US 9446022 B2 - Pro-neurogenic Compounds - The Lens - Free & Open Patent and Scholarly Search

Pro-neurogenic Compounds

Published: Sep 20, 2016
Earliest Priority: Jul 07 2010
Family: 23
Cited Works: 99
Cited by: 3
Cites: 100
Additional Info: Cited Works Full text Published

Abstract

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.

Claims

A method for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the method comprising administering an effective amount of a compound having formula (III) or a pharmaceutically acceptable salt thereof:
wherein:

each of R¹, R², R⁴, R⁵, R⁷, and R⁸is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, and cyclopropyl;

R³is selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano;

R⁶is selected from hydrogen, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano;

each of L¹and L²is, independently, C₁-C₃alkylene, which is optionally substituted with from 1-2 independently selected R^c;

A is CR^A1R^A2, wherein one of R^A1and R^A2is halo, and the other of R^A1and R^A2is hydrogen or C₁-C₃alkyl;

Z is —NR¹⁰R¹¹or —OR¹²or —S(O)_nR¹³, wherein n is 0, 1, or 2;

each of R¹⁰and R¹¹is independently selected from:
(a) hydrogen;

(b) C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b; or

(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R^b;

wherein one of R¹⁰and R¹¹is (b) or (c);

each of R¹²and R¹³is:
(i) C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b; or

(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R^b;

R^bat each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
(aa) C₁-C₆alkoxy; C₁-C₆haloalkoxy; C₁-C₆thioalkoxy; C₁-C₆thiohaloalkoxy; —O—(CH₂)_1-3—[O(CH₂)_1-3]_1-3—H; C₁-C₆alkyl, C₁-C₆haloalkyl, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆alkyl);

(bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl; C₂-C₆alkenyl; C₂-C₆alkynyl; —C(O)H; —C(O)(C₁-C₆alkyl); —C(O)(C₁-C₆haloalkyl); C(O)OH; —C(O)O(C₁-C₆alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆alkyl); —C(O)N(C₁-C₆alkyl)₂; —SO₂(C₁-C₆alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆alkyl); —SO₂N(C₁-C₆alkyl)₂;

(cc) C₃-C₆cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C₁-C₆alkyl), NC(O)(C₁-C₆alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆alkyl), C₁-C₆alkoxy; C₁-C₆haloalkoxy; C₁-C₆thioalkoxy; C₁-C₆thiohaloalkoxy; C₁-C₆alkyl, and C₁-C₆haloalkyl;

and

R^cat each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆alkyl), and cyano.
The method of claim 1, wherein said post-natal mammalian neurogenesis includes hippocampal and/or hypothalamic neurogenesis.
The method of claim 1, wherein said neuronal cell death includes hippocampal and/or hypothalamic neuronal cell death.
The method of claim 1, wherein R³is halo.
The method of claim 4, wherein R³is bromo.
The method of claim 5, wherein each of R¹, R², and R⁴is hydrogen.
The method of claim 4, wherein R⁶is selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano.
The method of claim 4, wherein R⁶is halo or C₁-C₆alkyl.
The method of claim 4, wherein R⁶is halo.
The method of claim 4, wherein R⁶is bromo.
The method of claim 10, wherein each of R⁵, R⁷, and R⁸is hydrogen.
The method of claim 4, wherein Z is —NR¹⁰R¹¹.
The method of claim 12, wherein one of R¹⁰and R¹¹is:
(b) C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b; or

(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R^b;

and the other of R¹⁰and R¹¹is hydrogen.
The method of claim 4, wherein Z is —OR¹².
The method of claim 14, wherein R¹²is C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b.
A method for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the method comprising administering an effective amount of a compound having formula (III) or a pharmaceutically acceptable salt thereof:
wherein:

each of R¹, R², R⁴, R⁵, R⁷, and R⁸is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, and cyclopropyl;

R³is selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano;

R⁶is selected from hydrogen, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano;

each of L¹and L²is, independently, C₁-C₃alkylene, which is optionally substituted with from 1-2 independently selected R^c;

A is CR^A1R^A2, wherein one of R^A1and R^A2is halo or OR⁹, wherein R⁹is hydrogen or C₁-C₃alkyl that is optionally substituted with hydroxyl or C₁-C₃alkoxy, and the other of R^A1and R^A2is hydrogen or C₁-C₃alkyl;

Z is —OR¹²;

R¹²is:
(i) C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b; or

(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R^b;

R^bat each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:
(aa) C₁-C₆alkoxy; C₁-C₆haloalkoxy; C₁-C₆thioalkoxy; C₁-C₆thiohaloalkoxy; —O—(CH₂)_1-3—[O(CH₂)_1-3]_1-3—H; C₁-C₆alkyl, C₁-C₆haloalkyl, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂;

(bb) halo; hydroxyl; cyano; nitro; —NH₂; azido; sulfhydryl; C₂-C₆alkenyl; C₂-C₆alkynyl; —C(O)H; —C(O)(C₁-C₆alkyl); —C(O)(C₁-C₆haloalkyl); C(O)OH; —C(O)O(C₁-C₆alkyl); —C(O)NH₂; —C(O)NH(C₁-C₆alkyl); —C(O)N(C₁-C₆alkyl)₂; —SO₂(C₁-C₆alkyl); —SO₂NH₂; —SO₂NH(C₁-C₆alkyl); —SO₂N(C₁-C₆alkyl)₂;

(cc) C₃-C₆cycloalkyl or heterocyclyl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C₁-C₆alkyl), NC(O)(C₁-C₆alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C₁-C₃alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH₂; —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆alkyl), C₁-C₆alkoxy; C₁-C₆haloalkoxy; C₁-C₆thioalkoxy; C₁-C₆thiohaloalkoxy; C₁-C₆alkyl, and C₁-C₆haloalkyl;

and

R^cat each occurrence is, independently selected from halo, C₁-C₆alkoxy, C₁-C₆thioalkoxy, C₁-C₆haloalkoxy, C₁-C₆thiohaloalkoxy, C₁-C₆alkyl, C₁-C₆haloalkyl, —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, —NHC(O)(C₁-C₆alkyl), and cyano.
The method of claim 16, wherein R³is halo.
The method of claim 16, wherein R³is bromo.
The method of claim 18, wherein each of R¹, R², and R⁴is hydrogen.
The method of claim 17, wherein R⁶is selected from halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₂-C₆alkynyl, cyclopropyl, —N₃, and cyano.
The method of claim 17, wherein R⁶is halo or C₁-C₆alkyl.
The method of claim 17, wherein R⁶is halo.
The method of claim 17, wherein R⁶is bromo.
The method of claim 23, wherein each of R⁵, R⁷, and R⁸is hydrogen.
The method of claim 17, wherein R¹²is C₆-C₁₀aryl that is optionally substituted with from 1-4 R^b.
The method of claim 1, for the treatment of a disease, disorder, or condition caused by unwanted neuronal cell death or associated with insufficient neurogenesis in a subject in need thereof.
The method of claim 26, wherein the disease, disorder, or condition is a neuropsychiatric and/or neurodegenerative disease selected from the group consisting of: 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, and cognitive decline associated with normal aging, and chemotherapy.
The method of claim 16, for the treatment of a disease, disorder, or condition caused by unwanted neuronal cell death or associated with insufficient neurogenesis in a subject in need thereof.
The method of claim 28, wherein the disease, disorder, or condition is a neuropsychiatric and/or neurodegenerative disease selected from the group consisting of:
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, and cognitive decline associated with normal aging, and chemotherapy.