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Novel hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists

A hydroxyl and alkylamino technology, applied in the field of tricyclic hydroxycarboxamides, 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 hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
  • Novel hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists
  • Novel hydroxy cyclohexenyl phenyl carboxamides tocolytic oxytocin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0265] 1-[[[10-[5-chloro-4-(1-cyclohex-1-en-1-yl)-2-methoxybenzoyl]-10,11-dihydro-5H-pyrrolo [2,1-c][1,4]Benzodiazepine-3-yl]carbonyl]methylamino]-1-deoxy-D-glucitol

[0266] Step A. 4-Amino-5-chloro-2-methoxy-benzoic acid methyl ester

[0267] 4-Amino-5-chloro-2-methoxybenzoic acid (50.0 g, 248 mmol) was suspended in methanol (500 mL), the slurry was cooled to 0 ° C, and then thionyl chloride (54.3 mL, 744mmol). The initially clear solution turned into a white suspension, and the reaction solution was warmed to room temperature and stirred for 3 hours. Methanol was evaporated and the resulting syrup was suspended in ether (1 L). The solid was filtered and rinsed well with diethyl ether to give the title compound hydrochloride (50.9g). The salt was suspended in 1N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and rinsing well with water gave the title compound free base as a white solid. Melting point: 136-137°C.

[0268] 1 H NMR (DMSO-d 6 , 400MH...

Embodiment 2

[0307] 10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-methyl-N-[(2S, 3R, 4R, 5R)-2, 3,4,5,6-pentamethoxyhexyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0308] 1-[[[10-[5-chloro-4-(1-cyclohex-1-en-1-yl)-2-methoxybenzoyl]-10,11-dihydro -5H pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]methylamino]-1-deoxy-D-glucitol (0.140g, 0.214mmol) Dissolve in anhydrous tetrahydrofuran (2.1 mL), and add sodium hydride (0.051 g, 2.14 mmol). The mixture was stirred at room temperature until gas evolution ceased (about 15 minutes), then methyl iodide (0.266 mL, 4.28 mmol) was added. After stirring at room temperature for 72 hours, the reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% methanol in chloroform to afford 0.140 g of...

Embodiment 3

[0313] 10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-[((4S,5S)-5-{(R)hydroxyl[(4R )-2-oxo-1,3-dioxolan-4-yl]methyl}-2-oxo-1,3-dioxolan-4-yl)methyl]-N-methyl -10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0314] 1-[[[10-[5-chloro-4-(1-cyclohex-1-en-1-yl)-2-methoxybenzoyl]-10,11-dihydro -5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]carbonyl]methylamino]-1-deoxy-D-glucitol (0.190g, 0.290mmol ) and N,N-diisopropylethylamine (0.202 mL, 1.16 mmol) were dissolved in anhydrous dichloromethane (5.8 mL), and the solution was cooled to 0°C. N,N'-carbonyldiimidazole (0.094 g, 0.580 mmol) was added and the reaction was stirred at 0°C for 1 hour, then allowed to warm to room temperature and stirring continued for 1.5 hours. The solution was diluted with dichloromethane, washed with 0.1N hydrochloric acid and saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by fla...

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Abstract

The present invention provides substituted 10,11-Dihydro-5H-benzo[e]-pyrrolo[1,2-a][1,4]diazepine and 9,10-Dihydro-4H-3a,5,9-triaza-benzo[f]azulene 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 prevention and / or suppression of preterm labor, suppression labor at term prior to caesarean deliver, and for the treatment of dysmenorrhea. These compounds are also useful in enhancing fertility rates, enhancing survival rates and synchronizing estrus in farm animals.

Description

[0001] The present invention relates to novel tricyclic hydroxycarboxamides useful as competitive oxytocin receptor antagonists, processes for their preparation, methods of treatment and pharmaceutical compositions utilizing these compounds. [0002] The compounds of the present invention are useful therapeutic agents in mammals, especially humans. More specifically, they are useful for preventing and / or inhibiting preterm labor, for inhibiting term labor prior to caesarean section, for facilitating anti-labor delivery to medical devices and for treating dysmenorrhea. These compounds are also used to improve fertility, enhance survival and estrus synchronization in farm animals. Background of the invention [0003] Preterm birth is the leading cause of perinatal mortality and morbidity. Child mortality decreases dramatically with increasing gestational age. The survival rate of babies born prematurely increased from 20% at 24 weeks to 94% at 30 weeks. In addition, the costs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517A61P5/12A61P15/06A61P43/00C07D487/04
CPCC07D487/04A61P5/12A61P15/06A61P43/00
Inventor 阿米德·阿图罗·法伊利威廉·詹宁斯·桑德斯尤金·约翰·特雷布尔斯基
Owner WYETH LLC
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