Treatment of neurodegenerative diseases through inhibition of HSP90

Patent metadata

Field	Value
Publication number	US-10336757-B2
Application number	US-30706307-A
Country	US
Kind code	B2
Filing date	Jul 2, 2007
Priority date	Jun 30, 2006
Publication date	Jul 2, 2019
Grant date	Jul 2, 2019

Abstract

Treatment of neurodegenerative diseases is achieved using small molecule purine scaffold compounds that inhibit Hsp90 and that possess the ability to cross the blood-brain barrier or are other wise delivered to the brain.

First claim

The invention claimed is:

1. A method for treatment of neurodegenerative disease, comprising administering to an individual in need of such treatment a therapeutically effective amount of a compound having structure:

wherein R is hydrogen, or a C 1 to C 10 alkyl, C 2 to C 10 alkynyl, or C 2 to C 10 alkoxyalkyl group, optionally including heteroatoms;
Y 1 and Y 2 are independently C or N;
X 4 is hydrogen or halogen;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl; and
X 2 is halogen, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkylm NH 2 , OH, or CN; and
X 1 has the formula —X—Y—Z— wherein, X, Y and Z are independently C, N, S or O, connected by single or double bonds and with apporpriate hydrogen substitution to satisfy valence, or Y may be (CH 2 ) 2 ,

wherein one of X and Z is bonded at the 5′-position to the aryl ring and the other is bonded to the 4′position, and wherein the compound is optionally in the form of an acid addition salt;
wherein the neurodegenerative disease is selected from the group consisting of complete androgen insensitivity syndrome (CAIS), spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), Alzheimer's Disease (AD), sporadic frontotemporal dementia with parkinsonism (FTDP), familial FTDP-17 syndromes, Parkinson's disease, and Huntington disease.

2. The method of claim 1 , wherein the compound and the mode of administration are selected such that the compound is delivered to the brain.

3. The method of claim 2 , wherein at least one of X, Y and Z is a carbon atom.

4. The method of claim 3 , wherein X 1 is —O—(CH 2 ) n —O—, wherein n is 1 or 2.

5. The method of claim 1 , wherein at least one of X, Y and Z is a carbon atom.

6. The method of claim 5 , wherein X 1 is —O—(CH 2 ) n —O—, wherein n is 1 or 2.

7. The method of claim 6 , wherein X 2 is halogen.

8. The method of claim 7 , wherein X 2 is Br or I.

9. The method of claim 6 , wherein R is an alkyl group containing a nitrogen heteroatom.

10. The method of claim 9 , wherein R is 3-isopropylaminopropyl, 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl.

11. The method of claim 10 , wherein R is 3-(methyl(prop-2-ynyl)amino)propyl.

12. The method of claim 10 , wherein R is 2-(isobutylamino)ethyl.

13. The method of claim 10 , wherein R is 2-(neopentylamino)ethyl.

14. The method of claim 10 , wherein R is 3-isopropylaminopropyl.

15. The method of claim 10 , wherein X 2 is halogen.

16. The method of claim 15 , wherein X 2 is Br or I.

17. The method of claim 6 , wherein X 4 is halogen.

18. The method of claim 17 , wherein X 2 is halogen.

19. The method of claim 18 , wherein X 2 is Br or I.

20. The method of claim 17 , wherein R is an alkyl group containing a nitrogen heteroatom.

21. The method of claim 20 , wherein R is 3-isopropylaminopropyl, 3-(isopropyl(methyl)amino)propyl, 3-(isopropyl(ethyl)amino)propyl, 3-((2-hydroxyethyl)(isopropyl)amino)propyl, 3-(methyl(prop-2-ynyl)amino)propyl, 3-(allyl(methyl)amino)propyl, 3-(ethyl(methyl)amino)propyl, 3-(cyclopropyl(propyl)amino)propyl, 3-(cyclohexyl(2-hydroxyethyl)amino)propyl, 3-(2-methylaziridin-1-yl)propyl, 3-(piperidin-1-yl)propyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 3-morpholinopropyl, 3-(trimethylammonio)propyl, 2-(isopropylamino)ethyl, 2-(isobutylamino)ethyl, 2-(neopentylamino)ethyl, 2-(cyclopropylmethylamino)ethyl, 2-(ethyl(methyl)amino)ethyl, 2-(isobutyl(methyl)amino)ethyl, or 2-(methyl(prop-2-ynyl)amino)ethyl.

22. The method of claim 20 , wherein R is 3-(methyl(prop-2-ynyl)amino)propyl.

23. The method of claim 20 , wherein R is 2-(isobutylamino)ethyl.

24. The method of claim 20 , wherein R is 2-(neopentylamino)ethyl.

25. The method of claim 20 , wherein R is 3-isopropylaminopropyl.

26. The method of claim 20 , wherein X 2 is halogen.

27. The method of claim 26 , wherein X 2 is Br or I.

28. The method of claim 4 , wherein R is a terminal alkyne.

29. The method of claim 28 , wherein R is propynyl.

30. The method of claim 29 , wherein X 2 is halogen.

31. The method of claim 1 , wherein the compound has the formula: PUDZ8

or an acid addition salt thereof.

32. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

33. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

34. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

35. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

36. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

37. The method of claim 1 , wherein the compound has the formula

or an acid addition salt thereof.

38. The method of claim 4 , wherein the compound crosses the blood brain barrier.

39. The method of claim 2 , wherein the neurodegenerative disease is one in which aggregate, plaque or tangle formation occurs.

40. The method of claim 2 , wherein the neurodegenerative disease is Alzheimer's Disease.

41. The method of claim 1 , wherein the neurodegenerative disease is one in which aggregate, plaque or tangle formation occurs.

42. The method of claim 1 , wherein the neurodegenerative disease is Alzheimer's Disease.

43. A compound:

or an

Assignees

• Chiosis Gabriela
• Greengard Paul
• Dou Fei
• Luo Wenjie
• He Huazhong
• Zatorska Danuta
• Sloan Kettering Inst Cancer Res
• Univ Rockefeller

Inventors

• Chiosis Gabriela
• Greengard Paul
• Dou Fei
• Luo Wenjie
• He Huazhong
• Zatorska Danuta

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P39/02

  Antidotes · CPC title

• A61P25/36

  Opioid-abuse · 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

• A61P25/16

  Anti-Parkinson drugs · CPC title