THERAPEUTIC PIPERAZINES

摘要

The invention includes a compound of formula I:;;wherein R1, Y, A, n, R4 and Z have any of the values described herein, as well as salts of such compounds, compositions comprising such compounds, and therapeutic methods that comprise the administration of such compounds. The compounds are inhibitors of PDE4 function and are useful for improving cognitive function and/or treating cognitive disorders or impairment, traumatic and/or ischemic injuries of the central and peripheral nervous system and/or psychiatric disorders in animals, especially humans.

主权项

1. A method comprising:
improving cognitive function in an animal by administering to the animal an effective amount of a compound of formula (I): wherein: R1 is H, (C1-C6)alkyl, halo(C1-C6)alkyl, RaRbN(C1-C6)alkyl, hydroxy(C1-C6)alkyl, alkoxy(C1-C6)alkyl, het(C1-C6)alkyl, het(C1-C6)haloalkyl, aryl(C1-C6)alkyl, aryl(C1-C6)haloalkyl, aryl-(C═O)—, or het-(C═O)—; Y is a direct bond, —CH2, or (C═O); n is an integer from 0 to 6 inclusive; Each of the n instances of A is independently a direct bond or—(CRcRd)—; R4 is aryl or heteroaryl; Z is a phenyl ring substituted with one or more substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C8)cyclo alkyl, (C3-C8)cyclo alkyl(C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, (C3-C8)cycloalkoxy, (C3-C8)cycloalkyl(C1-C6)alkoxy, piperidinyloxy, piperidinyloxy(C1-C6)alkyl, or cyano; each Ra and Rb is independently H, (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, het, or het(C1-C6)alkyl; each Rc and Rd is independently H, OH, NH2, or (C1-C6)alkyl, or R, and Rd taken together may join to form a 3 to 5 member ring consisting of C atoms and optionally one or more O atoms and/or N(X), wherein X is absent, H, O, OH, (C1-C4)alkyl, phenyl or benzyl; wherein any phenyl, aryl, het, or heteroaryl of R1 or R4 is optionally substituted with one or more substituents independently selected from (C1-C6)alkyl, hydroxy, hydroxy(C1-C6)alkyl, phenyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy, halo(C1-C6)alkoxy, cyano, nitro, halo, (C1-C6)carboxy, or NRcRd; and wherein the piperazine core ring of formula (I) is optionally substituted at one or more carbon atoms with one or more substituents independently selected from oxo, halogen, (C1-C6)alkyl, or (C1-C6)alkoxy; and when R1 is C1alkyl, then Y-(A)n-R4 taken together is not aryl(C1-C6)alkyl or hydroxy(C1-C6)alkyl; or a pharmaceutically acceptable salt thereof.