URIDINE DIPHOSPHATE DERIVATIVES, PRODRUGS, COMPOSITIONS AND METHODS FOR TREATING NEURODEGENERATIVE DISORDERS

摘要

This disclosure relates to prodrugs of uridine diphosphate (UDP) derivatives, compositions comprising therapeutically effective amounts of those prodrugs of the UDP derivatives and methods of using those prodrugs 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.

主权项

1. A prodrug of a compound having a structure 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; 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)cyclo alkyl, or a (C3-C10)heterocyclyl; andwherein 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); each occurrence of R8 is independently selected from:
H— and (C1-C6)-aliphatic-.