Method for treating cachexia with retinoid ligands

Abstract

The present invention relates to a method of treatment of cachexia in a subject in need of treatment. More specifically, the present invention relates to the use of retinoid compounds that act on retinoid X receptors (RXRs) for the treatment of cachexia in a subject in need of treatment. The cachexia is associated with, in other words a complication of, a primary disease, condition or disorder. Primary diseases, conditions and disorders include, but are not limited to, cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases (e.g., rheumatoid arthritis and systemic lupus erythematosus), tuberculosis, cystic fibrosis, gastrointestinal disorders (e.g., irritable bowel syndrome and inflammatory bowel disease), Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the actual body weight (in grams) of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 2 is a graph showing the percentage of survival of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 3 is a graph showing the actual body weight of severe combined immunodeficiency (SCID) mice bearing metastatic H446 tumors versus days post transplant, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 4 is a graph showing the weight of the right gastrocnemius muscle of mice bearing H292 tumor xenograft 62 days after transplantation, with and without treatment by an RXR agonist compound in accordance with the invention.

FIG. 5 is a graph showing the average food intake of nude mice with and without H292 xenografts, and with and without treatment by an RXR agonist compound (Compound 1) in accordance with the invention.

FIG. 6 is a graph showing the actual body weight (in grams) of nude mice bearing H292 xenografts versus days post tumor transplant, with and without treatment by a RXR agonist compound (Compound 2) in accordance with the invention.

FIG. 7 is a graph showing the average food intake of nude mice bearing H292 xenografts with and without treatment by an RXR agonist compound (Compound 2) in accordance with the invention.

Claims

1. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (I):

2. The method of claim 1, wherein Y is cyclopropyl, phenyl, pyridyl, thienyl or furyl.

3. The method of claim 2, wherein Y is cyclopropyl or phenyl.

4. The method of claim 3, wherein Y is

5. The method of claim 1, wherein R1 is H or methyl.

6. The method of claim 1, wherein B is —COOH or a pharmaceutically acceptable salt thereof, —COOR8 or —CONR9R10.

7. The method of claim 1, wherein Z is represented by Structural Formula (II) and n is 2.

8. The method of claim 1, wherein Z is represented by Structural Formula (III) and X is S or O.

9. The method of claim 1, wherein the cachexia is associated with cancer.

10. The method of claim 9, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.

11. The method of claim 1, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, diabetes mellitus, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.

12.-19. (canceled)

20. The method of claim 1, wherein the compound is represented by Structural Formula (IV):

21.-29. (canceled)

30. The method of claim 20, wherein the compound is represented by the formula:

31. The method of claim 20, wherein the compound is represented by the formula:

32. The method of claim 1 the compound is represented by Structural Formula (V):

33.-41. (canceled)

42. The method of claim 1, wherein the compound is represented by Structural Formula (VI):

43.-51. (canceled)

52. The method of claim 1, wherein the compound is represented by Structural Formula (VII):

53.-61. (canceled)

62. The method of claim 1, wherein:Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, said groups being optionally substituted with one or two R4 groups, and wherein Y is substituted by the Z and —CR1═CR1—CR1═CR1— groups on adjacent carbons; andX is NR5.

63.-71. (canceled)

72. The method of claim 1,

73.-91. (canceled)

92. The method of claim 1, wherein the compound is represented by Structural Formula (VIII):

93.-101. (canceled)

102. The method of claim 1,

103.-111. (canceled)

112. The method of claim 1,

113.-121. (canceled)

122. The method of claim 1,

123.-131. (canceled)

132. The method of claim 1, wherein the compound is represented by Structural Formula (VIII):

133.-141. (canceled)

142. The method of claim 1, wherein the compound is represented by Structural Formula (IX), (X) or (XI):

143.-151. (canceled)

152. The method of claim 142, wherein the compound is represented by Structural Formula (IX), R3 is H or methyl and B is —COOH or —COOCH2CH3.

153. The method of claim 142, wherein the compound is represented by Structural Formula (X), R3 is H and B is —COOH or —COOCH2CH3.

154. The method of claim 142, wherein the compound is represented by Structural Formula (XI), R3 is H, B is —COOH or —COOCH2CH3 and X is O or S.

155. The method of claim 1, wherein the compound is represented by Structural Formula (XII):

156.-164. (canceled)

165. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIII), (XIV) or (XV):

166.-174. (canceled)

175. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XVIII):

176.-184. (canceled)

185. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XIX):

186.-194. (canceled)

195. A method of treating cachexia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XX):

196.-204. (canceled)

205. A method of treating cachexia associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of an RXR agonist compound.

206.-218. (canceled)

219. A method of treating cachexia associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia in a subject in need thereof, the method comprising administering to said subject a therapeutically effective amount of a compound represented by Structural Formula (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIIa) or (XXVIIb):

220. The method of claim 219, wherein the RXR agonist compound is represented by the formula:

221. The method of claim 219, wherein the cachexia is associated with cancer.

222. The method of claim 221, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, gastrointestinal cancer, liver cancer, biliary cancer, breast cancer, esophageal cancer or leukemia.

223. The method of claim 219, wherein the cachexia is associated with one or more diseases, disorders or conditions selected from the group consisting of cancer, AIDS, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease, chronic cardiac failure, immune system diseases, tuberculosis, cystic fibrosis, gastrointestinal disorders, Parkinson's disease, anorexia nervosa, dementia, major depression, an aged condition and sarcopenia.

224.-229. (canceled)