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US 2017/0247383 A1Published application
Neuroactive compounds and methods of using the same
AssigneeThe General Hospital Corporation
InventorsRandall T. PETERSON, Andrew J. RENNEKAMP, David KOKEL, You WANG
Life of this patent
Estimating the term…
Abstract
The invention described herein relates generally to neuroactive compounds and compositions for the treatment psychotic disorders, methods for treating psychosis using these neuroactive compounds, and methods for screening for novel neuroactive compounds. Certain aspects are directed to a family of compounds called “finazines.” Certain aspects are directed to in vivo screening methods using high-through-put behavioral assays in zebrafish.
Claims20
A compound of Formula I:
- wherein:
- L1 is C2 alkylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is an aryl substituted with at least one halogen, nitro, alkyl or alkoxy;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (ii) L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is an heteroaryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (iii) L1 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (iv) L1 is C2 alkylene, which can be substituted with 1 or 2 independently selected substituents;
- L2 is a C1-C6 alkylene, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R1 is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (v) L1 is C2 alkylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 1;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (vi) L1 is a C2 alkylene substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- or
- (vii) L1 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a C3-C6 enone;
- R1 is an aryl, which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4.
60 more elements
A compound of Formula II:
- wherein:
- L21 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L22 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R21 is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R23 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- and
- p is 0, 1, 2, 3 or 4.
4 more elements
A method for treating psychosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of:
- Formula I:
- wherein:
- L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- (ii) Formula II:
- wherein:
- L21 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L22 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R21 is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R23 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- and
- p is 0, 1, 2, 3 or 4;
- (iii) Formula III:
- wherein:
- L31 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L32 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R32 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, cycloalkyl, and CO2R34;
- R33 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- R34 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents
- q is 0, 1, 2 3 or 4;
- t is 0, 1, 2, 3 or 4;
- and
- b is 1 or 2;
- or
- (iv) any combination of (i)-(iii).
28 more elements
A method for modulating a fear response in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:
- compound of Formula I:
- wherein:
- L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- (ii) compound of Formula II:
- wherein:
- L21 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L22 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R21 is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R23 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- and
- p is 0, 1, 2, 3 or 4;
- (iii) compound of Formula III:
- wherein:
- L31 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L32 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R32 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, cycloalkyl, and CO2R34;
- R33 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- R34 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents
- q is 0, 1, 2 3 or 4;
- t is 0, 1, 2, 3 or 4;
- and
- b is 1 or 2;
- and
- (iv) any combination of (i)-(iii).
28 more elements
An antipsychotic composition comprising a compound selected from the group consisting of:
- compound of Formula I:
- wherein:
- L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- (ii) compound of Formula II:
- wherein:
- L21 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L22 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R21 is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R23 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- and
- p is 0, 1, 2, 3 or 4;
- (iii) compound of Formula III:
- wherein:
- L31 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L32 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R32 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, cycloalkyl, and CO2R34;
- R33 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- R34 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents
- q is 0, 1, 2 3 or 4;
- t is 0, 1, 2, 3 or 4;
- and
- b is 1 or 2;
- and
- (iv) any combination of (i)-(iii).
28 more elements
A method for modulating a sigma-1 receptor, comprising contacting the sigma-1 receptor with a compound selected from the group consisting of:
- (i) compound of Formula I:
- wherein:
- L1 is a bond, C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L2 is a bond, C1-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R1 is aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R2 is for each occurrence independently selected C1-C6 alkyl, halogen, alkyl, alkoxy, and cycloalkyl;
- R3 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- m is 0, 1, 2, 3 or 4;
- and
- n is 0, 1, 2, 3 or 4;
- (ii) compound of Formula II:
- wherein:
- L21 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L22 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R21 is an aryl or heteroaryl, each of which can be substituted with 1, 2, 3 or 4 independently selected substituents;
- R23 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- and
- p is 0, 1, 2, 3 or 4;
- (iii) compound of Formula III:
- wherein:
- L31 is a bond, C3-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents;
- L32 is a bond, C3-C6 alkylene, C2-C6 alkenylene or C2-C6 alkynylene, each of which can be substituted with 1 or 2 independently selected substituents;
- R32 is for each occurrence independently selected from the group consisting of C1-C6 alkyl, halogen, alkyl, alkoxy, cycloalkyl, and CO2R34;
- R33 is for each occurrence independently selected from the group consisting of halogen, alkyl, and alkoxy, or two R3 together with the carbons they are attached to form a 5-8 membered cyclyl or heterocyclyl, which can be substituted with 1 or 2 substituents;
- R34 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenylene, C2-C6 alkynylene, aryl, heteroaryl, cyclyl or heterocyclyl, each of which can be substituted with 1 or 2 independently selected substituents
- q is 0, 1, 2 3 or 4;
- t is 0, 1, 2, 3 or 4;
- and
- b is 1 or 2;
- and
- (iv) any combination of (i)-(iii).
28 more elements
(canceled)
A method for screening for a neuroactive compound, comprising:
- (a) Subjecting zebrafish larvae to a stimulus and measuring the zebrafish larvae's amount of motion as a function of time to determine a control phenotype;
- (b) Treating zebrafish larvae with a test compound while being subjected to the stimulus, and measuring the zebrafish larvae's amount of motion as a function of time to determine a behavioral phenotype;
- and
- (c) Comparing the behavioral phenotype with the control phenotype to evaluate the neuroactive properties of the test compound.
1 more element
Dependencies are inferred from the claim text.