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Isoquinoline carboxylic acid compound as well as preparation method and application thereof

A technology of isoquinoline carboxylic acid and compound, which is applied in the field of diseases, can solve the problems of unsatisfactory therapeutic effect and limited wide use, and achieve the effect of expanding drug types and inhibiting activity

Pending Publication Date: 2021-08-24
JIANGSU SUZHONG PHARM GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Although the prior art such as WO2004108681A1 discloses isoquinoline compounds for regulating HIF and / or EPO, its therapeutic effect is still not very satisfactory, which greatly limits its wide use in clinical applications

Method used

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  • Isoquinoline carboxylic acid compound as well as preparation method and application thereof
  • Isoquinoline carboxylic acid compound as well as preparation method and application thereof
  • Isoquinoline carboxylic acid compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0149] Example 1: Preparation of [(1-cyclopropyl-4-hydroxyl-7-m-chlorophenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (1r)

[0150]

[0151] Step 1: Preparation of 4-(3-chlorophenoxy)phthalonitrile (1c)

[0152]

[0153] 4-nitrophthalonitrile (1a) (9.2g, 53.0mmol), 3-chlorophenol (1b) (6.8g, 53.0mmol), dimethylsulfoxide (40mL), potassium carbonate (7.3g, 53.0 mmol) into a three-neck flask in turn, stirred at room temperature for 2 hours, heated to 60° C. for 4 hours, TLC showed that almost no raw materials remained, and the heating was stopped. The reaction solution was cooled to room temperature, slowly poured into 300 mL of water, a brick-red solid was precipitated, filtered, and the filter cake was dried to obtain 12.6 g of a red solid compound with a yield of 93.1%.

[0154] Step 2: Preparation of 4-(3-chlorophenoxy)phthalic acid (1d)

[0155]

[0156] Add 4-(3-chlorophenoxy)phthalonitrile (1c) (10.0g, 39.0mmol), water (150mL), methanol (100mL), sodium hydro...

Embodiment 2

[0181] Example 2: Preparation of [(1-cyclopropyl-4-hydroxyl-6-m-chlorophenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (1s)

[0182]

[0183] The compound [(1-cyclopropyl-4-hydroxyl-6-m-chlorophenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid methyl ester 0.20g (1q, 0.47mmol) prepared by the aforementioned method , 2 mL of water, 30 mL of methanol, and 120 mg of anhydrous lithium chloride were added to a 100 mL single-necked bottle, stirred at room temperature 20-25°C overnight, and the solid disappeared. Sampling by TLC to detect the disappearance of raw materials, concentration under reduced pressure at 40°C to remove methanol, adding 30mL of water, a white floc appeared, adjusted to pH = 2 with 2N hydrochloric acid, ultrasonically dispersed, filtered, washed with water, and dried to obtain compound 1-cyclopropyl -7-(3-Chlorophenoxy)-4-hydroxyisoquinoline-3-carbonylaminoacetic acid (1s) 0.16 g (0.39 mmol) white solid, yield 82.7%. NMR data: 1 H NMR (500Hz, CDCl 3 )...

Embodiment 3

[0184] Example 3: Preparation of [(1-cyclopropyl-4-hydroxyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid (2i)

[0185]

[0186] In Reference Example 1, the material 3-chlorophenol in Step 1 was replaced with phenol, and the remaining operations were referred to Example 1. Finally, 0.16 g of white solid was obtained. NMR data: 1 H NMR (500Hz, CDCl 3 )δ13.13(s,1H),δ9.01(s,1H),δ8.59(d,1H),δ7.61(m,1H),δ7.54(m,2H),δ7.52( m,2H),δ7.50(m,1H),δ7.43(m,1H),δ7.31(m,1H),δ7.22(m,2H),δ4.02(s,2H), δ2.50(m, 1H), δ1.18(m, 2H), δ1.01(m, 2H); MS m / z: 377.3(M+1).

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PUM

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Abstract

The invention discloses an isoquinoline carboxylic acid compound as well as a preparation method and application thereof, as well as the isoquinoline carboxylic acid compound, or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate or prodrug thereof can be used as a prolyl hydroxylase inhibitor.

Description

technical field [0001] The present invention relates to isoquinoline carboxylic acid compounds, pharmaceutical compositions containing them, and methods for diseases such as renal anemia mediated by prolyl hydroxylase activity. Background technique [0002] Anemia is a disorder of blood metabolism involving a decrease in circulating red blood cells (RBC) or hemoglobin. Chronic kidney disease (CKD), cancer, chronic inflammatory lesions, nutritional and genetic defects, inappropriate drug therapy, etc. lead to anemia. Chronic kidney disease, chemotherapy regimens for cancer, and chronic inflammatory diseases lead to reduced erythropoietin (EPO) production and steady-state iron deficiency. Anemia associated with chronic kidney disease (CKD) is treated with erythropoietin (EPO) analogs or erythropoiesis-stimulating agents (ESAs). Chronic kidney disease (CKD) showing iron deficiency requires iron supplementation. Functional iron deficiency is a major problem in most patients r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D217/26A61P7/06A61P17/02A61P11/00A61P13/12A61K31/472
CPCC07D217/26A61P7/06A61P17/02A61P11/00A61P13/12
Inventor 唐海涛岳永力汤凡葛海涛王正俊种法政
Owner JIANGSU SUZHONG PHARM GRP CO LTD
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