Uridine diphosphate derivatives, prodrugs, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-9913855-B2
Application number	US-201314432104-A
Country	US
Kind code	B2
Filing date	Sep 27, 2013
Priority date	Sep 28, 2012
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

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 an inflammatory condition 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 3- to 10-membered aromatic or non-aromatic ring having up to 5 heteroatoms independently selected from N, O, S, SO, or SO 2 , wherein the aromatic or non-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 , —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)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 inflammatory condition is selected from any of an inflammatory skin condition, an autoimmune condition, a rheumatoid condition, an inflammatory bowel condition, an inflammatory joint condition, an inflammatory condition of the eye, an inflammatory condition of the lungs, an inflammatory condition of the kidney, an inflammatory condition caused by an allergic reaction, and an inflammatory condition caused by an infectious agent.

3. The method of claim 1 , wherein the inflammatory condition is mediated, in whole or in part, by an elevated interleukin level in the subject.

4. The method of claim 1 , wherein the method comprises reducing the level of one or more interleukins in a tissue or body fluid of the subject.

5. The method of claim 1 , wherein the inflammatory condition is not a neural or neurodegenerative condition.

6. A method for reducing the plasma concentration of a cytokine in a subject having an inflammatory condition, comprising administering to the subject a therapeutically effective amount of
a compound of formula I:

or a salt thereof, wherein:
A is a 3- to 10-membered aromatic or non-aromatic ring having up to 5 heteroatoms independently selected from N, O, S, SO, or SO 2 , wherein the aromatic or non-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 , —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 3 , —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-Cl0)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

Assignees

• Univ Tufts

Inventors

• Haydon Philip G
• Lee Jinbo

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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