Uridine diphosphate derivatives, prodrugs, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-11241450-B2
Application number	US-202016849946-A
Country	US
Kind code	B2
Filing date	Apr 15, 2020
Priority date	Sep 28, 2012
Publication date	Feb 8, 2022
Grant date	Feb 8, 2022

Abstract

This disclosure relates to the use of uridine diphosphate (UDP) derivatives, salts and/or prodrugs thereof for the treatment of inflammatory conditions (e.g., psoriasis) and glaucoma, to prodrugs of UDP derivatives, compositions comprising therapeutically effective amounts of those prodrugs of the UDP derivatives and methods of using those prodrugs for treating various disorders including, e.g., neuronal disorders, including neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease) and traumatic CNS injury, pain, Down Syndrome (DS), glaucoma, and inflammatory conditions, e.g., psoriasis and rheumatoid arthritis.

First claim

What is claimed is:

1. A method for treating glaucoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I:

or a salt thereof, wherein:
A is a (C5-C10)-aromatic ring having up to 5 heteroatoms independently selected from N, O and S, wherein the aromatic ring is independently and optionally 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 method of claim 1 , wherein the glaucoma is marked by elevated intraocular pressure.

3. The method of claim 1 , wherein the glaucoma is selected from the group consisting of open-angle glaucoma (primary or chronic glaucoma), angle-closure glaucoma (acute glaucoma or narrow-angle glaucoma), congenital glaucoma, and secondary glaucoma.

4. The method of claim 3 , wherein the glaucoma is open-angle glaucoma (primary or chronic glaucoma) or angle-closure glaucoma (acute glaucoma or narrow-angle glaucoma).

5. The method of claim 4 , wherein the open-angle glaucoma (primary or chronic glaucoma) or angle-closure glaucoma (acute glaucoma or narrow-angle glaucoma) is selected from the group consisting of secondary glaucoma, pigmentary glaucoma, pseudoexfoliative glaucoma, traumatic glaucoma, neovascular glaucoma, and iridocorneal endothelial syndrome (ICE).

6. The method of claim 1 , wherein the glaucoma is low-tension or normal-pressure glaucoma.

7. The method of claim 1 , wherein A is

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

8. The method of claim 1 , wherein X is —O—.

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

10. The method of claim 9 , wherein R 1 is —H.

11. The method of claim 1 , wherein Z is ═O or ═S.

12. The method of claim 11 , wherein Z is ═O.

13. The method of claim 1 , wherein W is ═O or ═S.

14. The method of claim 13 , wherein W is ═O.

15. The method of claim 1 , wherein R 2 and R 3 are each independently —OR 5 .

16. The method of claim 1 , wherein R 2 is —OH and R 3 is —OH.

17. The method of claim 1 , wherein Y is a C 1 -aliphatic group optionally substituted with one or more R 4 .

18. The method of claim 1 , wherein Y is —CH 2 —.

19. The method of claim 1 , wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:

20. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Tufts

Inventors

• Haydon Philip G
• Lee Jinbo

Classifications

• C07H19/067

  with ribosyl as the saccharide radical · CPC title

• A61K31/7072 Primary

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61P25/14

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07F9/65744

  condensed with carbocyclic or heterocyclic rings or ring systems · CPC title