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 compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (II):
wherein R 1a is selected from the group consisting of: —CH 2 —C(O)—Z 1a and —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2a ;
R 3a and R 4a are each independently selected from the group consisting of: hydrogen, halo, hydroxyl, C 1-3 alkoxyl, cyano, carboxyl, and formamide;
wherein Z 1a is selected from the group consisting of: hydroxyl; C 1-6 alkoxyl; amine optionally substituted with 1 or more C 1-12 alkyl, C 2-12 alkenyl, C 3-12 cycloalkyl, C 1-12 sulfonyl optionally substituted with 1-6 halo, C 6-12 aryl sulfonyl optionally substituted with 1-6 halo, C 4-12 heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12 carbonyl optionally substituted with 1-6 halo, and/or C 2-12 carboxyalkyl optionally substituted with 1-6 halo; C 2- 12 heterocyclyi; C 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; and C 4-12 heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl;
wherein one of R A1 and R A2 is hydroxyl, halo, or amine optionally substituted with 1 or more C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 2-6 heterocyciyi, C 6-12 aryl, and/or C 4-12 heteroaryl; and the other of R A1 and R A2 is hydrogen;
wherein Z 2a is selected from the group consisting of: halo, O(R a ), S(R b ) and N(R c )(R d );
wherein R a and R b are each independently selected from the group consisting of: C 1-12 alkyl; C 2-12 alkenyl; C 3-12 cycloalkyl; C 2-6 heterocyclyl; C 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; and C 4-12 heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl;
wherein R c and R d are each independently selected from the group consisting of: hydrogen; C 1- 12 alkyl; C 2-12 alkenyl; C 3-12 cycloalkyl; C 2-6 heterocyclyl; C 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; and C 4-12 heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; or wherein R c and R d together with the nitrogen they are attached to form a C 4-14 heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl.
2 . The compound or salt of claim 1 , wherein R 3a and R 4a are both hydrogen or both bromo.
3 . The compound or salt of claim 1 , wherein Z 1a is hydroxyl or amine optionally substituted with 1 or more C 1-12 alkyl, C 2-12 alkenyl, and/or C 3-12 cycloalkyl.
4 . The compound or salt of claim 1 , wherein one of R A1 and R A2 is hydroxyl or halo; and the other of R A1 and R A2 is hydrogen.
5 . The compound or salt of claim 1 , wherein Z 2a is O(R a ) or S(R b ).
6 . The compound or salt of claim 1 , wherein Z 2a is N(R c )(R d ).
7 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (III):
wherein R 1b is selected from the group consisting of: hydrogen; C 1-6 alkyl optionally substituted with 1 or more halo, hydroxyl, cyano and/or azide; —CH(R5)—C(O)—Z 1b ; and —CH 2 —C(R A1 )(R A2 )—CH 2 —Z 2 b;
wherein R 5 is hydrogen or C 1-3 alkyl;
wherein one of R A1 and R A2 is hydroxyl or halo and the other is hydrogen;
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 sulfonyl optionally substituted with 1-6 halo, C 6-12 aryl sulfonyl optionally substituted with 1-6 halo, C 4-12 heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12 carbonyl optionally substituted with 1-6 halo, and/or C 2-12 carboxyalkyl optionally substituted with 1-6 halo;
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 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; C 1-12 sulfonyl optionally substituted with 1-6 halo; C 6-12 aryl sulfonyl optionally substituted with 1-6 halo; and C 4-12 heteroaryl sulfonyl optionally substituted with 1-6 halo; wherein no more than one of R 6 and R 7 is hydrogen; 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.
8 . The compound or salt of claim 7 , wherein when R 1b is optionally substituted C 1-6 alkyl, R 1b is selected from unsubstituted C 1-6 alkyl or C 3-6 alkyl substituted with 1 hydroxyl or C 1-6 alkyl substituted with 1 cyano.
9 . The compound or salt of claim 8 , wherein when R 1b unsubstituted C 1-6 alkyl, R 1b is unsubstituted C 2-6 alkyl.
10 . The compound or salt of claim 7 , wherein when R 5 is hydrogen, Z 1b is amine optionally substituted with a hydroxyl, C 1-12 sulfonyl optionally substituted with 1-6 halo, C 6-12 aryl sulfonyl optionally substituted with 1-6 halo, C 4-12 heteroaryl sulfonyl optionally substituted with 1-6 halo, C 2-12 carbonyl optionally substituted with 1-6 halo, and/or C 2-12 carboxyalkyl optionally substituted with 1-6 halo.
11 . The compound or salt of claim 7 , wherein Z 2b is azide or N(R 6 )(R 7 ).
12 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (IV):
wherein:
R 1c is selected from the group consisting of: hydrogen, C 1-6 alkyl, C 1-6 carboxyalkyl, C 1-12 sulfonyl optionally substituted with 1-6 halo, C 6-12 aryl sulfonyl optionally substituted with 1-6 halo and C 4-12 heteroaryl sulfonyl optionally substituted with 1-6 halo;
R 2c is selected from the group consisting of: hydrogen; hydroxyl; cyano; halo; amine optionally substituted with 1 or more C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, and/or heteroaryl; and C 1-12 alkoxyl;
R 3c is selected from the group consisting of: carboxyl; C 1-6 alkoxycarbonyl; hydroxyl; C 1-12 alkoxyl;
cyano; halo; and amine optionally substituted with 1 or more C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, aryl, and/or heteroaryl;
R 4c is selected from the group consisting of: hydrogen, halo, hydroxyl, and C 1-3 alkoxyl; and
one or both of Q 1 and Q 2 are nitrogen.
13 . The compound or salt of claim 12 , wherein R 2c is hydrogen; hydroxyl; or C 1-12 alkoxyl.
14 . The compound or salt of claim 12 , wherein R 3c is carboxyl; C 1-6 alkoxycarbonyl; hydroxyl; or amine substituted with 1-2 C 1-6 alkyl.
15 . A compound or pharmaceutically acceptable salt thereof, for promoting neurogenesis and/or reducing neuronal cell death, the compound having formula (V):
wherein R 1d is selected from the group consisting of: hydrogen and CH 2 —C(R A1 )(R A2 )—CH 2 —N(R 6 )(R 7 );
wherein one of R A1 and R A2 is hydroxyl or halo and the other is hydrogen; and
wherein R 6 and R 7 are each independently selected from the group consisting of: hydrogen; C 6-12 aryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl; and C 4-12 heteroaryl optionally substituted with 1 or more halo, hydroxyl, C 1-6 alkyl and/or C 1-6 alkoxyl;
wherein R 2d is selected from the group consisting of: halo, hydroxyl, C 1-12 alkoxyl, cyano, aryl, and heteroaryl;
wherein R 3d is selected from the group consisting of: hydrogen and amine optionally substituted with 1 or more C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, C 2-6 heterocyclyl, aryl, and/or heteroaryl; and
wherein R 4d is selected from the group consisting of: hydrogen, halo, hydroxyl, and C 1-3 alkoxyl.
16 . The compound or salt of claim 15 , wherein R 2d is cyano, and R 4d is hydrogen, bromo or methoxy.
17 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of claim 1 .
18 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of claim 7 .
19 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective anount of the compound or salt of claim 12 .
20 . A method of treating a disease, disorder, or condition associated with unwanted neuronal cell death or insufficient neurogenesis, the method comprising administering an effective amount of the compound or salt of claim 15 .