Aminopyrimidine derivative used as PPAR-gamma regulator

A phenyl, group technology, applied in the field of aminopyrimidine derivatives as PPAR-γ regulators, can solve problems such as application limitations, insufficient research and the like

Inactive Publication Date: 2015-12-02
CHENGDU UNIVERSITY OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the lack of thorough research on it at present, and reports have shown that PPAR can inhibit the function of mitochondrial complex I, its application is limited.

Method used

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  • Aminopyrimidine derivative used as PPAR-gamma regulator
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  • Aminopyrimidine derivative used as PPAR-gamma regulator

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1: 1-(2-amino-4-(4-(3-ureidophenyl)benzylamino)-6-chloropyrimidin-5-yl)-6-(piperidin-1-yl)- Preparation of 2-hexyn-1-one

[0066]

[0067] The first step: N-(3-(4-formylphenyl)phenyl)urea (compound number 1)

[0068]

[0069] After deoxygenation by nitrogen bubbling in advance and continuous nitrogen protection, anhydrous potassium carbonate (27.6g, 0.2mol), palladium acetate (0.90g, 4.0mmol) and Molecular sieves (2.0g, previously activated by high-temperature roasting in a muffle furnace) were sequentially added with p-bromobenzaldehyde (18.5g, 0.1mol) and m-ureidophenylboronic acid (18.0g, 0.1mol, refer to Journal of the American Chemical Society; vol.81; ( 1959); p.3017) in a mixed solution of tetrahydrofuran (150 mL) and water (40 mL). Under the protection of nitrogen, the oil bath was heated to reflux, and the reaction was kept for about 6 hours. Ethyl acetate (300 mL) was added, stirred for half an hour, the insoluble matter was removed by filtra...

Embodiment 2

[0092] Example 2: 1-(2-amino-4-(4-(4-methoxyphenyl)anilino)-6-chloropyrimidin-5-yl)-5-methoxy-2-pentyne- Preparation of 1-keto

[0093]

[0094] The first step: 2-amino-4-(4-(4-methoxyphenyl)anilino)-6-chloropyrimidine-5-carbaldehyde (compound number 9)

[0095]

[0096] Under nitrogen protection, 4-(4-methoxyphenyl)aniline (11.4g, 57.3mmol, can refer to the literature RazlerTMetal.JournalofOrganicChemistry; vol.74; nb.3; (2009); p.1381-1384 was added Synthesis) in anhydrous tetrahydrofuran (120 mL) was cooled with an ice-water bath, and sodium hydrogen (60% mineral oil powder, 4.6 g, 114.6 mmol) was added carefully in batches. After the addition was complete, the stirring reaction was continued for about half an hour, and then 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (10.0 g, 52.1 mmol) was added. The ice-water bath was removed, and the reaction system was allowed to react at room temperature for about 8-10 hours, monitored by TLC (petroleum ether:ethyl acetate=2...

Embodiment 3

[0104] Example 3: (E)-1-(2-amino-4-(4-(4-methoxyphenyl)anilino)-6-chloropyrimidin-5-yl)-6-methoxy-2 - Preparation of hexen-1-one

[0105]

[0106] The first step: (E)-1-(2-amino-4,6-dichloropyrimidin-5-yl)-6-methoxy-2-hexen-1-one (compound number 12)

[0107]

[0108] 1-(2-amino-4,6-dichloropyrimidin-5-yl)ethanone (10.0g, 48.5mmol, reference WO2005 / 28434, (2005), (A2) or WO2014 / 96423, (2014 ), (A1) to be synthesized) in anhydrous tetrahydrofuran (100mL) was cooled to -78°C with a liquid nitrogen ethanol bath, and lithium diisopropylamide (LDA, 2.0M n-hexane solution, 24.3mL, 48.5mmol ) solution, the control dripped in about half an hour. Keeping at -78°C and under the protection of nitrogen, add 4-methoxy-1-butyraldehyde (5.0 g, 48.5 mmol) dropwise, refer to the literature WO2009 / 7814, (2009), (A1), BorbasK, et al.Organic Letters; vol.10; nb.10; (2008); p.1931-1934 or ChauST, etal.Organic Letters; vol.13; nb.4; (2011); p.756-759 to synthesize) anhydrous tetrahydrofura...

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Abstract

The invention relates to an aminopyrimidine derivative used as a PPAR-gamma regulator, specifically to a 2,4-diamino-6-chloropyrimidone derivative as shown in a formula I which is described in the specification, and/or medicinal salts thereof, a preparation method thereof, and application of the derivatives and/or medicinal salts thereof in treatment and/or prevention of disease related to peroxidase proliferator-activated acceptor subtype PPAR-gamma, e.g., inflammations (including rheumatoid arthritis), atherosclerosis, diabetes type I or II, diabetic complications, obesity, hyperlipidemia, impaired glucose tolerance, cerebral ischemia, Parkinson's disease, insulin resistance and osteoporosis. The invention also relates to a pharmaceutical composition containing the derivative. In the formula I, two substituents, i.e., R1 and R2 are defined in the specification.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, and in particular relates to a kind of aminopyrimidine derivative and its physiologically acceptable salt described in the claims, their preparation and their therapeutic and / or prophylaxis and inflammation (including rheumatoid arthritis) Inflammation), atherosclerosis, type Ⅰ or type Ⅱ diabetes, diabetic complications, obesity, hyperlipidemia, impaired glucose tolerance, cerebral ischemia, Parkinson's syndrome, insulin resistance and osteoporosis-related diseases the use of. technical background [0002] Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily, including PPAR-α, PPAR-β / δ and PPAR-γ. Of these phenotypes, PPAR-γ is the most intensively studied. The activation of PPAR plays an irreplaceable role in regulating a wide range of metabolic processes in the body. [0003] Peroxidas...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/48A61K31/506A61P29/00A61P19/02A61P9/10A61P3/10A61P3/04A61P3/06A61P25/16A61P5/50A61P19/10
CPCC07D239/48
Inventor 周立宏
Owner CHENGDU UNIVERSITY OF TECHNOLOGY
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