Tricyclic diazepines as tocolytic oxytocin receptor antagonists

A technology of halogen and medicinal salt, applied in the field of novel tricyclic diazepines

Inactive Publication Date: 2004-06-02
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since peptide oxytocin antagonists also exhibit vasopressin antagonist activity, they are not orally active and many of these peptides are non-selective antagonists

Method used

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  • Tricyclic diazepines as tocolytic oxytocin receptor antagonists
  • Tricyclic diazepines as tocolytic oxytocin receptor antagonists
  • Tricyclic diazepines as tocolytic oxytocin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0273] 10-[(2-methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1- c][1,4]benzodiazepine-3-carboxylic acid

[0274] Step A. Methyl 4-bromo-3-methylbenzoate

[0275] To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated at reflux overnight and a homogeneous solution was obtained after several minutes of heating. After cooling, methanol was removed under vacuum and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 10.2 g of the title compound as a brown solid, m.p. 41-43°C.

[0276] 1 H NMR (DMSO-d 6 , 400MHz): δ2.39(s, 3H), 3.85(s, 3H), 7.64-7.72(m, 2H), 7.88-7.89(m, 1H).

[0277] MS [EI, m / z]: 228 [M] + .

[0278] Elemental Analysis: C 9 h 9 BrO 2 Calculated for: C 47.19, H 3.90....

Embodiment 2

[0305] (4-methyl-piperazin-1-yl)-[10-(2-methyl-2'-trifluoromethyl-[1,1'-biphenyl-4-yl)-carbonyl]-10, 11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl-methanone

[0306] 10-[( 2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][ 1,4] A suspension of benzodiazepine-3-carboxylic acid (1.65 g, 3.36 mmol). After gas evolution had ceased, the reaction mixture was refluxed for another 15 min. The cooled solution was evaporated to dryness to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (10 mL) and slowly added to 1-methylpiperazine (1.5 mL, 13.5 mmol) and N,N-diisopropylethylamine (3.5 mL, 20.1 mmol) in dichloro methane (25 mL). After stirring overnight, water was added to quench the reaction. The organic layer was washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown o...

Embodiment 3

[0311] 10-[(2-methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1 -c][1,4]benzodiazepine-3-carboxylic acid bis-(3-dimethylamino-propyl)amide

[0312] 10-[ (2-Methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl)-carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c] A suspension of [1,4]benzodiazepine-3-carboxylic acid (0.50 g, 1.02 mmol). After gas evolution had ceased, the reaction mixture was refluxed for an additional 15 minutes. The cooled solution was evaporated to dryness to give the crude acid chloride as a brown solid. The acid chloride was then dissolved in dichloromethane (5 mL) and slowly added to bis-(3-dimethylamino-propyl)-amine (0.90 mL, 4.04 mmol) and N,N-diisopropylethylamine ( 1.1 mL, 6.31 mmol) in dichloromethane (5 mL). After stirring for 2 hours, water was added to quench the reaction. The organic layer was washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and ...

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Abstract

This invention provides novel tricyclic diazepine compounds as well as methods and pharmaceutical compositions utilizing these compounds for the treatment and / or prevention and / or suppression of disorders which may be remedied or alleviated by oxytocin antagonist activity, including treatment of preterm labor, dysmenorrhea, endometritis, and for suppressing labor prior to caesarean delivery. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals; and may be useful in the prevention and treatment of disfunctions of the oxytocin system in the central nervous system including obsessive compulsive disorder (OCD) and neuropsychiatric disorders.

Description

[0001] The present invention relates to novel tricyclic diazepines which are competitive oxytocin receptor antagonists, as well as processes for their preparation, methods of treatment and pharmaceutical compositions using these compounds. [0002] The compounds of the present invention are useful therapeutic agents in mammals, especially humans. More specifically, they are useful for the prevention and / or suppression of preterm labor, for the suppression of term labor prior to caesarean delivery, for the anti-labor delivery of medical devices, and for the treatment of dysmenorrhea. These compounds are also useful for increasing fertilization rates, increasing survival rates, and synchronous estrus in farm animals; and are useful in the prevention and treatment of oxytocin system dysfunction in the central nervous system, including obsessive-compulsive disorder (OCD) and neurological Psychiatric disorders. Background of the invention [0003] Preterm birth of babies is a lead...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P15/00A61P15/04A61P15/06A61P25/18A61P43/00C07D487/04C07D487/14C07D519/00
CPCC07D487/14C07D487/04A61P15/00A61P15/04A61P15/06A61P25/18A61P43/00
Inventor 阿米德·阿图罗·法伊利杰伊·斯科特·舒姆斯基托马斯·约瑟夫·卡贾诺约瑟夫·彼得·萨巴图奇凯文·安东尼·梅莫利尤金·约翰·特雷布尔斯基
Owner WYETH LLC
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