CA2075621A1 - Imidazole angiotensin ii antagonists incorporating a substituted benzyl element - Google Patents

Abstract

Substituted imidazoles attached through a methylene bridge to novel substituted phenyl derivatives of formula (I), are useful as angiotensin II antagonists.

Description

TITLE OF T~ TI~
IMIDAZOLE ANGIOTENSIN II ANTAGONISTS INCORPORATING A
SUBSTITUTED BENZYL ELEMENT

BACKGROUND OF THE IN~NTION
The present invention is a continuation in part of Serial No. 479,780 filed February 13, 1990.
The Renin-angiotensin syætem (RAS) plays a central role in the regulation of normal blood preæsure and ~eems to be critically involved in hypertension development and ma ntena~ce as well aæ
congestiYe heart failure. Angiotensin II (A II), is an octapeptide hormone produced mainly in the blood during the cleavage of angioten~in I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels o lung, kidney, and many other organs. It i~ ~he end product of the renin-angiotensin s~stem (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes.

8U13STITUTE SHEET' ~ 5~ P~T/US91/OiO~1 .;-, . . ~- . .

One of the possible modes of controlling the RAS is , I
angiotensin II receptor antagon.i~m. Se~eral peptide analogs of A II are known to inhibit the effect o$
this hormone by competitively blocking the receptors, but their experimental and clinica~ applications have been limited by partial agoni~t activity and lack of oral absorption [M. Antonaccio. Clin. ~
~ypertea~ A4, 27-46 (1982); D. ~. P. Streeten and G. H. Anderson, Jr. - HandboQk of Hyp~rtensi~, Clinical PharmacolQgy of A~tihyp~rten~iv~ç Dru~, ed.
A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984~.
Recently, ~everal non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are thoæe disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847 in European Patent Applications 028,834; 245,637;
253,310; and 291,969; and in articles by A.T. Chiu, et ~al. C~r. J Pharm. E~p. T~rap. 157, 13-21 (1988)] and by P.C. Wong, et ~1- [J. Pha~m. E~
The~a~, 247, 1-7(1988)]. All of the U.S. Patents, European Pate~t Applications 028,834 and 253,310 and the two articles disclose subgtituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloses derivatives of 4,5,6,7-tetrahydro-2~-imidazot4,5-c~-pyridine-6-carboxylic acid and analogs thereof as antihyper-tensive agents.
None of the compounds disclosed within this application have been identified in any US Patent, European Applications or articles nor are they of the SLIBST~TUTE 5~1EET

WO9l/12002 PCT/USgl/O1001 .. .

~5~

type containing substituted heterocycles bonded through an alkyl bridge to a novel subætituted phenyl. The sub~tituted imidazoles, have been disclosed in patents to DuPont ~EP0 253,310 and EPO
324,377) focusing on the design of Angiotensin II
Antagonists.
The compounds of this invention have central nervous system (CNS) activity. They are useful in the treatment of co~nitive dysfunctions including Alzheimer's disease, amnesia and senile dementia.
These compou~d~ also have anxiolytic and antidepre~sant prOpertieB and are therefore, use~ul in the relie~ of symptoms of an~iety and tension and in the treatment of patients with depressed or dysphoric mental states.
In addition, these compounds eæhibit antidopaminergic properties and are thus useful to treat disorder8 that involve dopamine dy~function such as schi~ophrenia. The compounds of this invention are e8pecially useful in the treatment of these conditions ;n patients who are also hypertensive or have a conge~tive heart failure condition.

$UBSTITIJTE. S~

W091/12~2 PCT/US91/01001 ;~7~
_ 4 --DETAILED D~S~RI~IQN OF TH~_INV~NrlON

This in~ention relates to compounds of Formula I:

R3 ~ N~ ~ B-4 ~ ~
R9 ~ Rl X~z Rll y--R12 FORMULA I

or a pharmaceutically acceptable salt thereof.

wherei~:
Rl is:
(a) (Cl-C6)-alkyl, (C2-C~)-alkenyl or (C2-C63-alkynyl each of which is unsubstituted or substituted ~ith a substituent ~elected ~rom the group consistin~ of:
i) aryl as defined below, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, iv) COOR2, vii) N[((Cl-C4)-al3~Yl)]2 vi i i ~ NHS02R2, SllBSTlTl,lTE S4~E~T

W091/120~2 PCT/US91/U1001 7~
.~...:, ; .

ix) CF3, x) COOR2, or t xi) S02NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with l or 2 substituents 3elected from the group consisting of:
i) Cl, Br, F, I, ii) (Cl-C4)-alkyl, iii) (Cl-C4)-alkoxy, iv) N02 v) CF3 vi ) S02NR2aR2a, vii) (Cl-C4)-alkylthlo, viii) hydroxy, -ix) amino, x) (C3-C7~-cycloalkyl, xi) (C3-ClO)-alkenyl; and (c) heteroaryl, wherein heteroaryl i5 deXined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members ~elected from the group consisting of:
i) Cl, Br, F, I, ii) OE, iii) 5~, c iv) M02, v) (Cl-C4 )-alkyl, ~i) (C2-C4)-alkenyl, SlJlE3STlTllT SHE~ET

WO91/1200~ PCT/US91/o~00 2~7~J~

vii) (C2-C4)-alkynyl, viii) (Cl-C4)-alkoxy, or ix) CF3, or (d) per~luoro-(Cl-C4)-alkyl; and is:
(a) a single bond, (b) -S(0)x(CH2)s~, or (c) -0-;and is 0 to 2, s is 0 to 5;
m is 1 to 5;
p is 0 to 3;
n i3 1 to 10;

R2, iS:
(a) H, or (b) (Cl-C6)-alkyl, and R2a is:
(a) R2, - (b) C~2-aryl, or ~c) aryl; and R is: , (a) ~, (b) (Cl-C6)-alkyl, (C2-C~>-alkenyl or (C2-C6)-alkynyl, SUE~STITUTE~ ~IEET

WO91/12002 PCT~USgl/OI~Ol 2C~

. ~ .

(c) Cl, Br, I, F, (d) N02 c ( e ) ( C l-C8 ) -pe rf luor oalkyl, (f) C6Fs, (g) CN, (h) NH2 ~
( i ) NH[ (Cl-C4)-alkyl], (j) N[(Cl-C4)-alkyl]2~
(k) N~CCO(Cl-C4~-alkyl~, (1) N[(Cl-C4)-alkyl)-(CO(Cl-C4)-alkyl)], (m) N(Cl-C4)-alkyl-COaryl, ~n) N(Cl-C4 )alkyl-S02aryl, (O) C02H, (p) C02R2a, (q) phe~yl, (r) phenyl-(Cl-C3)-alkyl, (s) phenyl and phenyl-(Cl-C3)-alkyl ~ubstituted on the phenyl ring wlth one or two sub6tituents selected from:
i) (Cl-C4)-alkyl, ii ) (Cl-C4)-alkoxyl, iii) F, Cl, Br, I, iv) hydroxyl, v) methoxyl, vi) C~3, vii) C02R2a, or viii) N02; and R4 is:
(a) H, (b) CN, (c) (Cl~C8)-alkyl, ~ UBST5TUTE S~HE~T' WO 91/12û02 Pcr ~7~

( d ) ( C 3 -C ~, ) -alkenyl, (e) (C1-C8)-perfluoroalkyl, (f ~ (Cl-C8)~perfluoroalkenyl, (g) NH2, (h) ~I(Cl-C4)-alkyl, ( i ) N[ ( Cl-C4 ) -alkyl ] 2 (j) NH(Cl-C4)-acyl, (k) N[ ( (C1-C4)-acyl) ( (Cl-C4)-alkyl)~, (1) C02H, (m) C02R2a, ( n ) phenyl, (o) phenyl-(C2-C6)-alkenyl, O
(P) C-Rl6 oR17 O
( r ) ( CH2 )noCR14, ( s ) ( CH2 )nSR15, o (t) CH=C~(C~2)soCR~5, (u) CH=c~(CH~)sCRl7, (v) (CH~)S-CH-CRl5, o o (w) (C}I2)nCR15, ( x ) ( CH2 )nOCNHR1 6, S

( y ) ( CH2 ) nOCNHRl 6, SUBST~ E SHE3~

Z ~7 ~~

_ 9 _ 1 ~z) (CH2)nNHSO2Rl6, (aa) (C~2)nF' (ab) (CH2)m-imidazol-l-yl, (ac) (CH2)~-l,2,3-triazolyl, unsubstituted or ~ubstituted with one or two substituents selected from:
i ) C02C~3, ii) (Cl-C4)-alkyl.
(ad) tetrazol-5-yl, (ae) -CONH-S02-aryl, (af) -CON~-S02-(Cl-C8)-alkyl, wherein the alkyl group i~ unsubstituted or ~ub~tituted with a substituent selected from the group consisting of: -OH, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -C2~ -co2-(cl-c4)-alkyl, -N~2, -N~[(Cl-C4)-alkyl], -N~(Cl-C4)-alkyl]2; and (ag) -CON~-S02-perfluoro-(Cl-C4)-alkyl, (ah) -CON~S02NR2aR2a; and N ~N
ag) - ( CH2 ) ~

N--N
C a h) - ~ CH2 ) 1~
H CF3, or ( ai) - CH= N- NH--< ~; and N

SUBSTI~TE SH~T

WOgl/12~02 PCT/USgl/01001 R5 is:
(a) CN, (b) N02, or (c) C02R2a; and R9 and R10 are independently:
(a) H, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (Cl-C6)-alkoxy, (g) when R9 and R10 are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(Cl-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (Cl-C6)-al~yl, (j) aryl; and X is:
(a) -0-, (b) -S(0)~-, (c) _NR13_ (d) -CH20-, (e) ~CH2S(O)n, (f) -C~2NR13 -, ( g ) -OCH2-, (h) -NR13CH2-, (i ) ~s(~)ncH2-, ( j ) -C~I2- , .
(k) -(C~2)2-' (1) ~ingle bond, or $lJE3STlTUTE S~EET

WOs1/12002 PCT/US91/01001 .
2~

! (m) -C~=, wherein Y and Rl2 are absent forming a -C=C- bridge to the carbon bearing Z and Rll; and Y is:
(a) single bond, (b) _o_, (c) -S(O)n-, (d) _NR13_ or (e) -CH2-; and Except that ~ and Y are not defined in ~uch a way that the ~arbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (0, N, S, SO . SO2 ) Rll and Rl2 are independently:
(a) ~, (b) (Cl-C6)-alkyl un~ubstituted or ~ubstituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, unsub~tituted or ~ubstituted with l to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (Cl-C6)-alkyl, iii) [(Cl-C5)-alkenyl]C~2-, iv) [(~l-c5)-alkynyl]c~2 v) (Cl-C5)-alkoxy, vi~ (Cl-C5)-alkylthio, vi i ) -N02 , SlJB~::TlTI ITF ~r WO91/12~2 PCT/VS9t/Olool ~5~

viii) -CF3, ix) -C02R2a, or ~) -OH; and (d) aryl-~Cl-C2)-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the ~roup consisting of:
i) Cl, Br, I, F, ii) (Cl-C6)-alkyl, iii) ~(Cl-C5)-alkenylJCH2-, iv) [(Cl-C5)-alkynyl~CH2-, v) ~Cl-C5)-alko~y, vi) (Cl-C5~-alkylthio, vi i ) -N02 ~
viii) -CF3, ix) -C02R2a, or x) -OH; and (e) (C3-C7)-cycloalkyl: and ~13 is:
(a) H, (b) (Cl-C6)-alkyl, (c) aryl, (d) aryl-(Cl-C6)-alkyl-(C=O)-, (e) (Cl-C6)-alkyl-(C=O)-, (f) [(C2-C5)-alkenyl]C~2-, (g) ~(C2 C5)-alkYnyl]CH2-, or (h) aryl-C~2-; and .
Z i3:
(a) -CO2~, (b) -CO2-(Cl-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) SUB5rlT~ E StlEET

W091/1~002 P~T/US91/010~1 % ~ ~$i~,~

(e~ -CON~-SO~-aryl, (f) -CON~-S02-(Cl-C8)-alkyl, wherein the alkyl group is un~ubstituted or substituted with a substituent selected from the group consisting o~: -OH, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -C02H- -co2-(cl-c4)-alkyl, -NH2, -NE[(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl]2; and (g) -CONH-S02-perfluoro-(Cl-C4) alkyl, (h) -CON~-S02-heteroaryl, or (i) -CON~S02~R2aR2a; and (j) -S02NHCO-aryl, (k) -S02NHCO-(Cl-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the ~roup consistin~ of: -O~, -SH, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -C02~. -co2-(cl-c4)-alkyl, -NH2, -N~[(Cl-C4)-alkyl], -N[(C~-C4)-alkyl]2; and (1) -so2N~co-perfluoro-(cl-c4)-alkyl, (m) -SO2NHCO-heteroaryl, (n) -SO2N~CONR2aR2a;
(o) -PO(OH)2~
(p) -PO(OR2)2, or (g) -PO(OH)(OR2); and .

R14 is:
- . (a) H, (b) (Cl-C8)-alkyl, (c) (Cl-C8)-perfluoroalkyl, (d) (C3-C6)-cycloalkyl, (e) phenyl, or (f) benzyl; and SaJBSTl~lJTE~ SH~ET

WO91tl2002 PCT/~S91/01001 ;,-, 2~ ~?~, R15 is:
~a) H, (b) (Cl-C6)-alkyl, (c) (C3-C6)-cycloalkyl, (d) (CH2)p-phen (e) oR17, (f~ morpholin-4-yl, or (g) NR18Rl9; and R16 is:
(a) (Cl-C8)-alkyl, (b) (~l-C~)-perfluoroalkyl, (c) l-adamantyl, (d) l-naphthyl, (e) (l-naphthyl)ethyl, or (f) -(C~2)p-ph~nyl; and R17 is:
(a) H, (b) (Cl-C6)-al~yl, <c) (C3-C6)-cycloalkyl, (d) phenyl, or (e) benzyl; and R18 and R19 are independently:
(a) ~, (b) (Cl-C4)-alkyl, (c) phenyl, (d) benzyl, or (e) a-methylbenzyl; and $UBSTlTllTE 5HlEE~'r W091/1~002 P~T/US91/0100~
. . .

Z~

R20 is:
(a) aryl, or (b) heteroaryl, unsubstitl1ted or substituted with one or two subst:ituents selected from the group consisting of:
(i~ (Cl-C4)-alkyl, (ii) (Cl-C4)-alkoxyl, (iii) Br, Cl, I, F, or (iv) CH~-aryl.

The alkyl sub6titutents recited above denote straight and branched chain hydrocarbons o~ the length æpecified such as methyl, ethyl~ isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl and alkynyl substituents denote alkyl groups as described above which ar modified so that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes ring~ compo~ed of 3 to 8 methlene groups, each which may be substituted or unsubstitued with other hydrocarbon substituents, and include for e2ample cyclopropyl, cyclopentyl, cyclohegyl and 4-methylcyclohexyl.
The alko~y substituent represent~ an alkyl group as described above attached through an oxygen bridge.
The aryl substituent recited above repre~ents phenyl or naphthyl.
The heteroaryl substituent recited above represents a~y 5- or 6-membered aromatic ring containing from one to three heteroatoms ~elected from the group consisting of nitrogen, o~ygen, and sulfur, for e~ample, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl.

SUE~STiTUl~E ` S~EET

WO91/12~2 PCT/US91/01001 rd_~.

P~efQrre~-~mid2zQles:

2-Butyl~ 4-(1-carboxy-1-phenyl)methoxyphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

1-[4-(1-Carbo~y-l-phenyl~methoxyphenyl]methyl-4-chloro-5-hydroxymethyl-2-propylimidazole, 2-Butyl-5-carboxy-1-[4-(1-carboxy-1-phenyl)methoxy-phenyl]methyl-4-chloroimidazole;

2-Butyl-5-carbomethoxy-1-C4-(1-carboxy-1-phenyl)-methoxyphenyl]methyl-4-chloroimidazole;

2-Butyl-5-carboxy-1-[4-(1-carboxy-l-phenyl)methoxy-phenyl}methyl-4-pentafluoroethylimidazole;

2-Butyl-5-carboxy-1-[4-(1-carbo~y-l-phenyl)me~hoxy-phenyl]methyl-4-trifluoromethylimidazole;

2-Butyl-5-carboxy-1-[4-~1-carboxy-~-phenyl)metho~y-phenyl]methyl-4-nitroimidazole;

2-Butyl-1-[4-(1-carboxy-1-phenyl)methogyphenyl~methyl-5-hydro2ymethyl-4-nitroimidazole;

2-Butyl-5-carbometho~y-1-~4~ carboxy-1-phenyl)-methoxyphenyl~methyl-4-nitroimidazole;

5-Carboxy-1-[4-(1-carboxy-1-(2-chloro)phenyl)methoxy-phenyl]methyl-2-propyl-4-trifluoromethylimidazole;

S~ BSrlTUTE 9UHE~

Wo9I/12002 PCT/US91/OIOOl ~ ~ 2~

5-Carboxy-2-propyl-1-[4-(1-carboxy-1-(2-methyl)-phenyl)methoxyphenyl~methyl-4-trifluoromethyl-imidazole;

5-Carbo~y-1-[4-(1-carboxy-1-(2,6-dichloro)phenyl)-methoxyphenyl]methyl-2-propyl-4-trifluoromethyl-imidazole;

5-Carboxy-l-t4-(1-carboxy-1-(2-trifluromethyl)phenyl)-metho~yphenyl]methyl-2-propyl-4-trifluoromethyl-imidazole;

5-Carbo~y-1-~4-(1-carboxy-1-(2-methoxy)phenyl)methoxy-phenyl]methyl-2-propyl-4-trifluoromethylimidazole;

S-Carboxy-2-propyl-1-[4-(1-carboxy-1-(2-chloro)-phenyl)methoxy-3-chlorophenyl]methyl-4-trifluoro-methylimidazole;

5-Carboxy-1-~4-~1-carbogy-1-(2-ehloro)phenyl)methoxy-3,5-dichlorophe~yl]methyl-2-propyl-4-trifluoromethyl-imidazole;

5-Carboxy-1-[4-(1-carboxy-1-(2-chloro)phcnyl)methoxy-phenyl~methyl-4-chloro~2-propylimldazole;

5-Carboxy-1-[4-(1-carboxy-1-(2-methyl)phenyl)metho~y-phenyl]methyl 4-chloro-2-propylimidazole;

5-Carboxy-1-[4-(1-carboxy-1-(2,6-dichloro)phenyl)-- methoxyphenyl]methyl-4-chloro-2-propylimidazole;

~U B5TITUTE S~HEE~

Wosl/l2oo2 PCT/US91/01001 - ~ 18 -5-Carboxy-1-[4~ carboxy-1-(Z-trifluoromethyl)-phenyl)methoxyphenyl]methyl-4-chloro-2-propyl-imidazole;

5-Carboxy-1-[4-(1-carboxy-1-(2-methoxy)phenyl)methoxy-phenyl]methyl-4-chloro-2-propylimidazole;

5-~arbo~y-1-[4-(1-carboxy-1-(2-chloro)phenyl)methoxy-3-chlorophenyl]methyl-4-chloro~2-propylimidazole;

5-Carboxy-1-[4-(1-carboxy-1-(2~chloro)phenyl)methoxy-3,5-d;chlorophenyl]methyl-4-chloro-2-propylimidazole;

2-Butyl-4-chloro-5-hydro~ymethyl-1-C4-(1-(tetrazol-5-yl)-l-phenyl)metho~yphenyl]methylimidaæole;

4-Chloro-5-hydroxymethyl-2-propyl-1-[4-(1-(tetraæol-5-yl)-l-phenyl)methoxyphenyl]methylimidazole;

2-Butyl-4-chloro-5-carboxy-1-[4-(1-(tetrazol-5-yl)-1-phenyl)methoxyphenyl]methylimidazole;

2-Butyl-4-chloro-5-carbomethoxy-1-~4-(1-(tetrazol-5-yl)-l-phenyl)methoxyphenylJmethylimidazole;

2-Butyl-5-carbo~y-4-pentafluoroethyl-1-[4-(1-(tetra-zol-5-yl)-1-phenyl)methoxyphenyl]methylimidazole;

2-Butyl-5-carboxy-1-[4-(1-(tetrazol-5-yl)-1-phenyl)-methoxyphenyl]methyl-4-trifluoromethylimidazole;

2-Butyl-5-carbogy-4-nitro-1-[4-(1-(tetrazol-5-yl)~
phenyl)metho~yphenyl~methylimidazole;

S~ STITUli- SI~EFr WOsl/12002 PCT/US91fO100]
.. ..

