US2006106050A1PendingUtilityA1
Thrombin receptor antagonists
Est. expiryOct 18, 2021(expired)· nominal 20-yr term from priority
A61P 9/12A61P 9/10A61P 9/06A61P 9/00A61P 9/04A61P 35/00A61P 43/00A61P 7/02A61P 29/00A61P 13/12A61P 19/00A61P 11/00A61P 19/02C07D 491/04C07D 493/04C07D 495/04C07D 491/048
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Claims
Abstract
Heterocyclic-substituted tricyclics of the formula or a pharmaceutically acceptable salts thereof, wherein: n 1 and n 2 are independently 0-2; Het is an optionally substituted mono-, bi- or tricyclic heteroaromatic group; B is alkyl or optionally substituted alkenyl; R 22 is —COR 23 or a carboxy, sulfinyl, sulfonyl, sulfonamide or amino acid derivative; R 23 is haloalkyl; alkenyl; haloalkenyl; alkynyl; optionally substituted cycloalkyl; cycloalkyl-alkyl; aryl; arylalkyl; heteroaryl; heterocycloalkyl; or —COOH and/or —SO 3 H substituted alkyl; R 1 , R 2 , R 3 , R 9 , R 10 and R 11 are as defined in the specification; are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds.
Claims
exact text as granted — not AI-modified1 . A compound represented by the structural formula
or a pharmaceutically acceptable salt thereof, wherein:
R is 1 to 3 substituents independently selected from the group consisting of H, C 1 -C 6 alkyl, halogen, hydroxy, amino, (C 1 -C 6 )alkyl-amino, (C 1 -C 6 )-dialkylamino, (C 1 -C 6 )alkoxy, —COR 16 , —COOR 17 , —SOR 16 , —SO 2 R 16 , —SO 2 NR 17 R 18 , —NR 17 SO 2 R 18 , —NR 16 COR 16a , —NR 16 COOR 16a , —NR 16 CONR 4 R 5 , fluoro-(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl, aryl(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, amino-(C 1 -C 6 )-alkyl, aryl and thio(C 1 -C 6 )alkyl;
R 1 and R 2 are independently selected from the group consisting of H, C 1 -C 6 alkyl, fluoro(C 1 -C 6 )alkyl, difluoro(C 1 -C 6 )alkyl, trifluoro-(C 1 -C 6 )alkyl, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, aryl(C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, aryl and thio(C 1 -C 6 )alkyl; or R 1 and R 2 together form an ═O group;
R 3 is H, hydroxy, C 1 -C 6 alkoxy, aryloxy, aryl(C 1 -C 6 )alkyloxy, heteroaryloxy, heteroaryl(C 1 -C 6 )alkyloxy, (C 3 -C 6 )cycloalkyloxy, —SOR 16 , —SO 2 R 17 , —SO 2 NR 18 R 19 , —SR 18 , —SO 3 H, —C(O)OR 17 , —C(O)NR 18 R 19 , —OC(O)R 32 , —OC(O)NR 33 R 34 , —(CR 33 R 34 ) n OR 32 , —NR 4 R 5 , —NR 33 COOR 32 , —NR 33 COR 32 , —NR 33 S(O) 2 R 32 , —NR 33 CONR 33 R 34 , —NR 33 S(O) 2 NR 33 R 34 , —(CR 33 R 34 ) n NR 4 R 5 , —(CR 33 R 34 ) n NR 33 COOR 32 , —(CR 33 R 34 ) n NR 33 COR 32 , —(CR 33 R 34 ) n NR 33 S(O) 2 R 32 , —(CR 33 R 34 ) n NR 33 CONR 33 R 34 , —(CR 33 R 34 ) n NR 33 S(O) 2 NR 33 R 34 , (C 1 -C 6 )alkyl, halogen, C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, —CN, aryl, heteroaryl, heterocycloalkyl, —P(O)(OR 7 ) 2 or (C 1 -C 6 )alkyl substituted by 1 to 3 substituents independently selected from the group consisting of halogen, —OH, —NH 2 , aryl, —COOH, —SO 3 H, thio and (C 1 -C 6 )alkylthio;
n is 1, 2, 3 or 4;
n1 and n2 are independently 0-3, provided both are not 0;
Het is a mono-, bi- or tricyclic heteroaromatic group of 5 to 14 atoms comprised of 1 to 13 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of N, O and S, wherein a ring nitrogen can form an N-oxide or a quaternary group with a C 1 -C 4 alkyl group, wherein Het is attached to B by a carbon atom ring member, and wherein the Het group is substituted by 1 to 4 substituents, W, independently selected from the group consisting of C 1 -C 6 alkyl;
—NR 4 R 5 ; —NHCOR 26 ; —NHSO 2 R 16 ;
R 21 -aryl; aryl wherein adjacent carbons form a ring with a methylenedioxy group; and R 21 -heteroaryl;
R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl, benzyl and C 3 -C 6 cycloalkyl, or R 4 and R 5 together are —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 2 NR 7 —(CH 2 ) 2 — and form a ring with the nitrogen to which they are attached;
