Uridine nucleoside derivatives, compositions and methods of use

Patent metadata

Field	Value
Publication number	US-10138265-B2
Application number	US-201414210333-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 13, 2013
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

This disclosure relates to uridine nucleoside derivatives, compositions comprising therapeutically effective amounts of those nucleoside derivatives and methods of using those nucleoside derivatives or compositions in treating disorders that are responsive to ligands, such as agonists, of P2Y6 receptor, 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.

First claim

What is claimed is:

1. A method for treating a neurodegenerative disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising 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 the bicyclic aromatic ring is independently and optionally substituted with one or more R 7 ;
X is selected from:
H, —C(O)R 5 , and —C(O)OR 5 ;

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 , —OC(O)R 5 , —OC(O)NR 5 R 6 , and —OC(O)OR 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 , and —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, and 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 , and —P(O)(H)(OR 8 );

each occurrence of R 8 is independently selected from:
H— and (C1-C6)-aliphatic-;
and a pharmaceutically acceptable carrier, adjuvant or excipient.

2. The method of claim 1 , wherein the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease, Mild Cognitive Impairment (MCI), Huntington's disease, multiple sclerosis and cerebral vascular accidents.

3. The method according to claim 1 , wherein the composition is administered by a route selected from topical, pulmonary, internal topical, interdermal, intravenous, subcutaneous, intranasal, epidermal, ophthalmic, oral, intraventricular, and intrathecal.

4. The method of claim 1 , wherein treating comprises providing a beneficial effect selected from one or more of: improving cognitive function, preventing or delaying cognitive decline, improving memory and/or learning, decreasing amyloid plaque load, increasing synaptic plasticity, improving hippocampal long-term potentiation, and enhancing beta amyloid clearance.

5. The method of claim 1 , wherein the neurodegenerative disorder is Alzheimer's disease.

6. The method of claim 1 , wherein said compound is:

or a pharmaceutically acceptable salt thereof.

7. A method for treating pain in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising 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 the bicyclic aromatic ring is independently and optionally substituted with one or more R 7 ;
X is selected from:
—H, —C(O)R 5 , and —C(O)OR 5 ;

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 , —OC(O)R 5 , —OC(O)NR 5 R 6 , and —OC(O)OR 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 ) 1-2 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 , and —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, and 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 o

Assignees

• Univ Tufts

Inventors

• Haydon Philip G
• Lee Jinbo

Classifications

• A61P27/06

  Antiglaucoma agents or miotics · 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

• A61P25/04

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

• A61K31/7072

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