2-Butyl-5-hydroxymethyl-4-nitro--1-[4~ (tetrazol-S-yl)-l-phenyl)methoxyphenyl]methylimidazole;

2-Butyl-5-hydroxymethyl-4-nitro-1-[4-(1-(tetrazol-5-yl)-l-phenyl)~ethoxyphenyl]methylimidazole;

5-Carboxy-4-pentafluoroethyl-2-propyl-1-t4-(1-(tetra-zol-5-yl)-1-(2-chloro)phenyl)metho~yphenyl]methyl-imidazole;

5-Carbo~y-4-pentafluoroethyl-2~propyl-1-[4-(1-(tetra-zol-5-yl)-1-(2-methyl)phenyl)methoxyphenyl]methyl-imidazole;
.
5-Carboxy-2-propyl-1-[4-(1-(tetrazol-5-yl)-1-(2,6-dichloro)phenyl3methoxyphenyl]methyl-4-pentafluoro-ethylimidazole;

5-Carboxy-4-pentafluoroethyl-2-propyl-1-[4-(1-(tetra-zol-5-yl)-1-(2-trifluoromethyl~phenyl)methoxyphenyl]-methylimidazole;

5-Carbo~y-4-pentafluoroethyl-2-propyl-1-~4-(1-(tetra-zol-5-yl)-1-(2-metho~y)phenyl)methoxyphe~yl]methyl-imidazole; - -5-Carboxy-4-pentafluoroethyl-2-propyl-1-~4-(l-(tetra-zol-5-yl)-1-(2-chloro)phenyl)methoxy-3-chlorophenyl]-methylimidazole;

5-Carboxy-4-pentafluoroethyl-2-propyl-1-[4~ (tetra-zol-$-yl)-1-(2-chloro)phenyl)methogy-3,5-dichloro-phenyl]methyli.midazole;

SlJE~STJTUTE SW ET

WOsl/12~2 PCT/US9ttO1001 2 ~7~

5-Carboxy-4-chloro-2-propyl~ 4-(1-(tetrazol-5-yl)-1- , (2-chloro)phenyl)methoxyphenyl]methylimidazole;

5-Carboxy-4-chloro-2-propyl-1-[4-(1-(tetrazol-5-yl)-1-(2-methyl)phenyl)metho2yphenyl]methylimidazole;

5-Carboxy-4-chloro-2-propyl-1-[4-(1-(tetrazol-5-yl)-1-~2,6-dichloro)phenyl)methoxyphenyl]methylimidazole;

5-Carboxy-4-chloro-2-propyl-1-[4-(1-(tetrazol-5-yl)-1-(2-trifluoromethyl)phenyl)metho~yphenyl]methyl-imidazole;

5-Carboxy-4-chloro-2-propyl-1-[4-(1-~tetrazol-5-yl)-1-(2-methoxy)phenyl)methoxyphenyl]methylimidazole;

5-carboxy-4-chloro-2-propyl~ 4-(1-(tetrazol-5-rl)-1-(2-chloro~phenyl)metho~y-3-chlorophenyl]methyl-imidazole;

5-carbo~y-4-chloro-2-propyl-1-~4-(1-(tetrazol-5-yl)-1-(2-chloro)phe~yl)methoxy-3,5-dichlorophenyl]methyl-imidazole;

5-Carbo~y-4-chloro-1-~4~ ((N-phenyl~ulfonyl)carbox-amido) l-(2-chloro)phenyl)metho2yphenyl]methyl-2-propylimidazole;

5-Carboxy-1-[4-(l-((M-phenylsulfonyl)carboxamido-l-(2-chlo r o)phenyl)methoæyphenyl~methyl)-2-propyl-4-tri-fluoromethylimidazole;

SUBSTITUTE Sl IEET

WO91/12002 PCT/U~91lO1001 , 5-Carboxy-1-[4~ carboxy-1-(2-chloro)phenyl)methoxy-phenyl]methyl-2-propylimidazole;-5-Carboxy-l-t4-(1-carboxy-1-(2-methyl)phenyl)methoxy-phenyl]methyl-2-propylimidazole;

5-Carboxy-1-~4-(1-carbo~y-1-(2-trifluoromethyl)-phenyl)metho~yphenyl]methyl-2-propylimidazole;

5-Carboxy-1-~4-(1-carboxy-1-(2-ethyl)phenyl)methoxy-phenyl~methyl-2-propylimidazole;

5-Carbomethoxy-l-t4-(1-carboæy-1-(2-chloro)phenyl)-methoxyphenyl]methyl-2-propylimidazole;

5-Carbomethoxy-1-[4-(1-carboxy-1-(2-methyl)phenyl)-methoxyphenyl~methyl-2-propylimidazole;

5-Carbomethogy-1-[4-(l-carbo2y-1-(2-triIluoromethyl)-phenyl)metho2yphenyl]methyl-2-propylimidazole;.

S-Carbometho~y-1-[4-(1-carboxy-1-(2-ethyl)phenyl~-methoxyphenyl]methyl-2-propylimidazole;

5-Carboæy-1-[4-(1-carbometho~y-1-(2-chloro3phenyl)-methoxyphenyl]methyl-2-propylimidazole;

5-Carbo~y-1-~4-(1-carbomethoxy-1-(2-methyl)phenyl)- i methoxyphenyl]methyl-2-propylimidazole;

5-Carboxy-1-[4 (1-carbometho~y-1-(2-trifluoromethyl)- i phenyl)methoxyphenyl]methyl-2-propylimidazole;

C~ l l el C!Tl lr l IT~ ~.I~ t .. . i 7 ~

5-Carboxy-1-[4~ carbomethoxy-1-(2-ethyl)phenyl)-methoxyphenyl]methyl-2-propylimidazole;

5-Carboxy-1-[4-(1-(tetrazol-5-yl)-1-(2-chloro)-phenyl)methoxyphenyl]methyl-2-propylimidazole;

5-Carboxy-l-C4-(l-(tetrazol-5-yl~ (2-methyl)phenyl)-methoxyphenyl]methyl-2-propylimidazole;

5-Carbo~y-1-[4-(1-(tetra~ol-5-yl)-1-(2-trifluoro-methyl)phenyl~methoxyphenyl]~ethyl-2-propylimidazole;

5-Carboxy-1-[4-(1-(tetrazol-5-yl)-1-(2-ethyl)phenyl)-methoxyphenyl]methyl-2-propylimidazole;

5-Carboxy-1-[4-(1-(N-methyl~ulfonylcarboxamido)-1-(2-chloro)phenyl)methogyphenylJmethyl-2-propylimidazole;

5-Carboxy-1-[4-(1-(N-methylsulfonylcarboxamido)-1-(2-methyl)phenyl)metho~yphenyl]methyl-2-propylimidazole;

5-Carbogy-1-[4-(1-(N-methylsulfonylcarboxamido)-1-(2-trifluoromethyl)phenyl)methoxyphenyl]methyl-2-propyl-imidazole;

5-Carboxy-1-[4-(1-(N-methylsulfonylcarboxamido)-1-(2-ethyl)phenyl)methoxyphenyl]methyl-2-propylimidazole;

5-Carbomethoxy-1-[4-(1-(N-methylsulfonylcarboxamido)-1-(2-chloro)phenyl)methoxyphenyl]methyl-2~propyl-imidaæole;

SUBSTITUTE ~E~

WO91/12~2 ~7~ PCT/US91/01001 5-Carbomethoxy-~-[4-(1-(N-methylsulfonylcarboxamido)-1-(2-methyl)phenyl)methoxypheny:l]methyl-2-propyl-imidazole;

5-Carbometho~y-l-t4-(1-(N-methylsulfonylcarbo~amido)-1-(2-trifluoromethyl)phenyl)methoxyphenyl3methyl-2-propylimidazole;

5-Carbomethoxy-1-[4-(1-(N-methyl~ulfonylcarboxamido)-1-(2-ethyl)phenyl)methoxyphenyl~methyl-2-propyl-imidazole;

4-Acetamido-2-butyl-5-carboxy-1-[4-(1-carboxy-1-(2-chloro)phenyl)methoxyphenyl]methylimidazole;

4-Acetamido-2-butyl-5-carbo~y-1-~4-(1-carboxy-1-(2-methyl)phenyl)metho~yphenyl]methylimidazole;

4-Acetamido-2-butyl-5-carboxy-1-[4-(1-carboxy-l-(2-trifluoromethyl)phenyl)metho~yphenyl]methylimidazole;

4-Acet~mido-2-butyl-5-carboxy-1-[4-(1-carboxy-1-(2-ethyl)phenyl)methoxyphenyl]methylimidazole;

4-(N-Acetyl-N-methyl)amino-2-butyl-5-carbo~y-1-[4 carboxy-1-(2-chloro)phenyl)methoæyphenyl]methyl-imidazole;
.
4-(N-Acetyl-N-methyl)amino-2-butyl-5-carboxy-1-[4--~l-carboxy~ methyl)phenyl)methoxyphenyl]methyl-imidazole;

Slll~STiTli ~ E ~E~ T

WO91/12002 pcTJussl/o1oo1 2~?7.~ ?~.

4-<N-Acetyl-N-methyl)amino-2-butyl-5-carboxy-1-[4-~l-carboxy-1-(2-trifluoromethyl)phenyl)methoxy-phenyl]methylimidazole;

4-(N-Acetyl-N-methyl)amino-2-butyl-5-carboxy-1-[4 carboxy-1-(2-ethyl)phenyl)metho:~yphenyl]methyl-imidazole;

4-(N-Acetyl-N-methyl)amino-2-butyl-5-carboxy-1-[4-(1-carbomethoxy-l-(2-chloro)phenyl)methoxyphenyl]methyl-imidazole;

4-(N-Acetyl-N-me~hyl)amino-2-butyl-5-carboxy-1-[4-(1-carbomethoxy-1-(2-methyl)phenyl~methoxyphenyl]methyl-imidazole;

4-~N-Acetyl-N-methyl~amino-2-butyl-5-carboxy-1-[4-(1-carbomethoxy-l-(2-trifluoromethyl~phenyl)metho~y-phenyl]methylimidazole;

4-(N-Acetyl-N-methyl~amino-2 butyl-5-carbo~y-1-[4-(1-carbometho~y-1-(2-ethyl)phenyl)metho~yphenyl]methyl-imidazole;

5-Carboxy-4-chloro-1-[4-(1-(N-~2-chloro)phenylsul~-onyl)carboxamido-1-(2-chloro)phenyl)metho~yphenyl]-methyl-2-propylimidazole;

5-Carboxy-4-chloro-1-[4-(1-(N-phenylsulfonyl)carbox-amido-1-(2-chloro)phenyl)methoxyphenyl]methyl-2-penta-fluoroethylimidazole;

5 IJE~STiTU ~ E ~E~T

WO91~12002 PCT/US91/01001 .~ Z~

5-Carboxy-4-chloro-1-t4-(1-(N-methylsulfonyl)carbox-amido-1-(2-chloro)phenyl)methoxyphenyl]methyl-2-propylimidazole;

5-Carboxy-4-chloro-1-[4~ (N-methylsulfonyl~carbox-amido-1-(2-chloro)phenyl)methoxyphenyl]methyl-4-chloro-2-pentafluoroethylimidazole;

5-Carbo~y-4-chloro-2-propyl-1-[4-(1-(N-trifluoro-methylsulfonyl)carboxamido-1-(2-chloro)phenyl)methoxy-phenyl]methylimidazole;

5-Carboxy-4-chloro-2-pentafluoroethyl-1-[4-(1-(N-tri-fluoromethylsulfonyl)carboxamido-1-(2-chloro)phenyl)-methoxyphenyl~methylimidazole;

5-Carboxy-4-chloro-2-propyl-1-[4-(1-(N-(pyridin-4-yl)-sul~onyl)carboxamido-1-(2-chloro)phenyl)metho~y-phenyl]methylimidazole;

5-Carboxy-4-chloro-2-pentafluoroethyl-1-~4-(1-(N~
(pyridin-4-yl)sulfonyl)car~oxamido-1-(2-chloro)-phenyl)metho~yphenyl]methylimidazole.

~ Pl. ~T~O~S FOR PREPARATIO~ OF CQMPO~D~ OF
GEN~RAL FORM~LA I:

The methods described below illustrate the preparation o~ angiotensin II antagonists of Formula I. There are several general approaches to the synthesis of antagonists of Formula I, and it is taken as a general principle that one or another SaJE3~;Tl~U~E~ ~EET

wos1~12002 PCT/US91/0~001 2 ~ 7~ ?,~ - 26 -method may be more readily applicable for the preparation of a given antagonist; some o~ the approaches illustrated below may not be readily applicable for the preparation of certain antagonists of Formula I.
It should be recognized that antagonists of Formula I consist of a heterocyclic component designated above by Formula I and a substituted benzyl substitutent which is attached to the heterocyclic component at a nitrogen atom. Thus, two generally applicable approaches to antagonists of formula I are these:

l. A substituted imidazole is prepared as described below. Then the imidazole is alkylated at a nitrogen atom with a substituted benzyl halide or pseudohalide gi~ing an alkylated imidazole in the Schemes below, this alkylating agent is often designated as "ArC~2-Q where Q is a halide (-Cl,Br,I) or pseudolialide (-OMs, OTs, OT~). In some cases, alkylation may take place at both nitrogen atoms of the imidazole, and in these cases, separation by ~ractional crystallization or by chromotographic methods may be necessary for isolation o~ the de~ired product. In some cases, the alkylation ~tep produces a fully-assembled antagonist of Formula I, except that functional groups in the alkylating agent or in the imidazole may be present in protected form and reguire deprotection steps to be carried out to complete the synthesis. In other cases, the alkylation is carried out with a substituted benzylic halide or pseudohalide ("ArC~2-Q"), but here the alkylation step is followed by subsequent steps which ~ U BST~T1J~ S~H~F~
.

woslJl2~2 PCT/US91/0100t J~

are required to assemble the substituted benzyl element of the antagonist of Formula I. The alkylation steps and subsequent steps used to prepare antagonists of formula I, are descrlbed below.

2. In another approach to antagoni~ts of formula I, a substituted benzyl element is introduced at the beginning of, or during the preparation of the imidazole. Routes of this type are illustra~ed below. In most cases where this general approach is used, the substituted benzyl component ~hich is introduced during the syntheæis of the het~rocycle must be ~ubjected to further synthetic transformations in order to complete the synthesis of the antagonist of Formula I. In the Schemes shown below, this substituted benzyl component is designated as "-C~2Ar," and is usually introduced by an alkylation step with a substituted benzyl halide or pseudohalide designated ArCH2-Q (where Q is, for ~xample, Clt Br, I, F, OTæ, or OMs), or is introduced by a route which starts with a substituted benzylamine, designated "ArC~2N~". The required substituted benzylamine derivativeæ may be prepared by standard methods, for example from the substituted benzylic halides or pseudohalides ("Ar-C~2Q").
Substituted benzyl halides or pseudohalides which are useful in the preparation of alkylated imidazoles described are illustrated by those listed below in Table l. Substituted benzyl amines which are useful in the preparation of the alkylated heterocycles described are illustrated by those listed below in Table 2. In cases where these benzylic halides, pseudohalides and amines are not commercially SUBST7TU~E ~EE~

WoslJ1~002 PCT/US91/01~0 2~?7.J~ 28 -available, they are prepared as described below or by standard methods of organic synthesis. Subsequent steps which may be required to complete the synthesis of antagonists of Formula I are described below.
The compounds of this invention maybe resolved using the techniques known in the art. The diastereomeric salts and esters of the enantiomers are separated and the desired compound is the more active stereoisomer. The compounds of this invention, their pharmaceutically acceptable salts and their prodrug ~orms are included within the scope of this invention.

SUBSTITUTE S~EET

WO 91~12002 PCI'/US91/0100]

TABLE

CH2Br CH2Br CH2Br ~OCH3 OCH2Ph OCH2Ph OCH2Ph CH2:E3r CH2Br CH2Br Cl~ Cl~Cl [~CH3 OCH2Ph OCH2Ph OCH2Ph CH2Br CH2Br CH2Br:

CN CO2CH, CH20TBD~
CH2~r CH2Br CH20T~

SCH2Ph N2 CH20TBD~B

R~::TITI ITE ~E}~T

WO 91~12002 PCI/US91/0100 2~7~$?~ 3 --CH2NH2 CH2~2 CH2NH2 N02 OCH2Ph CO2CH3 CHzNHz CH2NH2 CHzNH2 [~ ~CH3 CN OCH2Ph CH20TBDMS

~H3 ~1~
SCH2Ph OC~2Ph OCH2Ph SUBSTITl3TE !!~ IEE~

W091/12002 PCT/US91tO1001 Abreviation6 used in schemes and examples are listed in Table 3.

Rea~ents NBS N-bromosuccinimide AIBN Azo(bis)isobutyronitrile DDQ Dichlorodicyanoquinone Ac20 acetic anhydride TEA tsiethylamine DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine TFA trifluroacetic acid TMS-Cl trimethyl~ilyl chloride Im imidazole AcSK potassium thioacetate p-TsOH p-toluenesulfonic acid DIPEA Diisopropylethylamine TBS-Cl Tributylsilyl chloride TBAF tetrabutylæmmonium fluoride TMSCN trimethylciIyl cyanide Solvent~:

DME dimethyl~ormamide EOAc (AcOH) acetic acid EtOAc (EtAc) ethyl acetate Hex hexane THF tetrahydrofuran DMSO dimethylsulfoxide SU~:~TITl31T~ SHE~E~

WO91/12~2 PCT/US91/01001 2~7~

MeOH methanol iPrO~ isopropanol HMPA hexamethylphosphoramide Others:

Phe phenylalanine rt room temperature TBDMS t-butyldimethylsilyl OTf OSO2CF3 Ph phenyl FAB-MS (FSBMS) Fast atom bombardment mass spectroscopy NOE Nuclear Overhauser Effect SiO2 silica gel trityl triphenylmethyl Bn benzyl PA~T I: Preparation of the.im~azo.lea ~ Formula I

R3yN~B ~' N
R

The :imidazoles required in for alkylation to the substituted benzyl element can be prepared by a number of methods well known in the literature including those described in EPO publications 253,310 and 324,377 by DuPont and EPO publication by Merck 401,030.

~IIR~TITUTE SHEE~

2r~ 2~.
!

!

PART II: Preparation os substituted benzyl derivatives of the general_Fo~mula I

The synthesis of Angioten6in II Antagoni~ts incorporating a ~ubstituted benzyl group as shown in Formula I may be accomplished by reactions in the presence of a base o~ an imidazole with a benzylic compound bearing a good leaving group, and the appropriate ~ubstituents R9, R~0, Rll, Rl2, X, Y and Z as shown in Formula I. Alternatively, compounds with ~tructures according to Formula I may also be synthesized in stages from a benzyl-substituted imidazole which contains the ~ubstituents R9, Rl0 and X, followed by reaction with an intermediate (such as a substituted alpha-bromophenylacetic ester) which introduces the ~ub~tituents at Rll, Rl2 and Z.
Examples of this latter methodology in which a benzyl-substituted heterocyclic intermediate iB
prepared first, and then elaborated to afford compound~ with ~tructures described by Formu~a I, are shown in the Schemes II-l, II-2 and II-3. The preparation o~ compound 5 of Formula I wherein: B= a single bond, R9, Rl0 and Rll are H, ~= 0, Y= a single bond, Z= C02~ and Rl2= phenyl appears in Scheme II-l. Deprotonation of a ~ub~tituted imidazole with strong ba~es such as ~odium hydride or potassium tert-butoxide in DMF for a period of 1-24 hours at temperatures of 20-100C, followed by alkylation with 4-benzyloxybe~zyl chloride affords the protected ether 2. The benzyl ether is next removed by hydrogenolysis using hydrogen and an appropriate SUBS~îTUTE SHEt WO91/12~02 PCT/US91/01001 2~ .J ~ ?~L r ~ 34 ~

catalyst such as Pd/C, Pd(0~)2/C or Pt/C which affords the intermediate phenol 3. The phenolic proton is then abstracted, and the phenolate is alkylated with methyl 2-bromophenylacetate to ~urnish e~ter 4. Finally, the ester is hydrolyzed and the ~ree acid 5 is obtained.

SC~ME II-l X~>~ ~n DMF Rl~ H" Pd~:

B~ O Br10 P~OH

R~ ~n Dl F Rl_~

~D~ ~CO,~
~CO,~

1 ) ~0~ I hOH R ~X
J
2~ ~ICl ,~

6~CO,~

5U13STiTUTE SIHEE~

Wo91/12~2 PCT/US91fO1001 The synthesis o~ compound lO of Formula I
wherein: B= a single bond, R9, RlO and Rll are H, X-O, Y= a single bond, Z- C02~ and Rl2- phenyl is presented in Scheme II-2 ~ Deprotonation of a substituted imidazole <6) with sodium hydride in DMF, followed by trea~ment with 4-benzyloxybenzyl chloride gives compound 7. The benzyl ether is removed by hydrogeno~ysis to give the phenol 8, which is then deprotonated with potassium hydride and 18-crown-6 in DMF and alkylated with methyl 2-bromophenylacetate to give the ester 9. Basic hydrolysis of 9 gives the free acid lO. Alkylation o~ the phenol 8 with substituted 2-bromophenylacetic ester~, followed by ester hydrolysis leads to compounds of Formula I
where Rl2 is a ~ubstituted phenyl group.

SVBSTlTlJTE~ ~EE~

2~?7~
St~ElEM~3 II-2 N DMF Rl~ ~.' .3i~
H ~¢~Cl ,~ 9 ~OH

R~N 3~ DIY R1_~
oJ3~ 9 1 ) ~ON, ~OH R~
2) 1~ 10 ~a~,H

SU13ST7TLITE ~EET

WO91/1~0~ PCT/US9l/0100 - 37 ~

The synthesis of compound lS of Formula I
wherein:B= a single bond, R9, ~10 and Rll are ~, X=
O, Y= a single bond, Z= C02~ and R12= 2-methylphenyl is shown in Scheme II-3. Deprotonation of imidazole (11) with a strong base such as sodium hydride in DMF, followed by treatment with 4-benzyloxybenzyl chloride produces the ether lz, The benzyl ether is removed by hydrogenolysis to give the phenol 13, which is then deprotonated ~ith potassium hydride and 18-crown-6 in DMF and al~ylated with methyl 2-bromo-2'-methylphenylacetate to give the ester 14.
Alkaline hydrolysis o~ 14 gives ~he free ac~d 15.
Reaction of the phenol 13 with other sub~tituted alpha-bromophenylacetic esters followed by alkaline hydrolyæis leads to additional derivatives in this imidazole series.

