24-sulfoximine vitamin D3 compounds
View Patent ↗The present invention provides novel sulfoximine compounds, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the compounds of the invention 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 is selected from the group consisting of OH, OC 1-4 alkyl, and halo;
R 2 is selected from the group consisting of H, OH, OC 1-4 alkyl, and halo;
each R 3 are either both H or together form ═CH 2 ;
R 4 is C 1-4 alkyl;
represents a single or a double bond;
each R 5 can be the same or different and is selected from the group consisting of hydrogen, halo and C 1-4 alkyl or each R 5 can be taken together to form a C 3-6 cycloalkyl ring;
R 6 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1–5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo;
R 7 is selected from the group consisting of H, C 1-6 alkyl and C(O)R 8 ; and
R 8 is selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, aryl-C 1-4 alkyl, aryl and heteroaryl, wherein each of C 1-6 alkyl, C 3-6 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1–5 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo,
provided that when there is a double bond between C22 and C23, there is only one R 5 group attached to C23 and R 5 is selected from the group consisting of hydrogen, halo and C 1-4 alkyl, wherein the prodrug is a phenyl ester, aliphatic (C 8–C 24 ) ester, acyloxymethyl ester, carbamate or amino acid ester formed from an available hydroxy, thiol, amino or carboxy group of said compound of Formula I.
2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of OH, OCH 3 and fluoro.
3. The compound according to claim 2 , wherein R 1 is OH.
4. The compound according to claim 1 , wherein R 2 is selected from the group consisting of H, OH, OCH 3 and fluoro.
5. The compound according to claim 4 , wherein R 2 is selected from the group consisting of H, OH and fluoro.
6. The compound according to claim 5 , wherein R 2 is selected from the group consisting of H and OH.
7. The compound according to claim 1 , wherein R 1 and R 2 are both OH.
8. The compound according to claim 1 , wherein each R 3 together form ═CH 2 .
9. The compound according to claim 1 , wherein each R 3 is H.
10. The compound according to claim 1 , wherein R 4 is CH 3 .
11. The compound according to claim 1 , wherein each R 5 is selected from the group consisting of F, C 1-4 alkyl and H or are taken together to form a C 3-5 cycloalkyl ring.
12. The compound according to claim 11 , wherein each R 5 is selected from the group consisting of F, CH 3 and H or are taken together to form a C 3-4 cycloalkyl ring.
13. The compound according to claim 12 , wherein both of R 5 are CH 3 , F or H or are taken together to form a cyclopropyl ring.
14. The compound according to claim 13 , wherein each R 5 is H.
15. The compound according to claim 13 , wherein each R 5 are taken together to form a cyclopropyl ring.
16. The compound according to claim 1 , wherein R 6 is selected from the group consisting of C 1-4 alkyl, C 3 scycloalkyl, aryl and heteroaryl, wherein each of C 1-4 alkyl, C 3-5 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1–3 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo.
17. The compound according to claim 16 , wherein R 6 is selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, aryl and heteroaryl, wherein each of C 1-4 alkyl, C 3-5 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1–2 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo.
18. The compound according to claim 17 , wherein R 6 is selected from the group consisting of C 1-4 alkyl and aryl, wherein aryl is either unsubstituted or substituted with 1–2 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo.
19. The compound according to claim 18 , wherein R 6 is selected from the group consisting of C 1-4 alkyl and phenyl, wherein phenyl is either unsubstituted or substituted with 1–2 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo.
20. The compound according to claim 19 , wherein R 6 is a phenyl group either unsubstituted or substituted with 1–2 substituents independently selected from the group consisting of CH 3 , OCH 3 , NO 2 , F and Cl.
21. The compound according to claim 20 , wherein R 6 is an unsubstituted phenyl or phenyl substituted with 1 substituent independently selected from the group consisting of CH 3 , OCH 3 , NO 2 , F and Cl.
22. The compound according to claim 19 , wherein R 6 is t-butyl.
23. The compound according to claim 1 , wherein R 7 is selected from the group consisting of C 1-4 alkyl and H.
24. The compound according to claim 23 , wherein R 7 is selected from CH 3 or H.
25. The compound according to claim 1 , wherein R 7 is C(O)R 8 .
26. The compound according to claim 25 , wherein R 8 is selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, aryl-C 1-2 alkyl, aryl and heteroaryl, wherein each of C 1-4 alkyl, C 3-5 cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1–3 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 and halo.
27. The compound according to claim 26 , wherein R 8 is selected from the group consisting of C 1-4 alkyl, C 3-5 cycloalkyl, PhCH 2 and phenyl, wherein each of C 1-4 alkyl, C 3-5 cycloalkyl, PhCH 2 and phenyl are either unsubstituted or substituted with 1–2 substituents independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , F and Cl.
28. The compound according to claim 26 , wherein R 8 is selected from the group consisting of C 1-4 alkyl, PhCH 2 and phenyl, wherein each of C 1-4 alkyl, PhCH 2 and phenyl are either unsubstituted or substituted with 1 substituent independently selected from the group consisting of C 1-4 alkyl, OC 1-4 alkyl, CF 3 , NO 2 , F and Cl.
29. The compound according to claim 1 , wherein R 6 is C 1-6 alkyl and between C16 and C17 is a double bond.
30. The compound according to claim 1 , wherein between C22–C23 represents a single bond.
31. The compound according to claim 1 , wherein between C16–C17 represents a single bond.
32. The compound according to claim 1 , wherein both represents a single bond.
33. The compound according to claim 1 , having the following relative stereochemistry:
34. The compound according to claim 31 , having the following relative stereochemistry:
35. The compound according to claim 1 , having the following relative stereochemistry:
36. The compound according to claim 1 that is selected from the group consisting of:
37. The compound according to claim 36 , selected from the group consisting of I(a); I(c); I(e); I(g); I(i); I(j); I(l); I(m); I(n); I(o); I(p) and I(q).
38. The compound according to claim 37 , selected from the group consisting of I(a), I(c), I(e), I(g), I(i), I(j), I(l), I(n) I(o) and I(p).
39. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.