Novel 10-cyclohexenyl-phenyl pyrrolobenzodiazepine-3-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists

A cycloalkyl and alkyl technology, applied in the field of new tricyclic carboxamides, can solve the problems 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 and many of these peptides are non-selective antagonists

Method used

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  • Novel 10-cyclohexenyl-phenyl pyrrolobenzodiazepine-3-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists
  • Novel 10-cyclohexenyl-phenyl pyrrolobenzodiazepine-3-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists
  • Novel 10-cyclohexenyl-phenyl pyrrolobenzodiazepine-3-carboxamides and derivatives thereof; tocolytic oxytocin receptor antagonists

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preparation example Construction

[0141] The present invention also provides processes for the preparation of the compounds of the present invention.

[0142] Method of the invention

[0143] Compounds of the invention can be prepared according to one of the general methods outlined below.

[0144] The compound of general formula (I) can be prepared very conveniently by the method shown in scheme I, wherein R, R 3 and R 4 defined above.

[0145] Option I

[0146]

[0147] According to the preferred method above, in the presence of an organic base such as N,N-diisopropylethylamine (Hunig's base), in an aprotic organic solvent such as dichloromethane at a temperature ranging from -10°C to ambient temperature, The tricyclic diazepines of general formula (1), wherein R 3 and R 4 Reaction with a perhaloalkanoyl halide, preferably trichloroacetyl chloride, as defined above, provides the desired trichloroacetyl intermediate of general formula (2). Subsequent hydrolysis of (2) with an aqueous base such a...

Embodiment 1

[0247]Example 1: 4-chloro-5-cyclohex-1-en-1-yl-2-[(3-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1- Base]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10(11H)-yl)carbonyl]phenyl methyl ether

[0248] Step A. Methyl 4-amino-5-chloro-2-methoxybenzoate

[0249] 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 rinsed well with ether to give the hydrochloride salt of the title compound (50.9 g). The salt was suspended in 1N sodium hydroxide and stirred vigorously for 30 minutes. Filtration and rinsing thoroughly with water gave the title compound free base as a white solid,...

Embodiment 2

[0293] Example 2: 10-(5-chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-N-[3-(dimethylamino)propyl]-N -Methyl-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide

[0294] 10-(5-Chloro-4-cyclohex-1-en-1-yl-2-methoxybenzoyl)-10,11-dihydro-5H-pyrrolo[2 , 1-c][1,4]benzodiazepine-3-carboxylic acid (0.200 g, 0.419 mmol), (3-dimethylaminopropyl)methylamine (0.074 ml, 0.503 mmol) , 1-hydroxybenzotriazole (0.062 g, 0.461 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.088 g, 0.461 mmol) Mixed with amine-free N,N-dimethylformamide (1.7 mL), followed by the addition of N,N-diisopropylethylamine (110 mL, 0.629 mmol). The reaction was stirred at room temperature for 12 hours, then diluted with ethyl acetate (60 mL), washed with water, saturated aqueous sodium bicarbonate and brine. The combined aqueous washes were saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and co...

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Abstract

The present invention provides tricyclic carboxamide compounds and methods and pharmaceutical compositions for their use in treatment, prevention, 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 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; 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 carboxamides useful as competitive oxytocin receptor antagonists, processes for their preparation, methods of treatment and pharmaceutical compositions employing 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 premature labor, for inhibiting term labor prior to caesarean section, and for facilitating prenatal delivery of medical devices, as well as for treating dysmenorrhea. These compounds are also useful for increasing fertilization rates, increasing survival rates and synergizing estrus in farm animals, and for preventing and treating dysfunction of the oxytocin system in the central nervous system, including obsessive-compulsive disorder (OCD) and neuropsychiatric disorders. Background of the invention [0003] Premature delivery remains the leading cause of neonatal death ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551A61K31/5517A61P5/10A61P5/12A61P5/24A61P15/00A61P15/06C07D487/04C07D487/14
CPCC07D487/04A61P15/00A61P15/06A61P5/10A61P5/12A61P5/24
Inventor 阿米德·阿图罗·法伊利威廉·詹宁斯·桑德斯尤金·约翰·特雷布尔斯基杰伊·斯科特·舒姆斯基
Owner WYETH LLC
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