SUI;5TITUTE~ SHEEl~

WO gl/12002 PCI/US91/01001 Z~ 38 -SC~

R1N~ DMF N~R~ , Pd/C

R , ~nO Cl~no 12 ~bOH

R <N~ K}~ D~ Rl~R3 1 8-crown-6 N~R'~

HO,13J 13 ~CO2~ OJ3J 14 CH3 ~CO
C~

1 ) N~O~i ~OH
2) HCl ,J3J

¢~H~

æ,t~STlTUTlE $H~E~

WO91/1~002 pcr/us~l/o1ool ;~,7 ~

Subætituted 2-bromophenylacetic esters are typically employed in the synthesis of compounde of general Formula I when it is desired that Rl2 be a substituted phenyl group, Rl~ ls hydrogen, Y is a single bond and Z is a carbo~y].ic acid. These substituted 2-bromophenylacetic: esters are readily prepared from substituted phenyl acetic acids (16) by a Hell-Volhard-Zelinsky reaction as shown in 5cheme II-4. Alternatively, substituted 2-bromophenylacetic esters may also be obtained from benzaldehydes (18) as shown in Scheme II-5. Reaction of the substituted benzaldehydes (18) with trimethylsilyl cyanide affords the trimethylsilyl-cyanohydrins l9.
Treatment of l9 with acidic ethanol produce~ the hydro~y e6ters 20, and subsequent reaction with carbon tetrabromide and triphenylphosphine provides the substituted 2-bromophenylacetic esters 17.

SC~EME II-4 R R Br ~C02H 1 ) SOCl2- 2,~ ~C02~?

W091~12~2 P~T/US91/0~0~1 - , i 2~ r~

SiCN, RCN ~ R::l. EtOH
1 8-cro~-6 18 1g R OH R ~r ~O~Et PPh3 ~ ~ ~02Et The synthesis of Angiotensin II Antagoni~ts incorporating a substituted benzyl element defined by Formula I may also be accompli~hed by the alkylation reaction of an imidazole with a be~zylic intermediate bearing a good leaving group, and with all o~ the appropriate substituents R9, RlO, Rll, Rl2, ~, g and Z in place. This approach, which is generally preferred when either R9 or RlO are non-hydrogen, i8 - illustrated in Scheme II-6. Deprotonation of p-cre~ol (~l) with strong bases such as pota~ium hydride or potas~ium tert-butoxide in DME and alkylation with methyl 2-bromo-2-phenylacetate ~ives the ether 22. Bromination of 22 at the benzylic methyl group with N-bromosuccinimide gives the al~ylating agent 23. Deprotonation of imidazole (ll) with sodium hydride in DME, followed by reaction with bromide 23, and subsequent e~ter hydrolysis provides the acid 24.

su~ 2'u~ FE I

WO91/12002 ~ ~ PCT/US91/01001 ~ ~, <J~

~ ~.; . ....

SGHEME_EI-6 0-l~rolm d , ,13,cH3 O N139, ~N
21 ~Lco~ ~M3 CCl~ r~Flux R

oJ~ NaH~ DMF 1~ rbOH. M~OH oJ3J

2~ ~ 24 A strategy similar to that of Scheme:II-6 is applied when substitution at Rll i8 desired as shown in Scheme II-7. Intermediate ethers such as 22 in Scheme II-6 are deprotonated with strong bases such as lithium bis(trimethyl~ilyl)amide in TaF and can then be reacted with an alkylating agent such as an alkyl halide or mesylate. In this case, reaction of the anion deriYed from ether 22 with methyl iodide affords the alkylated product 25. Reaction of 25 with N-bromosuccinimide ~ives bromide 26, which is in turn used for alkylation of the imidazole. Scheme II-7 illu~trates the alkylation of lmidazole 6 with bromide 26 which after ester hydrolysis affords acid 27.

8U85~lT~JTE: ~;H~:T

WO 91~12002 PCT~/US91/01001 , 2~7S~2~

SCH~ME II-7 ,~f-7- C I ~f CCl~ r~ ux ~H
t~Z7 The synthesis of compound 32 of Formula I
wherein: B= a single bond, R9, RlO and Rll are ~, X=
O, Y= C~2, Z= C02~ and Rl2- phenyl is shown in Scheme II-8. In thiæ example, p-hydro~ybenzyl alcohol S28) is selectively alkylated at the phenolic hydro2yl group with methyl bromoacetate when they are reflu~ed with potassium carbonate in acetone. After the remaining hydroxyl group i8 protected as a `tert-butyldimethyl~ilylether, this ether (29~ may then be deprotonated with-a stro~g base such as potassium bis(trimethylsilyl)amide and reacted with an alkylating agent in a manner similar to that shown for intermediate 22 in Scheme II-7. Alkylation of ether 29 with benzyl bromide provides 30. Silylether 3Ui3~ i1TE 5~ FF

WO91/12~02 PCT/US91/01001 ~7,~

hydrolysis of 30 and bromination of the resulting alcohol affords an alkylating agent (3l~ which is then used to alkylate the imidazole. Alkylation of the anion derived from imidazo:Le ll, ~ollowed by ester hydrolysis af~ords the acid 32 shown in Scheme II-8.

SC~EME II-8 ~OH 1) ~rC~CO7CH3 ~D~S 13 I~N(8iMe3)~
,~1 K~CO3~ ac~on~
2~ Z) t~ 8iC1 29 2) PhCR~Elr DM~P, C~Cl~ "CO~

,~D~; ~¢~1r fi~ 0 1?, n BU~lNF, THF~ ç~ o 2) CEc~clPPh3 ~CO~
3~ 31 1 ) N~E~ DMF 1 ) N!~OE~ ~OH R~
~ Z) ~1 Z~
1 1 0~o~H

Scheme II-9 illustrates the preparation of an antagonist of Formula I wherein: B= a single bond, R9, RlO and Rll are ~, X is a single bond, Y=
0, Z= C02~ and, Rl2= phenyl. In this example, the ~ell-Volhard-Zelinsky reaction converts 4'-methylphenylacetic acid (33) to the SU135TITUTE~ T

Wosl/l2oo2 PCT/V~gl/01001 2 ~ ~5~¢;~

alpha-bromoester 34, which is in turn reacted with the potassium salt of phenol to yield 35. Benzylic bromination of 35 provides alky.lating agent 36 which is then reacted with an imidazo:le. When the sodium salt of imidazole 6 is alkylated with the bromide 36 in DMF, ester 37 is obtained. Alkaline hydrolysis of ester 37 then provides acid 38.

$C~EME I~=~

~cJ3~ 1~ SOCl~, Br~ ~o,c~f P nol M~O~C~C
33 2) ~OH Br 34 1 ~-cro~ 6 ND9, AIE~N ~ N~H, DMF
CCI~ r~rl~lK ~O~C~

~f 35 Rl~ 6 Rl~ 1 ) NaOH, ~O~I
C~ 2) R l ~ ~3 ~ 37 ~

~UBST31T~ 81~

WO91/12002 2~7~ PCT/USgl/0100 Schemes II-lO and II-ll illustrate the preparation of analogs where B= a single bond, R9 and RNlO are ~, Y= a single bond, Rl2 is phenyl, Z=
C02~ and X is either methyne or methylene. A
Reformatsky reaction is first employed to prepare methyl 3-hydro~y-3-(4-methylphenyl)-2-phenyl-propanoate (39) from the starting materials shown in Scheme II-lO. When heated in the presence of p-toluenesulfonic acid in benzene 39 is dehydrated to the trans-Etilbene derivative 40, and then benzylic bromination of 40 gives the alkylating agent 41.
Deprotonation of heterocycle 6 with ~odium hydride in DMF and treatment with 41 gives ester 42. Alkaline hydrolysis of 42 affords the product 43, in which X
is a methyne group (Rll is absent) doubly bonded to the carbon atom bearing sub~tituents R12 and Z as shown in Scheme II-ll. Catalytic hydrogenation of 43 gives the derivative 44 where X is a methylene group and Rll is a hydrogen atom (Scheme II-ll).

8UBS7!7 1 UTIE~; 5~EElr -WO 91/12002 PCI`/US91/0100 ;2~ 7 sc~

3 + ,~ Zn, TH~, cat I~ , $~

p~ TD OH ~ ~C
, b~ e ~ N~ N
~O~Me CCl4, r~
~ 0~CO~

S

Rt~ 2) ~ R1~

N~O}~ M~OH R1~ C ~4 ~3~ Et OAC ~

~COzH 43 (3~ 44 SU8STlTlJ TE ~IE~E~

WO91/12~2 PCT/US91/01001 The synthesis of compound 47 of Formula I
which has the ~ame substituent~ a~ compound lO
(~cheme II 2) with the e~ception that Z is a tetrazol-5-yl group, is illustrated in Scheme II-l2.
E~posure of ester 9 to excess a~monia in methanol produces the corresponding amide which i8 then dehydrated with phosphorous oxychloride and triethylamine to give the nitrile 45. Reaction of the nitrile 45 with trimethylstannyl azide in reflu~ing toluene provide~ the tetrazole derivative 46.

SC~ 12 R1~3 R1~ R3 1 ) NH3, M3OH `'Q
,[3~ 2) POC13- Et3N ,13J

[3J~o~ ~ 9 ~N

"N_~
-1 ) ~3SnN3 R
t ~l~nD r~ x `R~
I
2) H~ ~
0'~3~ 46 ~ ~,~!

SV8STITVTE ~IIEEl' Wosl/120~2 PCT/U~91/01001 ~.
~7.J~
~ .

i Scheme II-13 illustrates the preparation of a tetrazole analog (52) similar to structure 46 wherein R12 is a 2-chlorophenyl group. In this synthesis, the ester group of intermediate 47 is converted to a nitrile prior to alkylating a substituted imidazole (Part I) with this substituted benzyl element. Thus, reaction of ester 47 with ammonia in methanol, followed by dehydration of amide 48 produces nitrile 49. Benzylic bromination affords 50, which is then reacted with the ~odium salt of heterocycle 6 in DMF to give intermediate 51.
Finally, reaction of nitrile Sl with trimethylst~nnyl azide in reflu~ing toluene gives the tetrazole 52 shown in Scheme II-13.

SC~ME II-13 0~ ~' ~~, o~f POCl" ~e,N
~ 7 ~ 49 oJ~f t~ ~N R~ N~3~
~ ccl.. r~

R~ N~
,J ~). P~3Sr~N3 ~J
o~ o--W 52 ~N 51 ~

W091~12~02 PCT/US91/0~001 2~

The preparation of a derivative of Formula I analogous to tetrazole 47 (Scheme II-12) which ha~
a methylene group for the X substituent, is shown in Scheme II-15. In thi~ synthe~is, phenylacetonitrile is deprotonated with lithium bis(trimethylsilyl~amide and then alkylated with bromide 5~ (preparation of bromide 53 is shown in Scheme II-14) to yield nitrile 54. The silylether group in compound 54 is directly converted to the bromide 55 by treatment with carbon tetrabromide, triphenylphosphine and acetone in dichloromethane (Mattes, H.; Benezra, C. Tetrahedron Lett., 1987, 1697). Alkylation of the sodium 3alt of imidazole 6 with bromide 55, followed by reaction of 56 with trimethylstannyl azide in rsfluxing toluene, yields the te~razole 57.

SC~EM~

E3r~ 3H3, THF ~3r~OH

t-13u~2SiCl, DMI~P ~aIBDl~g3 Br 1 ~J
i- PrEt 2N, CH2C12 SUBSTITU~E ~E~

WO91/12~2 PCT/US91/01001 ,~
!
2 ~ br~ 50 SC~EME II~

1 ) Li~ S1M33) 2 THF ~OT~DM3 ~CN HMPA. -78nC ll ~
2) ~OT13D~ ~ PPh3, CE3r4 r E3r ~ 3 ~CN CHaCla, acet one 3 R~
~CN - 4 6 ~lJ

~CN

1 ) ~3SnN~ 3 toulen~ reflux ~ N~R
2 ) HDAc }~R~
~J
~J 57 Scheme II-16 illustrates the preparation of a derivative of Formula I where B i8 a single bond, R9, RlO and Rll are H, X= 0, Y- a single bond, Rl2 is 2-methylphenyl, and Z is a phosphonic acid group.
Reaction of o-tolualdehyde (58) with dimethylphosphite in the presence of triethylamine affords the phosphonate ester 59. Bromination of the hydro~yl group of 59 with carbon tetrabromide and triphenylphosphine in dichloromethane gives bromide 60. Deprotonation of p-hydro~ybenzyl alcohol ~ith SUBSTITUTE ~E~

WO9l~12~2 PCT/USsl/01001 2~7.,r;~1.

~ ~ ., sodium hydride in DMF followed by addition of bromide 60 affords intermediate 61. A.second bromination reaction (CBr4, PPh3, C~2C12) converts alcohol 61 to the bromide 62 which is then used to alkylate the imidazole. Scheme II-16 illustxates the case where the anion of imidazole 11 is reacted with bromide 62 to give upon workup, the phosphonate mono-ester 63.
Phosphonic acid 64 may be obtained by treatment of ester 63 with trimethylsilyl bromide.
SCHEME~ 16 OH }3r (~O)2POH ~OMa)2 Pph3~ r4 ~OMa)2 H3 Et 3N ~3 CH2Cl2 H3 O PPh~, C~ O~r Nl3H, DMF CN3 61 ~P( ~) 2 N~- 1l 0 I~Sl~r DMF (~PO( O~3 ~ OH ~PO( OH) z SUIBSTITUTE ~

W091/12~2 PCT/US91/~1001 2~ J;~J~, - 52 - .

The synthesis of a derivative of Formula I
where Z is an acyl-sulfonamide group is illustrated in Scheme II-17. Alkylation of the anion derived from heterocycle ll with bromide 65 (synthesis described in F~ample 28 of the e~perimental section) and alkaline hydrolysis of the resulti~g ester (66) affords the acid 67. Reaction of acid 67 with l,l'-carbonyldiimidazole in T~F at elevated temperatures gives an acylimidazolide which may be reacted with a sulfonamide (benzenesulfonamide in this example) and DBU in THF to provide the target compound (68) where Z is the acyl-sulfonamide group.

~CHE~ l7 N R3 1 ) NelH, DMF
R~ . N R3 N--R" 2) C~

~CO2Ma 66 ~ 65 ~CO,t~3 N OH C1~ CDI. 11~ R~
2) PhSO2NH2. D9U 68 ~C02H ~D,~3 O o SllBSTlTUTE SH~ET

WOgl/12002 PCT/US91/U1001 2 ~7 ~

Precursors for the cynthesis of AII
Antagonists incorporating a substituted benzyl element wherein either substituents R9 or R10 are non-hydrogen include substituted p-cresols (Scheme II-6), 4-hydroxybenzyl alcohols, 4-hydroxybenzaldehydes, 4-hydro~ybenzoic acids and their esters as sho~n in Schemes II-18 thru II-20.
Commercially a~ailable benzyl alcohols such as 3-chloro-4-hydro~y-5-metho~ybe~zyl alcohol may be selectively alkylated by alpha-bromophenylacetic esters when they are reflu~ed together in the presence of bases such as anhydrous potassium carbonate, giving 2-pheno~yesteræ like 69 shown in Scheme II-18. Conversion of the be~zyl alcohol group in 6g to a bromide (CBr4, PPh3, C~2Cl~) affords an alkylating agent (70). An imidazole is then alkylated with bromide 70; ~.ydrolysis of the intermediate ester affords 71. Alternatively, the imidazole may be directly coupled with benzyl alcohols like 69 uæing Mitgunobu reaction conditions (diethyl azodicarboxylate, PPh3, T~F). Again, hydrolysis of the resulting ester completes the synthesis.

SUBSTITUTIE ~EEl WO 91/12002 PCI/US9t/01001 2~7~

SCHEM~18 Cl~H acetone, heat O~OH

o~ ~C02~ ~C02~

c~
PPh3, C~r4 O
CH2Cl2 [3~co N~ 1 ) NaH, DMF NaOH N~R4 C~ ~OH cl~J

2~ ¢~C002H 71 Scheme II-19 illustrates the use of commercially available 3-ethoxy-4-hydroxybenzald~hyde ~7~) to prepare an AII Antagonist of Formula I
bearing a 3-ethoxy group (R9) on the substituted benzyl element. Alkylation of the phenolic group of 72 with methyl 2-bromophenylacetate gives the SUBSTITUTE ~ET

aldehyde 73 which is then reduced to a benzyl alcoholwith sodium borohydride in methanol or ethanol. The alcohol is converted to the bro:mide 74, and the synthesis of product 75 is completed as previously described.
SCHE~E II-l~

C2~0~CHo K2C3 C2E3~0~C~
HOJ~J acetonB~ reFlux o~
72~C02~e ~C2~3 C2H5~E~r 1~ NaE3E~. EtOH, o~i 2) PPh3. CBr4 CH2Cl2 ~CO2~4 R ~N3~ 1 )NaH, DMF NaOH R~
H 114 C2E~ C H~0~3J

~CO2Me ~CO2H

SUBSTITI~TE S~IEE~

WO91/1200~ PCT/US91/01001 z~7~

Substituted 4-hydro~ybenzoic esters are .
also convenient precursors for the synthesis of the substituted benzyl element defined in AII Antagonists of Formula I. In this approach, the phenolic hydroxyl group is usually first ~rotected with a suitable protecting group, the ester i8 then reduced to a hydro~ymethyl group, and depro~ection affords a 4-hydro~ybenzyl alcohol derivative. Scheme II-20 illustrates the preparation of derivative 80 using this sequence starting from methyl 3,5-dichloro-4-hydroxybenzoate (76). Silylation of phenol 76 ~ollowed in turn by lithium aluminum hydride reduction of the ester and silylether deprotection affords 3t5-dichloro-4-hYdroxYbenzyl alcohol (77).
Phenol 77 was then selectively alkylated with methyl 2-bromophenylacetate, and the synthesis of derivative 80 was completed using the previously described methods.

SlJBSTlTVTE~ ~ET

~V91/12~2 PCT/US91/01001 SC~EME II~

1 ) t~ 1Cl Clx~3 Cl~bH
Cl~ ~CO~ DM11P, CH~Cl~ catona, rolf ux Cl J 2) LlAIH4. n~F }~f Br ~CO~
~1 3) n-13u~NF, THF

7~
PPh3, CE~r~ Rl~R3 ~ ? Nl~- DMF ~J
79 2) N~O~L Me OH '~'1 ~,H BO

A variety of 2-substituted phenols are selectively carboxylated when refluxed with carbon tetrachloride, 50% aqueous ~odium hydrogide and powdered copper (European Patent Application #193,853, lO-Sept-86) to afford the corresponding substituted 4-hydroy benzoic acids. ThiQ reaction.
may be added to the synthetic sequence ~hen it i~
convenient to derivè the desired ~ubstituent on the benzyl portion o~ the target AII A~tagoniæt from a readily available 2-substituted phenol. This strategy is illustrated f~r fhe preparation of derivative 84 shown in Scheme II-21. Carbo~ylation of 2-ethylphenol provides 3-ethyl-4-hydro~ybenzoic acid (81). Acid 81 is then esterified, silylated, reduced and desilylated to give the 3-ethyl-4-SU8STlTllTE ~.EET

W~9ltl2~2 PCT/USgl/OlOOl 2~7~~
- s8 -hydroxybenzyl alcohol 82. Alcohol 8Z may then be used to complete the synthesis of AII Antagonist 84 shown in Scheme II-21 using the previously discussed methodology.

SCHEME II-~l 1 ) }~0~ ~o, 2) t-~u~lCl C~
C,~3 CCl~, Cu ~COj~H DM1~P, CB,Cl2 ~ ~)H
~ 50% N~OH 4) a- au~ ~ 32 1) Br ~CO
008t~n~3-- r~X 0~ ~ R

CH~Cl~ DMF
a3 2) NoO~ ~SOH 0~
~co~H 34 SUE~STlTl) r~ Et Wo9ltl20U2 PCT/U~91/~1001 ~ ?~ :

_ 59 _ The Clai en rearrangement of phenyl-allylether~ offers another useful technique ~or the introduction of alkyl sub~titutents ~R9 or R10) at the meta position of the ~ub~tituted benzyl element. In Scheme II-22, Clai~en rearrangement at 185C of allyl ether 85 provides the allylphenol 86.
Silylation of this phenol (86), ~ollo~ed by reduction of the ester group and bromination leads to the benzyl bromide 87. Al~ylation of the imidazole 11, followed by ~ilylether removal gives intermediates related to 88. Alkylation of 88 with methyl 2-bromophenylacetate followed by alkaline hydrolysis gives a derivative of Formula I (89) wherein R9 is a meta-allyl group. Hydrogenation of intermediate 88 ~ollowed by the same sequence provide~ derivative 90 where R9 is the meta-propyl group as sho~n in Scheme II-2~.

SU13STI rllTE~ ;HE~E~

WO91/12002 PCT/US91~01001 2 ~7~5 ~d ~ _ 60 -S~H~M~ -22 q C~1 ) t-8u~31Cl ~CO~ 1 B5C , ~ DMI~P, Cl~aCl~ ~ ~r 0~ ,~Ci H:)2) LlAlH~, THF TEID~90 ~J5 ~ 8~ 3) PP4, CE~r~ ~7 cH~

2) n-}~u4NF, T~

R1_<~R~

~3Jeg or ~3J
~CO~H ~CO2H
The Claisen rearrangement strategy for the introduction o~ a meta-alkyl gubstituent onto the ~ubstituted benzyl element o~ an AII Antagonist of Formula I ~ay be exercised twiee when it is desired that both R9 and RlO be meta-alkyl ~ubstituents.
Thu~, allyl phenol 86 may be converted to itR
0-allylether and subjected to a ~econd Claisen rearrangement to provide the phenol (9l) shown in Scheme II-23. Silylation of phenol 9l, followed by catalytic hydrogenation and reduction of the ester group with li~hium aluminum hydride gives the benzyl alcohol 92. A Mitsunobu reaction of the benzyl alcohol 92 with a heterocyle (ll) de3cribed in Part ~:UBSTITUTE SH~E~

Wosl/l2oo2 PCT/US91/01001 J~

I, followed by silylether deprotection gives an intermediate related to 93. The phenolic hydro~yl group of 93 may then be alkylated with a substituted alpha-bromoester and the ester hydrolyzed to yield the acid ~4 in which R9 and RlO are meta-propyl groups as shown in Scheme II-23 and ~ample 52.

