VMAT inhibitory compounds
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.
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.