Tetrahydroazepine derivatives useful as dopamine d3 receptor modulators (antipsychotic agents)

A technology of compound and alkyl, applied in the field of novel tetrahydrobenzazepine derivatives

Inactive Publication Date: 2004-03-31
SMITHKLINE BECKMAN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clearly, the association of these compounds with dopamine D 3 Recepto

Method used

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  • Tetrahydroazepine derivatives useful as dopamine d3 receptor modulators (antipsychotic agents)
  • Tetrahydroazepine derivatives useful as dopamine d3 receptor modulators (antipsychotic agents)
  • Tetrahydroazepine derivatives useful as dopamine d3 receptor modulators (antipsychotic agents)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 173

[0506] 7-(5-methyl-isoxazol-3-yl)-3-{4-[4-methyl-5-(2-methyl-quinolin-6-yl)-4H-[1,2 ,4] Triazol-3-yl]-butyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0507] a) 4-[1,3]dioxan-2-yl-butyric acid methyl ester

[0508] Methyl 5,5-dimethoxyvalerate (20.0 g, 0.114 mol), propane-1,3- Diol (13 g, 0.17 mol) and p-toluenesulfonic acid (2.17 g, 0.0114 mol) for 4 hours. The mixture was cooled to room temperature, diluted with diethyl ether (100ml), then neutralized with solid sodium bicarbonate, the solid filtered and the filtrate evaporated to give a pale yellow oil (22.3g). 10 g of this material was purified by silica gel chromatography (eluent: 30% ethyl acetate:hexane) to obtain the title compound (6.82 g) as a colorless oil.

[0509] b) 4-[1,3]dioxan-2-yl-butanoic acid

[0510] 4-[1,3]dioxan-2-yl-butyric acid methyl ester (6.8 g, 0.036 mol), the mixture was stirred at room temperature for 18 hours, then the solvent was evaporated. The resulting residue was partitioned with ethyl ...

Embodiment 174

[0529] 3-14-[5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-yl]-butyl}-7-(5-methyliso Oxazol-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine

[0530] Mass spectrometry (API + ): measured value 460 (MH + ). C 27 h 30 N 5 OF expects 459.

[0531]

Embodiment 175

[0533] 7-Ethylsulfonyl-3-[4-(4-methyl-5-quinolin-6-yl-4H-[1,2,4]triazol-3-ylthio)butyl]-2,3 , 4,5-Tetrahydro-1H-benzo[d]azepine

[0534] a) 6-{5-[3-(5,5-dimethyl-[1,3]dioxan-2-yl)-propylthio]-4-methyl-4H-[1,2, 4] Triazol-3-yl}-quinoline

[0535] In dimethylformamide, 4-methyl-5-quinolin-6-yl-4H-[1,2,4]triazole-3-thiol (0.5g, 2.07mmol) was heated at 100°C , 2-(3-bromopropyl)-5,5-dimethyl-[1,3]dioxane (0.49g, 2.07mmol) and lithium hydroxide (50mg) for 3 hours, the mixture was cooled and washed with water ( 80ml) and ethyl acetate (100ml). After separating the aqueous and organic layers, the aqueous layer was re-extracted with ethyl acetate (100ml). The combined organic phases were washed with brine (100ml), and washed with Na 2 SO 4 Drying, filtration and evaporation gave a colorless oily substance. Purification by silica gel chromatography (eluent: ethyl acetate-10% methanol: ethyl acetate) afforded the title compound (0.53 g, 65%) as a colorless solid.

[0536] Mass sp...

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Abstract

The invention provides compounds of formula (I), wherein R1-R4, A, B and t are as defined in claim 1. The compounds are modulators of dopamine D3 receptors and have potential in the treatment of psychotic conditions (e.g. schizophrenia) or substance abuse.

Description

[0001] This invention relates to a novel tetrahydrobenzazepine derivative, its preparation process, intermediates used in the process, pharmaceutical compositions containing this substance, and as dopamine D 3 Receptor modulators, especially for therapeutic use as neuroleptics. Background of the invention [0002] U.S. Patent No. 5,294,621 describes derivatives of tetrahydropyridine of the formula: [0003] [0004] in [0005] [0006] is an optionally substituted thienyl or an optionally substituted benzene ring; R 1 , R 2 and R 3 are H atoms; X is (CH 2 ) m NR 7 CO, where m is 2-4; Ar 1 is an optionally substituted heterocycle or an optionally substituted benzene ring. The compound is said to be useful as an antiarrhythmic drug. [0007] Patent EPA 431,580 describes certain dopaminergic agents useful as tranquillizers, antihypertensives, etc. Patent WO 95 / 10513 describes benzothiophene derivatives and related compounds, which are useful as estrogen agonists....

Claims

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Application Information

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IPC IPC(8): A61K31/55A61P25/16A61P25/18A61P25/22A61P25/24A61P25/30A61P43/00C07D223/16C07D401/12C07D401/14C07D403/04C07D403/12C07D403/14C07D405/12C07D405/14C07D409/14C07D413/04C07D413/12C07D413/14C07D417/12C07D471/04C07D495/04
CPCC07D223/16C07D471/04C07D413/14C07D403/04C07D403/12C07D405/12C07D403/14C07D409/14C07D413/12C07D495/04C07D401/14C07D401/12C07D413/04C07D405/14C07D417/12A61K31/55A61P25/00A61P25/16A61P25/18A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00
Inventor 迈克尔·S·哈德利安德鲁·P·莱特富特格雷戈尔·J·麦克唐纳杰弗里·斯坦普
Owner SMITHKLINE BECKMAN CORP
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