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Details for Patent: 6,894,065

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Details for Patent: 6,894,065

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.
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