Compounds and method for treatment of cancer
The present invention is directed to methods of use of a compound of Formula I: and/or a pharmaceutically-acceptable salt, hydrate, solvate, tautomer, optical isomer, or combination thereof, a composition comprising the thiosemicarbazone, a method of administration thereof, and use thereof to treat a cancer.
1. A compound of Formula I or IA:
a pharmaceutically-acceptable salt, tautomer, optical isomer, and/or combination thereof;
wherein:
R 1 and R 2 together form a substituted or unsubstituted polycyclic ring comprising at least two ring systems, said at least two ring systems comprising a first ring system bonded to C1 and a second ring system fused to the first ring system, wherein:
the first ring system is a substituted or unsubstituted aromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or
the first ring system is a substituted or unsubstituted heteroaromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or
the first ring system is a substituted or unsubstituted saturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted unsaturated carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom; or
the first ring system is a substituted or unsubstituted unsaturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom; or
the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and
R 3 to R 11 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic;
R 12 is selected from H or a hydrocarbyl group;
Y is a heteroatom;
Ring is selected from a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, wherein the nitrogen in the Ring is bonded to A;
A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; and
n is 0 or 1,
when n is 1 and the Ring is selected from a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic.
2. The compound according to claim 1 , wherein the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group.
3. The compound according to claim 1 , wherein the first ring system is a substituted or unsubstituted unsaturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group; or a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom.
4. The compound according to claim 1 , wherein the first ring system is a substituted or unsubstituted carbocyclic group and the second ring system is a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom.
5. The compound according to claim 3 , wherein X 1 is N and X 2 to X 6 is carbon.
6. The compound according to claim 4 , wherein X 1 is N and X 2 to X 6 is carbon.
7. The compound according to claim 5 , wherein the ring B is fused to the first ring system at X 2 and X 3 .
8. The compound according to claim 6 , wherein the ring B is fused to the first ring system at X 2 and X 3 .
9. The compound according to claim 1 , wherein the first ring is a five-membered ring.
10. The compound according to claim 1 , wherein the first ring is a six-membered ring.
11. The compound according to claim 1 , wherein the substituted or unsubstituted polycyclic ring further comprises a third ring system fused to the first ring system.
12. The compound according to claim 11 , wherein the third ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group.
13. The compound according to claim 12 , wherein the third ring system is a substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterocyclic group.
14. The compound according to claim 1 , wherein n is 0.
15. The compound according to claim 1 , wherein n is 1 and A is a substituted or unsubstituted heteroaromatic group.
16. The compound according to claim 15 , wherein A is a pyridinyl group.
17. The compound according to claim 1 , wherein Y is a nitrogen atom.
18. The compound according to claim 17 , wherein R 7 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted heteroaromatic group and R 3 to R 6 and R 8 to R 12 are each independently selected from H or a substituted or unsubstituted hydrocarbon group.
19. The compound according to claim 17 , wherein R 7 is the substituted or unsubstituted alkyl group or a substituted or unsubstituted pyridyl group and R 3 to R 6 and R 8 to R 12 are each H.
20. The compound according to claim 1 , wherein the compound penetrates the blood brain barrier of a mammal.
21. The compound according to claim 1 , wherein at least about 50% of the compound is orally absorbed by a mammal.
22. The compound according to claim 1 , wherein the compound has an IC 50 for a cancer cell population of less than about 1000 nM.
23. The compound according to claim 1 for treatment of a cancer.
24. The compound according to claim 23 , wherein the cancer is selected from lung cancer, cervical cancer, ovarian cancer, cancer of CNS, skin cancer, prostate cancer, sarcoma, breast cancer, leukemia, colorectal cancer, head cancer, neck cancer or kidney cancer.
25. The compound according to claim 23 , wherein the cancer is selected from small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain cancer.
26. The compound according to claim 23 , wherein the cancer is a carcinoma.
27. The compound according to claim 26 , wherein the carcinoma is selected from small cell carcinomas, cervical carcinomas, glioma, astrocytoma, prostate carcinomas, ovarian carcinomas, melanoma, breast carcinomas, or colorectal carcinomas.
28. The compound according to claim 26 , wherein the carcinoma is small cell lung carcinoma.
29. A pharmaceutical composition comprising the compound according to claim 1 and at least one pharmaceutically acceptable carrier and/or diluent.
30. A pharmaceutical composition comprising an anti-cancer agent and the compound according to claim 1 .
31. A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formula I or IA:
a pharmaceutically-acceptable salt, tautomer, optical isomer, and/or combination thereof;
wherein:
R 1 and R 2 together form a substituted or unsubstituted polycyclic ring comprising at least two ring systems, said at least two ring systems comprising a first ring system bonded to C1 and a second ring system fused to the first ring system, wherein:
the first ring system is a substituted or unsubstituted aromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or
the first ring system is a substituted or unsubstituted heteroaromatic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; or
the first ring system is a substituted or unsubstituted saturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted unsaturated carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom; or
the first ring system is a substituted or unsubstituted unsaturated carbocyclic group, the second ring system is a substituted or unsubstituted aromatic group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted ring B:
wherein X 1 to X 6 are each independently selected from carbon or a heteroatom; or
the first ring system is a substituted or unsubstituted heterocyclic group, the second ring system is a substituted or unsubstituted heteroaromatic group, a substituted or unsubstituted carbocyclic group, or a substituted or unsubstituted heterocyclic group; and
R 3 to R 11 are each independently selected from H, a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic;
R 12 is selected from H or a hydrocarbyl group;
Y is a heteroatom;
Ring is selected from a substituted or unsubstituted thiomorpholinyl group, a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, wherein the nitrogen in the Ring is bonded to A;
A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted heterogeneous group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic; and
n is 0 or 1,
when n is 1 and the Ring is selected from a substituted or unsubstituted morpholinyl group, or a substituted or unsubstituted piperidinyl group, A is selected from a substituted or unsubstituted hydrocarbon group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic, wherein the cancer is selected from small cell lung cancer, non-small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain cancer.
32. The method according to claim 31 , wherein the compound is co-administered with radiation therapy.
33. A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the composition according to claim 29 , wherein the cancer is selected from small cell lung cancer, non-small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain cancer.
34. A method for treating a cancer in a mammal, comprising administering to the mammal a therapeutically effective amount of the composition according to claim 30 , wherein the cancer is selected from small cell lung cancer, non-small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain cancer.
35. The method according to claim 33 , wherein the composition is co-administered with radiation therapy.
36. The method according to claim 31 , wherein the mammal is a human.
37. The method according to claim 31 , wherein the compound inhibits development of a drug resistant form of the cancer.
38. The method according to claim 31 , wherein the cancer is a carcinoma.
39. The method according to claim 38 , wherein the carcinoma is selected from small cell lung carcinomas, breast carcinomas, or colorectal carcinomas.
40. The method according to claim 39 , wherein the carcinoma is small cell lung carcinoma.
41. The method according to claim 31 , wherein the compound is administered orally and/or parenterally.
42. A method for preparing the compound of claim 1 , the method comprising:
a) reacting a compound of Formula II:
to form an intermediate of Formula III:
b) reacting the Intermediate of Formula III with R 12 NHNH 2 to form an Intermediate of Formula IV:
c) reacting the Intermediate of Formula IV with a ketone:
under condensation conditions, to form the compound of Formula I.
43. The method according to claim 42 , wherein n is 0.
44. The method according to claim 31 , wherein A is a substituted or unsubstituted heteroaromatic group.