Pro-neurogenic compounds
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 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.
1. A method of treating a neuropsychiatric or neurodegenerative disease, disorder, or condition, the method comprising administering to a subject in need thereof an effective amount of a compound having formula (III), or a pharmaceutically acceptable salt thereof:
wherein R 1b is selected from the group consisting of: hydrogen; C 1-6 alkyl optionally substituted with one or more halo, hydroxyl, cyano and/or azide; —CH(R 5 )—C(O)—Z 1b ; and —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2b ;
wherein R 5 is hydrogen or C 1-3 alkyl;
wherein Z 1b is selected from the group consisting of: hydroxyl; C 1-6 alkoxyl; and amine optionally substituted with a hydroxyl, C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, C 4-12 heteroaryl sulfonyl, C 2-12 alkyl carbonyl, and/or C 2-12 carboxyalkyl; wherein each of the C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, C 4-12 heteroaryl sulfonyl, C 2-12 alkyl carbonyl, and C 2-12 carboxyalkyl is optionally substituted with 1-6 halo, hydroxyl, C 1-6 alkyl, and/or C 1-6 alkoxyl;
wherein one of R A1 and R A2 is hydroxyl or halo and the other is hydrogen;
wherein Z 2b is selected from the group consisting of: C 1-3 alkyl, azide, and N(R 6 )(R 7 );
wherein R 6 and R 7 are each independently selected from the group consisting of:
hydrogen; carboxamide optionally substituted with 1 or more C 1-6 alkyl, C 6-12 aryl and/or C 4-12 heteroaryl; C 1-12 alkyl sulfonyl; C 6-12 aryl sulfonyl; and C 4-12 heteroaryl sulfonyl; wherein each of the C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, and C 4-12 heteroaryl sulfonyl is optionally substituted with 1-6 halo; wherein no more than one of R 6 and R 7 is hydrogen;
or wherein one of R 6 and R 7 is C 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; and the other of R 6 and R 7 is C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, or C 4-12 heteroaryl sulfonyl, wherein each of the C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, and C 4-12 heteroaryl sulfonyl is optionally substituted with 1-6 halo; and
wherein R 3b and R 4b are each independently selected from the group consisting of: hydrogen, halo, hydroxyl, C 1-3 alkoxyl, cyano, carboxyl, and formamide;
wherein the disease, disorder, or condition is selected from one or more 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 neuro-active drugs, retinal degeneration, spinal cord injury, peripheral nerve injury, physiological weight loss, and cognitive decline associated with normal aging, radiation therapy, and chemotherapy.
2. The method of claim 1 , wherein R 1b is optionally substituted C 1-6 alkyl.
3. The method of claim 2 , wherein R 1b is selected from unsubstituted C 1-6 alkyl or C 3-6 alkyl substituted with one hydroxyl or C 1-6 alkyl substituted with one cyano.
4. The method of claim 3 , wherein R 1b is unsubstituted C 1-6 alkyl.
5. The method of claim 4 , wherein R 1b is unsubstituted C 2-6 alkyl.
6. The method of claim 3 , wherein R 1b is C 3-6 alkyl substituted with one hydroxyl.
7. The method of claim 3 , wherein R 1b is C 1-6 alkyl substituted with one cyano.
8. The method of claim 1 , wherein R 1b is —CH(R 5 )—C(O)—Z 1b .
9. The method of claim 8 , wherein R 5 is hydrogen.
10. The method of claim 9 , wherein Z 1b is amine optionally substituted with a hydroxyl, C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, C 4-12 heteroaryl sulfonyl, C 2-12 alkyl carbonyl, and/or C 2-12 carboxyalkyl; wherein each of the C 1-12 alkyl sulfonyl, C 6-12 aryl sulfonyl, C 4-12 heteroaryl sulfonyl, C 2-12 alkyl carbonyl, and C 2-12 carboxyalkyl is optionally substituted with 1-6 halo, hydroxyl, C 1-6 alkyl, and/or C 1-6 alkoxyl.
11. The method of claim 10 , wherein Z 1b is C 6-12 aryl sulfonyl optionally substituted with 1-6 halo, hydroxyl, C 1-6 alkyl, and/or C 1-6 alkoxyl.
12. The method of claim 11 , wherein the compound is 2-(3,6-dibromo-9H-carbazol-9-yl)-N-(phenylsulfonyl)acetamide.
13. The method of claim 1 , wherein R 1b is —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2b .
14. The method of claim 12 , wherein Z 2b is azide or N(R 6 )(R 7 ).