WITHAFERIN A ANALOGS AND USES THEREOF

• US 20110230551A1
• Filed: 09/15/2009
• Published: 09/22/2011
• Est. Priority Date: 09/15/2008
• Status: Abandoned Application

• Current Assignee: Arizona Board of Regents (University of Arizona), Whitehead Institute for Biomedical Research
• Original Assignee: Arizona Board of Regents (University of Arizona)
• Inventors: Whitesell, Luke, Gunatilaka, Leslie, Wijeratne, Ekanayake Mudiyanselage Kithsiri, Xu, Ya-Ming, Lindquist, Susan L.
• Application Number:
  US13/063,825
• Publication Number:
  US 20110230551A1
• Time in Patent Office: Days
• US Class Current: 514/460
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/585 containing lactone rings, e.g. oxandrolone, bufalin
• CPC Class Codes: A61K 41/0038 Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy radiotherapy per se A61N5/10
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: C07D 309/30 Oxygen atoms, e.g. delta-lactones
• CPC Class Codes: C07D 407/08 linked by a carbon chain containing alicyclic rings
• CPC Class Codes: C07J 71/001 Oxiranes

Abstract

The present invention provides a novel class of withanolides that have been isolated from W. somnifera under aeroponic conditions or produced semi-synthetically from withanolide natural products. The invention also provides pharmaceutical compositions thereof and methods for using the same in proliferative diseases, neurodegenerative diseases, autoimmune, and inflammatory diseases.

Claims

1. A compound of formula:

2. The compound of claim 1 wherein R² is hydrogen, —

OH, —

OR^B, —

OSO₃H, or —

OAc.

7. The compound of claim 1 wherein R³ is hydrogen, —

OH, —

OR^C, —

OSO₃H, or —

OAc.

12. The compound of claim 1 wherein R⁴ is hydrogen, —

OH, —

OR^C, —

OSO₃H, or —

OAc.

17. The compound of claim 1 wherein R⁵ is hydrogen.

22. The compound of claim 1 wherein R⁴ and R⁵ are both hydrogen.

23. The compound of claim 1 of formula:

24. The compound of claim 1 of formula:

25. The compound of claim 1 of formula:

26. The compound of claim 1 of formula:

27. The compound of claim 1 of formula:

30. The compound of claim 1 with one of the following structures:

138. A pharmaceutical composition comprising a compound of claim 1;

and a pharmaceutically acceptable excipient or vehicle.

140. A method of treating a subject having a proliferative disease, the method comprising administering a compound of claim 1 to a subject.

143. A method of treating a subject having cancer, the method comprising administering a compound of claim 1 to a subject, wherein said compound is a radiosensitizer.

148. A method of treating a subject having a neurodegenerative disease, the method comprising administering a compound of claim 1 to a subject.

150. A method of treating a subject having an inflammatory disease, the method comprising administering a compound of claim 1 to a subject.

154. A method of treating a subject having a protein aggregation disorder, the method comprising administering a compound of claim 1 to a subject.

157. A method of activating a heat shock response in a cell, the method comprising contacting a cell with an amount of a compound of claim 1 sufficient to induce a heat shock response.

3-6. -6. (canceled)

8-11. -11. (canceled)

13-16. -16. (canceled)

18-21. -21. (canceled)

28-29. -29. (canceled)

31. (canceled)

32. A compound of formula:

33. The compound of claim 32 wherein is a double bond.

57. The compound of claim 32 of formula:

79. The compound of claim 32 with one of the following structures:

34-56. -56. (canceled)

58-78. -78. (canceled)

80. A compound of formula:

97. The compound of claim 80 with one of the following structures:

81-96. -96. (canceled)

98-137. -137. (canceled)

139. (canceled)

141-142. -142. (canceled)

144-147. -147. (canceled)

149. (canceled)

151-153. -153. (canceled)

155-156. -156. (canceled)

158-159. -159. (canceled)

160. A method of isolating a withanolide, the method comprising steps of:

growing Withania somnifera aeroponically;

extracting aeroponically-grown W. somnifera with a solvent to provide an extract; and

isolating said withanolide from said extract.

161-182. -182. (canceled)