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Novel 3-c(o)r substituted 10-cyclohexylbenzoyl pyrrolobenzodiazepines; tocolytic oxytocin receptor antagonists

A technology of substituents and arylalkyl groups, used in medical preparations containing active ingredients, drug combinations, sexual diseases, etc., can solve problems such as lack of oral activity

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

Peptide oxytocin antagonists lack oral activity as they also display vasopressin antagonist activity, many of these peptides are non-selective antagonists

Method used

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  • Novel 3-c(o)r substituted 10-cyclohexylbenzoyl pyrrolobenzodiazepines; tocolytic oxytocin receptor antagonists
  • Novel 3-c(o)r substituted 10-cyclohexylbenzoyl pyrrolobenzodiazepines; tocolytic oxytocin receptor antagonists
  • Novel 3-c(o)r substituted 10-cyclohexylbenzoyl pyrrolobenzodiazepines; tocolytic oxytocin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0300] 10-(4-cyclohexylbenzoyl)-3-[(4-methyl-1-piperazinyl)carbonyl-10,11-dihydro-5H-pyrrolo[2,1-c][1, 4] Benzodiazepine-8-carboxylate methyl ester hydrochloride

[0301] Step A. [4-(2-Formyl-1H-pyrrol-1-yl)methyl-3-nitro]-benzoic acid methyl ester

[0302] A suspension of N,N-dimethylcarboxamide (25 ml) containing sodium hydride (8.1 g, 60% suspension in oil) was added dropwise to pyrrole-2-aldehyde (9.1 g, 1 equiv) within 25 minutes N,N-dimethylcarboxamide (25ml) solution. After the dropwise addition, the reaction mixture was stirred for 30 minutes and then cooled to 0 °C. A solution of N,N-dimethylcarboxamide (25ml) containing 4-bromomethyl-2-nitrobenzoic acid (25.0g, 1 equivalent) was added dropwise to the above solution within 20 minutes, and after the dropwise addition , the reaction mixture was stirred at room temperature for 1 h, then indolylmethane (1.2 equiv) was added. The mixture was stirred overnight at room temperature and diluted with water (200ml). The sol...

Embodiment 2

[0317] 10-(4-Cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-8-carboxylic acid sodium salt

[0318] To the stirred 10-(4-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Example 1, Step C To a solution of methyl -8-carboxylate (0.200 g) in absolute ethanol (2 ml) was added 2.5 N sodium hydroxide (1 equivalent). The reaction mixture was stirred at room temperature for three days, the solvent was removed in vacuo to afford the title compound as a pale yellow hygroscopic solid after drying at 60°C using phosphine pentoxide.

[0319] 1 H NMR (DMSO-d 6 , 400MHz): δ1.20(m, 1H), 1.39(t, 4H), 1.70(m, 5H), 2.40(m, 1H), 5.20(br, 4H), 5.90(m, 2H), 6.80( t, 1H), 7.05 (d, 2H), 7.20 (d, 2H), 7.35 (d, 2H), 7.64 (dd, 1H).

[0320] Elemental Analysis: Calculated Value: C 26 h 25 N 2 o 3 Na+1.5H 2 O: C 67.38, H 6.09, N 6.04. Measured values: C 67.14, H 5.9, N, 5.93.

[0321] MS [(+)ESI, m / z]: 415 [M+H] + . Measured value: C 26 h 27 N...

Embodiment 3

[0323] 10-(4-cyclohexylbenzoyl)-3-[(4-methyl-1-piperazinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1 , 4] benzodiazepine-8-carboxylic acid

[0324] To Example 1, step D of 10-(4-cyclohexylbenzoyl)-3-[(4-methyl-1-piperazinyl)carbonyl]-10,11-dihydro-5H-pyrrolo[ 2,1-c][1,4]Benzodiazepine-8-carboxylic acid methyl ester (1.1g, 1.93mmol) in ethanol (10ml) was added 2.5N sodium hydroxide (1.5eq) and The reaction mixture was stirred overnight at room temperature. One equivalent of 2N hydrochloric acid was added to neutralize the solution and the solvent was removed in vacuo. The residue was extracted with dichloromethane, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with 10% methanol in dichloromethane to afford the title compound as a white crystalline solid, m.p. 195-210.

[0325] 1 H NMR (DMSO-d 6 , 400MHz): δ1.20(m, 1H), 1.30(t, 4H), 1.70(m, 5H), 2.20(s, 3H), 2.30(s, 4H), 2.40(m, 1H), 3.40( br, 2H), 3.60(t, 2H), 5.15(...

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Abstract

The present invention provides novel tricyclic benzodiazepine carboxamides compounds and methods and pharmaceutical compositions utilizing them for the treatment and / or prevention and / or suppression of disorders which may be remedied or alleviated by oxytocin antagonist activity, including prevention and / or suppression suppression of preterm labor, suppression of labor at term prior to caesarean delivery, and for the treatment of dysmenorrhea. 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 treatmraent 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 benzodiazepine carboxamides which act as competitive oxytocin receptor antagonists; and processes for their manufacture, 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 can be used to prevent and / or inhibit premature labor, inhibit term labor prior to caesarean section, facilitate delivery of medical devices, and treat dysmenorrhea. They are also useful for increasing fertilization rates, increasing survival rates and coordinating estrus in farm animals; and they are also useful for preventing and treating dysfunctions of the oxytocin system in the central nervous system, including obsessive-compulsive disorder (OCD) and neuropsychiatric disorders. Background of the invention [0003] Preterm birth is the leading cause of perinatal mortality and morbidity. Child ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P5/10A61P5/24A61P15/00A61P15/06C07D487/04C07D521/00
CPCC07D231/12C07D249/08C07D487/04C07D233/56A61P5/10A61P5/24A61P15/00A61P15/06
Inventor 阿米德·阿图罗·法伊利约翰·保罗·杜沙尤金·约翰·特雷布尔斯基凯文·安东尼·梅莫利杰伊·斯科特·舒姆斯基
Owner WYETH LLC
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