Quinazolines as biogenic amine transport modulators

Patent metadata

Field	Value
Publication number	US-10087148-B2
Application number	US-201514960023-A
Country	US
Kind code	B2
Filing date	Dec 4, 2015
Priority date	Dec 5, 2014
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

The present disclosure relates to certain amine derivatives of fused bicyclic heterocycles that inhibit the amine reuptake function of the biogenic amine transporters, dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET). Compounds of the present disclosure are potent inhibitors of the reuptake of dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) with full or partial maximal efficacy. The compounds with partial maximal efficacy in inhibiting reuptake of all three biogenic amines are herein referred to as partial triple uptake inhibitors (PTRIs). Compounds of the present disclosure are useful for treating depression, pain and substance abuse and relapse to substance abuse and addiction to substances such as cocaine, methamphetamine, nicotine and alcohol. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound selected from the group consisting of:
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-2-yl)ethyl)quinazolin-4-amine
N-(4-(4-((2-Hydroxy-2,2-diphenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-((2-(4-(Dimethylamino)phenyl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
N-(4-(4-((2-Cyclohexyl-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(2-Cyclohexyl-2-phenylethyl)-2-(4-(dimethylamino)phenyl)quinazolin-4-amine;
N-(4-(4-((2-Phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(4-(4-((2-Phenyl-2-(1H-pyrrol-2-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(piperidin-1-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-morpholino-2-phenylethyl)quinazolin-4-amine;
N-(4-(4-((2-Morpholino-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2-(4-methylpiperazin-1-yl)-2-phenylethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
N-(4-(4-((2-Phenyl-2-(pyridin-3-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2,3-diphenylpropyl)quinazolin-4-amine;
(5-(2-((2-(4-(Dimethylamino)-2-methylphenyl)quinazolin-4-yl)amino)-1-phenylethyl)-1H-pyrrol-2-yl)methanol;
N-(3-Methyl-4-(4-((2-phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2-(pyridin-3-yl)-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(2,2-Di(pyridin-4-yl)ethyl)-2-(4-(dimethylamino)phenyl)quinazolin-4-amine;
N-(4-(4-((2,2-Di(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2,2-diphenylpropyl)quinazolin-4-amine;
N-(4-(4-((2,2-Diphenylpropyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(1,2-diphenylethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(3-methyl-2-phenylbutyl)quinazolin-4-amine;
N-(4-(4-((3-Methyl-2-phenylbutyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
2-(4-(Dimethylamino)phenyl)-N-(2-phenoxy-2-phenylethyl)quinazolin-4-amine;
N-(4-(4-((2-Phenoxy-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

2. A compound having a structure selected from:

3. A pharmaceutical composition comprising a compound according to claim 2 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

4. The compound of claim 1 , selected from the group consisting of:
N-(4-(4-((2-Hydroxy-2,2-diphenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Cyclohexyl-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Phenyl-2-(1H-pyrrol-2-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Morpholino-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Phenyl-2-(pyridin-3-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(3-Methyl-4-(4-((2-phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2,2-Di(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2,2-Diphenylpropyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((3-Methyl-2-phenylbutyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Phenoxy-2-phenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

5. The compound of claim 1 , selected from the group consisting of:
N-(4-(4-((2-Hydroxy-2,2-diphenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(4-(4-((2-Phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide;
N-(3-Methyl-4-(4-((2-phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

6. The compound of claim 1 , selected from the group consisting of:
N-(4-(4-((2-Hydroxy-2,2-diphenylethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

7. The compound of claim 1 , selected from the group consisting of:
N-(4-(4-((2-Phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

8. The compound of claim 1 , selected from the group consisting of:
N-(3-Methyl-4-(4-((2-phenyl-2-(pyridin-4-yl)ethyl)amino)quinazolin-2-yl)phenyl)methanesulfonamide; and
pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , selected from the group consisting of:
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-2-yl)ethyl)quinazolin-4-amine
2-((2-(4-(Dimethylamino)phenyl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
N-(2-Cyclohexyl-2-phenylethyl)-2-(4-(dimethylamino)phenyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(piperidin-1-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-morpholino-2-phenylethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-(4-methylpiperazin-1-yl)-2-phenylethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2,3-diphenylpropyl)quinazolin-4-amine;
(5-(2-((2-(4-(Dimethylamino)-2-methylphenyl)quinazolin-4-yl)amino)-1-phenylethyl)-1H-pyrrol-2-yl)methanol;
2-(4-(Dimethylamino)phenyl)-N-(2-(pyridin-3-yl)-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(2,2-Di(pyridin-4-yl)ethyl)-2-(4-(dimethylamino)phenyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2,2-diphenylpropyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(1,2-diphenylethyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(3-methyl-2-phenylbutyl)quinazolin-4-amine;
2-(4-(Dimethylamino)phenyl)-N-(2-phenoxy-2-phenylethyl)quinazolin-4-amine; and
pharmaceutically acceptable salts thereof.

10. A pharmaceutical composition comprising a compound according to claim 1 or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

11. The compound of claim 2 , wherein the compound has a structure:

12. The compound of claim 2 , wherein the compound has a structure:

Assignees

• Ananthan Subramaniam
• Rothman Richard B
• The Us Secretary Department Of Health And Human Services Office Of Technology Transfer National Inst
• Southern Res Inst

Inventors

• Ananthan Subramaniam
• Rothman Richard B

Classifications

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/24

  Antidepressants · CPC title