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Isoquinoline sulfonyl derivatives and their applications

A drug and compound technology, applied in the field of isoquinolinesulfonyl derivatives and their pharmaceutical compositions, can solve the problems of unsatisfactory pharmacokinetic properties and hERG activity, and achieve low potential risk, reduced clearance rate, and improved half-life Effect

Active Publication Date: 2022-02-01
CHINA RESOURCES PHARMA HLDG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This compound has good enzymatic activity as a ROCK kinase inhibitor, but its pharmacokinetic properties and hERG activity are not ideal

Method used

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  • Isoquinoline sulfonyl derivatives and their applications
  • Isoquinoline sulfonyl derivatives and their applications
  • Isoquinoline sulfonyl derivatives and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072]

[0073] first step

[0074] A solution of 1a (30.00g, 173.24mmol), triethylamine (43.83g, 433.00mmol) in N,N dimethylformamide (500mL) was cooled to 0°C and O-(7-azabenzotriazepine was added Azol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphine salt (79.05 g, 208.00 mmol). The resulting reaction solution was stirred at 0°C for 10 minutes. Then N-methoxymethylamine hydrochloride (18.59 g, 191.00 mmol) was added and stirred at 20° C. for 16 hours. The reaction solution was poured into water (1.00L) and extracted with ethyl acetate (2.00L x2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude product was separated and purified on a silica gel column (petroleum ether / ethyl acetate = 100-0%), yielding 1b.

[0075] 1 H NMR (400MHz, CD 3 OD) δ4.13-4.07(m, 2H), 3.74(s, 3H), 3.37(s, 1H), 3.21(s, 3H), 1.37-1.35(m, 2H), 1.26-1.22(m, 3H) ), 1.03-1.00 (m, 2H).

[0076] second step

[0077] To a solut...

Embodiment 2

[0097]

[0098] first step

[0099] Compound 1h and compound 2a were synthesized according to compound 1 to obtain compound 2.

[0100] MS-ESI calculated value [M+H] + 364, the measured value is 364.

[0101] 1 H NMR (400MHz, D 2 O) δ9.30(s, 1H), 8.67(s, 1H), 8.62(d, J=7.6Hz, 1H), 8.46(d, J=8.4Hz, 1H), 7.86(t, J=8.0Hz , 1H), 4.05-3.94(m, 2H), 3.82-3.77(m, 1H), 3.57-3.55(m, 1H), 3.38-3.22(m, 2H), 2.42-2.39(m, 1H), 2.08 -2.04 (m, 1H), 1.06-0.79 (m, 4H).

Embodiment 3

[0103]

[0104] first step

[0105] Compound 1h and compound 3a were synthesized according to compound 1 to obtain compound 3.

[0106] MS-ESI calculated value [M+H] + 348, the measured value is 348.

[0107] 1 H NMR (400MHz, CD 3 OD) δ9.25(s, 1H), 8.67(d, J=8.0Hz1H), 8.53(d, J=8.0Hz, 1H), 8.45(d, J=8.0Hz, 1H), 7.86(t, J =8.0Hz, 1H), 3.85-3.73(m, 2H), 3.43(s, 1H), 3.06-2.98(m, 1H), 2.72-2.65(m, 1H), 2.15-2.05(m, 1H), 1.73-1.71 (m, 1H), 0.97-0.87 (m, 1H), 0.82-0.79 (m, 2H), 0.69-0.60 (m, 2H).

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Abstract

Disclosed is a class of isoquinoline compounds as RHO protein kinase inhibitors, and their application in the preparation of drugs for treating diseases related to RHO protein kinase, specifically disclosing the compound represented by formula (I) and its pharmaceutically acceptable of salt.

Description

[0001] References to related applications [0002] This application claims the following priority: [0003] CN201710590957.X, application date 2017-07-19. technical field [0004] The invention relates to a class of isoquinolinesulfonyl derivatives as RHO protein kinase inhibitors and pharmaceutical compositions thereof. Specifically, the present invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. Background technique [0005] Fasudil is a new type of drug with a wide range of pharmacological effects. It is a RHO kinase inhibitor. It expands blood vessels by increasing the activity of myosin light chain phosphatase, reduces the tension of endothelial cells, and improves the microcirculation of brain tissue without producing and It aggravates blood stealing in the brain, and at the same time antagonizes inflammatory factors, protects nerves against apoptosis, and promotes nerve regeneration. The results show that fasudi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D471/04C07D401/12A61K31/4725A61K31/55A61P9/10A61P9/12A61P27/06
CPCA61P9/10A61P9/12A61P27/06C07D487/04C07D487/10A61K31/4725
Inventor 姚元山张丽陈兆国赵乐乐吴凌云陈曙辉
Owner CHINA RESOURCES PHARMA HLDG CO LTD