 2-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyll-4-(l-hydroxyet~yl)imidazole-5-carboxamide A solution of 0.15 g of 1-[(2~-t-butoxycarbonyl-biphenyl-4-yl)methyll-2-butyl-4-(1-hydroxyethyl)-imidazole-5-carboxamide [prepared as described in step (c) above] dicsolved in 3 ml of a 4 N solution of hydrogen chloride in dioxane wa3 allowed to stand overnight at room temperature. The solution was then concentrated by evaporation under reduced pressure. The resulting recidue was triturated in he~ne and the powder thuc obtained was collected by filtration, to af~ord 0.105 g of the hydrochloride of the title compound a~ an amorphous solid, melting at 212 - 214~C
(wlth decompocition).

Nuclear Mag~etic Reconance Spectrum ~CDC~3) ~ ppm:
0.94 (3H, triplet, J - 7.5 Hz);
1.3 - 1.6 (2H, multiplet);
1.59 (3H, doublet, J - 6.5 Hz);
1.6 - 2.0 (2H, multiplet);
3.0 - 3.4 (2H, multiplet);
5.16 (lH, quartet, J ~ 6.5 Hz);
5.41 & 5.58 (each lH, A3-quartet, J . 15 Hz);
7.1 - 7.9 (8H, multiplet).

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

~ - 232 - 20~16Q7 2-~utyl-1-~(2~-carboxybiphenyl-4-yl)methyll-4-(1-hydroxypropyl)imidazole-5-carboxamide (Compound No . 5 - 6 5 ) 46(a) 1-~(2'-t-~utoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-~ro~ionylimidazole- 5 - carbonitrile Following a procedure similar to that described in Example 45~a) but u~ing 0.923 g of 2-butyl-4-propionyl-~m~zole-5-carbonitrile (prepared a~ described in Preparation 25), 1.56 g of t-butyl 4'-tbromomethyl)-biphenyl-2-carboxylate and 196 mg of sodium hydride (as a 55~ w/w dlsper~ion in mineral oil) in 20 ml of ~,~-dimethylacetamide, l.a4 g of the title compound were obtAine~ a~ a vi~cous oil.

Nuclear Magnetic Resonance Spectrum ~CDCQ3) ~ ppm:
0.91 ~3H, triplet, J . 7 Hz);
1.0 - 2.1 (4H, multiplet);
1.25 ~9H, einglet);
2.72 ~2H, triplet, J . 7 Hz);
3.02 ~2H, quartet, J - 7 ~z);
5.30 ~2H, einglet);
7.0 ~ 8.0 ~8~, multiplet).

46(b) l-~(2~-t-Bueo~y~Arbo~ylbi~he~yl 4-yl)methyll-2-butyl-4-(1-~y~roxyproDyl)~m~zole-5-carbonitrile Following a procedure eimilar to that de~cribed ln Example ~5~b), but uslng 451 mg o~ 1~1(2~t~but carbonylbiphenyl-4-yl)methyll-2-butyl-4-propionyl-- lmldazole-5-carbonitrile lprepared ae described ln step ~a) abovel and 36 mg Of sodium borohydrlde in 10 ml o~
ethanol, 369 mg o~ the tltle compound were obtalned as a vl~cou~ oil.

.

,, :

, 20~ ~07 Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.91 (3H, triplet, J = 7 Hz);
0.99 (3H, triplet, J = 7 HZ);
l.o - ~.3 (6H, multiplet);
1.25 (9H, ~inglet);
2.70 (2H, triplet, J - 7 HZ);
3.16 (lH, doublet, J - 6.5 HZ);
4.74 (lH, quartet, J - 7 Hz);
5.21 (2H, ~inglet);
7.0 - ~.0 (8H, multiplet).
,~
46(c) 1-~(2'-t-Butoxycarbo~ylbiphP~yl-4-yl)mPtbyll-2-butyl-4-(1-~ydroxy~rolpyl)~ m~ ole- 5- carbn~m~de 20 ml o~ a 1 N aqueou~ ~olution of ~odium hydroxide were added to a ~olution of 363 mg of 1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-- propyl)~ m~ AA zole-5-carbonitrile ~prepared a~ described in atep (b) above] di~solved in 20 ml o~ ethanol, and the re~ultlng mixture wac heated under reflux for 6 hour~. At the end of this time, the reaction mlxture was worked up in a stm~lAr manner to that de~cribed in Example 45(c), to a~ord 316 mg o~ the title compound a~
- an amorphou~ ~olid.
;' - Nuclear Magnetlc Re~onAnce 9pectrum (CDCI3) ~ ppm:
0.99 (6H, triplet, J . 7 Hz);
1.0 ~ 2.3 (6H, multiplet);
1.24 (9H, einglet);
- 2.61 (2H, trlplet, J . 7 Hz);
-~ 4.76 (lH, trlplet, J - 7 Hz);
- 5.52 ~ 5.a3 (each lH, A3-quartet, ~ - 17 Hz);
,- 6.9 ~ 7.9 (3H, multiplet).

... .

!~ .' j~, ~, ~'' . ~'' ~ " .
. ,~ ~ .', ~ , 206~ 6Q7 46(d) 2-Butyl-1-~(2~-carboxybiphenyl-4-yl)methyll-4-(l-hydroxypropyl)imidazole-5-carboxamide Following a procedure ~imilar to that described in Example 45(d), but using 316 mg of 1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4-(l-hydroxy-propyl)imidazole-5-carbox~m;~e [prepared as described in step (c) above] and 10 ml of a 4 N solution of hydrogen chloride in dioxane, 148 mg of the hydrochloride of the title compound were obtained as an amorphous powder, melting at above 120~C (with softening).

Nuclear Magnetic Reso~nce Spectrum (hPxA~euterated dimethyl sulfoxide) ~ ppm:
0.80 (3H, triplet, ~ . 7.5 Hz);
0.87 (3H, triplet, J - 7.5 Hz);
1.1 - 2.0 (6H, multiplet);
2.94 (2H, triplet, J . 7.5 Hz);
4.85 (lH, triplet, ~ . 7 Hz);
5.68 (2H, singlet);
7.0 ~ 7.8 (8H, multiplet).

E~XAM~T .~! 47 2-Butyl~ (2'-~rbo~yb~Dhe~yl-4-yl)met~yll-4-(1-~y~ ro~ybUtyl ) im1 ~A 7nle ~ 5-carboxamlde (Cn~ol-n~ No. 5-66) 47(a) ~-~(2~ t-~ueo~ycarbo~ylbiah~yl-4-yl)m~thvll-2-butyl-4-butyryllmi~zole-5-carbonitrile Followlng a procedur~ ~lmllar to that described in Example ~5(a), but u~ing 0.877 g of 2-butyl-~-butyryl-lmidazole-5-carbonltrlle (prepared as described ln Preparation 26), 1.53 g o~ t-butyl ~'-(bromomethyl)-blphenyl-2-carboxylaee and 0.175 g o~ sodlum hydride (as a 55~ w/w di~percion in mineral oil) in 18 ml o~

?

.

.~ . , .
, .
~.,,; ' , 20~16~7 N,N-dimethylacetamide, o.ss g of the title compound was obtained as a viscou~ oil.

Nuclear Magnetic Re~onance Spectrum (CDC~3) ~ ppm:
0.93 (3H, triplet, J = 7 Hz);
1.01 (3H, triplet, J = 7 Hz);
1.28 (9H, singlet);
1.4 - 2.1 (6H, multiplet);
2.74 (2H, triplet, J ~ 7 Hz);
3.00 (2H, triplet, J - 7 Hz);
5.30 (2H, singlet);
7.0 - 8.0 (8H, multiplet).

47(b) 1-~(2'-t-~utoxycarbn~ylbiphenyl-4-yl)methyll-2-bu~yl-4-(1-~ydroxybutyl)~ m~ ~ zole-5-carbonitrile Followlng a procedure similar to that described ln Example 45(b), but uslng 0.99 g of 1-~2'-t-butoxy-carbonylbiphenyl-4-yl)methyl-2-butyl-4-butyrylimidazole-5-carbonitrile ~prepared a~ de~cribed in 9tep (a) abovel and 0.077 g o~ ~odium borohydrlde in 20 ml of ethanol, 0.88 g o~ the tltle compound was obtained as a viscous -oll.

Nuclear Magnetlc Resonance Spectrum ~CDCQ3) ~ ppm:
0.7 - 1.2 ~6H, multiplet);
,~ 1.2 - 2.1 (aH, multlplet);
; 1.23 ~9H, ~lnglet);
~, 2.71 (2H, trlplet, J - 7 Hz);
f~Y 4.28 ~lH, doublet, J . 6 Hz);
~, 4.82 ~lH, qYartet, J ~ 6 Hz);
s 5.28 ~2H, slnglet);
. 7.0 - 8.0 ~8H, multlplet).

. .
~4.
~' ~'" .: ' ' ., ' , ,- -.; .
';''- ' . . ' ~

20~1607 47(c) l-[(2~-t-sutoxycarbonylbiphenyl-4-yl)methyll-2-butyl-4-(1-hydroxybutyl)imidazole-5-carboxamide 14 ml of a 1 N aqueous Qolution of sodium hydroxide were added to a solution of 0.86 g of 1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxybutyl)-imidazole-5-carbonitrile [prepared as described in step (b) above] in 14 ml of ethanol, and the resulting mixture was heated under reflux for 10 hours. At the end of this time, the reaction mixture was worked up in a ~imilar manner to that described in Example 45(c) to afford 0.58 g of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.90 ~3H, triplet, J . 7.5 Hz);
: 0.94 (3H, triplet, J - 7.5 Hz);
1.23 ~9H, einglet);
1.3 - 2.1 (8H, multiplet);
2.63 (2H, triplet, J - 8 Hz);
4.91 (1~, tr~plet, J - 7 Hz);
5.56 ~l5.77 (each lH, A3-quartet, J ~ 16 Hz);
7.0 - 7.8 (8H, multiplet).

~7~d) 2-Bu~yl-1-~(2'-carboxybiphe~yl-4-yl)methyl]-4-~l-hy~o~ybutyl)lmidazole-S-carboYAm~de ,, Pollowing a procedure similar to that described ln - ~xample 45~d~, but using 0.58 g o~ (2'-t-butoxy-carbonylblphonyl-4-yl)methyl]-2-butyl-4-~1-hydroxybutyl)-lm~dAzole-5-carbox~Am~e ~prepared as described in step ~ (c) above] and 13 ml o~ a 4 N solution of hydrogen chloride in dloxane, 0.55 g o the hydrochloride of the tltle ccmpound wae obtained as an amorphous powder, .; meltlng at above 110~C ~with ~o~tening).
.~..
.,~
~;f . j , -,, , , , ,. .i- .
,. . . .

Nuclear Magnetic Resonance spectrum (hexadeuterated dimethyl 9ul foxide) ~ ppm:
0.80 (3H, triplet, J = 7.5 Hz);
0.89 (3H, triplet, J = 7.5 Hz);
1.1 - 1.9 (8H, multiplet);
2.96 (2H, triplet, J = 7.5 Hz);
4.96 (lH, triplet, J = 7.5 Hz);
5.68 (2H, singlet);
7.2 - 7.8 (8H, multiplet).

2-Butyl-1-[(2'-carbo~ybiphe~yl-4-yl)methyll-4-(1-~y~ro~y-2 _~at~ylpropyl ) 1 m~ ~A 701e-5-carbox~mide (Com~ol~n~ No. 5-67) 48(a) 1-~(2'-t-buto~y~rhn~ylbl~h~yl-4-yl)mQ~yll-2-butyl-4-i~obutyryl~n~t~A701e-5-~rhrnttrile -, Followlng a procedure clmilar to that deccribed in Example 45~a), but using 0.85 g of 2-butyl-4-i3Obutyryl-imidazole-5-carbonitrile ~prepared as described in Preparation 27), 1.34 g of t-butyl 4'-~bromomethyl)-biphenyl-2-carboxylate and 170 mg of sodium hydride (a3 a 55~ w/w dispersion in mineral oil) ln 15 ml of -dimethylacetamlde, 1.62 g o~ the title compound were obt~ine~ a~ a ~l~cous oll.

~' Nuclear Magnetlc Reson~nce Spectrum (CDCe3) ~ ppm:
0.93 ~3H, triplet, J ~ 7 Hz);
1.0 - 2.1 ~4H, multiplet);
-1 1.21 ~6H, doublet, J ~ 7 Hz);
1.22 ~9H, ~lnglet)i ~ 2.73 ~2H, trlplet, J ~ 7 Hz);
*1 3.66 ~lH, septet, J . 7 Hz);
~ 5.30 ~2H, singlet);
: 7.0 - 8.0 ~8H, multlplet).
, ".

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

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

2~1607 48(b) l-~(2~-t-sutoxycarbonylbiphenyl-4-yl)methyll-2 butyl-4-(1-hydroxy-2-methylpropyl)imidazole-5-carbonitrile Following a procedure similar to that de~cribed in Example 45(b), but using 500 mg of 1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4-i~obutyryl-imidazole-5-carbonitrile [prepared a~ described in step (a) above] and 25 mg of sodium borohydride in 10 ml of ethanol, 297 mg of the title compound were obtAined as a vi~cous oil.

Nuclear Magnetic Resonance Spectrum (CDCR3) ~ ppm:
0.7 - 1.2 (9H, multiplet).
1.0 - 2.5 (5H, multiplet);
1.27 (9H, ~inglet);
2.70 (2H, doublet, J - 7 ~z);
3.01 (lH, doublet, J - 7 Hz);
.54 (lH, triplet, J ~ 7 Hz);
5.23 (2H, slnglet);
7.0 - 8.0 (8~, multiplet).

48(c) 1-~(2'-t-~uto~ycarb~ylblghP~yl-4-yl)me~yll~2-~; butyl-4-~1-hydoxy-2-methyl~ro~yl)~ m~ ~A zole-5-~ArhnYAm~ ~

- 20 ml o~ a 1 N aqueou~ solution of sodium hydroxide were added to a eolutlon o~ 297 mg o~ 1-[~2'-t-butoxy~
.~ carbonylblphenyl~4-yl)methyl]-2-butyl-4-(1-hydroxy-2-- methylpropyl)imidazole-5-carbonltrlle ~prepared a~
de~cribed ln ~tep (b) above] in 20 ml o~ ethanol, and the re~ul~ing mlxture wa0 heated under re~lux ~or 8 .' hour~. At the end o thi0 tlme, the reactlon mlxture ~. wa~ worked up in a slmllar mAnner to that descrlbed in ; Example 45~c), to a~ord 151 mg o~ the title compound a~
i~ an amorphou0 ~olid.
. , i ,. .
, . .
' ;. . .

I ~> 2 0 20~1607 Nuclear Magnetic Re~onance Spectrum (CDCQ3) ~ ppm:
0.66 (3H, doublet, J = 7 Hz);
0.85 (3H, triplet, J = 7 Hz);
1.01 (3H, doublet, J = 7 Hz);
1.0 - 2.4 (5H, multiplet);
: 1.22 (9H, singlet);
2.59 (2H, triplet, J = 7 Hz);
4.40 (lH, doublet, J = 7 Hz);
5.53 ~ 5.83 (each lH, AB-quartet, J , 17 Hz);
6.9 - 7.9 (8H, multiplet).

48 (d) 2-Butyl~ (2' -carboxybi~heny1-4-yl)methyll-4-(1-h~ydro~y-2-met~ylpropyl)imidazole-5-carboxamide i Followlng a procedure cimilar to that described in Example 45(d), but using 151 mg of 1~(2'-t-butoxy-- carbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2-methylpropyl)-5-carbox~m~Ae ~prepared as descrlbed in ,. step (c) abovel and 5 ml o~ a 4 N eolution o~ hydrogen chloride in dioxane, 119 mg o~ the hydrochloride of the title compound were obtalne~ ac an amorphous powder, meltlng at above 131~C (with so~tenlng).

- Nuclear Magnetic Re~onance Spectrum (h~x~euterated dlmethyl sul~oxlde) ~ ppm:
~- 0.73 (3H, doublet, J . 6.5 Hz);
0.79 ~3H, triplet, J ~ 7.5 Hz);
0.98 (3H, doublet, J ~ 6.5 Hz);
1.6 (4H, multiplet);
1.9 - 2.1 (lH, multlplet);
.,,,! 2.98 (2H, triplet, J - 7.5 Hz);
4.65 (lH, doublet, J . 8 Hz);
5.69 (2H, cinglst);
7.1 ~ 7.8 (8H, multiplet).

,, .

, ;

-, .

.. ; , ....

. ~ 2 o - - 240 - 20616~7 1-~2~-Carboxybiphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2-propylimidazole-5-carboxamide (Compound No . 5 -4) 49~a) 1-~(2'-t-~utoxycarbonylbi~henyl-4-yl)methyll-4-butyryl-2-propylimidazole-5-carbonitrile Following a procedure similar to that described in Example 45~a), but using 1.026 g of 4-butyryl-2-propyl-imidazole-S-carbonitrile (prepared a~ de~cribed in Preparation 28), 1.91 g of t-butyl 4'-(bLo..,~ cthyl)-blphenyl-2-carboxylate and 0.209 g of sodium hydride (as a 55% w/w diepersion ln mineral oil) in 20 ml of ~,~-dimethylacetPm~de, 1.70 g of the title compound were obt~l~ed ac a viscou~ oil.

Nuclear Magnetlc Resonance Spectrum (CDCQ3) ~ ppm:
1.00 (6H, triplet, J ~ 7.5 Hz);
1.25 (9H, singlet);
1.7 - 1.9 (4H, multiplet);
2.70 (2H, triplet, J ~ 7.5 Hz);
2.99 (2H, triplet, J - 7.5 Hz);
5.31 ~2H, 6inglet);
7.1 - 7.9 (8H, multiplet).

49~b~ 1-t(2~-t-Buto~y~rbo~ylbi~h~yl-4-yl)met~yll-4-~l-by~ro~yhutyl)-2-propylimi~Azole-5-~rbonitrile Followlng a procedure slmilar to that descrlbed in Example 45~b), but using 1.13 g o~ (2'-t-butoxy-carbonylblphenyl-4-yl)methyl~-4-butyryl-2-propyl-lmidazole~5-carbonitrlle ~prepared a~ de~crlbed in step (a) above] and 0.091 g o~ sodlum borophydride in 23 ml o~ ethanol, 1.07 g o~ the title compound were obtalned ae A vl~coue oil.

.~
.
;, ., ' - 241 - 2061~07 Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.87 (3H, triplet, J = 7.5 Hz);
o.go (3H, triplet, J = 7.5 Hz);
1.17 (9H, singlet);
1.2 - 1.4 (2H, multiplet);
1.5 - 1.7 (4H, multiplet);
2.67 (2H, triplet, J = 7.5 Hz);
4.5B (lH, multiplet);
- 5.34 (2H, ~inglet);
- 5.41 (lH, doublet, J , 4.5 Hz);
7.1 - 7.7 (BH, multiplet).
,' 49 (C) 1- [(2'-t-3utoxycarbonylblphenyl-4-yl)methyl]-4-(1-bY~ro~Ybutyl)-2-propylim~dazole-S-carbnY~m~de 16 ml o~ a 1 N aqueou~ solution of sodium hydroxide were added to a solution of 1.07 g of 1-~(2'-t-butoxy-- carbonylbiphenyl-4-yl)methyl~-4-(1-hydroxybutyl)-2-propylimidazole-5-carbonitrile [prepared a~ described in step (b) abo~e] in 16 ml of ethanol, and the resulting mlxture wai worked up in a slmilar manner to that ~-~' deccribed in Example 45(c), to a~ford 0.B2 g of the ~- title compound as an amorphous solid.
, ., ; Nuclear Magnetic Re~o~nce Spectrum (CDC~3) ~ ppm:
0.93 (3H, triplet, J . 7.5 Hz);
0.95 (3H, triplet, J - 7.5 Hz);
1.23 ~9H, 6inglet);
1.2 - 2.1 (6H, multiplet);
2.60 (2H, triplet, J . B Hz);
4.89 (lH, triplet, J ~ 7.5 H~);
5.56 & 5.77 (each lH, AB-quartet, J . 16 Hz);
7.0 - 7. a (8H, multiplet).
-"

- :
,,:
~ . ~

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

; ~ 2 0 20616~7 49(d) 1-[(2'-Carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-butyl)-2-propylimidazole-s-carboxAmide Following a procedure similar to that described in Example 45(d), but u~ing a ~olution of 0.82 g of 1-[~2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2-propylim~AA~ole-5-carbox_mide [prepared ae deecribed in step (c) above] in 17 ml of a 4 N
eolution of hydrogen chloride in dioxane, 0.78 g of the hydrochloride of the title compound was obtained as an amorphoue powder, melting at 11~ - 121~C (with softening).

