24-sulfoximine vitamin D
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 method for treating diseases which benefit from an inhibition of the catabolism of 1α,25-dihydroxy vitamin D 3 , or analogs thereof, said disease 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 to a cell or animal in need thereof, an effective amount of a compound selected from a compound of Formula I, and pharmaceutically acceptable salts 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 a compound of Formula I.
2. The method according to claim 1 , wherein the disease is selected from the group consisting of psoriasis, hyperparathyroidism, secondary hyperparathyroidism and osteoporosis.
3. The method according to claim 1 , wherein the disease is selected from breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, Kaposi's sarcoma and leukemia.
4. The method according to claim 1 , wherein the compound of formula I has the following relative stereochemistry:
5. The method according to claim 1 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts and prodrugs thereof.
6. The method according to claim 5 , wherein the compound of Formula I is 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), I(q) and pharmaceutically acceptable salts and prodrugs thereof.
7. The method according to claim 6 , wherein the compound of Formula I is selected from the group consisting of I(a), I(c), I(e), I(g), I(i), I(j), I(l), I(n) I(o), I(p) and pharmaceutically acceptable salts and prodrugs thereof.
8. A method for increasing the efficacy of a vitamin D receptor agonist comprising co-administering, to an animal or cell in need thereof, an effective amount of a vitamin D receptor agonist and an effective amount of a compound selected from a compound of Formula I, and pharmaceutically acceptable salts 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 a compound of Formula I.
9. The method according to claim 8 , wherein the vitamin D receptor agonist is 1α,25-dihydroxy vitamin D 3 (calcitriol), or an analog thereof.
10. A method for treating a disease 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: co-administering, to an animal or cell in need thereof, an effective amount of a vitamin D receptor agonist and an effective amount of a compound selected from a compound of Formula I and pharmaceutically acceptable salts 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 a compound of Formula I.
11. The method according to claim 10 , wherein the disease is selected from the group consisting of psoriasis, hyperparathyroidism, secondary hyperparathyroidism and osteoporosis.
12. The method according to claim 10 , 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 and leukemia.
13. The method according to claim 8 , wherein the compound of formula I has the following relative stereochemistry:
14. The method according to claim 8 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts and prodrugs thereof.
15. The method according to claim 14 , wherein the compound of Formula I is 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), I(q) and pharmaceutically acceptable salts and prodrugs thereof.
16. The method according to claim 15 , wherein the compound of Formula I is selected from the group consisting of I(a), I(c), I(e), I(g), I(i), I(j), I(l), I(n) I(o), I(p) and pharmaceutically acceptable salts and prodrugs thereof.
17. A method of treating a disease 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 to an animal or cell in need thereof and in combination with one or more therapies or therapeutics to treat said disease, a compound selected from a compound of Formula I, and pharmaceutically acceptable salts 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 a compound of Formula I.
18. The method according to claim 17 , wherein the one or more therapies or therapeutics to treat said breast cancer, lung cancer, prostate cancer, colon cancer, colorectal cancer, kidney cancer, head and neck cancer, pancreatic cancer, cancer are selected from the group consisting of surgery, radiation, chemotherapy and biotherapy.
19. The method according to claim 17 , wherein psoriasis is treated.
20. The method according to claim 19 , wherein the one or more therapies or therapeutics to treat psoriasis are selected from the group consisting of ultraviolet B radiation, chemotherapy and biotherapy.
21. The method according to claim 17 , wherein the compound of formula I has the following relative stereochemistry:
22. The method according to claim 17 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts and prodrugs thereof.
23. The method according to claim 22 , wherein the compound of Formula I is 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), I(q) and pharmaceutically acceptable salts and prodrugs thereof.
24. The method according to claim 23 , wherein the compound of Formula I is selected from the group consisting of I(a), I(c), I(e), I(g), I(i), I(j), I(l), I(n) I(o), I(p) and pharmaceutically acceptable salts and prodrugs thereof.
25. The method according to claim 10 , wherein the compound of formula I has the following relative stereochemistry:
26. The method according to claim 10 , wherein the compound of formula I is selected from the group consisting of:
and pharmaceutically acceptable salts and prodrugs thereof.