PHENOXY AND BENZYLOXY SUBSTITUTED PSYCHOPLASTOGENS AND USES THEREOF
Disclosed herein are compounds, compositions, and methods for promoting neuronal growth and/or improving neuronal structure with the compounds and compositions disclosed herein. Also described are methods of treating diseases or disorders that are mediated by the loss of synaptic connectivity and/or plasticity, such as neurological diseases and disorders, with phenoxy or benzyloxy substituted psychoplastogens.
1 . A compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:
wherein:
R 1 is OR a , wherein R a is an optionally substituted arylalkyl;
R 2 is hydrogen;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is an unsubstituted or substituted alkyl, or hydrogen; and
R 6 is an unsubstituted or substituted alkyl, or hydrogen.
2 . The compound of claim 1 , wherein R 5 is hydrogen.
3 . The compound of claim 1 , wherein R 5 is methyl.
4 . The compound of claim 1 , wherein R 6 is hydrogen.
5 . The compound of claim 1 , wherein R 6 is methyl.
6 . The compound of claim 1 , wherein R 1 is an unsubstituted or substituted benzyloxy.
7 . The compound of claim 1 , wherein R 1 is selected from the group consisting of unsubstituted benzyloxy and benzyloxy substituted with at least one halogen.
8 . The compound of claim 1 , wherein R 1 is selected from the group consisting of benzyloxy and 4-fluorobenzyloxy.
9 . The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt or solvate thereof.
10 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
11 . A method for treating a neurological disease or disorder in a mammal, the method comprising administering to the mammal the compound of claim 1 , or any pharmaceutically acceptable salt or solvate thereof.
12 . The method of claim 11 , wherein the neurological disease or disorder is a neurodegenerative, a neuropsychiatric, or a substance use disease or disorder.
13 . The method of claim 11 , wherein the neurological disease or disorder is selected from the group consisting of an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, and a factitious disorder.
14 . The method of claim 11 , wherein the mammal is a human.
15 . A compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:
wherein:
R 1 is hydrogen;
R 2 is hydrogen;
R 3 is OR a , wherein R a is an optionally substituted arylalkyl;
R 4 is hydrogen;
R 5 is an unsubstituted or substituted alkyl, or hydrogen; and
R 6 is an unsubstituted or substituted alkyl, or hydrogen.
16 . The compound of claim 15 , wherein R 5 is hydrogen.
17 . The compound of claim 15 , wherein R 5 is methyl.
18 . The compound of claim 15 , wherein R 6 is hydrogen.
19 . The compound of claim 15 , wherein R 6 is methyl.
20 . The compound of claim 15 , wherein R 3 is an unsubstituted or substituted benzyloxy.
21 . The compound of claim 15 , wherein R 3 is selected from the group consisting of unsubstituted benzyloxy and benzyloxy substituted with at least one halogen.
22 . The compound of claim 15 , wherein R 3 is selected from the group consisting of benzyloxy and 4-fluorobenzyloxy.
23 . The compound of claim 15 , wherein the compound is
or a pharmaceutically acceptable salt or solvate thereof.
24 . A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
25 . A method for treating a neurological disease or disorder in a mammal, the method comprising administering to the mammal the compound of claim 15 , or any pharmaceutically acceptable salt or solvate thereof.
26 . The method of claim 25 , wherein the neurological disease or disorder is a neurodegenerative, a neuropsychiatric, or a substance use disease or disorder.
27 . The method of claim 25 , wherein the neurological disease or disorder is selected from the group consisting of an anxiety disorder, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, a sexuality disorder, an impulse control disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, and a factitious disorder.
28 . The method of claim 25 , wherein the mammal is a human.
29 . A process for the preparation of a compound according to Group 1, Group 2, Group 3, Group 4, or Group 5:
Group 1: a process for the preparation of Compound A, Compound A′, or a pharmaceutically acceptable salt thereof:
comprising reacting Compound 1-4:
with Compound I-5:
in the presence of an acid to form Compound A, Compound A′, or a pharmaceutically acceptable salt thereof;
wherein Ar is substituted or unsubstituted aralkyl; or
Group 2: a process for the preparation of Compound B, Compound B′, or a pharmaceutically acceptable salt thereof:
comprising reacting Compound A or Compound A′ with formaldehyde to form Compound B, Compound B′ or a pharmaceutically acceptable salt thereof;
wherein Ar is substituted or unsubstituted aralkyl; or
Group 3: a process for the preparation of Compound C, or a pharmaceutically acceptable salt thereof:
comprising the steps of
i) reacting Compound A with Boc 2 O to form Compound I-6:
ii) reacting Compound I-6 with an alkylating agent to form Compound I-7:
and
iii) deprotecting Compound I-7 to form Compound C,
wherein Ar is substituted or unsubstituted aralkyl; or
Group 4: a process for the preparation of Compound D, or a pharmaceutically acceptable salt thereof:
comprising reacting Compound C with formaldehyde to form Compound D, or a pharmaceutically acceptable salt thereof,
wherein Ar is substituted or unsubstituted aralkyl; or
Group 5: a process for the preparation of a Compound 2, or a pharmaceutically acceptable salt thereof:
comprising the steps of:
i) reacting Compound I-4g:
with Compound I-5b:
in the presence of an acid to form Compound 29:
and
ii) reacting Compound 29 in the presence of a reducing agent to form Compound 2, or a pharmaceutically acceptable salt thereof.
30 . A compound selected from:
or a salt thereof.