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Pyrimidine compound and preparation method thereof

A technology of compounds and hydrates, applied in drug combination, organic chemistry, digestive system, etc., can solve the problems that patients with severe specific pulmonary fibrosis cannot benefit, affect the quality of life, and cannot improve the quality of life of patients

Pending Publication Date: 2021-03-09
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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  • Pyrimidine compound and preparation method thereof
  • Pyrimidine compound and preparation method thereof
  • Pyrimidine compound and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0150] Preparation Example 1: Preparation of Intermediate A

[0151] 2-((2,3-Dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (Intermediate A)

[0152] 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylic acid (Intermediate A)

[0153]

[0154] The synthetic route of intermediate A is as follows:

[0155]

[0156] Dissolve 2-chloropyrimidine-5-carboxylic acid (2g, 12.61mmol) in N-methylpyrrolidone (10mL), add 2-aminoindane hydrochloride (2.57g, 15.14mmol), N,N-diiso Propylethylamine (8.15g, 63.1mmol) was heated to 100°C for 24h. The reaction solution was evaporated to remove the solvent under the oil pump, ethyl acetate (30 mL) was added to the residue to disperse, filtered, the filter cake was beaten with water (30 mL), filtered, and air-dried at 50°C for 3 hours to obtain a gray solid 2-(2,3-di Hydrogen-1H-inden-2-ylamino)pyrimidine-5-carboxylic acid (2.4 g, 74.5% yield). Intermediate A used in the following examples can be obtained by referring to t...

preparation example 2

[0158] Preparation Example 2: Preparation of Intermediate B

[0159] 4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidine hydrochloride (Intermediate B)

[0160]4-(((1H-1,2,3-triazol-4-yl)methoxy)methyl)piperidine hydrochloride (Intermediate B)

[0161]

[0162] The synthetic route of intermediate B is as follows:

[0163]

[0164] The first step: the synthesis of tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate (2)

[0165] tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate

[0166]

[0167] At 0°C, tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (150 g, 697 mmol) was added to THF (1000 mL), then sodium hydride (33.4 g, 836 mmol, 60% purity ), stirred at room temperature for 1 h, then cooled to 0° C., slowly added 3-bromopropyne (104 g, 871 mmol) dropwise, and stirred at room temperature for 8 h after the addition was completed. After the reaction was completed, the reaction solution was poured into saturated aqueous ammonium ch...

Embodiment 1

[0178] Embodiment 1: the preparation of target compound I-1

[0179] (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-indene -2-yl)amino)pyrimidin-5-yl)methanone (target compound I-1)

[0180] (4-(((2H-1,2,3-triazol-4-yl)methoxy)methyl)piperidin-1-yl)(2-((2,3-dihydro-1H-inden-2-yl)a mino)pyrimidin-5-yl)methanone

[0181]

[0182] The synthetic route of target compound 1-1 is as follows:

[0183]

[0184] The first step: the synthesis of tert-butyl 4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate (I-1B)

[0185] tert-butyl4-((prop-2-yn-1-yloxy)methyl)piperidine-1-carboxylate

[0186]

[0187] Dissolve tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (I-1A) (2g, 9.29mmol) in tetrahydrofuran (20mL), cool to 0°C, add sodium hydride (409mg, 10.22mmol , 60%), followed by dropwise addition of 3-bromopropyne (1.66 g, 14 mmol), and reacted at room temperature for 18 hours after the addition was completed. Add water (50mL) to quench, ...

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Abstract

The invention relates to pyrimidine compounds, in particular to a pyrimidine compound, a preparation method of the pyrimidine compound and an application of the pyrimidine compound in preparation of medicines. The invention provides the compound shown as a formula (I), or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug of the compound shown as theformula (I). The compound has an obvious inhibiting effect on ATX enzyme, shows excellent liver metabolism stability, and is slow in metabolism in a human body and high in exposure amount.

Description

[0001] priority information [0002] This application requests the priority of two patent applications submitted to the State Intellectual Property Office of China on September 6, 2019. The application number of patent application 1 is 201910841159.9, and the application name is "pyrimidine compounds and their preparation methods"; the application of patent application 2 is The number is 201910846545.7, and the title of the application is "Pyrimidine Derivatives and Their Uses", and its entire content is incorporated in this application by reference. technical field [0003] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to pyrimidine compounds. More specifically, the present invention relates to pyrimidine compounds, their preparation methods, and their use in the preparation of medicines. Background technique [0004] Autotaxin (abbreviated as ATX) is a secreted glycoprotein with phosphodiesterase (PDE) activi...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D403/14A61K31/506A61P35/00A61P3/00A61P13/12A61P1/16A61P11/00A61P29/00A61P25/04A61P37/00A61P9/00A61P25/00A61P17/00A61P3/10A61P19/02
CPCC07D401/14C07D403/14A61P35/00A61P3/00A61P13/12A61P1/16A61P11/00A61P29/00A61P25/04A61P37/00A61P9/00A61P25/00A61P17/00A61P3/10A61P19/02A61K31/506A61P43/00
Inventor 张学军李莉娥沈洁魏文军雷四军丁肖华臧杨孙红娜付强强
Owner WUHAN HUMANWELL INNOVATIVE DRUG RES & DEV CENT LTD CO
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