Vinylogous phenethylamines as neurotransmitter releasers

Patent metadata

Field	Value
Publication number	US-10899699-B2
Application number	US-201716300436-A
Country	US
Kind code	B2
Filing date	May 11, 2017
Priority date	May 12, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The disclosure provides monoamine neurotransmitter releaser and/or monoamine uptake inhibitor compounds having biogenic amine transporter activity but lacking substantial activity at 5-HT2 receptor subtypes. The phenethylamine or vinylogous phenethylamine compounds of the disclosure are useful in treating diseases, conditions and/or disorders mediated by activity of one or more of the monoamine neurotransmitters.

First claim

What is claimed is:

1. A method of mediating dopamine transporter (DAT) and norepinephrine transporter (NET) activity with a substrate type releaser, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the structure of Formula I:

wherein A is C 3-4 alkynyl or C 2-4 alkenyl; R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 alkyl, optionally substituted C 1-2 alkoxy, optionally substituted C 2-3 alkenyl, optionally substituted C 2-3 alkynyl, halo, amino, CN, CF 3 , and NO 2 ; and R 10 and are H or C 1-3 alkyl; or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

2. The method according to claim 1 , wherein A is C 2-4 alkenyl.

3. The method according to claim 2 , wherein the compound is represented by the structure of formula II:

wherein R 6 and Ware each independently selected from H or C 1-3 alkyl and R 8 is selected from H, OH, optionally substituted C 1-3 alkyl, optionally substituted C 1-2 alkoxy, optionally substituted C 2-3 alkenyl, optionally substituted C 2-3 alkynyl, halo, amino, CN, CF 3 , and NO 2 ; or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

4. The method according to claim 3 , wherein R 10 and R 11 are H.

5. The method according to claim 3 , wherein the compound is selected from (3E)-1-Methyl-4-phenyl-but-3-enylamine, (3Z)-1-Methyl-4-phenyl-but-3-enylamine and stereoisomers thereof.

6. The method according to claim 3 , wherein the compound is represented by formula IIa:

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

7. The method according to claim 1 , wherein A is C 3-4 alkynyl.

8. The method according to claim 1 , wherein A is C 3 alkynyl and R 10 and R 11 are H.

9. The method according to claim 1 , wherein the compound is a serotonin transmitter (SERT) releaser.

10. A method of mediating dopamine transporter (DAT) and norepinephrine transporter (NET) activity with a substrate type releaser, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to the structure of Formula II:

R 1 -R 5 and R 9 are each independently selected from H, OH, optionally substituted C 1-3 alkyl, optionally substituted C 1-2 alkoxy, optionally substituted C 2-3 alkenyl, optionally substituted C 2-3 alkynyl, halo, amino, CN, CF 3 , and NO 2 ; R 6 and R 7 are each independently selected from H or C 1-3 alkyl; R 8 is selected from H, OH, optionally substituted C 1-3 alkyl, optionally substituted C 1-2 alkoxy, optionally substituted C 2-3 alkenyl, optionally substituted C 2-3 alkynyl, halo, amino, CN, CF 3 , and NO 2 ; and R 10 and R 11 are H or C 1-3 alkyl; or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

11. The method of claim 10 , wherein the compound is represented by formula IIa:

Zone Name: or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

12. The method of claim 10 , wherein the compound is a serotonin transmitter (SERT) releaser.

Assignees

• Res Triangle Inst

Inventors

• Blough Bruce
• Decker Ann
• Rothman Richard

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• C07C211/28 Primary

  having amino groups linked to the six-membered aromatic ring by unsaturated carbon chains · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61K31/135

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title