2-piperazino alkylatnino benzoazole derivatives: dopamine receptor subtype sepcific ligands

A technology of alkylamino and alkylsulfonyl, which is applied in the field of pharmaceutical compositions containing the compound, and can solve problems such as delayed dyskinesia

Inactive Publication Date: 2001-12-05
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, neuroleptics often produce undesired extrapyramidal side effects (EPS) and delayed dys...

Method used

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  • 2-piperazino alkylatnino benzoazole derivatives: dopamine receptor subtype sepcific ligands

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0109] 1-(5-fluoropyrimidin-2-yl)-4-(4-aminobutyl)piperazine

[0110] At 80°C, 4-bromo-N-butylphthalimide (8.37g) and 1-(5-fluoropyrimidin-2-yl)piperazine (5.4g) containing potassium carbonate (8.2g) A solution of dimethylformamide (100 mL) was stirred for 12 hours. After cooling, the mixture was poured into water and extracted with ether. The ether layer was dried over sodium sulfate, filtered and concentrated to give the intermediate as a yellow solid. The resulting phthalimide was then dissolved in hydrazine monohydrate (100ml) and refluxed under nitrogen overnight. After cooling, the mixture was poured into a 30% solution of potassium carbonate (500ml) and extracted with diazomethane, dried and concentrated to give an orange semi-solid (4.66g). This material was dissolved in a 10% methanol / isopropanol mixture (50ml), treated with fumaric acid (4.27g, 2eq) and the solvent volume reduced to 20ml. The resulting yellow crystals (6.5 g) were collected by filtration.

Embodiment 2

[0112] 1-(5-fluoropyrimidin-2-yl)-4-(2-[6-benzothiazol-2-ylamino]butyl)piperazine hydrogen fumarate

[0113]Acetonitrile solution (10 mL) of 2-chlorobenzothiazole (920 mg) and 1-(5-fluoropyrimidin-2-yl)-4-(4-aminobutyl)piperazine (254 mg) ) was refluxed under nitrogen for 10 hours. After cooling, the mixture was concentrated and the resulting residue was partitioned between ethyl acetate and water. The organic phase was separated and extracted with 10% citric acid. The acidic aqueous phase was basified with 10N NaOH solution and extracted with chloroform. The chloroform layer was then dried over sodium sulfate, filtered and concentrated to give the title compound as a white solid (0.31 g). [also known as benzothiazol-2-yl{4-[4-(5-fluoropyrimidin-2-yl)piperazinyl]butyl}amine]. This material was dissolved in 10% methanol / isopropanol and treated with fumaric acid (190 mg). The solvent volume was reduced a portion and the resulting crystals (347 mg, m.p. 168-170°C) were iso...

Embodiment 3

[0115] 1-(2-Methylhydrophenyl)-4-(2-[6-fluorobenzothiazol-2-ylamino]ethyl)piperazine hydrogen fumarate

[0116] A solution of 6-fluoro-2-aminobenzothiazole (5 g) and triethylamine (5 ml) in chloroform (100 ml) was stirred vigorously during the dropwise addition of a solution of chloroacetyl chloride (5 ml) in chloroform (10 ml). The reaction mixture was stirred overnight, filtered and concentrated. The residue was triturated with isopropanol to give a white solid (3.82g).

[0117] A portion of this solid (150mg, 0.61mmol) was dissolved in acetonitrile (10ml) and phased. To the resulting solution were added 1-(2-methoxyphenyl)piperazine (118mg) and potassium carbonate (150mg). The mixture was refluxed overnight. After cooling, the solvent was removed and the resulting residue was partitioned between ethyl acetate and water. The organic phase was dried and evaporated to give a yellow oil which was purified by preparative thin layer chromatography eluting with 9% methanol / ch...

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Abstract

Disclosed are compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein: A is (un)substituted alkylene; R1 and R2 are the same or different and represent hydrogen, halogen, alkyl, alkoxy, alkylthio, hydroxy, (un)substituted amino, cyano, nitro, sulfonamide, trifluoromethyl or trifluoromethoxy; R3, R4, R5, R6 and R8 are independently hydrogen or alkyl; and X is sulfur, oxygen or NR7 where R8 is defined herein; m is an integer chosen from 0, 1 or 2; and Ar is an aryl or heteroaryl group as further defined herein, which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

Description

Background of the invention [0001] invention technical field [0002] The present invention relates to 2-piperazinylaminobenzopyrrole derivatives and to pharmaceutical compositions containing the compounds. It also relates to the use of such compounds in the treatment or prevention of psychiatric disorders such as schizophrenia and other central nervous system disorders. [0003] Description of relevant prior art [0004] It is generally believed that commonly used antipsychotic drugs, called neuroleptics, work by blocking dopamine receptors. However, neuroleptics often produce undesired extrapyramidal side effects (EPS) and delayed dyskinesias, which are due to the blockage of D in the striatal region of the brain. 2 caused by receptors. Dopamine D receptor subtypes have recently been identified (Nature, 350:610 (Van Tol et al., 1991); Nature, 347:146 (Sokoloff et al., 1990)). Its specific location in the limbic region and its differential recognition of various neurolep...

Claims

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Application Information

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IPC IPC(8): C07D277/82A61K31/495A61K31/496A61K31/506A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30C07D209/48C07D235/30C07D263/58C07D401/12C07D403/12C07D413/12C07D417/12C07D419/12
CPCC07D209/48C07D401/12A61K31/495C07D235/30C07D277/82C07D403/12A61K31/506A61K31/496C07D417/12C07D419/12C07D413/12C07D263/58
Inventor 何晓舒
Owner NEUROGEN
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