Details for Patent: 6,894,065
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Title: | Thrombin receptor antagonists |
Abstract: | Heterocyclic-substituted compounds of the formula ##STR1## or a pharmaceutically acceptable salt thereof, are disclosed, wherein: Z is --(CH.sub.2).sub.n --; ##STR2## wherein R.sup.10 is absent; or ##STR3## wherein R.sup.3 is absent; the single dotted line represents an optional double bond; the double dotted line represents an optional single bond; n is 0-2; Het is an optionally substituted mono-, bi- or tricyclic heteroaromatic group; B is --(CH.sub.2).sub.n3 --, wherein n.sub.3 is 0-5, --CH.sub.2 --O--, --CH.sub.2 S--, --CH.sub.2 --NR.sup.6 --, --C(O)NR.sup.6 --, --NR.sup.6 C(O)--, ##STR4## optionally substituted alkenyl or optionally substituted alkynyl; X is --O-- or --NR.sup.6 -- when the double dotted line represents a single bond, or X is H, --OH or --NHR.sup.20 when the bond is absent; Y is .dbd.O, .dbd.S, (H, H), (H, OH) or (H, C.sub.1 -C.sub.6 alkoxy) when the double dotted line represents a single bond, or when the bond is absent, Y is .dbd.O, .dbd.NOR.sup.17, (H, H), (H, OH), (H, SH), (H, C.sub.1 -C.sub.6 alkoxy) or (H, substituted-amino); R.sup.22 and R.sup.23 are independently --OH, --OC(O)R.sup.30, OC(O)NR.sup.30 R.sup.31, or optionally substituted alkyl, alkenyl, alkynyl, heterocycloalkyl, aryl, cycloalkyl, cycloalkenyl, carbonyl, amino, alkoxy, alkenyloxy, alkynyloxy, heterocycloalkyloxy, cycloalkyloxy, or cycloalkenyloxy; or R.sup.22 and R.sup.10, or R.sup.23 and R.sup.11, can form a carbocyclic or heterocyclic ring; and the remaining variables are as described in the specification. Also disclosed are pharmaceutical compositions containing said compounds and their use as thrombin receptor antagonists and binders to cannabinoid receptors. |
Inventor(s): | Chackalamannil; Samuel (East Brunswick, NJ), Chelliah; Mariappan V. (Edison, NJ), Xia; Yan (Edison, NJ) |
Assignee: | Schering Corporation (Kenilworth, NJ) |
Filing Date: | Jun 09, 2003 |
Application Number: | 10/457,256 |
Claims: | 1. A compound represented by the structural formula ##STR163## or a pharmaceutically acceptable salt thereof, wherein: Z is --(CH.sub.2).sub.n --; ##STR164## wherein R.sup.10 is absent; or ##STR165## wherein R.sup.3 is absent; the single dotted line represents an optional double bond; the double dotted line represents an optional single bond; n is 0-2; R.sup.1 and R.sup.2 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, fluoro(C.sub.1 -C.sub.6)alkyl, difluoro(C.sub.1 -C.sub.6)alkyl, trifluoro-(C.sub.1 -C.sub.6)alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, aryl(C.sub.1 -C.sub.6)alkyl, aryl(C.sub.2 -C.sub.6)alkenyl, hydroxy-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkylamino-(C.sub.1 -C.sub.6)alkyl, aryl and thio(C.sub.1 -C.sub.6)alkyl; or R.sup.1 and R.sup.2 together form a .dbd.O group; R.sup.3 is H, hydroxy, C.sub.1 -C.sub.6 alkoxy, --NR.sup.18 R.sup.19, --SOR.sup.16, --SO.sub.2 