Benzylpiperazinyl-indolinylethanones

Inactive Publication Date: 2002-09-12
NEUROGEN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

0005] This invention provides benzylpiperazinyl-indolinylethanone compounds that bind, preferably with high affinity and selectivity, to the D.sub.4 receptor subtype, including human D.sub.4 receptors. These compounds are therefore useful in treatment of a vari

Problems solved by technology

However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tard

Method used

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  • Benzylpiperazinyl-indolinylethanones

Examples

Experimental program
Comparison scheme
Effect test

example 1

2-{4-[(4-Chlorophenyl)methyl]piperazinyl}-1-(3-methylindolinyl)ethan-1-one

Part A: 3-Methylindoline

[0095] 17

[0096] Hydrochloric acid (10.5 N, 6 mL) is added dropwise to a stirred mixture of 3-methylindole (3.93 g, 30 mmol) and trimethylamine-borane (8.75 g, 120 mmol) in room temperature dioxane (30 mL). The mixture is then heated at reflux for about 30 min. After cooling to room temperature, 6 N hydrochloric acid (24 mL) is carefully added and the mixture is refluxed for 15 min. Most of the dioxane is then removed under reduced pressure, and the residue is diluted with water (200 mL). Some insoluble material is extracted with ether, and the aqueous solution is basified with 30% aqueous sodium hydroxide to pH.about.10. The oily product is extracted with ether, the extracts are washed with water and brine, dried over anhydrous MgSO.sub.4, filtered and evaporated under reduced pressure to provide the product as a light yellow oil (3.75 g, 94% yield).

[0097] .sup.1HNMR (CDCl.sub.3) .delta...

example 2

1-((2R,3R)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl- }ethan-1-one, and

1-((2S,3S)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl- }ethan-1-one

Part A: cis- and trans-2,3-Dimethylindolines

[0103] 20

[0104] These two indolines are prepared starting from 2,3-dimethylindole according to a literature procedure. (Synthesis, 508, (Berger, 1974)).

Part B: 2-Chloro-1-(cis-2,3-Dimethylindolinyl)ethan-1-one

[0105] 21

[0106] The title compound is prepared by the procedure as described in Example 1 (part B) to provide a colorless solid in 75% yield. mp 83-84.degree. C.; .sup.1HNMR (CDCl.sub.3) .delta.8.17 (m, 1H), 7.28-7.08 (m, 7H), 4.24 (m, 1H), 4.18 (s, 2H), 2.90 (m, 1H), 1.32 (d, J=6.3 Hz, 3H), 1.25 (d, J=6.9 Hz, 3H); LC-MS (APCI, m / z) 224 (M+1).sup.+.

Part C: 1-((2R,3R)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]pip- erazinyl}ethan-1-one and

1-((2S,3S)-2,3-Dimethylindolinyl)-2-{4-[(4-Chlorophenyl)methyl]piperazinyl- }ethan-1-one

[0107] 22

[0108] These tw...

example 3

Methyl (2S)-1-(2-{4-[(4-chlorophenyl)methyl]-piperazinyl}indoline-2-carbox- ylate

Part A: Methyl (2S)-1-(2-chloroacetyl)indoline-2-carboxylate

[0109] 23

[0110] The title compound is prepared starting from methyl (2S)-1-(2-chloroacetyl)indoline-2-carboxylate monohydrate (J. Org. Chem. 62, Bertini Gross, 7679 (1997)) and chloroacetyl chloride by the procedure described in Example 1 (step B, 3 eq. triethylamine is used) to provide the product as a colorless oil in 89% yield. .sup.1HNMR (CDCl.sub.3) .delta.7.29-7.06 (m, 4H), 5.16 (m, 1H), 4.12 (s, 2H), 3.77 (s, 3H), 3.64 (m, 1H), 3.41-3.35 (m, 1H); LC-MS (APCI, m / z) 254 (M+1).sup.+.

Part B: Methyl (2S)-1-(2-{4-[(4-chlorophenyl)methyl]piperazinyl}indoline-2- -carboxylate

[0111] 24

[0112] The title compound is prepared starting from methyl (2S)-1-(2-chloroacetyl)indoline-2-carboxylate and [(4-chlorophenyl)methyl- ]piperazine by the procedure described in Example 1 (Part C), and purified by crystallization from ethyl acetate and hexanes to provi...

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Abstract

Disclosed are benzylpiperazinyl-indolinylethanone compounds which 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. Pharmaceutical compositions, including packaged pharmaceutical compositions, are further provided. Compounds of the invention are also useful as probes for the localization of GABA.sub.A receptors in tissue samples.

Description

BACKGROUND OF THE INVENTION[0001] This application claims priority to provisional application No. 60 / 138,974 filed Jun. 14, 1999, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002] This invention relates to benzylpiperazinyl-indolinylethanones, and to compounds that bind to dopamine receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the treatment of central nervous system (CNS) diseases, particularly the treatment or prevention of psychotic disorders such as schizophrenia. Additionally this invention relates to the use of compounds as probes for the localization of dopamine receptors in tissue sections.DESCRIPTION OF THE RELATED ART[0003] The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardi...

Claims

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Application Information

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IPC IPC(8): C07D209/08C07D209/10C07D209/12C07D209/14C07D209/42C07D209/86
CPCC07D209/08C07D209/10C07D209/12C07D209/14C07D209/42C07D209/86
Inventor ZHAO, HETHURKAUF, ANDREW
Owner NEUROGEN
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