SCHEM~ -2~

c~eoD~ f ~ ~ } CnlCl3 ~bH
a~ 2) 1 ~c. ~ ~D~ 2) ~S,A1 R~l;~ 11 Rl~N~

YPh~, eCO?CN=t~Et ~ C~tD_ r~rl~ ~ ~
2) n~ ~ a) Nl10~ ~OH ~1~ 94 ~H

The synthesis of compounds of Formula I
wherein: B= a ~ingle bond, R9, R10 and Rll are ~, Y=
a single bond, Z= C02H R12= phenyl, and X= NR, are presented in the following two Schemes. To access these analogs, an imidazole (ie. 11) defined in Part I is alkylated with p-nitrobenzyl bromide to yield .~1 IR.~TITUTE 9~EF~

WO91/12~2 PCT/US91/01001 2~7~

nitro compounds such as 95 in Scheme II-24.
Catalytic hydrogenation of the nitro group provides an aniline derivative (96) which is then alkylated by an alpha-bromoester. The ester 97 is sub6equently hydrolyæed to a~ford a derivative of Formula I (98) where X= NH.
SC~EME II-24 1 ) NaE~ DMF R~ 3 H;" Pd/C Rt~
N ,R3 ~ N MEtOH N
R~ R 2) f~ ~J 95 ,~J 96 11 02N O~N H2N

R1~N~3 R,~_l,R3 2) F~r 13J tOH ,~J
~C02M~t ~C2~53 ~ 02H

~:1 IR~:TlTuTE ~IEE~l WO91/12002 PCT/US9~/0100l 2 ~;7 ~ , i d~

The preparation of AII Antagonists of Formula I similar to 98 in Scheme II-24 but having ~=
NR may be accompli~hed by methodology sho~n in Scheme II-25. The subætituted aniline (96> presented above J
is readilY con~erted to the N-tert-butylcarbamate (BOC) 99. Carbamates such as 99 may be deprotonated at the amide nitrogen atom when reacted wlth bases such as sodium hydride in DMF, and then reac~ed with an alkyl halide. Subsequent tr~a~ment of the intermediate with tri~luoroacetic acid remove~ the BOC group providing the mono-alkylated aniline derivative lOO. The aniline nltrogen in lOO may be deprotonated again with sodium hydride in DMF and alkylated a second time with a sub~tituted alpha-bromoe~ter to provide esters such as lOl.
Alternatively, the order o~ introduction o~ the substituent3 on the nitrogen atom may be reversed.
Intermediate 97 (Scheme II-24) may algo be deprotonated by ~trong bases such as lithium bi6(trimethyl6ilyl)amide in T~F and then reacted with an alkyl halide to yield similar productR (lOl).
~6ter lOl prepared by either ~ynthetic route, is then hydrolyzed to afford the targeted AII Antagonist6 (102) of Formula I where g= NR.

SUE~STITUTE ~EET

WO 91/12002 PCI/US91~01001 Z6~7~J~ 64 -SC~IEME II-25 R~ 3 R1~3 1~ ~H, I)MF
N~ OC~t), N ~ ~ Br ~,J E~ 3N. CH,Cl, ~J
~2N96 ~ ~ 9J CE~Cl~

R1~ 13J`co~

~ 101 R~JrR 1 ) L.iN~i(CH3~,, ~
N--R~ THF /

HNJ~ 2) ~Nr N~ MaOH

Rl (~NNXR

~3J 102 ~ '.

SUB8TITLIT Sl~lEE~t WO91/12002 PCT/USgl/01001 - 65 - .

Scheme II-26 describe~ the preparation of the intermediate aldehyde lQ~. Th~ synthetic routes to 2,4,5-trisubstituted imidazoles are described in DuPont applications (EPO 0324377 and 0253310) and Merck application EPO 0401030 and are hereby incorporated by reference. The imidazole substituents are suitably protected as e~emplified by the use of the t-butyldimethyl~ilyl group. The deprotonation of the protected imidazole with sodium hydride and alkylation of the salt with the appropriate methyl 4-bromomethylbenzoate gives the tetraQubstitu~ed imidazole 103. An alkyl metal hydride reduc~ion gi~es the benzyl~lcohol which undergoes a Swern o~idation to aldehyde 104.

~UEISTITLITE SHEEt WO 91/12002 PCr/US91/01001 2~ A ~ ~:~3. 66 ---SC~ MP' II-26 R4 ~Br R4 R ~ R10~9 NnH/DMF R34~N~

R1 ~R 1 03 R3-~N R3 Li~lH~ {F" N~~B Rl CC~l)2 , ~ --~B
-50 to 0C f r~O/C~Cl~ I
R10~}Rg -70 cR~o~''R9 HO O H

SVE~STITUl E SHE~

wo 91/1~002 PCI/llS91/01001 ~ ~7~

. . .

SC~SME II-27 R3~N

R4 ~N
R3~N ~ 1 05 ~>~

R9~R1 ~ Rl 1 04 O ~L-PheO~ R3~N
N~CN/Et ~ N~

~N' R1 i~ n-butyl 106 ~CO2cH3 E~ is a s ingl~a bond R~ ir CH20- TE3D~ ~\
R4 is Cl \~
R9 and R1 ar~ hydrogon T13DMS i~ a t-butyldin~thylsilyl group 8lJ~3~TITUTE SHEIET

WO91/12~2 PCT/US91/01001 Schem~ 7 describes the reductive amination of the aldehyde with both the D- and L-phenylalanine methyl ester to give adducts 105 and lQ~ respectively. Further elaboration of adduct lQ~
by acylation with valeroyl chloride, dihydrocinnamoyl chloride and phenylacetyl chloride is described in Scheme II-28. The acylation of adduct lQ~ with valeroyl chloride is also shown. The amides formed were desilylated and hydrolyzed to the acids.

SVBSTI~UTE~

WO 91tl20112 PCI~/VS9~/0l001 2~7~

~o Cl HO Cl 1 05 + ~ 2~ ~1 N~

107 ¢~0 ~1O

~CO~H

3 ~ ~ ~ ~;N HO~N

'` ' ~0~ ~

10 9 C~OzC H3 110 CO2H

1 0 6 + ~0 ~ T~3A~ 4~
~L-1~omr~ Cl 2) HCl SUBSTITLJTE SHEET

Wosl/12002 PCT/US91/01001 . . .
Z~

The synthesis of the benzylphenylalanine methyl ester is described in Scheme II-22. The imine is formed by treating phenylalanine methy1 e~er with benzaldehyde followed by deprotonation with lithium hexamethyldisilazide to generate the anion and alkylation with benzylbromide to glve l-benzylphenylalanine methyl ester 11~-SC~EME II 2~

C~2ClZ

[3 E'hCH~r ~/
~N 02CH3 H2 02CH3 Sche~e II-30 describes the reduetive amination of the aldehyde 104 with the amino acid 115 using sodium cyanoborohydride in ethanol. The adduct formed compound 116 was desilylated using tetrabutylammonium fluoride and hydrolyzed to the acid with base to give the free acid 118.

SIJBSTITUTE~ SHcE~

Wo 91/12002 PCr/US91/0100 - SCHEME II.

~ TEID~BO~ Nl13N~CN/~ Oll~

1 j5 NH2 + ~
~J 1 04 T~D~o Cl CHO Cl ,N HO
~N~ ~N~

totrobutYlo~nlu~
~ ~luorid- ~) - ~CO2CH3 ~CO2CH3 116 ~ 117 HO Cl ~N

~ ~ .
1 ) NaOH
2) ~
~ ~NH , ~C2 H
~ 11 8 R~:TITI IT~ F~l' WO 91/12002 PCr/US91/01001 Z~:?7~;;J~

S~ ; II-31 TBDMS O Cl T~D~ O Cl h2CH2NH2 ~N D
~MS CN N~

o4 I~H119 CHO
NC NH

TBD~ O Cl ~3 ~N HO Cl ~N~_ ~,N

1 ) ~C83~)39nN~
~1 1 20 PhCEl?~h~At ~

NClN ~Ht:l ~ 121 ~3 N~ `~ ~/

SllE357-lTUTE $HEE~

W~91/1200~ PCTtU~91/01001 , 2~?7~2~

The synthesis of a tet:razole containing hybrid described in Scheme II-31 ~as accomplished using the intermediate aldehyde 104. The imine is formed with benzylamine and addition of trimethyl silyl cyanide to give the cyano-benzylamine adduct ll2. Acylation of 11~ with valeroyl chloride to give the amide li~Q. A 1,3-dipolar addition of trimethylstannyl azide to the cyano group followed by the treatment with ~Cl gives the tetrazole adduct l~
SC~E~ 2 R3 ,Cl E?3 R'~

~R1 ~ ~ +
O~z 122 o~z l23 o~z T~D~3o Cl 123 1 ) P~ C \~,N

2) yhJ~co~ci~oH~
ro~

1 24 o7~2CH3 2 ) ~;OH
3)H~

125 0~

~IUIBSTITUT 5HE~ET

WO91/12~2 PCT/U591/~100l 2~ 7~ ~rJ~, ~ 74 ~

The synthesis of a substituted benzyl phenyl ester is described in S~heme II--32. The protected substituted imidazole was deprotonated with Na~ and alkylated with 4-benzylo~ybenzyl chloride to give the l-substituted and 3-substituted imidazole. The 3-sub~tituted imidazole was hydrogenoly~ed to the free hydro~yl, which is deprotonat@d and alkylated with methyl 2-bromo-2-phenylacetate to give the ether 124. The silyl ether was removed with fluoride and hydrolysis of the ester group with base and pro~onation of the ~alt with acid to give ~he desired inhibitor compound 125.

$~E~

SCHEM~ 3 3 Elr ~02HI 11001 ¢~CO2CH3 p-cr~l~ol~H

CH3 CH2~3r Nl~ N ~ ~/
CCll~r-rlux H
Dlff 123 (~ 7) DD~o~N>_r/ HO ~N~/
~)~, 1. NoOH~CH~OH ,l~
l~J 2. l N ~D:Vl~F ~J
oyCo2cH3 O~,CO2H
[~fl ¢~fl ~ R~TITllTE ~ t WO91/12~02 PCT/US~ 1001 The o-chloro analog was prepared using similar synthetic procedures and i~ shown in Scheme II-33. The order of those ~teps were altered. The substituted phenyl benzyl ether was prepared first and then used to alkylate the substituted imidazole.
2-~1-(2-chlorophenyl~] acetic acid 126 was treated with thionyl chloride to generat~ the acid chloride, bromination to prepare the 2-bromo 2-[1-2-chloro-phenyl]acetylchloride and esteri~ication with methanol to generate methyl 2-bromo-2[1-(~'-chlorophenyl)]-acetate 128. Deprotonation of p-cre~ol and al~ylation with the bromide 127 ga~e the phenyl benzyl ether 127. The bromination of 1~8 gave the benzylbromide 12~. The deprotonation of the imidazole and alkylation with 129 gives the protected inhibitor 130. ~ydroly~is of 130 with base iR KOH
and acidification with HCl give6 the desired inhibitor 1~1-S~heme II-34 describes the preparation o~
the benzophenone derivative 1~-4-Methylbenzophenone 1~ is halogenated with N-bromosuccinimide and a catalytic amount of AIBN to give the 4-bromomethyl derivative 133. Deprotonation of the imidazole with sodlum hydride in DNF alkylation with the bromide 133 give~
the imidazole sub~tituted benzophenone 134.
Treatment o~ 134 with trimethysilylcyanide and potassium cyanide in methylene chloride with a catalytic amount of 18-crown-6 gives the cyano silyloxy adduct 1~. The cyano group undergoes a 1,3- dipolar cycloaddition of the azide to give the methylene substituted with tertiary alcohol and tetrazole 136. The deprotection of the t-butyldi~ethylsilylo~y group ~ith 6N ~Cl in l~ to ~ive the compound 137.

S LIE~STITUTE SHEET

Wo 91/12002 PC~/US91/01001 2~

SC~: II-34 CH3 CH2BrCl N

ccl4/reFlux [~N~l`~DMF
~3 ~

Cl N Cl TBDM30J~ TBD~;O

T~SCN/~CN . ~q ~ 1 8-crown-6 C~2C12 T~S O~ ~) Cl Cl N~ HCl T~3DMSO~ HO ~
CCH~ SnN3 toluane ~ :~ 6N ~Cl/rHF ~
rof lux ~ ~J
~3 H~

SUBSTITUTE SHEET

WO 91J12002 Pcr/us9l/oloo1 ~5 sc~

- ~Br ~Br ~13r ~H3-THF ~ T:E~S-Cl(1. 2 eq) ~J DIPEA ~1. a uq) ~l T ~ DMI~P C 1 eq) ~ 13 8 C2 H ~OHcH2clz OTBS
Ph 1 ) LiN(TP~)2 (2. 5 eq) ~N
Ph I~F, -78C ~ Ph3P

- 78C t o 68C ~Jo ( CH3) zCO

~N TBS

~Br .

SUBSTITUTE~ SHET

W091/1~2 PCT/US91/Oi~1 .
Z~7~

sç~

~~)~n- 8~ Bu C1 ~ 1 )(CU3)~811N3 ~N ~ DMF ~ ~oluon~ 0C ~
9~h~~ 10 ~J ~ IIF ~3 1 J.2 ~CN ~<P~N
1~1 Ph N--N

Compound~ of Formula I where Z i8 -CONHS02R20 (where R20 i8 alkyl, aryl, or heteroaryl) may be prepared from the correspondi~g carbo~ylic acid derivative3 of Formula I can be converted into the corresponding acid chloride by treatment with reflu~ing thionyl chloride or preferably with oxalyl chloride and a catalytic amount of dimethylformamide a~ low temperature ~A. W. Burgstahler, L. O. Weigel, and C. G. Shae~er, Synthe~i~, 767, (1976)). The acid chloride the~ can be treated with the alkali metal salt o~ R20SO~N~2 to form the de~ired acylsulfonami~e Alternati~ely, these acylsulfonamide3 ~ay be also prepared from ~he carbo~ylic acids using N,N-diphenylcarba~oyl anhydride inter~ediates (F. J.
Brown, et. al., ~uro~ean Pat~nt_~lication, EP
199,543, ~. L. Shepard and W. ~alczenko, J. ~et.
Chem., 16, 321 (1979). Preferrably the carbo~ylic acids can be converted into acylimidazole intermediates, which then can be treated with an appropriate aryl or alkylsulfonamide and diazabicycloundecane (DBU) to gi~e the desired acylsulfonamide 45 (J. T. Drummond and G. John~on, Tetrahed~Q~_Let~~., 2g, 1653 (1988)).

SUBS'rlTUTE SHEET

WOgl~l2~2 PCT/US91/0100~ , ;2r~7S~ii21 SCH~ME II~:17 X~B R ) COrbOnJ~ 01. ~XN~R
R \ 2) R2080,N~, DE~V R
CH2 C~2 Alt orn~ t o n~t hod~ I
R9-~ R9-~R1 o X CO2H X CO~ SO2R2 R R12 R R1a *Al~ernate N~thod~:

a) (i) SOC12, reflux (ii) R20S02NE-M~ (where M i~
Na or Li~
b) (i) (COCl)2, DMF, -20C; (ii) R20SO~N~-M+
c) (i) N-(N,N-Diphenylcarbamoyl)pyridinium chloride, aq. NaO~; (ii) R20S02NH-M+

~UE~STITl3TE~ 5HE~Fll`

The compounds of this invention form salts with various inorganic and organic acids and bases which are also within the scope of the invention.
Such salts include ammonium salts, alkali metal salts like sodium and potassium salt~, alkaline earth metal salts like the calcium and magnesium salts, salt6 with organic bases; e.g., dicyclohe~ylamine salts, N-methyl-D-~lucamine, salts with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared; e.g., ~Cl, HBr, ~S04, ~3P04, methane-sulfonic, toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non toæic, physiologically, acceptable salts are preferred, although other salts are also useful;
e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a Qolvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by e~changing the cations of anexisting salt for another cation on a suitable ion egchange re in.
Angiotensin II (AII) i8 a powerful arterial vasoconstrictor, and it e~erts its action by interacting with specific receptors present on cell membranes. The compounds described in the present invention act as eompetitive antagonists of AII at the receptors. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established.

SUBSTIl lJTE SHET

WO91/1~002 PCT/US91/01~01 2~7S~
i . , . ;

- 8~ -Receptor binding assay using rabbit aortae membrane prepa~ation Three frozen rabbit aortae (obtained from Pel-Freeze Biologicals) were suspended in 5 m~
Tris-0.25M Sucrose, pH 7.4 buffer (50 mL) homogenized, and then centrifuged. The mi~ture was filtered through a cheesecloth and the supernatant was centrifuged for 30 minutes at 20,000 rpm at 4C. The pellet thus obtained was resuspended in 30 mL of 50 mM Tris-S mM MgC12 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL Bacitracin and the suspension was used for lO0 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 5I-SarlIle8-angiotensin II [obtained from New ~ngland Nuclear] (lO mL; 20,000 cpm) with or without the test sample and the mi~ture was incubated at 37C
for 90 minute~. The mi~ture was then diluted with ice-cold 50 mM Tris-0.9% NaCl, pH 7.4 (4 mL) and filtered through a gla88 fiber fil~er ~GF/B Whatman 2.4" diameter). The filter was soa~ed in ~cintillation cocktail ~lO mL) and counted for radioactiYity using Packard 266~ Tricarb liquid scintillation counter. The inhib7tory conce~tration (IC50) of potential AII antagonist which gives 50%
displacement of the total specifically bound l25I-SarlIle8-angiotensin II was pre~ented as a measure of the efficacy of such compounds as AII
antagonists.

5UE3STITUTE SHE t W091/12~2 PCT/US91/01~1 ~7;~

Receptor as3ay using Bovine adrenal cortex pr~pa~tion _ _ _ Bo~ine adrenal corte~ was selected as the source of AII receptor. Weighed tissue (0.1 g is needed for 100 as~ay tubes) wa~: suspended in Tris ~Cl (50 mM), pE 7.7 buffer and homogenized. The homogenate was centrifuged at ~0,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na2HP04 (10 mM)-~aCl (120 mM)-di~odium EDTA (5 mM) containing phenylmethane sulfonyl fluoride (PMSF)~0.1 mM)]. (For screening of compounds, generally duplicates o~ tubes are uæed).
To the membrane preparation ~0.5 mL) there was added 3H-angiotensin II (50 mM) (lO mL) ~ith or without the test sample and the mixture was incubated at 37C for 1 hour. The mi~ture was then diluted with Tris buffer (4 mL) and filtered through a glasæ fiber filter (GF/B Whatman 2.4" diameter). The filter was soaked in scintillation cocktail (10 mL> and counted for radioactivity u~ing P~ckard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagoni~t which gives 50%
displacement of the total ~pecifically bound 3~-angiotensin II wa~ pre~ented as a measure of the efficacy of such compounds as AII antagonists.
The potential antihypertensive effectæ of the compound~ dcscribed in the present invention may be evaluated using the methodology described below:
Male Charles River Sprague-Dawley rats (300-375 gm>
were anesthet:ized with methohexital ~Brevital; 50 mg/kg i.p.) and the trachea was cannulated with PE

SUBSTITIJTE~ SHEET

Wosl/l2002 PCT/US91/0l001 ~ 5~

. ~ . ...

205 tubing. A stainle~s steel pithing rod ~1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a ~arvard Rodent Ventilator (rate - 60 strokes per minute7 volume -1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37"C by a thermostati-cally controlled heating pad which seceived input from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (l mg/kg i.v.). Thirty minutes later an~,iotensin II or other agvnists were administered intravenously at 30 minute intervals and the increase in the diastolic blood pressure was recorded before and after drug or vehicle administration.
Using the methodology deRcribed above, representative compounds of the inYention were evaluated and fou~d to exhibit an activity of at least IC50 ~ 50 mM thereby demonstrating and confirmi~g the utility of the co~pounds of the invention as effective AII antagonists.
Thus, the compounds of the invention are useful in t~eating hypertension. They are al~o o~
value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure and renal SIJBSTITUTE S~EET

WO91/12002 PCr/USsl/olool 2~7~`~f~

vascular hypertension, and in the management of vascular disorders such as migraine or Raynaudls disease. The application of the compounds of this invention for these and similar disorders will be apparent to those ~killed in the art.
The compounds of this invention are also useful to treat elevated intraocular pre~sure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, cap~ules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like.
Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound of thiæ invention.
In the management of hypertension and the clinical conditions noted above, the compounds o~
this invention may be utilized in compositions such a~ tablets, capsules or eliæirs for oral administra-tion, suppositories for rectal administration, sterile solution~ or suspensions for parenteral or intramuscular admi~istration, and the like. The compounds of this invention ca~ be admini~tered to patients (animals and human) in need of such treatme~t in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being follo~ed by a patient, concurrent medication, and other factors which those skilled in SUBSTlTlJTE SHEE~

W091/12~2 PCT/US91/0100l :, ' Z~jjd~

the art will recognize, the do~age range willgenerally be about 1 to 1000 mg per patient per day which can be administered in sin~le or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg per patient per day; more preferably about 2.5 to 75 mg per patient per day.
The compounds of this invention can al80 be administered in combination with other antihyperten-sives and/or diuretic~ and/or angioten~in converting enzyme inhibitor~ and/or calcium channel blockers.
For e~ample, the compounds of this invention can be - given in combination ~ith such compounds as amiloride, atenolol, bendroflumethiazide, chlorothal;done, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene ~ulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclot~iazide, methyldopa, methyldopate hydro-chloride, ~ino~idil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, re~cinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, ~urosemide, merethoxylline proeaine, sodium e~hacrynate, captopril, delapril hydrochloride, . enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zo~enopril calcium, diflunisal, diltiazem, ~elodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, and the like, . as well as admi~tures and combinations thereof.