Nuclear Magnetic Reeonance Spectrum (CDCQ3) ~ ppm:
0 90 (3H, trlplet, J . 7.5 Hz);
0.93 (3H, triplet, J ~ 7.5 Hz);
1.1 - l.S (2H, multiplet)i 1.7 - 2.1 (4H, multiplet);
2.9 - 3.1 (2H, multiplet);
5.00 (lH, triplet, J . 7.5 Hz);
5.46 ~ 5.56 (each lH, A3-quartet, J . 15.5 Hz);
7.1 - 7.9 (BH, multiplet).

EXAMP~B 50 ' 2-Butyl-1 [~2~A rboxybiphenyl-4-yl~meth~yll-4~
hydro~y-l-m~t~yleth~yl)~m~dazole-5-carboYAm1de ~ (C~ und No. 5-69) :;
'~ SO(a) 1-~(2'-t-Buto~ycarbo~ylblDhe~yl-4-yl)meth~yll-2-: butyl-4-~1-hydro~y-1-meth~ylet~yl)im~dazole-5-~A rb~Yslm~ ~D

- 10 ml o~ a 1 N aqueoue solution o~ eodium hydroxide - were added to a solution o~ 232 mg o~ (2'-t-butoxy-- carbonylbiphenyl-4-yl)methyl]-2-butyl-4-~1-hydroxy-1-methylethyl)imidazole-5-carbonltrile ~prepared ae ~.

, . , : , , .

20616~7 described in Example lO(a)] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours.
At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 185 mg of the title compound a~ an amorphou~ 901 id.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.~9 (3H, triplet, J , 7 Hz);
1.0 - 2.0 (4H, multiplet);
1.23 (9H, ~inglet);
1.68 (6H, singlet);
2.62 (2H, triplet, J , 7 Hz);
5.63 (2H, singlet);
6.9 - 7.9 (8H, multiplet).

,5 ~Q~) 2-Butyl-1-l(2'-carbo~ybi~h~yl-4-yl)m~t~yl1-4-i (1-~y~ro~y-1-met~yle~yl ) im~ ~A 7nle ~ 5-carbnY~m~de Following a procedure similar to that described in Example 45(d), but uslng 185 mg o~ 1-[(2'-t-butoxy-carbonylbiphenyl-4-yl)methyll-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carbo~m~de [prepared as de~cribed in ~tep (a) above] and 10 ml o~ a 4 N ~olutlon - o~ hydrogen chloride in dioxane, 88 mg o~ the hydrochloride o~ the title compound were obt~ine~ as an amorphou3 ~olld, meltlng at 130 - 138~C ~with so~tening).

Nuclear Magnetic Re~onance Spectrum (h~deuterated dimethyl ~ul~oxide) ~ ppm:
. 0.78 ~3H, triplet, J - 7 Hz);
-~ 1.17 - 1.30 (2H, multiplet);
1.30 ~ 1.42 (2H, multiplet);
1.61 (6H, slngle~);
2.96 ~2H, triplet, J ~ 7.5 Hz);
5.55 (2H, clnglet);
; 7.20 - 7.75 ~8H, multiplet).
.~ ., , ........................................................................ .
, ,' ' ;~ ' ~'' ' 2~16~7 2 - ~utyl -1- ~ ( 2'-carboxybiphenyl-4 yl)methyll-4-[1-hydroxy-2-methyl-1-(l-methylethyl)propyllimidazole-S-carboxamide (Compound No. 5-333) 51(a) 1-1(2'-t-~utoxycarbonylbiphenyl-4-yl)methyll-2-butyl-4-(1-hydroxy-2-methyl-1-(l~methylethyl)-Dropyllimidazole-5-carbonitrile Following a procedure ~imilar to that described in Example 45(a), but using 282 mg of 2-butyl-4-~1-hydroxy-2-methyl-1-(l-methylethyl)propyl~imidazole-5-carbonitrile ~prepared as described in Preparation 30), 409 mg of t-butyl 4'-(b-. - -thyl)biphenyl-2-carboxylate and 47 mg o~ sodium hydride (aq a 55~ w/w dispersion in mineral oil) in 5 ml of ~,N-dimethylacetamide, 513 mg of the tltle compound were obtained as a viscous oil.
r ~
~, Nuclear Magnetic Re~o~nce Spectrum (CDCQ3~ ~ ppm:
t 0.7 ~ 1.1 (15H, multiplet);
~ 1.0 - 2.0 (4H, multiplet);
- 1.21 (9H, ~inglet);
- 2.15 - 2.60 (2~, multiplet);
;f 2.68 (2H, triplet, J - 7 Hz);
3.20 (lH, singlet);
5.26 (2H, einglet);
- 6.9 ~ 8.0 (8H, multiplet).

~ 51(b) 1 l(2~-t-autoxyrarho~ylhi~h~yl-4 yl)methyll-2-i butyl-4-~1-hydro~y-2-me~yl~ 1-moth~ylethyl)-- ~rQ~yll~ m~ fla zole-5- ra rb~YAm~ ~
:, 10 ml o~ a 1 N aqueoue eolution o~ sodium hydroxlde were added to a solutlon o~ 500 mg o~ (2'-t-butoxy-carbonylbiphenyl-~-yl)methyl~-2-butyl-4~ hydroxy-2--. me~hyl-l-~l-methylethyl)propyl~imidazole-5-carbonitrile , ~.
.
~, . . . . .
~ " ~ .
:, . ,.. ~. ,.,.,, . ,,, " ... ..
, ~ .. , ,i; , . ,; . .

i ~ 2 ~

- 245 - 20~607 [prepared as described in step (a) above] in 10 ml of ethanol, and the resulting mixture was heated under reflux for 20 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to give 220 mg of the title compound as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDC~3) ~ ppm:
0.7 - 1.1 (15H, multiplet);
1.0 - 2.1 (4H, multiplet);
1.20 (9H, ~inglet);
2.2 - 2.9 (4H, multiplet);
5.59 (2H, ~inglet);
6.8 - 7.9 (8H, multiplet).

51(c) 2-Butyl-~ 2'-carbo~ybiph~yl-4-yl)methyll-4-~1-hy~ro~y-2-methyl-1-(1-methylethyl)propyllimidazole-5 ~!Arbl'lYAm'l ~ P

Following a procedure similar to that described inExample 45(d), but using 220 mg o~ (2~-t-butoxy-carbonylblphenyl-4-yl)methyll-2-butyl-4-~1-hydroxy-2-methyl-l-(l-methylethyl)propyl~imldazole-5-carboxamide tprepared a~ de~cribed in ~tep (b) above] and 4.5 ml of a 4 N solution o hydrogen chloride in dioxane, 201 mg o~ the hydrochloride o~ the title compound were obtained a~ an amorphous 901 id, melting at 178 - 181~C.

Nuclear Magnetic Resonance Spectrum ~hexadeuterated dimethyl ~ul~oxide) ~ ppm:
0.76 (3H, triplet, J ~ 7.5 Hz);
- 0.~ ~ 0.9 (12H, multiplet);
' 1.1 ~ 1.4 (~H, multiplet);
2.2 ~ 2.4 (2H, multiplet);
2.8 ~ 3.1 (2H, multiplet);
5.51 (2H, singlet);
7.2 ~ 7.3 (8H, multiplet).

. ;~

' ~. 2 0 20~1~07 2-Butyl-1-~(2'-carboxybiphenyl-4-yl)methyll- 4 -hydroxymethylimidazole-5-carboxamide (Compound No. 5-63) , ,.
52(a) Succinimido 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)met~yll-2-butyl-4-hydroxymethylimidazole-5-carbo~ylate 206 mg of N,N-dicyclohexylcarbodiimide were added to ;; . a suspen~ion of 464 mg of 1-[~2'-t-butoxycarbonyl-blphenyl-4-yl)methyl]-2-butyl 4-hydroxymethylimidazole-5-carboxylic acid (prepared as described in Example 4) and 140 mg of ~-hydroxysuccinimide in 10 ml of tetrahydro~uran, and the resulting mixture was stirred at room temperature ~or 16 hours. At the end of this tlme, the material which had precipitated wae filtered o~ and the flltrate was concentrated by evaporation under reduced pressure. The concentrate was purlfied by ; column chromatography through sillca gel, using a 1 : 15 by volume mixture of methanol and methylene chloride as the eluent, to a~ford 0.52 g o~ the title compound as cry~tals, melting at 107 - 109~C.

Nuclear Magnetic Resonance Spectrum (CDC~3) 6 ppm:
0.09 ~3H, triplet, J - 7 Hz);
1.0 - 2.0 ~4H, multiplet);
1.23 ~9H, ~inglet);
2.70 ~2H, triplet, J ~ 7.5 Hz);
; 2.69 ~4H, slnglet);
~ 4.10 ~lH, broad 61nglet);
4.96 ~2H, slnglet);
5.56 ~2H, 61nglet);
7,00 - 7.90 ~H, mul~iplet).

. ~

", . ...
', , ,' ,,:, ; ' , ' , ' ' ' ' ,' . ,':
': ' . ' . ,' .
.:, , , "
.

! 6 ~ O

52(b) 1-~(2'-t-~utoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxamide O.5 ml of concentrated aqueous ammonia was added to a solution of 0.60 g of succinimido 1-[(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethyl-imidazole-5-carboxylate [prepared as described in step (a) above] in 6 ml of tetrahydrofuran, and the title compound etarted to separate immediately. The solvent wa~ removed by distillation under reduced pressure, and the re~ulting residue was ~he~ with diethyl ether and with water, to afford 0.38 g of the title compound as a powder, melting at 222 - 224~C.

Nuclear Magnetic Resonance Spectrum (h~x~Aeuterated dimethyl eulfoxide) ~ ppm:
0.~5 (3H, triplet, J ~ 7 Hz);
1.19 (9H, einglet);
1.0 - 1.9 (4H, multiplet);
2.57 (2H, trlplet, J . 7.5 Hz);
4.52 ~2H, doublet, J . 4.5 Hz);
5.63 (2H, singlet);
5.83 (lH, triplet, J . 4.5 Hz);
6.95 - 7.~ (~H, multiplet).

52~c) 2-Butyl-1-~(2~-carboxybiphenyl-4-yl)methyll ~-~ydro~ymet~ylimi ~A zole-5-rA~b~YAm~de A ~olution of 0.28 g o~ 1-1(2'-t-butoxycarbonyl-biphenyl-4-yl)methyll-2-butyl-4-hydroxymethylimidazole 5-carboxAm~de ~prepared a6 de~cribed in step (b) above]
ln 3 ml of a 4 N ~olution of hydrogen chloride in dioxane wae stirred at room temperature ~or 5 hours and ~hen conc~ntrated by evaporation under reduced pree~ure. The concentrate wae triturated with a mixture of ethyl acetate and diethyl ether, and the ~olldlfied material was collected by ~iltration, to afford 0.26 g .

.
. , .

of the hydrochloride of the title compound, which softened at above 150~C and completely decomposed at 235~C.

Nuclear Magnetic Resonance Spectrum (h~x~deuterated dimethyl sulfoxide) ~ ppm:
0.80 (3H, triplet, J = 7.5 Hz);
1.20 - 1.31 (2H, multiplet);
1.43 - 1.54 (2H, multiplet);
2.96 (3H, triplet, J ~ 7.5 Hz);
4.68 ~2H, singlet);
5.71 (2H, singlet);
7.21 - 7.75 (8H, multiplet).

~X'~PT.1;! 53 N-Met~y1-2-butyl~ 2'-rArboxybi~hP~yl-4-yl)methyll-4-~ydroxymeth~ylim~ le-5- r~ rh~YAm~de No. 5-71) 53(a) N-mQtbyl-1-~(2'-t-buto~yrArb~ylhi~hP~yl-4-yl)-methyll-2-butYl-4-}~ydro ~ ~tl~ m~ ole-5-rA rhnY:~m~ AD

0.4 ml Or a 40~ by volume ~olution of methylamine in water wac added at room temperature to a solution o~
0.27a g o~ euccl~mt~o 1 [~2~-t butoxycarbonylblphen 4-yl)methyl]-2-butyl-4-hydroxymethyllmidazole-5-carboxylate ~prepared as deecribed ln ~xample 52(a)] ln a mlxture o 3 ml o~ methylene chlorlde and 2 ml o~
methanol, and the re~ulting mixture wac allowed to stand ~or 16 hour~ at room temperature. At the end o~ thie ~lme, the colution wac concentrated by evaporation under ~educed prec~ure, and the concentrate was dls~olved in e~hyl acetate. The re~ulting solutlon wae wa~hed wlth an aqueous solutlon of potaoelum blsul~ate and with an aqueou~ ~olutlon o~ ~odlum hydrogencarbonate, in that I .,, . . ", ~, , " . , , ~ , .

- 249 - 20~1 6~ 7 order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting re~idue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 176 mg of the title compound as a gla~s.

Nuclear Magnetic Resonance Spectrum (CDCR3) ~ ppm:
0.~5 (3H, triplet, ~ ~ 7 Hz);
1.23 (9H, singlet);
1.0 - 2.0 ~4H, multiplet);
2.54 (2H, triplet, J , 7.5 Hz);
2.91 (3H, doublet, J ~ S HzJ;
4.70 (2H, singlet);
5.62 (2H, singlet);
6.9 - 7.85 (8H, multiplet);
8.38 (lH, quartet, J . 5 Hz).

S3(b) N Me~hyl-2-butyl-1-~(2'-rArbo~ybiph~yl-4-yl)-met~yll-4-hydro~ymet~ylim~ ~A zole-S-carb~Y~m~de A solutlon of ~-methyl-1-~(2'-t-butoxycarbonyl-blphenyl-4-yl)methyl~-2-butyl-4-hydroxymethyllmldazole-5-carboxAm~e ~prepared as descrlbed ln 3tep (a) above]
in 2 ml o~ a 4 N solutlon o~ hydrogen chloride in dloxane wae allowed to ~tand at room temperature for 16 hours and then concentrated by evaporatlon under reduced pres~ure. The resulting cry~talline resldue was washed wlth a mixture o~ ethyl acetate and dlethyl ether, to afford 0.15 g o the hydrochloride of the title compound, meltlng at 205 - 203~C ~with decomposltion).
.
~f Nuclear Magnetlc Re~onance Spectrum ~hPxAAeuterated - dlmethyl ~ulfoxlde) 6 ppm:
0.81 ~3H, triplet, J ~ 7.5 Hz);
1.25 ~2H, sextet, J ~ 7.5 Hz);
1.49 ~2H, qulntet, J . 7.5 Hz);

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

.
,:, - 250 - 20~1~07 2.75 (3H, doublet, J = 4.5 Hz~;
2.96 (2H, triplet, J = 8 Hz);
5.64 (2H, ~inglet);
7.21 - 7.75 (8H, multiplet);
8.91 (lH, quartet, J = 4.5 Hz).

N-Ethoxycarb~ylmethyl- 2 -butyl-1-~(2~-carboxybi~henyl-4-yl)met~yll-4-hydroxymethyl~ m~ dazole-5-caxboxamide (C~ound No. 5-126) Followlng a procedure similar to that described in Example 53, but using 0.307 g of ~uccinimido 1-[(2~-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxy-methylimidazole-5-carboxylate [prepared as descrlbed in Example 52(a)~, 89 mg of ethyl glycinate hydrochloride and 0.089 ml o~ triethylamine, 0.202 g of the hydrochloride of the title compound was obt~ine~ a~ an amorphous powder, mel~ing at above 80~C ~wlth 30ftenlng).

Nuclear Magnetlc Recon~nce Spectrum (h~xA~euterated - -dlmethyl sulfoxide) ~ ppm:
0.80 ~3H, trlplet, J . 7.5 Hz);
~ 1.18 (3H, trlplet, J - 7 Hz);
1.20 - 1.33 (2H, multiplet);
1.47 ~2H, quintet, J - 7.5 Hz);
. 2.94 (2H, triplet, J - 8 Hz);
4.05 ~2H, doublet, J - 6 Hz);
4.12 (2H, quartet, J - 7 Hz);
.72 ~2H, 61nglet);
5.63 ~2H, 81nglet);
7.24 - 7.75 ~8H, multiplet);

- 9.37 ~lH, triplet, J . 6 Hz).

.
,, f ' ' '' : , ' ' ,' ~ ' '' ' ' , "' ' , ' , ' ~ ';, ~' ':

I ~ 2 0 - 251 - 2061~07 N- CarbQxymethyl - 2 -butyl-1-[(2~-carboxybiphenyl-4-yl)-methyll-4-hydroxymethylimidazole-5-carboxamide (Compound No . 5 - 12 5 ) Following a procedure similar to that de~cribed in Example 53, but using 0.32 g of ~uccinimido 1-[(2~ -t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxy-methylim~zole-5-carboxylate [prepared as described in Example 52(a)], 0.11 g of t-butyl glycinate hydrochloride and 80 mg of 4-dimethylaminopyridine, 0.21 g of the hydrochloride of the title compound was obtA~ned a~ an amorphous powder, melting at above 110~C
(with ~oftening).

Nuclear Magnetic Resonance Spectrum (hexadeuterated dlmethyl sul~oxide) ~ ppm:
0.01 (3H, triplet, J . 7.5 Hz);
1.25 ~2H, sextet, J . 7.5 Hz);
1.43 (2H, qulntet, J - 7.5 Hz);
2.95 (2H, triplet, J ~ 8 Hz);
3.98 (2H, doublet, J . 6 ~z);
4.71 (2H, singlet);
5.64 ~2H, slnglet);
7.26 - 7.7S ~8H, multiplet);
9.22 ~lH, triplet, J ~ 6 Hz).
: ~, -EthoxY~Arbo~ylet~yll-2-butyl~ (2'-carbo~y-bl~h~yl-4-yl)meth~yll-4-h~ro~ym~t~ylimi~zole-5-rArh~YAm~ und No. 5-128~
',,~' Following a procedure ~imilar to that de3cribed in ~xample 53, but uslng 0.39 g o~ succinimldo 1-~2'-t-butoxycarbonylblphenyl-4-yl)methyl]-2-butyl-4-hydroxy-~ , .

