Withaferin a analogs and uses thereof

Patent metadata

Field	Value
Publication number	US-2017066797-A1
Application number	US-201615175967-A
Country	US
Kind code	A1
Filing date	Jun 7, 2016
Priority date	Sep 15, 2008
Publication date	Mar 9, 2017
Grant date	—

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.

First claim

1 - 182 . (canceled)

183 . A compound of the formula:

or a pharmaceutically acceptable salt thereof; wherein
R 2 is hydrogen, —OR B or —C(R D ) 3 ;
each of R 3 , R 4 and R 5 is independently hydrogen or —OR C ;
each R B and R C is hydrogen, —SO 3 H, —PO 3 H 2 , —C(═O)R D , —C(═O)N(R D ) 2 , —CO 2 R D , —SOR D , —SO 2 R D or —C(R D ) 3 ; and
each R D is independently a hydrogen, a halogen, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy, or heteroarylthio moiety.

184 . The compound according to claim 183 , wherein R 2 is selected from the group consisting of hydrogen, —OH, —OSO 3 H, and —OAc.

185 . The compound according to claim 183 , wherein each of R 3 , R 4 and R 5 is independently selected from the group consisting of hydrogen, —OH, —OSO 3 H, and —OAc.

186 . The compound according to claim 183 of the formula:

wherein R 2 , R 3 , R 4 and R 5 are those defined in claim 183 .

187 . A compound of formula:

or a pharmaceutically acceptable salt thereof; wherein
denotes a single or double bond;
R 1 is hydrogen or —OR A ;
R 2 is hydrogen or —OR B ;
each of R 4 and R 5 is independently hydrogen or —OR C ;
each of R A , R B and R C is independently hydrogen, —SO 3 H, —PO 3 H 2 , —C(═O)R D , —C(═O)N(R D ) 2 , —CO 2 R D , —SOR D , —SO 2 R D or —C(R D ) 3 ; and
each R D is independently a hydrogen, a halogen, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety, an aryl moiety, a heteroaryl moiety, alkoxy, aryloxy, alkylthio, arylthio, amino, alkylamino, dialkylamino, heteroaryloxy or heteroarylthio moiety.

188 . The compound according to claim 187 , wherein is a double bond.

189 . The compound according to claim 187 , wherein is a single bond.

190 . The compound according to claim 187 , wherein R 1 is selected from the group consisting of hydrogen, —OH, —OSO 3 H and —OAc.

191 . The compound according to claim 187 , wherein R 2 is selected from the group consisting of hydrogen, —OH, —OSO 3 H and —OAc.

192 . The compound according to claim 187 , wherein R 4 is selected from the group consisting of hydrogen, —OH, —OSO 3 H and —OAc.

193 . The compound according to claim 187 , wherein R 5 is selected from the group consisting of hydrogen, —OH, —OSO 3 H and —OAc.

194 . The compound according to claim 187 , wherein R 4 and R 5 are hydrogen.

195 . The compound according to claim 187 of the formula:

wherein R 1 , R 2 , R 4 and R 5 are those defined in claim 187 .

196 . The compound according to claim 187 , wherein R 2 is —OH or —OAc.

197 . A method of treating a clinical condition associated with heat shock protein, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of claim 183 , wherein said clinical condition is selected from the group consisting of a proliferative disease, a cardiovascular disease, a neurodegenerative disease an inflammatory disease, an autoimmune disease and a protein aggregation disorder.

198 . The method according to claim 197 , wherein the proliferative disease is cancer.

199 . The method according to claim 197 , wherein the cardiovascular disease comprises hypertension or ischemia.

200 . The method according to claim 197 , wherein the neurodegenerative disease is Parkinson's disease.

201 . The method according to claim 197 , wherein the inflammatory disease comprises arthritis or asthma.

202 . The method according to claim 197 , wherein the protein aggregation disorder comprises Huntington's disease or Alzheimer's disease.

Assignees

• Whitehead Inst Biomedical Res
• Univ Arizona

Inventors

• Gunatilaka Leslie
• Wijeratne Ekanayake Mudiyanselage Kithsiri
• Xu ya-ming
• Whitesell Luke
• Lindquist Susan L

Classifications

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P25/28

  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 title

• C07D309/30

  Oxygen atoms, e.g. delta-lactones · CPC title

• A61K31/585

  containing lactone rings, e.g. oxandrolone, bufalin · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title