Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-11
1998-08-04
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514303, 514341, 514397, 549 79, 546118, 5462751, 544333, 5483151, A61K 3144, A61K 31505, C07D40312, C07D40314
Patent
active
057894159
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a certain class of azacyclic-heterocyclic compounds which have utility as regulators of the action of angiotensin II (AII), mediated by the AII receptor, in mammals, including humans, and accordingly, are useful in the treatment of hypertension, congestive heart failure, glaucoma and other conditions for which the action of AII is implicated. This invention relates also to pharmaceutical compositions containing these compounds, methods of inhibiting AII in mammals by administration of such compounds and also to certain intermediates in the preparation of such compounds.
The renin-angiotensin system (RAS) acts as a crucial regulatory mechanism in the control of homeostasis and fluid/electrolyte balance in mammals, including humans. Consequently, RAS activity has a direct influence on blood pressure and has been found to play an important role in congestive heart failure and in the development and maintenance of hypertension. Additionally, AII activity has been implicated in the development of elevated intraocular pressure, for example, as caused by glaucoma. AII, an octapeptide hormone produced via the cleavage of angiotensin I (AI) by angiotensin converting enzyme (ACE), is a potent and direct arterial vasoconstrictor, thereby effecting an increase in vascular resistance and blood pressure. AII is also known to stimulate the release of aldosterone, resulting in vascular congestion and hypertension by promoting the retention of sodium and fluids. The present invention concerns the potential beneficial effects of regulating the actions of AII which are mediated by the AII receptor.
Various azacyclic-benzyl-derived compounds have been described as AII antagonists. For example, see D. J. Carini et al., J. Med. Chem., 33,1330-6 (1990), U.S. Pat. No. 4,207,324, EP 399731, EP 399732, EP 411766 A1, EP 412594 A2 and WO 91/11999.
SUMMARY OF THE INVENTION
The present invention relates to a class of compounds, and their pharmaceutically acceptable salts, having the formula ##STR2## wherein:
Q is naphthyl, a 5 to 7 member heterocycle having from 1 to 3 atoms independently selected from nitrogen, oxygen and sulfur, or an 8 to 11 member heterobicycle having from 1 to 4 atoms selected from nitrogen, oxygen and sulfur, said heterocycle or heterobicycle being saturated, partially saturated or unsaturated and said naphthyl, heterocycle or heterobicycle optionally substituted with 1 to 4 W.sup.1 substituents;
each W.sup.1 substituent is independently selected from halo, hydroxy, nitro, cyano, C.sub.1 to C.sub.8 alkyl, C.sub.3 to C.sub.7 cycloalkyl, C.sub.1 to C.sub.7 alkoxy, amino, C.sub.1 to C.sub.7 alkylamino, di(C.sub.1 to C.sub.7 alkyl)amino, C.sub.1 to C.sub.7 alkylthio, C.sub.1 to C.sub.7 alkylsulfinyl, C.sub.1 to C.sub.7 alkylsulfonyl, --CONRR, --COOR and phenyl, said alkyl, cycloalkyl, alkoxy, alkylamino, dialkylamino, alkylthio, alkylsulfinyl and alkylsulfonyl optionally substituted with 1 or more W.sup.2 substituents, and said phenyl optionally substituted with 1 or more W.sup.3 substituents;
each R is independently hydrogen or C.sub.1 to C.sub.8 alkyl, said alkyl optionally substituted with 1 or more W.sup.2 substituents;
each W.sup.2 substituent is independently selected from halo, hydroxy, oxo, C.sub.3 to C.sub.7 cycloalkyl, C.sub.1 to C.sub.7 alkoxy, acyloxy, phenyl and 5 to 7 member heterocycle having 1 to 3 atoms selected from nitrogen, oxygen and sulfur, said phenyl and heterocycle optionally substituted with 1 or more W.sup.3 substituents;
each W.sup.3 substituent is independently selected from halo, hydroxy, nitro, C.sub.3 to C.sub.7 cycloalkyl, C.sub.1 to C.sub.7 alkoxy, amino, C.sub.1 to C.sub.7 alkylamino, di(C.sub.1 to C.sub.7 alkyl)amino, C.sub.1 to C.sub.7 alkylthio, C.sub.1 to C.sub.7 alkylsulfinyl and C.sub.1 to C.sub.7 alkylsulfonyl;
R.sup.1 and R.sup.2, when taken separately, are each independently selected from hydrogen, hydroxy, C.sub.1 to C.sub.10 alkyl, C.sub.1 to C.sub.7 alkylthio, C.sub.1 to C.sub.7 alkylsulfinyl, C.sub.1 to C.sub.7 a
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Carpino Philip A.
Larson Eric R.
Mylari Banavara L.
Benson Gregg C.
Grumbling Matthew V.
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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