Eponemycin and epoxomicin analogs and uses thereof
The present invention provides compounds having formula (1): wherein R 1 -R 6 , A, J, D, E, G, Q, w, x, y, and z are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof in the treatment of cancer and/or inflammatory disorders, and more generally as proteasome inhibitors.
1. A compound having the structure (I):
or pharmaceutically acceptable derivative thereof;
wherein each occurrence of A, J, E, D and G is independently CR A , CR A R B , C═O, O, S, NR A , or N, wherein each occurrence of R A and R B is independently hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
A and J, J and D, D and E, and D and G are each independently linked by a single or double bond as valency permits;
w, x, y and z are each independently 0, 1, 2, 3, 4, 5 or 6, but the sum of x, y and z is 2-6;
R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, —CN, —OR C , —SR C , —NR C R D , —(C═O)R C or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of R C and R D is independently hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or R C and R D , taken together, form a heteroalicyclic or heteroaryl moiety; or wherein any two adjacent groups R 1 , R 2 , R 3 and R 4 , taken together, form an alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety;
R 5 and R 6 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Q is an epoxycarbonyl moiety having the structure:
wherein R Q1 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, an oxygen protecting group or a prodrug moiety.
2. The compound of claim 1 , wherein the compound has the structure:
3. The compound of claim 1 , wherein R 5 is —CH 2 OR 5a and the compound has the structure:
wherein R 5a is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, an oxygen protecting group or a prodrug moiety.
4. The compound of claim 1 , wherein R 5 is aryl or heteroaryl and the compound has the structure:
wherein AR is an aryl or heteroaryl moiety.
5. The compound of claim 1 , wherein R 5 is —CH 2 NR 5a R b or heteroaryl and the compound has the structure:
wherein R 5a and R 5b are each independently hydrogen, a nitrogen protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or a prodrug, or R 5a and R 5b , taken together, form a heteroalicyclic or heteroaryl moiety.
6. The compound of claim 1 , wherein x, y and z are each 1, and A, J, and E are each CH 2 and D is CH.
7. The compound of claim 1 , wherein G is CH 2 and w is 0, 1, or 2.
8. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 ; D is CH; G is CH 2 and w is 0, 1, or 2.
9. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 and the compound has the structure:
wherein w is 0, 1 or 2; and R 1 , R 2 , R 3 and R 4 are each independently hydrogen, OR C , halogen, or NR C R D , wherein each occurrence of R C and R D is independently hydrogen or lower alkyl.
10. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 and the compound has the structure:
wherein AR is an aryl or heteroaryl moiety; w is 0, 1 or 2; and R 1 , R 2 , R 3 and R 4 are each independently hydrogen, OR C , halogen, or NR C R D , wherein each occurrence of R C and R D is independently hydrogen or lower alkyl.
11. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein R 5a and R 5b are each independently hydrogen, a nitrogen protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or a prodrug, or R 5a and R 5b , taken together, form a heteroalicyclic or heteroaryl moiety; w is 0, 1 or 2; and R 1 , R 2 , R 3 and R 4 are each independently hydrogen, OR C , halogen, or NR C R D , wherein each occurrence of R C and R D is independently hydrogen or lower alkyl.
12. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein w is 0, 1 or 2, each occurrence of R C is independently lower alkyl, and q is 0, 1, 2, 3 or 4.
13. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein AR is an aryl or heteroaryl moiety; w is 0, 1 or 2, each occurrence of R C is independently lower alkyl, and q is 0, 1, 2, 3 or 4.
14. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein R 5a and R 5b are each independently hydrogen, a nitrogen protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or a prodrug, or R 5a and R 5b , taken together, form a heteroalicyclic or heteroaryl moiety; w is 0, 1 or 2, each occurrence of R C is independently lower alkyl, and q is 0, 1, 2, 3 or 4.
15. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein w is 0, 1 or 2; and q is 0, 1, 2, 3 or 4.
16. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein AR is an aryl or heteroaryl moiety; w is 0, 1 or 2; and q is 0, 1, 2, 3 or 4.
17. The compound of claim 1 , wherein x, y and z are each 1; A, J, and E are each CH 2 , D is CH and the compound has the structure:
wherein R 5a and R 5b are each independently hydrogen, a nitrogen protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or a prodrug, or R 5a and R 5b , taken together, form a heteroalicyclic or heteroaryl moiety; w is 0, 1 or 2; and q is 0, 1, 2, 3 or 4.
18. The compound of any one of claims 1 , 2 , or 3 - 5 , wherein x, y and z are each 1 and A-J-D-E together represent —CH 2 —CH 2 —CH 2 —CH 2 —.
19. The compound of any one of claims 1 , 2 , 3 - 5 , wherein x is 0, y and z are each 1, and J-D-E together represent —CH 2 —CH 2 —CH 2 —.
20. The compound of any one of claims 1 , 2 , 3 - 5 , wherein x is 0, z is 0 and E is absent and J-D together represents —CH 2 —CH 2 —.
21. The compound of any one of claims 1 , 2 , 3 - 5 , wherein x, y and z are each 1 and A-J-D-E together represent —N═CH—CH═N—.