R.sup.17, --C(O)OR.sup.17, --C(O)NR.sup.18 R.sup.19, C.sub.1 -C.sub.6 alkyl, halogen, fluoro(C.sub.1 -C.sub.6)alkyl, difluoro(C.sub.1 -C.sub.6)alkyl, trifluoro(C.sub.1 -C.sub.6)alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.2 -C.sub.6 alkenyl, aryl(C.sub.1 -C.sub.6)alkyl, aryl(C.sub.2 -C.sub.6)alkenyl, hydroxy--(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, aryl, thio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl; R.sup.34 is (H, R.sup.3), (H, R.sup.43), .dbd.O or .dbd.NOR.sup.17 when the optional double bond is absent; R.sup.34 is R.sup.44 when the double bond is present; Het is pyridyl or quinolyl, 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 heterocycloalkyl; heterocycloalkyl substituted by C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, OH--(C.sub.1 -C.sub.6)alkyl, or .dbd.O; heteroaryl(C.sub.1 -C.sub.6)alkyl; heteroaryl(C.sub.2 -C.sub.6)-alkenyl; heteroaryloxy; heteroaryl-NH; R.sup.41 -heteroaryl; and heteroaryl wherein adjacent carbon atoms form a ring with a C.sub.3 -C.sub.5 alkylene group or a methylenedioxy group; R.sup.4 and R.sup.5 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl and C.sub.3 -C.sub.7 cycloalkyl, or R.sup.4 and R.sup.5 together are --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 -- or --(CH.sub.2).sub.2 NR.sup.7 --(CH.sub.2).sub.2 -- and form a ring with the nitrogen to which they are attached; R.sup.6 is independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, phenyl, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl and amino(C.sub.1 -C.sub.6)alkyl; H.sub.7 is H or (C.sub.1 -C.sub.6)alkyl; R.sup.8, R.sup.10 and R.sup.11 are independently selected from the group consisting of R.sup.1 and --OR.sup.1, provided that when the optional double bond is present, R.sup.10 is absent; R.sup.9 is H, OH, C.sub.1 -C.sub.6 alkoxy, halogen or halo(C.sub.1 -C.sub.6)alkyl; B is --CH.dbd.CH--; X is --O--; Y is .dbd.O; R.sup.15 is absent; R.sup.16 is C.sub.1 -C.sub.6 lower alkyl, phenyl or benzyl; R.sup.17, R.sup.18 and R.sup.19 are independently selected from the group consisting of H, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl; R.sup.20 is H, C.sub.1 -C.sub.6 alkyl, phenyl, benzyl, --C(O)R.sup.6 or --SO.sub.2 R.sup.6 ; R.sup.21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, --CF.sub.3, --OCF.sub.3, halogen, --NO.sub.2, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, (C.sub.1 -C.sub.6)alkylamino, di-((C.sub.1 -C.sub.6)alkyl)amino, amino(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)-alkylamino(C.sub.1 -C.sub.6)alkyl, di-((C.sub.1 -C.sub.6)alkyl)-amino(C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.1 -C.sub.6)alkyl, --COOR.sup.17, --COR.sup.17, --NHCOR.sup.16, --NHSO.sub.2 R.sup.16, --NHSO.sub.2 CH.sub.2 CF.sub.3, or --C(.dbd.NOR.sup.17)R.sup.18 ; R.sup.22 and R.sup.23 are independently selected from the group consisting of hydrogen, R.sup.24 --(C.sub.1 -C.sub.10)alkyl, R.sup.24- (C.sub.2 -C.sub.10)alkenyl, R.sup.24 --(C.sub.2 -C.sub.10)alkynyl, R.sup.25 -aryl, R.sup.25 -aryl(C.sub.1 -C.sub.6)alkyl, R.sup.29 --(C.sub.3 -C.sub.7)cycloalkyl, R.sup.29 --(C.sub.3 -C.sub.7)cycloalkenyl, --OH, --OC(O)R.sup.30, --C(O)OR.sup.30, --C(O)R.sup.30, --C(O)NR.sup.30 R.sup.31, --NR.sup.30 R.sup.31, --NR.sup.30 C(O)R.sup.31, --NR.sup.30 C(O)NR.sup.31 R.sup.32, --NHSO.sub.2 R.sup.30, --OC(O)NR.sup.30 R.sup.31, R.sup.24 --(C.sub.1 -C.sub.10)alkoxy, R.sup.24 --(C.sub.2 -C.sub.10)-alkenyloxy, R.sup.24 --(C.sub.2 -C.sub.10)alkynyloxy, R.sup.29 --(C.sub.3 -C.sub.7)cycloalkyloxy, R.sup.29 --(C.sub.3 -C.sub.7)cyclo-alkenyloxy, R.sup.29 --(C.sub.3 -C.sub.7)cycloalkyl-NH--, --NHSO.sub.2 NHR.sup.16 and --CH(.dbd.NOR.sup.17); or R.sup.22 and R.sup.10 together with the carbon to which they are attached, or R.sup.23 and R.sup.11 together with the carbon to which they are attached, independently form a R.sup.42 -substituted carbocyclic ring of 3-10 atoms, provided that when R.sup.22 and R.sup.10 form a ring, the optional double bond is absent; R.sup.24 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, halogen, --OH, (C.sub.1 -C.sub.6)alkoxy, R.sup.35 -aryl, (C.sub.1 -C.sub.10)-alkyl-C(O)--, (C.sub.2 -C.sub.10)-alkenyl-C(O)--, (C.sub.2 -C.sub.10)alkynyl-C(O)--, R.sup.26 --(C.sub.3 -C.sub.7)cycloalkyl, R.sup.26 --(C.sub.3 -C.sub.7)cycloalkenyl, --OC(O)R.sup.30, --C(O)OR.sup.30, --C(O)R.sup.30, --C(O)NR.sup.30 R.sup.31, --NR.sup.30 R.sup.31, --NR.sup.30 C(O)R.sup.31, --NR.sup.30 C(O)NR.sup.31 R.sup.32, --NHSO.sub.2 R.sup.30, --OC(O)NR.sup.30 R.sup.31, R.sup.24 --(C.sub.2 -C.sub.10)-alkenyloxy, R.sup.24 --(C.sub.2 -C.sub.10)alkynyloxy, R.sup.27 -heterocycloalkyloxy, R.sup.29 --(C.sub.3 -C.sub.7)-cycloalkyloxy, R.sup.29 --(C.sub.3 -C.sub.7)cyclo-alkenyloxy, R.sup.29 --(C.sub.3 -C.sub.7)cycloalkyl-NH--, --NHSO.sub.2 NHR.sup.16 and --CH(.dbd.NOR.sup.17); R.sup.26 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, halogen, --COOR.sup.36, --CN, --C(O)NR.sup.37 R.sup.38, --NR.sup.39 C(O)R.sup.40, --OR.sup.38, (C.sub.3 -C.sub.7)cycloalkyl, (C.sub.3 -C.sub.7)cycloalkyl-C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.7)cycloalkyl-(C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl(C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.6)alkyl, hydroxy(C.sub.1 -C.sub.6)alkyl, and (C.sub.1 -C.sub.5)alkoxy(C.sub.1 -C.sub.6)alkyl; or two R.sup.25 groups on adjacent ring carbons form a fused methylenedioxy group; R.sup.26 is 1, 2, or 3 substituents independently selected from the group consisting of hydrogen, halogen and (C.sub.1 -C.sub.6)alkoxy; R.sup.27 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, R.sup.28 --(C.sub.1 -C.sub.10)alkyl, R.sup.28 --(C.sub.2 -C.sub.10)alkenyl, R.sup.28 --(C.sub.2 -C.sub.10)alkynyl, R.sup.28 is hydrogen, --OH or (C.sub.1 -C.sub.6)alkoxy; R.sup.29 is 1, 2 or 3 substituents independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, --OH, (C.sub.1 -C.sub.6)alkoxy and halogen; R.sup.30, R.sup.31 and R.sup.32 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.10)-alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.10)-alkyl, R.sup.25 -aryl(C.sub.1 -C.sub.6)-alkyl, R.sup.33 --(C.sub.3 -C.sub.7)cycloalkyl, R.sup.34- (C.sub.3 -C.sub.7)cycloalkyl(C.sub.1 -C.sub.6)alkyl, R.sup.25 -aryl; R.sup.33 is hydrogen, (C.sub.1 -C.sub.6)alkyl, OH--(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; R.sup.35 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.5)alkyl, --OH, halogen, --CN, (C.sub.1 -C.sub.6)alkoxy, trihalo(C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, --OCF.sub.3, OH--(C.sub.1 -C.sub.6)-alkyl, --CHO, --C(O)(C.sub.1 -C.sub.6)alkyl)amino, --C(O)di((C.sub.1 -C.sub.6)alkyl)amino, --NH.sub.2, --NHC(O)(C.sub.1 -C.sub.6)alkyl and --N((C.sub.1 -C.sub.6)alkyl)C(O)(C.sub.1 -C.sub.6)alkyl; R.sup.36 is hydrogen, (C.sub.1 -C.sub.6)alkyl, halo(C.sub.1 -C.sub.6)alkyl, dihalo(C.sub.1 -C.sub.6)alkyl or trifluoro(C.sub.1 -C.sub.6)alkyl; R.sup.37 and R.sup.38 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.6)alkyl, phenyl and (C.sub.3 -C.sub.15)cycloalkyl, or R.sup.37 and R.sup.38 together are --(CH.sub.2).sub.4 --, --(CH.sub.2).sub.5 -- or --(CH.sub.2).sub.2 --NR.sup.39 --(CH.sub.2).sub.2 -- and form a ring with the nitrogen to which they are attached; R.sup.39 and R.sup.40 are independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, aryl(C.sub.1 -C.sub.6)alkyl, phenyl and (C.sub.3 -C.sub.15)-cycloalkyl, or R.sup.39 and R.sup.40 in the group --NR.sup.39 C(O)R.sup.40, together with the carbon and nitrogen atoms to which they are attached, form a cyclic lactam having 5-8 ring members; R.sup.41 is 1 to 4 substituents independently selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkylamino, di((C.sub.1 -C.sub.6)alkyl)amino, --OCF.sub.3, OH--(C.sub.1 -C.sub.6)alkyl, --CHO and phenyl; R.sup.42 is 1 to 3 substituents independently selected from the group consisting of hydrogen, --OH, (C.sub.1 -C.sub.6)alkyl and (C.sub.1 -C.sub.6)alkoxy; R.sup.43 is --NR.sup.30 R.sup.31, --NR.sup.30 C(O)R.sup.31, --NR.sup.30 C(O)NR.sup.31 R.sup.32, --NHSO.sub.2 R.sup.30 or --NHCOOR.sup.17 ; R.sup.44 is H, C.sub.1 -C.sub.6 alkoxy, --SOR.sup.16, --SO.sub.2 R.sup.17, --C(O)OR.sup.17, --C(O)NR.sup.18 R.sup.19, C.sub.1 -C.sub.6 alkyl, halogen, fluoro(C.sub.1 -C.sub.6)alkyl, difluoro(C.sub.1 -C.sub.6)alkyl, trifluoro(C.sub.1 -C.sub.6)alkyl, C.sub.3 -C.sub.7 cycloalkyl, C.sub.2 -C.sub.8 alkenyl, aryl(C.sub.1 -C.sub.6)alkyl, aryl(C.sub.2 -C.sub.6)alkenyl, heteroaryl(C.sub.1 -C.sub.6)alkyl, heteroaryl(C.sub.2 -C.sub.6)alkenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, amino(C.sub.1 -C.sub.6)alkyl, aryl, thio(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkylamino(C.sub.1 -C.sub.6)alkyl; and R.sup.45 is H, C.sub.1 -C.sub.6 alkyl, --COOR.sup.16 or --SO.sub.2. 2. A compound of claim 1 wherein n is zero. 3. A compound of claim 1 wherein the double dotted line represents a single bond. 4. A compound of claim 1 wherein R.sup.2, R.sup.8, R.sup.10 and R.sup.11 are each hydrogen, R.sup.2 is hydrogen, OH, C.sub.1 -C.sub.6 alkoxy, --NHR.sup.18 or C.sub.1 -C.sub.6 alkyl, and R.sup.34 is (H,H) or (H,OH). 