Low-calcemic 16,23-diene 25-oxime analogs of 1α,25-dihydroxy vitamin D
The present invention provides novel 16,23-diene 25-oxime ether analogs of 1,25-dihydroxy vitamin D3, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the novel compound of the invention are useful for treating diseases which benefit from a modulation of the levels of 1,25-dihydroxy vitamin D3, for example, cell-proliferative disorders.
1. A compound selected from a compound of Formula 1, and pharmaceutically acceptable salts thereof:
wherein
R 1 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, cyclo(C 3 -C 6 )alkyl and cyclo(C 3 -C 6 )alkenyl, with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with one or more halo groups or with 1-4 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, NH 2 , NHC 1-4 alkyl and N(C 1-4 alkyl)(C 1-4 alkyl), and with cyclo(C 3 -C 6 )alkyl and cyclo(C 3 -C 6 )alkenyl being unsubstituted or substituted with 1-5 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl)(C 1-4 alkyl), CN, C(O)OH, C(O)OC 1-4 alkyl, C(O)NHC 1-4 alkyl, NHC(O)C 1-4 alkyl, OC(O)C 1-4 alkyl, SOC 1-4 alkyl, SO 2 C 1-4 alkyl, SO 2 NHC 1-4 alkyl and SO 2 NH 2 ;
R 2 is selected from the group consisting of H, C 1-6 alkyl and C 2-6 alkenyl, with C 1-6 alkyl and C 2-6 alkenyl being unsubstituted or substituted with one or more halo groups or with 1-4 groups independently selected from C 1-4 alkyl, OC 1-4 alkyl, OH, halo, NH 2 , NHC 1-4 alkyl and N(C 1-4 alkyl)(C 1-4 alkyl);
R 3 is selected from the group consisting of OH, OC 1-6 alkyl, and halo; and
R 4 are either both H or together form ═CH 2 .
2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of CF 3 , C(CF 3 ) 3 , cyclopropyl and t-butyl.
3. The compound according to claim 2 , wherein R 1 is t-butyl.
4. The compound according to claim 1 , wherein R 2 is selected from the group consisting of CH 3 , ethyl and allyl.
5. The compound according to claim 4 , wherein R 2 is CH 3 .
6. The compound according to claim 1 , wherein R 3 is selected from the group consisting of OH and fluoro.
7. The compound according to claim 6 , wherein R 3 is OH.
8. The compound according to claim 1 , wherein R 4 together form CH 2 .
9. The compound according to claim 1 , wherein the geometry about the C═N double bond of the oxime is trans.
10. The compound according to claim 1 having the following relative stereochemistry:
11. The compound according to claim 10 , wherein the stereochemistry at C-20 is R.
12. The compound according to claim 1 that is selected from the group consisting of:
13. The compound according to claim 11 , wherein the oxime double bond is in the E configuration.
14. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier.
15. A method of treating a disease which benefits from an inhibition of the catabolism of 1α,25-dihydroxyvitamin D 3 , wherein the disease is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, Kaposi's sarcoma, leukemia, psoriasis, hyperparathyroidism, secondary hyperparathyroidism, and osteoporosis, comprising administering an effective amount of a compound as defined in claim 1 to a cell or animal in need thereof.
16. The method according to claim 15 , wherein the disease is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, Kaposi's sarcoma, leukemia.
17. A method for increasing the efficacy of a vitamin D receptor agonist which is a CYP24 substrate, comprising contemporaneously administering an effective amount of a compound according to claim 1 and an effective amount of the vitamin D receptor agonist to a cell or animal in need thereof.
18. The method according to claim 17 , wherein the vitamin D receptor agonist is 1α,25-dihydroxyvitamin D 3 .
19. The method according to claim 17 , used to treat a disease selected from one or more of breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, Kaposi's sarcoma, leukemia, psoriasis, hyperparathyroidism, secondary hyperparathyroidism and osteoporosis.
20. The method according to claim 19 , wherein the disease is selected from the group consisting of breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, Kaposi's sarcoma, leukemia, psoriasis, hyperparathyroidism, secondary hyperparathyroidism and osteoporosis.
21. The method of claim 17 , wherein the compound of claim 1 is
22. The compound, of claim 12 which is
23. The pharmaceutical composition of claim 14 wherein the compound of claim 1 is