Urea and amide derivatives of aminoalkylpiperazines and use thereof

Patent metadata

Field	Value
Publication number	US-9969743-B2
Application number	US-201715463051-A
Country	US
Kind code	B2
Filing date	Mar 20, 2017
Priority date	Oct 11, 2012
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

Provided are compounds represented by the formula:

In which:
Y is an unbranched, saturated or unsaturated hydrocarbon chain with 2-5 hydrocarbon atoms R 1 =aryl R 2 =NR 3 R 4 wherein R 3 and R 4 together form a heterocycle or R 2 =4-substitutedcyclohexyl, 1-substitutedpiperidine-4-yl or imidazo(1,2-a)azine-2-yl when Y is as defined above and R 1 is a heterocycle other than benzothiophene pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, solvates thereof, and mixtures thereof.

The compounds can be used for treating a patient suffering from a condition that is capable of treatment with a partial agonist or antagonist of the dopamine D2/D3 receptors. The compounds are especially useful for patients suffering from schizophrenia, depressions, neurodegenerative diseases such as Parkinson's, dyskinesias, substance abuse and relapse to substance abuse and addiction to substances such as cocaine, methamphetamine, nicotine and alcohol, glaucoma, cognitive disorders, restless leg syndrome, attention deficit hyperactivity disorders, hyperprolactinemia, autism, motor disturbances such as akathisia, rigor, dystonias as well as various disorders of the urinary tract and other neurologic disorders. Also provided are processes for the preparation of compounds of the present disclosure.

First claim

What is claimed is:

1. A compound selected from the group consisting of:
4-Phenyl-N-(4-(4-phenylpiperazin-1-yl)butyl)piperazine-1-carboxamide,
4-Phenyl-N-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(3-Cyano-5-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(6-(tert-Butyl)-2-methylpyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-cyclopropylpyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2,6-Di-tert-butylpyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
4-Phenyl-N-(4-(4-(quinolin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
N-(4-(4-(7-Chloroquinolin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)quinazolin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(2-chlorophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(3-chlorophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(4-chlorophenyl)piperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-cyano-4-phenylpiperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(2,3-dichlorophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(2-methoxyphenyl)piperazine-1-carboxamide),
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(3-methoxyphenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(4-methoxyphenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(m-tolyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(p-tolyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(2,3-dimethylphenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(2-cyanophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(3-cyanophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(3-(trifluoromethyl)phenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(pyridin-3-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(pyridin-4-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert Butyl-)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(pyrimidin-2-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(pyrazin-2-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(quinolin-4-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-cyclopropylpiperazine-1-carboxamide,
4-Benzyl-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
4-Benzoyl-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-3-(pyridin-4-yl)azetidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)isoindoline-2-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-5-methoxyisoindoline-2-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxamide,
4-([1,1′-Biphenyl]-2-yl)-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
4-([1,1′-Biphenyl]-3-yl)-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
4-([1,1′-Biphenyl]-4-yl)-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)butyl)-4-(phenylsulfonyl)piperazine-1-carboxamide,
N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)-4-phenylpiperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-phenylpiperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-hydroxy-4-phenylpiperidine-1-carboxamide,
4-Benzyl-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-phenoxypiperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-methylpyrimidin-4-yl)piperazin-1- yl)butyl)-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)- 8-cyano-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxamide,
N-(4-(4-(2,6-Di-tert-butylpyrimidin-4-yl)piperazin-1-yl)butyl)-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole-2-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(4-chlorophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-(o-tolyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-(4-cyanophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-(3,4-dichlorophenyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin- 1-yl)butyl)-4-(3-cyano-5-(trifluoromethyl)phenyl)piperazine-1-carboxamide,
4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)-N-(4-(4-(2-(tert-butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-(7-chloroquinolin-4-yl)piperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-methylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4-ethylpiperazine-1-carboxamide,
N-(4-(4-(2-(tert-Butyl)-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)butyl)-4

Assignees

• Southern Res Inst

Inventors

• Ananthan Subramaniam

Classifications

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/32

  Alcohol-abuse · CPC title