Therapeutic compounds
View Patent ↗The invention provides compounds of formula I or a salt thereof as described herein. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for inducing apoptosis or treating cancer using compounds of formula I.
1. A compound of formula I:
wherein:
Z 1 is CR 4 , Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N; or Z 1 is N, Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N; or Z 1 is CR 4 , Z 2 is N, Z 3 is CR 6 and Z 4 is N; or Z 1 is CR 4 , Z 2 is CR 5 , Z 3 is N and Z 4 is N;
R 1 is adamantyl, nor-adamantyl, bicyclooctyl or (C 2 -C 10 )alkynyl, wherein any adamantyl, nor-adamantyl, bicyclooctyl or (C 2 -C 10 )alkynyl of R 1 may be optionally substituted with one or more groups selected from —OH, oxo(═O), ═CH 2 , and —NH 2 ;
R 2 is —OH, —OC(═O)R a , —OC(═O)NR h R c or —OC(═O)OR a , and R 3 is H, halo, —CN, —NO 2 , (C 1 -C 6 )alkyl, —OH, (C 1 -C 3 )alkoxy, —NR d R e , —CO 2 R f , —C(═O)R f , —NR f (C═O)R g , —C(═O)NR d R e , wherein any alkyl or alkoxy of R 3 may be optionally substituted with one or more groups selected from halo, oxo, hydroxy, —NR z1 R z2 and (C 1 -C 3 )alkoxy; or R 2 and R 3 together with the atoms to which they are attached form an alkylenedioxy ring wherein alkylenedioxy ring is optionally substituted with one or more (C 1 -C 6 )alkyl;
R 3a is H, halo, —OH, —(C 1 -C 6 )alkyl or (C 1 -C 3 )alkoxy;
A is —CR h ═CR h —;
R 4 is H, halo, —CN, —NO 2 , —N 3 , —OH, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, —NR m R n , —NR o (C═O)R p or —CO 2 R, wherein any alkyl or alkoxy of R 4 may be optionally substituted with one or more groups selected from halo, oxo, hydroxy, —CN, —NR z1 R z2 , —C(═O)NR z1 R z2 and (C 1 -C 3 )alkoxy;
R 5 is H or F;
R 6 is H or F;
R 8 is H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl;
each R a is independently (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl;
R b and R c are each independently selected from H or (C 1 -C 6 )alkyl; or R b , and R c together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
R d and R e are each independently H or (C 1 -C 6 )alkyl; or R d and R e together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
each R f is independently H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl;
each R g is independently (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl;
each R h is independently H or F;
R m and R n are each independently H or (C 1 -C 6 )alkyl; or R m and R n together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
each R o is independently H, (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl;
each R p is independently (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl; and
R z1 and R z2 are each independently selected from H or (C 1 -C 6 )alkyl; or R z1 and R z2 together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino, or thiomorpholino;
or a salt thereof.
2. The compound of claim 1 wherein Z 1 is N, Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N.
3. The compound of claim 1 wherein Z 1 is CR 4 , Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N.
4. The compound of claim 1 wherein R 4 is H or halo.
5. (Original; The compound of claim 1 wherein Z 1 is CR 4 , Z 2 is N, Z 3 is CR 6 and Z 4 is N.
6. The compound of claim 1 wherein Z 1 is CR 4 , Z 2 is CR 5 , Z 3 is N and Z 4 is N.
7. The compound of claim 1 wherein R 1 is adamantyl wherein any adamantyl of R 1 may be optionally substituted with one or more groups selected from —OH and oxo(═O).
8. The compound of claim 1 wherein R 2 is —OH or —OC(═O)R a .
9. The compound of claim 1 wherein R 3 is H or (C 1 -C 3 )alkoxy.
10. The compound of claim 1 wherein R 2 and R 3 together with the atoms to which they are attached form a alkylenedioxy ring, wherein the alkylenedioxy ring is optionally substituted is with one or more (C 1 -C 6 )alkyl.
11. The compound of claim 1 wherein R 8 is H or (C 1 -C 6 )alkyl.
12. The compound of claim 1 which is:
or a salt thereof.
13. A composition comprising a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.
14. A method for inducing cell death or apoptosis in a pancreatic cancer stem cell in a mammal in need of such treatment comprising administering to the mammal an effective amount of a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 wherein:
Z 1 is CR 4 , Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N; or Z 1 is N, Z 2 is CR 5 , Z 3 is CR 6 and Z 4 is N;
R 1 is adamantyl, nor-adamantyl, bicyclooctyl or (C 2 -C 10 )alkynyl, wherein any adamantyl, nor-adamantyl, bicyclooctyl or (C 2 -C 10 )alkynyl of R 1 may be optionally substituted with one or more groups selected from —OH, oxo(═O), ═CH 2 , and —NH 2 ;
R 2 is —OH or —OC(═O)R a and R 3 is H or (C 1 -C 3 )alkoxy; or R 2 and R 3 together with the atoms to which they are attached form an alkylenedioxy;
R 3a is H, —(C 1 -C 6 )alkyl or (C 1 -C 3 )alkoxy;
A is —CR h ═CR h —;
R 4 is H or halo;
R 5 is H or F;
R 6 is H or F;
R 8 is H or (C 1 -C 6 )alkyl;
each R a is independently (C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl or aryl; and
each R h is independently H or F;
or a salt thereof.
16. A method for treating cancer in a mammal comprising administering to the mammal an effective amount of compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is leukemia or pancreatic cancer.
17. A method for treating cancer in a mammal comprising administering to the mammal an effective amount of compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is acute myelogenous leukemia, chronic myelogenous leukemia or pancreatic cancer.