22. The compound of any one of claims 1 , 2 , 3 - 5 , wherein x, y and z are each 1 and A-J-D-E together represent —CH 2 —CH 2 —CH 2 —CH 2 — and G is CH 2 and w is 0, 1 or 2.
23. The compound of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, protected or unprotected hydroxyl, protected or unprotected thiol, protected or unprotected amino, alkyl, alkoxy, thioalkyl, mono-or di-substituted alkylamino, or wherein any two adjacent groups R 1 , R 2 , R 3 or R 4 , taken together are a cycloalkyl, heterocycloalkyl, aryl or heteroaryl moiety,
whereby each of the alkyl moieties is independently substituted or unsubstituted, linear or branched, cyclic or acyclic, and each of the aryl and heteroaryl moieties is independently substituted or unsubstituted.
24. The compound of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each independently hydrogen or lower alkoxy.
25. The compound of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each independently hydrogen or methoxy.
26. The compound of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are each methoxy.
27. The compound of claim 1 , wherein R 1 is hydrogen and each of R 2 , R 3 and R 4 are independently lower alkoxy.
28. The compound of claim 1 , wherein R 1 is hydrogen and each of R 2 , R 3 and R 4 are methoxy.
29. The compound of claim 1 , wherein R 5 is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, C 1-6 OR 5a , C 1-6 NR 5a R 5b , aryl or heteroaryl; wherein R 5a and R 5b are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, —C(NH 2 )═N(NO 2 ), —C(═O)OR 5c , —C(═O)R 5c or a protecting group; wherein R 5c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl.
30. The compound of any one of claim 1 , wherein R 5 is alkyl, cycloalkyl, —CH 2 OR 5a , —CH 2 NR 5a R 5b , —CH 2 aryl or —CH 2 heteroaryl; wherein R 5a and R 5b are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, —C(NH 2 )═N(NO 2 ), —C(═O)OR 5c , —C(═O)R 5c or a protecting group; wherein R 5c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl.
31. The compound of claim 1 , wherein R 5 is alkyl, cycloalkyl, CH 2 OR 5a , CH 2 NR 5a R 5b or substituted or unsubstituted —CH 2 Ph; wherein R 5a and R 5b are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, —C(NH 2 )═N(NO 2 ), —C(═O)OR 5c , —C(═O)R 5c or a protecting group; wherein R 5c is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl.
32. The compound of claim 1 , wherein R 5 is —CH 2 OH or benzyl.
33. The compound of claim 1 , wherein R 6 is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl or heteroaryl.
34. The compound of claim 1 , wherein R 6 is lower alkyl or aryl.
35. The compound of claim 1 , wherein R 6 is —CH 2 CH(CH 3 ) 2 .
36. The compound of claim 1 , 2 , 3 or 4 , wherein Q has the structure:
37. The compound of claim 36 , wherein Q has the structure:
38. A pharmaceutical composition comprising a compound of claim 1 ; and
a pharmaceutically acceptable carrier or diluent, and optionally further comprising an additional therapeutic agent.
39. The pharmaceutical of claim 38 wherein the compound is present in an amount effective to exert an antiproliferative and/or anticancer effect.
40. The pharmaceutical of claim 38 wherein the compound and the additional therapeutic agent are present in an amount effective to exert an antiproliferative and/or anticancer effect.
41. The pharmaceutical of claim 38 wherein the compound is present in an amount effective to exert an anti-inflammatory effect.
42. The pharmaceutical of claim 38 wherein the compound and the additional therapeutic agent are present in an amount effective to exert an anti-inflammatory effect.
43. A method for treating cancer comprising:
administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 ; and
optionally further administering an additional therapeutic agent.
44. The method of claim 43 , wherein the method is used to treat prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer or lymphoma, leukemia, or multiple myeloma.
45. The method of claim 43 , wherein the cancer is a solid tumor.
46. The compound of claim 2 , wherein Q is a moiety having the structure:
47. The compound of claim 46 , wherein Q is a moiety having the structure:
48. The compound of claim 46 , wherein Q is a moiety having the structure:
or pharmaceutically acceptable derivative thereof;
wherein each occurrence of J, D and G is independently CR A , CR A R B , C═O, O, S, NR A , or N, wherein each occurrence of R A and R B is independently hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety;
J and D, and D and G are each independently linked by a single or double bond as valency permits;
w is independently 0, 1, 2, 3, 4, 5 or 6,
R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, —CN, —OR C , —SR C , —NR C R D , —(C═O)R C or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, wherein each occurrence of R C and R D is independently hydrogen, a protecting group, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, or R C and R D , taken together, form a heteroalicyclic or heteroaryl moiety; or wherein any two adjacent groups R 1 , R 2 , R 3 and R 4 , taken together, form an alicyclic or heteroalicyclic moiety, or an aryl or heteroaryl moiety;
R 5 and R 6 are each independently an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety; and Q is an epoxycarbonyl moiety having the structure:
wherein R Q1 is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl or heteroaryl moiety, an oxygen protecting group or a prodrug moiety.
49. The compound of claim 48 , wherein J is CH 2 and D is CH.
50. The compound of claim 48 , wherein the compound is:
51. The compound of claim 1 , wherein the compound is selected from the group consisting of the following compounds:
52. The compound of claim 51 , wherein the compound is selected from the group consisting of the following compounds: