Uridine diphosphate derivatives, compositions and methods for treating neurodegenerative disorders

Patent metadata

Field	Value
Publication number	US-9227993-B2
Application number	US-201414323690-A
Country	US
Kind code	B2
Filing date	Jul 3, 2014
Priority date	Sep 30, 2011
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

This disclosure relates to uridine diphosphate (UDP) derivatives, compositions comprising therapeutically effective amounts of those UDP derivatives and methods of using those derivatives or compositions in treating disorders that are responsive to ligands, such as agonists, of P 2 Y 6 receptor, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease) and traumatic CNS injury, as well as pain.

First claim

The invention claimed is:

1. A compound of formula I:

or a salt thereof, wherein:
A is a bicyclic aromatic ring having up to 4 heteroatoms selected from N, O and S, wherein A is optionally further substituted with one or more R 7 ;
X is independently selected from —O—, —S—, —N(R 5 )— and a (C1-C3)-aliphatic group independently and optionally substituted with one or more R 4 ;
Y is a bond or a (C1-C5)-aliphatic group independently and optionally substituted with one or more R 4 ;
Z and W are each independently selected from ═O, ═S, ═N(R 5 ), and ═NOR 5 ;
R 1 is selected from:
—H, halogen, —OR 5 , —CN, —CF 3 , —OCF 3 and a (C1-C6)-aliphatic group optionally substituted with one or more R 7 ;

R 2 and R 3 are each independently selected from —OR 5 , —SR 5 , —NR 5 R 6 and —OC(O)R 5 ;
each occurrence of R 4 is independently selected from:
halogen, —OR 5 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 5 , 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 5 ) 2 , —SR 5 , —SOR 5 , —SO 2 R 5 , —SO 2 N(R 5 ) 2 , —SO 3 R 5 , —C(O)R 5 , —C(O)C(O)R 5 , —C(O)CH 2 C(O)R 5 , —C(S)R 5 , —C(S)OR 5 , —C(O)OR 5 , —C(O)C(O)OR 5 , —C(O)C(O)N(R 5 ) 2 , —OC(O)R 5 , —C(O)N(R 5 ) 2 , —OC(O)N(R 5 ) 2 , —C(S)N(R 5 ) 2 , —(CH 2 ) 0-2 NHC(O)R 5 , —N(R 5 )N(R 5 )COR 5 , —N(R 5 )N(R 5 )C(O)OR 5 , —N(R 5 )N(R 5 )CON(R 5 ) 2 , —N(R 5 )SO 2 R 5 , —N(R 5 )SO 2 N(R 5 ) 2 , —N(R 5 )C(O)OR 5 , —N(R 5 )C(O)R 5 , —N(R 5 )C(S)R 5 , —N(R 5 )C(O)N(R 5 ) 2 , —N(R 5 )C(S)N(R 5 ) 2 , —N(COR 5 )COR 5 , —N(OR 5 )R 5 , —C(═NH)N(R 5 ) 2 , —C(O)N(OR 5 )R 5 , —C(═NOR 5 )R 5 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , —P(O)(OR 5 ) 2 , or —P(O)(H)(OR 5 );

each occurrence of R 5 is independently selected from:
H—,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C3-C10)-heterocyclyl-,
(C6-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, and
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein two R 5 groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, O, S, SO, or SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl; and
wherein each R 5 group is independently and optionally substituted with one or more R 7 ;

R 6 is selected from:
—R 5 , —C(O)R 5 , —C(O)OR 5 , —C(O)N(R 5 ) 2 and —S(O) 2 R 5 ;