, . , , ' ' ;
. . .

methylimidazole-s-carboxylate [prepared as descr ~Q~ ~ 0 7 Example 52(a)], 0.13 g of ethyl (S)-alanate hydrochloride and 0.21 ml of triethylamine, 0.27 g of the hydrochloride of the title compound waR obtained as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl ~ulfoxide) ~ ppm:
0.82 (3H, triplet, J - 7.5 Hz);
1.17 (3H, triplet, J - 7 Hz);
1.20 - 1.35 (2H, multiplet);
1.34 (3H, doublet, J - 7 Hz);
1.43 - 1.58 ~2H, multiplet);
2.98 (2H, triplet, J ~ 7.5 Hz);
4.10 (2H, quartet, J - 7 Hz);
; 4.44 (lH, quintet, J ~ 7 Hz);
~- 4.70 ~2H, einglet);
5.63 (2H, AB-quartet, ~ - 0.10 ppm, J ~ 16 Hz);
7.24 - 7.76 (8H, multiplet);
9.39 (lH, doublet, J . 7.5 Hz).
,, , ~zXl~MpT.~ s7 ~- N-(2-EthnYy~Arb~ylet~yl)-2-butyl-l-~(2~-r~rb bi~h~yl-4-yl)met~yll-4-~ydro~meth~yl~ m~ ~ zole-S rArb~Y~m~de (C~m~o~n~ No. 5-130) ., Following a procedure similar to that described in Example 53, but ucing 30S mg o~ euccinimido 1-[(2'-t-- butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxy-methyllmidazole-5-carboxylate lpreparet ae described in - Example 52(a)~, 96 mg o~ ethyl ~-alanate hydrochloride and 0.088 ml o~ triethylamine, 0.20 g o~ the hydrochlorlde o~ the title compound wae obtained ae an .~ ~morphous solld.

;, . -'-. .... . .
,...
~y,! i . . . ' .,~ . . .
,. . . ~ . . .
:
, .

~" - 253 - 2 0~1 60 7 Nuclear Magnetic Re~onance Spectrum (hexadeuterated dimethyl ~ulfoxide) ~ ppm:
0.82 (3H, triplet, J = 7.5 Hz);
1.16 (3H, triplet, J = 7 Hz);
1.20 - 1.38 (2H, multiplet);
1.42 - 1.58 (2H, multiplet);
2.97 (2H, triplet, J = 7.5 Hz);
3.3 - 3.6 (4H, multiplet);
4.04 (2H, quartet, J ~ 7 Hz);
4 60 (2H, singlet);
5.63 (2H, singlet);
7.21 - 7.76 (8H, multiplet);
9.01 (lH, broad triplet).

R.~I~PT.P! 5~

Me~yl (S)-N-~2-butyl-1-~(2'-rArboxybl~hP~yl-4-yl)met}~yll -4-~,ydro~;ymethyllm~1Azole-5-~rhn~l~ -prol~ n A te (Compo-- n~ No. 5-335) Following a procedure ~imllar to that described in ~xample 53, but u~ing 529 mg o~ succ~m~o 1-i~2'-t-butoxycarbonylbiphenyl-4-yl)methyl~-2-bu~yl-4-hydroxy-methylimldazole-5-carboxylate lprepared a~ de~cribed in Example 52~a)~, 180 mg o~ methyl ~)-prolinate hydrochloride and 0.2 ml o~ triethylamine, 0.39 g o~ the hydrochloride o~ the title compound wa~ obtAlne~ as an amorphouY powder, melting at above 120~C (with eo~tenlng).

- Nuclear Magnetic Reeon~nce Spectrum ~hPYA~euterated dime~hyl ~ul~oxlde) ~ ppm:
0.8~ (3~, triplet, J . 7.5 Hz);
1.34 ~2H, sextet, J ~ 7.5 Hz);
1.4 ~ 2.25 ~6H, multlplet);
7 2.9 ~ 3.7 ~2H, multlplet);
3.64 (3H, einglet);

:
; ,~
~.~, , I
... . .

.
, . .

20616~7 4.34 (lH, triplet, J = 7.5 Hz);
4.55 (2H, singlet);
5.25 ~ 5.56 (each lH, AB-quartet, J = 15.5 Hz);
7.26 - 7.77 (8H, multiplet).

2-Butyl-1-[(2'-carboxybi~henyl- 4-yl) methyll -4-(l-hy~roxy-2.2-dimethyl~roDyl)imidazole-5-carboxamide (C~ -n~ No. 5-6a) s9(a) Met~yl 1-~(2'-t-butoxycarbonylbi~h~yl-4-yl)-met~ 2-butyl-4-forT~ m~ ole-5-carbo~cylate 5.07 ml of triethyl~m~ne and 6.0 g of ~ulfur trioxide/pyridine complex were added, ln turn, at a temperature of 10~C to 15~C to a solutlon of 3.0 g of methyl 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl~4-hydroxymethyllmldazole-4-carboxylate [prepared a~ descrlbed ln ~xample l(b)~ ln 1~ ml o~ dlmethyl sul~oxide, and the reculting mixture was ctirred at the same temperature ~or 45 minutee. At the end of thl~
tlme, the reactlon mlxture wa~ mlxed wlth water and extracted wlth ethyl acetate. The extract was washed with water and with an aqueou~ solutlon o sodlum hydrogencarbonate, ln that order, after whlch lt was dried over anhydrou~ magnecium Yul ate, and the solvent wae removed by distillatlon under reduced pres~ure. The resulting recldue wa~ puri~led by column chromatography ~hrough clllca gel, u~lng a 1 : 1 by volume mixture of hexAne and ethyl acetate a~ the eluent, to a~ord 2.88 g o~ the title compound a~ an amorphous solld.
"
Nuclear Magnetic Re~onance Spectrum ~CDC~3) ~ ppm:
~ 0.90 ~3H, ~riplet, ~ ~ 7 Hz);
'~ 1.25 ~9H, ~inglet);
2.1 ~4H, multiplet);

, ~ , , ~, , :, ,, '~ ' ,', '~',, ' ~,''''' , ' ' . , , .~ , , ' ~ 2 0 - 255 - 2~616~7 2.77 (2H, triplet, J = 8 Hz);
3.91 ~3H, singlet);
5.65 (2H, ~inglet);
6.9 - 7.9 (8H, multiplet);

10.48 (lH, singlet).

59lb) Methyl 1-~(2/-t-butoxycarbonylbiphenyl-4-yl)-methYl1-2-butyl-4-(1-hydroxy-2.2-dimethylpropyl)-imidazole-5-carboxylate 2.77 ml of a 2 M solution of t-butylmagnesium bromide in tetrahydrofuran were added at -55~C and under an atmo~phere of nitrogen to a solution of 1.32 g of methyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-~ormyl~ m~ d~zole-5-carboxylate [prepared as descrlbed in step (a) above] in 26 ml of tetrahydroruran, and the resulting mixture was stirred at a temperature of -55~C to -50~C for 30 minutes. At ; the end o~ this time, the reactlon mixture was diluted with 50 ml o ethyl acetate and wlth a saturated aqueous ~olutlon of ammonium chlorlde. The organlc layer was separated and dried over anhydrous magnesium sulfate and the solvent wae removed by distillation under reduced pressure. The re~idue was purified by column chxomatography through silica gel, u~lng a 2 : 1 by volume mixture o~ he~ne and ethyl acetate as the - eluent, to a~ ord 0.87 g o~ the title compound as an -~ amorphous eolid.

Nuclear Magnetic Reso~nce Spectrum ~CDC~3) ~ ppm:
- 0.90 ~3H, triplet, J . 7.5 Hz);
0.93 ~9H, oinglet);
1.0 ~ 2.0 (4H, multiplet);
~; 1.19 (9H, cinglet);
- 2.68 (2H, triplet, J ~ 7.5 Hz);
;' 3.41 (lH, doublet, J . 10 Hz);
3.74 (3H, singlet);
' :

. ~ , . . .
. . .

,. . . . .
"

- 256 - 20~1~07 4.92 (lH, doublet, J = 10 Hz);
5 . 59 (2H, singlet);
6.9 - 7.9 (8H, multiplet).
i 59 (c) 1- r (2' -t-Butoxycarbonylbiphenyl-4-yl)methyll -2-butyl-4-(1-hydroxy-2.2-dimethyl~ropyl)imidazole-5-carboxylic acid Following a procedure similar to that described in Example 4, 0.87 g of methyl 1-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyll-2-butyl-4-(1-hydroxy-2,2-dimethyl-propyl)imidazole-5-carboxylate [prepared as described in step (b) above] was hydrolyzed, using 342 mg of lithium hydroxide monohydrate, to afford 0.73 g of the title compound ae crystals, melting at 199 - 201~C (with decompoeltion).

Nuclear Magnetic Resonance Spectrum (hPxA~euterated dimethyl sul$oxide) ~ ppm:
0.84 (3H, triplet, J . 7.5 Hz);
0.89 ~9H, singlet);
1.16 ~9H, ~inglet);
- 1.22 - 1.4 (2H, multiplet);
1.58 ~2H, quintet, J ~ 7.5 Hz);
2.64 ~2H, triplet, J ~ 7.5 Hz);
4.7a (lH, singlet);
5.68 ~2H, AB-quartet, ~ ~ 0.1~ ppm, J . 17 Hz);
7.02 ~2H, doublet, J . 8 Hz);
7.22 - 7.58 (5H, multiplet);
7.65 (lH, doublet, J . 7.5 Hz).

~Ql~L Succlnimldc l-l(2'-t-buto~y~Arbonylbi~hP~yl-4-yl~-~i m~yll-2-butyl-4-(1-~ydroxy-2 2-dlmet~ylpro~yl)-'7A zole~ - 5 ~ ~:arbo~ylA te Following a procedure simllar ~o that de~cribed in ~xample 52(a), but uslng 600 mg o~ 1-[(2'-t-butoxy-- .

, . ~ , , -,; :

- 257 - 2061~Q7 carbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)imidazole-5-carboxylic acid [prepared as described in step (c) above], 172 mg of N-hydroxy-succinimide and 250 mg of N,N-dicyclohexylcarbodiimide, 663 mg of the title compound were obtained as an amorphous solid.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.92 (3H, triplet, J - 7.5 Hz);
1.01 (9H, singlet);
1.21 (9H, singlet);
1.38 (2H, sextet, J - 7.5 Hz);
1.73 (2H, quintet, J - 7.5 Hz);
2.71 (2H, triplet, J . 7.5 Hz);
2.84 (4H, singlet);
4.99 (lH, doublet, J , 7.5 Hz);
5.53 (2~, singlet);
7.03 (2H, doublet, J . 8.5 Hz);
~ 7.26 - 7.50 (5H, multiplet);
7.77 (lH, doublet, J - 8 Hz).

~9(e) 1-l~2'-t-Buto~ycarbo~ylblphenyl-~-yl)methyll-2-~ butyl-4-~ ydro~y-2 2-~mPt~ylDropyl)~m~dazole-~f 5-~A rbnY~mi de Followlng a procedure similar to that described in Example 52(b), but using 0.66 g of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy~
2,2-dimethylpropyl)imidazole-S-carboxylate ~prepared as - de6cribed in ~tep ~d) abovel, 0.33 g of the title compound wa~ obtained a~ an amorphous solid.

Nuclear Magnetic Re~onance Spectrum (CDC~3) ~ ppm:
0.~9 (3H, triplet, J . 7.5 Hz);
0.96 (9H, singlet);
1.22 (9H, ~inglet);
; 1.34 (2H, ~extet, J ~ 7.5 Hz);
''' .

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

2~61607 1.64 (2H, quintet, J = 7.5 Hz);
2.62 (2H, triplet, J = 7.5 Hz);
4.67 (lH, doublet, J = 5.5 Hz);
5.48 & 5.~2 (each lH, AB-quartet, J = 16 Hz);
7.02 (2H, doublet, J = ~.5 Hz);
7.23 - 7.50 (5H, multiplet);
7.76 (lH, doublet, J = 6.5 Hz).

59(f) 2-~utyl-1-~(2'-carboxyb~henyl-4-yl)methyll-4-(1-hydro~y-2,2-dimethylpro~yl)imidazole-5-carb~m~de Following a procedure similar to that described in Example 52~c), but using 326 mg of 1-~(2'-t-butoxy-carbonylblphenyl-4-yl)methyl~-2-butyl-4-(1-hydroYy-2,2--' dimethylpropyl)imldazole-S-carhox~m~e [prepared as descrlbed in step ~e) above], 228 mg o~ the - hydrochlorlde of the tltle compound were obt~lned as a powdery eolld, melting at 150 - 154~C (with softenlng).

Nuclear Magnetic ReYonance Spectrum (h~Y~deuterated dlmethyl ~ul~oxide) ~ ppm:
O.B0 (3H, triplet, J - 7.5 Hz);
0.91 (9H, elnglet);
1.24 (2H, sextet, J - 7.5 Hz);
1 1.~5 (2H, quintet, J ~ 7.5 Hz);
2.99 (2H, triplet, J . 7.5 Hz);
4.7B ~lH, einglet);
5.69 (2H, einglet);
7.21 (2H, doublet, ~ ~ 8 Hz);
7.33 - 7.61 (5H, multlplet);
7.75 (lH, doublet, J ~ 8 Hz).

~.~

f ., ' ' ' .
' ',': , ' . ~ 2 0 - - 259 - 2~61~Q7 1-[(2~-Carboxybiphenyl-4-yl)methyll-4-(1-hydroxy-2, 2 - dimethylpropyl)- 2 - propylimidazole-5-carboxamide (Compound No. 5-6) ~Q~L Diet~yl 1-~(2~-t-butoxycarbonylbi~henyl-4-yl) met~yll-2-~ro~ylimidazole-4.5-dicarboxylate Following a procedure similar to that described in Example l(a), but using 9.0 g of diethyl 2-propyl-imldazole-4,5-dicarboxylate (prepared as de~cribed in Preparation 12), 12.3 g of t-butyl 4'-bromomethyl-~ biphenyl-2-carboxylate and 4.1 g of potassium t-butoxide ; as a base, 16.47 g of the title compound were obtained as a viscous oil.

Nuclear Magnetic Resonallce Spectrum (CDCQ3) a ppm:
i 0.95 (3~, trlplet, J - 7.5 ~z);
' 1.5 - 2.0 (2H, multlplet);
1.23 ~9H, singlet);
'~ 1.25 (3H, trlplet, J . 7 Hz);
1.37 ~3H, triplet, J . 7 Hz);
2.69 (2~, triplet, J . 7 Hz);
4.26 (2H, quartet, J ~ 7 Hz);
l 4.3a (2H, quartet, J - 7 Hz);
! t 5.4~ (2H, singlet);
7.0 - 7.9 ~8H, multiplet).
, 60(b~ ~t~yl 1 ~(2'-t-buto~ycarbn~ylbl~h~yl-4-yl)met~yll-4-~ydro~ t~yl-2-pro~yllml~lA~ole-5-carho~,yl~te Followlng a procedure ~lmilar ~o that de3cribed ln ~xample l(b), 16.47 g o~ diethyl 1-~(2'-t-butoxy-carbonylbiphenyl-4-yl)methyll-2-propylimldazole-4,5-dlcarboxylate lprepared ac de~crlbed ln ~ep (a) above]
--~ were reduced, uslng 44.4 ml of a 1.5 M solutlon of .
,. . . .
,~ , .. ..

. , .
, , , ~ ., ~' - 260 - 20~1~07 diisobutylall-m;nllm hydride in tetrahydrofuran, to afford 10.83 g of the title compound as crystals, melting at 108 - 110~C.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.98 (3H, triplet, J = 7.5 Hz);
1.23 (9H, singlet);
1.31 (3H, triplet, J , 7 Hz);
1.79 (2H, sextet, J - 7.5 Hz);
2.67 (2H, triplet, J ~ 7.5 Hz);
4.27 (2H, guartet, J ~ 7 Hz);
4.87 (2H, singlet);
5.59 (2H, ~inglet);
7.00 ~2H, doublet, J . 8.5 Hz);
7.24 - 7.75 (5H, multiplet);
7.7~ ~lH, doublet, J ~ 7 Hz).

60(c) ~t4yl 1-~(2'-t-buto~ycarbo~ylbl~h~yl-4-yl)meth~yll-.~ 4-for~yl-2-~ropyl~ m~ ~ zole-S-carboxyl~te .~ , -. Following a procedure similar to that described in Example 59~a), 2.71 g of ethyl 1-~2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-4-hydroxymethyl-1-propylimidazole-5-carboxylate [prepared a~ described in step ~b) above]
were oxidized with 4.6 ml of triethylamine and 5.5 g of sulfur trioxide/pyridine complex in 17 ml of dimethyl ~- ~ul oxide, to afford 2.57 g of the title compound as ': cry~tals, melting at 117 - 119~C.

- Nuclear Magnetic Re~onance Spectrum (CDC~3) 6 ppm:
. 0.99 ~3H, triplet, J ~ 7.5 Hz);
~,. j 1.26 ~9H, singlet);
1.39 ~3H, triplet, J . 7 Hz);
1.94 ~2H, sextet, J ~ 7.5 Hz);
2.73 ~2H, trlplet, J . 7.5 Hz);
4.40 ~2H, quartet, J ~ 7 Hz);
5.67 ~2H, singlet);

.

.. !

. .
.

7.02 (2H, doublet, J = 8.5 Hz);
7.29 - 7.s4 (5H, multiplet);
7.80 (lH, doublet, J = 8 Hz);
10.48 (lH, singlet).

60(d) Ethyl 1-~(2l-t-butoxycarbonylbiphenyl-4-yl)methyll-; 4-(1-hydroxy-2.2-dimethylpro~yl)-2-~ro~ylimidazole-5-carboxylate Following a procedure similar to that described in Example 59(b), 1.14 g of ethyl 1-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-4-formyl-2-propylimidazole-5-carboxylate [prepared as described in step (c) above]
was reacted with 2.4 ml of a 2 M solution of t-butyl-magnesium bromide in tetrahydrofuran, to afford 0. 78 g of the title compound as a viscous oil.
.:
Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.97 (3H, triplet, J . 7.5 Hz);
1.00 (9H, singlet);
1.25 ~9H, singlet);
1.35 (3R, triplet, J . 7 Hz);
1.77 ~2H, ~extet, J . 7.5 ~z);
2.68 (2H, triplet, J - 7.5 Hz);
3.46 ~lH, doublet, J . 9 Hz);
4.29 ~2H, quartet, J . 7 Hz);
- 4.99 (lH, doublet, J . 9 Rz);
-~j 5.62 ~2H, einglet);
7.00 ~2H, doublet, ~ . 8 Hz);
7.29 - 7.54 ~5H, multiple~);
7.80 ~lR, doublet, J . 7.5 Hz).

60~q) 1-~(2'-t Buto~ycarbo~ylbiphenyl-4-yl)meth~yll-4-hy~ro~y-2.2-dlmethyl~ro~yl)~2-Dro~ylimldazole-5 . r~ rbo~yllc acid Following a procedure similar to that de~cribed in :- ., ;, .
.
- ' , ,' , ' ' '~,, .,' '~ .
~ , ~ ~ . , ' . ' '' ' ,' ~ ' ' 20~1~07 Example 4, 0.78 g of ethyl 1-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]-4-(1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxylate [prepared as described in step (d) above] wa~ hydrolyzed, using 209 mg of lithium hydroxide monohydrate, to afford o.62 g of the title compound as crystals, melting at 207~C.

: Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.8~ (3H, triplet, J ~ 7.5 Hz);
0.89 (9H, singlet);
q 1.15 (9H, ~inglet);
1.63 (2H, sextet, J . 7.5 Hz);
2.63 (2H, triplet, J ~ 7.5 Hz);
4.79 (lH, ~inglet);
5.63 & 5.76 (each lH, AB-quartet, J ~ 18.5 Hz);
7.02 (2H, doublet, J ~ 8 Hz);
7.22 - 7.67 ~6H, multiplet).
~, ~Ql~L Succ~n~m~ (2'-t-3uto~y~rb~ylblDh~yl-4-yl)m~t~yl~-4-~1-hydroxy-2.2~d~mat~yl~ro~yl)-2-~rQ~yl~ m~ ~ zole-S-carbo~ylate Pollowlng a procedure ~imilar to that described in Exam~le 52~a), but using 300 mg of 1-l(2~-t-butoxy-carbonylbiphenyl-4-yl)methyl]-4-~1-hydroxy-2,2-dime t hyl-- propyl)-2-propyl~mid~zole-5-carboxylic acid [prepared as de~cribed in etep ~e) above], 110 mg of N-hydroxy-~ucclnim~de and 130 mg of ~,~-dicyclohexylcarbodiimide, 321 mg o~ the title compound were obtained as an amorphous ~olid.

