Uridine diphosphate derivatives, prodrugs, compositions and methods for treating neurodegenerative disorders

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 SO2, wherein the aromatic or non-aromatic ring is independently and optionally substituted with one or more R7;
• X is independently selected from —O—, —S—, —N(R5)— and a (C1-C3)-aliphatic group independently and optionally substituted with one or more R4;
• Y is a bond or a (C1-C5)-aliphatic group independently and optionally substituted with one or more R4;
• Z and W are each independently selected from ═O, ═S, ═N(R5), and ═NOR5;
• R1 is selected from:
• —H, halogen, —OR5, —CN, —CF3, —OCF3 and a (C1-C6)-aliphatic group optionally substituted with one or more R7;
• R2 and R3 are each independently selected from —OR5, —SR5, —NR5R6, —OC(O)R5, —OC(O)NR5R6, and —OC(O)OR5;
• preferably, R2 and R3 are each independently selected from —OR5, —SR5, —NR5R6 and —OC(O)R5;
• each occurrence of R4 is independently selected from:
• halogen, —OR5, —NO2, —CN, —CF3, —OCF3, —R5, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R5)2, —SR5, —SOR5, —SO2R5, —SO2N(R5)2, —SO3R5, —C(O)R5, —C(O)C(O)R5, —C(O)CH2C(O)R5, —C(S)R5, —C(S)OR5, —C(O)OR5, —C(O)C(O)OR5, —C(O)C(O)N(R5)2, —OC(O)R5, —C(O)N(R5)2, —OC(O)N(R5)2, —C(S)N(R5)2, —(CH2)0-2NHC(O)R5, —N(R5)N(R5)COR5, —N(R5)N(R5)C(O)OR5, —N(R5)N(R5)CON(R5)2, —N(R5)SO2R5, —N(R5)SO2N(R5)2, —N(R5)C(O)OR5, —N(R5)C(O)R5, —N(R5)C(S)R5, —N(R5)C(O)N(R5)2, —N(R5)C(S)N(R5)2, —N(COR5)COR5, —N(OR5)R5, —C(═NH)N(R5)2, —C(O)N(OR5)R5, —C(═NOR5)R5, —OP(O)(OR5)2, —P(O)(R5)2, —P(O)(OR5)2, or —P(O)(H)(OR5);
• each occurrence of R5 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 R5 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 SO2, 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 R5 group is independently and optionally substituted with one or more R7;
• R6 is selected from:
• —R5, —C(O)R5, —C(O)OR5, —C(O)N(R5)2 and —S(O)2R5;
• each occurrence of R7 is independently selected from:
• halogen, —OR8, —NO2, —CN, —CF3, —OCF3, —R8, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R8)2, —SR8, —SORB, —SO2R8, —SO2N(R8)2, —SO3R8, —C(O)R8, —C(O)C(O)R8, —C(O)CH2C(O)R8, —C(S)R8, —C(S)OR8, —C(O)OR8, —C(O)C(O)OR8, —C(O)C(O)N(R8)2, —OC(O)R8, —C(O)N(R8)2, —OC(O)N(R8)2, —C(S)N(R8)2, —(CH2)0-2NHC(O)R8, —N(R8)N(R8)COR8, —N(R8)N(R8)C(O)OR8, —N(R8)N(R8)CON(R8)2, —N(R8)SO2R8, —N(R8)SO2N(R8)2, —N(R8)C(O)OR8, —N(R8)C(O)R8, —N(R8)C(S)R8, —N(R8)C(O)N(R8)2, —N(R8)C(S)N(R8)2, —N(COR8)COR8, —N(OR8)R8, —C(═NH)N(R8)2, —C(O)N(OR8)R8, —C(═NOR8)R8, —OP(O)(OR8)2, —P(O)(R8)2, —P(O)(OR8)2, or —P(O)(H)(OR8);
• and
• each occurrence of R8 is independently selected from:
• H— and (C1-C6)-aliphatic-.

