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Pyrrolopyrimidine derivatives and uses thereof

A use and drug technology, applied in the field of biomedicine, can solve the problems of patients with severe specific pulmonary fibrosis not benefiting, affecting the quality of life, and unable to improve the quality of life of patients, achieving excellent liver metabolic stability and cardiac safety advantages, giving Effects of low dose and frequency of administration and good pharmacokinetic properties

Active Publication Date: 2022-07-29
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 derivatives and uses thereof
  • Pyrrolopyrimidine derivatives and uses thereof
  • Pyrrolopyrimidine derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: 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 the target compound I-1 is as follows:

[0092]

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

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

[0095]

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

Embodiment 2

[0112] Example 2: 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 the target compound I-1R is shown below:

[0117]

[0118] Step 1: Synthesis of (R)-2-(butyl-3-yn-1-oxy)propionic acid (2C)

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

[0120]

[0121] 3-Butyn-1-ol (350 mg, 5 mmol) was added to DMF (5 mL), cooled to 0 °C, NaH (400 mg, 10 mmol, 60%) was added, and stirred for 30 minutes, the starting material (S) was added at 0 °C -2-Bromopropionic acid (700 mg, 4.5 mmol), stirred at the same temperature for 5 h. Water (10 mL) was added to the reaction solution at 0°C, pH=1~2 was adjusted wit...

Embodiment 3

[0132] Example 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- yl)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- yl)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 compounds were separated by SFC:

[0139] The racemate 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 ...

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Abstract

The present invention proposes a new compound that effectively inhibits ATX, which is a compound represented by formula I, or a tautomer, stereoisomer, hydrate, solvate, salt or prodrug of the compound represented by formula I: where: R 1 and R 2 independently selected from -H or -CH 3 , provided that R 1 and R 2 Not both ‑H or not both ‑CH 3 .

Description

technical field [0001] The present invention belongs to the field of biomedicine, in particular, the present invention relates to pyrrolopyrimidine derivatives, more particularly, the present invention relates to pyrrolopyrimidine derivatives and a preparation method thereof, as well as their use in preparing medicines. Background technique [0002] Autotaxin (abbreviated as ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activity and is a member of the extracellular pyrophosphatase / phosphodiesterase (ENPP) family. Called ENPP2. ATX also has lysophospholipase D (LysoPLD) activity, which can hydrolyze lysophosphatidylcholine (LPC) to 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, lymphocyte h...

Claims

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Application Information

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Patent Type & Authority Patents(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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