~~ Nuclear Magnetic Resonance Spectrum ~CDCQ3) ~ ppm:
0.94 ~3H, triplet, J - 7.5 Hz);
0.98 ~9H, singlet);
1.18 ~9H, ~inglet);
1.75 ~2H, aex~et, J ~ 7.5 Hz);

. , .
;, , 2.64 (2H, triplet, J = 7.5 Hz);
3.12 (lH, doublet, J = 9.5 Hz);
4.98 (lH, doublet, J = 9.5 Hz);
5.52 (2H, singlet);
7.0 - 7.9 (8H, multiplet).

60 (g) 1- ~(2'-t-Butoxycarbonylbi~henyl-4-yl)methyll-4-(1-hydroxy-2.2-dimethyl~ro~yl)-2-propylimidazole-5-carboxamide Following a procedure similar to that described in Example 52(b), but u~ing 0.13 g of ~uccinimido 1-~(2~-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-~1-hydroxy-2,2-dimethylpropyl)-2-propylimidazole-5-carboxylate [prepared as de~cribed in step (f) abo~e], 0.12 g o~ the - title compound was obtained ae a glaee.

Nuclear Magnetic Resonance Spectrum ~CDC~3) ~ ppm:
0.88 ~3H, triplet, J - 7.5 ~z);
0.90 ~9H, singlet);
1.24 ~9H, einglet);
~2 1.60 (2H, aextet, J . 7.5 Hz);
2.58 (2H, triplet, J . 7.5 Hz);
- 4.65 (lH, doublet, J - 6 Hz);
~ 5.53 & 5.07 (each 1~, AB-quartet, ~ . 16 Hz);
- 7.02 (2H, doublet, J . 8 Hz);
7.23 - 7.4~ (SH, multiplet);
7.78 (1~, doublet, J - 6.5 Hz).

~quhL 1-~(2~ rArbo~ybl~he~yl 4-yl)methyll-4-~ y~roxy-2.2-dlmQt~ylDro~yl)-2-pro~yl~ m~ ~ zole - 5 - rA rbnY~ m ~ de Followlng a procedure elmilar to that descrlbed in - ~xampl0 52~c), but uelng 139 mg o~ 2'-t-butoxy-carbonylbiphenyl-~-yl)methyl]-4-~1-hydroxy-2,2-dimethyl-propyl)-2 propylimidazole-5-carboxamide ~prepared a~
- de~cribed in step (g) abovel, 96 mg of the hydrochloride ' .. . .
: . ,, , :.
''' '' , , ".:

; ; . , ,, :
':, ~ ' ,, , : ' ' ., . C 2 0 - 264 - 2061~07 of the title compound were obtained as a powder, melting at above 160~C (with softening).

Nuclear Magnetic Re~onance Spectrum (hPx~euterated dimethyl sulfoxide) ~ ppm:
0,~2 (3H, triplet, J = 7.5 Hz);
0.90 (9H, singlet);
1.53 (2H, sextet, J = 7.5 Hz);
2.97 (2H, triplet, J . 7.5 Hz);
4.79 (lH, singlet);
5.69 (2H, singlet);
- 7.19 - 7.75 (~H, multiplet).
.
~X ~MpT . ~! 61 (5-Met~yl-2-oxo-1.3-dioxolPn-4-yl)methyl 4~ ydroxy-l-met~ylet~yl)-2-proDyl~ 4-~2-(tetrazol-5-yl)~hPr~yll~hpr~yl~met~ylim~lAzole~5~r~rboxylate (ComDo~n~ No. 2-17) 61~a) (5-Met~yl~2-oxo-1.3-~ioxol~n~4~yl~ m~t~yl 4- (1-4ydro~y-1-meth~yleth~yl)-2-~roDyl-1-~4-~2-(trityl--~ tetrA7nl-5-yl)phP~ll~har~yl~n~th~lim~Azole-5 r;-rhrl~yl;~ te - A euepencion o~ 0.97 g of potasslum carbonate ln100 ml o~ -dimethylacetamtde wae warmed at 60~C, and then a solutlon o~ 1.14 g o~ (5-me~hyl-2-oxo-1,3-; dloxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propylimldazole-5-carboxylate ~prepared ae deecribed in Preparation 31) and 2.35 g o~ 4-~2-~trltyltetrazol-5-yl)phenyl]benzyl bromlde ln 50 ml o~ -dlmethyl acetamide wa~ added dropwlce to the warm suspeneion, whll~t etirring. The reaction mixture wae etlrred at 60~C ~or 3.5 houre, and it wae then diluted with ethyl -~. acetate. The ethyl acetate layer wae eeparated, washed . wlth water and dried over anhydroue magneeium eul~ate, ... .
,~, - i ; ' ., ~,, , , .,.. , - . ......... . ., ~ - 265 - 2~1607 and then the solvent wa~ removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.4 g of the title compound as an amorphou~ solid. Thi~ product was crystallized from diisopropyl ether, to give pure title compound, melting at 98 - 99~C (with decomposition).

Nuclear Magnetic Resonance Spectrum (CDCe3), ~ ppm:
0.89 (3H, triplet, J - 7.5 Hz);
1.62 (6H, ~inglet);
1.6 - 1.75 (2H, multiplet);
1.97 (3H, singlet);
2.54 (2H, triplet, J - 8 Hz);
4.70 (2H, einglet);
5.30 ~2H, ~inglet);
5.61 (lH, ~lnglet);
6.68 (2H, doublet, J ~ 7.5 Hz);
- 6.90 - 7.52 (20H, multiplet);
7.87 (lH, doublet, ~ . 7.5 Hz).

-' 61(b) (5-Met~yl-2-oxo-1.3-~oxol~n-4-yl)methyl 4-(1-~y~ro~y. l-methylet4yl)-2-prQ~yl-1-(4-~2-- (tetrA~ol-5-yl)phe4yllphe~yl~methyli m~ ~ zole-5-r~ r~nYyl ~te , A mlxture o~ 1.4 g of (S-methyl-2-oxo-1,3-dioxolen-~-yl)meth~l 4-(1-hydroxy-1-methylethyl)-2-propyl-1-(4-~2~(trityltetrazol-5-yl)phenyl~phenyl)me~hyllmldazole-5-carboxylate ~prepared as described ln ~tep (a) above]
and 48 ml o~ 75~ v/v aqueou~ acetic acid was stirred at 60~C ~or 1 hour, a~ter which lt was concentrated by evaporatlon under reduced pre~ure. The reeldue wa~
di~olved ln toluene, and the resulting 601utlon was concentrated by dlstlllatlon under reduced pres~ure;
thi~ wa~ repeated a ~urther time in order to remo~e the ~, .
.

- 266 - 2~ 7 remaining water and acetic acid. The residue thus obtained wa~ purified by column chromatography through silica gel using 1 : 9 and 1 : 4 by volume mixtures of methanol and methylene chloride as the eluent, to give 0.73 g of the title compound, melting at 170 - 172~C.

Nuclear Magnetic Resonance Spec~rum (CDCQ3), ~ ppm:
0,93 (3H, triplet, J , 7.5 Hz);
.63 t6H, singlet);
1.6 - 1.8 (2H, multiplet);
2.19 (3H, einglet);
2.70 (2H, triplet, J , 7.5 Hz);
5.00 (2H, einglet);
5.45 (2H, einglet);
6.B3 (2H, doublet, J - 8 Hz);
7.10 (2H, doublet, J - 8 Hz);
7.42 - 7.63 (3H, multiplet);
7.83 (lH, doublet of doublete, J ~ 1 & 7.5 Hz).

EX~MPr~ 62 piv~loyloxymeth,yl 4-(l-by~roxy-l-metbylethyl)~2-~ro~yl-1-~4-~2-(te.razol-5-yl)~henyll~hP~yl)met~yl-~ A~ole-5-c~rbo~ylate (C~m~ol~n~ No. 2-15) ~2~al PivAloyloxymet~yl 4-(1-bydroxy-1-methylet~yl)-2-propyl-1-~4-~2-(trltyltetrazol-5-yl)~h~yll-ah~yl~matbyllmidazole-5-carbox,ylate -: Followlng a procedure eimilar to that deecrlbed in xample 61~a), but uelng 0.35 g of plvaloyloxymethyl 4-11-hydroxy-1-methylethyl)-2-propyllmidazole-5 "' carboxylate lprepared as deecribed in Preparation '~' 22~11)], 1.52 g of 4-12-(trltyltetrazol-5-yl)phenyl]-,' benzyl bromlde and 0.72 g o~ potas~lum carbonate, 1.02 g of the title compound were obtained ae an amorphoue 0011d.

'~ ~
-~

~ ., , . .
, . , ~ .

- 267 - 20~1S07 The Nuclear Magnetic Resonance spectrum of this compound wa~ identical with that of the compound obtained as described in Example 20(a).

62(b) Pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-pro~yl-1-~4-~2-(tetrazol-5-yl)phenyllphenyl}-methylimidazole-5-carboxylate The pivaloyloxymethyl 4-~1-hydroxy-1-methylethyl)-2-propyl-1-~4-[2-trityltetrazol-5-yl)phenyl]phenyl}-methylimidazole-5-carboxylate prepared a~ described in step (a) above wa~ detritylated following a procedure similar to that described in Example 20(b), to give the hydrochloride of the title compound in an 80~ yield.

The melting point and Nuclear Magnetic Resonance epectrum of thie compound were identical wlth those of ~ the compound obtained as de~cribed in Example 20(b).

~XA~PL~ 63 PhthAli~yl 4-(1-by~roxy-1-met~ylet~yl)-2-pro~yl-1-~4-~2-(tetrazol-5-yl)phe~yll~h~yl~met~yl-~ m ~ rl;~ ~nl e - 5 . rA rboxylate ( Cn~ound No . 2 - 6 5 ~

63(a) Phth~lidyl 4-~1-hydro~y-1-met~ylet~yl)-2-Dro~yl-l-~ ~4-~2-(trityltetrAzol-5-yl~henyllphenyl)-met~yl~ m~ lA zole-5-~A rbo~ylAte Following a procedure ~imllar to that dee.cribed in ~xample 61~a~, but u~lng 0.~56 g o~ phthalldyl 4-~1-- hydroxy-l-methylethyl)-2-propyllmldazole-5-carboxylate ~prqpared a~ deacr~bed in Preparation 32), 0.736 g o~
~-~2-~trltyltetrazol-5-yl)phenyl]benzyl bromide and 0.366 g o~ potac~ium carbonate, 0.196 g of the title eompound wa~ obtalned, melting at llB - 120~C.

,~

. .
.... . .

;, . . .

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

I ~> 2 0 Nuclear Magnetic Re~onance Spectrum (CDCQ3), ~ ppm:
0.95 (3H, triplet, J = 7.5 Hz);
1.66 (6H, singlet);
1.65 - 1.80 (2H, multiplet);
2.60 (2H, triplet, J = 7.5 HZ);
5.09 (2H, singlet);
- 6. 92 - 7.56 (27H, multiplet);
7.93 (lH, doublet of doublets, J , 1 & 8 ~z).

63(b) PhthAlidyl 4~ hydxo~y-1-methylet~yl)-2-~ro~yl--~4-~2-(tetrazol-5-yl)~h~yll~h~yl~met~yl-mi dazole-S-caxboxylate Following a procedure similar to that described in ; Example 61(b), 0.196 g of phthalldyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-12-(trityltetrazol-5-yl)-phenyl]phenyl}methylimidazole-S-carboxylate ~prepared as de~crlbed in step (a) above] was detritylated by heating it with 75~ v/v aqueous acetic acid to glve 0.110 g o~ the title compound, melting at 168 - 170~C.

Nuclear Magnetlc Re~onance Spectrum (CDCQ3), ~ ppm:
~ 0.92 (3H, triplet, J . 7.5 Hz);
1.57 (6H, singlet);
1.60 - 1.77 (2H, multiplet);
2.65 ~2H, triplet, J . 7.5 Hz);
5.13 ~2H, singlet);
~? 6.91 - 7.57 (12H, multiplet);
i 7.80 (lH, doublet, J - 7.5 Hz).

j, .

~ ,, , ' .

. - .

.

:. . .

Isopropoxycarbonyloxymethyl 4- (1-hydroxy-1-methyl-eth~1)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl~methylimidazole-5-carboxylate (Compound No . 2 - 21 ) 64(a) I~opro~oxycarbonyloxymethyl 4-(1-hydroxy-1-methyl-- ethyl)-2-~ro~yl-1-~4-[2-(trityltetrazol-5-yl)-~henyllphe~yl~methylimidazole-5-carboxylate -;
Pollowing a procedure similar to that described in Example 61(a), but using 656 mg of isopropoxycarbonyl-oxymethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 33), 1.20 g of 4-~2-(trityltetrazol-5-yl)phenyl]benzyl - bromide and 0.51 g of potassium carbonate, 0.78 g of the title compound was obtai~e~ as a vlecous liquid.

Nuclear Magnetic Reeonance Spectrum (CDCQ3), ~ ppm:
~ O.B7 (3H, triplet, J . 7.5 Hz);
- 1.24 ~6H, doublet, J - 6 Hz);
- 1.63 (6H, ~inglet);
' 1.65 - l.B0 (2H, multiplet);
2.52 ~2H, triplet, J - 7.5 Hz);
; 4.B7 ~lH, quintet, J . 6 Hz);
; 5.35 (2H, einglet);
- 5.42 (lH, einglet);
5.66 ~2H, singlet);
6.7~ - 7.87 (22H, multiplet);
7.B7 - 7.96 (lH, multiplet).
-.~
c ~ L I~Q~ro~o~yrArbo~yloxymet~yl 4-(1-~ydro~y-1-methyl~
I e t~yl ) - 2-propyl~ 4-~2-(tetrAzol-5-yl)phe~yll-phe~yl)m~thylimidazole-5- rA rbo~ylate ' f Following a procedure eimilar to that described ln '1 , . ~
s - -i, , :, . ' ': ' ' - 270 - 2 ~61 60 7 - Example 61(b), 0.78 g of isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-l-{4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above]
was detritylated by heating it with 75% v/v aqueous acetic acid, to give 0.48 g of the title compound as an amorphou~ ~olid.

Nuclear Magnetic Resonance Spectrum (CDC~3), ~ ppm:
0.96 (3H, triplet, J , 7.5 Hz);
1 21 (6H, doublet, J . 6 Hz);
1.63 (6H, singlet);
1.72 ~2H, ~extet, J ~ 7.5 Hz);
2.60 (2H, triplet, J . 7.5 Hz);
4.72 (lH, quintet, J - 6.5 Hz);
j 5.33 (2H, singlet);
: 5.76 (2H, singlet);
6.77 ~2H, doublet, J . 7.5 Hz);
,. 6.92 ~2H, doublet, J - 7.5 Hz);
~ 7.37 - 7.60 (3H, multiplet);
7.~7 ~lH, doublet, J . 7.5 Hz).

. .
-':;

''' ., : .

271 20~1 6~ 7 M&C FOLIO: 64868/FP-9205 WANGDOC: 1621H

Ethyl 1-~(2'-t-butoxycarbonylbiphenyl-4-yl)methyll-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (Com~ound No. 1-130) O.337 g of potassium t-butoxide was added to a solution of 0.68 g of ethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (prepared as de~cribed in Preparation 37) in 7 ml of N,N-dimethyl-acetamide, and the resulting mixture wa~ ~tirred at room temperature for 10 minutes. 1.04 g o~ t-butyl 4'-bromomethylbiphenyl-2-carboxylate was then added to the resulting solution, and the reaction mixture was stirred at room temperature for 4 hour~. At the end of thi~ time, it was mixed with ethyl acetate and water.
The ethyl acetate layer wa~ separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue wac purl~ied by column chromatography through silica gel, using a 1 : 1 by volume mixture o~ ethyl acetate and he~ne as the eluent, to give 1.32 g o~ the title compound as a gum.
:j ;~ Nuclear Magnetic Reconance Spectrum (CDCQ3) ~ ppm:
1.23 ~9H, cinglet);
. 1.23 ~3H, triplet, J ~ 7.5 Hz);
-; 1.29 ~3H, triplet, J . 7.5 Hz);
.. ~ 1.63 ~6H, cinglet);
2.73 ~2H, quartet, J . 7.5 Hz);
- ~.26 (2H, quartet, J } 7.5 Hz);
~ 5.54 ~2H, ~inglet);
5.73 ~lH, singlet);
. 6.9~ ~2H, doublet, J ~ ~.5 Hz);
7.5 - 7.9 ~6H, multlplet).
., :-:
,, . :

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

Ethyl 1-[(2~-carboxybiphenyl-4-yl)methyll-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate (Compound No . 1- 131 ) Following a procedure ~imilar to that described in Example 7, but u~ing 1.32 g of ethyl 1-[(2'-t-butoxy-carbonylbiphenyl-4-yl)methyl]-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-S-carboxylate (prepared a~
de~cribed in Example 65) and a 4 N solution of hydrogen , chloride in dioxane, 0.94 g of the hydrochloride of the ~ title compound wa~ obt~ned as an amorphou~ powder.

Nuclear Magnetic Resonance Spectrum (h~ euterated i dlmethyl sul~oxide) ~ ppm:
-- 1.09 (3H, triplet, J - 7.5 Hz);
1.15 ~3H, triplet, J ~ 7.5 Hz);
- 1.61 ~6H, singlet);
3.03 ~2H, quartet, J - 7.5 Hz);
4.22 ~2H, quartet, J ~ 7.5 Hz);
5.64 l2H, singlet);
7.16 ~2H, doublet, J ~ ~.5 Hz);
-- 7.32 - 7.75 ~6H, multiplet).

. EXAMPLE 67 2~-Carbo~yb~Dhe~yl-4-yl)methyl]-2-ethyl-4-Jl~ydroxy-l-methylethyl)~m~7~1e-5-carboxylic acid ~Ca~Dound No. 1-132) '.';
Followlng a procedure eimilar to that de~cribed ln Example 17, but u~lng 0.40 g o the hydrochloride o~
q~hyl 1-~2'-carboxybiphenyl-4-yl)methyl~-2-ethyl-4 ~1-hydroxy-l-methylethyl)im~azole-5-carboxylate (prepared ae deecrlbed in Example 66) and 0.1~ g o~ lithium hydroxlde monohydrate, 0 25 g or the title compound wa~

: .

, , , , r _ 273 - 2 0 6 1 6 0 7 obtained as an amorphous powder.

Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl ~ulfoxide) ~ ppm:
1.17 (3H, triplet, J = 7.5 Hz);
1.64 (6H, singlet);
2.85 (2H, quartet, J = 7.5 Hz);
5.74 (2H, singlet);
7.10 (2H, doublet, J - 8 Hz);
7.30 - 7.76 (6H, multiplet).