R 7 is H or (C 1 -C 6 )alkyl;
R 8 , R 10 and R 11 are independently selected from the group consisting of R 1 and —OR 1 ;
R 9 is H, OH, —NR 4 R 5 , C 1 -C 6 alkoxy, halogen or halo(C 1 -C 6 )alkyl;
B is —(CH 2 ) n 3 — or cis or trans —(CH 2 ) n 4 CR 12 ═CR 12a (CH 2 ) n 5 , wherein n 3 is 0-5, n 4 and n 5 are independently 0-2, and R 12 and R 12a are independently selected from the group consisting of H, C 1 -C 6 alkyl and halogen;
R 16 and R 16a are independently selected from the group consisting of C 1 -C 6 alkyl, phenyl and benzyl;
R 17 , R 18 and R 19 are independently selected from the group consisting of H, C 1 -C 6 alkyl, phenyl and benzyl;
R 21 is 1 to 3 substituents independently selected from the group consisting of H, —CF 3 , —OCF 3 , halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , (C 1 -C 6 )-alkyl-amino, di-((C 1 -C 6 )alkyl)amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )-alkylamino(C 1 -C 6 )alkyl, di-((C 1 -C 6 )alkyl)-amino(C 1 -C 6 )alkyl, hydroxy-(C 1 -C 6 )alkyl, —COOR 17 , —COR 17 , —CONR 24 R 25 , —NHCOR 6 , —NHSO 2 R 16 , —NHSO 2 CH 2 CF 3 , —SO 2 NR 24 R 25 , —NR 29 C(O)NR 24 R 25 , —SO 2 R 30 , —P(O)(OR 29 ) 2 , aryl, aryl(C 1 -C 6 )alkyl, heteroaryl, heterocycloalkyl, and —CR 29 (═NOR 28 );
R 22 is —COR 23 , —S(O)R 31 , —S(O) 2 R 31 , —SO 2 NR 24 R 25 or —COOR 27 ;
R 23 is halo(C 1 -C 6 )alkyl; C 2 -C 6 alkenyl; halo(C 2 -C 6 )alkenyl; C 2 -C 6 alkynyl; C 3 -C 7 -cycloalkyl; (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; (C 3 -C 7 )cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of halo, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy and C 1 -C 6 alkoxy; aryl; aryl(C 2 -C 6 )alkyl; heteroaryl; heterocycloalkyl; (C 1 -C 6 )alkyl substituted by 1-3 substituents independently selected from —COOH and —SO 3 H; or
wherein R 35 and R 36 are independently selected from the group consisting of H, alkyl, or R 37 -substituted C 1 -C 6 alkyl, wherein R 37 is selected from the group consisting of HO—, HS—, CH 2 S—, —NH 2 , phenyl, p-hydroxyphenyl and indolyl;
R 24 and R 25 are independently selected form the group consisting of H, C 1 -C 6 alkyl, halo(C 1 -C 6 )alkyl, C 2 -C 6 alkenyl, halo(C 2 -C 6 )alkyl, C 2 -C 6 alkynyl, aryl, aryl-(C 1 -C 6 )alkyl, C 3 -C 7 -cycloalkyl, halo(C 3 -C 7 )cycloalkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )-alkyl, hydroxy and C 1 -C 6 alkoxy;
R 26 is C 3 -C 7 -cycloalkyl, aryl, aryl-(C 1 -C 6 )alkyl, heteroaryl, heteroaryl-(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylamino;
R 27 is C 1 -C 6 alkyl, phenyl, benzyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )-alkyl, (C 3 -C 7 )-cycloalkyl, carboxy(C 1 -C 6 )alkyl, sulfo(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkyl substituted by NR 18 R 19 and carboxy;
R 28 is H, C 1 -C 6 alkyl, phenyl, benzyl or (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl;
R 29 and R 30 are independently selected from the group consisting of H and C 1 -C 6 alkyl;
R 31 is (C 1 -C 6 )alkyl; halo(C 1 -C 6 )alkyl; C 2 -C 6 alkenyl; halo(C 2 -C 6 )alkyl; C 2 -C 6 alkynyl; C 3 -C 7 -cycloalkyl; (C 3 -C 7 )cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of halo, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy and C 1 -C 6 alkoxy; aryl; aryl(C 1 -C 6 )alkyl; heteroaryl; heterocycloalkyl; (C 1 -C 6 )alkyl substituted by 1-3 substituents independently selected from —COOH and —SO 3 H; or (C 1 -C 6 )alkoxy;
R 32 is R 35 —(C 1 -C 6 )alkyl, R 35 —(C 3 -C 7 )cycloalkyl, R 35 —(C 2 -C 6 )alkenyl, R 35 —(C 2 -C 6 )-alkynyl or R 35 -aryl, wherein R 35 is 1 or 2 substituents independently selected from the group consisting of H, —COOH, —NH 2 , —SO 3 H, ═O and ═NOR 28 ; and
R 33 and R 34 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl and C 3 -C 7 -cycloalkyl.