each occurrence of R 7 is independently selected from:
halogen, —OR 8 , —NO 2 , —CN, —CF 3 , —OCF 3 , —R 8 , oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R 8 ) 2 , —SR 8 , —SOR 8 , —SO 2 R 8 , —SO 2 N(R 8 ) 2 , —SO 3 R 8 , —C(O)R 8 , —C(O)C(O)R 8 , —C(O)CH 2 C(O)R 8 , —C(S)R 8 , —C(S)OR 8 , —C(O)OR 8 , —C(O)C(O)OR 8 , —C(O)C(O)N(R 8 ) 2 , —OC(O)R 8 , —C(O)N(R 8 ) 2 , —OC(O)N(R 8 ) 2 , —C(S)N(R 8 ) 2 , —(CH 2 ) 0-2 NHC(O)R 8 , —N(R 8 )N(R 8 )COR 8 , —N(R 8 )N(R 8 )C(O)OR 8 , —N(R 8 )N(R 8 )CON(R 8 ) 2 , —N(R 8 )SO 2 R 8 , —N(R 8 )SO 2 N(R 8 ) 2 , —N(R 8 )C(O)OR 8 , —N(R 8 )C(O)R 8 , —N(R 8 )C(S)R 8 , —N(R 8 )C(O)N(R 8 ) 2 , —N(R 8 )C(S)N(R 8 ) 2 , —N(COR 8 )COR 8 , —N(OR 8 )R 8 , —C(═NH)N(R 8 ) 2 , —C(O)N(OR 8 )R 8 , —C(═NOR 8 )R 8 , —OP(O)(OR 8 ) 2 , —P(O)(R 8 ) 2 , —P(O)(OR 8 ) 2 , or —P(O)(H)(OR 8 ); and

each occurrence of R 8 is independently selected from:
H— and (C1-C6)-aliphatic-.

2. The compound of claim 1 , wherein X is —O—.

3. The compound of claim 1 , wherein R 1 is —H, bromine, iodine, methyl, ethyl or —CF 3 .

4. The compound of claim 3 , wherein R 1 is —H.

5. The compound of claim 1 , wherein Z is ═O or ═S.

6. The compound of claim 5 , wherein Z is ═O.

7. The compound of claim 1 , wherein W is ═O or ═S.

8. The compound of claim 7 , wherein W is ═O.

9. The compound of claim 1 , wherein Y is a C1-aliphatic group optionally substituted with one or more R 4 .

10. The compound of claim 9 , wherein Y is —CH 2 —.

11. The compound of claim 1 , wherein Y is a C2-aliphatic group optionally substituted with one or more R 4 .

12. The compound of claim 11 , wherein Y is —CH 2 —C(R 4 ) 2 —.

13. The compound of claim 12 , wherein Y is —CH 2 —CH 2 —.

14. The compound of claim 12 , wherein each occurrence of R 4 is independently selected from halogen.

15. The compound of claim 14 , wherein both occurrences of R 4 are —F.

16. The compound of claim 12 , wherein each occurrence of R 4 is independently a (C1-C3)-aliphatic group.

17. The compound of claim 16 , wherein both occurrences of R 4 are —CH 3 .

18. The compound of claim 1 , wherein R 2 is —OR 5 .

19. The compound of claim 18 , wherein R 2 is —OH.

20. The compound of claim 1 , wherein R 3 is —OR 5 .

21. The compound of claim 20 , wherein R 3 is —OH.

22. The compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant or vehicle.

24. A method for treating a disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 , wherein said disorder is selected from a neurodegenerative disorder, a traumatic brain injury and pain.

25. The method of claim 24 , wherein the disorder is a neurodegenerative disorder.

26. The method of claim 25 , wherein the neurodegenerative disorder is Alzheimer's disease.

27. The method of claim 25 , wherein the neurodegenerative disorder is Parkinson's disease.

28. The method of claim 24 , wherein the disorder is a traumatic brain injury or pain.

29. The compound according to claim 1 , wherein A is selected from:

wherein A is optionally further substituted with one or more R 7 .

30. A compound of formula II:

or a salt thereof, wherein:
A is selected from:
a phenyl group that is substituted with at least one (C1-C5)-aliphatic group or halogen;
a naphthalene group;
a 5- to 10-membered heteroaryl group having up to 5 heteroatoms independently selected from N, O and S ; and
a 3- to 10-membered non-aromatic ring having up to 5 heteroatoms independently selected from N, O, S, SO, or SO 2 ;
wherein A is optionally further substituted with one or more R4;

X is independently selected from —O—, —S—, —N(R 5 )—and a (C1-C3)-aliphatic group independently and optionally substituted with one or more R 4 ;
Y 1 is a (C1-C5)-aliphatic group substituted with at least one oxo and further independently and optionally substituted with o

Assignees

• Univ Tufts

Inventors

• Haydon Philip G
• Lee Jinbo
• Dong Jinghui
• MOSS Stephen
• Revilla-Sanchez Raquel

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title