US2008214647A1PendingUtilityA1
Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
Est. expiryJun 20, 2021(expired)· nominal 20-yr term from priority
Inventors:Hassan Mahmoud ElokdahGeraldine Ruth McfarlaneDavid Zenan LiLee Dalton JenningsDavid Leroy Crandall
A61P 7/04A61P 7/02C07D 209/12A61P 43/00
60
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Claims
Abstract
This invention provides compounds of the formula: wherein: X is a chemical bond, —CH 2 — or —C(O)—; R 1 is alkyl, cycloalkyl, —CH 2 — cycloalkyl, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl; R 2 is H, alkyl, cycloalkyl, —CH 2 -cycloalkyl, or perfluoroalkyl; R 3 is H, halo, alkyl, perfluoroalkyl, alkoxy, cycloalkyl, —CH 2 -cycloalkyl, —NH 2 , or —NO 2 ; R 4 is optionally substituted phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, or the salt or ester forms thereof, as well as methods for using the compounds as inhibitors of plasminogen activator inhibitor-1 (PAI-1) and as therapeutic compositions for treating conditions resulting from fibrinolytic disorders such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.
Claims
exact text as granted — not AI-modified1 - 16 . (canceled)
17 . A method for treatment of thrombosis or fibrinolytic impairment in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
18 . A method of claim 17 wherein the thrombosis or fibrinolytic impairment is associated with formation of atherosclerotic plaques, venous and arterial thrombosis, myocardial ischemia, atrial fibrillation, deep vein thrombosis, coagulation syndromes, pulmonary fibrosis, cerebral thrombosis, thromboembolic complications of surgery or peripheral arterial occlusion.
19 . (canceled)
20 . A method for the treatment of stroke associated with or resulting from atrial fibrillation in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
21 . A method for the treatment of deep vein thrombosis in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
22 . A method for the treatment of myocardial ischemia in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
23 . A method for the treatment of cardiovascular disease caused by noninsulin dependent diabetes mellitus in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
24 . A method for the treatment of the formation of atherosclerotic plaques in a mammal comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
25 . A method for the treatment of chronic obstructive pulmonary disease in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , or —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
26 . A method for the treatment of renal fibrosis in a mammal, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula (I):
wherein:
X is a chemical bond, —CH 2 — or —C(O)—;
R 1 is selected from C 1 -C 8 alkyl, preferably C 1 -C 6 alkyl, (—CH 2 ) n —C 3 -C 6 cycloalkyl, wherein n is an integer of from 0 to 3, pyridinyl, —CH 2 -pyridinyl, phenyl or benzyl, the rings of the cycloalkyl, pyridinyl, phenyl and benzyl groups being optionally substituted by, from 1 to 3 groups selected from, halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , or —NO 2 ;
R 2 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, or C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —CH 2 OH or CH 2 OAc;
R 3 is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, —NH 2 , —NO 2 ;
R 4 is selected from C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, —CH 2 —C 3 -C 6 cycloalkenyl, phenyl, benzyl, benzyloxy, pyridinyl, or —CH 2 -pyridinyl, with the rings of these groups being optionally substituted by from 1 to 3 groups selected from halogen, C 1 -C 4 alkyl, C 1 -C 3 perfluoroalkyl, preferably —CF 3 , —O—C 1 -C 3 perfluoroalkyl, preferably —O—CF 3 , C 1 -C 3 alkoxy, —OH, —NH 2 , —NO 2 or (CO)C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt or ester form thereof.
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