2 . A compound of claim 1 wherein the sum of n1 and n2 is 3.
3 . A compound of claim 1 wherein R 1 , R 10 and R 11 are independently selected from the group consisting of H and C 1 -C 6 alkyl; R 2 and R 8 are each hydrogen; and R 9 is H, OH or C 1 -C 6 alkoxy.
4 . A compound of claim 1 wherein R is H, halogen, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or amino.
5 . A compound of claim 1 wherein B is —CH═CH—.
6 . A compound of claim 1 wherein Het is pyridyl, W-substituted pyridyl, quinolyl or W-substituted quinolyl.
7 . A compound of claim 6 wherein W is —NR 4 R 5 , —NHCOR 26 , —NHSO 2 R 16 , R 21 -aryl or heteroaryl.
8 . A compound of claim 7 wherein R 21 is 1 to 3 substituents independently selected from the group consisting of H, —CF 3 , —OCF 3 , halogen, —CN, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 and —CR 29 (═NOR 28 ).
9 . A compound of claim 1 wherein R 3 is H, hydroxy, C 1 -C 6 alkoxy, halogen, C 3 -C 6 cycloalkyl, —CN, (C 1 -C 6 )alkyl, —COOR 17 or —NR 4 R 5 .
10 . A compound of claim 1 wherein R 22 is —COR 23 , —S(O) 2 R 31 or —COOR 27 .
11 . A compound of claim 10 wherein R 23 is C 3 -C 7 -cycloalkyl; (C 3 -C 7 )cycloalkyl substituted by 1 to 3 substituents selected from the group consisting of halo, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, hydroxy and C 1 -C 6 alkoxy; (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl; aryl; or aryl(C 2 -C 6 )alkyl.
12 . A compound of claim 11 wherein R 23 is C 3 -C 7 -cycloalkyl; (C 3 -C 7 )cycloalkyl(C 1 -C 6 )alkyl or aryl-(C 2 -C 6 )alkyl.
13 . A compound of claim 10 wherein R 31 is (C 1 -C 6 )alkyl, C 3 -C 7 -cycloalkyl, aryl or aryl(C 1 -C 6 )alkyl.
14 . A compound of claim 10 wherein R 27 is C 1 -C 6 alkyl, phenyl, benzyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl or (C 3 -C 7 )cycloalkyl.
15 . A compound of claim 1 selected from the group consisting of compounds of the formula
wherein W and R 22 are as defined in the table:
W
R 22
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 Et
—CO 2 CH 2 CH 2 OMe
and compounds of the formula
wherein W is as defined in the following table:
W
16 . A pharmaceutical composition comprising an effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.
17 . A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1 .
18 . A method of treating thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolytic stroke, peripheral vascular diseases, inflammatory diseases, respiratory diseases, cerebral ischemia or cancer, comprising administering to a mammal in need of such treatment an effective amount of at least one compound of claim 1 .
19 . A compound selected from the group consisting of compounds of the formula
wherein W and Z are as defined in the following table:
W
Z
—S—
—S(O)—
—O—
—O—
—O—
—O—
—O—
—O—
—NH—
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