24-Sulfur-substituted analogs of 1α,25-dihydroxy vitamin D
View Patent ↗The present invention provides novel C24-sulfone analogs of 1α,25-dihydroxy vitamin D 3 , compositions comprising these compounds and methods of using these compounds as selective 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 and R 2 are independently selected from the group consisting of OH, OC 1-4 alkyl, and halo;
R 3 is C 1-4 alkyl;
R 4 is selected from the group consisting of aryl and heteroaryl with both aryl and heteroaryl being unsubstituted or substituted with 1–5 groups independently selected from C 1-4 alkyl, hydroxy-substituted C 1-6 alkyl, OC 1-4 alkyl, OH, CF 3 , OCF 3 , halo, SH, SC 1-4 alkyl, NH 2 , nitro, 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, CH═N—OC 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 are either both H or together form ═CH 2 ;
R 6 and R 7 are both H or are taken together to form a C 3-6 cyloalkyl ring;
x is 0–2; and
represents a single or a double bond.
2. The compound according to claim 1 , wherein R 1 and R 2 are independently selected from the group consisting 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 unsubstituted and substituted phenyl, pyridyl, thienyl, furanyl and pyrrolo.
6. The compound according to claim 5 , wherein R 4 is selected from unsubstituted or substituted phenyl.
7. The compound according to claim 1 , wherein both aryl and heteroaryl are either unsubstituted or substituted with 1–3 groups independently selected from C 1-4 alkyl, hydroxy-substituted C 1-6 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, CH═N—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 .
8. The compound according to claim 7 , wherein both aryl and heteroaryl are either unsubstituted or substituted with 1–2 groups independently selected from methyl, 3-hydroxy-3-pentyl, methoxy, OH, CF 3 , OCF 3 , halo, NH 2 , NMe 2 and CH═N—OMe.
9. The compound according to claim 8 , wherein both aryl and heteroaryl are either unsubstituted or substituted with 1–2 groups independently selected from methyl, 3-hydroxy-3-pentyl, Cl, F and CH═N—OMe.
10. The compound according to claim 6 , wherein R 4 is selected from the group consisting of phenyl, 4-chlorophenyl, 3,4-dichloropheny, 4-fluorophenyl, 4-methylphenyl, 3,4-difluorophenyl, 4-(3-hydroxy-3-pentyl)phenyl, 4-(CH═N—OMe)phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl and 4-nitrophenyl.
11. The compound according to claim 10 , wherein R 4 is selected from the group consisting of 4-chlorophenyl, 3,4-dichloropheny, 4-(3-hydroxy-3-pentyl)phenyl, 4-fluorophenyl and 4-methylphenyl.
12. The compound according to claim 1 , wherein R 6 and R 7 are both H or are taken together to form a C 3-4 cyloalkyl ring.
13. The compound according to claim 1 , wherein x is 2.
14. The compound according to claim 1 , wherein represents a single bond.
15. 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 1-4 alkyl, and halo;
R 3 is C 1-4 alkyl;
R 4 is selected from the group consisting of aryl and heteroaryl with both aryl and heteroaryl being unsubstituted or substituted with 1–5 groups independently selected from C 1-4 alkyl, hydroxy-substituted C 1-6 alkyl, OC 1-4 alkyl; OH, OCF 3 , halo, SH, SC 1-4 alkyl, NH 2 , nitro, 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 are either both H or together form ═CH 2 ;
R 6 and R 7 are both H or are taken together to form a C 3-6 cyloalkyl ring;
x is 0–2; and
represents a single or a double bond.
16. 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 1-4 alkyl, and halo;
R 3 is C 1-4 alkyl;
R 4 is selected from the group consisting of aryl and heteroaryl with both aryl and heteroaryl being unsubstituted or substituted with 1–5 groups independently selected from C 1-4 alkyl, hydroxy-substituted C 1-6 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, CH═N—OC 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 are either both H or together form ═CH 2 ;
x is 0–2; and
represents a single or a double bond.
17. The compound according to claim 1 selected from the group consisting of:
and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof.
18. The compound according to claim 17 , selected from the group consisting of I(a), I(e), I(g), I(i), I(m), I(o), I(q), I(u), J(cc), I(ee), I(jj), I(ll), I(nn) and I(oo).
19. The compound according to claim 17 , selected from the group consisting of I(a), I(e), I(g), I(i), I(u), I(cc), I(ee), I(jj), I(nn) and I(oo).
20. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.