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
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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 R8 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, and cyclopropyl;
R3 is selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano;
R6 is selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano;
each of L1 and L2 is, independently, C1-C3 alkylene, which is optionally substituted with from 1-2 independently selected Rc;
A is CRA1RA2, wherein one of RA1 and RA2 is halo, and the other of RA1 and RA2 is hydrogen or C1-C3 alkyl;
Z is —NR10R11 or —OR12 or —S(O)nR13, wherein n is 0, 1, or 2;
each of R10 and R11 is independently selected from:
(a) hydrogen;
(b) C6-C10 aryl that is optionally substituted with from 1-4 Rb; 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-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 Rb;
wherein one of R10 and R11 is (b) or (c);
each of R12 and R13 is:
(i) C6-C10 aryl that is optionally substituted with from 1-4 Rb; 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-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 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 5-6 ring atoms, wherein from 1-2 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 5-6 ring atoms, wherein from 1-2 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 1-3 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;
and
Rc at each occurrence is, independently selected from halo, C1-C6 alkoxy, C1-C6 thioalkoxy, C1-C6 haloalkoxy, C1-C6 thiohaloalkoxy, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), 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 R3 is halo.
- The method of claim 4, wherein R3 is bromo.
- The method of claim 5, wherein each of R1, R2, and R4 is hydrogen.
- The method of claim 4, wherein R6 is selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano.
- The method of claim 4, wherein R6 is halo or C1-C6 alkyl.
- The method of claim 4, wherein R6 is halo.
- The method of claim 4, wherein R6 is bromo.
- The method of claim 10, wherein each of R5, R7, and R8 is hydrogen.
- The method of claim 4, wherein Z is —NR10R11.
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The method of claim 12, wherein one of R10 and R11 is:
(b) C6-C10 aryl that is optionally substituted with from 1-4 Rb; 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-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 Rb;
and the other of R10 and R11 is hydrogen.
- The method of claim 4, wherein Z is —OR12.
- The method of claim 14, wherein R12 is C6-C10 aryl that is optionally substituted with from 1-4 Rb.
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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 R8 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, and cyclopropyl;
R3 is selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano;
R6 is selected from hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano;
each of L1 and L2 is, independently, C1-C3 alkylene, which is optionally substituted with from 1-2 independently selected Rc;
A is CRA1RA2, wherein one of RA1 and RA2 is halo or OR9, wherein R9 is hydrogen or C1-C3 alkyl that is optionally substituted with hydroxyl or C1-C3 alkoxy, and the other of RA1 and RA2 is hydrogen or C1-C3 alkyl;
Z is —OR12;
R12 is:
(i) C6-C10 aryl that is optionally substituted with from 1-4 Rb; 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-C3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 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;
(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 5-6 ring atoms, wherein from 1-2 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 5-6 ring atoms, wherein from 1-2 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 1-3 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;
and
Rc at each occurrence is, independently selected from halo, C1-C6 alkoxy, C1-C6 thioalkoxy, C1-C6 haloalkoxy, C1-C6 thiohaloalkoxy, C1-C6 alkyl, C1-C6 haloalkyl, —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —NHC(O)(C1-C6 alkyl), and cyano.
- The method of claim 16, wherein R3 is halo.
- The method of claim 16, wherein R3 is bromo.
- The method of claim 18, wherein each of R1, R2, and R4 is hydrogen.
- The method of claim 17, wherein R6 is selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cyclopropyl, —N3, and cyano.
- The method of claim 17, wherein R6 is halo or C1-C6 alkyl.
- The method of claim 17, wherein R6 is halo.
- The method of claim 17, wherein R6 is bromo.
- The method of claim 23, wherein each of R5, R7, and R8 is hydrogen.
- The method of claim 17, wherein R12 is C6-C10 aryl that is optionally substituted with from 1-4 Rb.
- 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.
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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.
Owners (US)
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Board Of Regents Of The University Of Texas System
(Aug 12 2011)
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Applicants
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Univ Texas
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Inventors
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Mcknight Steven L
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Pieper Andrew A
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Ready Joseph M
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De Brabander Jef K
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CPC Classifications
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C07D209/88
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A61K31/403
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A61K31/404
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A61K31/4045
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A61K31/4155
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A61K31/4188
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A61K31/4192
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A61K31/422
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A61K31/437
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A61K31/4439
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A61K31/506
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C07D209/08
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C07D209/82
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C07D209/86
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C07D401/06
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C07D401/12
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C07D403/06
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C07D403/12
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C07D405/12
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C07D413/06
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C07D471/04
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C07D495/04
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C07F5/022
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IPC Classifications
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A61K31/403
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A61K31/404
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A61K31/4045
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A61K31/4155
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A61K31/4188
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A61K31/4192
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A61K31/422
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A61K31/437
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A61K31/4439
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A61K31/506
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C07D209/08
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C07D209/82
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C07D209/86
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C07D209/88
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C07D401/06
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C07D401/12
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C07D403/06
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C07D403/12
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C07D413/06
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Document Preview
- Publication: Sep 20, 2016
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Application:
Jul 2, 2015
US 201514790313 A
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Priority:
Jul 2, 2015
US 201514790313 A
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Priority:
Jul 7, 2011
US 201113177981 A
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Priority:
Jul 7, 2010
US 83205610 A
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Priority:
Jan 11, 2010
US 68565210 A
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Priority:
Jan 9, 2009
US 14375509 P