Ethyl 2-ethyl-4-(1-hy~ro~y-1-methylethyl)-1-{4-~2-(tetr~zol-5-yl)~hP~yll~hP~yl~methylimidazole-5-carboxylate (Com~o~n~ No. 2-72) ~~ ~~131 ~t~yl 2-eth~yl-4 (l-h~y~ro~y-l-met~ylet~yl)-l-{4 ~2-(trityltetrazol-5-yl)phenyll~h~yl)me~hyl-imi~zole-S-carbo~ylate 0.52 g of pota~eium t-butoxide wa~ added to a ~olutlon o~ 1.00 g of ethyl 2-ethyl-4-~1-hydroxy-1-methylethyl)imidazole-5-carboxylate ~prepared as ~- de~cribed in Preparation 37) in 26 ml of ~,~-dimethyl-acetamide, and the re~ulting mixture was stirred at room temperature ~or 10 minutes. A ~olution of 2.71 g o~
~ 4-[2-~trityltetrazol-5-yl)phenyl]benzyl bromlde in 35 ml o N,~-dimethylacet~m~e wa~ then added dropwi~ ~o ~he resulting solution, a~ter which the reae~ion mixture wa~ stirred at 50~C ~or 4 hours. At ~h~ end o~ thi~ time, the reaction mixture wae worked up in a ~imilar manner to that described ln Example 18~a), - go give 2.01 g o~ ~he ~itle compound as crystals, mql~lng ak 150 - 152~C.
., '::

.

~ D 2 .

Nuclear Magnetic Resonance spectrum (CDC~3) ~ ppm:
1 . 10 (3H, triplet, J = 7 5 Hz);
1.18 (3H, triplet, J = 7.5 Hz);
: 1.6S (6H, singlet);
2.52 (2H, quartet, J = 7.5 Hz);
4.14 (2H, quartet, J = 7.5 Hz);
5.35 (2H, ~inglet);
5.80 (lH, singlet);
6.73 (2H, doublet, J , 8.5 Hz);
. 6.93 - 7.52 (20H, multiplet);
' 7.87 (lH, doublet, J - 7.5 Hz).

68(b) Et~yl 2-et~yl-4-(1-~ydroxy-1-methylethyl)-1- ~4-- ~2-(tetxazol-5-yl)ph~yll~hP~yl)met~ylimidazole-5-carbo~ylate A solution of 1.9 g of ethyl 2-ethyl-4-(1-hydroxy-~:- l-methylethyl)-1-(4-~2-(trityltetrazol-S-yl)phenyl]-phenyl~methylimldazole-S-carboxylate [prepared as de~crib~d in ctep ~a) above] in 2~ ml o~ 75~ v/v aqueous acetlc acid wae stirred at 60~C for 2 houre. At the end o~ this tlme, the reaction mlxture was dlluted wlth 7 ml of water and cooled to room temperature. Preclpltated - trltyl alcohol was removed by filtration, and the iltrate wa~ concentrated by evaporation under reduced prescure. The eyrupy residue was crystallized ln d~l~opropyl ether, to glve 1.21 g of the title compound, meltlng at 166 - 167~C.

Nuclear Magnetlc Resonance Spectrum (CDC43) ~ ppm:
1.14 ~3H, trlplet, J - 7.5 Hz);
1.20 ~3H, trlplet, J - 7.5 Hz);
1.4~ ~6H, slngle~);
: 2.52 ~2H, quartet, J ~ 7.5 Hz);
4.19 ~2H, quartet, J . 7.5 Hz);
- 5.41 ~2H, ~lnglec);
6.79 ~2H, doublet, J ~ 8.5 Hz);

.

~ , .

..
, ", . '~',.',' ' ' , , ~- - 275 -2 ~~i 6 07 7.09 (2H, doublet, J = 8.5 Hz);
7.41 - 7. 62 (3H, multiplet);
7.85 (lH, doublet, J = 7.5 Hz).

2-Ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-~2-tetrazol-- S-yl)~henyll~henyl~methylimidazole-5-carboxylic acid (Com~ound No. 2-68) A solution of 0.54 g of lithium hydroxide ~- monohydrate in 10 ml of water was added to a solution of ethyl 2-ethyl-4-~1-hydroxy-1-methylethyl)-1-~4-[2-(tetrazol-5-yl)phenyl]phenyl~methylimidazole-5-carboxylate ~prepared as described in Example 68(b)] in -~ 10 ml of dloxane, and the resulting mixture was ~tirred at room temperature for 4 hours. At the end of this -~. tlme, the dioxane was removed by evaporation under - reduced pressure, and 12.6 ml of lN aqueous hydrochloric i acid were added to the resulting aqueous residue.
-~ Collectlon o~ precipitated crystals by filtration gave 0.93 g o~ the title compound, melting at 179 - 181~C.

Nuclear Magnetic Resonance Spectrum (hex~deu~erated - dlmethyl sul~oxide) 6 ppm:
1.09 (3H, triplet, J . 7.5 Hz);
1.55 ~6H, ~lnglet);
- 2.63 ~2H, quartet, J . 7.5 ~z);
.- 5.65 ~2H, slnglet);
: 6.96 ~2H, doublet, J ~ 8.5 ~z);
~~ 7.03 ~2H, doublet, J . 8.5 Hz);
7.08 - 7.64 ~4H, multlplet).

,. .

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

- - 276 - 206~ 60 7 Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-[2-(tetrazol-5-yl)phenyllphenyl~methylimidazole-5-carboxylate (Compound No. 2- 7 ) ; ~
7 0 ( a) Et~yl 1-(2'-cyanobi~henyl-4-yl)methyl-4-(1-~ydro~y-1-methylethyl)-2-~ro~ylimidazole-5-carbo~ylate Following a procedure similar to that as described in Example 68(a), but using 4.01 g of ethyl ~ 4-~1-hydroxy-1-methylethyl)-2-propylimidazole-5-. carboxylate ~prepared as described in Preparation 9), - 5.0 g of 4'-bromomethylbiphenyl-2-carbonitrile and 1.97 g of potassium t-butoxide, 6.86 g of the title compound were obtained as crystals, melting at 92 - 93~C.

Nuclear Magnetic Resonance Spectrum ~CDCQ3) ~ ppm:
0.97 ~3H, trlplet, J ~ 7.5 Hz);
1.16 (3H, triplet, J . 7 HzJ;
; 1.65 (6H, 3inglet);
1.74 (2H, sextet, J - 7.5 Hz);
2.67 (2H, trlplet, J . 7.5 Hz);
4.24 (2H, quartet, J . 7 Hz);
- 5.52 (2H, singlet);
5.77 (lH, ainglet);
- 7.05 (2H, doublet, J . 8.5 Hz);
7.42 - 7.67 (5H, multiplet);
7.76 (lH, doublet, J . a Hz).

~-~ lQl~L ~hyl 4~ hydro~y-l-met~yleth~yl)-2-proDyl-1-(4-~2-~tetrazol-5-yl)chenyllDhe~yl~meth~yl-~ m~ ~ zole-5-car~o~yl~te A ~olu~ion o~ 2.00 g o~ ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-, . .

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

c::

; ~ 2 ' - 277 - 20~1 6~ 7 imidazole-5-carboxylate [prepared as described in step (a) above] and 2.00 g of tributyltin azide in 15 ml of toluene wa~ stirred at 100~C for 5 days. At the end of this time, the reaction mixture wa~ concentrated by evaporation under reduced pressure, and the residue was dissolved in 30 ml of a 4 N solution of hydrogen chloride in dioxane. The solution wa~ allowed to stand at room temperature for 16 hours, after which it was concentrated by evaporation under reduced pre~ure. The residue was triturated in diisopropyl ether, to give 2.00 g of the hydrochloride of the title compound.
"
The Nuclear Magnetic Resonance Spectrum of this compound wac identical with that of the compound obtAine~ a3 described in Example l~(b).
' !. EXAMP~E 71 Et~yl 4~ ydro~y-1-met~ylet~yl)-2-~roDyl-1-~-[~-(tetrAzol-5-yl)RhP~yllphenyllmethylim~dazole-s-~Arbo~ylAte (Com~ound No. 2-7) 71(a) Et4yl 1-~4-~2-(t-butyl~m~nnrArbo~yl)phe~yll-' ~hP~yl~m~t~yl 4-(l-~y~roxy~l~met~ylethyl)-2-prol~yl~m~-~Azole-5-carbo~ylate Followlng a procedure similar to that described in ~xample 68~a), but using 4.16 9 of ethyl 4-~1-hydroxy-1--~ methylethyl)-2-propyl~m~zole-5-carboxylate (prepared a~ de~crlbed ln Preparation 9), 6.00 g o~ N-t-butyl-4'-, bromomethylblphenyl-2-carboYAm~de ~prepared a~ de~cribed -,~ ln ~reparatlon 3a) and 2.14 g o~ potasslum t-butoxide, 5.87 g o ~he tltle compound was obtained as cry~tal~, - meltlng ~t 145 - 146~C.

Nuclear Magnetlc Resonance Spectrum (CDCQ3) b ppm:
0.97 ~3H, trlplet, J . 7.5 Hz);

,~ , . . ..

,: ' :,. . .
, . , . . ' , ' - 278 - 2~61 60 7 1.12 (9H, singlet);
1.24 (3H, triplet, J = 7 Hz);
1.64 (6H, singlet);
1.75 (2H, sextet, J = 7.5 Hz);
2.66 (2H, triplet, J = 7.5 Hz);
4.25 ~2H, quartet, J = 7 Hz);
5,03 (lH, singlet);
5.52 (2H, singlet);
5.69 (lH, ~inglet);
6.98 (2H, doublet, J - 8.5 Hz);
7.28 - 7.47 (5H, multiplet);
7.65 (lH, doublet, J - 7 Hz).

71 (b) Et~yl 1-~2'-cy~n~hi~hP~yl-4-yl)methyl-4-(1-~ydroxy-1-meth~ylethyl)-2-pro~ylimidazole-5-carboxylAte 0.345 ml of oxalyl chloride wa~ added dropwise, whil~t ice-cooli~g, to a solution of 1.00 g of ethyl 12-(t-butylamlnocarbonyl)phenyl]phenyl}methyl-~ hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate ~prepared as de~cribed in step (a) above] ln 10 ml of methylene chlorlde, and the mlxture wa~ stlrred at the same temperature ~or 2 hour~. At the end o~ thi~
tlme, the reaction mixture was diluted with an aqueou~
~olutlon o~ ~odlum hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magneeium eulfate and concentrated by evaporation under reduced pre~ure. The re~idue wa~
puri~led by column chromatography through ~lllca gel, uHing a 1 : 1 by volume mixture o~ ethyl acetate and h0xan~ a~ ~he eluent, ~o give 0.69 g o~ the title campound a~ crystal~.

5~r The melting point and Nuclear Magnetic Reeonance Spectrum o~ thi~ compound were identical wlth tho~e of ~he compound obtalned a~ de~crlbed ln Example 70 (a).

: :

, . .
.. . .
. ~ , .

- 279 - 20 ~1 ~0 7 71(c) Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1--~2-(tetrazol-5-yl)phenyllphenyl}methyl-imidazole-5-carboxylate Following a procedure ~imilar to that described in Example 70(b), but using ethyl 1-(2~-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-l-methylethyl)-2-propylimidazole-;: 5-carboxylate [prepared as de~cribed in step (b) above], - the title compound was obtained in a 91~ yield.

The Nuclear Magnetic Resonance Spectrum of this compound wa~ identical with that of the compound obtained as de~crlbed in Example 18(b).

EXAMPT~ 72 Et~yl 4-(~-hydroxy-~ t~yle~-~yl)-2-propyl~ 4-~2-(tetrazol-5-yl~phPr~,rl1~hPr~ me~ m~dazole-- s-~Arboxyl~te (Cn~Ro~n~ ~o. 2-7) ' : ?2(a) Ethyl 1-~(2'-t-buto~y~Arbn~ylhi~hA~yl~4-yl)-met~yll-4-(1-hy~ro~y-1-meth,ylet~yl)-2-proDyl-zole-5-carboxyl A te .~
~' Followlng a procedure simllar to that described in Example 6~a), but using 4.80 g of ethyl 4-~1-hydroxy-1-- methylethyl)-2-propyltm~d~zole-5-carboxylate (prepared -- as de~cribed ln Preparation 9), 6.94 g of t-butyl ~'-bromomethylbiphenyl-2-carboxylate and 2.28 g of ~ potaeslum t-butoxide, 7.50 g of the tltle compound were ;- ob~alned ac cry6tals, melting at 90 - 91~C.
,, ;; Nuclear Magnetic Reeonance Spectrum (CDCQ3) 6 ppm:
2 0 ~ 97 ~3H, triplet, J ~ 7 Hz);
1.23 (~H, trlplet, J . 7 Hz);
~; 1.25 (9H, clnglet);
; 1.60 (6H, slnglet);

~ , , .,; . ...

.' , - , , ~ ' , .

. ~ ' , , .

,, , - 280 - 20S1~07 1.82 (2H, sextet, J = 7 Hz);
2.67 (2H, triplet, J = 7 Hz);
4.24 (2H, quartet, J = 7 Hz);
5 . 51 (2H, singlet);
5 . 72 (lH, singlet);
: 6 . 87 - 7 . 85 (8H, multiplet~.

72(b) Ethyl 1-~(2~-carboxybiphenyl-4-yl)methyll-4-(1-hy~roxy-1-methylethyl)-2-~ro~ylimidazole-5-carbo~ylate Following a procedure similar to that described in ~ Example 18 (b), but using 0.80 g o$ ethyl 1-~(2~-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared a~ de~cribed ln step (a) above] and a 4 N solution of hydrogen chloride in dioxane, 0.67 g Or the hydrochlorlde of title compound was obtained as an amorphoue powder.

Nuclear Magnetic Re~onance Spectrum (hPY~euterated dimethyl sul~oxide) ~ ppm:
- 0.88 ~3H, triplet, J . 7 Hz);
1.14 (3H, triplet, J ~ 7 Hz);
1.50 - 1.65 ~2H, multiplet);
1.60 (6H, singlet);
~ 3.00 (2H, triplet, J ~ 7 Hz);
,~ 4.20 (2H, quartet, J . 7 Hz);
5.63 ~2H, ~lnglet);
7.13 - 7.75 (8H, multiplet).
i ,~
~ L ~thyl 1-~(2'- ~A rhAm~ylb~Dhe~yl-4-yl)methyll-4-,,, (l-hy~roxy-l-meth,yleth,yl)-2-~ropyltm~lAzole-S~
r~ rboxyl ~ te . .
~; 3 ml o~ oxalyl chloride were added dropwise, whilst lce-coollng, to a ~olution o~ 4.00 g Or the . ~

:.
- .

, , .. .

~, .
.~, :, .

- 281 - 2~S1 ~0 7 hydrochloride of ethyl 1-[(2~-carboxybiphenyl-4-yl)-methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as de~cribed in step (b) above]
in 40 ml of methylene chloride, and the resulting mixture was ~tirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure.
~enzene wa~ then added to the residue, and the mixture wa~ concentrated again by evaporation under reduced pressure, to remove the rPm~in;ng oxalyl chloride. The cryetalline residue wa~ ~uspended in 100 ml of ethyl acetate and mixed with 15 ml of concentrated agueous ammonia, whilst ice-cooling, and then the mixture was stirred at room temperature for 10 minute~. The ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The crystalline residue waY then washed with diisopropyl ether, to give 2 97 g of the tltle compound, melting at 148 - 151~C.

Nuclear Magnetic Resonance Spectrum ~CDC~3) ~ ppm:
0.96 (3H, triplet, J ~ 7.5 Hz);
- 1.19 ~3H, triplet, J ~ 7 Hz);
- 1.64 ~6H, singlet);
1.73 ~2H, sextet, J . 7.5 Hz);
2.65 ~2H, triplet, J . 7.5 Hz);
- 4.24 ~2H, quartet, J ~ 7 Hz);
-~ 5.36 ~lH, broad singlet);
~' 5.~9 ~2H, 9 inglet);
5.66 ~lH, broad ~inglet);
5.76 ~lH, singlet);
6.99 ~2H, doublet, J ~ 8 H~);
- 7.32 ~ 7.53 ~5H, multiplet);
7.71 ~lH, doublet, J ~ 6 Hz).

- 282 - 20S1 ~0 7 72(d) Ethyl 1-(2~-cyanobiphenyl- 4 - yl ) methyl)-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate 264 ~Q of trifluoroacetic anhydride were added, whilst cooling on a bath cont~;n-ng a mixture of ice and sodium chloride, to a solution of 0.70 g of ethyl 1-[(2'-carbamoylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared a~ described in step (c) above~ and 0.43 ml of ~ triethylAm~ne in 7 ml of methylene chloride, and the reculting mixture was stirred at the same temperature ~or 30 minutes. At the end of this time, the reaction mixture was diluted with an aqueous solution of sodium hydrogencarbonate and ethyl acetate, and the ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pres~ure. The re~idue wa~ purified by column chromatography through silica gel, uelng a 1 : 1 by volume mixture of ethyl acetate and h~x~ne as the - eluent, to give 0.60 g of the title compound as crystals.
c The meltlng point and Nuclear Magnetic Re~onance Spectrum o~ thi~ compound were identical with those of ~l the compound obtained as de~cribed in Example 70 (a).

~1 72(e) ~t~yl 4~ ydro~y-1-met~ylet~yl)-2-proDyl-1-~4-~2-~tetrazol-5-yl)phe~yllphe~yl~methyl-~ m~ ~ 7~1e-S-carbo~ylate Following a procedure ~lmilar to that described in .~ ~xample 70~b), but using ethyl 1-(2'-cyanobiphenyl-~-~ yl)methyl~4-~l-hydroxy~1-methylethyl)-2-propylimidazole--~ 5-carboxylate ~prepared ac described in step (d) above]
~he ~ltle compound was obtained in a 90~ yield.

The Nuclear Magnetic Reeonance 9pectrum o~ thi~

, -- , .
.. ..

, , , - 283 - 20 Sl 6Q 7 compound was identical with that of the compound obtained as described in Example 18(b).

Pivaloyloxymethyl 4-(1-hydroxyethyl)-2-~ropyl-1-{4-~2-tetrazol-5-yl)~henyl]~henyl}methylimidazole-5-carboxylate (Com~ound No.4-31) 73(a) Pivaloylo~ymethyl 4-(1-hydroxyethyl)-2-~ro~yl-1-{4-~2-(trityltetrazol-5-yl)~henyll~henyl}-methyli m~ dazole-5-carboxylate A solution of 196 mg of lithium hydroxide monohydrate in 15 ml of water wae added to a solution of 2.87 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-~2-(trityltetrazol-S-yl)phenyl]phenyl}methylimidazole 5-carboxylate [prepared as deecribed in Example 42(a)] in 30 ml of dioxane, and the resultlng mixture wae etirred at room temperature for 16 hour~. At the end of thie time, small piecee o~ dry ice were added to the mixture, which wae then concentrated by evaporation under reduced pressure to drynese. The resldue wae dieeolved in 40 ml o ~,~ dlmethylacetamide, and 0.45 g of pota~sium carbonate and then 1.1 ml o pivaloyloxymethyl chloride were added to the eolution. The resultlng mixture was etirred at 50~C ~or 3 houre. At the end o~ this tlme, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer wae separated, drled over anhydrou~ magneeium eul~ate and concentrated by evaporatlon under reduced preesure. The reeidue was purl~led by column chromatography through ellica gel, ueing a 1 : 1 by volume mixture o~ ethyl acetate and hexane ae the eluent, to give 2.41 g of the title compound ae an amorphoue powder.
.; .

. ..

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

1 6 2 .

- 284 - 20 ~1 ~Q 7 Nuclear Magnetic Resonance spectrum (CDCQ3) ~ ppm:
O . 88 (3H, triplet, J = 7 . 5 Hz);
1.17 (9H, singlet);
1.50 (3H, doublet, J = 6 Hz);
1.69 (2H, ~extet, J = 7 . 5 HZ);
2.51 (2H, triplet, J = 7.5 Hz);
3.62 (lH, doublet, J = 8 Hz);
5.17 - 5.29 (lH, multiplet);
5.37 (lH, doublet, J , 16.5 Hz);
5.46 (lH, doublet, J , 16.5 Hz);
' 5.77 (lH, doublet, J , 5.5 Hz);
- 5.~2 (lH, doublet, J = 5.5 Hz);
6.75 (2H, doublet, J - 8.5 Hz);
6.92 - 7.89 (20H, multiplet);
7.90 (lH, doublet, J - 7.5 Hz).

