Compositions and methods of treating cell proliferation disorders
The invention relates to compounds and methods for treating cell proliferation disorders.
1. A method of lessening a disease or disorder that is modulated by tyrosine kinase inhibition selected from the group consisting of: diabetic retinopathy, macular degeneration, psoriasis, solid tumors, lung cancer, breast cancer, colon cancer, ovarian cancer, brain cancer, liver cancer, pancreatic cancer, prostate cancer, malignant melanoma, non-melanoma skin cancer, hematologic tumors, childhood leukemia, lymphoma, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic or cutaneous origin, acute or chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm, epidermic or dermoid cysts, lipomas, adenomas, capillary or cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, dysplastic masses, and dysplasias, wherein the lessening results in the improvement of the disease or disorder;
comprising administering a pharmaceutical composition comprising a compound according to Formula I:
or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof, wherein:
T is a bond;
X y is CY, N, or N—O;
X z is CZ;
Y is hydrogen, hydroxyl, halogen, lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, or O-benzyl;
X a is CR a , N, or N—O;
X b is CR b , N, or N—O;
X c is CR c , N, or N—O;
X d is CR d , N, or N—O;
X e is CR e , N, or N—O;
R a , R b , R c , R d , R e , R 4 , R 5 , and R 6 are, independently, hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, COOH, COO-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, SO 2 -lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl;
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —;
R 7 , R 8 , R 9 , R 10 , and R 11 are, independently, hydrogen, hydroxyl, halogen, unsubstituted C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, unsubstituted C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, unsubstituted C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O—C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl,
R 1 , R 2 , and R 3 are independently H or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl;
n is 1 or 2; and
m is 1,
wherein at least one of X a , X b , X c , X d , and X e is N; provided that when X a is N, X e is not N.
2. The method of claim 1 , wherein X y is CY.
3. The method of claim 1 , wherein Y is hydrogen.
4. The method of claim 1 , wherein Z is
5. The method of claim 1 , wherein R b is C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy.
6. The method of claim 1 , wherein R b is
wherein W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl; and V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —.
7. The method of claim 6 , wherein V is a bond.
8. The method of claim 1 , wherein X a is N, X b is CR b , X e is CR c , X d is CR a and X e is CR e .
9. The method of claim 1 , wherein said compound is a pharmaceutically acceptable salt.
10. The method of claim 1 , wherein said compound is selected from the group consisting of
11. The method of claim 1 , wherein said compound has the formula:
or a pharmaceutically acceptable salt, tautomer or prodrug thereof.
12. The method of claim 1 , wherein said compound has the formula:
13. A method of lessening a disease or disorder that is modulated by tyrosine kinase inhibition selected from the group consisting of: diabetic retinopathy, macular degeneration, psoriasis, solid tumors, lung cancer, breast cancer, colon cancer, ovarian cancer, brain cancer, liver cancer, pancreatic cancer, prostate cancer, malignant melanoma, non-melanoma skin cancer, hematologic tumors, childhood leukemia, lymphoma, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic or cutaneous origin, acute or chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm, epidermic or dermoid cysts, lipomas, adenomas, capillary or cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, dysplastic masses, and dysplasias, wherein the lessening results in the improvement of the disease or disorder;
comprising administering a pharmaceutical composition comprising a compound that is
or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
14. A method of lessening a disease or disorder that is modulated by tyrosine kinase inhibition selected from the group consisting of: diabetic retinopathy, macular degeneration, psoriasis, solid tumors, lung cancer, breast cancer, colon cancer, ovarian cancer, brain cancer, liver cancer, pancreatic cancer, prostate cancer, malignant melanoma, non-melanoma skin cancer, hematologic tumors, childhood leukemia, lymphoma, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic or cutaneous origin, acute or chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm, epidermic or dermoid cysts, lipomas, adenomas, capillary or cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, dysplastic masses, and dysplasias, wherein the lessening results in the improvement of the disease or disorder;
comprising administering a pharmaceutical composition comprising a compound according to Formula II:
or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof, wherein:
R b , R 4 , R 5 , R 8 , and R 10 are, independently, hydrogen, hydroxyl, halogen, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkoxy, O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl-aryl, O-benzyl, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-OH, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-O-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, COOH, COO-lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl, SO 2 H, or SO 2 -lower (C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 ) alkyl,
W is H, C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl, or C 1 , C 2 , C 3 , C 4 , C 5 , or C 6 alkyl-aryl; and
V is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —O—CH 2 —, —OCH 2 CH 2 —, or —OCH 2 CH 2 CH 2 —.
15. A method of lessening a disease or disorder that is modulated by tyrosine kinase inhibition selected from the group consisting of: diabetic retinopathy, macular degeneration, psoriasis, solid tumors, lung cancer, breast cancer, colon cancer, ovarian cancer, brain cancer, liver cancer, pancreatic cancer, prostate cancer, malignant melanoma, non-melanoma skin cancer, hematologic tumors, childhood leukemia, lymphoma, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic or cutaneous origin, acute or chronic leukemia, acute lymphoblastic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm, epidermic or dermoid cysts, lipomas, adenomas, capillary or cutaneous hemangiomas, lymphangiomas, nevi lesions, teratomas, nephromas, myofibromatosis, osteoplastic tumors, dysplastic masses, and dysplasias, wherein the lessening results in the improvement of the disease or disorder;
comprising administering a pharmaceutical composition comprising a compound selected from the group consisting of
or a pharmaceutically acceptable salt, tautomer, or prodrug thereof, and at least one pharmaceutically acceptable excipient to a subject in need thereof.
16. The method of claim 1 , wherein the disease or disorder that is modulated by tyrosine kinase inhibition is psoriasis.
17. The method of claim 13 , wherein the disease or disorder that is modulated by tyrosine kinase inhibition is psoriasis.
18. The method of claim 14 , wherein the disease or disorder that is modulated by tyrosine kinase inhibition is psoriasis.
19. The method of claim 15 , wherein the disease or disorder that is modulated by tyrosine kinase inhibition is psoriasis.