Low-calcemic oxime analogs of 1α,25-dihydroxy vitamin D3
View Patent ↗The present invention provides novel 16-ene-C25-oxime and 16-ene-C-25-oxime ether analogs of 1α,25-dihydroxy vitamin D 3 , compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the compound of Formula I are useful for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxy vitamin D 3 , for example, cell-proliferative disorders.
1. A compound of Formula I, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof:
wherein
R 1 and R 2 are independently selected from the group consisting of OH, OC 1-6 alkyl, and halo;
R 3 is C 1-6 alkyl;
R 4 is selected from the group consisting of H, C 1-6 alkyl, aryl and heteroaryl, with C 1-6 alkyl being unsubstituted or substituted 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), and with aryl and heteroaryl 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 5 is selected from the group consisting of C 1-6 alkyl, cyclo(C 3 -C 6 )alkyl, aryl and heteroaryl, aryl-C 1-6 alkyl and heteroaryl-C 1-6 alkyl, with C 1-6 alkyl being unsubstituted or substituted 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), and with cyclo(C 3 -C 6 )alkyl, aryl, heteroaryl, aryl-C 1-6 alkyl and heteroaryl-C 1-6 alkyl, 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 ; and
R 6 are either both H or together from ═CH 2 .
2. The compound according to claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of OH, OCH 3 , and fluoro.
3. The compound according to claim 2 , wherein R 1 and R 2 are both OH.
4. The compound according to claim 1 , wherein R 3 is CH 3 .
5. The compound according to claim 1 , wherein R 4 is selected from the group consisting of H, phenyl and C 1-4 alkyl.
6. The compound according to claim 5 , wherein R 4 is selected from the group consisting of H, phenyl, allyl and CH 3 .
7. The compound according to claim 1 , wherein R 5 is selected from the group consisting of isopropyl, s-butyl, t-butyl, and neopentyl.
8. The compound according to claim 7 , wherein R 5 is t-butyl.
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 , wherein both R 6 are H.
11. The compound according to claim 1 , having a relative stereochemistry as shown below:
12. The compound according to claim 1 that is selected from the group consisting of:
13. The compound according to claim 11 that is selected from the group consisting of compound I(a), I(c), I(e), I(g), I(i) and I(k).
14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
15. A method for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxy vitamin D 3 comprising administering an effective amount of a compound according to claim 1 to a cell or animal in need thereof.
16. A method for treating diseases which benefit from an inhibition of the catabolism of 1α,25-dihydroxy vitamin D 3 comprising administering an effective amount of a compound according to claim 1 to a cell or animal in need thereof.
17. The method according to claim 15 , wherein the disease is selected from the group consisting of breast cancer, lung cancer, prostate cancer, dermatological disorders and bone disorders.
18. The method according to claim 17 , wherein the disease is selected from the group consisting of breast cancer, lung cancer, prostate cancer, psoriasis and osteoporosis.
19. A method for inhibiting cell proliferation comprising administering an effective amount of a compound according to claim 1 to a cell or animal in need thereof.
20. The method according to claim 19 , wherein the cell is a cancer cell.
21. The method according to claim 20 , wherein the cancer is selected from breast cancer, lung cancer and prostate cancer.
22. A method of inhibiting CYP24 activity in a cell by administering an effective amount of a compound according to claim 1 .
23. A method to modulate the levels of 1α,25-dihydroxy vitamin D 3 in an animal by administering a compound according to claim 1 to an animal in need thereof.
24. A method to inhibit the catabolism of 1α,25-dihydroxy vitamin D 3 in an animal by administering a compound according to claim 1 to an animal in need thereof.
25. A method to modulate the levels of 1α,25-dihydroxy vitamin D 3 in an animal by administering a pharmaceutical composition comprising a compound according to claim 1 to an animal in need thereof.
26. A method to inhibit the catabolism of 1α,25-dihydroxy vitamin D 3 in an animal by administering a pharmaceutical composition comprising a compound according to claim 1 to an animal in need thereof.
27. A method to inhibit cell proliferation in an animal by administering a compound according to claim 1 to an animal in need thereof.
28. A method to inhibit cell proliferation in an animal by administering a pharmaceutical composition comprising a compound according to claim 1 to an animal in need thereof.
29. A method to inhibit CYP24 activity in an animal by administering a compound according to claim 1 to an animal in need thereof.
30. A method to inhibit CYP24 activity in an animal by administering a pharmaceutical composition comprising a compound according to claim 1 to an animal in need thereof.
31. A method for increasing the efficacy of a vitamin D receptor agonist comprising co-administering an effective amount of a compound according to claim 1 and an effective amount of the vitamin D receptor agonist.
32. The method according to claim 21 , wherein the vitamin D receptor agonist is 1α,25-dihydroxy vitamin D 3 (calcitriol).
33. A method to increase the efficacy of a vitamin D receptor agonist in an animal by administering a compound according to claim 1 to an animal in need thereof.
34. A method to increase the efficacy of a vitamin D receptor agonist in an animal by administering a pharmaceutical composition comprising a compound according to claim 1 to an animal in need thereof.
35. The method according to claim 33 , wherein the vitamin D receptor agonist is 1α,25-dihydroxy vitamin D 3 (calcitriol).
36. The method according to claim 34 , wherein the vitamin D receptor agonist is 1α,25-dihydroxy vitamin D 3 (calcitriol).
37. A method for preparing a compound of Formula I comprising reacting a compound of Formula II or salts, hydrates or solvates thereof
with a compound of Formula III, or a salt, hydrate or solvate thereof:
NH 2 —OR 4 III
wherein
R 1 and R 2 are independently selected from the group consisting of OH, OC 1-6 alkyl, OPG and halo; PG is a protecting group; R 3 in C 1-6 alkyl;
wherein R 4 is selected from the group consisting of H, C 1-6 alkyl, aryl and heteroaryl, with C 1-6 alkyl being unsubstituted or substituted 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) and with aryl and heteroaryl 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 5 is selected from the group consisting of C 1-6 alkyl, cyclo(C 3 -C 6 )alkyl, aryl and heteroaryl, aryl-C 1-6 alkyl and heteroaryl-C 1-6 alkyl, with C 1-6 alkyl being unsubstituted or substituted 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), and with cyclo (C 3 -C 6 )alkyl, aryl, heteroaryl, aryl-C 1-6 alkyl and heteroaryl-C 1-6 alkyl, 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 7 , 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 ; and
R 6 are either both H or together form ═CH 2 , in the presence of a non-nucleophilic amine; and removal of any protecting groups, if present.
38. The method according to claim 37 , wherein the amine is pyridine.
39. The compound, according to claim 1 wherein the compound is:
40. The compound, according to claim 1 wherein the compound is:
41. The compound according to claim 1 wherein the compound is:
42. The method according to claim 15 , wherein the disease is selected from the group consisting of hyperparathyroidism, hypoparathyroidism, Pseudohypoparathyroidism, secondary hyperparathyroidism, diabetes, medullary carcinoma, psoriasis, wound healing, sarcoidosis, tuberculosis, chronic renal disease, hypophosphatemic VDRR, vitamin D dependent rickets, convulsion, fibrogenisis imperfecta ossium, osteitits fibrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy and rickets.