Small molecule inducers of GDNF as potential new therapeutics for neuropsychiatric disorders

Patent metadata

Field	Value
Publication number	US-9988377-B2
Application number	US-201214240681-A
Country	US
Kind code	B2
Filing date	Aug 24, 2012
Priority date	Aug 24, 2011
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

This invention provides a compound having the structure

wherein
A is a ring structure, with or without substitution;
Z is present or absent and when present is

wherein
n is 0, 1, 2, 3, or 4;
Y is —(CR 11 R 12 )—, —NH(CR 11 R 12 )—, or —O(CR 11 R 12 )—,
wherein R 11 and R 12 are each hydrogen or combine to form a carbonyl;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, hydroxyl, amino, ester or amide;
α represents a bond, which is present or absent and when α is present, then R 7 and R 8 are absent;
R 7 and R 8 are present when α is absent and are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, hydroxyl, amino, ester, amide or R 5 and R 7 combine to form a carbonyl or R 6 and R 8 combine to form a carbonyl;
R 9 and R 10 are each hydrogen or combine to form a carbonyl; and
when α is present, Z is

 where n=1, Y is —(CR 11 R 12 )— where R 11 and R 12 are H, A is unsubstituted indole attached at the 3-position of the indole, R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are each H, and one of R 1 or R 2 is H, then the other one of R 1 or R 2 is other than H or ethyl,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

First claim

What is claimed is:

1. A compound of the structure:

wherein
A is a ring structure, with or without substitution;
Z is present or absent and when present is

wherein
n is 0, 1, 2, 3, or 4;
Y is —CH 2 —;

R 1 is H and R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, unsubstituted hydroxyl, amino, or amide, or R 2 is H and R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, unsubstituted hydroxyl, amino, or amide;
R 3 and R 4 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, hydroxyl, amino, ester or amide;
R 5 and R 6 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, hydroxyl, amino, ester or amide;
α represents a bond, which is present or absent and when α is present, then R 7 and R 8 are absent;
R 7 and R 8 are present when α is absent and R 5 and R 7 combine to form a carbonyl or R 6 and R 8 combine to form a carbonyl;
R 9 and R 10 are each hydrogen or combine to form a carbonyl; and
when α is present, Z is

 where n=1, Y is —CH 2 —, A is unsubstituted indole attached at the 3-position of the indole, R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are each H, and one of R 1 or R 2 is H, then the other one of R 1 or R 2 is other than H or ethyl,
wherein the ring structure A is an indole,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

2. The compound of claim 1 ,
wherein the ring structure A is,

wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently H, alkyl, aryl, heteroalkyl, heteroaryl, ester, or halide, each with or without substitution,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

3. The compound of claim 2 , wherein
wherein R 12 , R 13 and R 15 are each independently H, F, Cl, Br, CH 3 , CF 3 , OMe, OCF 3 , C(O)OR 16 ,
wherein R 16 is alkyl, and

R 11 and R 14 are each independently H, F, Cl, Br, CH 3 , CF 3 , OMe, OCF 3 , C(O)OR 16 ,
wherein R 16 is alkyl

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

4. The compound of claim 3 ,
wherein the ring structure A is,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

5. The compound of claim 1 ,
wherein the ring structure A is

wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently H, alkyl, aryl, heteroalkyl, heteroaryl, ester, or halide, each with or without substitution; and
R 17 is alkyl, aryl, heteroalkyl, or heteroaryl, each with or without substitution,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

6. The compound of claim 5 , wherein
wherein R 11 , R 12 , R 13 , R 14 and R 15 are each independently H, F, Cl, Br, CH 3 , CF 3 , OMe, OCF 3 , C(O)OR 16 ,
wherein R 16 is alkyl; and

R 17 is phenyl, benzyl, or tolyl,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

7. The compound of claim 6 ,
wherein the ring structure A is,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

8. The compound of claim 1 ,
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 1 is H and R 2 is alkyl or CH 2 -aryl, or
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 2 is H and R 1 is alkyl or CH 2 -aryl,
wherein the alkyl and aryl are each unsubstituted,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

9. A compound of the structure:

wherein
A is an indole, with or without substitution;
Z is present or absent and when present is

wherein
n is 0, 1, 2, 3, or 4;
Y is CH 2 ;

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, hydroxyl, amino, ester or amide;
α represents a bond, which is present or absent and when α is present, then R 7 and R 8 are absent;
R 7 and R 8 are present when α is absent and R 5 and R 7 combine to form a carbonyl or R 6 and R 8 combine to form a carbonyl;
R 9 and R 10 are each hydrogen or combine to form a carbonyl; and
when α is present, Z is

 where n=1, Y is —CH 2 —, A is unsubstituted indole attached at the 3-position of the indole, R 3 , R 4 , R 5 , R 6 , R 9 and R 10 are each H, and one of R 1 or R 2 is H, then the other one of R 1 or R 2 is other than H or ethyl,
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 3 is H and R 4 is alkyl, ester, or CH 2 -aryl, or
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 4 is H and R 3 is alkyl, ester, or CH 2 -aryl,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

10. The compound of claim 1 ,
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 1 is H and R 2 is —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 —O—CH 2 -aryl, —CH 2 —O—CH 2 -heteroaryl, or
wherein Z is

 Y is —CH 2 —, n=0, 1 or 2, R 2 is H and R 1 is —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 —O—CH 2 -aryl, —CH 2 —O—CH 2 -heteroaryl,

or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof.

11. The compound of claim 1 ,
wherein Z is

 Y i

Assignees

• Sames Dalibor
• Li Xiaoguang
• Li Shu
• Kruegel Andrew
• Karpowicz Richard
• Carrera Ignacio
• Rakshit Souvik
• Univ Columbia

Inventors

• Sames Dalibor
• Li Xiaoguang
• Li Shu
• Kruegel Andrew
• Karpowicz Richard
• Carrera Ignacio
• Rakshit Souvik

Classifications

• C07D453/06 Primary

  containing isoquinuclidine ring systems · CPC title