SlJBSTlTUTE SHEE~

WO91/1~2 PCT/US91/0100 2 ~7~ 86 -Typically, the individual daily dosages for .
these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
To illustrate these combinations, one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per day range can be effectively combined at leve~s at the 0.5-250 milligrams per day range with the following compounds at the indicated per day do~e range: hydrochlorothiazide (15-200 mg)1 chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg~, amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate (5-60 mg), methyldopa (65-2000 mg), felodipine (5~60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plu~
miloride (5-20 mg) plu8 angiotensin II antagonist o~
this invention (3-200 mg~ or hydrochlorothiazide (15-200 Mg) plus ~imolol maleate (5-60) plus an angiotensin II antagonist o~ this invention (0.5-250 mg) or hydrochlorothia~ide ~15-200 mg) and nifedipine (5-60 mg) plus an angiotensin II antagonist of this invention (0.5-250 m~) are effecti~e combinations to control blood pressure in hypertensive patients.
Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily do6age and, a~ noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.

3UBSTITU~E S~IEET

. . .

Typically, these combinations can be formulated into pharmaceutical compoæitions as discussed below.
About l to lO0 mg of compound or mixture o~
compounds of Formula I or a physiologically acceptable salt is compounded ~ith a physiologically acceptable vehicle, carrier, e~cipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparation~ i8 such that a suitable dosage in the range indicated is obtained.
Illu~trative of ~he adjuvants ~hich can be incorporated in tablets, capsules and the like are the following: a binder such a~ gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulose; a di~integrating agent such as corn starch, pregelatinized ~tarch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a ~lavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform is a capsule, it may containl in addition to materials of the above type, a liquid carrier ~uch aæ
fatty-oil. Variou~ other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Sli E3~TIT~JTE ~EET~

WO9ltl2002 PCT/US91/01001 2~ 2~ - 88 -Sterile compositionæ for injection can be formulated according to conventional pharmaceutical practice by dissolving or suspending the active substance in a vehicle such as water for injection, a naturally occuring vegetable oil like ~esame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antioæidants and the like can be incorporated as required.
The compounds of thi~ invention are also useful to treat elevated intraocular pressure and can be administered to patients ln need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well a~ topical ocular formulations in the form of solutions, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular pres3ur~
would typically contain about 0.1% to 15% by weight, and preferably 0.~% to 2 0% by weight of a compound of this invention.
Thus, the compounds of the invention are u eful in treating hyperten~ion. They are alRo of value in thé management of acute and chronic congestive heart ~ailure, in the treatment of ~econdary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of vascular disorders such as migraine or Raynaud's disease. The application of the SIJBÇTITllTE~ S~IEl~`

W091/1~Q02 PCT/US91/01001 - 2~

/
compounds of this inventivn for these and ~imilar disorders will be apparent to those skilled in the art.
The u~eful central nervous system (CMS) activities of the compounds of this invention are demonstrated and exemplified by the ensuing assays.

COÇNITIV~ FUNCTION AS~AY

The efficacy of these compounds to enhance cognitive ~unction can be demonstrated in a rat passive avoidance assay ;n which cholinomimetics such as physostigmine and nootropic agents are known to be active. In this assay, ratæ are trained to inhibit their natural tendency to enter dark areas. The test apparatus u~ed consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On e~tering the dark chamber, they receive a brief electric shock to the feet. The te~t animals are pretreated with 0.2 mg/kg of the muscarinic antago~i~t scopolamine which disrupte learning or are treated with ~copolamine and the compou~d which i8 to be tested for possible reversal of the scopolamine effect. Twenty-four hour~ later, the rats are returned to the illuminated chamber.
Upon return to the illuminated chamber, normal young rats who have been ~ubjected to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been e~posed to the apparatus but who have not received a shock. Rats treated with scopolamine before training do not show this he~itation when tested 24 hours later. Efficacious test compo~nds can SUBSTITUTE SHEE~ .

WO91tl2002 PCT/US91/01001 7~v~.~ - 90 -overcome the disruptive effect on learning ~hich scopolamine produceæ. Typically, compounds o~ this invention should be efficacious in this passive avoidance as~ay in the dose range of from about Q.l mg/kg to about lO0 mg/kg.

AN~IOLYTIC AS$A~

The an~iolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam ie a clinically useful ~n~iolytic which i~ active in this as~ay. In the CER protocol, male Sprague-Dawley rats (250-350 g) are trained to press a le~er on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly (five day~ per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each ses~ion partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a ~ixed LlDlL2D2L3 sequence. During both periods (L or D), pres~ing a lever delivers food pelletæ on a VI 60 second æchedule: in the dark (D), lever presses al80 elicit mild footshock (0.8 mA, O.5 sec) on an independent 3hock presentation schedule of VI 20 seconds. Lever preæsing is ~uppre~sed during the dark periods reflecting the formation of a conditioned emotional response (CER).
Drug testing in this paradigm is carried out under e~tinction conditionæ. During extinction, animals learn that reEponding for food in the dark is no longer pu~ikhed by shock. Therefore, response rates gradual].y increase in the dark period~ and SIJE~STITUT~ SHIEE~S

W091/1200~ PCT~US91/OlOOt 2 .~7;J,~?9~1 animals treated wit~1 an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of f rom about O.l mg/kg to about lOO mg/kg.

~ PRESSION ASSAY

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

SCHIZQP~RENIA ASSAY

The antidopaminergic activity of the compounds of this invention can be demonstrated in an apomorphine-i~duced sterotypy model. A clinically uæeful antipsychotic drug that is used as a positive control in this assay is haloperidol. The a~say method is based upon the observation that stlmulation SIJ!BSTITUTE~ T

WO91/120~2 PCT/US91/01001 2~ .2~.

of the dopaminergic system in rats produces stereo-typed motor behavior. There is a strong correlation between the effectiveness of cla3sical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptoms. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a k~ypad linked to a microcomputer. Compounds of the inven-tion should be ef~icacious in this assay in the range of from about O.l mg/kg to about lO0 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of this inve~tion may be utilized in compositions such as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspen-sions for parenteral or intramuscular administration, and the like. The compounds o~ thi~ inventio~ can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose - will vary from patient to patient depending upon the nature and severity of disea~e, the patient's weight, special diets then being followed by a patient, concurrent medicativn, and other factors which those skilled in the art will recognize~ the dosage range will generally be about 5 to 6000 mg.
per patient per day which can be administered in single or multiple doses. Perferably, the dosage range will be about lO to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.
In order to obtain m æimal enhancement of cognitive function, the compounds of this invention SUE~STITUTE~ T

may be combined with other cognition-enhancing agents. These include acetylcholineRterase inhibitors such as heptylphysostigmine and tetrahydroacridine ~THA; tacrine), muscarinic agonistæ such as 020tremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel bloekers and as nimodipine, and nootropic agent~ ~uch as piracetam.
In order to achieve optimal aDxioly~ic activity, the compounds of this invention may be combined with other anxiolytic agents such as alprazolam, lorazepam, diazepam, and busipirone.
In order to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepresæants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine oxidase inhibitors such as tranylcypromine.
In order to obtain ~a~imal antip~ychotic activi~y, the compounds of this invention may be combined with other antipsychotic agents such as promethazinç, fluphenazine and haloperidol.
The ~ollowing examples illuetrate the preparation of the compounds o~ Eormula I and their incorporation into pharmaceutical compositions and as such are not to be considered as limiting the invention set forth in the claims appended hereto.

SLIBSTITUTE ~HE1 WO91/12002 pcT/u~sl/~lool 2~75.~

9~

EXAMPLE 1.
2-Butyl-l-C4-(N-(l(R)-carbometho2y-l-benzyl~methyl) aminomethylphenyl~methyl-4-chloro-5-hydroxymethyl-imidazole ~Scheme II-2,. ~om~ound ~) .St~p_A: Preparation of Methyl 4-(bromomethyl)benzoate To a solution of l.0 eq of 4-(bromomethyl)benzoic acid in 20 ml of methanol and 50 ml of toluene; was added dropwise 2.05 eg of trimethylsilyldiazomethane while stirring at room temperature. The reaction was titrated until a persistant pale yellow color existed from the addition of excess trimethylsilyldiazo-methane. Let stir at room temperature for l hr to insure the complete evolution of N2. Thin layer chromatography in 1:1 hexame:ethyl acetate indicated the disappearance of starting material and the appearance of desired ester with an Rf of 0.7.

FAB-MS M+H = 230, 228.

H NMR (300m~z, CDCl3, ppm) ~8.02 (d, 2H); 7.46 (d, 2H~; 4.50 (s, 2~); 3.93 (s, 3H) Sa)BSTlTl,lTE. SHE~

W091/12~02 PCT/US91/01001 Step B: Preparation of 2-Butyl-5-t-butyl dimethylsilyloxymethyl-1-(4-carbomethoxyphenyl) meth~l-4-chloroimidazole ~ _ _ To a suspension of l.2 eq Na~ in 5 ml DME
was added dropwise a ~olution ol the product of Example 1, Step A (2.0 g, 6.57 mmol) at 0C causing immediate reaction, as evidenced by the evolution of H2 gas. The reaction mi~ture turned pale yellow and was stirred at 0 C until the g~s evolution ceased.
At 0 C, l.l eq of methyl 4-(bromomethyl)benzoate was added, the reaction was warmed to room temp rature and followed by TLC in 4:1 he~ane: ethyl acetate.
After 2.5 hours, the reaction appeared to be complete. The DMF ~as removed in vacuo and the residue dissolved in 100 ml ethyl acetate and washed with 0.5 N citric acid (the aqueous wash ~as back washed with saturat2d Na~C03 solution~ and brine;
dried over MgS04, filtered a~d removed the solvent.
The ~iscous yellow oil which was isolated (3.12 g) contained two spots. The crude material ~a~
dissol~ed in CH2Cl2. treated ~ith 0.5 eq of dimethylaminopyridine (DMAP), cooled to 0 C under N2 and then 0.33 eq t-butyldimethylsilyl chloride (0.33 g) was added. When the ~uspension dissolved, the solution was ~armed to room temperature and stirred for 2 hours. The C~2C12 was evaporated off and the residue, a elush, was dissolved in ethyl acetate and the DMAP HCl was filtered off. Some DMAP HCl remained and was removed by filtering through a silica plug. The residue was chromatographed on a sili~a gel column using a medium pressure liquid SUE3 STITUTE 9HEEl WO91/12~2 PCT/US91~0100 ~7 5~ 96 -chromatography (MPLC) setup, eluting with a 4:1 hexane: ethyl acetate, Isomer a, 2-butyl-5-t-butyldimethyl~ilyloxymethyl-1-(4-carbomethoxyphenyl)methyl-4-ch].oro-imidazole isolated in 80 % yield (2.34 g) and isomer b, 2-butyl-4-t-butyl-dimethylsilylo~ymethyl-1-(4-carbomethoæyphenyl)methyl-5-chloroimidazole, isolated in 12.8 % yield (0.38 g).

FAB-MS: i~omer a M+l= 451 isomer b M+l= 451 1~ NMR i~ome~ a: (300m~z, CDC13, ppm) ~.00 (d, 2~);
7.06 (d, 2~); 5.25 (s, 2~); 4.50 (s, 2~); 3.90 (s, 3~); 2.50 (t, 2H~; 1.70-1.55 (m, 2~); 1.37-1.23 (m, 2~); 0.8-0.76 (m, 12~); 0.02 (s, 6~).
i~mQ-~: (300mHz, CDC13, ppm) ~8.00 (d, 2H);
7.0B (d, 2~); 5.14 (s, 2~>; 4.65 (s, 2E); 3.90 (s, 3E); 2.55 (t, 2~); 1.68-1.55 (m, 2~); 1.32 (m, 2H); 0.92 (s, 9H); 0.85 (t, 3~); 0.10 (s, 6~.

S~p : Preparation of 2-Butyl-5 t-butyldimethyl-silvl~y~ethyl-4-chloIo-1-(4-~y~o~y~ayl)~e~hyl imidazole The product of Example 1, Step B, isomer a (2.22 g, 4.93 mmol) was di~solved in ethyl acetate, dried over MgSO~, filtered and the solvent evaporated in Yacuo. To a 35 ml dry T~F solution of isomer a, a pale yellow oil, cooled under N2 to -50C, was added dropwise 1.2 eq of a l.OM T~F solution of LiAlH4.
The reaction was allowed ~o warm to -25C. After 30 minutes, 243 ~l-of H20 was added dropwise at -25C
causing H2 evolution and was followed by the addition .

SUBSTll llT S~IEEl WO91/12~2 ~ ~ ~tr~ ~ PCT/USgl/0l001 of 243 ~1 15% NaOH and 243 ~1 H20~ gradually warming to room temperature. The reaction was continually stirred until the gelatinous precipitate became granular. The solid aluminum salts were removed by filtration rinsing with T~F. The filtrate was dried over MgS04, filtered, and stripped of solvent to give a colorless oil in 100% yield (2.11 g).

FAB-MS: M~E= 423 H NMR: (300m~z, CDC13, ppm) ~7.33 (d, 2~); 7.00 (d, 2~); 5.20 (s, 2E); 4.68 (d, 2H); 4.50 (s, 2~);2.50 (t, 2H~; 1.70-1.55 (m, 3H); 1.30 (m, 2H~;
0.90-0.72 (m, 12E); 0.02 (s, 6H).

S~ep D: Preparation of 2-Butyl-5-t-butyldimethyi-silylo~ymethyl-1-(4-carbo~aldehydophenyl)methyl-4-chloroimidazole To a solution of 636 ~1 of oxalyl chloride in 30 ml of dichloromethane (CH2C12), cooled to -78C, was added dropwise a solution of 1.03 ml dim~thylsulfo~ide in 5.0 ml C~2C12. After 15 ~inutes at -70C, a solution of the product of Eæample 1, Step C (2.2 g, 5.21 mmol) in 30 ml of CH2C12 wa~
added dropwise. After stirring at -70C for 45 min, 3.19 ml of triethylamine wa~ added, and the reaction was warmed to room temperature. The reaction was diluted with 100 ml of E20, the layers separated and the organic layer was washed with H20 and brine, and dried over MgS04. Removal of solvent in vacuo gave a viscous pale yellow oil, which became a cry~talline solid when refrigerated. The desired aldehyde had an Rf of 0.35 in 3:2 hexane:ethyl acetate.

~ B~:TlTuTE !E;HE~

Wosl/12002 PCTtUS91/01001 .

FAB-MS: M+l of 421 H NMR: (300m~z, CDC13, ppm) ~10.0 (s, lE+); 7.85 (d, 2~); 7.15 (d, 2~); 5.26 (s, 2~); 4.50 (s, 2H);
2.50 (t, 2~); 1.70-1,50 (m, 2~): 1.40-1.20 (m, 2 0.80-0.68 (m, 12H); 0.02 (s, 6~).

~Step ~: Preparation of 2-Butyl-5-t-butyldimethyl-silyloxymethyl-1-~4-(N-(l(R)-carbometho~y-l-benzyl)-methyl)aminomethylphenyll~ethYl-4-~loroimi~Q
To a solution of 1.1 eq of HCl D-phenylalanine methyl ester (O.46 g, 2.11 mmol) in 10 ml of dry ethanol over 3A powdered molecular sieve~
~as added a Folution o~ the product of E~ample 1, Step D (0.81 g, 1.92 mmol) in 10 ml ethanol. A~er stirring for 35 minutes, 3 eq of 1.0 M NaBH3CN in THF
(5.8 ml, 5.77 mmol~ was added, and the reaction stirred overnight at room temperature under N2 atmosphere. The reaction ~ol~e~t was removed in vacuo and the residue chromatographed on an L~-20 column eluting with CH30H. This failed to remove all the TEA.HCl and NaB~3CN and was rechromatographed on a silica gel column elu~ing with 30% ethyl acetate in hexane. The product wa~ i~olated in 78% yield (0.38 g) FAB-MS: M+l at 584.

1~ MMR: (300m~z, CDC13, ppm) ~7.35-7.1 (m, 7~); 5.15 (s, 2H), 4.50 (s, 2H); 3.80 (d, 1~); 3.65 (s, 3H);
3.60 (d, 1~); 3.50 ~t, lH); 2.95 (m, 2~) 2.50 (t, 2H~; 1.70-1.55 (m, 2H); 1.40-1.22 (m, 2H);
0.95-0.80 (m, 12~); 0.02 (s, 6~).

~Uæ~TIT~TE ~F~

WO91/12~2 PCT/V~91/01001 Z~

_ 99 ~

Step F: Preparation of 2-Butyl-1-[4-(N-(l(R)-carbomethoxy-l-benzyl)methyl)aminomethylphenyl]-methyl-4-chloro-5-hydroxymethylimidazole (Scheme Il=i~_Compound 3~ _ To a solution o~ the product of Example 1, Step E (53 mg, 91 ~mol~ in 1.O ml THF was added 0.11 ml of a l.OM T~F solution of tetrabutylammonium fluoride and the reaction was stirred overnight at room temperature under N2. The reaction was then filtered through a silica gel plug eluting with ethyl acetate to remove the ba~eline tetrabutylammonium fluoride. The pale yellow oil was chromatographed on silica gel eluting with 3:2 hexane:ethyl acetate and the product wa~ i~olated in a 76% yield (32 mg).
FAB-MS: M+l of 470 .

1~ NMR: (300m~z, CDC13, ppm) ~7.30-7.10 (m, 7~);
6.90 (d, 2~); 5.17 (s, 2~) 4.46 (s, 2~); 3.80 (d, lE); 3.64 (æ, 3~); 3.60 (d, lH); 3.50 (t, 1~) 2.95 (m, 2H) 2.55 (t, 2H); 1.65 (m, 2H); 1.35 ~m, 2H), O.gO
(t, 3~)-E~P~E 22-Butyl~ 4-(N-(l~R)-carbo~y-l-benzyl)methyl)ami~o-methylphenyl]methyl-4-chloro-5-hydroxymethylimidazole sodium s~lt To a solution of the product of Example 1, Step F (37 mg,78 ~mol) in 3:1 CH30~:H20 was added 47 ~1 of 2.ON ~aO~ and the reaction was stirred at room temperature overnight. The solvent was removed in vac~o and the re3idue was dissolved in 1.5 ml C~30 filtered and chromatographed on a Sephadex column SUBSTITI..ITE SHE~ET

WO91/12~02 PCT/US91/0l001 .

(L~-20) eluting with C~30H. Two overlapping peaks were observed which by mass npectrometry were found to be the sodium salt and the ~ree acid, and were combined and isolated in a ~lOOZo yield (35 mg).

FAB-MS: M+l i~ 456 (~ree acid) and M~Na (Na salt) lE NMR: (300mHz, CD30D, ppm) ~7.30-7.10 (m, 7~);
6.98 (d, 2~); 5.30 ~s, 2H); 4.45 (s, 2~); 3.85-3.70 (m, 1~); 3.63-3.50 (m, lH); 3.35 (m, 1~); 3.10-2.93 (m, lH); 2.92-2.78 (m, lH); 2.55 (t, 2H); 1.53 (m, 2~); 1.30 (m, 2H); 0.88 (t, 3~).
E~AMPLE 3 2-Butyl-l-t4-(N-(l(R)-carbomethocy-l-benzyl)methyl-methyl-N-pentanoyl)aminomethylphenyl]-4-chloro-5-hydro2y~ethy1imid~zole ._ Step A: Preparation of 2-Butyl-5-t-butyldimethyl-silyoxymethyl-1-~4-(N-(l(X)- carbomethoxy-l-benzyl~methyl-N-pentanoyl)aminomethylphenyl]-4-chloroimidazole To a ~.O ml THF ~olution of the product of E~ample 1, Step E (0.12 g, 0.20 mmol) under N2 was added 1.5 eq of TEA followed by the addition of 1.2 eq of valeroyl chloride, which resulted in the precipitation of TEA-8Cl. The reaction was warmed, and when checked by TLC after l-hr it was complete.
The TEA ECl was ~iltered from the reaction and the filtrate was e~aporated down to give a yellow oil.
The residue contained two spots which were presumed to be the silylated and unsilylated products. The residue ~as chromatographed on silica gel eluting with 30% ethyl acetate in hexane and the product isolated in 92% yield (124 mg~.

SUE~STlTl,llrE SH~

WO91/12~2 P~T/~S91/010~1 z~7~,~Z~

- 101 - f ., ", ., FAB-MS: M+l of 668 ;.
H NMR: (300 m~z, CDC13, ppm) ~7.30-7.05~; (m, 7~);
6.90 (d, 2~); 5.15 (s, 2~); 4.50 (s, 2~); 4.40 (d, 1~); 4.30 (m, lH) 3.73 (d, lH) 3.64 (~, 3H);
3.4-3.2 (m, 2~); 2.5 (t, 2H); 2.24 (m, 2~); 1.6 (m, 4H); l.3 (m, 4~); 0.85 (m, 15H); 0.02 (s, 6~).

S~e~ B: Preparation of 2-Butyl-l-r4-(N-(l(R)-carbometho~y-l-benzyl)methyl)methyl-N-pe~tanoyl)-amiaomethYll;h~nyll-4-ehloro-5-hvd~Q~vmethylimida~le To a solution of the product of Example 3, Step A (O.ll g, 0.16 mmol) in 2 ml TEF under N2 at room temperature was added 1.2 eq of a 1.0 M ~olution of tetrabutylammonium fluoride and followed the procedure of Egample 1, Step F. The product was i~olated in a 73X yield (63 mg).

