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Pyrrolopyrimidine compound and application thereof

A compound and hydrate technology, applied in the field of pyrrolopyrimidine compounds and their preparation, pyrrolopyrimidine compounds, can solve the problem that patients with severe specific pulmonary fibrosis cannot benefit, cannot reverse pulmonary fibrosis, and cannot improve the quality of life of patients and other problems, to achieve the effects of excellent hepatic metabolism stability, inhibition of ATX enzyme activity, and excellent pharmacokinetic properties

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 compound and application thereof
  • Pyrrolopyrimidine compound and application thereof
  • Pyrrolopyrimidine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0121] Preparation Example 1: Synthesis of Intermediate B

[0122] 2-(2-(1H-1,2,3-Triazol-4-yl)ethoxy)acetic acid (Intermediate B)

[0123] The synthetic route of target compound intermediate B is as follows:

[0124]

[0125] The first step: Synthesis of 2-(butyl-3-yn-1-oxyl)methyl acetate (compound B-2)

[0126]The raw material 3-butynol (compound B-1) (2.8g, 0.4mol) was added to dry tetrahydrofuran (100mL), cooled to 0°C, 60% sodium hydrogen (2.4g, 0.6mmol) was added, and the After stirring at 0°C for 0.5h, the raw material 2-bromoacetate methyl ester (7.3g, 0.48mmol) was added to the reaction liquid, and the mixture was naturally warmed to room temperature, and stirred for 16h. Add water (100mL), extract with ethyl acetate (50mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the residue is separated and purified by silica gel column (petroleum ether: ethyl acetate (V / V )=5:1) Compound B-2 was obtained as a colorless liquid...

Embodiment 1

[0138] Embodiment 1: the synthesis of compound 1

[0139] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-dichlorophenethyl)amino)-5,7- Dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 1)

[0140] The synthetic route of target compound 1 is as follows:

[0141]

[0142] The first step: 2-((3,5-dichlorophenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (compound 1C )Synthesis

[0143] 2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.75g, 2.93mmol) and 2-(3,5-dichlorobenzene Base) ethylamine (compound 1A) (0.557g, 2.93mmol), N,N-diisopropylethylamine (1.025mL, 5.87mmol) was dissolved in N-methylpyrrolidone (5mL), stirred at 80°C for 16 hours . Cool to room temperature, add distilled water (10 mL) to dilute, extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic phase with saturated brine (10 mL×2), separate the layers, and dry the organic phase with anhy...

Embodiment 2

[0151] Embodiment 2: the synthesis of compound 2

[0152] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((3,5-bis(trifluoromethyl)phenethyl)amino) Synthesis of -5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)ethan-1-one (compound 2)

[0153] The synthetic route of compound 2 is as follows:

[0154]

[0155] The first step: 2-((3,5-bis(trifluoromethyl)phenethyl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid Synthesis of tert-butyl ester (Compound 2C)

[0156] 2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (compound 2B) (0.145g, 0.567mmol) and 2-(3,5 - Bis(trifluoromethyl)phenyl)ethylamine hydrochloride (compound 2A) (200mg, 0.68mmol), diisopropylethylamine (0.297mL, 1.701mmol) dissolved in N-methylpyrrolidone (5mL) , stirred at 80°C for 16 hours. Cool to room temperature, add distilled water (10 mL) to dilute, extract with ethyl acetate (10 mL×3), combine the organic phases, wash the organic phase with saturated brine (10 m...

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Abstract

The invention provides a pyrrolopyrimidine compound 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, a pharmaceutically acceptable 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 compounds. More specifically, the present invention relates to pyrrolopyrimidine compounds, their preparation methods, and their use 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 including cancer, l...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P11/00A61P1/16A61P13/12A61P35/00A61P3/00A61P29/00A61P9/00A61P37/06A61P25/28A61P17/00A61P3/10A61P19/02
CPCC07D487/04A61P11/00A61P1/16A61P13/12A61P35/00A61P3/00A61P29/00A61P37/06A61P9/00A61P25/28A61P17/00A61P3/10A61P19/02
Inventor 张学军李莉娥臧杨孙红娜杨成兵刘哲丁肖华魏文军吕剑波
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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