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Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives

a technology of cycloalkylfused indole and indene derivatives, which is applied in the direction of drug compositions, sexual disorders, metabolic disorders, etc., can solve the problems of reducing the latency period, reducing the energy or motivation of people, and feeling of sadness or emptiness, so as to increase the serotonin level and reduce the latency period

Inactive Publication Date: 2008-04-03
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide.
Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt.
In addition to the personal costs of depression, the disorder also results in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism.
Although they have a favorable side effect profile compared to tricyclic antidepressants (TCAs), they have their own particular set of side effects from the non-selective stimulation of serotonergic sites.
They have a slow onset of action, often taking several weeks to produce their full therapeutic effect.

Method used

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  • Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives
  • Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives
  • Cycloalkylfused indole, benzothiophene, benzofuran and indene derivatives

Examples

Experimental program
Comparison scheme
Effect test

example 1

N-[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine

6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylic acid (I)

[0248] 4-fluorophenylhydrazine (0.90 g, 7.14 mmol) was dissolved in glacial acetic acid (25 mL) under a nitrogen atmosphere and added dropwise to a refluxing solution of 3-cyclohexanonecarboxylic acid ethyl ester (1.73 g, 10 mmol) dissolved in glacial acetic acid (15 mL). After the addition was complete, the solution was heated under reflux for 1 hr, cooled to room temperature and allowed to stir overnight. The orange solution was evaporated under reduced pressure to give a yellow-brown solid. The solid was suspended in 10% sulfuric acid and heated under reflux for 5 hrs, cooled to room temperature and allowed to stir overnight. The brown solid was collected by filtration and recrystallized from acetic acid and water to give the compound I (1.21 g), mp: >200° C. MS [M−H] m / z 232.

[(2S)-8-met...

example 2

N-[(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine

[0253] 6-Fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid ethyl ester (III)

[0254] 4-Cyclohexanonecarboxylic acid ethyl ester (25 g, 0.14 m) and 4-fluorophenyhydrazine hydrochloride (22.5 g, 0.13 m) were dissolved in ethanol (450 mL) and heated under reflux for 16 hrs. After cooling, the white solid was filtered off and the solvent removed under reduced pressure. After partitioning the residue between water and ethyl acetate, the organic portion was separated, dried (MgSO4), and evaporated under reduced pressure to give compound III (35.5 g, 0.13 m). The crude product was recrystallized from heptane. mp: 115-117° C. MS: [M+H]+@m / e=262. [Lit. ref: Block, M. H., et al. J. Med. Chem. 2002,45, 3509].

(6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-methanol (IV)

[0255] Lithium aluminum hydride (800 mg) was added portion-wise to a solution of ester III...

example 3

S,S-(6-Fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylmethyl)-(8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-amine

[0258] The mixture of diastereomers in Example 2 was separated by chromatography using a Varian Prep with Chiralpak AD (0.2×15 cm); mobile phase: methanol with diethylamine. The title product [mp 80-84° C.; MS (ES) m / z 430.2] was dissolved in ethanol and treated with two equivalents of ethereal HCl. Yellow dihydrochloride precipitated out immediately. The compound was isolated by filtration and was washed with ethanol. After drying in vacuo, the title compound was obtained as the dihydrochloride sesquihydrate. mp 253-263° C., MS: [M+H]+ @ (m / z 432.2.

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Abstract

The present invention provides cycloalkylfused indole, benzothiophene, benzofuran, and indene derivatives, and methods for using them to, for example, treat, prevent and / or ameliorate central nervous system diseases by antagonizing 5-HT1A receptors and modulating serotonin levels.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation of application Ser. No. 11 / 355,452 filed on Feb. 16, 2006, which claims benefit of Provisional Application Ser. No. 60 / 653,666, filed Feb. 17, 2005, the disclosures of which are hereby incorporated by reference in their entireties.FIELD OF THE INVENTION [0002] The present invention relates to cycloalkylfused indole, benzothiophene, benzofuran, and indene derivatives, pharmaceutical compositions containing them and methods for their use as, for example, serotonin modulators. BACKGROUND OF THE INVENTION [0003] Major depressive disorder affects an estimated 340 million people worldwide. Depression is the most frequently diagnosed psychiatric disorder, and according to the World Health Organization, it is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some ca...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D491/02C07D209/82C07D333/50
CPCC07D209/88C07D493/04C07D491/04C07D233/76A61P15/10A61P25/18A61P25/22A61P25/24A61P25/28A61P25/34A61P25/36A61P3/04A61P43/00
Inventor SABB, ANNMARIE LOUISEVOGEL, ROBERT LEWISSTACK, GARY PAULEVRARD, DEBORAH ANNFAILLI, AMEDEO ARTUROKRISHNAN, LALITHACHAN, ANITA WAI-YINREN, JIANXINGUINOSSO, CHARLES J.BAUDY, REINHARDT BERNHARDSZE, JEAN YI-CHINGLI, YANFANGSTANTON, CHARLES JOHN IIINIKITENKO, ANTONIA
Owner WYETH LLC
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