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Benzazepine derivatives

A technology of benzoazepines and benzodiazepines, which is applied in the field of benzoazepine derivatives and their salts, can solve problems such as ignorance, and achieve the effect of favorable metabolic stability

Pending Publication Date: 2020-03-17
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Various compounds are known to have a benzoheterocyclic structure (PTL 1 to 9), but compounds having difluorine and a hydroxyl group at the 4 and 5 positions of the benzazepine ring in the benzoheterocycle are not known to have Vasopressin V 1a and V 2 vasopressin antagonism

Method used

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  • Benzazepine derivatives
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Examples

Experimental program
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Effect test

Embodiment approach

[0087] [chemical formula 2]

[0088]

[0089] where the wavy line is the binding point, and A 1 and A 2 Same as defined above.

[0090] The present invention includes the embodiments shown below.

[0091] Item 1. A benzazepine compound of formula (1) or a salt thereof,

[0092] [chemical formula 3]

[0093]

[0094] where R 1 is deuterium, OH, COOH, optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkyl-O-CO- or optionally substituted C 2-6 Alkenyl;

[0095] L is a direct bond or -C(=O)-NH-;

[0096] Ring A 1 is a hydrocarbon ring or a heterocycle;

[0097] Ring A 2 is a hydrocarbon ring or a heterocycle; and

[0098] Ring A 1 and A 2 Each of may have at least one substituent.

[0099] Item 2. The compound or salt thereof according to Item 1, wherein Ring A 1 is a saturated or unsaturated 3 to 8 membered monocyclic hydrocarbon ring, or a saturated or unsaturated 3 to 15 membered monocyclic, bicyclic or tricyclic ring containing 1 to 5 het...

example

[0214] The present invention is described in detail in the following Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. These examples may be modified without departing from the scope of the invention.

[0215] The following abbreviations may be used herein.

[0216] REX: Reference instance number

[0217] EX: instance number

[0218] STR: Structural formula (In the formula, a structure with "chirality" refers to the absolute configuration.)

[0219] RProp: Preparation method (The product was prepared according to the method described in the referenced example with number, using the corresponding starting material.)

[0220] Prop: Preparation method (The product was prepared according to the method described in the numbered examples using the corresponding starting materials.)

[0221] Data: Physical data (NMR1: 1 δ(ppm) in H-NMR (dimethyl sulfoxide-d 6 ); NMR2: 1 δ(ppm)(CDCl in H-NMR 3 ); NMR3: 1 δ(ppm)(CD in H-NMR 3 OD...

example 1

[0517] To a solution of 6-(2-chlorobenzamido)pyridine-3-carboxylic acid (113 mg) in DMA (1.0 mL) was added SOCl under ice cooling under nitrogen atmosphere 2 (30.0 μL), and the mixture was stirred at the same temperature for 2 hours. To this was added 7-chloro-4,4-difluoro-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ol at the same temperature (90.0 mg), and the mixture was stirred at room temperature for 3 days. Add saturated NaHCO 3 Aqueous solution and water were added to the reaction solution, and the precipitate was filtered and purified by basic silica gel column chromatography (hexane / AcOEt) to give 2-chloro-N-{5-[7-chloro-4,4-di Fluoro-5-hydroxy-5-(hydroxymethyl)-2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl]pyridin-2-yl}benzamide (50.0 mg).

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Abstract

The present invention provides novel benzazepine compounds of Formula (1), or salts thereof, having vasopressin V1a and V2 antagonisms, and medical uses thereof. In the formula, R1 is optionally substituted C1-6 alkyl, etc.; L is -C(=O)-NH-, etc.; the ring A1 is a hydrocarbon ring, etc.; the ring A2 is a hydrocarbon ring, etc.; and each of the rings A1 and A2 may have at least one substituent.

Description

technical field [0001] The present invention relates to benzazepine derivatives and salts thereof. The present invention also relates to medicaments comprising benzazepine derivatives and salts thereof as active ingredients, which can be used for diagnosing, preventing and / or treating diseases related to vasopressin receptors. Background technique [0002] Vasopressin is an antidiuretic hormone known to increase blood pressure. Vasopressin V 1a receptor and vasopressin V 2 The receptors are considered a subgroup of vasopressin receptors, each involved in vasoconstriction and water reabsorption in the collecting duct. [0003] Tolvaptan has a benzoheterocyclic structure and is used in the treatment of various diseases, especially as a vasopressin V 2 receptor antagonists. It is known to be metabolized mainly by the hepatic metabolizing enzyme CYP3A4 (NPL 1 to 3). Various compounds are known to have a benzoheterocyclic structure (PTL 1 to 9), but compounds having difluor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D223/16C07D401/14C07D401/06C07D401/10C07D403/06C07D405/12C07D409/12A61P13/12A61K31/55
CPCA61P13/12C07D223/16C07D401/06C07D401/10C07D401/14C07D403/06C07D405/12C07D409/12A61K31/55
Inventor 菅庆三多久和正训田中博隆藤原荣人山边北斗松田聪大达一弘羽成泰贵校条康宏漆岛达哉藤田繁和
Owner OTSUKA PHARM CO LTD
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