Novel tricyclic pyridyl benzazepine carboxyamides and derivatives their tocolytic oxytocin leceptor antagonists

A technology of alkyl and hydroxyl, applied in the field of novel tricyclic pyridyl carboxamide, which can solve the problem of lack of oral activity

Inactive Publication Date: 2004-09-22
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 tricyclic pyridyl benzazepine carboxyamides and derivatives their tocolytic oxytocin leceptor antagonists
  • Novel tricyclic pyridyl benzazepine carboxyamides and derivatives their tocolytic oxytocin leceptor antagonists
  • Novel tricyclic pyridyl benzazepine carboxyamides and derivatives their tocolytic oxytocin leceptor antagonists

Examples

Experimental program
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preparation example Construction

[0086] The present invention also provides processes for the preparation of the compounds of the present invention.

[0087] The method of the invention

[0088] Compounds of the invention can be prepared according to one of the general methods outlined below.

[0089] The compound of general formula (I) can be prepared very conveniently by the method shown in scheme I, wherein R 4 is part B-C, wherein B is selected from (a) or (b), and C is selected from (c), (d), (e) and (f) as defined above.

[0090] Option I

[0091]

[0092] 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, affords the desired trichloroacetyl inter...

Embodiment 1

[0218] 10-[(2-Methyl-2'-trifluoromethyl-biphenyl-4-carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzo Diazepin-3-yl]-(4-pyridin-4-yl-piperidin-1-yl)methanone

[0219] Step A. Methyl 4-bromo-3-methylbenzoate

[0220] To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated overnight at reflux and a homogeneous solution was obtained after a few minutes of heating. After cooling, methanol was removed in vacuo and the residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown solid, m.p. 41-43°C.

[0221] 1 H NMR (DMSO-d 6 , 400MHz): δ2.39(s, 3H), 3.85(s, 3H), 7.64-7.72(m, 2H), 7.88-7.89(m, 1H).

[0222] MS [El, m / z]: 228 [M]+.

[0223] C 9 h 9 BrO 2 Calculated values: C47.19, H3.90. Measured values: C47.22,...

Embodiment 2

[0254] Example 2: 10-{[2-methyl-2'-trifluoromethyl-[1,1'-biphenyl]-4-yl]carbonyl}-3-(4-[(1-pyridine oxide- 3-yl)methyl]piperazin-1-yl)carbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine

[0255] Step A. 3-Chloromethyl-pyridine-1-oxide

[0256] To a solution of 3-hydroxymethyl-pyridine N-oxide (1.0 g, 8.0 mmol) in dichloromethane (40 mL) was added thionyl chloride (10 mL, 137 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted repeatedly with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 0.60 g of the title product as a white solid, mp 133-137°C.

[0257] 1 HNMR (DMSO-d 6 , 400MHz): δ4.74(s, 2H), 7.40-7.45(m, 2H), 8.17-8.20(m, 1H), 8.35(s, 1H).

[0258] MS[(+)APCI, m / z]: 144[M+H]+.

[0259] C 6 h 6 ClNO analysis calculat...

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Abstract

This invention provides novel substituted tricyclic pyridyl carboxamides which act as oxytocin receptor competitive antagonists, as well as methods of their manufacture, pharmaceutical compositions and methods of their use in treatment, inhibition, suppression or prevention of preterm labor, dysmenorrhea, endometritis, suppression of labor at term prior to caesarean delivery, and to facilitate antinatal transport to a medical facility. 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 oxytocin receptor antagonists, as well as methods for their manufacture, 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 de...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551A61K31/5517A61P5/24A61P15/00A61P15/06A61P25/00C07D471/14C07D487/04C07D487/14
CPCC07D471/14C07D487/04A61P15/00A61P15/06A61P25/00A61P5/24
Inventor 阿米德·阿图罗·法伊利杰伊·斯科特·舒姆斯基托马斯·约瑟夫·卡贾诺约瑟夫·彼得·萨巴图奇凯文·安东尼·梅莫利尤金·约翰·特雷布尔斯基
Owner WYETH LLC
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