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Substituted isoquinoline derivatives

A technology of isoquinoline and derivatives, applied in the field of isoquinoline-6-sulfonamide derivatives, to achieve excellent effect of lowering intraocular pressure

Active Publication Date: 2016-04-06
株式会社D.西医疗法研究所
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are few reports on compounds in which the 6-position of the isoquinoline skeleton is substituted by an aminosulfonyl group. The cannabinoid receptor antagonist disclosed in Patent Document 1, the mitochondrial F1FOATPase inhibitor disclosed in Patent Document 2, and the The disclosed methods for the manufacture of compounds with phenoxy groups are equivalent to those reported

Method used

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  • Substituted isoquinoline derivatives
  • Substituted isoquinoline derivatives
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Examples

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Embodiment

[0172] Production examples of synthetic intermediates and compounds of the present invention, and evaluation examples of biological activity are shown below. It should be noted that these illustrations are for better understanding of the present invention and do not limit the scope of the present invention. In addition, unless otherwise specified, Boc in the chemical structural formula represents a tert-butoxycarbonyl group.

reference example 1

[0175] Synthesis of 6-aminoisoquinoline (reference compound 1)

[0176]

[0177]17.2 g of 6-bromoisoquinoline (refer to WO2008 / 077553) was weighed in an autoclave, 200 mL of 28% ammonia water and 10.8 g of copper sulfate pentahydrate were added and sealed, and stirred at 190 degrees for 6 hours. After cooling to room temperature, the reaction solution was poured into 250 mL of 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate (100 mL×5). The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained crude product was suspended with dichloromethane, and filtered off to obtain 10.2 g (85%) of the target product as light brown crystals.

[0178] 1 H-NMR spectrum (CDCl 3 , δppm): 5.54(brs, 2H), 6.58(s, 1H), 7.00(d, J=9.0Hz, 1H), 7.35(d, J=5.5Hz, 1H), 7.75(d, J=9.0Hz , 1H), 8.32(d, J=5.5Hz, 1H), 8.98(s, 1H)

reference example 2

[0180] Synthesis of 6-chlorosulfonylisoquinoline (reference compound 2)

[0181]

[0182] Suspend 4.0 g of 6-aminoisoquinoline (reference compound 1) in 40 mL of concentrated hydrochloric acid (35%) at 0°C, add 4.0 g of sodium nitrite little by little, and stir for 30 minutes. This reaction solution was dropped into a mixed solution of 20 mL of acetic acid saturated with sulfur dioxide gas generated from sodium bisulfite and sulfuric acid and 298 mg of copper chloride at 0° C., and stirred for 1 hour. It was neutralized by adding saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (100 mL×2). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Since the target product was unstable, the obtained methylene chloride solution was used in the following reaction without further purification.

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Abstract

The present invention provides an isoquinoline-6-sulfonamide derivative used as a new drug. The present invention provides isoquinoline-6-sulfonamide derivatives represented by general formula (1), salts thereof, or solvates thereof (in the formula, X and Y each independently represent a direct bond, NH, CH=CH , O or S; R1 and R2 each independently represent a hydrogen atom, a halogen atom, a cyano group, an alkyl group, etc.; R3 and R4 each independently represent a hydrogen atom, an alkyl group, etc., or R3 and R4 can together form an alkylene or alkenylene and bridge between 2 carbons at any position; l, m and n represent numbers from 1 to 4).

Description

technical field [0001] The present invention relates to isoquinoline-6-sulfonamide derivatives for the prevention and treatment of diseases or disorders caused by glaucoma, cardiovascular system diseases, neurodegeneration or nerve damage. Background technique [0002] Among compounds having an isoquinoline skeleton, there are many compounds useful as pharmaceuticals. However, there are few reports on compounds in which the 6-position of the isoquinoline skeleton is substituted by an aminosulfonyl group. The cannabinoid receptor antagonist disclosed in Patent Document 1, the mitochondrial F1FOATPase inhibitor disclosed in Patent Document 2, and the The disclosed production methods of compounds having a phenoxy group correspond to these reports. [0003] patent documents [0004] Patent Document 1: US Laid-Open Publication US-20060079556 [0005] Patent Document 2: International Publication WO2006 / 073448 [0006] non-patent literature [0007] Non-Patent Document 1: Tetr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/02A61K31/407A61K31/4725A61K31/496A61K31/5377A61K31/551A61P9/00A61P25/28A61P27/06C07D401/12C07D413/12C07D487/08
CPCA61K31/407A61K31/4725A61K31/496A61K31/5377A61K31/551A61P9/00A61P25/00A61P25/28A61P27/06C07D217/02C07D401/12C07D487/08C07D217/04
Inventor 日高弘义高桥康一井上佳宏鹫见贤吾中村良平
Owner 株式会社D.西医疗法研究所
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