73(b) Pivaloylo~ymet~yl 4-(l-hy~roxyetbyl)-2-~ro~yl-1-~4-~2-(tetrazol-5-yl)~h~yl]Qh~yl~metbyl-m~ dazole-S ~rbo~ylate Following a procedure ~imilar to that described in ~xample 35~c), but ueing 2.37 g of pivaloyloxymeth~l 4~ hydroxyethyl)-2-propyl-1-(4-12-(trltyltetrazol-5 yl)phenyl]phenyl~methylim~zole-5-carbox~rlate ~prepared as described in step (a) above] and 75~ v/v aqueou~ acetic acid, 1.21 g of the title compound wa~
~ obtained as a powder.

- Nuclear Magnetic Resonance Spectrum ~CDCQ3) ~ ppm:
- 0.90 ~3H, triplet, J - 7.5 Hz);
1.13 (9H, ~lnglet);
1.43 (3H, doublet, J ~ 6.5 ~z);
1.67 (2~, ~extet, J - 7.5 Hz);
2.55 (3H, triplet, J ~ 7.5 Hz);
5.16 ~lH, quartet, J - 6.5 Hz), 5.40 ~lH, doublet, J . 16.5 Hz);
5.51 ~lH, doublet, J ~ 16.5 Hz);

.

- . , . . . ' ~ i ,, . , , " ~, '' ' ' . . ' .',... , . '" ' , ,.

~' 2~Sl~7 5.80 (lH, doublet, J = 6 Hz);
5.85 (lH, doublet, J = 6 Hz);
6.86 (2H, doublet, J = 8 Hz);
7.08 (2H, doublet, J = 8 Hz);
7.40 - 7.61 (3H, multiplet);
7.92 (lH, doublet, J = 7.5 Hz).

4~ Hydroxy-2 2-dimethylpropyl)-2-propyl-1-~4-~2-(tetrazol-5-yl)phenyll~henyl~met~ylimidazole-5- r~ rboxamide (~ ound No. 5-37) .
74(a) 2-Pro~yl-4-~ivaloyl-1-~4-~2-(txityltetrazol-5-yl)~?hPr~ hPr~ thyl~m~dazole-5-carbonitrile 1.0~ g of potaseium t-butoxide was added, whilst ice-coollng, to a eolution of 2.00 g of 2-propyl-4-pivaloylim~zole-5-carbonitrile (prepared as described in Preparation 41) in 20 ml of N,~dimethylacetamide, and the reeultlng mlxture wae etlrred at same temperature ~or 10 minute~. 6.10 g o~ 4-~2-(trityl-tetrazol-5-yl)phenyl~benzyl bromide were then added to the eolution, and the reeulting mixture was 3tlrred at 50~C or 4 houre. At the end o~ this time, ethyl acetate and water were added to the mixture, and the ethyl acetate layer was eeparated, dried over anhydrous magne~lum sul~ate and concentrated by evaporation under re~uce~ pree~ure. The syrupy reeidue was puri~ied by column chromatography through eilica gel, using 1 : 3 and 1 : 2 by volume mixturee o~ ethyl acetate and he~ne ae the eluent, to give 5.44 g o~ the title compound as cry~tal6, melting at 107 - 110~C.

Nuclear Magnetic Reeonance Spectrum (CDCQ3) ~ ppm:
0.92 ~3H, trlplet, J ~ 7.5 Hz);
1.42 ~9H, einglet);

.
,, 1, . .
~, , , -. ~ , . .

2 ~ Q 7 1.72 (2H, sextet, J = 7.5 Hz);
2.50 (2H, triplet, J = 7.5 Hz);
5.09 (2H, singlet);
6.92 (2H, doublet, J = 8 Hz);
7.13 - 7.53 (20H, multiplet);
7.95 (lH, doublet, J = 7 Hz).

74(b) 4-(1-Hydroxy-2,2-dimethyl~ropyl)-2-~ropyl-1-~4-~2-(trityltetrazol-S-yl)~henyllphenyl)methyl-m~ ~A ~ole-S-carbonitrile A solution of 108 mg of sodium borohydride in 20 ml : of ethanol was added to a solution of 2.00 g of 2-propyl-4-pivaloyl-1-(4-[2-(trityltetrazol-5-yl)-phenyl]phenyl~methylimidazole-5-carbonitrile ~prepared as deccribed in ~tep (a) above] in 40 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 hours, At the end of this time, the reactlon mixture wae concentrated by evaporatlon under ~ reduced pre~ure, and the residue was dissolved in a ~ mixture o~ ethyl acetate and water. The ethyl acetate ;~ layer wac separated, washed with water, dried over -~ anhydrouc magne~ium ~ul~ate and concentrated by evaporation under reduced pressure. The ~yrupy residue wac crystallized in a 1 : 4 by volume mixture of ethyl , acetate and heY~ne, to give 1.93 g of the title compound a~ crystals, melting at 115 - 117~C, Nuclear Magnetic Re~onance Spectrum ~CDCQ3) ~ ppm:
0.~7 ~3H, triplet, J . 7.5 Hz);
,, 0.99 (9H, singlet);
1.64 ~2H, ~extet, J ~ 7.5 Hz);
2.~9 ~2H, triplet, J ~ 7.5 Hz);
2.76 ~lH, double~, J ~ 7.5 Hz);
4.46 ~lH, doublet, J ~ 7.5 Hz);
5.04 ~2H, clnglet);
.. 6.35 - 7.53 (22H, multiplet);

, ' ' ; , ' , , .
, "
,: , , .

;' , . , , . : , . ,: , 20~1 6o 7 7.95 (lH, doublet, J = 7.5 Hz).

74(c) 4-(1-Hydroxy-2 2-dimethylpropyl)-2-propyl-1-~4-r2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile A suspension of i.65 g of 4-(1-hydroxy-2,2-dimethyl-propyl)-2-propyl-1-~4-[2-(trityltetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carbonitrile ~prepared as de~cribed in step ~b) above] in 24 ml of 75~ v/v aqueous acetic acid was stirred at 60~C for 2 hours. At the end of this time, 6 ml of water was added to the reaction mixture, which was then cooled with ice. The trityl alcohol which precipitated was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.07 ~ of the title compound as a glass.
... .
Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
~ 0.37 (3H, triplet, J - 7.5 Hz);
-~ 0.92 (9H, singlet);
- 1.63 ~2H, ~extet, J . 7.5 Hz);
- 2.58 ~2H, triplet, J - 7.5 Hz);
4.36 ~lH, singlet);
5.15 ~2H, singlet);
7.00 ~2H, doublet, J . ~ Hz);
- 7.07 ~2H, doublet, J . a Hz);
7.30 - 7.61 ~3H, multiplet);
7.aO (lH, doublet, J . 7.5 Hz).

74~d) 4~ ydro~y-2.2-dimet~y~propyl)-2-propyl-l-(4 2-~tetrAzol-5-yl)~he~yllphe~yl~meth~l~mldazole-z' 5.~Arhr~YAm~la -;
-~ A m~xture o~ 0.70 g o~ 4-~1-hydroxy-2,2-dimethyl-propyl)-2-propyl-1-~4-12-~tetrazol-5-yl)phenyl]-} phenyl~methylimidazole-5-carbonitrile ~prepared as ., ..
. .
.. . .
-.,, ; , .. ".. ~ , , <.

'' .; . .
~ . , - 288 - 2 0~1 607 described in step (c) above] in 14 ml of 1 N aqueous sodium hydroxide and 7 ml of ethanol wa~ heated under reflux for 2 hours. At the end of this time, the ethanol in the reaction mixture was removed by evaporation under reduced pressure, and ethyl acetate and 14 ml of 1 N aqueou~ hydrochloric acid were added to the residue. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pre~sure, to give 0.45 g of the title compound as a powder, melting at 174 - 176~C.

Nuclear Magnetic Reso~Ance Spectrum (hP~A~euterated dimethyl sulfoxide) ~ ppm:
0.83 ~3H, triplet, J - 7.5 Hz);
0.88 ~9H, ~inglet);
1.44 - 1.63 ~2H, multiplet);
2.46 ~2H, triplet, J - 7.5 Hz);
4.45 ~lH, singlet);
~ 5.39 (lH, doublet, J . 16 Hz);
5.77 ~lH, doublet, J ~ 16 Hz);
6.20 ~lH, doublet, J - 4.5 Hz);
6.91 ~2H, doublet, J - 8.5 Hz);
.. 7.04 ~2H, doublet, J - 8.5 Hz);
7.47 - 7.63 ~4H, multiplet);
I

PT.~;! 75 ~-Bu~yl-4 ~ ydro~y-2 2-~mQtkylpro~yl)-1-~4-~2-(tetrA~ol-5-yl)pher~yllphe~ meth,yl~r~tlAzole-5-carb~YAmi~Q (Co~m~o1ln~ No. 5-99) 75~a) 2-~u~yl-4-plvAloyl-1-~4-~2-(trityltetrA~01-5-yl)~her~ hPr~,yl~mQthylim~f~Azole-5-carbnn~trile Following a procedure ~imilar to that described in ~xample 74~a), but uclng 2.04 g o~ 2-butyl-4-plvaloyl-imidazole-5-carbonitrile ~prepared as described in - : , : , .
, . . .
. ~ . , .

- 289 - 2~ 07 ~ Preparation 40), 5.6 g of 4-[2-(trityltetrazol-s-yl)-phenyl]benzyl bromide and 1.06 g of potassium t-butoxide, 5.43 g of the title compound were obtained a~ crystals, melting at 103 - 105~C.

Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
0.88 (3H, triplet, J = 7.5 Hz);
1.32 (2H, sextet, J - 7.5 Hz);
1.41 ~9H, einglet);
1.66 (2H, quintet, J - 7.5 Hz);
2.53 (2H, triplet, J , 7.5 Hz);
~ 5.09 (2H, slnglet);
6.91 - 7.50 (22H, multiplet);
7.96 (lH, doublet, J . 7.5 Hz).

75(b) 2-~utyl-4-(1-hydro~y-2.2-~mat~yl~ropyl)~ 4-~ e ~2-(trltyltetrA~ol-5-yl)~h~yll~h~yl~methyl-~ m~ ~ 7~1e - s-carb~nitrlle Followlng a procedure eimllar to that de~cribed in ~xample 7g(b), but using 4.03 g o~ 2-butyl-~-pivaloyl-1-(4-l2-~trityltetrazol-5-yl)phenyl]phenyl~methyl-imldazole-5-carbonitrile ~prepared ae deecrlbed in step - (a) above] and 0.22 g of ~odlum borohydride, 3.79 g of the tltle compound was obtained as crystals, melting at -- 134 - 135~C.

Nuclear Magnetic Reeonance Spectrum (CDC~3) ~ ppm:
0.85 ~3H, trlplet, J - 7.5 Hz);
0.99 (9H, singlet);
1.27 (2H, Hext~t, J ~ 7.5 Hz);
2.52 ~ 2.67 (2H, multlplet);
2.51 (2H, trlplet, J ~ 7.5 Hz);
- 2.7~ , doublet, J ~ 7.5 Hz);
.45 (lH, doublet, J ~ 7.5 Hz);
; 5.0~ ~2H, elnglet);
. 6.~5 - 7.53 (22H, multlplet);

,';,, , .. . .

, ~

-- 290 - 2~S1 6~ 7 7.95 (lH, doublet, J = 7.5 Hz).

L 2-Butyl-4-(l-Hydroxy-2~2-dimethylpropyl)-l-~4-r2-(tetrazol-5-yl)phenyl]phenyl)methylimidazole-5-carbonitrile Following a procedure similar to that described in Example 74(c), but using 1.00 g of 2-butyl-4-(1-hydroxy-2,2-dimethylpropyl)-1-~4-[2-(trityltetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carbonitrile [prepared ac de~cribed in step (b) above] in 75% v/v aqueous acetic acid, 0.65 g of the title compound was obtained as a glacs.

Nuclear Magnetic Reconance Spectrum (CDC~3) ~ ppm:
- 0.91 (3H, triplet, J ~ 7 5 Hz);
0.96 ~9H, ~inglet);
1.2B - 1.42 (2H, multiplet);
1 . 5a - 1.74 ~2H, multiplet);
2.69 ~2H, triplet, J . 7.5 ~z);
I 4.~0 ~lH, slnglet);
J 5.21 ~2H, cinglet);
7.10 - 7.32 (4H, multiplet);
7.43 ~ 7.65 (3H, multlplet);
~ 8.06 (lH, doublet, J ~ a Hz).

75(d) 2-Butyl-4~ 4ydro~y 2.2-~m~t~ylpro~yl)-1-(4-- ~2-(tetr~zol-5-yl)phP~yllphe~yl)met~yl~m~Azole-5 _ ~;1 rh~ram l ~1Q

Following a procedure cimilar to that described ln ~xample 74~d), but uclng 0.3~ g o~ 2-butyl-4~ hydroxy-- 2,2-dimethylpropyl)-1-(4-12-~tetrazol-5 yl)phenyll-phenyl~methyllmldazole-S-carbonltrlle lprepared as ~ deccribed in ctep (c) above] in a l N aqueous solution s, o~ ~odium hydroxide, 0.30 g o~ the title compound wa~
obt~lne~ as a powder, meltlng at 157 - 160~C.
' ,:-, , :

~, , ,': ... . .
~........................................ . . . .
:r. -2o6l 6o7 Nuclear Magnetic Resonance Spectrum (hexadeuterated dimethyl sulfoxide) ~ ppm:
0.79 (3H, triplet, J = 7.5 Hz);
0 88 (9H, singlet);
1.16 - 1.30 (2H, multiplet);
1.39 - 1.54 (2H, multiplet);
2.59 (2H, triplet, J = 7.5 Hz);
4.51 (lH, singlet);
5.46 (lH, doublet, J , 16 Hz);
; 5.73 (lH, doublet, J , 16 Hz);
6 21 (lH, doublet, J - 4.5 Hz);
6.97 (2H, doublet, J - 8.5 Hz);
7.06 (2H, doublet, J . 8.5 Hz);
7.51 - 7.70 (4H, multiplet).

EXA~Pn~ 76 4~ ydro~y-2-met~yl~ropyl)-2-~ro~yl-1-~4-~2-- (tetrAzol-5-yl)phe~yl]ph~ ~l}met~ m~zole-5-carb~Y:~m~de (C~olln~ No. s-36L

76(a) 4-I~obu~yryl-2-propyl-1-l4 ~2-~trltyltetrazol-5-' yl~ahPr~ ph~r~l)met~yl~m~zole~5~ rbnn~trile Following a procedure similar to that descrlbed ln Bxample 74(a), but u~ing 0.97 g o~ 4-isobutyryl-2-propyl~m~zole-5-carbonitrile (prepared as described in Preparatlon 39), 2.90 g of 4-12-(trityltetrazol-5-yl)-, phenyl]benzyl bromide and 0.56 g of potassium --~ t-butoxlde, 1.90 g o~ the title compound wa3 obtained as cry~tal~, melting at 133 - 134~C.
r ; Nuclear Magnetlc Resonance Spectrum (CDC~3) ~ ppm:
~- 0.91 (3H, trlplet, J . 7.5 Hz);
.j 1.22 (6H, doublet, J ~ 6.5 Hz);
1.69 ~2H, 6extet, J ~ 7.5 Hz);
, 2.54 ~2H, trlplet, J ~ 7.5 Hz);
:~ I

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

1 6 ~. ~

3.64 (lH, quintet, J = 6.5 Hz); 2~ 7 5.12 (2H, singlet);
6.7 - 8.0 (23H, multiplet).

- 76(b) 4-(1-Hydroxy-2-methylpro~yl)-2-propyl-1- ~4-[2-(trityltetrazol-S-yl)phenyllphenyl}methyl-imidazole-5-carbonitrile Following a procedure similar to that described in Example 74(b), but u~ing 1.60 g of 4-i~obutyryl-2-propyl-1-{4-12-(trityltetrazol-5-yl)phenyl]phenyl~-- methylimidazole-5-carbonitrile [prepared as described in : etep ~a) above] and 0.13 g of codium borohydride, 1.50 g o~ the title compound was obtained as crystals, melting at 154 - 155~C.
-Nuclear Magnetic Resonance Spectrum (CDCQ3) ~ ppm:
- 0.87 ~3H., triplet, J . 7.5 Hz);
. 0.94 ~3H, doublet, J - 6.5 Hz);
1.00 (3H, doublet, J ~ 6.5 Hz);
~~ 1.66 (2H, ~extet, J . 7.5 Hz);
- 2.12 (lH, sextet, J . 6.5 Hz);
2.50 (2H, trlplet, J - 7.5 Hz);
4.54 (lH, doublet, J . 6 Hz);
r 5.04 (2H, singlet);
6.85 - 6.95 ~6H, multlplet);
: 7.14 (2H, doublet, J - 8.5 Hz);
:. 7.23 - 7.53 ~14H, multlplet);
- 7.94 ~lH, doublet, J . 7.5 Hz).
, ., s 76~c1 4-(1 Hy~roxy 2 met~ylDro~yl) 2 pro~yl 1 (4 ~2-(tetr~7~1-5-yl)~he~yll~henyl~met~ylimidazole-5.~nrbonl~rile ;,; ~
Following a procedure similar to that described in Example 74~ci, but w lng 1.36 g o~ 4~ hydroxy-2-methylpropyl)-2-propyl-1-~4-l2-~trityltetrazol-5-.{~
;iY, ,;
.. . ~

.-~
. . . .

,,~ , , .
. j " , .
, ~,~ ,. . .

... , . i, . .

yl)phenyl]phenyl}methylimidazole-S-carbonitrile [prepared a~ described in step (b) above] in 75~ v/v aqueous acetic acid, 0.87 g of the title compound was obtained as a glass.

Nuclear Magnetic Resonance Spectrum (CDC~3) ~ ppm:
0.77 (3H, doublet, J - 6.5 Hz);
0.81 (3H, triplet, J , 7.5 ~z);
0.93 (3H, doublet, J - 6.5 Hz);
1.54 ~2H, sextet, J - 7.5 Hz);
1.92 - 2.07 (lH, multiplet);
2.55 (2H, triplet, J ~ 7.5 Hz);
4.33 (lH, doublet, J - 7.5 Hz);
5.12 (2H, singlet);
6.96 - 6.99 (4H, multiplet);
7.35 - 7.69 (3H, multiplet);
7.71 (lH, doublet, J ~ 7.5 Hz).

76(d) 4-(1-Hydroxy-2-met~yl~ro~yl)-2-~ro~yl~ 4-~2-(tetrAzol-5-yl)~he~yllph~yl~metbyllm~dazole-5-~A ,b~ de - Following a procedure similar to that de~cribed in Example 74(d), but u~lng 0.90 g o~ 4-(1-hydroxy-2 ~ methylpropyl)-2-propyl~ 4-t2-(tetrazol-5-yl)-; phenyl]phenyl~methylimidazole~S-carbonitrlle [prepared a~ described in step (c) above] in a 1 N aqueou~
~olutlon o~ sodium hydroxide, 0.64 g of the title compound wa3 obtained as a powder, melting at 153 - 157~C.

Nuclsar Magnetlc Resonance Spectrum (hexAdeuterated dime~hyl ~ul~oxlde) b ppm:
0.69 (3H, doublet, J ~ 6.5 Hz);
O.ql (3~, tr~plet, J ~ 6.5 Hz);
0.99 ~3~, triplet, J ~ 6.5 Hz);
1.49 ~2H, sextet, J ~ 7.5 Hz);

, . .