5. A compound of claim 1 wherein R.sup.9 is H, OH or C.sub.1 -C.sub.6 alkoxy. 6. A compound of claim 1 wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl. 7. A compound of claim 1 wherein W is R.sup.41 -heteroaryl. 8. A compound of claim 1 wherein R.sup.22 and R.sup.23 are independently selected from the group consisting of OH, (C.sub.1 -C.sub.10)alkyl, (C.sub.2 -C.sub.10)-alkenyl, (C.sub.2 -C.sub.10)alkynyl, trifluoro(C.sub.1 -C.sub.10)-alkyl, trifluoro(C.sub.2 -C.sub.10)-alkenyl, trifluoro(C.sub.2 -C.sub.10)alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, R.sup.25 -aryl, R.sup.25 -aryl(C.sub.1 -C.sub.6)alkyl, R.sup.25 -arylhydroxy(C.sub.1 -C.sub.6)alkyl, R.sup.25 -arylalkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.3 -C.sub.7)cycloalkyloxy, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, OH--(C.sub.1 -C.sub.6)alkyl and trifluoro(C.sub.1 -C.sub.10)alkoxy. 9. A compound of claim 1 wherein R.sup.22 and R.sup.23 are independently selected from the group consisting of (C.sub.1 -C.sub.10)alkyl and OH--(C.sub.1 -C.sub.10)alkyl. 10. A compound of claim 1 wherein n is zero; the double dotted line represents a single bond; R.sup.2, R.sup.8, R.sup.10 and R.sup.11 are each hydrogen; R.sup.3 is hydrogen OH, C.sub.1 -C.sub.6 alkoxy, --NHR.sup.18 or C.sub.1 -C.sub.6 alkyl; R.sup.9 is H, OH or C.sub.1 -C.sub.6 alkoxy; and R.sup.1 is C.sub.1 -C.sub.6 alkyl. 11. A compound of claim 10 wherein R.sup.22 and R.sup.23 are independently selected from the group consisting of OH, (C.sub.1 -C.sub.10)alkyl, (C.sub.2 -C.sub.10)-alkenyl, (C.sub.2 -C.sub.10)alkynyl, trifluoro(C.sub.1 -C.sub.10)-alkyl, trifluoro(C.sub.2 -C.sub.10)-alkenyl, trifluoro(C.sub.2 -C.sub.10)alkynyl, (C.sub.3 -C.sub.7)cycloalkyl, R.sup.25 -aryl, R.sup.25 -aryl(C.sub.1 -C.sub.6)alkyl, R.sup.25 -arylhydroxy(C.sub.1 -C.sub.6)alkyl, R.sup.25 -arylalkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.7)-cycloalkyl-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.10)alkoxy, (C.sub.3 -C.sub.7)cycloalkyloxy, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, OH--(C.sub.1 -C.sub.6)alkyl and trifluoro(C.sub.1 -C.sub.10)alkoxy. 12. A compound of claim 10 wherein R.sup.22 and R.sup.23 are independently selected from the group consisting of (C.sub.1 -C.sub.10)alkyl and OH--(C.sub.1 -C.sub.10)alkyl. 13. A compound of claim 1 selected from the group consisting of compounds of the formula ##STR166## wherein R.sup.3, R.sup.22, R.sup.23 and W are as defined in the following table (Me is methyl, Et is ethyl, Ac is acetyl and Ph is phenyl): 14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier. 15. A method of treating thrombosis, platelet aggregation or coagulation comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1. 16. A method of treating atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, peripheral vascular diseases or cerebral ischemia comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1. |