FAB-MS: M~l at 554 H NMR: (300m~z, CDC13, ppm~ ~7.30-7.02 (m, 7~);
6.90 (d, 2H); 5.15 (8, 2~); 4.44 (8, 2H); 4.48 (d, lE); 4.26 ~m, lH); 3.74 (d, lH); 3.63 (8, 3~);
3.4-3.17 (m, 2~; 2.50 (t, 2H), 2.2 (m, 2~); 1.6 (m~
4~), 1.28 (m, 4~3; 0.85 (m, 6~) XAM~LE 4 2-Butyl-1-~4-(N-(l(R)-carboxy-l-benzyl)methyl-N-pentanoyl)aminomethylphenyl~methyl-4-chloro-5-hydro~y~
e~hvlimidazole ~odium salt (~b~me_LI=3~ Go~Q5u~L-LL~
Followi~g the procedure o~ Egample 2, Step A
the product of E~ample 3, Step B wa~ hydrolyzed to SU13~1iTlTllTE~ SHÇ~E~

W091/12~2 P~T/~S9~/0100 ~5'c~ 102 -give the sodium salt in 58% yield (24.5 mg).

FAB-MS: M~l at 562 and M+Na at 584.

H NMR: (300m~z, CD30D, ppm) 7.3-6.82 (m, 9~); 5.25 (d, 2~), 5.00 (d, 1~); 4.6 (m, lH); 4.44 (s, 2~);
4.30 (d, lH); 3.4-2.8 (m, 2~); 2.1 (m, 2~); 2.4-2 (m, 2E); 1.6-1.1 (m, 8H); 009-0.75 (m, 6H).

EgAMPLE 5 ~-Butyl~ 4-(N-(l(R)carbomethoxy-l-benzyl)methyl-N-(3-phenyl)propionyl)aminomethylphenyl]methyl-4-chloro-5-hydrQ~ymethvli~idazole ~heme I-3, Com~Qund 132 _ Step A: Preparation of 2-Butyl-5-t-butyldimethyl-silyloxymethyl~l-[4-(N-(l(R)-carbomethoxy-l-benzyl)-methyl-N-(3-phenyl)propionyl)aminomethylphenyl]methyl-4-&hlorOimida~Ql~
Following the procedure of Example 3, Step A, the product of Example 1, Step E (0.11 g, 0.195 mmol) was treated with hydrocinnamoyl chloride and the product was isolated in a 78% yield (110 mg).

FAB-MS: ~+1 at 716 1~ NMR: (300m~z, CDC13, ppm) ~7.30-6.8 (m, 14~);
5.13 (s, 2E); 4.48 (d, 2~); 4.35 (d, 1~); 4.27 (m, lH); 3.7 (d, lH); 3.62 (s, 3H); 3.4-3.1 (m, 2~); 2.93 (m, 2H+) 2.5 (m, 4H) 1.6 (m, 2H); 1.3 (m, 2~); 1.83 (m, 3~.

Step B: Prep~ration of 2-Butyl-1-[4-(N-(l(R)-carbo-methoxy-l-benzyl)methyl-N-(3-phenyl)propionyl)amino-methylphen~ ethyl-4-chloroimidazole . Following the procedure of E~amplc 1, Step F
and using the product of E~ample 5, Step A as.the Sl)BSTlTVTE SHEE~

WO91/120~2 PCT/US9~/0l001 5~ ~

- 103 - ^` `;~;`

subætrate 7 ~he de~ired product was i~olated in a 61%
yield (55 mg) FAB-MS: M~l at 602, M-18 at 584 (108s of H20) a~d M-188 at 414 (loss of imidazole fragment) 1~ NMR: (300m~z, CDC13, ppm) ~7.30-6.8 (m, 14~);
5.15 (s, 2H); 4.43 (d, 2~); 4.32 {d, lH); 4.27 (m, lH); 3.7 (d, lH); 3.62 (~, 3H); 3.4-3.1 (m, 2H); 2.93 (m, 2~+) 2.5 (m, 3H) 2.28 (m, 1~); 1.64 (m, 2~); 1.40 (m, 2~) 0.88 (t, 3~).

E~am~le 6 2-Butyl-1-~4-(N-(l(R~-carbo~y-l-benzyl)methyl-N-(3-phenyl)propionyl)aminomethylphenyl~methyl-4-chloroimidazole Following the procedure of Example 2, Step A
and U8 i~g the product of E~ample 5, Step B in two productæ of 61ightly different Rfs resulted ~hich ~ere combined and treated with ~Cl in THF to obtain the free acid/~Cl salt.

FAB ~S: M~l at 588 and M-18 at 570 H NMR: (300m~z, CD30D, ppm) ~7.3-7.0 (m, 14~); 5.5 (s, 2~); 4.53 (8, 2~; 4.45-4.3 (m, 2~); 3.9 (d, 1~);
3.25-3.1 (m, 1~); 2.~5-2.75 (m, 4~); 2.7 2.4 (m, 2H); 1.6-1.4 (m, 2H); 1.38-1.2 (m, 2~) O.g2-0.78 ~m, 3~)-~ Z
2-Butyl-1-~4-(N-(l(R)-carbomethoxy-l~benzyl)methyl-N phenylacetyl)aminomethylphenyl~methyl-4-chloro-5-hydro~yme~h~limidaæole SUBSTITUTE SH ET

WO~1~12~2 PC~/US91/01001 ~7~ J~' , ;

~ep A: 2-Butyl-5-t-butyldimet:hylsilylo~ymethyl-1-[4-(N-(l(R)-carbomethoxy-l-ben~yl)methyl-N-(phenyl-acetyl)aminomethvlph~Pyl]methyl-4-~hloroimida~le Following the procedure of Example 3, Step A
the product of Example 1, Step E (0.12 g, 0.209 mmol) was treated with phenylacetyl c~loride and the product was isolated in a 57/O yield (60 mg) based on recovered starting material.

FAB-MS: M+l at 702 lH NMR: (300m~z, CDC13, ppm) ~7.38-7.15 (m, 9E);
7.0-6.95 (m, 5~); 5.15 (s, 2~); 4.48 (s, 2H); 4.44 (d, lE); 4.15 (m, lH); 3.67 (s, 3~); 3.63 (67 2H);
3.60 (d, 1~); 3.38-3.13 (m, 2H); 2.5 (t, 2E); 1.6 (m, 2H); 1.3 (m, 2H); 0.85 (m, 12H); 0.02 (s, 6E).

Step_B: Preparation of 2-Butyl-1-~4-N-(l(R)-carbo~
methoxy-l-benzyl)methyl-N-(phenylacetyl)aminomethyl-henyllm~thyl-4-~hlQro-S-hYdrQ~nrmethyli~idazQle . Following the procedure of ~xample 1, Step F
and u~ing the product of Example 7, Step A as the ~ubstrate, the desired product was i~olated in a 50%
yield (24 mg).

FAB-MS: M+l at 588, M-18 at 570 (loss of H20) and M-188 at 400 (loss of imidazole ~ragment) 1~ NMR: (300m~z, CDC13, ppm) ~7.37-6.8 (m, 14E);
5.15 (s, 2H); 4.45 (d, 2~); 4.43 (d, lE); 4.15 (m, lH); 3.6 (m, 6~); 3.4-3.15 (m, 2H); 2.52 ~t, 2H);
1.65 (m, 2~); 1.3 (m, 2~); 0.8 (t, 3~).

SUBSTITUTE ~HEE~

WO91/12~2 z~7~ PCT/~S91/OlO01 ExAMpLæ E~
2-Butyl-1-[4-(N~ R)-carboxy-l-benzyl)methyl-N-(phenylacetyl~aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole (Scheme I-3, Compound_16) .
Following the procedure of F,~ample 6, Step A
and u~ing the product of E~ample 7, Step B the desired product was isolated in a 61% yield (16 mg).

FAB-MS: M+l at 574, M-18 at 556 and 2M+1 at 1148 H NMR: (300m~z, CD30D, ppm) ~7.3-6.7 (m, 14H); 5.25 (d, 2H); 5.00 (d, 0.6H); 4.9-4.8 (m, 0.4~) 4.7-4.6 (m, 1~); 4.45 (~, 2H); 4.45-4.3 (m, lH); 3.72-3.48 (m, 2H); 3.38-3.05 (m, 1.4H); 2.70 (m, 0.6H); 2.55 (m, 2~); 1.50 (m, 2H); 1.~6 (dt, 2H); 0.85 (t, 3~).

~ AMPL~ S
2-Butyl-1-[4-(N-(1(S)-carbomethoxy-l-benzyl)amino-methylpheny~L ethvl-4-chloro-~-hyd~Q~ymethyL~ 3~ole Step A: Preparation of 2-Butyl-5-t-butyldimethyl silylogymethyl-1-[4-(N-(l(S)-carbometho~y-l-ben~yl)ami~o~thylphenyllme~hvl-4-chl~rimidazole Following the proccdure o~ E~ample 1, Step E
but uæing 1.1 eg L-phenylalanine methyl ester ~Cl (116 mg, 0.538 mmol) and 1.0 eq of the aldehyde prepared in E~ample 1, Step D in 2-3 ml ethanol over - 3A molecular sieves, the product was isolated in a 59% yield (168 mg).

FAB-MS: M~l at 584 1~ NMR: (300 m~z, CDC13, ppm) ~7.32-7.22 (m, 7H);
6.90 ~d, 2H), 5.15 ~s, 2~); 4.50 (s, 2H); 3.80 (d~

$ ~ ~STIT~ Er W~91/12002 PCT/US91/0100l 2 ~

lE~; 3.65 (s, 3H); 3.60 (d, 1~); 3.50 (t, lH); 2.95 (m, 2~); 2.50 (t, 2H); 1.6 (m, 2~); 1.30 (dt, 2H) 0.85 (t,s, 12H); 0.02 (5, 6~).

Step B: Preparation of 2-Butyl-1-[4-(N-(l(S)-carbo-methoxy-l-benzyl)aminomethylphenyl]methyl-4-chloro-5-hy,droxvmethYllmidazole. ~
Followi~g the procedure of Example 1, Step F, and using the product of Example 9, Step A, the desilylated product was obtained in a 65% yield (13 mg).

FAB-MS: M~l at 470 1H NMR: (300m~z, CDC13, ppm): ~7.30-7.10 (m, 7H);
6.90 (d, 2H), 5.17 (s, 2~); 4.46 (8, 2~); 3.80 (d, 1~); 3.64 (s, 3~); 3.60 (d, lH); 3.50 (t, 1~); 2.95 (m, 2H); 2.55 (t, 2~); 1.65 (m, 2h); 1.35 (dt, 2~) 0.90 (t, 3E).
E~Q
2-Butyl-1-~4-(N-(l(S)-carboxy-l-benzyl)aminomethyl-phenyllmethyl-4-chloro-5-hy~o~ymethylimidazole Following the hydrolysi~ procedure described in Example 2, Step A, but using the product of E~ample ~, Step B, the free acid wa~ isolated in a 82% y;eld (12 mg).

FAB-MS: M+l at 456, trace amount of ester at 470 and M~NA at 478 H NMR: (300mHz, CD30D, ppm) ~7.3-7.1 (m, 7H); 7.00 (d, 2H); 5.27; (s, 2~); 4.45 (s, 2~); 3.75 (d, 1~);
3.53 (d, lH); 3.02-2.90 (m, l~; 2.87-2.77 ~m, 1~);
2.55 (t, 2~); 1.53 (m, 2~); 1.27 (dt, 2H); 0.85 (t, 3~) S~JBSTIT~9TE SHEET

WO91tl2~2 Z~75~?~ PCT/VS9~/01001 ~ XAMPLE 11 2-Butyl-1-[4-(N-(l(S~-carbomethoxy-l-benzyl)-N-pentanoyl)aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole (schQme I-3, Com~ound 10 Step A: Preparation of 2-Butyl-~-t-butyldimethyl-silyloxymethyl-l-C4-(N-(l(S)-carbometho~ eIlzyl-N-pentanoyL~a~aQmethyl~he~llmethyl-4-chlo~imidazole Following the procedure of Example 3, Step A
but using the product of Example 9, Step A and acylating with valeryl chloride gave the de~ired product in a 90% yield (97 mg).

FAB-MS: M+l at 668 H NMR: (300m~z, CDC13, ppm) ~7.3-7.0 (m, 7H); 6.90 ~d, 2~); 5.13; (s, 2H); 4.48 (~, 2H); 4.40 (d, i~);
4.26 (t, 1~); 3.75 (d, 1~); 3.65 (s, 3H); 3.4-3.15 (m, 2H); 2.48 (t, 2~); 2.20 (m, 2~); 1.68-1.46 (m, 4E); 1.38-1.18 (m, 4H); 0.93-0.73 (m, 15~); 0.02 (6, 6~).

Step B: Preparation of 2-Butyl-1-~4-(N-(l(S)-carbometho~y-l-benzyl-N-pentanoyl)aminomethylphenyl]-methyl-4-~hLQ~o-5~h~drogymethylimidazole - To-a solution of Example 11, Step A (94 mg,0.14 mmol) in THE was added 0.17 ml of 1.O M
tetrabutylammonium fluoride and following the procedure of Example 1, Step F the product was isolated in a 52% yield (40.5 mg) .

FAB-MS: M+l at 554 and M-18 at 536.

~ilR.~TITUTE SHEET

WO91/12002 pcT/ussl~oloo1 ..

H NMR: (300m~z, CDC13, ppm3 ~7.3-7.02 (m, 7~); 6.90 (d, 2~); 5.18; (s, 2~); 4.45 (s, 2H); 4.38 (d, 1~);
4.27 (m, 1~); 3.73 (d, lH); 3.62 (8, 3H), 3.4-3.15 (m, 2~); 2.53 (t, 2H); 2.3-2.1 m, 2H); 1.75-1.5 (m, 4H); 1.4-1.2 (m, 4~); 0.85 m, 6H).

2-Butyl-1-[4-(N-(1(S)-carboxy-l-benzyl)methyl-N-pent-anoyl)aminomethylphenyl]methyl-4-chloro-5-hydroxy-me~hylimidazolQ-Ec~ly~ salt C~sh~e I-3, compQ~D~-l2 Following the procedure of ~ample 2, Step A the methyl ester of E~ample 11, Step B waæ hydrolyzed to give a 73% yield (23 mg) of the sodium salt.
FAB-MS: M+l at 562, M+Na at 584, 2M+1 at 1124 and ~M~Na at 1145 1~ NMR: (300mEz, CD30D, ppm) ~7.28-6.82 (m, 9~);
5.25 (d, 2~); 5.00 ~d, 1~); 4.6 (m, 1~; 4.45 (s, 2~); 4.28 (d, 1~); 3.4-3.2 (m, 1~); 3.10-2.98(m, 0.4~); 2.85-2.75 (m, 0.6H); 2.55 (m, 2~); 2.38-1.95 (m, 2~); 1.6-1.1 (m, 8~); 0.90-0.73 (m, 6H).

EXA~PLE 13 2-Butyl-5-t-butyldimethylsllyloxymethyl-1-[4-(1-carbo-methoxy-l,l-dibenzyl)methyl)aminomethylphenyl~methyl-4-chlo~imid~æGl~ (Scheme I-5. Compound 18) Step A: Preparation of N-benzylidene-D-phenylalanine methyl es~r To a suspension of 1.0 eq D-phenylalanine HCl (1.6 g, 7.4 mmol) was added 1.0 eq triethylamine ~-to dissolve the D-phenylalanine. To this solution was added 1 eguiv. of MgS04 followed by the addition of 1.0 eq benzaldehyde, the reaction ~as stirred S UB~TITIIT~ ~CCT

W091/12~2 PCT/~J~l/01001 ~ 75~

-- 109 -- , .. .
overnight at room temperature under N2 atmosphere.
The reaction mixture was srippecl of solvent and pumped on the residue contained a good deal of triethylamine hydrochloride which was removed by dissolving the product in THF and filtering out the TEA ~Cl. The crude benzylidene looked fine by NMR
and was all taken on in the ne2t step.
H NMR: (300mHz, CDC13, ppm) 7.90 (s, 1~); 7.68 (d, 2H); 7.4 (m, 3~); 7.~6-7.12 (m, 5~); 4.17 (m, lH); 3.72 (s, 3~); 3.38 (dd, lH), 3.15 (dd, lH).

Step B: Preparation of Methyl-2-amino-3-phenyl-2-phenvlme~hyprQpionate (Sehe~e I-4~ Compound 17) To a solution of the benzylidene, Example 13, Step A, in 25 ml dry THE at -78C was added 1.05 eq of 1.0 M lithium he~amethyldi~ilylazide in THF
(7.8 ml) over 10 minutes. After 30 minutes, a solution of 1.05 eg benzyl bromide in lS ml T~F was added over 15 minute~. The reaction ~iæture wa~
stirred at -70C ~or 15 ~in. and then gradually warmed to -40 to -35C and stirred at this temperature for 1.5 hours, after which the reaction appeared to be co~plete. The reaction mi~ture was quenched at -35C by the addition of S0 ml of 1.0 N
~Cl and it was then allo~ed to warm to room temperature with ~t~rring. The reaction miæture was then egtracted twice with hexane to remove the bezaldehyde which had been formed. The aqueous layer was then extracted three times with ethyl acetate, and the combined extracts were washed with saturated NaHC03 and brine, then dried over MgS04. The solvent was removed in vacuo to give ~24 mg of a yellow ~;UB!~:TI~I~T~ r r WO91/12~2 Pcr/us~l/olool ~
;'' Z ~7 ~
crystalline solid. The p~ of the aqueous layer was adjusted from 1.4 to 11.8 using 3N NaO~ producing a milky white solution, which became clear upon addition of ethyl acetate. The basic aqueous layer was eætracted twice more with ethyl acetate, and the combined e~tracts were washed with brine and dried over MgS04. The solvent was removed in vacuo to give a colorless oil (1.37 g) giving a total yield of 85%.
FAB-MS: M+h =270 1~ NMR: (300~z, CDC13, ppm); ~7.3-7.15 (m, 10~), 3.65 (s, 3~); 3.37 (d, 2H); 2.74 (d, 2~).

~tep C: Preparation of 2-Butyl-5-t-butyldimethyl-silyoxymethyl-1-[4-(l-carbometho~:y-l,1-dibenzyl)methyl)aminomethylphenyl]methyl-4-chloroimidazole (Scheme I-5. Compound 18) To a solution of 1.1 eg of the product of Example 13, Step B (0.32 g, 1.2 mmol) in 15 ml C~2C12 over MgS04 after 15 min wa~ added 1.0 e~ o~ the aldehyde of Egample 1, Step D (O.46 g, 1.09 mmol) and the reaction mi~ture was allowed to stir at room temperature under N2 over the weekend. The reaction mi~ture was then filtered and concentrated in vacuo.
The reaction mixture was disso~ved i~ toluene and warmed to reflu2 under a Dean-Stark trap for 3 hrs.
The reaction mixture was then cooled to room temperature under N2 and 3.0 eq of 1.O M NaCNB~3 was added. The reaction mixture was stirred at room temperature overnight, then the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and water, and the layers separated slowly and the orga~ic layer ~s~d with~rine,~drie~ ver~gS04, $1JBSTIl'UTE~ SHE:ET

'- 2~ ?~

filtered and stripped of solvent. The residue was chromatographed on silica gel eluting with 4:l hexane:ethyl acetate and two fractions were isolated. The first fraction contained a mixture of the Schiff's base and the desired product ~378 mg, 51%) and the second fraction contained the product (43 mg). The mi~ture was reehromatographed eluting with 15% ethyl acetate and hexa~e and the product (108 mg) wa~ isolated in the first fraction to give a total yield of 20.5% (153 mg). The second fraction con~ained 90 mg of a miæture of the Schiff's base and the desired product.

FAB-MS: M+H- 674 lH NMR: (300m~z, CDCl3, ppm) ~7.3-7.15 (m, l2Hs;
6.95 (d, 2H); 5.17 (s, 2H); 4.53 (s, 2~); 3.87 (s, 2~); 3.63 (s, 3H); 3.23 (d, 2~); 3.07 (d, 2~; 2.54 (t, 2H); 1.66 (m, 2~); 1.34 (dt, 2H); 0.86 (m, 12~);
0.04 (s, 6~).

~ AMPL~ 14 2-Butyl l-~4-(N-(l-carbomethoxy 1,l-dibenzyl)methyl)-aminomethylphenyl3methyl-4-chloro-5-hydro~ymethyl-imid~zole (Sch~me I-~. Com~ound l~) To a solution of the product of Eæ~mple 13, Step C (67 mg, O.lO mmol) in 2.0 ml of THF, was added l.~ eq of l.OM tetrabutylammonium fluoride in THF and ~he procedure of Example 1, Step F was followed. The desilylated product was isolated ~65 mg; lOO~/u).

FAB-MS: M+H= 560 ~;IJ13STITVT SHEET

WO91/~2 PCT/~ssl/olool 2~ 112 ~H NMR: (300m~z, CDC13 ppm) ~7.35-7.15 (m, 12~
6.90 (d, 2H); 5.20 (s, 2H); 4.45 (s, 2~); 3.87 (s, 2H); 3.64 ~s, 3E); 3`.20 ~d, 2~); 3.05 (d, 2H); 2.55 (t, 2E); 1.67 (m, 2~); 1.35 (m, 2~); 0.88 (t, 3H~.

E~AMP~E l~
2-Butyi-l-t4-(N-(l-carboxy-l,l-dibenzyl)methyl)amino-methylphe~yl]phenyl]methyl-4-chloro-5-hydro2ymethyl-imidazole (~heme l-5~ Compou~d_20) _ _ _ The hydrolysis procedure of Example 2, Step A was ~ollowed using the product of E~ample 14, Step B. The reaction was run overnight, but appeared to be incomplete, and was refluxed at 100C for 4 hrs.
An additional 2 eq of 2.ON NaOH (0.1 ml) wa~ added a~d the reaction ~i~ture was allowed to reflux ~or two days. The reaction mixture became cloudy on cooling to room temperature and was filtered. The filtrate ~a~ acidified with concentrated HCl and stirred for 1 ~r. The solvent was removed in ~acuo and the water azeotroped o~f with toluene and acetonitrile. The residue was chromatographed on a ~ephadex column, eluting with ~ethanol yielding bo~h the acid and eæter. This fraction was chromatographed on silica gel eluting with 11:1 C~2C12:C~30~ to elute the ester and then 11:1:0.5 - CE2C12:CH30~:~0Ac to elute the acid in a 44% yield (27 mg).

