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Pyrrolopyrimidine derivative and use thereof

A kind of use and drug technology, applied in the field of biomedicine, can solve the problems of inability to improve the quality of life of patients, the impact of quality of life, and the large amount of clinical medication, and achieve the effects of excellent pharmacokinetic properties, novel structure, and good druggability

Active Publication Date: 2020-08-11
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.
[0017] 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 use thereof
  • Pyrrolopyrimidine derivative and use thereof
  • Pyrrolopyrimidine derivative and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Embodiment 1: the preparation of target compound I-1

[0088] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1)

[0089] 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-5,7 -dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1)

[0090]

[0091] The synthetic route of target compound 1-1 is as follows:

[0092]

[0093] The first step: the synthesis of tert-butyl 2-(but-3-yn-1-yloxy)propionate (1C)

[0094] tert-butyl 2-(but-3-yn-1-yloxy) propanoate (1C)

[0095]

[0096] At 0°C, 3-butyn-1-ol (15g, 214mmol) was added into dichloromethane (300mL), followed by tetrabutylammonium bisulfate (7.27g, 21.40mmol), sodium hydroxide (300mL , 3.57mmol, 40% aq), tert-butyl 2-bromopropionate (49.2g, 235mmol), then slowly warmed to room temperature, stirred at room temperature for 2 hours, the reaction mixture was dil...

Embodiment 2

[0112] Embodiment 2: the preparation of target compound I-1R

[0113] (R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-indene-2 -yl)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1R)

[0114] (R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydr o-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1R)

[0115]

[0116] The synthetic route of target compound I-1R is as follows:

[0117]

[0118] The first step: the synthesis of (R)-2-(butyl-3-yn-1-oxyl)propionic acid (2C)

[0119] (R)-2-(but-3-yn-1-yloxy) propanoic acid (2C)

[0120]

[0121] Add 3-butyn-1 alcohol (350mg, 5mmol) into DMF (5mL), cool to 0°C, add NaH (400mg, 10mmol, 60%), and stir for 30 minutes, then add raw material (S) at 0°C -2-Bromopropionic acid (700mg, 4.5mmol), stirred at the same temperature for 5h. Add water (10 mL) to the reaction solution at 0°C, adjust the pH to 1-2 with hydrochloric aci...

Embodiment 3

[0132] Embodiment 3: Preparation of target compound I-1R and target compound I-1S

[0133](R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-indene-2- Base) amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1R)

[0134] (R)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydr o-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1R)

[0135] (S)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-indene-2- Base) amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1S)

[0136] (S)-2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-inden-2-yl)amino) -5,7-dihydr o-6H-pyrrolo[3,4-d]pyrimidin-6-yl)propan-1-one (target compound I-1S)

[0137]

[0138] The target compound was separated by SFC to obtain:

[0139] The racemate 2-(2-(1H-1,2,3-triazol-4-yl)ethoxy)-1-(2-((2,3-dihydro-1H-indene-2- Base)amino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin...

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Abstract

The invention provides a novel compound capable of effectively inhibiting ATX. The compound is a compound represented by formula I, or a tautomer, a stereoisomer, a hydrate, a solvate, a salt or a prodrug of the compound represented by formula I. In the formula I, R1 and R2 are independently selected from-H or-CH3, respectively, with the proviso that R1 and R2 are not-H or-CH3 at the same time.

Description

technical field [0001] The present invention belongs to the field of biomedicine. Specifically, the present invention relates to pyrrolopyrimidine derivatives. More specifically, the present invention relates to pyrrolopyrimidine derivatives, 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, lymph...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P13/12A61P3/10A61P1/16A61P29/00A61P37/06A61P11/00A61P9/00A61P25/28A61P17/00A61P25/04A61P19/02
CPCC07D487/04A61P35/00A61P13/12A61P3/10A61P1/16A61P29/00A61P37/06A61P11/00A61P9/00A61P25/28A61P17/00A61P25/04A61P19/02A61K31/519A61K45/06A61K2300/00A61P43/00
Inventor 张学军叶大炳李莉娥沈洁丁肖华孙红娜刘哲臧杨魏用刚
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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