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Tricyclic chinoline and quinoxaline derivatives

A technology of quinoxalines and compounds, which is applied in drug combinations, digestive system, metabolic diseases, etc., and can solve problems affecting patient compliance and limiting treatment efficacy, etc.

Inactive Publication Date: 2015-03-18
ABBVIE DEUTSHLAND GMBH & CO KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The appearance of secondary negative symptoms not only limits the efficacy of treatment, but also negatively impacts patient compliance along with these side effects

Method used

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  • Tricyclic chinoline and quinoxaline derivatives
  • Tricyclic chinoline and quinoxaline derivatives
  • Tricyclic chinoline and quinoxaline derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] 1-fluoro-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepine And[1,7,6-de]pyrrolo[1,2-a]quinoxaline, trifluoroacetic acid

[0102]

[0103] 1.1 Preparation of pyrrolidine-2-methyl carboxylate

[0104] SOCl at 0°C 2 (250ml) was added dropwise to a solution of pyrrolidine-2-carboxylic acid (75g, 651mmol) in methanol (750ml) and the reaction mixture was stirred at 20°C for 16 hours. Set up an additional vial in the same manner. The two reaction mixtures were combined and concentrated under reduced pressure to obtain the title compound (90 g, 543 mmol, yield 50%).

[0105] 1 H NMR (400MHz, DMSO-d 6 ): δ[ppm]: 9.83(s, 1H), 4.32(t, J=7.6Hz, 1H), 3.72(s, 3H), 3.21-3.15(m, 2H), 2.22-2.20(m, 1H) , 1.96-1.87(m, 3H)

[0106] 1.2 Preparation of 1-(2-fluoro-6-nitro-phenyl)-pyrrolidine-2-carboxylic acid methyl ester

[0107] Triethylamine (26.3 mL, 189 mmol) and 1,2-difluoro-3-nitrobenzene (15 g, 94 mmol) were added to methyl pyrrolidine-2-carboxylate (17.18 g, 104 mmol) in a...

Embodiment 2

[0133] 1-bromo-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepine And[1,7,6-de]pyrrolo[1,2-a]quinoxaline

[0134]

[0135] 2.1 Preparation of 11-(2-bromo-6-nitro-phenyl)-pyrrolidine-2-carboxylate

[0136] A mixture of 1-bromo-2-fluoro-3-nitrobenzene (60 g, 273 mmol), methyl pyrrolidine-2-carboxylate (54.2 g, 327 mmol; see Example 1.1) and triethylamine (83 g, 818 mmol) Heated at 70°C for 16h. The mixture was then cooled, diluted with ethyl acetate (1000ml), washed successively with 2N HCl (500ml), K 2 CO 3 Aqueous solution (300ml) and brine (300ml) were washed and the aqueous phase was re-extracted with ethyl acetate (500ml). Ethyl acetate layer with Na 2 SO 4 Drying, filtration, concentration, and the residue was purified by column chromatography on silica gel (eluted with petroleum ether: ethyl acetate = 50:1 to 10:1) to give the title compound as a yellow solid (66 g, yield rate of 74%).

[0137] 1 HNMR (400MHz, CDCl 3 ), δ [ppm] 7.80-7.78 (m, 1H), 7.64-7.62 (m, ...

Embodiment 3

[0155] 1-methyl-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepine And[1,7,6-de]pyrrolo[1,2-a]quinoxaline, trifluoroacetic acid

[0156]

[0157] 3.1Boc-protected 1-bromo-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepine Preparation of [1,7,6-de]pyrrolo[1,2-a]quinoxaline

[0158] Triethylamine (6.4g, 63.3mmol) and Boc 2 A solution of O (10.1 g, 46.4 mmol) in DCM (20 ml) was added to 1-bromo-5,6,7,9,9a,10,11,12-octahydro-4H-[1,4]diazepine miscellaneous A solution of a[1,7,6-de]pyrrolo[1,2-a]quinoxaline (13 g, 42.2 mmol) in dichloromethane (DCM) (260 ml) was then allowed to warm to 23 ° C and stirred for 16h. The reaction was diluted with DCM (250ml), washed with 2N HCl (200ml), saturated K 2 CO 3 Aqueous solution (150ml) and brine (150ml) were washed, and the aqueous phase was re-extracted with DCM (200ml). The combined organic phases were washed with Na 2 SO 4 Dry, filter, and concentrate, and the residue was purified by column chromatography on silica gel (eluted w...

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Abstract

The invention relates to application of tricyclic chinoline and quinoxaline derivatives as well as a pharmaceutical composition containing the tricyclic chinoline and quinoxaline derivatives as a modifier, in particular agonists or partial agonists of a 5-HT2C receptor, application of the tricyclic chinoline and quinoxaline derivatives to preparing drugs for preventing or treating regulation response conditions and diseases of the 5-HT2c receptor, a method used for preventing or treating the regulation response conditions and diseases of the 5-HT2c receptor, and a method for preparing the compounds and the composition.

Description

field of invention [0001] The present invention relates to tricyclic quinoline and quinoxaline derivatives, pharmaceutical compositions containing such compounds as 5-HT 2C Use of receptor modulators, in particular agonists or partial agonists, for the preparation of prophylaxis or treatment of 5-HT 2c Use of a medicament for conditions and disorders that modulate response of receptors, for the prevention or treatment of 5-HT 2c Methods of modulating receptor response to conditions and disorders, and methods of making such compounds and compositions. Background of the invention [0002] which requires 5-HT 2C Diseases, disorders and conditions modulated are eg depression, anxiety, schizophrenia, bipolar disorder, obsessive compulsive disorder, migraine, pain, epilepsy, substance abuse, eating disorders, obesity, diabetes, erectile dysfunction and others. [0003] Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter and local hormone formed by hydroxylatio...

Claims

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Application Information

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IPC IPC(8): C07D487/16C07D471/06A61K31/5517A61K31/5513A61P25/00A61P1/14A61P27/02A61P9/00A61P1/00A61P3/10
CPCC07D471/06C07D487/16
Inventor W·布拉耶H·马克H·库尔曼
Owner ABBVIE DEUTSHLAND GMBH & CO KG
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