Thienylbenzoylbenzapines as vasporessin agonists

A technology of azepine and benzo, applied in the field of tricyclic aryl thiophene, can solve problems such as synthesis defects

Inactive Publication Date: 2002-03-06
AMERICAN HOME PRODUCTS CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In patients and animals with central or neurogenic diabetes insipidus, there is a defect in the synthesis of vasopre

Method used

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  • Thienylbenzoylbenzapines as vasporessin agonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1 (2-chloro-4-thiophen-2-yl-phenyl)-(5H-10,11-dihydro-pyrrolo[2,1-c][1,4]

[0067] Benzodiazepin-10-yl)-methylketone Step A. (4-Bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzene Diazepin-10-yl)-methyl ketone

[0068] N,N-Dimethylformamide (1 drop) was added to a solution of 4-bromo-2-chlorobenzoic acid (2.30 g) in anhydrous tetrahydrofuran (20 ml). Oxalyl chloride (1.46g) was added and the mixture was heated to reflux. The resulting solution was cooled to room temperature and then evaporated to dryness to give crude 4-bromo-2-chlorobenzoyl chloride as a golden viscous liquid which was used without further purification.

[0069] To 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.44g) and triethylamine (0.95g) cooled in an ice bath To the mixture in methyl chloride (40ml) was added dropwise a solution of crude 4-bromo-2-chlorobenzoyl chloride (2.42g) in dichloromethane (20ml). The cooling bath was removed, and after...

Embodiment 2

[0076]Example 2 [2-chloro-4-(5-chlorothiophen-2-yl)-phenyl]-(5H,10,11-dihydropyrrolo[2,1-

[0077] c][1,4]benzodiazepin-10-yl)-methyl ketone

[0078] 5-Chlorothiophene-2-boronic acid (0.65 g, 4 mmol) was added to (4-bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2,1-c][ 1,4] Benzodiazepin-10-yl)-methylketone (1.61g, 4mmol) and sodium carbonate (1.02g, 9.6mmol) in toluene (36ml), ethanol (10ml) and water (20ml) in the mixture. In the resulting solution, nitrogen was charged for 10 minutes, then tetrakis(triphenylphosphine)palladium(0) catalyst (0.18g, 0.16mmol) was added, the solution was heated to reflux for 41 hours, cooled to room temperature, filtered through diatomaceous earth, and then washed with Ethyl acetate rinse. The combined filtrates were diluted to 140 mL with water / ethyl acetate (1:1). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue (brown foam) was purified by flash chromatography on...

Embodiment 3

[0080] Example 3 [2-chloro-4-(5-methylthiophen-2-yl)-phenyl]-(5H,10,11-dihydropyrrolo[2,1-

[0081] c][1,4]benzodiazepin-10-yl)-methyl ketone

[0082] The title compound was prepared essentially according to the conditions set forth by Ohta et al., Heterocycles, 31, 1951 (1990). Potassium acetate (0.44 g, 4.5 mmol) was added to (4-bromo-2-chlorophenyl)-(5H,11H-pyrrolo[2 , 1-c][1,4]benzodiazepin-10-yl)-methyl ketone (1.2g, 3mmol) and 2-methylthiophene (1.5ml, 15.49mmol) N,N-di Methylacetamide (7.5ml) solution. The resulting solution was purged with nitrogen for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) catalyst (0.17 g, 0.15 mmol) was added, and the sealed test tube was heated at 150° C. in an oil bath for 16.5 hours under vacuum The solvent was removed and the residue was triturated with water (10ml) and extracted with dichloromethane. The organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to give ...

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Abstract

The present invention provides compounds of general formula: (I) wherein Y is a moiety selected independently, from NH OR -(CH2)- wherein n is 1; m is an integer from 1 to 2; and the moiety (a) represents: (1) a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen (wherein A is nitrogen, and B and C are CH), (2) a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen (wherein A is carbon, B is nitrogen, and C is -CH-CH-), (3) a 6-membered aromatic (unsaturated) ring (wherein A is carbon, B is CH, and C is -CH-CH-); as well as methods and pharmaceutical compositions utilizing these compounds for the treatment of disorder which may be remedied or alleviated by vasopressin agonist activity, including diabetes insipidus noctural enuresis, nocturia, urinary incontinence, bleeding and coagulation disorders, or temporary delay of urination.

Description

[0001] The present invention relates to vasopressin V 2 Agonists of tricyclic arylthiophenes, and methods of treatment and pharmaceutical compositions using these compounds. Background of the invention [0002] Vasopressin (ADH), a non-peptide hormone and neurotransmitter, is synthesized in the supraoptic nucleus of the hypothalamus of the brain, transmitted to the posterior pituitary via the supraoptic pituitary tract and stored here. When brain osmoreceptors sense an increase in plasma osmolality or a decrease in blood volume or blood pressure (detected by baroreceptors and volume receptors), vasopressin is released into the circulation, causing vasopressin V on blood vessels to 1a Receptor activation, causing vasoconstriction and blood pressure increase; vasopressin V in nephrons of the kidney 2 Receptor activation, causing reabsorption of mainly water and a small amount of electrolytes, resulting in increased blood volume (Cervoni and Chan, Diuretic Agents, in Kirk-Othme...

Claims

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Application Information

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IPC IPC(8): A61K31/5513A61K31/5517A61P7/04A61P7/12A61P13/02A61P43/00C07D471/04C07D487/04
CPCC07D471/04C07D487/04A61P7/04A61P7/12A61P13/02A61P43/00
Inventor A·A·费利D·K·威廉斯T·J·卡吉尔诺J·S·舒姆斯基M·A·阿斯维尔
Owner AMERICAN HOME PRODUCTS CORPORATION
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