2.05 (lH, quintet, J= 6.s HZ);
2.68 (2H, triplet, J = 7.5 Hz);
4.45 (lH, doubletr J = 7.5 Hz);
5.55 (lH, doublet, J = 16.5 Hz);
5.70 (lH, doublet, J = 16.5 Hz);
7.02 (2H, doublet, J = 8.5 Hz);
7.08 (2H, doublet, J = 8.5 Hz);
7.51 - 7.71 (4H, multiplet);

~XAMPLE 77 2-~utyl-4-(1-hydro~y-2-methylDro~yl)-1-~4-~2-(tetr~ 701- 5 -yl ) phP~yll ~hP~yl~tbylimidazole 5 ~rb~Y~m~ (Co~pol~n~ No. 5-98) 77(a) 2-3utyl-4-l~obutyryl-1-~4-~2-(trityltetrazol-5-- yl)~he~ ?hPr~l~m~ m~ zole-5-carbonitrile - Following a procedure ~imilar to that described in . ~xample 74~a), but using 1.42 g o~ 2-butyl-4-isobutyryl-- imldazole-5-carbonitrile ~prepared as de~cribed in Preparation 27), 4.49 g o~ 4-~2-~trityltetrazol-5-yl)-phenyl]benzyl brr ~e and Q.76 g o potassium ~-butoxide, 3.04 g o~ the tltle compound wa~ obtained as - crystal~, melting at 115 - 116~C.

Nuclear Magnetic Reeonance 8pectrum ~CDCQ3) ~ ppm:
o.a7 ~3H, triplet, J ~ 7.5 Hz);
1.22 ~6H, doublet, J. 6.5 Hz);
1.31 ~2H, 6extet, J. 7.5 HZ);
. 1.63 ~2H, quintet, J - 7.5 Hz);
2.57 ~2H, trlplet, J ~ 7.5 Hz);
3.64 ~lH, septet, J~ 7.5 Hz);
5.11 ~2H, e~nglet);
6.90 ~ 7.52 ~22H, multiplet);
~ 7.96 ~lH, doublet, J . 9 Hz).

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

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

206~607 77(b) 2-~utyl-4-(1-hydroxy-2-methylpropyl)-1- ~4- [2-(trityltetrazol-5-yl)phenyllphenyl}methyl-imidazole-5-carbonitrile Following a procedure eimilar to that described in ! Example 74(b), but using 2.00 g of 2-butyl-4-isobutyryl-1-~4-~2-(trityltetrazol-5-yl)phenyl]phenyl}methyl-1A~zole-5-carbonitrile [prepared as described in step (a) above~ and 0.22 g of sodium borohydride, 1.68 g of the title compound wae obtained as crystals, melting at 127 - 128~C.

Nuclear Magnetic Reson~nce Spectrum (CDC~3) ~ ppm:
0.85 (3H, triplet, J ~ 7.5 ~z);
0.93 (3H, doublet, J . 6.5 Hz);
1.00 (3H, doublet, J . 6.5 Hz);
- 1.26 ~2H, sextet, J ~ 7.5 ~z);
1.59 (2H, quintet, J . 7.5 Hz);
2.13 (lH, sextet, J ~ 6.5 Hz);
2.52 (2H, triplet, J - 7.5 Hz);
4.53 ~lH, doublet, J ~ 6 ~z);
5.04 ~2H, slnglet);
6.a5 - 7.52 ~22H, multiplet);
7.95 ~lH, doublet, J - 9 Hz).

77(c) 2-~ yl-4-(1-~ydro~y-2-methyl~roDyl)-1-~4-~2-(tetr~Y~1-5-yl)ph~yl l~he~yllmet~ylimi~Azole-- 5~Arh~n~trile Following a procedure cimilar to that de~cribed in ~ le 74~c), but ueing 1.29 g o 2-butyl-4-~1-hydroxy-2-mothylpropyl)-1-l4-~2-(trityltetra~ol-5-yl)phenyl]-phenyl~mothyllmidazole-5-carbonitrile ~prepared as de~crlbed in ~tep ~b) above] in 75% v/v aqueous acetic acld, 0,83 g o the title compound wa~ obtained ae a gl~

, , , .. . .

- 296 - 20616~7 Nuclear Magnetic Resonance Spectrum (CDCe3) ~ ppm:
0.81 (3H, doublet, J = 6.5 Hz);
0.83 (3H, triplet, J = 7.5 HZ);
0.95 (3H, doublet, J = 6.5 HZ);
1.26 (2H, ~extet, J = 7.5 Hz);
1.54 (2H, quintet, J= 7.5 Hz);
1.97 - 2.09 (lH, multiplet);
2.59 (2H, triplet, J = 7.5 Hz);
4.37 (lH, doublet, J = 6.5 Hz);
5.14 (2H, singlet);
6.98 (2H, doublet, J - ~.5 Hz);
7.05 (2H, doublet, J - 8.5 Hz);
7.32 - 7.60 ~3H, multiplet);
7.77 (lH, doublet, J - 7.5 Hz).

jJ 77(d) 2-Butyl-4-(1-hydro~y-2-m~t~ylpro~yl)-1-~4-~2-,- (tetrazol-S-yl)~hDr~yll~h~r~,yl}met~ylimldazole- 5-rArbnY~m~de Followlng a procedure eimilar to that de~cr~bed in Example 74~d), but u3ing 0.34 g o~ 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-(4-l2-(tetraznl-5-yl)phenyl~-phenyl~methylimidazole-5-carbonitrlle ~prepared a3 de~cribed in step (c) abovel in a 1 N aqueous solution ~ o~ sodlum hydroxide, 0.24 g of the title compound wa~
obt~ne~ as a powder, melting at 155 - 157~C.

Nuclear Magnetlc Reeonance Spectrum (he~ uterated dimethyl sul~oxlde) ~ ppm:
0.69 (3H, double~, J - 6.5 Hz);
0.79 (3H, triplet, J ~ 7.5 Hz);
0.93 (3~, double~, J - 6.5 Hz);
~ 1.22 (2H, oextet, J ~ 7.5 Hz);
1.45 (2H, quintet, J~ 7.5 Hz);
- 2.00 - 2.12 (iH, multiplet);
- 2.65 (2H, triplet, J - 7.5 Hz);
~ ~.41 (lH, doublet, J ~ 8 Hz);
. . , .. .
., ,~ .. . .
, :
, , , ... . . .

~ 6 2 ~

- 297 - 20~1607 5.53 (lH, doublet, J = 16 Hz);
5.71 (lH, doublet, J = 16 Hz);
7.00 (2H, doublet, J = 8.5 Hz);
7.07 (2H, doublet, J = 8.5 Hz);
7.50 - 7.71 (4H, multiplet).

(5-Met~yl-2- OXQ-1. 3-dioxolen-4-yl)methyl 4-(1-hydroxy-l-me~ylethyl)-2-propyl-1-{4-~2-(tetrazol-5-yl)-Dhenyll~hP~yl)methyl1~dazole-5-carboxylate (C~ound No. 2-17) 78(a) (5-Met~yl-2-oxo-1.3-dioxol~n-4-yl)methyl 4-(1-hy~ro~y-l-meth~yletbyl)-2-propyl-1-~4-~2-~trityl-tetr~ol-5-yl)ph~yll phenyl~me~hylimi~Azole-5-~A rboxyl~te A solutlon o~ 2.65 g o~ lithium hydroxide monohydrate in 158 ml of water was added, whilst ice-cooling, to a ~olution o~ 30 g o~ ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-~4-~2-(trityl-tetrazol-5-yl)phenyl]phenyl)methylimidazole-5-carboxylate lprepared aY de~cribed ln Example 18(a)] in 344 ml o~ dioxane, and the resultlng mixture was stirred at 5 - 10~C ~or 20 hours. At the end o~ this time, small pieces o~ dry ice were added to the mixture, which wac then co~centrated by evaporation under reduced ~recsure to a volume o about 100 ml. Ethyl acetate and ~odlum chlorlde were added to the concentrat0, and the mlxture wa~ ctlrred. The ethyl acetate layer was 0epara~d, drlsd over anhydrou~ ~odium sul~ate and concentrated by evaporation under reduced pre~sure, to give lithium 4-(1-hydroxy-l-methylethyl)-2-propyl-1-~ 2-~trityltetrazol-5-yl)phenyllphenyl~methyl-imldazole-5-carboxylate ac a glaec. 6.08 g o~ potas~ium carbonate were added, whil~t ice-coollng, to a ~olution .

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

2~616~7 of whole of this lithium carboxylate in 160 ml of N, N-dimethylacetamide, and then a solution of 11.2 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (74~ purity) in 26 ml of N,N-dimethylacetamide was added dropwise, whilst ice-cooling, to the mixture. The resulting mixture was stirred at 50~C for 3 hours. At the end of thi~ time, water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, dried over anhydrous magne~ium sulfate and concentrated by evaporation under reduced pres~ure. The re~idue was crystallized in diisopropyl ether, to give 29.3 g of the title compound as crystals, melting at 9~ - 100~C (with decomposition).

The Nuclear Magnetic Resonance Spectrum of this compound was identical with that of the compound obtained a~ de~cribed in Bxample 61~a).

7~(b) (5-Met~yl-2-oxo-1.3-dioxol~n-4-yl)me~yl 4-(1 ~ydroxy-l-metbyletbyl)-2-pro~yl-l-~4-~2~
(tetrAZol-5-yl)~h~ h~l)lnDt~l~lm~
5 ~A rboxyl A te .:
75 ml o water were added to a suspension o~ 29.3 g of (5-methyl-2-oxo-1,3-dioxolen-4~yl)methyl 4-(1-- hydroxy-l-methylethyl)-2-propyl-1-~4-[2-(trityl-tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate ~prepared ae descrlbed in ~tep (a) above] ln ; 225 ml o~ acetic acid, and the re~ulting mixture wa~
~tirred at 60~C ~or 1.5 hour~. A~ the end of thie time, 75 ml o water were added to the mixture, which wae then cooled. Preclpltated trityl alcohol was removed by 5~ ~iltration, and the ~iltrate wae concentrated by evaporatlon under reduced pressure. Toluene wa~ added to the re~due, and the mixture wac again concentrated . by evaporatlon under reduced pre~ure, to remove the remainlng water and acetlc acid. The re~idue was ~'~

~ t~
,~ . ,- , .; , , , ~,.' .

''.': . ', ,:' : ~ 2 .

2061~07 crystallized in ethyl acetate, to give 16.6 g of the title compound as crystals, melting at 177 - 180~C (with decomposition).

The Nuclear Magnetic Re~onance Spectrum of this compound was identical with that of the compound obtained a~ described in Example 61(b).

(5-Met~yl-2-oxo-1.3-dioxolen-4-yl)methyl 4-(1-hydroxy-l-m~ylet~yl)-2-proDyl-1-~4-~2-(tetrazol-5-yl)-phP~yllph~yl~methyl1 m~ dazole-5-carboxylate (C~ound No. 2-17) l9(a) ~t~yl 4-(1-hydro~y-1-~thylet~yl)-2-~ro~yl-1-~4-l2-(trityltetrazol-5-yl)~h~yllrh~yl~-met~ylim~ ole-5-r~rbo~ylAte A solution o~ 1.00 g of ethyl 1-~2'-cyanobiphenyl-~-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-lmldazole-5-carboxylate [prepared aa de~crlbed in Example 71(b)l and 1.00 g of tributyltin azide in 7.5 ml o~ toluene wae ctirred at 100~C ~or 5 daye. 2.5 g of sodium hydrogencarbonate and 20 ml o~ water were then added to the mixture, and the re~ulting mixture was etirred at room temperature for 8 hours. At the end o~
thic time, the mixture wa~ diluted with ethyl acetate and acldi ied with 3 N aqueou~ hydrochloric acid to a pH
value o~ 3. The ethyl acetate layer wa~ separated, dried over anhydrou~ magneslum ~ul~ate and concentrated by evaporation under reduced pressure, to give ethyl ~-(l-hydroxy-l-methylethyl)-2-propyl-1-{4-~2~te~razol-5-yl)phenyl~phenyl~methylimidazole-5-carboxylate as a syrup. 0. ao g o trityl chloride was added ~o a colution o~ the whole o~ thi~ ~yrup in 15 ml o~ pyridine, and the mixture was ~tirred at 60~C ~or .

.

hours. At the end of this time, the reaction mixture wa~ concentrated by evaporation under reduced pres~ure, and the re~idue wa~ purified by column chromatography through silica gel, using a 1 : 1 by volume mixture of ethyl acetate and h~ne as the eluent; it was then crystallized in diisopropyl ether, to give 1.15 g of the title compound as crystals.

The Nuclear Magnetic Resonance Spectrum of this compound wa~ identical with that of the compound obtAine~ as de~cribed in Example 18(a).

79(b) (5-Methyl-2-oxo-1,3-dioxolPn-4-yl)m~thyl 4-(1-~Y~r~XY-l-met~ylethyl)-2-pro~yl-1-~4-~2-( tetrA 7~1-5-yl)~h~yllphenyl~met~ylimidazole 5-~A r~o~ylAte Following procedures similar to tho~e described in Example 78(a) and 78~b), but uslng ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-(4-~2-(trityltetrazol-5 yl)-phenyl]phenyl}methyl~m1d~zole-5-carboxylate ~prepared ac deccribed in ctep (a) above], the tltle compound wa~
obt~i~ed ln a 71~ yield.

The Nuclear Magnetic Reso~nce 9pectrum o~ thl~
compound wae ldentlcal with that of the compound obtalne~ aa de~cribed ln Example 61(b).

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Claims (39)

1. A compound of formula (I):

in which:

R1 represents an alkyl group having from 1 to 6 carbon atoms or an alkenyl group having from 3 to 6 carbon atoms;

R2 and R3 are the same or different and each represents:

an alkyl group having from 1 to 6 carbon atoms;
an alkenyl group having from 3 to 6 carbon atoms;
a cycloalkyl group having a total of from 3 to 10 ring carbon atoms in one or more saturated carbocyclic rings;
an aralkyl group in which the alkyl part has from 1 to 6 carbon atoms and the aryl part is as defined below;
an aryl group as defined below; or a fused ring system in which an aryl group, as defined below, is fused to a cycloalkyl group having from 3 to 10 carbon atoms;
R4 represents:
a hydrogen atom;
an alkyl group having from 1 to 6 carbon atoms;
an alkanoyl group having from 1 to 6 carbon atoms;
a substituted alkanoyl group having from 2 to 6 carbon atoms and substituted by at least one substituent selected from halogen atoms and alkoxy groups having from 1 to 6 carbon atoms;
an alkanoyl group having from 3 to 6 carbon atoms;
an arylcarbonyl group in which the aryl part is as defined below;
an alkoxycarbonyl group in which the alkyl part has from 1 to 6 carbon atoms;
a tetrahydropyraryl, tetrahydrothiopyranyl, tetrahydrothienyl or tetrahydrofuryl group;
a substituted tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl or tetrahydrofuryl group which is substituted by at least one substituted selected from halogen atoms and alkoxy groups having from 1 to 6 carbon atoms;
a group of formula -SiR a R b R c, in which 1, 2 or 3 of the groups represented by R a, R b and R c are the same or different and each represents an alkyl group having from 1 to 6 carbon atoms, and 2, 1 or 0 of the groups represented by Ra, Rb and Rc are independently selected from the group consisting of aryl groups, as defined below;
alkoxymethyl groups in which the alkoxy part has from 1 to 6 carbon atoms;
(alkoxyalkoxy)methyl groups in which each alkoxy part has from 1 to 6 carbon atoms;
haloalkoxymethyl groups in which the alkoxy part has from 1 to 6 carbon atoms;
aralkyl groups, in which an alkyl group having from 1 to 6 carbon atoms is substituted by at least one aryl group, as defined below; or alkanoyloxymethoxycarbonyl groups in wbich the alkanoyl part has from 1 to 6 carbon atoms;

R5 represents a carboxy group or a group of formula -CONR8R9, wherein R8 and R9 are independently selected from the group consisting of hydrogen atoms, unsubstituted alkyl groups having from 1 to 6 carbon atoms, and substituted alkyl groups which have from 1 to 6 carbon atoms and which are substituted by at least one substituent selected from the group consisting of substituents (a), defined below, or R8 and R9 together represent an unsubstituted alkylene group having from 2 to 6 carbon atoms or a substituted alkylene group which has from 2 to 6 carbon atoms and which is substituted by at least one substituent selected from the group consisting of carboxy groups and alkoxycarbonyl groups in which the alkyl part has from 1 to 6carbon atoms;

R6 represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms, an alkoxy group having from 1 to 6 carbon atoms or a halogen atom;

R7 represents a carboxy group or a tetrazol-5-yl group;
said substituents (a) are selected from the group consisting of:
aryl groups as defined below;
heterocyclic groups having 5 or 6 ring atoms, of which from 1 to 4 are hetero-atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms;
halogen atoms;
hydroxy groups;
alkoxy groups having from 1 to 6 carbon atoms;
carboxy groups;
alkoxycarbonyl groups in which the alkyl part has from 1 to 6 carbon atoms;
amino groups; and acylamino groups, in which the acyl part is an alkanoyl group having from 1 to 6carbon atoms or an arylcarbonyl group, in which the aryl part is as defined below;

said aryl groups are aromatic carbocyclic groups which have from 6 to 14 ring atoms and which are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents (b), defined below; and said substituents (b) are selected from the group consisting of nitro groups, cyano groups, halogen atoms, unsubstituted carbocyclic aryl groups having from 6 to 10 ring atoms, alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, carboxy groups, alkoxycarbonyl groups in which the alkoxy part has from 1 to 6 carbon atoms and alkylenedioxy and alkylidenedioxy groups having from 1 to 3 carbon atoms;
and pharmaceutically acceptable salts and esters thereof.

2. The compound of Claim 1, wherein said compound is an ester in which R5 is a group of formula -COOR5a, where R5a represents:
an alkyl group having from 1 to 6 carbon atoms;
a haloalkyl group having from 1 to 6 carbon atoms;
a hydroxyalkyl group having from 1 to 6 carbon atoms;

an alkoxyalkyl or alkoxyalkoxyalkyl group in which the alkoxy and the alkyl parts each have from 1 to 6 carbon atoms;

a phenacyl group or a phenacyl group which is substituted by one or more of substituents (b), defined in Claim 1;

an alkoxycarbonylalkyl group, in which the alkoxy and the alkyl parts each have from 1 to 6 carbon atoms;
a cyanoalkyl group having from 1 to 6 carbon atoms;
an alkylthioalkyl group in which each alkyl part has from 1 to 6 carbon atoms;

an arylthioalkyl group in which the alkyl part has from 1 to 6 carbon atoms, and the aryl part is as defined in Claim 1;
an alkylsulfonylalkyl group in which each alkyl part has from 1 to 6 carbon atoms;

an arylsulfonylalkyl group in which the alkyl part has from 1 to 6 carbon atoms, and the aryl part is as defined in Claim 1;
an aryl group as defined in Claim 1;

an aralkyl group in which the alkyl part has from 1 to 6 carbon atoms, and the aryl part is as defined in Claim 1;

a group of formula -SiRdReRf (in which Rd, Re and Rf are as defined in Claim 1 in relation to Ra, Rb and Rc);

an alkanoyloxyalkyl group in which each of the alkanoyl and the alkyl parts has from 1 to 6 carbon atoms;

a cycloalkanoyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has from 1 to 6 carbon atoms;
an alkoxycarbonyloxyalkyl group in which each of the alkoxy and the alkyl parts has from 1 to 6 carbon atoms;

a cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl parts has from 1 to 6 carbon atoms;

a [5-(aryl- or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl groups in which the alkyl part has from 1 to 6 carbon atoms and the aryl part is as defined in Claim 1; or a phthalidyl group.