F~B-MS: M+l at 546 and M-l9 at 528.

1~ NMR: (300m~z, CD30D, ppm) ~7.5-7.12 (m, 12H), 7.00 (d, 2E); 5.30 (s, 2H); 4.45 (s, 2H); 4.06 (s, 2~); 3.43 (8j ~H); 3~18 (d, 2~); 2.52!(t,~ .2 (t, 2H); 1.28 (m, 2E); 0.85 (m, 3H).

~;UBSTITUTE SffEET

WO gl/12002 Z~75~J~ PCT/US91/01001 4~ (N-benzyl-N-pentanoyl)amino-l-(tetrazol-5-yl)methylphenyl]methyl-2-butyl-5-t-butyldimethylsilyl-o~ymethyl-4-chlQ~Qimidazole (S~ Gom~ound 23) Step A: Prepasation~of 1-[4-(1-~N-benzyl)amino-l-cyano)methylphenyl~methyl-2-butyl-5-t-butyldimethyl-silvloxymQthyl-4-chloroimid~zole __ _ To a solution of the product of Eæample 1, Step D in 2-3 ml of C~2C12 over MgS04 was added 1.7 eq of benzylamine and the reaction mi~ture wa~
allowed to stir for 2 day~. The Schiff base formation ~as not complete, as indicated by TLC.
Trimethylsilylcyanide (1.1 eq) was added and the reactlon mixture was allowed to stir overnight at room temperatur~. The reaction mi~ture was fiitered and the filtrate was stripped o.~ C~2C12, dissolved in ethyl acetat~, washed twice with water and once with brine, and then dried over MgS04. The solvent wa~
removed in vacuo, and the residue wa~ acylated in the next step.

FAB-MS: M+l at 537 H NMR: (300m~z, CDC13, ppm) ~7.50 (d, 2~); 7.3-7.2 (m, 5~); 7.03 (d, 2~); 5.20 (s, 2~); 4.73 (s, lE);
4.50 (s, 2~); 4.05 (d, 1~); 3.95 (d, lH); 2.50 (t, 2~); 1.65 (m, 2~); 1.30 (dt, 2H); 0.85 (m, 12H);
0.02 (s, 6H).
.
Step B: Preparation of 1-[4-(1-(N-benzyl-N-pentanoyl-ami~o-l-cyano)methylphenyl]methyl-2-butyl-5-t-butyldi-methylsilylQ2ymethyl--4---çhloroimidazole ......

SIJBSTITUTE Sl~liE~

Wosl/l2oo2 PCT/US91/01001 ~75~ 114 -Following the acylation procedure of Example 3, Step A but using the product of Example 16, Step A
(132 mg, 0.246 mmol) and 1.2 eq of valeroyl chloride (35 ul, 0.295 mmol) and 1.5 eq of triethylamine (Sl ~1, O.368 mmol). The reaction appeared to be incomplete after ~tirring for a few hours and ~as allowed to continue overnight. The reaction mi~ture was filtered and the filtrate was stripped of solvent. The residue was chromatographed on ilica gel eluting with 4:1 he~ane:ethyl acetate. The two fractions isolated were mixtures 9 containing both the acylated product and starting materials. These two fractions were combined and acylated again u~ing 1.6 eq valeroyl chloride and 1.9 eq triethylamine in THF, stirring at room temperature overnight. The same workup procedure as described above wax u~ed, and the material was chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The product was isolated in a 33% yield (50 mg).

FAB-MS: M~l at 621 1~ NMR: (300m~z, CDC13, ppm) ~7.4-6.96 (m, 9E); 5.15 (æ, 2H); 4.55-4.4 (m, 5~); 2.48 (t, 2~); 2.28 (t, 2H); 1.63 (m, 4H); 1.3 (m, 4~); 0.85 (m, 1 0.02 (s, 6~).

Step C: Preparation of 1-[4~ (N-benzyl-N-pent-anoyl)amino-l-(N-trimethylstannyltetrazol-5-yl)) methylphenyl]methyl-2-butyl-5-t-butyldimethylsilyloxy-meth~l-4-chloroimidazole To a solution of 1. O eq of the product of Example 16, Step B in 2 ml of dry toluene wa~ added ~IIR~TITIITF ~EET

WO91/12~2 PCT/US91/01001 2~75~

1.~ eg trimethyl~tannylazide and the mixture was gradually warmed to reflux in toluene overnight. The TLC and crude l~ NMR indicated the disappearance of starting material, and the crude material was carried on to the next step.

H NMR: (300mHz, CDC13, ppm) ~7.6-6.6 (m, 9H); 5.12 ~s, 2H); 4.95 (d, lH); 4.75 (d, l~); 4.55-4.37 (m, 3E); 2.6-2.4 (m, 2H); 2.4-2.1 (m, 2~); 1.7-1.5 (m, 4H); 1.4-1.2 ~m, 4H); 1.00-0.8 (m~ 12~); 0.70 (s, 6~) 0.02 (s, 6H).

Step D: Preparation o~ 1-[4-(1-(N-Benzyl-N~p~nt-anoyl)amino-l-(tetrazol-5-yl))methylphenyl~methyl-2-~ut;vl-4-chlorQ-S-hvdroxymethvlimidazole To a 2 ml solution of the product of Example 16, Step C (theoretically 66 mg, 0.08 mmol) at room temperature was added 5 drop~ of conce~trated HCl.
The reaction mi~ture became hot, wa~ cooled with an ice bath and stirred, and ~a~ then allowed to warm to room temperature. The reaction mi~ture was stirred for about an hour at room temperature and appeared to be complete. The 801v~nt was removed in vacuo and the residue chromatographed on ~ilica gel eluting with 40:10:1 C~C13:CH30~:N~40~ and the product i~olated in a 25~ yield (10 mg).

FAB-MS: M+l at 550, M~Na at 572 and M-18 at 532 H NMR: (300mHz, CD30D, ppm) ~7.5-6.7 (m, 9H); 5.25 (s, 2H~; 5.0-4.7 (m, 2~); 4.35 (s, 2H); 2.63 (m, 0.5H); 2.52 (t, 2~); 2.30 (t, 1.5H); 1.68-1.45 (m, 4~); 1.4-1.15 (m, 4H); 0.95-0.75 (m, 6H).

SllBSTlT~JTE~ SHEEl``

WO91~12002 PCT~US91/~1001 .
., r~J~ ~ 116 -~A~P~E 17 2-Butyl-4-chloro-5-hydroxymethyl-3-[4-(1-hydroxy-l-phenyl~ ~azol-~yl ~ ~methylph~Tlyl~by~1 e ( S chelne I-9 ~ C~mpound 3 9 ,Step A: Preparation of 4-b~o~omethvlbenz~phen~ne 1 To a solution of 4-methylbenzophenone (3.0g, 15.3 mmol) in 60 ml CC14 was added N-bromosuccinimide (3.0 g, 1.1 eq) and AlBN (30 mg). The solution was refluxed for 4.5 h, then cooled to room temperature.
The succinimide were removed by ~iltration, and the filtrate was concentrated to dryness.
Recrystallization required large amounts of sol~ent and chromatography appeared a better alternative.
The residue was chromatographed on silica gel eluting with 5% Ethyl Acetate/~exane (3.44 g; 82% yield).

lNMR (300 M~z, CDCl~, ppm): ~4.55 (~, 2H); 7.5 (m, 4H, 7.6 ~m, 1~); 7.8 (m, 4~).

Step ~, Preparation of 1-(4-benzoyl)phenylmethyl-2-butyl-5-t-butyldimethylsilylo~ymethyl-4-chloro-imidazole To a suspension of Ma~I (0.21 g, 6.97 mmol) in 15 ml of DME was added 2-butyl-5 t-butyldimethyl-silyloxymethyl-4-chloroimidazole (2.0 g, 6.62 mmol) and the solution was stirred for 45 min. under N2.
To this solution ~as added 4-bromomethylbenzophenone (1. 82 g, 6 . 62 mmol) and the mi~ture was stirred ~or 4.5 hrs. The reaction mixture was quenched with saturated ammonium chloride, a~d the solvent was ~ Rc:TlTuTE SHEEl wo 9lrl2~Z Z~7_~21 PCT/US9l/0l00l removed in vacuo. The residue was di~solved in ethyl acetate, washed with H20 and br:ine, dried o~er ~gS04 - filtered and concentrated in vacuo. The crude product was chromatographed on ~3ilca gel (170 mm X 50 mm) in two batches, eluting with 15% ethyl acetate in hexane. The product was ieolated in a 71% yield (2.36 g).

H NMR (300 MHz, CDC13, ppm): ~0.1 (s, 6~), 0.80-1.0 (m, 12~, 1.3-1.45 (m, 2~), 1.6~1.75 (m, 2E), 2.5-2.6 (t, 2~), 4.55 (s, 2H, 7.1 (d, 2H), 7.5 (d, 2H, 7.6 (m, 1~),7:7-7.8 (m, 4H).
Step C: Preparation of 2-butyl-5-t-butyldimethyl-silyloxymethyl-4-chloro-1-~4-(1-cyano-1-phenyl-1-trimethyl~ilyloæy)met~ylphenvllmet~ylimidazQle To a 2 ml CH2C12 solution of the ketone ofEæample 17, Step B (0.50 g, 1.0 mmol) under N2 was added tri~ethylsilylcyanide (TMSCN) (85 mg, 1.2 mmol), ~ollowed by the addition of KCN (10 mg~ and 18-crown-6 (10 mg). The reaction was followed by TLC, and wa~ complete in 3 hrs. The solution was diluted with diethyl ether (~30 ml and ~ashed wi~h dilute NaHCO3. and brine then organic extract wa~
dried over MgS04., filtered and the colvent remov~d invacuo. The product was i~olated in a 67Z yield (0.40 g) H NMR (300 M~, CDC13, ppm): ~0.05(s, 9H~, 0.10 (s, 6H), 0.8-O.9(m, 12H), 1.3-1.45(m, 2H), 1.55-1.65(M, 2~), 2.4-2.5(t, 3H), 4.5(s, 2H), 5.2 (s, 2~) 7.0(d, 2~), 7.3-7.4(M, 3H), 7.4-7.5(m, 4H~

SUBSTITUTE SHEET

WO91~12~2 PCT/US91/01001_ Z ~ - 118 -S~ep D: Preparation of 2-butyl--5-t-butyldimethyl-silyloxymethyl-4-chloro-l-t4-(l-hydro~y-l-phenyl-l-~tetrazol-5_yl~2methvlph~nvllme~:hvlimid~zole To a solution of ~xample 17, Step C (O.l g, O.17 mmol) in 500 ml of toluene was added trimethylstannyl azide (41 mg, 0.20 mmol) at room temperature and the reaction was then heated to reflux ~or 24 hr~. The reaction wa~ follo,wed by TLC
and after 7 days was 60% complete. The residue was chromatographed o~ silica gel (120 x 15 ~m), eluting with 15Z ethyl acetate in heæane containing a few drops of CH30~. The product was i~olated in a 15%
yield (20 mg).
1~ NMR (300 MHz, CDCl3, ppm): ~O.l (~, 6H), 0.8-0.9 (m, 12~, 1.25-1.40 (m, 2H), 1.6-1.7~m, 2~), 2.5(t, 2H), 4.5(s, 2H), 5.25(s, 2~3, 7.l(d, 2H), 7.4-7.6(m, 3H),7.7-7.8(m, 4H).

E~AE~h~_L8 2-Butyl-l-[4-(l-carboxy-l-(2-chloro)phenyl)m~thogy-phenyl]methyl-4-chloro-5-hydro~ymethylimidazole (Scheme I-8~ GQ~ound .~
Step A:. Preparation of Methyl 2-bromo-~'-chloro-phenvlacetate o-Chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 ml, 36.6 mmol) are heated to reflux. Bromine (1.51 ml, 29.3 mmol) was added dropwise over lO minutes and continued to reflux.for 17 hrs. The reaction was cooled to room temperature and 30 ml of CH30H was added slowly. The solvent wa~ removed in vacuo and the residue chromatographed on silica gel eluting with 5% ethyl acetate in hexane. The product wa~ iRolated in a 28%
yield (2.13 g).

8 ~ ~ ~ 8 WO~1/12~2 PcT/ussl/
2 ~7 ~

- 119 - .,.

1~ NMR (300 MHz , CDC13, ppm): 3.8 (s, 3E); 5.95 (s, 1~); 7.25-7.45 (m, 3~); 7.7-7.8 (m, lH).

Step B: Preparation of Methyl ~-(4-methylphenoxy)-2-(2'-~ch~ henyl~acetate _ ~ _ __ To a guspen~ion of gH (0.53 g, 4.63 mmol) in 5 ml of DMF under N2 at 0C was added p-creso~ (0.5 g, 4. 63 mmol) . The reaction mi~ture ~as stirred until the evolution of H2 was complete. Then 50 mg of 18-crown-6 ether wa~ added, followed by the product o~ E~ample 18, Step A (1.22 g, 4.63 mmol) in 5 ml DMF. The reaction mixture was ~tirred at 0C
for 30 minutes and then allowed to warm to room temprature. The reaction mixture was concentrated ;n - vacuo and chromatographed on silca gel (130 mm x 30 min) eluting ~ith 5~ ethyl acetate in heæane. The product wa~ isolated in a 77Z yield (1.03 g).

FAB-MS: 290,292 1~ NMR ~300 M~z, CDC13, ppm): ~ 2.25 (S, 3H0 3.8 ~S, 3H) 6.15 (S, lE) 6.8-6.9 (d, 2~) 7.25-7.35 (m, 2H) 7.4-7.5 ~m,~ 1~) 7.6-7.7 (m, lH~ 7.6-7.7 (m, lE).

Ste~ C: Preparation of Methyl 2-(4-bromomethylphe~
o~y)-2-(2'-chloro~he~Yl~a~etate - A solution of the product of Example 18, Step B (0.2 g, 0.69 mmol), N-bromosuccinimide (117 mg, 166 mmol) and a catalytic amount of AIBN in 2 ml - CC14 was re~lu~ed for 30 minutes. The reactio~
mi~ture was concentrated in vacuo and chromatographed SUBSTITIJTE SHEET

WO91/12002 PCT/USg1/01001 on silica gel (125 x 20 mm) eluting with 5% ethyl acetate in hexane. Tbe product was isolated in a 73%
yield (186 mg).

FAB-MS: 368, 370, 372 (10:13:3 isotopic ratio due to the presence of a chlorine and a bromine).

lH NMR (300 M~z, CDC13, ppm): 3.~ (s, 3H) 4.5 (S, 2H); 6.15 (s, lH); 6.B5-6.95 (d, 2H); 7.25-7.35 (m, 4H~; 7.4-7.5 (m, lH); 7.6-7.7 (m, 1~).

S~e~D: Preparation of 2-butyl-5-t-butyldimethyl-Rilyloxymethyl~ 4-(1-carbomethoxy-1-(2-chloro)-To a ~uspen6ion of NaH (2.7 mg, 89 mmol) in250 ~1 DMF wa~ added 2-butyl-4-chloro-5-t-butyldi-methylsilyloxymethylimidazole and ~tirred for 15 minutes. To this solution was added a ~olution of the product of E~ample 18, Step C (30 mg, 81.3 mmol) in DME (0;25 ml) and the reaction miæture was stirred for 2 hrs at room temperature. The reaction mi~ture was stored over the weekend at -30C and then warmed to room temperature and stirred ~or 4 hrs. The reaction was concentrated in vacuo and chromatographed on silca gel (130 æ 20 mm) eluting with 15% ethyl acetate in he~ane. The product was isolated in a 65% yield (31 mg).

lH NMR (300 MHz, CDC13, ppm): ~0.05 (s, 6X);
0.8-0.9 (m, 12H); 1.2-1.35 (m, 2H); 1.5-1.65 (m, 2H);
1.95-2.05 (t, 2H); 3.75 (s, 3H); 4.5 (s, 2H) 15.1 (s, 2H) 6.1 (s, lH); 6.85-6.95 (m, 4~; 7.25-7.35 (m, 2H); 7.4-7.5 (m, lH); 7.5-7.6 (m, 1~).

SUBSTITL)TE Sl 3EET

WOgl/12002 PCT/US91/01001 - 121 - . . .

Step E: Preparation of 2-Butyl--l-(l-carboxy-1-(2-chloro)phenyl)methoxyphenyl3methyl~4-chloro-5-hvdro~vmethYlimidazole To a solution of the product of Example 18, Step D (30 mg, 0.51 mmol) in CH3O~ (0.5 ml) was added in NaOH until the reaction became cloudy (500 ul).
The reaction mixture was stirred for 24 hours and then concentrated in vacuo. The residue was dissolved in 5 ml of a 1:1 concentrated ~Cl:THF
solution and stirred overnight. The reaction mixture was neutralized with 6N NaOH, and concentrated in vacuo. The residue was di~olved in ethyl acetate, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (120 x 15mm) eluting with 100:3:1 CHC13: C~3O~:C~3CO2~.
The product was isol~ted in a 38% yield (9 mg).

lH NMR (300 MHz, CD30D, ppm): ~0.75-0.85 (t, 3~), 1.2-1.35 (m, 2H~, 1.35-1.5 (m, 2~), 2.5-2.6 (t, 2H), 4.5 (s, 2H), 5.2 8, 2~), 6.1 (s, 1~), 6.9-7.1 (m, 4H), 7.3-7.4 (m, 2~), 7.4-7.5 (m, 1~), 7.55-7.65 (m, lE).

Exa~p~

2-Butyl-4-chloro-5-hydroxymethyl-1-t4-(1-phenyl-1-tetrazol-5-yl))methylphenyl]methylimidazole (Schçm~. I-ll. Compound ~
Step A: ~reparatisn of 4-(bromomethvl)benzvlalcohol A ~uspension of 4-bromomethylbenzoic acid (5.04; 23.3 mmol) in T~F (30 ml) was cooled to 0 C
and treated with borane/ T~F (35 mmol). The ice ba~h ~UBSTITUTIE~ SHE~Eqr Wo91/12002 pcT/ussl/

2 ~
was removed and the mixture was allowed to warm to room tempe~ature and stirred fo:r 1.5 hours. The excess borane waæ quenched with MeOH, and then wi~h water, and the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 4 % HCl, water NaHC03, brine, dried (MgS04), filtered, concentrated in vacuo to afford 4.44 g ( 94 %) of the title compound.

1~ NMR: (300 MHz, CDC13,ppm): 7.38 (q,4~); 4.70 ( R ~ 2~); 4.51 (8,2~).

FAB MS: m/e = 202 (M+H).

Step B: Preparation of 4-(bromomethyl)-t-butyl-dimethyl~ilylo~ymethvl~a~e~e To a ~olution o~ the product of Example 19, Step A (4.44 g, 22.1 mmol) in C~2C12 was added N,N-diisopropylethyl amine (1.2 eq.) a~d 4-dimethylaminopyridine (0.1 eq), and t-butyl-dimethylsilyl chloride (1.2 eq). The mixture was stirred ~or 1.5 hour~ at room temperature, then concentrated i~ vacuo. The residue was dissolved in ethyl acetate and washed with water, brine, dried ~MgS04), filtered, and concentrated in vacuo. The residue was chromatographed on silica (ethyl acetate/hexanes (2.5/97.5)) to afford 5.0 g (71 %) of the title compound.
LH N~R (300MHZ, CDC13, ppm) : 7 . 34 (q, 4H); 4 . 74 (S,~); 4.59 (S,2~); 0.95 (S,9H); 0.11 (S,6~0.

~tep C: Preparation of 3-(4-t-butyldimethylsilyl-o~yme~h~ heD~ =p~ Dvlpropionitrile T~ TE SHE~ET

WO91/12002 P~TIUS91/OlO01 ~ ~7 ~

A solution of benzyl cyanide (1.5 ml, 12.7 mmol) in THF (40 ml) containing HMPA (11 ml, 63.4 mmol) was cooled to -78 C and treated with lithium bis trimethylsilyamide (16 ml, 16 mmol of 1.O M in T~F) dropwi~e to maintain temperature below -73 C.
The reaction was stirred at -78 C for 1.5 hours. A
solution of the product of E~ample 19, Step B (2.0 g, 6.34 mmol) i~ T~F (8 ml) was added dropwise while the temperature was maintained below -70 C . The reaction temperature was maintained ~elow -6~ C ~or 3 hours. The reaction mixture was quenched at this temperature with lN Na~S04. After warmi~g to room temperature, the ~ixture was e~tracted ~ith EtOAc, the combined organic layers were wa~hed with water, saturated Na~C03, brine,dried (MgS04), filtered, then concentrated in vacuo. The residue was chromatographed on silica (ethyl/ he~anes (5/95)~ to afford 1.5 g (67 %) of product.

1 ~MR ( 300 M~z,CDC13,ppm): ~7.40-7.30 (m,3~);
7.30-7.72 (m,4H); 7.10 (d,2H); 4.73 (8,2~); 3.98 (t,l~); 3,23-3.08 (m,2H); 0.94 (s,9~); 0.10 (9,6~).

FAB MS : m/e=294 (loss of t-Bu).

Step D: Preparation 3-(4-bromomethyl)phenyl-2-phenvll?ropionitrile The product of F.xample 19, Step C (1.5 g, 4.27 mmol) was treated with CBr4 (1 eq.) and Ph3P (1 eq) in a 1:1 mixture of acetone and acetonitrile, affording in 575 mg (45 %) of the title compou~d after silica chromatography (ethyl acetate/hexanes (5l95))-WOsl/12002 PCT/US91/01~0 2 ~ 2~. - 124 -1H NMR (300M~z, CDC13, ppm): ~7.48-7.10 (m,9H); 4.50 (s,2H); 4.00 (t,lH); 3.26-3.10 (m,2H);.

