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Pyrrolopyrimidine derivative and application thereof

A compound and hydrate technology, applied in the preparation of drugs, pyrrolopyrimidine derivatives and its preparation, the field of pyrrolopyrimidine derivatives, can solve the problem that patients with severe specific pulmonary fibrosis cannot benefit and cannot improve the quality of life of patients , can not reverse pulmonary fibrosis and other problems, and achieve significant heart safety advantages, excellent liver metabolism stability, and high intestinal absorption

Pending Publication Date: 2022-01-18
WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The quality of life of IPF patients will be seriously affected, and neither pirfenidone nor nintedanib can improve the quality of life of patients in clinical trials
While both drugs may improve overall outcome, they only slow the course of the disease but do not reverse pulmonary fibrosis, so patients with severe specific pulmonary fibrosis may not benefit
At present, GLPG-1690, which is developing rapidly in the treatment of IPF drugs, shows a trend of reversing the course of the disease, but there are problems of low enzyme activity, large amount of clinical medication, and poor medication compliance.
Therefore, the current therapy is not satisfactory, and there are still a large number of patients who need new treatments with higher activity and better efficacy, which can slow down or even reverse the disease process to a greater extent, improve medication compliance, and allow more of idiopathic pulmonary fibrosis patients benefited

Method used

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  • Pyrrolopyrimidine derivative and application thereof
  • Pyrrolopyrimidine derivative and application thereof
  • Pyrrolopyrimidine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Embodiment 1: the synthesis of compound 1, compound 1S and compound 1R

[0146] 2-(2-(1H-1,2,3-triazol-4-yl)propoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 1)

[0147] (S)-2-(2-(1H-1,2,3-triazol-4-yl)propoxy)-1-(2-((2,3-dihydro-1H-indene-2- Base) amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 1S)

[0148] (R)-2-(2-(1H-1,2,3-triazol-4-yl)propoxy)-1-(2-((2,3-dihydro-1H-indene-2- Base) amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 1R)

[0149] The synthetic routes of target compound 1, compound 1S and compound 1R are as follows:

[0150]

[0151] The first step: the synthesis of 3-((tert-butyldimethylsilyl)oxy)-2-methylpropan-1-ol (compound 1B)

[0152] To a solution of 2-methylpropane-1,3-diol (compound 1A) (15 g, 166 mmol) in dichloromethane (200 mL) was added tert-butyldimethylsilyl chloride (25.09 g, 166 mmol) and triethylamine (33.7g, 333mm...

Embodiment 2

[0179] Embodiment 2: the synthesis of compound 2

[0180] 3-((1H-1,2,3-triazol-4-yl)methoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5 ,7-dihydro-6H-pyrrole[3,4-d]pyrimidin-6-yl)butan-1-one (Compound 2)

[0181] The synthetic route of target compound 2 is as follows:

[0182]

[0183] The first step: (E)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrole[3,4-d] Synthesis of pyrimidin-6-yl)but-2-en-1-one (compound 2B)

[0184] Crotonic acid (compound 2A) (142mg, 1.646mmol), N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrole[3,4-d] Pyrimidin-2-amine dihydrochloride (535mg, 1.646mmol), N,N-diisopropylethylamine (2.127g, 16.46mmol) was dissolved in N,N-dimethylformamide (5mL), and the reaction The solution was stirred and cooled to about 0°C, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphoric acid-2,4,6-trioxide (1.257g, 1.975mmol, 50% N,N-dimethylformamide solution), the dropwise addition was completed, and the reaction was carried out at room temperature f...

Embodiment 3

[0193] Embodiment 3: the synthesis of compound 3

[0194] 2-(2-(1H-1,2,3-triazol-1-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 3)

[0195] The synthetic route of target compound 3 is as follows:

[0196]

[0197] The first step: 2-chloro-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d Synthesis of ]pyrimidin-6-yl)ethan-1-one (compound 3B)

[0198] At room temperature, triethylamine (0.289ml, 2.072mmol) was added dropwise into the stirring N-(2,3-dihydro-1H-inden-2-yl)-6,7-dihydro-5H-pyrrolo[ 3,4-d] Pyrimidin-2-amine dihydrochloride (200 mg, 0.615 mmol) in dichloromethane (5 mL). After 5 minutes, chloroacetyl chloride (81 mg, 0.713 mmol) was added dropwise into the above reaction solution at 0° C., and stirred overnight at room temperature. After monitoring the reaction, add distilled water (20mL) for dilution, extract with ethyl acetate (30mL×3), combine the organic phases, w...

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Abstract

The invention provides a pyrrolopyrimidine derivative and application thereof, and particularly provides a novel compound capable of effectively inhibiting ATX. The novel compound is a compound as shown in a formula (I) which is described in the specification, or a tautomer, a stereoisomer, a hydrate, a solvate, salt or a prodrug of the compound as shown in the formula (I).

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to pyrrolopyrimidine derivatives. More specifically, the present invention relates to pyrrolopyrimidine derivatives, their preparation methods, and their application in the preparation of medicines. Background technique [0002] Autotaxin (abbreviated as ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activity and a member of the extracellular pyrophosphatase / phosphodiesterase (ENPP) family, so it is also Called ENPP2. ATX also has lysophospholipase D (LysoPLD) activity, which can hydrolyze lysophosphatidylcholine (LPC) into biologically active lysophosphatidic acid (LPA). LPA is an intracellular lipid mediator that affects many biological and biochemical processes. [0003] Studies show that inhibition of ATX reduces LPA levels under pathological conditions, thereby providing therapeutic benefit for unmet clinical needs includi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D519/00A61K31/519A61K31/5365A61P35/00A61P29/00A61P1/16A61P11/00A61P13/12A61P17/00A61P9/00A61P37/02A61P25/00
CPCC07D487/04C07D519/00A61P35/00A61P29/00A61P1/16A61P11/00A61P13/12A61P17/00A61P9/00A61P37/02A61P25/00
Inventor 张学军李莉娥臧杨孙红娜杨成兵刘哲魏用刚龙艳田华
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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