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Novel indole derivatives

A technology of indole and compound, applied in the field of new indole derivatives, can solve the problem of lack of extrapyramidal activity and the like

Inactive Publication Date: 2003-08-20
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

dopamine D 4 - Receptors are predominantly located in brain regions other than the striatum, implying that dopamine D 4 -Receptor ligand has psychoactive effects and lacks extrapyramidal activity

Method used

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  • Novel indole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0174] 1a. 4-{4-[3-(2-Chloro-phenoxy)-propyl]-piperazin-1-yl}-1H-indole

[0175] To a slurry of sodium hydride (47 mmol) in tetrahydrofuran (50 mL) was added dropwise a solution of 2-chlorophenol (5 g) in tetrahydrofuran (25 mL) at room temperature. The mixture was stirred for 30 minutes. The reaction mixture was warmed to reflux, after which 2-bromo-1-propanol (3.5 mL) in tetrahydrofuran (25 mL) was added over 5 minutes. The mixture was refluxed overnight, another equivalent of 3-bromo-1-propanol was added, and the mixture was refluxed for an additional 12 hours. The mixture was cooled, brine and ethyl acetate were added and washed using standard procedures. The combined organic phases were dried and evaporated. The crude product 3-(2-chlorophenoxy)-1-propanol was dissolved in acetonitrile (500 mL), and carbon tetrabromide (38.7 g) was added. To the cooled (0° C.) mixture was added triphenylphosphine (25.5 g) portionwise over 30 minutes. The reaction was allowed to proce...

Embodiment 2

[0177] 2a. 4-{4-[3-(2-Chloro-phenylthio)-propyl]-piperazin-1-yl}-1H-indole, 0.75 oxalate

[0178]To a slurry of sodium hydride (38 mmol) in dimethylformamide was added a solution of 2-chlorothiophenol (5 g) in dimethylformamide (50 mL) dropwise over 15 minutes at room temperature. The mixture was stirred for 30 minutes. The reaction mixture was added slowly (10 minutes) to a solution of 1,3-dibromopropane in dimethylformamide (25 mL) at room temperature. The final mixture was stirred for an additional 60 minutes. The reaction was quenched by adding sufficient water to consume excess sodium hydride, acidified with etherified hydrochloric acid, and evaporated. The crude product was purified by flash chromatography on silica gel (heptane:ethyl acetate:triethylamine / 95:2.5:2.5) to give 3-(2-chlorophenylthio)-1-propyl bromide (5.7 g). (1H-indol-4-yl)piperazine (1.1 g), potassium carbonate (2.3 g), potassium iodide (catalyst ) and 3-(2-chlorophenylthio)-1-propyl bromide (1.5 g) ...

Embodiment 3

[0190] 3a. 4-{4-[2-(2-Chloro-4-fluoro-phenylthio)-ethyl]-piperazin-1-yl}-1H-indole, 1.25 oxalate

[0191] To a mixture of (1H-indol-4-yl)piperazine (2.50 g) and triethylamine (3.8 g) in dry tetrahydrofuran was added dropwise a solution of chloroacetyl chloride (1.86 g) over 10 minutes at room temperature. Solution in water tetrahydrofuran (5 mL). After 40 minutes the reaction was quenched with water and washed (ethyl acetate) using standard procedures. Drying and evaporation gave 3.5 g of the chloroacetylated derivative. This crude product was used directly in the next step. 2-Chloro-4-fluorothiophenol (1.1 g) was dissolved in tetrahydrofuran (40 mL), and potassium tert-butoxide (0.84 g) was added, followed by stirring for 10 minutes. The above mixture was treated dropwise with a solution of the chloroacetylated derivative prepared above (1.70 g) in tetrahydrofuran (20 mL). The reaction was allowed to proceed at room temperature for 1 hour, then at reflux for 20 minutes be...

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Abstract

The invention provides compounds of formula (I) wherein X represents O or S; n is 2, 3, 4, 5, 6, 7, 8, 9 or 10; m is 2 or 3; Y represents N, C or CH; and the dotted line represents an optional bond; R<1>, R<1'>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R<10>, R<11> and R<12> are as defined in the description. The compounds are ligands of the 5-HT1a-receptor.

Description

[0001] The present invention relates to 5-HT 1A - New receptor-binding indole derivatives, pharmaceutical compositions containing these compounds and their use in the treatment of certain psychiatric and neurological diseases. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and / or D 4 Ligands are therefore thought to be particularly useful in the treatment of depression and psychosis. Background of the invention [0002] Clinical and pharmacological studies have shown that 5-HT 1A - Agonists and partial agonists are useful for the treatment of a range of affective disorders such as generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, depression and aggression. [0003] 5-HT has also been reported 1A - The ligands are useful in the treatment of ischemia. [0004] to 5-HT 1A - A review of antagonists and proposed potential therapeutic targets for these inhibitors based on preclinical and clinical data is described...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/496A61P1/14A61P25/18A61P25/20A61P25/22A61P25/24A61P43/00C07D209/08
CPCC07D209/08A61P1/14A61P25/18A61P25/20A61P25/22A61P25/24A61P43/00A61K31/496
Inventor T·鲁兰德C·克罗格-詹森M·罗特莱恩德G·米克尔森K·安德森E·K·莫尔岑
Owner H LUNDBECK AS
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