Conformationally restricted angiotensin II antagonists

Conformationally restricted compounds are described which are therapeutically effective as angiotensin II antagonists for the treatment of circulatory disorders. Compounds of particular interest are of Formula I ##STR1## wherein W is N or CH.sub.2 ; wherein X is N or CR.sup.2 ; wherein Y is (CH.sub.2).sub.n and n is 1 to 3; wherein Z is C.dbd.R.sup.3 or CR.sup.4 R.sup.5, or wherein Y and Z together forms --CR.sup.6 .dbd.CR.sup.7 --, --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 or --CR.sup.6 .dbd.CR.sup.7 --CH.sub.2 --CH.sup.2 --; wherein the remainder of the variables are as defined in the specification; or a pharmaceutically suitable salt or tautomer thereof.

FIELD OF THE INVENTION 
Conformationally restricted non-peptide angiotensin II (AII) antagonists 
are described for use in treatment of circulatory disorders such as 
hypertension and congestive heart failure. Of particular interest are 
heteroatom- containing fused bicyclic compounds having a substituted 
biphenyl moiety attached thereto. 
BACKGROUND OF THE INVENTION 
Angiotensin II is the primary hormone active in the renin-angiotensin 
system and elicits effects on the regulation of arterial pressure, volume 
homeostasis and hypertension. Activation of the renin-angiotensin cascade 
begins with renin secretion from the juxtaglomerular apparatus of the 
kidney and culminates in the formation of angiotensin II, the primary 
active species of this system. Angiotensin II is an octapeptide which is a 
potent vasoconstrictor and also promotes aldosterone secretion, promotes 
sodium and fluid retention, inhibits renin secretion and increases 
vasopressin secretion. 
Previous studies have shown that antagonizing angiotensin II at the 
receptor level is a viable approach to controlling the renin-angiotensin 
system. There are several known angiotensin II antagonists, many of which 
are peptidic in nature. Such peptidic compounds are of limited use due to 
their lack of oral bioavailability or their short duration of action. 
Also, commercially-available peptidic angiotensin II antagonists (e.g., 
Saralasin) have a significant residual agonist activity which further 
limits their therapeutic application. 
Non-peptidic compounds with angiotensin II antagonist properties are known. 
For example, the sodium salt of 
2-n-butyl-4-chloro-1-(2-chlorobenzyl)imidazole-5-acetic acid has specific 
competitive angiotensin II antagonist activity as shown in a series of 
binding experiments, functional assays and in vivo tests [P. C. Wong et 
al, J. Pharmacol. Ext. Ther., 247(1), 1-7 (1988)]. Also, the sodium salt 
of 2-butyl-4-chloro-1-(2-nitrobenzyl)imidazole-5-acetic acid has specific 
competitive angiotensin II antagonist activity as shown in a series of 
binding experiments, functional assays and in vivo tests [A. T. Chiu et 
al, European J. Pharmacol., 157, 13-21 (1988)]. A family of 
1-benzylimidazole-5-acetate derivatives has been shown to have competitive 
angiotensin II antagonist properties [A. T. Chiu et al, J. Pharmacol. Exp. 
Ther., 250(3), 867-874 (1989)]. U.S. Pat. No. 4,816,463 to Blankey et al 
describes a family of 
4,5,6,7-tetrahydro-1H-imidazo(a,5-c)-tetrahydro-pyridine derivatives 
useful as antihypertensives, some of which are reported to antagonize the 
binding of labeled angiotensin II to a rat adrenal receptor preparation 
and thus cause a significant decrease in mean arterial blood pressure in 
conscious hypertensive rats. EP No. 253,310, published 20 Jan. 1988, 
describes a series of aralkyl imidazole compounds, including in particular 
a family of biphenylmethyl substituted imidazoles, as antagonists to the 
angiotensin II receptor. EP No. 323,841 published 12 Jul. 1989 describes 
four classes of angiotensin II antagonists, namely, 
biphenylmethylpyrroles, biphenylmethylpyrazoles, 
biphenylmethyl-1,2,3-triazoles and biphenylmethyl 
4-substituted-4H-1,2,4-triazoles, including the compound 
3,5-dibutyl-4-[(2'-carboxybiphenyl-4-yl)methyl]-4H-1,2,4-triazole. U.S. 
Pat. No. 4,880,804 to Carini et al describes a family of 
biphenylmethylbenzimidazole compounds as angiotensin II receptor blockers 
for use in treatment of hypertension and congestive heart failure. 
There are several families of 1,2,4-triazole compounds having substituents 
attached to the nitrogen atom at the one-position of the 1H-triazole. For 
example, U.S. Pat. No. 4,118,487 to Regel et al describes a family of 
azol-1-yl-methane compounds for use as antimycotic and antibacterial 
agents including, specifically, the compound 
(1-biphenyl-4-yl-1-phenyl)methyl-1H-1,2,4-triazole. U.S. Pat. No. 
4,381,306 to Regel et al describes a family of hydroxypropyl-triazole 
compounds for use as antimycotic agents including, specifically, the 
compound (1,2,4-triazol-1-yl)methyl-4-chlorobenzyl-biphenyl-4-yl-carbinol. 
U.S. Pat. No. 4,480,114 to Regel describes a family of 
2-(4-biphenyl)-2-(halophenyl)-oxirane compounds having antimycotic 
activity including, specifically, the compound 
(1,2,4-triazol-1-yl)methyl-4-chlorophenyl-4-chlorobiphenyl-4-yl-carbinol. 
However, not much is known about the conformations and interactions of 
these non-peptide antagonists with the vascular angiotensin II receptors. 
It has been established in the literature that there are distinct 
angiotensin II receptor subtypes with differing functions [A. T. Chiu et 
al, Biochem. Biophys. Res. Comm., 165, 196-203 (1989)]. The receptor 
subtypes affecting vascular constriction is believed to be an important 
target for the treatment of hypertension [P. C. Wong et al, J. Pharmacol. 
Exp. Ther., 255, 584-592 (1990)]. Compounds which conformationally 
restrict the possible orientations of the pharmacophores incorporated 
therein may maximize the interaction between those pharmacophores and the 
binding site of the receptor subtype or subtypes of interest. Therefore, 
conformationally restricted angiotensin II antagonists may increase the 
selectivity to the specific receptor subtype of interest, thereby reducing 
possible side effects associated with binding to the other receptor 
subtypes not involved in the hypertension pathway. 
There are several families of conformationally restricted angiotensin II 
antagonists reported in the literature. For example, tricyclic 
benzoxazepines [A. P. Thomas et al, J. Med. Chem., 35, 877-885 (1992)] 
were used to potentially lock in a phenyl group in an energetically 
favorable conformation. Conformationally restricted imidazoles having a 
biphenyl radical substituted with bulky side groups to sterically limit 
the rotation of the phenyl groups and form a more rigid spatial 
relationship were described in P. R. Bovy et al, J. Med. Chem., 34, 
2410-2414 (1991). These previous attempts to lock the conformation of 
angiotensin II antagonists do not stabilize conformations axial to a 
heterocyclic ring by means of orthogonally attaching a substituted 
biphenyl radical to a non-aromatic bridging ring.