Urea and amide derivatives of aminoalkylpiperazines and use thereof

Patent metadata

Field	Value
Publication number	US-2017190711-A1
Application number	US-201715463051-A
Country	US
Kind code	A1
Filing date	Mar 20, 2017
Priority date	Oct 11, 2012
Publication date	Jul 6, 2017
Grant date	—

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 represented by the formula:

wherein:
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-aryl-1-cyclohexyl or 1-aryl-4-piperidinyl 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.

2 . A compound represented by following formula (I)

In which:
Y is an unbranched, saturated or unsaturated hydrocarbon chain with 2-5 hydrocarbon atoms
R 1 =heterocycle other than benzothiophene
R 2 =4-substituted cyclohexyl, 1-substituted piperidine-4-yl or imidazo(1,2-a)azine-2-yl,
pharmaceutically acceptable salts thereof, deuterated forms thereof, isomers thereof, solvates thereof, and mixtures thereof.

3 . The compound of claim 1 being 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)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxamide,
N-(4-(4-(2,6-Di-tert-butylpyrimidin-4-yl)piperazin-1-yl)butyl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxamide

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

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/36

  Opioid-abuse · CPC title