Anti-depression compounds

摘要

This technology relates generally to compounds and methods for stimulating neurogenesis (e.g., post-natal neurogenesis, including post-natal hippocampal and hypothalamic neurogenesis) and/or protecting neuronal cell from cell death. Various compounds are disclosed herein. In vivo activity tests suggest that these compounds may have therapeutic benefits in neuropsychiatric and/or neurodegenerative diseases such as schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of a neuro-active drug, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss associated with various conditions, as well as cognitive decline associated with normal aging, chemotherapy, and the like.

主权项

1. A method for treating a depressive disorder comprising: administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the following formula: wherein: R3 and R6 are each independently selected from halo, C1-C6 alkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano; A is CRA1RA2, wherein RA1 is selected from hydrogen, halo, C1-C3 alkyl, and OR9, and RA2 is selected from halo, C1-C3 alkyl, and OR9; Z is selected from —NHR10; —N(CH3)R11; —OR12; and —S(O)nR13, wherein n is 0, 1, or 2; R9 is hydrogen or C1-C3 alkyl that is optionally substituted with hydroxyl or C1-C3 alkoxy; R10, R11, R12 and R13 are each independently selected from:
(a) C6-C10 aryl that is optionally substituted with 1 to 4 Rb; or(b) heteroaryl containing from 6-14 ring atoms, wherein from 1-6 of the ring atoms are independently selected from N, NH, N(C1-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 to 4 Rb; Rb at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
(aa) C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; —O—(CH2)1-3—[O(CH2)1-3]1-3—H; C1-C6 alkyl, C1-C6 haloalkyl, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl);(bb) halo; hydroxyl; cyano; nitro; —NH2; azido; sulfhydryl; C2-C6 alkenyl; C2-C6 alkynyl; —C(O)H; —C(O)(C1-C6 alkyl); —C(O)(C1-C6 haloalkyl); C(O)OH; —C(O)O(C1-C6 alkyl); —C(O)NH2; —C(O)NH(C1-C6 alkyl); C(O)N(C1-C6 alkyl)2; —SO2(C1-C6 alkyl); —SO2NH2; —SO2NH(C1-C6 alkyl); —SO2N(C1-C6 alkyl)2;(cc) C3-C6 cycloalkyl or heterocyclyl containing from 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C1-C6 alkyl), NC(O)(C1-C6 alkyl), O, and S; and(dd) phenyl or heteroaryl containing from 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C1-C3 alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH2; —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 thioalkoxy; C1-C6 thiohaloalkoxy; C1-C6 alkyl, and C1-C6 haloalkyl; wherein when R3 and R6 are both halo, one of RA1 and RA2 is OH and the other is hydrogen, Z is —NHR10, and R10 is C6-C10 aryl that is optionally substituted with 1 to 4 Rb, then R10 is unsubstituted phenyl or phenyl substituted with 1 Rb.