VMAT inhibitory compounds

Patent metadata

Field	Value
Publication number	US-9546151-B2
Application number	US-201514815356-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Jul 31, 2014
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

Disclosed herein are compounds that bind to the vesicular monoamine transporter 2 (VMAT2), pharmaceutical compositions comprising those compounds, and methods of treatment using said compounds and pharmaceutical compositions.

First claim

The invention claimed is:

1. A method for treating a subject having a methamphetamine (MA) addiction comprising:
administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound with the formula:

wherein X is a substituted or unsubstituted 5- or 6-membered aryl or substituted or unsubstituted 5- or 6-membered heteroaryl,
Z is N or CH,
m is 1, 2, or 3,
Ar is a substituted or unsubstituted 5- or 6-membered aryl or a substituted or unsubstituted 5- or 6-membered heteroaryl,
R is H, ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted or unsubstituted 5-membered heteroaryl,
Y is H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers, crystal form, or isotopomer thereof.

2. The method of claim 1 , wherein the pharmaceutical composition reduces a pathological effect or symptom of the MA addiction.

3. The method of claim 1 , wherein the pharmaceutical composition binds vesicular monoamine transporter 2 (VMAT2).

4. The method of claim 1 , wherein the pharmaceutical composition inhibits or substantially inhibits vesicular monoamine transporter 2 (VMAT2) function.

5. The method of claim 1 , wherein the pharmaceutical composition reduces a craving for MA.

6. The method of claim 1 , further comprising identifying a subject having an MA addiction.

7. The method of claim 1 , wherein the subject is a human or a mammal.

8. The method of claim 1 , wherein R is ethyl ester, isopropyl ester, —C(O)-alkyl, or substituted or unsubstituted 5-membered heteroaryl.

9. The method of claim 8 , wherein R is ethyl ester.

10. The method of claim 8 , wherein R is —C(O)-alkyl.

11. The method of claim 1 , wherein Ar is phenyl, substituted phenyl, pyrrolyl, substituted pyrrolyl, pyridinyl, substituted pyridinyl, thiophene-yl, substituted thiophene-yl, or [1,4]-dioxinyl.

12. The method of claim 1 , wherein the structure of the compound is:

and
wherein A 1 , A 2 , A 3 , and A 4 , are independently H, alkyl, substituted alkyl, aryl, substituted aryl, halo, alkoxy, haloalkyl, haloalkoxy, ester, keto, hydroxyl, amino, substituted amino, amido, or nitro.

13. The method of claim 12 , wherein A 1 , A 2 , A 3 , and A 4 are independently H, methyl, ethyl, isopropyl, [1,4]dioxin-5-yl, fluoro, chloro, trifluoromethyl, amino, dimethylamino, methylamido, nitro, azo, benzyl, 2-phenyl ethyl, pyrrolyl, ethyl ester, 1-hydroxyethyl, hydroxyl, methoxy, trifluoromethoxy, or tert-butoxycarbonylamino.

14. The method of claim 12 , wherein A 1 and A 2 are H, and A 3 and A 4 are independently H, fluoro, or trifluoromethyl.

15. The method of claim 1 , wherein the structure of the compound is:

and
wherein A 3 is halo, and m is 2 or 3.

16. The method of claim 15 , wherein A 3 is fluoro.

17. The method of claim 1 , wherein the structure of the compound is:

wherein Y 1 is H, methyl, ethyl, or 2-benzylethyl, wherein Y 2 is H or halo, and wherein A 3 and A 4 are independently H or halo.

18. The method of claim 1 , wherein the structure of the compound is:

wherein A 1 , A 2 , A 3 , and A 4 are independently H, halo, or haloalkyl, and wherein Y is H or alkyl.

19. The method of claim 18 , wherein Y is H, A 1 and A 2 are H, and A 3 and A 4 are independently H, fluoro, or trifluoromethyl.

Assignees

• Univ Oregon Health & Science
• United States Dept Of Veterans Affairs
• Organix Inc
• The Us Dept Of Veteran Affairs

Inventors

• Janowsky Aaron
• Meltzer Peter

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title