A method for decreasing cytokine levels in plasma of 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 SO2, wherein the aromatic or non-aromatic ring is independently and optionally substituted with one or more R7;
• X is independently selected from —O—, —S—, —N(R5)— and a (C1-C3)-aliphatic group independently and optionally substituted with one or more R4;
• Y is a bond or a (C1-C5)-aliphatic group independently and optionally substituted with one or more R4;
• Z and W are each independently selected from ═O, ═S, ═N(R5), and ═NOR5;
• R1 is selected from:
• —H, halogen, —OR5, —CN, —CF3, —OCF3 and a (C1-C6)-aliphatic group optionally substituted with one or more R7;
• R2 and R3 are each independently selected from —OR5, —SR5, —NR5R6, —OC(O)R5, —OC(O)NR5R6, and —OC(O)OR5;
• preferably, R2 and R3 are each independently selected from —OR5, —SR5, —NR5R6 and —OC(O)R5;
• each occurrence of R4 is independently selected from:
• halogen, —OR5, —NO2, —CN, —CF3, —OCF3, —R5, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R5)2, —SR5, —SOR5, —SO2R5, —SO2N(R5)2, —SO3R5, —C(O)R5, —C(O)C(O)R5, —C(O)CH2C(O)R5, —C(S)R5, —C(S)OR5, —C(O)OR5, —C(O)C(O)OR5, —C(O)C(O)N(R5)2, —OC(O)R5, —C(O)N(R5)2, —OC(O)N(R5)2, —C(S)N(R5)2, —(CH2)0-2NHC(O)R5, —N(R5)N(R5)COR5, —N(R5)N(R5)C(O)OR5, —N(R5)N(R5)CON(R5)2, —N(R5)SO2R5, —N(R5)SO2N(R5)2, —N(R5)C(O)OR5, —N(R5)C(O)R5, —N(R5)C(S)R5, —N(R5)C(O)N(R5)2, —N(R5)C(S)N(R5)2, —N(COR5)COR5, —N(OR5)R5, —C(═NH)N(R5)2, —C(O)N(OR5)R5, —C(═NOR5)R5, —OP(O)(OR5)2, —P(O)(R5)2, —P(O)(OR5)2, or —P(O)(H)(OR5);
• each occurrence of R5 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 R5 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 SO2, 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 R5 group is independently and optionally substituted with one or more R7;
• R6 is selected from:
• —R5, —C(O)R5, —C(O)OR5, —C(O)N(R5)2 and —S(O)2R5;
• each occurrence of R7 is independently selected from:
• halogen, —OR8, —NO2, —CN, —CF3, —OCF3, —R8, oxo, thioxo, 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R8)2, —SR8, —SORB, —SO2R8, —SO2N(R8)2, —SO3R8, —C(O)R8, —C(O)C(O)R8, —C(O)CH2C(O)R8, —C(S)R8, —C(S)OR8, —C(O)OR8, —C(O)C(O)OR8, —C(O)C(O)N(R8)2, —OC(O)R8, —C(O)N(R8)2, —OC(O)N(R8)2, —C(S)N(R8)2, —(CH2)0-2NHC(O)R8, —N(R8)N(R8)COR8, —N(R8)N(R8)C(O)OR8, —N(R8)N(R8)CON(R8)2, —N(R8)SO2R8, —N(R8)SO2N(R8)2, —N(R8)C(O)OR8, —N(R8)C(O)R8, —N(R8)C(S)R8, —N(R8)C(O)N(R8)2, —N(R8)C(S)N(R8)2, —N(COR8)COR8, —N(OR8)R8, —C(═NH)N(R8)2, —C(O)N(OR8)R8, —C(═NOR8)R8, —OP(O)(OR8)2, —P(O)(R8)2, —P(O)(OR8)2, or —P(O)(H)(OR8);
• and
• each occurrence of R8 is independently selected from:
• H— and (C1-C6)-aliphatic-.