Novel pyridine- and cyclohexenyl-comprising pyrrolobenzodiazepi ne-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists

An alkyl, hydroxyl technology, applied in the field of new tricyclic pyridyl carboxamides, which can solve the problem of 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 pyridine- and cyclohexenyl-comprising pyrrolobenzodiazepi ne-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists
  • Novel pyridine- and cyclohexenyl-comprising pyrrolobenzodiazepi ne-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists
  • Novel pyridine- and cyclohexenyl-comprising pyrrolobenzodiazepi ne-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] 10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-methyl-N-(pyridin-3-ylmethyl)-10,11 -Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0203] Step A. Methyl 4-amino-5-chloro-2-methoxybenzoate

[0204] 4-Amino-5-chloro-2-methoxybenzoic acid (50.0 g, 248 mmol) was suspended in methanol (500 ml), and the slurry was cooled to 0°C. Thionyl chloride (54.3 ml, 744 mmol) was then added dropwise over 20 minutes. A clear solution initially formed, which later turned into a white suspension. The reaction was warmed to room temperature and stirred for 3 hours. Methanol was evaporated and the resulting slurry was suspended in ether (1 L). The solid was filtered and washed well with diethyl ether to give the title compound hydrochloride (50.9 g). The salt was suspended in 1 N aqueous NaOH and stirred vigorously for 30 minutes. Filtration and washing thoroughly with water gave the title compound free base as a white solid, m.p. 136-137°C.

[0205] 1 H NMR (DMS...

Embodiment 2

[0244] 10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-methyl-N-(pyridin-3-ylmethyl)-10,11 -Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide L-(+)-tartrate hemihydrate

[0245] 10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-methyl-N-(pyridin-3-yl-methyl) of Example 1 )-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide (0.200 g, 0.344 mmol) was dissolved in boiling ether. A solution of L-(+)-tartaric acid (0.0520 g, 0.344 mmol) in hot methanol (1 ml) was added, the mixture was cooled and the solvent was evaporated. Diethyl ether was added to the residue to form a white solid which was filtered and dried in vacuo to give 0.252 g of the title compound tartrate, m.p. 138-177°C.

[0246] 1 H NMR (DMSO-d 6 , 400MHz): δ12.66(br, 2H), 8.53-8.50(m, 2H), 7.71(d, 1H), 7.43-7.40(m, 2H), 7.31(d1H), 7.08(t, 1H), 6.98(t, 1H), 6.93(d, 1H), 6.54(s, 1H), 6.33(s, 1H), 6.05(d, 1H), 5.57(s, 1H), 5.37(s, 2H), 5.35 -4.80(br, 4H), 4.74(s, 2H), 4.30(s, 2H), ...

Embodiment 3

[0251] 10-[4-((3R)-3-Hydroxy-2-methyl-cyclohex-1-en-1-yl)-3-methylbenzoyl]-10,11-dihydro-5H-pyrrole And[2,1-c][1,4]benzodiazepine-3-carboxylic acid methyl-pyridin-3-ylmethylamide

[0252] Step A. (10,1-Dihydro-5H-pyrrolo[2,1q-c][1,4]benzodiazepine-10-yl)-[(3-oxo-2-methyl Cyclohex-1-en-1-yl)-3-methylphenyl]methanone

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Abstract

The present invention provides novel tricyclic pyridyl carboxamides as well as methods and pharmaceutical compositions utilizing them 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 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 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 pyridylcarboxamides 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 for mammals, especially humans. More particularly, they are useful for preventing and / or inhibiting preterm labor, inhibiting term labor prior to cesarean delivery, facilitating delivery of anti-labor devices to medical devices, and treating dysmenorrhea. [0003] These compounds are also useful in enhancing fertilization, enhancing survival, and coordinating estrus in farm animals; and are useful in the prevention and treatment of dysfunction of the oxytocin system in the central nervous system, including obsessive-compulsive disorder (OCD) and neuropsychiatric disorders . Background of the invention [0004] Premature delivery is a leading cause of death and m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/194A61K31/5517A61P3/00A61P5/10A61P5/24A61P7/00A61P7/02A61P9/04A61P9/08A61P9/12A61P15/00A61P15/06A61P25/00A61P25/22A61P27/02A61P27/06A61P27/16A61P43/00C07D471/14C07D487/04
CPCC07D471/14C07D487/04A61P15/00A61P15/06A61P25/00A61P25/22A61P27/02A61P27/06A61P27/16A61P3/00A61P43/00A61P5/10A61P5/24A61P7/00A61P7/02A61P9/04A61P9/08A61P9/12
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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