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ROCK inhibitor as well as preparation method and application thereof

A CH2, solvate technology, applied in the field of compounds that can inhibit ROCK activity and its preparation

Pending Publication Date: 2020-10-27
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] There are currently no marketed drugs that inhibit the ROCK pathway for the treatment of many conditions including fibrosis

Method used

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  • ROCK inhibitor as well as preparation method and application thereof
  • ROCK inhibitor as well as preparation method and application thereof
  • ROCK inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0185] Embodiment 1, the preparation of compound (QR001)

[0186]

[0187] 1.1 Preparation of compound (QR001-SM1)

[0188] Potassium carbonate (18g, 126mmol) was added to a solution of isopropylamine (5g, 84mmol) in dichloromethane (20mL) under ice-cooling, and then chloroacetyl chloride (12g, 100.8mmol) was slowly added dropwise, and reacted overnight at room temperature. Water was added, extracted with ethyl acetate, and the organic phase was dried and concentrated under reduced pressure to obtain 9 g of white solid.

[0189] 1 H NMR (DMSO-d 6 , 400MHz): δ8.04(s, 1H), 3.98(s, 2H), 3.85-3.80(m, 1H), 1.07(d, J=6.4Hz, 6H).

[0190] 1.2 Preparation of compound (QR001-3)

[0191] To a solution of compound QR001-SM1 (3 g, 13.6 mmol) in DMF (30 mL) was added potassium carbonate (2.8 g, 20.4 mmol) and 3-hydroxyphenylboronic acid pinacol ester (2.8 g, 20.4 mmol, CAS: 214360 -76-6), the addition was completed, and reacted at 80°C for 16 hours. Water (50 mL) was added, extrac...

Embodiment 2

[0200] Embodiment 2, the preparation of compound (QR003) and (QR004)

[0201]

[0202] 2.1 Preparation of Compounds (QR003-2) and (QR003-2A)

[0203] 2,4-Dichloropyrrole[2,1-f][1,2,4]triazine (1.2g, 6.4mmol) was dissolved in acetonitrile (40mL), and 1-chloromethyl- 4-Fluoro-1,4-diazobicyclo2.2.2-octanebis(tetrafluoroborate) salt (Selectfluor) (CAS: 140681-55-6) (2.5g, 7.06mmol) Fluorinated reagent, addition complete After stirring at room temperature for 2 hours, it was heated to 80° C., and the reaction was continued for 16 hours. After cooling and concentrating, it was purified by silica gel column chromatography to obtain 980 mg of the fluorinated product as a yellow solid, which was identified as a mixture of QR003-2 and QR003-2A by NMR.

[0204] 2.2 Preparation of compound (QR003-SM2)

[0205] 5-Nitroindazole (1.63 g, 10 mmol, CAS: 5401-94-5) was dissolved in 100 mL of anhydrous dichloromethane, and TEA (5 mL) and 2-(trimethylsilyl)ethane were added at 0 °C Oxymeth...

Embodiment 3

[0220] Embodiment 3, the preparation of compound (QR005)

[0221]

[0222] 3.1 Preparation of compound (QR005-2)

[0223] Compound QR001-2 (500mg, 1.299mmol), 3-hydroxyphenylboronic acid (213mg, 1.55mmol, CAS: 87199-18-6), K 3 PO 4 (550mg, 2.59mmol), Pd(OAc) 2 (30mg, 0.132mmol) and XPhos (61mg, 0.128mmol) were added to dioxane (20mL) and water (3mL), stirred overnight at 100°C. After the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 200 mg of a yellow solid.

[0224] LC-MS: [M+1] + = 343.1.

[0225] 3.2 Preparation of compound (QR005-3)

[0226] Compound QR005-2 (180mg, 0.52mmol) and dimethylaminopyridine (6mg, 0.05mmol) were dissolved in dichloromethane (20mL), and Boc anhydride (170mg, 0.78mmol) was added under ice cooling. After stirring at room temperature for 4 hours, the reaction was completed. Water and DCM were added for extraction, the organic phase was washed with saturated brine, dr...

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PUM

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Abstract

The invention discloses a compound represented by the following formula I and a racemate, a stereoisomer, a tautomer, an isotope marker, a nitrogen oxide, a solvate, a polymorph, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof. The compound shown in the formula I has excellent ROCK inhibition activity. In addition, the compound shown in the formula I has good safetyand metabolic stability. Furthermore, the potential cardiotoxicity risk of the compound shown in the formula I is low. Finally, the compound shown in the formula I is simple in preparation method andeasy to purify, so that the compound has a good application prospect.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a compound capable of inhibiting ROCK activity, a preparation method and application thereof. Background technique [0002] Idiopathic interstitial pulmonary fibrosis (IPF) is a chronic, diffuse pulmonary interstitial disease of unknown cause characterized by common interstitial pneumonia. For the performance of ordinary interstitial pneumonia. Because of its complex pathogenesis, the disease progresses irreversibly, and early diagnosis is difficult; after diagnosis, the survival rate of patients decreases significantly over time. The 3-year survival rate is 50%, and the 5-year survival rate is only 20%, which is higher than most cancers (such as : Leukemia, breast cancer, colon cancer, uterine tumor, kidney cancer, etc.) have a low survival rate and are called "cancer that is not cancer". At present, there is no sure significant effective drug for the treatment of IPF. According to th...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/53A61K31/5377A61P9/00A61P25/00A61P11/00A61P27/02A61P35/00A61P7/02A61P37/02A61P9/10A61P9/12A61P9/04A61P3/10A61P13/12A61P15/10A61P27/06A61P11/06A61P19/10A61P1/16A61P29/00
CPCC07D487/04A61P9/00A61P25/00A61P11/00A61P27/02A61P35/00A61P7/02A61P37/02A61P9/10A61P9/12A61P9/04A61P3/10A61P13/12A61P15/10A61P27/06A61P11/06A61P19/10A61P1/16A61P29/00A61K31/5377A61K31/53Y02P20/55
Inventor 刘军华陈永凯郭晓丹张轶涵曾弦钱丽娜王朝东
Owner WUHAN LL SCI & TECH DEV
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