Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-06
1996-09-10
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142342, 544127, 546118, A61K 31435, C07D47104
Patent
active
055546250
DESCRIPTION:
BRIEF SUMMARY
SUMMARY OF THE INVENTION
This invention is concerned with novel compounds of general structure I: ##STR2## wherein R.sup.2 is a non-functional substituent such as alkyl, alkoxy, or aryl which are angiotensin II (AII) antagonists demonstrating balanced AT.sub.1 /AT.sub.2 activity thus useful in the treatment of hypertension and related cardiovascular disorders and in ocular hypertension.
This invention is also concerned with novel pharmaceutical formulations with one of the novel compounds as active ingredients and the method of treating hypertension and related cardiovascular disorders or ocular hypertension with a novel compound or pharmaceutical formulation thereof.
The invention is also concerned with novel processes for preparing the novel compounds.
BACKGROUND OF THE INVENTION
The renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II) is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the reninangiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by the partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr.--Handbook of Hypertension, Clinics Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several non-peptide compounds have been described as A II antagonists. Illustrative of such compounds are those disclosed in U.S. Pat. Nos. 4,207,324; 4,340,598; 4,576,958; 4,582,847; and 4,880,804; in European Patent Applications 028,834; 245,637; 253,310; and 291,969; and in articles by A. T. Chiu, et al. [Eur. J. Pharm. Exp. Therap, 157, 13-21 (1988)] and by P. C. Wong, et al. [J. Pharm. Exp. Therap, 247, 1-7(1988)]. All of the U.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounds which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 399,731 and 400974 disclose imidazopyridines similar to those described herein which are also A-II antagonist.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds of this invention have structural formula I: ##STR3## or a pharmaceutically acceptable salt thereof;
wherein:
R.sup.1 is
R.sup.2 is
R.sup.3a and R.sup.3b are independently
R.sup.3a and R.sup.3b on adjacent carbons can be joined together to form a benzo group;
R.sup.4 and R.sup.4a are independently
R.sup.5 is hydrogen or C.sub.1-5 alkyl;
In the above definitions, aryl is meant to include phenyl, naphthyl and 2-, 3-, or 4-pyridyl.
The terms "alkyl" and "alkoxy", include both straight- and branched-chain groups where the number of carbons permit.
One embodiment of the novel compounds is that wherein R.sup.4 and R.sup.4a are both C.sub.1-3 alkyl, especially methyl, and R.sup.5 is C.sub.1-5 alkyl, especially ethyl.
A class of compounds within this embodiment is that wherein R.sup.2 is C.sub.1-6 alkyl, especially n-propyl.
Specific compounds exemplifying the novel compounds of this invention are described in Table I.
TABLE I ______________________________________
##STR4##
#(EX) SO.sub.2 NHCOR.sup.1
R.sup.2
______________________________________
1 SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3
CH.sub.3
2 SO.sub.2 NHCO(CH.sub.2).sub.4 CH.sub.3
CH.sub.2 CH.s
REFERENCES:
patent: 5102880 (1992-04-01), Chakravarty et al.
patent: 5128327 (1992-07-01), Chakravarty et al.
patent: 5223499 (1993-06-01), Greenlee et al.
patent: 5332744 (1994-07-01), Chakravarty et al.
Chakravarty Prasun K.
Greenlee William J.
Kevin Nancy J.
Mantlo Nathan B.
Rivero Ralph A.
Camara Valerie J.
Daniel Mark R.
Dentz Bernard
Merck & Co. , Inc.
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