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Details for Patent: 6,645,987

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Details for Patent: 6,645,987

Title: Nor-seco himbacine derivatives useful as thrombin receptor antagonists
Abstract:Heterocyclic-substituted compounds of the formula ##STR1## or a pharmaceutically acceptable salt thereof, are disclosed.
Inventor(s): Chackalamannil; Samuel (East Brunswick, NJ), Chelliah; Mariappan V. (Edison, NJ), Xia; Yan (Edison, NJ)
Assignee: Schering Corporation (Kenilworth, NJ)
Filing Date:Jun 13, 2001
Application Number:09/880,222
Claims:1. A compound represented by the structural formula ##STR161## or a pharmaceutically acceptable salt thereof, wherein: Z is --CH.sub.2 --; R.sup.1 is 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)alkyl, amino-(C.sub.1 -C.sub.6)alkyl, aryl or thio(C.sub.1 -C.sub.6)alkyl; R.sup.2 is H; 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)NR18R.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; Het is pyridyl, wherein the ring nitrogen can form an N-oxide or a quaternary group with a C.sub.1 -C.sub.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 of W, wherein W is 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; R.sup.21 -aryl(C.sub.1 -C.sub.6)alkyl; R.sup.21 -aryl-(C.sub.1 -C.sub.6)-alkenyl; R.sup.21 -aryloxy; R.sup.21 -aryl-NH--; hydroxy(C.sub.1 -C.sub.6)alkyl; dihydroxy(C.sub.1 -C.sub.6)alkyl; 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; thio(C.sub.1 -C.sub.6)alkyl; C.sub.1 -C.sub.6 alkoxy; C.sub.2 -C.sub.6 alkenyloxy; halogen; --NR.sup.4 R.sup.5 ; --CN; --OH; --COOR.sup.17 ; --COR.sup.16 ; --OSO.sub.2 CF.sub.3 ; --CH.sub.2 OCH.sub.2 CF.sub.3 ; (C.sub.1 -C.sub.6)alkylthio; --C(O)NR.sup.4 R.sup.5 ; --OCHR.sup.8 -phenyl; phenoxy-(C.sub.1 -C.sub.6)alkyl; --NHCOR.sup.16 ; --NHSO.sub.2 R.sup.16 ; biphenyl; --OC(R.sup.6).sub.2 COOR.sup.7 ; --OC(R.sup.6).sub.2 C(O)NR.sup.4 R.sup.5 ; (C.sub.1 -C.sub.6)alkoxy: --C(.dbd.NOR.sup.17)R.sup.18 ; C.sub.1 -C.sub.6 alkoxy substituted by (C.sub.1 -C.sub.6)alkyl, amino, --OH, COOR.sup.17, --NHCOOR.sup.17, --CONR.sup.4 R.sup.5, aryl, aryl substituted by 1 to 3 substutuents independently selected from the group consisting of halogen, --CF.sub.3, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and --COOR.sup.17, --C(O)NR.sup.4 R.sup.5 ; and R.sup.21 -aryl; 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 cycloalky; 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; R.sup.7 is H or (C.sub.1 -C.sub.6)alkyl; R.sup.8, R.sup.10 and R.sup.11 are each H; 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--; 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.21 is 1 to 3 substutuents independently selected from the group consisting of hydrogen, CN, --CF3, --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.sub.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)cyclo-alkenyl, --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; 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.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.25 is , 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.36, (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.6)alkoxy(C.sub.1 -C.sub.6)alkyl; 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.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, and 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.6)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, --OCF3, OH--(C.sub.1 -C.sub.6)alkyl, --CHO, --C(O)(C.sub.1 -C.sub.6)-alkylamino, --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; 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; and 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.

2. A compound of claim 1 wherein R.sup.8, R.sup.10 and R.sup.11 are each hydrogen, and R.sup.3 is hydrogen, OH, C.sub.1 -C.sub.6 alkoxy, --NHR.sup.18 or C.sub.1 -C.sub.6 alkyl.

3. A compound of claim 1 wherein R.sup.9 is H, OH or C.sub.1 -C.sub.6 alkoxy.

4. A compound of claim 1 wherein R.sup.1 is C.sub.1 -C.sub.6 alkyl.

5. A compound of claim 1 wherein W is C.sub.1 -C.sub.6 alkyl, or R.sup.21 -aryl.

6. A compound of claim 1 wherein R.sup.22 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.

7. 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.

8. A compound of claim 1 wherein R.sup.2 is 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.

9. A compound of claim 8 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.

10. A compound of claim 8 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.

11. A compound of claim 8 wherein B is trans --CH.dbd.CH--.

12. A compound of claim 1 selected from the group consisting of compounds of the formula ##STR162## 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):

13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of inhibiting thrombin receptors comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.
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