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Details for Patent: 7,183,298

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Details for Patent: 7,183,298

Title:Carbamic acid compounds comprising a sulfonamide linkage as HDAC inhibitors
Abstract: This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the following formula: (I) A is an aryl group; Q.sup.1 is a covalent bond or an aryl leader group; J is a sulfonamide linkage selected from: --S(.dbd.O).sub.2NR.sup.1-- and --NR.sup.1S(.dbd.O).sub.2--; R.sup.1 is a sulfonamido substituent; and, Q.sup.2 is an acid leader group; with the proviso that if J is --S(.dbd.O).sub.2NR.sup.1--, then Q.sup.1 is an aryl leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.
Inventor(s): Watkins; Clare J (Abingdon, GB), Romero-Martin; Maria Rosario (Didcot, GB), Moore; Kathryn G (Abingdon, GB), Ritchie; James (Abingdon, GB), Finn; Paul W (Abingdon, GB), Kalvinsh; Ivars (Riga, LV), Loza; Einars (Riga, LV), Dikovska; Klara (Riga, LV), Gailite; Vija (Riga, LV), Vorona; Maxim (Riga, LV), Piskunova; Irina (Riga, LV), Starchenkov; Igor (Riga, LV), Andrianov; Victor (Riga, LV), Harris; C. John (Sittingbourne, GB), Duffy; James E. S. (Sittingbourne, GB)
Assignee: Topotarget UK Limited (Abingdon, GB)
Filing Date:Sep 30, 2004
Application Number:10/953,106
Claims:1. A compound selected from compounds of the formula: ##STR00392## wherein: A is an aryl group; Q.sup.1 is a covalent bond or an aryl leader group; R.sup.1 is a sulfonamido substituent; and, Q.sup.2 is an acid leader group; and wherein: A, is a C.sub.5-20aryl group, and is optionally substituted; the aryl leader group, if present, is: a C.sub.1-7alkylene group; and is optionally substituted; the sulfonamido substituent, R.sup.1, is: hydrogen, C.sub.1-7alkyl, C.sub.3-20heterocyclyl, or C.sub.5-20aryl; the acid leader group, O.sup.2, is: C.sub.4-7alkylene having a backbone length of from 4 to 7 carbon atoms; and is optionally substituted; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

2. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group.

3. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a saturated C.sub.1-7alkylene group and is optionally substituted.

4. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a partially unsaturated C.sub.2-7alkylene group and is optionally substituted.

5. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is an aliphatic C.sub.1-7alkylene group and is optionally substituted.

6. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a linear C.sub.1-7alkylene group and is optionally substituted.

7. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a saturated aliphatic C.sub.1-7alkylene group and is optionally substituted.

8. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a saturated linear C.sub.1-7alkylene group and is optionally substituted.

9. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a partially unsaturated aliphatic C.sub.2-7alkylene group and is optionally substituted.

10. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is a partially unsaturated linear C.sub.2-7alkylene group and is optionally substituted.

11. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of at least 2 carbon atoms.

12. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of at least 3 carbon atoms.

13. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of from 2 to 7 carbon atoms.

14. A compound according to claim 7, wherein Q.sup.1 is an aryl leader group and has a backbone of from 2 to 7 carbon atoms.

15. A compound according to claim 9, wherein Q.sup.1 is an aryl leader group and has a backbone of from 2 to 7 carbon atoms.

16. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of from 3 to 7 carbon atoms.

17. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of 2 carbon atoms.

18. A compound according to claim 7, wherein Q.sup.1 is an aryl leader group and has a backbone of 2 carbon atoms.

19. A compound according to claim 9, wherein Q.sup.1 is an aryl leader group and has a backbone of 2 carbon atoms.

20. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of 3 carbon atoms.

21. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of 4 carbon atoms.

22. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and has a backbone of 5 carbon atoms.

23. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is unsubstituted.

24. A compound according to claim 7, wherein Q.sup.1 is an aryl leader group and is unsubstituted.

25. A compound according to claim 9, wherein Q.sup.1 is an aryl leader group and is unsubstituted.

26. A compound according to claim 13, wherein Q.sup.1 is an aryl leader group and is unsubstituted.

27. A compound according to claim 17, wherein Q.sup.1 is an aryl leader group and is unsubstituted.

28. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is substituted.

29. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: halo, hydroxy, ether, C.sub.5-20aryl, acyl, amido, and oxo.

30. A compound according to claim 7, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: halo, hydroxy, ether, C.sub.5-20aryl, acyl, amido, and oxo.

31. A compound according to claim 9, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: halo, hydroxy, ether, C.sub.5-20aryl, acyl, amido, and oxo.

32. A compound according to claim 13, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: halo, hydroxy, ether, C.sub.5-20aryl, acyl, amido, and oxo.

33. A compound according to claim 17, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: halo, hydroxy, ether, C.sub.5-20aryl, acyl, amido, and oxo.

34. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is unsubstituted or substituted with one or more groups selected from: --F, --Cl, --Br, --I, --OH, --OMe, --OEt, --OPr, -Ph, and .dbd.O.

35. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is selected from --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--, --CH.dbd.CH--CH.dbd.CH--, and C.sub.5cycloalkyl.

36. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is selected from --CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--, --CH.dbd.CH--, and --CH.dbd.CH--CH.dbd.CH--.

37. A compound according to claim 1, wherein Q.sup.1 is an aryl leader group and is selected from --CH.sub.2--, --CH.sub.2CH.sub.2--, and --CH.dbd.CH--.

38. A compound according to claim 1, wherein Q.sup.1 is a covalent bond.

39. A compound according to claim 1, wherein the acid leader group, Q.sup.2 is substituted.

40. A compound according to claim 1, wherein the acid leader group, Q.sup.2 is unsubstituted.

41. A compound according to claim 1, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

42. A compound according to claim 7, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

43. A compound according to claim 9, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

44. A compound according to claim 13, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

45. A compound according to claim 14, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

46. A compound according to claim 15, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

47. A compound according to claim 17, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

48. A compound according to claim 18, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

49. A compound according to claim 19, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

50. A compound according to claim 23, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

51. A compound according to claim 29, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

52. A compound according to claim 36, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

53. A compound according to claim 37, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

54. A compound according to claim 38, wherein the acid leader, Q.sup.2, is an unsubstituted saturated linear C.sub.4-7alkylene group.

55. A compound according to claim 1, wherein A is C.sub.5-20heteroaryl or C.sub.5-20carboaryl, and is optionally substituted.

56. A compound according to claim 1, wherein A is a C.sub.5-20aryl group derived from one of the following: benzene, pyridine, furan, indole, pyrrole, imidazole, naphthalene, quinoline, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole.

57. A compound according to claim 5, wherein A is an optionally substituted phenyl group.

58. A compound according to claim 7, wherein A is an optionally substituted phenyl group.

59. A compound according to claim 9, wherein A is an optionally substituted phenyl group.

60. A compound according to claim 13, wherein A is an optionally substituted phenyl group.

61. A compound according to claim 17, wherein A is an optionally substituted phenyl group.

62. A compound according to claim 23, wherein A is an optionally substituted phenyl group.

63. A compound according to claim 29, wherein A is an optionally substituted phenyl group.

64. A compound according to claim 36, wherein A is an optionally substituted phenyl group.

65. A compound according to claim 37, wherein A is an optionally substituted phenyl group.

66. A compound according to claim 38, wherein A is an optionally substituted phenyl group.

67. A compound according to claim 1, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

68. A compound according to claim 7, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

69. A compound according to claim 9, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

70. A compound according to claim 13, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

71. A compound according to claim 17, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

72. A compound according to claim 23, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

73. A compound according to claim 29, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

74. A compound according to claim 36, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

75. A compound according to claim 37, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

76. A compound according to claim 38, wherein A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl.

77. A compound according to claim 1, wherein R.sup.1 is hydrogen, C.sub.1-7alkyl, or C.sub.5-20aryl.

78. A compound according to claim 1, wherein R.sup.1 is hydrogen or C.sub.1-7alkyl.

79. A compound according to claim 1, wherein R.sup.1 is --H, -Me, or -Et.

80. A compound according to claim 1, wherein R.sup.1 is --H.

81. A compound selected from compounds of the formula: ##STR00393## wherein: Q.sup.1 is a covalent bond or an aliphatic C.sub.1-7alkylene group; Q.sup.2 is an unsubstituted saturated linear C.sub.4-7alkylene group; R.sup.1 is hydrogen, C.sub.1-7alkyl, or C.sub.5-20aryl; A is an optionally substituted phenyl group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

82. A compound selected from compounds of the formula: ##STR00394## wherein: Q.sup.1 is a covalent bond, --CH.sub.2--, --CH.sub.2CH.sub.2--, or --CH.dbd.CH--; Q.sup.2 is an unsubstituted saturated linear C.sub.4-7alkylene group; R.sup.1 is hydrogen, C.sub.1-7alkyl, or C.sub.5-20aryl; A is an optionally substituted phenyl group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

83. A compound selected from compounds of the formula: ##STR00395## wherein: Q.sup.1 is a covalent bond, --CH.sub.2--, --CH.sub.2CH.sub.2--, or --CH.dbd.CH--; Q.sup.2 is an unsubstituted saturated linear C.sub.4-7alkylene group; R.sup.1 is hydrogen, C.sub.1-7alkyl, or C.sub.5-20aryl; A is a phenyl group optionally substituted with one or more of the following groups: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, morpholino, amido, acetamido, acetyl, nitro, sulfonamido, and phenyl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof.

84. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00396##

85. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00397##

86. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00398##

87. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00399##

88. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00400##

89. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00401##

90. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00402##

91. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00403##

92. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00404##

93. A compound according to claim 1, selected from compounds of the following formula and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: ##STR00405##

94. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

95. A method of inhibiting HDAC in a cell comprising said cell with an effective amount of a compound according to claim 1.