3. The compound of Claim 2, wherein R5a represents:
a C1 - C4 alkyl group;
a phenyl, naphthyl or substituted phenyl groups having at least one substituent selected from the group consisting of methyl, ethyl, methoxy, ethoxy, fluoro and chloro substituents;
a benzyl, diphenylmethyl or .alpha.- or .beta.- naphthylmethyl group;
a substituted benzyl group having at least one substituent selected from the group concisting of methyl, ethyl, methoxy, ethoxy, fluoro and chloro substituents;

a group of formula SiRdReRf in which 1, 2 or 3 of the groups represented by Rd, Re and Rf are independently selected from the group consisting of aLkyl groups having from 1 to 4 carbon atoms, and 2, 1 or 0 are phenyl groups;

an alkanoyloxyalkyl group in which the alkanoyl group has from 1 to 5 carbon atoms and the alkyl group has from 1 to 4 carbon atoms;

cycloalkanoyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atomsand the alkyl part has from 1 to 4 carbon atoms;

an alkoxycarbonyloxyalkyl group in which each of the alkoxy part and the alkyl part has from 1 to 4 carbon atoms;

a cycloalkoxycarbonyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has from 1 to 4 carbon atoms;

a [5-(phenyl or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group in which the alkyl part has from 1 to 4 carbon atoms; or a phthalidyl group.

4. The compound of Claim 2, wherein R5a represents:
a C1-C4 alkyl group;
the benzyl group;
an alkanoyloxyalkyl group in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a cycloalkanoyloxyalkyl group in which the cycloalkyl part has from 5 to 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

an alkoxycarbonyloxyalkyl group in which the alkoxy part has from 1 to 4 carbon atoms and alkyl part has 1 or 2 carbon atoms;

a cycloalkoxycarbonyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a [5-(phenyl or alkyl-)-2-oxo- 1,3-dioxolen-4-yl]methyl group in which the alkyl part has 1 or 2 carbon atoms; or a phthalidyl group.

5. The compound according to Claim 2, in which R5a repersents a pivaloyloxymethyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, isopropoxycarbonyloxymethyl, (1-isopropoxycarbonyloxy)ethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl or phthalidyl group.

6. The compound according to Claim 1, in which:

R1 represents an alkyl group having from 2 to 5 carbon atoms or an alkenyl group having from 3 to 5 carbon atoms;

R2 and R3 are the same or different and each represents:
an alkyl group having from 1 to 4 carbon atoms, an alkenyl group having from 3 to 5 carbon atoms, a cycloalkyl group having 5 or 6 carbon atoms, a benzyl, naphthyl or phenyl group, or a substituted benzyl or phenyl group which is substituted by at least one of substituents (b'), defined below;

R4 represents:
a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkanoyl group having from 1 to 5 carbon atoms, a substituted alkanoyl group which has 2 or 3 carbon atoms and which is substituted by at least one substituent selected from fluorine and chlorine atom and methoxy and ethoxy groups, an alkenoyl group having from 3 to 5 carbon atoms, a naphthoyl group, a benzoyl group, a substituted benzoyl group which is substituted by at least one of substituents (b'), defined below, an alkoxycarbonyl group having from 2 to 5 carbon atoms, a tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl or tetrahydrofuryl group, a substituted tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrothienyl or tetrahydrofuryl group which is substituted by at least one substituent selected from chlorine and bromine atoms and methoxy groups, a group of formula -SiRaRbRc, in which 1, 2 or 3 of the groups represented by Ra, Rb and Rc are the same or different and each represents an aikyl group having from 1 to 4 carbon atoms, and 2, 1 or 0 of the groups represented by Ra, Rb and Rc are phenyl groups, a methoxymethyl, 1-methoxyethoxymethyl, 2,2,2-tri-ehloroethoxymethyl, bis(2-chloroethoxy)methyl, benzyl, diphenylmethyl or naphthylmethyl group or a substituted benzyl group which is substituted by at least one of substituents (b'), defined below, or a pivaloyloxymethoxycarbonyl group;

R5 represents a carboxy group, a group of formula -COOR5a or a group of formula -CONR8R9, in which:

R5a represents an alkyl group having from 1 to 4 carbon atoms, a phenyl, naphthyl, benzyl, diphenylmethyl or naphthylmethyl group, a substituted phenyl or benzyl group which is substituted by at least one of substituents (b'), defined below, a group of formula -SiRaRbRc, in which Ra, Rb and Rc are as defined above, an a alkanoyloxyalkyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, and the alkyl part has from 1 to 4 carbon atoms, a cycloalkanoyloxyalkyl group, in which the cycloalkanoyl part has 6 or 7 carbon atoms, and the alkyl part has from 1 to 4 carbon atoms, an alkoxycarbonyloxyalkyl group, in which the alkoxy part has from 1 to 4 carbon atoms, and the alkyl part has from 1 to 4 carbon atoms, a cycloalkoxycarbonyloxyalkyl group, in which the cycloalkoxy part has 5 or 6 carbon atoms, and the alkyl part has from 1 to 4 carbon atoms, a [5-(phenyl- or alkyl-)-2 oxo-1,3-dioxolen-4-yl]-methyl group in which the alkyl part has from 1 to 4 carbon atoms, or a phthalidyl group:

R8 and R9 are the same or different and each represents:
a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, and a substituents alkyl group which has from 1 to 4 carbon atoms and which is substituted by at least one of substituents (a'), defined below;
or R8 and R9 together represent an unsubstituted alkylene group which has 4 or 5 carbon atoms or a substituted alkylene group which has 4 or 5 carbon atoms and which is substituted by at least one substituent qelected from carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups;

substituents (a') are selected from the group consisting of phenyl groups, furyl groups, thienyl groups, fluorine atoms, chlorine atoms, hydroxy groups, methoxy groups, ethoxy groups, carboxy groups and alkoxycarbonyl groups having from 2 to 5 carbon atoms;

substituents (b') are selected from the group consisting of methyl, ethyl, methoxy and ethoxy groups and fluorine and chlorine atoms;

R6 represents a hydrogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a fluorine atom, a chlorine atom or a bromine atom;

R7 represents a carboxy group or a tetrazol-5-yl group; and the benzene ring which bears the substituents represented by R6 and R7 is at the 3- or 4- position of the benzyl group to which it is attached.

7. The compound of Claim 1, wherein:

R1 represents an alkyl group having from 2 to 5 carbon atoms or an alkenyl grouphaving from 3 to 5 carbon atoms;

R2 and R3 are independently selected from the group consisting of:
alkyl groups having from 1 to 4 carbon atoms, alkenyl groups having from 3 to 5 carbon atoms, cycloalkyl groups having 5 or 6 carbon atoms, and benzyl and phenyl groups;

R4 represents:
a hydrogen atom, a methyl or ethyl group, an alkanoyl group having from 1 to 5 carbon atoms, an alkenoyl group having from 3 to 5 carbon atoms, a benzoyl group, or an alkoxycarbonyl group having from 2 to 5 carbon atoms;

R5 represents a carboxy group, a group of formula -COOR5a or a group of formula -CONR8R9, in which:

R5a represents an alkyl group having from 1 to 4 carbon atoms, a benzyl group, an alkanoyloxyalkyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, and the alkyl part is a methyl or ethyl group, a cycloalkanoyloxyalkyl group, in which the cycloalkanoyl part has 6 or 7 carbon atoms, and the alkyl part is a methyl or ethyl group, an alkoxycarbonyloxyalkyl group, in which the alkoxy part has from 1 to 4 carbon atoms, and the alkyl part is a methyl or ethyl group, a cycloalkoxycarbonyloxyalkyl group, in which the cycloalkoxy part has 5 or 6 carbon atoms, and the alkyl part is a methyl or ethyl group, a [5-(phenyl-, methyl- or ethyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group, or a phthalidyl group;

R8 and R9 are the same or different and each represents:
a hydrogen atom, a methyl group, an ethyl group, or a substituted methyl or ethyl group which is substituted by at least one substituent selected from carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups;
or R8 and R9 together represent an unsubstituted alkylene group which has 4 or 5 carbon atoms or a substituted alkylene group which has 4 or 5 carbon atoms and which is subtituted by at least one substituent selected from carboxy groups, methoxycarbonyl groups and ethoxycarbonyl groups;

R6 represents a hydrogen atom, or it represents a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom or a chlorine atom on the 6-position of the benzene ring;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2- or 3- position of the benzene ring; and the benzene ring which bears the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it is attached.

8. The compound according to Claim 1, in which:

R1 represents an alkyl group having from 2 to 5 carbon atoms;

R2 and R3 are the same or different and each represents an alkyl group having from 1 to 4 carbon atoms;

R4 represents a hydrogen atom, a methyl group, an ethyl group or an alkanoyl group having from 1 to 5 carbon atoms;

R5 represents a carboxy group, a group of formula -COOR5a or a group of formula -CONR8R9, in which:

R5a represents a methyl, ethyl or benzyl group, an alkanoyloxymethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, a 1-(alkanoyloxy)ethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, an alkoxycarbonyloxymethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a [5-(phenyl- or methyl-)-2- oxo -1,3-dioxolen-4-yl]methyl group, or a phthalidyl group;

R8 and R9 are the same or different and each repsesents a hydrogen atom, a methyl group, an ethyl group, a methoxycarbonylmethyl group, an ethoxy-carbonylmethyl group or a carboxymethyl group; or R8 and R9 together represent a tetramethylene, petamethylene, 1-carboxytetramethylene or 1-carboxypentamethylene group;

R6 representc a hydrogen atom, or it represents a methyl group, an methoxy group, a fluorine atom or a chlorine atom at the 6-position of the benzene ring;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which bears the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it is attached.

9. The compound according to Claim 1, in which;

R1 represent an ethyl, propyl or butyl group;

R2 and R3 each represent a methyl group;

R4 represents a hydrogen atom or a methyl group;

R5 represents a carboxy group or a group of formula -COOR5a, in which R5a represents a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1-(e~hoxy-carbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a 1- (isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or a phthalidyl group;

R6 represente a hydrogen atom;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which bears the substituents represented by g6 and R7 ig at the 4-position of the benzyl group to which it is attached.

10. The compound according to Claim 1, in which:

R1 represents an ethyl, propyl or butyl group;

R2 and R3 both represent methyl groups;

R4 represents a hydrogen atom or a methyl group;

R5 represents a carboxy group or a group of formula -COOR5a, in which R5 represents a pivaloyloxymethyl group, an ethoxycarbonyloxymethyl group, a 1- (ethoxy-carbonyloxy)ethyl group, an isopropoxycarbonyloxymethyl group, a l-(isopropoxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or a phthalidyl group;

R6 represents a hydrogen atom;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which beare the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it is attached.

11. The compound of Claim 1, selected from the group consisting of 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

12. The compound of Claim 1, selected from the group consisting of pivaloyloxymethyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)- methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylace and pharmaceutically acceptable salts thereof.

13, The compound of Claim 1, selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydzoxy-1-methylethyl)imidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

14. The compound of Claim 1, selected from the group consisting of 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

15. The compound of Claim 1, selected from the group consisting of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

16. The compound of Claim 1, selected from the group consisting of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

17. The compound of Claim 1, selected from the group consisting of 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid and pharmaceutically acceptable salts thereof.

18. The compound of Claim 1, selected from the group consisting of pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

19. The compound of Claim 1, selected from the group consisting of pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

20. The compound of Claim 1, selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

21. The compound of Claim 1, selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically accepeable salts thereof.

22. The compound of Claim 1, selected from the group consisting of ethoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

23. The compound of Claim 1, selected from the group consisting of isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

24. The compound of Claim l, selected from the group consisting of 1-(ethoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

25. The compound of Claim 1, selected from the group consisting of 1-(isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

26. The compound of Claim 1, selected from the group consisting of pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)-phenyl]phenyl}methylimidazole-5-carboxylate and pharmaceutically acceptable salts thereof.

27. The compound of Claim 1, selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-(4-[2-(terrazol-5-yl)phenyl]phenyl]methylimidazole-5-carboxylate and pharmaceutically acceptable salta thereof.

28. The compound of Claim 1, selected from the group consisting of pivaloyloxymethyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5- carboxylate and pharmaceutically acceptable salte thereof.

29 The compound of Claim 1, selected from the group consisting of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methyl-ethyl)-2-propylimidazole-5-caxboxylate and pharmaceutically acceptable salts thereof.

30. The compound of Claim 1, selected from the group consisting of phthalidyl 1-[(2'-earboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate and pharmaceutically acceptable salts thereof.

31. A pharmaceutical composition for the treatment or prophylaxis of hypertension, which comprises an anti-hypertensive agent admixture with a pharmaceutically acceptable carrier or diluent, in which the anti-hypertensive agent is selected from the group consisting of compounds of formula (I) and pharmaceutically acceptable salts and esters thereof, as claimed in Claim 1.

32. The pharmaceutical composition according to Claim 31, in which the anti-hypertensive agent is a compound of formula (I) in which R5 represents a group of formula -COOR5a in which R5a represents:

a C1 - C4 alkyl group;

a benzyl group;

an alkanoyloxyalkyl group in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a cycloalkanoyloxyalkyl group in which the cyoloalkyl part has 5 or 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

an alkoxycarbonyloxyalkyl group in which the alkoxy part has from 1 to 4 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a cycloalkoxycarbonyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a [5-(phenyl or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group in which the alkyl part has 1 or 2 carbon atoms; or a phthalidyl group.

33. The pharmaceutical composition according to Claim 31, in which the anti-hypertensive agent is a compound of formula (I), in which:

R1 represents an alkyl group having from 2 to 5 carbon atoms;

R2 and R3 are the same or different and each represents an alkyl group having from 1 to 4 carbon atoms;

R4 represents a hydrogen atom, a methyl group, an ethyl group or an alkanoyl group having from 1 to 5 carbon atoms:

R5 represents a carboxy group, a group of formula COOR5a or a group of formula -CONR8R9, in which:

R5a represents a methyl, ethyl or benzyl group, an alkanoyloxymethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, a 1-(alkanoyloxy)ethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, an alkoxycarbonyloxymethyl group, in which the alkoxy part has from 1 to 5 carbon atoms, a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a [5-(phenyl- or methyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group, or a phthalidyl group;

R8 and R9 are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, a methoxycarbonylmethyl group, an ethoxy-carbonylmethyl group or a carboxymethyl group; or R8 and R9 together represent a tetramethylene, pentamethylene, 1-carboxytetramethylene or 1-carboxypentamethylene group;

R6 represents a hydrogen atom, or it represents a methyl group, an mechoxy group, a fluorine atom or a chlorine atom at the 6-position of the benzene ring;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which bears the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it is attached.

34 The pharmaceutical composition according to Claim 31, in which the anti-hypertensive agent is selected from the group consisting of:

2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid;

pivaloyloxymethyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methyl-ethyl)imidazole-5-carboxylate;

1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid;

1-[(2'-carboxybiphenyl-4-yl)methyl]-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid;

4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

ethoxycarboxyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

1-(ethoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

1-(isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methyl-ethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-[(2'-carboxy-biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

phthalidyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;
and pharmaceutically acceptable salts thereof.

35. The use of a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as claimed in Claim 1, for the manufacture of a medicament for the treatment or prophylaxis of hypertension.

36. The use according to Claim 35, in which the compound of fonmula (I) is one in which R5 represents a group of formula -COOR5a in which R5a represents:

a C1 - C4 alkyl group;

a benzyl group;

an alkanoyloxyalkyl group in which the alkanoyl part has from 1 to 5 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a cycloalkanoyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

an alkoxycarbonyloxyalkyl group in which the alkoxy part has from 1 to 4 carbon atoms and the alkyl part has 1 or 2 carbon atoms:

a cycloalkoxycarbonyloxyalkyl group in which the cycloalkyl part has 5 or 6 carbon atoms and the alkyl part has 1 or 2 carbon atoms;

a [5-(phenyl or alkyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group in which the alkyl part has 1 or 2 carbon atoms; or a phthalidyl group.

37. The use according to Claim 35, in which the compound of formula (I) is one in which:

R1 represents an alkyl group having from 2 to 5 carbon atoms;

R2 and R3 are the same or different and each represents an alkyl group having from 1 to 4 carbon atoms;

R4 represents a hydrogen atom, a methyl group, an ethyl group or an alkanoyl group having from 1 to 5 carbon atoms;

R5 represents a carboxy group, a group of formula -COOR5a or a group of formula -CONR8R9, in which:

R5a represents a methyl, ethyl or benzyl group, an alkanoyloxymethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, a 1-(alkanoyloxy)ethyl group, in which the alkanoyl part has from 1 to 5 carbon atoms, an alkoxycarbonyloxymethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a 1-(alkoxycarbonyloxy)ethyl group, in which the alkoxy part has from 1 to 4 carbon atoms, a [5-(phenyl- or methyl-)-2-oxo-1,3-dioxolen-4-yl]methyl group, or a phthalidyl group;

R8 and R9 are the same or different and each represents a hydrogen atom, a methyl group, an ethyl group, a methoxycarbonylmethyl group, an ethoxy-carbonylmethyl group or a carboxymethyl group; or R8 and R9 together represent a tetramethylene, pentamethylene, 1-carboxytetramethylene or 1-carboxypentamethylene group;

R6 represents a hydrogen atom, or it represents a methyl group, an methoxy group, a fluorine atom or a chlorine atom at the 6-position of the benzene ring;

R7 represents a carboxy group or a tetrazol-5-yl group at the 2-position of the benzene ring; and the benzene ring which bears the substituents represented by R6 and R7 is at the 4-position of the benzyl group to which it is attached.

38. The use according to Claim 35, in which the compound of formula (I) is selected from the group consisting of:

2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid;

pivaloyloxymethyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)-methyl]-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methyl-ethyl)imidazole-5-carboxylate;

1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid;

1-[(2'-carboxybiphenyl-4-yl)methyl]-2-ethyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid;

4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid;

pivaloyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-butyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl)methylimidazole-5-carboxylate;

ethoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

isopropoxycarbonyloxymethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

1-(ethoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methyl-imidazole-5-carboxylate;

1-(isopropoxycarbonyloxy)ethyl 4-(1-hydroxy-1-methyl-ethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(tetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate;

pivaloyloxymethyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 1-[(2'-carboxy-biphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

phthalidyl 1-[(2'-carboxybiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate;

and pharmaceutically acceptable salts thereof.

39. A process for preparing a compound according to Claim 1, which comprises the steps:

reacting a compound of formula (II):

[in which;

R1 is as defined in claim 1 and R d represents a group of formula wherein R2, R3 and R4 are as defined in Claim 1, or R d represents a group of formula -COOR f wherein R f represents a carboxy-protecting group, R d represents a group of formula -COR2, wherein R2 is as defined above, or R d represents a cyano group; and R e represents a cyano group, a carboxy group or a group of formula -COOR f, wherein R f is as defined above, with a compound of formula (III):

in which: R6 is as defined in Claim 1; R7a represents a protected carboxy group, a cyano group, a protected tetrazol-5-yl group, a carbamoyl group or an alkylcarbamoyl group; and X represents a halogen atom;

to give a compound of formula (IV):

wherein R d, R e, R l, R6 and R7a are as defined above; and in any order, removing protecting groups, and, if necessary, converting said group R d to a group of formula wherein R2, R3 and R4 are as defined above, and, if necessary, converting said group R e to a group R5, converting said group R7a to a group R7, or alkylating or acylating a hydroxy group in R4, to give a compound of formula (I); and optionally salifying or esterifying the product.