FAB MS : m/e=299/301.

~ E: Preparation of 4-chloro-2-butyl-5-t-butyl-dimethylsilylo3ymethyl-1-[4-(l-cyano-l-phenyl)methyl-phenyllm~thvli~idazole Sodium hydride (1.2 eq 16 mg of 80% oil dispersion) was su~pended in dry DME (1 ml) cooled to ooc under N2. and 1.O eq (137 mg, O.42 mmol) of 2-butyl-4-chloro-5-t-butyldimethylsilyloxy-methylimidazole in 1.5 ml DME ~as added dropwise, causing vigorous bubbling and foaming. The reaction was allowed to stir at 0C for 45 minutes, and then a solution of bromide (E~ample 19, Step D) in 1.5 ml DMF was added. The ice bath wa~ remo~ed, and the reaction mixture was allowed to warm gradually to room temperature. A gradual color change to darker reddish was visible. The TLC (20~ EtOAc/Ee~ane~
indicated that no bromide rem~ined. The reaction miæture was allowed to stir at room temperature overnight, and then the 801vent was removed in vacuo. The residue waY di~solved in EtOAc and washed wi~h ~2 The combined organic portion~ were e~tracted with H20 and brine, and dried (Na2S04~.
The crude material was chromatographed on silica gel u~ing MPLC eluting with 15Zo EtOAc in hexane, giving the desired product (69 mg; 29% yield).

FAB MS: M~E=522.

SUBSTITUTE~ SHEl' Wos~ oo2 PCT/US9l/0~001 2~?7~

Step F: Preparation of 2-butyl~-4-chloro-5-hydroxy-methyl-1-[4-(1-phenyl-1-(tetrazol-5-yl))methylphenyl]-methylimidazole _ _ _ _ __ The product of E~ample 19, Step D (6~ mg, 0.132 ~mol) was dissolved in 2 ml dry toluene, 1~2 eq of trimethylstannylazide ~as added and the mixture ~as heated to reflu~ under a blanket o~ N2. After reflu~ing for 22 hrs, the reaction was brown in color. By TLC (30% EtOAc/~exane) a substantial amount of unreacted nitrile still remained. The solvent was removed in vacuo and the reaction checked by NMR, which confirmed that 25% unreacted nitrile remained. An additional equivalent of trimethylstannylazide was added to a toluene solution of the mixture, and the solution was heated to re~lux for 5 hr, by TLC some nitrile stil remained. The reaction mixture was allowed to cool slowly to room temperature and was stirred overnight. The reaction - was stripped of toluene, di~solved in TEF cooled in ice and concentrated HCl (3 drops) was added. The solvent wa~ azeotroped off from tolueneJCH3CN. The crude material was chromatographed on æilica gel in 85:15 CEC13:10% N~40E/~eOE. The desired product was isolated in 35mg (60Z yield).

FAB MS: M+Hc451 , 1H NMR (300 m~z.CD30D~ppm): ~ 7.32-7.18 (m.5~;7.09 (d,2H); 6.90 (d,2~); 5.21(5,2~); 4.63(t,lH);
4.42(s.2~); 3.63-3.52 (dd,lE): 3.42-3.31(dd,1H);
2.50(t,2H); 1.52-1.39(m.2~); 1.32-1.18(m,2H);
0.82(t,3H).

SUBSTITUT~ '~HE~ET

WO91/12002 PCT/US91/0l001 2~7~2~

~XAMPLE 20 2-Butyl-1-[4-(N-(l-carboxy-1-(2-phenyl)ethyl)amino-phenyllmethyl-4-chloro-5-hydrQx~thylimi~azQle Step A: Preparation o~ 2-Butyl~ 4-(N-(l-carboxy-1-(2-phenyl)ethyl)aminophenyl~methyl-4-chloro-5-hvdroxymethyLimidazole A solution of 204 mg (0.500 mmol) (4-aminophenyl)methyl-2-butyl-4-chloro-5-butyldimethylsilyloxymethylimidazole in 0.25 ml methanol was treated with 132 mg (0.575 mmol) methyl-2-phenyl-2-bromoacetate and 50 mg (0.595 mmol) sodium bicarbonate and a crystal of potassium iodide. After stirring overnight the reaction mixture ~as concentrated under vacuum, exXracted into 5 ml methylene chloride and, after removal of the solvent under vacuuml charged with 1 ml methanol to a column of L~-20. The product-containing fraction~
were collected and evaporated to yield 241 mg ~87%) with correct NMR and mass spectrum and single spot hy TLC.

Step B: Preparation of 2-Butyl-5-t-butyldimethyl-silyloxymethyl~ 4-tN~(l-carboxy-l-phenyl)-methvl~aminophenyllm~thvl-4-chloroimidazQle A solution of 186 mg of the product of ~ample 20, Step A and 1 ml of 1 N sodium hydroxide in 2 ml of methanol was allowed to stir for 4 hrs.
After addition of 5 ml ethyl acetate the solution was extracted with ~ x 5 ml 5Z aqueous citric acid. The ethyl ~cetate solution was dried and concentrated to yield 2Zl mg (90%) citrate salt of the product which had correct mass spectrum and NMR.

SUBSTlTlJTE SHEEt WO91~12002 PCT/US91/01001 26?7 ~2,~. .

Step C: Preparation of 2-Butyl-l-[4-(N~ phenyl)-aminophenyl]methyl-4-chloro-5-hydroxymethyl-imidazQl~
A reaction mixture cont:aining 212 mg of the product of Example 20, Step B in 420 ml 1 Molar tetrabutylammonium fluoride was allowed to stand at room temperature overnight, concentrated under vacuum to an oil which was treated with 10 ml ethyl acetate and extracted with 4 x 15 ml 5% aqueous citric acid.
After drying and evaporation o~ the ethyl acetate there was obtained 143 mg (78%) of a citrate, single spot by TLC and with NMR and mass spectrum in accord with the structure.

Step D: Preparation of 2-Butyl-1-[4-N-~l-carboetho~y)-1-(2-phenyl)methyl)aminophenyl]-methyl-4-chlo~o~ -h~irQ ~ çth~lrlimidazQle A slurry of 207 mg (0.507 mmol) the product o~ ~xample 20~ Step C, 429 mg (2.081 mmol) ethyl2-oxo-4-phenylbutanoate, and 500 mg freshly flamed 3A finely ground molecular sieves in 5 ml methanol was ~tirred for 6 hrs and then treated over a 1/2 hr period with 80 mg (1.27 mmol) æodium cyanoborohydride in 2 ml methanol. After stirring for 41 hr, 165 mg (1.42 mmol) pyridine hydrochloride was added and after 1 hr stirring the reaction mixture was filtered and concentrated under vacuum to a viscous oil. The oil was dissolved in 10 ml methanol and charged to 80 ml Dowex 50 (H+) set up in methanol. Neutrals and anionics were removed with 200 ml methanol and the product was eluted ~ith 400 S~ TlTlJTE $~

WO91/12002 PCT/U~91/0100l 2~ 128 -ml 4% pyridine in methanol. The eluent was concentrated to an oil and charged with l ml methanol to a L~-20 column. The product containing fractions yielded on evaporation 122.5 mg (49.9%~ of product single spot TLC, correct NMR and mass spectra.

Step E: Preparation o~ 2-Butyl-1-[4-(N~ carboxy-1-(2-phenyl)ethyl)aminophenyl]me~hyl-4-chloro-5-hvdroxvmethyll~idazole A solution of 118 mg (0.252 mmol) of the product vf Example 20, Step D and 0.55 ml l N sodium hydro~ide in 1.5 ml of methanol were allowed ~o react for 5 hr at room temperature and for 16 hrs in the refrigerator. After addition of 5 ml ethyl acetate the reaction mi~ture was extracted with 2 x 5 ml 5%
aqueous citric acid. The ethyl acetate was dried, and concentrated under vacuum to yield 157 mg (96Zo) of the product as a citrate, with NMR and mass spectra in accord with the structure.

8VB$m~TE $HE~

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula 1 which is FORMULA I
or a pharmaceutically acceptable salt thereof wherein:

R1 is:
(a) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of:
i) aryl as defined below, ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, ii) COOR2, vii) N[((C1-C4)-alkyl)]2 viii) NHSO2R2, ix) CF3, x) COOR2, or xi) SO2NHR2a; and (b) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
i) Cl, Br, F, I, ii) (C1-C4)-alkyl, iii) (C1-C4)-alkoxy, iv) NO2 v) CF3 vi) SO2NR2aR2a, iii) (C1-C4)-alkylthio, viii) hydroxy, ix) amino, x) (C3-C7)-cycloalkyl, xi) (C3-C10-alkenyl, and (c) heteroaryl, wherein heteroaryl is defined as an unsubstituted, monosubstituted or disubstituted heteroaromatic 5- or 6-membered cyclic moiety, which can contain one or two members selected from the group consisting of N, O, S and wherein the substituents are members selected from the group consisting of:
i) Cl, Br, F, I, ii) OH, iii) SH, iv) NO2, v) (C1-C4,)-alkyl, vi) (C1-C4)-alkenyl, vii) (C2-C4)-alkynyl, viii) (C1-C4)-alkoxy, or ix) CF3, or (d) perfluoro-(C1-C4)-alkyl; and B is:
(a) a single bond, (b) -S(O)x(CH2)s-, or (c) -O-; and x is 0 to 2, s is 0 to 5;
m is 1 to 5;
p is 0 to 3;
n is 1 to 10;

R2 is:
(a) H, or (b) (C1-C6)-alkyl, and R2a is:
(a) R2, (b) CH2-aryl, or (c) aryl; and R3 is:
(a) H, (b) (C1-C6)-alkyl. (C2-C6)-alkenyl or (C2-C6)-alkynyl, (c) Cl, Br, I, F, (d) NO2 (e) (C1-C8)-perfluoroalkyl, (f) C6F5, (g) CN, (h) NH2, (i) NH[(C1-C4)-alkyl], (j) N[(C1-C4)-alkyl]2, (k) NH[CO(C1-C4)-alkyl], (l) N[(C1-C4)-alkyl)-(CO(C1-C4)-alkyl)], (m) N(C1-C4)-alkyl-COaryl, (n) N(C1-C4)alkyl-SO2aryl, (o) CO2H, (p) CO2R2a, (q) phenyl, (r) phenyl-(C1-C3)-alkyl, (s) phenyl and phenyl-(C1-C3)-alkyl substituted on the phenyl ring with one or two substituents selected from:
i) (C1-C4)-alkyl, ii) (Cl-C4)-alkoxyl, iii) F, Cl, Br, I, iv) hydroxyl, v) methoxyl, vi) CF3, vii) CO2R2a, or viii) NO2; and R4 is:
(a) H, (b) CN, (c) (C1-C8)-alkyl, (d) (C3-C6)-alkenyl, (e) (C1-C8)-perfluoroalkyl, (f) (C1-C8)-perfluoroalkenyl, (g) NH2, (h) NH(C1-C4)-alkyl, (i) N[(C1-C4)-alkyl]2, (j) NH(C1-C4)-acyl, (k) N[((C1-C4)-acyl)((C1-C4)-alkyl)], (l) CO2H, (m) CO2R2a, (n) phenyl, (o) phenyl-(C2-C6)-alkenyl, (p) ?-R16, (q) , (r) (CH2)nO?R14, (s) (CH2)nSR15, (t) CH=CH(CH2)SO?R15, (u) CH=CH(CH2)8?R17, (v) , (w) (CH2)n?R15, (x) (CH2)nO?NHR16, (y) (CH2)nO?NHR16, (z) (CH2)nNHSO2R16, (aa) (CH2)nF, (ab) (CH2)m-imidazol-1-yl, (ac) (CH2)m-1,2,3-triazolyl, unsubstituted or substituted with one or two substituents selected from:
i) CO2CH3, ii) (C1-C4)-alkyl, (ad) tetrazol-5-yl, (ae) -CONH-SO2-aryl, (af) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH , -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (ag) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (ah) -CONHSO2NR2aR2a; and (ag) (ah) , or (ai) ; and R5 is:
(a) CN, (b) NO2, or (c) CO2R2a; and R9 and R10 are independently:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (C1-C6)-alkoxy, (g) when R9 and R10 are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(C1-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (C1-C6)-alkyl, (j) aryl; and X is:
(a) -O-, (b) -S(O)n-, (c) -NR13-(d) -CH2O-, (e) -CH2S(O)n, (f) -CH2NR13-, (g) -OCH2-, (h) -NR13CH2-, (i) -S(O)nCH2-, (j) -CH2-, (k) -(CH2)2-, (l) single bond, or (m) -CH=, wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and R11; and Y is :
(a) single bond, (b) -O-, (c) -S(O)n-, (d) -NR13-, or (e) -CH2-; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO2).

R11 and R12 are independently:
(a) H, (b) (C1-C6)-alkyl unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]CH2-, iv) (C1-C5)-alkoxy, vi) (C1-C5)-alkylthio, vii) -NO2, viii) -CF3, ix) -CO2R2a, or x) -OH; and (d) aryl-(C1-C2)-alkyl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C6)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]CH2-, v) (C1-C5)-alkoxy, vi) (C1-C5)-alkylthio, vii) -NO2, viii) -CF3, ix) -CO2R2a, or x) -OH; and (e) (C3-C7)-cycloalkyl; and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, (d) aryl-(C1-C6)-alkyl-(C=O)-, (e) (C1-C6)-alkyl-(C=O)-, (f) [(C2-C5)-alkenyl]CH2-(g) [(C2-C5)-alkynyl]CH2-, or (h) aryl-CH2-; and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-SO2-aryl, (f) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2aR2a; and (j) -SO2NHCO-aryl, (k) -SO2NHCO-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (l) -SO2NHCO-perfluoro-(C1-C4)-alkyl, (m) -SO2NHCO-heteroaryl, (n) -SO2NHCONR2aR2a;
(o) -PO(OH)2, (p) -PO(OR2)2, or (q) -PO(OH)(OR2); and R14 is:
(a) H, (b) (C1-C8)-alkyl, (c) (C1-C8)-perfluoroalkyl, (d) (C3-C6)-cycloalkyl, (e) phenyl, or (f) benzyl; and R15 is:
(a) H, (b) (C1-C6)-alkyl, (c) (C3-C6)-cycloalkyl, (d) (CH2)p-phenyl, (e) OR17, (f) morpholin-4-yl, or (g) NR28R19; and R16 is:
(a) (C1-C8)-alkyl, (b) (C1-C8)-perfluoroalkyl, (c) 1-adamantyl, (d) 1-naphthyl, (e) (1-naphthyl)ethyl, or (f) -(CH2)p-phenyl; and R17 is:
(a) H, (b) (C1-C6)-alkyl, (c) (C3-C6)-cycloalkyl, (d) phenyl, or (e) benzyl; and R18 and R19 are independently:
(a) H, (b) (C1-C4)-alkyl, (c) phenyl, (d) benzyl, or (e) a-methylbenzyl; and R20 is:
(a) aryl, or (b) heteroaryl, unsubstituted or substituted with one or two substituents selected from the group consisting of:
(i) (C1-C4)-alkyl, (ii) (C1-C4)-alkoxyl, (iii) Br, Cl, I, F, or (iv) CH2-aryl.
2. A compound which is or a pharmaceutically acceptable salt thereof wherein:

R1 is (C2-C4)-alkyl, or cyclopropyl; and R3 is H,-Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkyl, aryl, CH2-aryl; and R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; and R9 and R10 are independently: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, (C3-C8)-cycloalkyl, or aryl wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Cl, Br, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl, (C3-C10)-alkenyl;
and R11 is phenyl, unsubstituted or substituted with Br, Cl, F, I, (C1-C4)-alkyl or (C1-C4)-acyl; and Z is tetrazol-5-yl, carboxyl or CO2(C1-C4)-alkyl.

3. A compound which is or a pharmaceutically acceptable salt thereof wherein:

Z is CO2H, CO2-(C1-C4)-alkyl or 1H-tetrazol-5-yl;
and R9 and R10 are independently: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, (C3-C8)-cycloalkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Cl, Br, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl, (C3-C10)-alkenyl; and R11 is H, or benzyl; and R13 is H, CH3(CH2)3C(=O)-, C6H5CH2CH2C(=O)-, or C6H5CH2C(=O)-.

4. A compound which is or a pharmaceutically acceptable salt thereof wherein:

R1 is: (C1-C4)-alkyl and cyclopropyl; and R2a is: H, (C1-C6)-alkyl, benzyl, or phenyl; and R3 is H, Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkylamino, (C1-C4)-acylamino; and R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; and R9 and R10 are independently: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, (C3-C8)-cycloalkyl, or aryl; and R11 is: aryl or aryl-CH2-, wherein the aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxyl, NO2, CF3, (C1-C4)-alkylthio, OH, -NR2aR2a and X is: O, NR13, CH2, or -CH=, which is double bonded to the carbon bearing Z and R11; and R13 is: H, (C1-C6)-alkyl, (C1-C6)-alkenyl, aryl;
and Z is: CO2H, CO2-(C1-C4)-alkyl. 1H-tetrazol-5-yl, -CONHSO2-aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
H, (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl, (C3-Cl0)-alkenyl, or -CONHSO2-heteroaryl, wherein heteroaryl is defined as a 5- or 6-membered heteroaromatic moiety, which can contain one or two members selected from the group consisting of N, O, S, and is unsubstituted, mono- or disubstituted with substituents selected from the group consisting of:
Br, Cl, F, I, OH, SH, NO2, (C1-C4)-alkyl, (C2-C4) alkenyl, (C2-C4)-alkynyl, (Cl-C4)-alkoxy, or CF3.

5. A compound which is or a pharmaceutically acceptable salt thereof wherein:

R1 is: (C1-C4)-alkyl and cyclopropyl; and R2a is: H, (C1-C6)-alkyl, benzyl, or phenyl; and R3 is H, Cl, (C1-C4)-perfluoroalkyl, (C1-C4)-alkylamino, (C1-C4)-acylamino; and R4 is CO2H, CH2OH, or CO2(C1-C4)-alkyl; and R9 and R10 are independently: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl, (C1-C4)-alkoxyl, Cl, Br, I, F, (C3-C8)-cycloalkyl, or aryl; and R11 is: aryl or aryl-CH2-, wherein the aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxyl, NO2, CF3, (C1-C
R4)-alkylthio, OH, -NR2aR2a and R12 is H, OH, or (C1-C4)-alkyl; and Z is CO2H, CO2-(C1-C4)-alkyl or 1H-tetrazol-5-yl.

6. A compound of claim 1 wherein said compound and its pharmaceutically acceptable salts is selected from the group consisting of:

2-Butyl-1-[4-(N-(1(R)-carbomethoxy-1-benzyl)methyl) aminomethylphenyl]methyl-4-chloro-5-hydroxymethyl-imidazole;

2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl)methyl)amino-methylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(R)-carbomethoxy-1-benzyl)methyl-methyl-N-pentanoyl)aminomethylphenyl]-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl)methyl-N-pentanoyl)aminomethyl-phenyl]methyl-4-chloro-5-hydroxy methylimidazole;

2-Butyl-1-(4-(N-(1-(R)-carboxy-1-benzyl)methyl-N-(3-phenyl)propionyl)aminomethylphenyl]methyl-4-chloroimidazole;

2-Butyl-1-(4-N-(1(R)-carbomethoxy-1-benzyl)methyl-N-(phenylacetyl)aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(R)-carboxy-1-benzyl-methyl-N-(phenylacetyl)aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)amino-methylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(S)-carboxy-1-benzyl)aminomethyl-phenyl]methyl-4-chloro-5-hydroxy-methylimidazole;

2-Butyl-1-[4-(N-(1(S)-carbomethoxy-1-benzyl)-N-pentanoyl)aminomethylphenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(N-(1(S)-carboxy-1-benzyl)methyl-N-pent-anoyl)aminomethylphenyl]methyl-4-chloro-5-hydroxy-methylimidazole;

2-Butyl-5-t-butyldimethylsilyloxymethyl-1-[4-(1-carbo-methoxy-1,1-dibenzyl)methyl)aminomethylphenyl]methyl-4-chlorimidazole;

2-Butyl-1-[4-(N-(1-carbomethoxy-1,1-dibenzyl)methyl)-aminomethylphenyl]methyl-4-chloro-5-hydroxymethyl-imidazole;

2-Butyl-1-[4-(N-(1-carboxy-1,1-dibenzyl)methyl)amino-methylphenyl]phenyl]methyl-4-chloro-5-hydroxymethyl-imidazole;

1-[4-(1-(N-benzyl-N-pentanoyl)amino-1-(tetrazol-5-ylmethylphenyl]methyl-2-butyl-5-t-butyldimethylsilyl-oxymethyl-4-chloroimidazole;

2-Butyl-4-chloro-5-hydroxymethyl-3-[4-(1-(1'-hydroxy-1-phenyl-1-tetrazol-5-yl)methylphenyl]methylimidazole;

2-Butyl-1-[4-(1-carboxy-1-(2-chloro)phenyl)methoxy-phenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-1-[4-(1-carboxy-1-phenyl)methoxy-3,5-dipropyl-phenyl]methyl-4-chloro-5-hydroxymethylimidazole;

2-Butyl-4-chloro 5-hydroxymethyl-1-[4-(1-phenyl-1-tetrazol-5-yl))methylphenyl]methylimidazole; and 2-Butyl-1-[4-(N-(1-carboxy-1-(2-phenyl)ethyl)amino-phenyl]methyl-4-chloro-5-hydroxymethylimidazole.

7. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.

8. The composition of Claim 7 which includes another antihypertensive agent selected from a diuretic, an angiotensin converting enzyme inhibitor a calcium channel blocker and a .beta.-blocker which are members selected from the group consisting of:
amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflunisal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, as well as admixtures and combinations thereof.

9. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Claim 1.

10. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of Claim 1.

11. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of Claim 1.

12. A method of treating cognitive dysfunction, anxiety, or depres ion comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of

Claim 1.