96. A method of treatment of a proliferative condition selected from the group consisting of malignant neoplasm, leukemia, bone disease, and atherosclerosis comprising administering to a subject suffering from said proliferative condition a therapeutically-effective amount of a compound according to claim 1.

97. A method of treatment of psoriasis comprising administering to a subject suffering from psoriasis a therapeutically-effective amount of a compound according to claim 1.

98. A method of treatment of a fibroproliferative disorder comprising administering to a subject suffering from a fibroproliferative disorder a therapeutically-effective amount of a compound according to claim 1.

99. A method of treatment of liver fibrosis comprising admistering to a subject suffering from liver fibrosis a therapeutically-effective amount of a compound according to claim 1.

100. A method of treatment of a smooth muscle proliferative disorder comprising administering to a subject suffering from a smooth muscle proliferative disorder a therapeutically-effective amount of a compound according to claim 1.

101. A method of treatment of atherosclerosis or restenosis comprising administering to a subject suffering from atherosclerosis or restenosis therapeutically-effective amount of a compound according to claim 1.

102. A method of treatment of a neurodegenative disease or spino-cerebellar degeneration comprising administering to a subject suffering from a neurodegenative disease or spino-cerebellar degeneration a therapeutically-effective amount of a compound according to claim 1.

103. A method of treatment of Alzheimer's disease, Parkinson's desease, Huntington's chores, or amyotropic lateral sclerosis comprising administering to a subject suffering from Alzheimer's disease, Parkinson's disease, Huntington's chorea, or amyotropic lateral sclerosis a therapeutically-effective amount of a compound according to claim 1.

104. A method of treatment of an inflammatory disease comprising administering to a subject suffering from an inflammatory disease a therapeutically-effective amount of a compound according to claim 1.

105. A method of treatment of osteoarthritis or rheumatoid arthritis comprising administering to a subject suffering from osteoarthritis or rheumatoid arthritis a therapeutically-effective amount of a compound according to claim 1.

106. A method of treatment of diabetic retinopathy comprising administering to a subject suffering from diabetic retinopathy a therapeutically-effective amount of a compound according to claim 1.

107. A method of treatment of a haematopoietic disorder comprising administering to a subject suffering from a haematopoietic disorder a therapeutically-effective amount of a compound according to claim 1.

108. A method of treatment of anaemia comprising administering to a subject suffering from anaemia a therapeutically-effective amount of a compound according to claim 1.

109. A method of treatment of sickle cell anaemia or thalassaeimia comprising administering to a subject suffering from sickle cell anaemia or thalassaeimia a therapeutically-effective amount of a compound according to claim 1.

110. A method of treatment of a fungal infection comprising admistering to a subject suffering from a fungal infection a therapeutically-effective amount of a compound according to claim 1.

111. A method of treatment of a parasitic infection comprising administering to a subject suffering from a parasitic infection a therapeutically-effective amount of a compound according to claim 1.

112. A method of treatment of malaria, trypanosomiasis, helminthiasis, or a protozoal infection comprising administering to a subject suffering from malaria, trypanosomiasis, helminthiasis, or a protozoal infection a therapeutically-effective amount of a compound according to claim 1.

113. A method of treatment of a bacterial infection comprising administering to a subject suffering from a bacterial infection a therapeutically-effective amount of a compound according to claim 1.

114. A method of treatment of a viral infection comprising administering to a subject suffering from a viral infection a therapeutically-effective amount of a compound according to claim 1.

115. A method of treatment of multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma, allergic rhinitis, or inflammatory bowel disease comprising administering to a subject suffering from multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma, allergic rhinitis, or inflammatory bowel disease a therapeutically-effective amount of a compound according to claim 1.

116. A method of treatment of lung cancer comprising administering to a subject suffering from lung cancer a therapeutically-effective amount of a compound according to claim 1.

117. A method of treatment of colon cancer comprising administering to a subject suffering from colon cancer a therapeutically-effective amount of a compound according to claim 1.

118. A method of treatment of breast cancer comprising administering to a subject suffering from breast cancer a therapeutically-effective amount of a compound according to claim 1.

119. A method of treatment of ovarian cancer comprising administering to a subject suffering from ovarian cancer a therapeutically-effective amount of a compound according to claim 1.

120. A method of treatment of prostate cancer comprising administering to a subject suffering from prostate cancer a therapeutically-effective amount of a compound according to claim 1.

121. A method of treatment of liver cancer comprising administering to a subject suffering from liver cancer a therapeutically-effective amount of a compound according to claim 1.

122. A method of treatment of pancreas cancer comprising administering to a subject suffering from pancreas cancer a therapeutically-effective amount of a compound according to claim 1.

123. A method of treatment of brain cancer comprising administering to a subject suffering from brain cancer a therapeutically-effective amount of a compound according to claim 1.

124. A method of treatment of skin cancer comprising administering to a subject suffering from skin cancer a therapeutically-effective amount of a compound according to claim 1.
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