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Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof

A ketone compound, 3-d technology, which can be used in drug combinations, medical preparations containing active ingredients, compounds of elements of Group 5/15 of the periodic table, etc., and can solve problems such as blood sugar rise.

Inactive Publication Date: 2016-02-17
SHANDONG HUIRUIDI BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is evidence that IR is also an effective anti-cancer target, but because the inhibition of IR has the risk of increasing blood sugar, IR inhibitors need to find a balance between benefit and safety risk when used in anti-cancer

Method used

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  • Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof
  • Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof
  • Phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound or pharmaceutically acceptable salt, pharmaceutical composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0283] trans-8-[4-(diethoxyphosphorylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3 The preparation of -pyridyl)-4-methylpyridin[2,3-d]pyrimidin-7-one (1-15), the specific reaction formula is as follows:

[0284]

[0285] The first step: add bromine (134g, 0.84mol) dropwise to a dichloromethane solution (4L) of 4-chloro-6-methylpyrimidin-2-amine (1-1, 100g, 0.70mol), and the resulting suspension The solution was stirred at room temperature for 2 hours, diluted with dichloromethane (5L), washed with saturated sodium bicarbonate solution (2x3L) and saturated brine (3L), dried over magnesium sulfate, filtered, and concentrated to obtain the product 5-bromo-4- Chloro-6-methylpyrimidin-2-amine (1-2), as a white solid (120 g, yield: 79%).

[0286] The second step: 5-bromo-4-chloro-6-methylpyrimidin-2-amine (1-2, 120g, 0.54mol), trans-4-aminocyclohexanol (1-3, 58g, 0.5mol) and A solution of diisopropylethylamine (110 g, 0.84 mol) in dimethylacetamide (4 L) was heat...

Embodiment 1

[0294] trans-2-amino-8-[4-(diethoxyphosphorylmethoxy)cyclohexyl]-6-(6-methoxy-3-pyridyl)-4-methylpyridinyl[2, 3-d] the preparation of pyrimidin-7-ketone (1-16), the specific reaction formula is as follows:

[0295]

[0296] trans-8-[4-(diethoxyphosphorylmethoxy)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3 -pyridyl)-4-methylpyridin[2,3-d]pyrimidin-7-one (1-15, 0.61 g, 1 mmol, prepared according to Example 1A) and hydroxylamine hydrochloride (0.35 g, 5 mmol) were dissolved in ethanol / water (10:1, 22 mL) and heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain trans-2-amino-8-[4-(diethoxyphosphorylmethoxy)cyclohexyl]-6-(6-methoxy- 3-pyridyl)-4-methylpyridin[2,3-d]pyrimidin-7-one (1-16, 210 mg, yield: 40%), as a yellow solid. NMR analysis results: 1 H-NMR (CDCl 3 ,400MHz):δ8.31(d,J=2.8Hz,1H),7.96(dd,J=2.4,8.4Hz,1H),7.74(s,1H),6.80(d,J=8.4Hz,1H) ,5.52(m,1H),5.31(s,2H)...

Embodiment 2A

[0302] cis / trans-8-[4-(diethoxyphosphorylmethylamino)cyclohexyl]-2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy The preparation of -3-pyridyl)-4-methylpyridin[2,3-d]pyrimidin-7-one (2A), the specific reaction formula is as follows:

[0303]

[0304] The first step: at 0°C, to trans-2-(2,5-dimethylpyrrol-1-yl)-8-(4-hydroxycyclohexyl)-6-(6-methoxy-3 -pyridyl)-4-methylpyridin[2,3-d]pyrimidin-7-one (1-13, 0.179g, 0.39mmol, synthesized according to the seventh step in Example 1A) and sodium acetate (64mg, 0.78 mmol) in dichloromethane (5mL) solution was added PCC (0.11g, 0.47mmol), the resulting mixture was stirred at room temperature for 4 hours, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography, petroleum ether / ethyl acetate Esters mixture (70 / 30) as eluent gave the compound 2-(2,5-dimethylpyrrol-1-yl)-6-(6-methoxy-3-pyridyl)-4-methyl -8-(4-oxocyclohexyl)pyridin[2,3-d]pyrimidin-7-one (2A-1, 0.093 g, yield: 52%). Mass...

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Abstract

The invention provides a phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound as shown in the formula (I) or its pharmaceutically acceptable salt, and also discloses a preparation method of the compound, a pharmaceutical composition containing the phosphorus-containing pyridine[2,3-d]pyrimidine-7-ketone compound and an application thereof. The compound is a protein kinase (such as PI3K) inhibitor and can be used in treating diseases caused by abnormal protein kinase activities, such as tumour, etc.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to phosphorus-containing pyrido[2,3-d]pyrimidin-7-one compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing the compounds and applications thereof. Background technique [0002] Protein kinases are a class of phosphotransferases, whose function is to transfer the γ-phosphate group of ATP to specific amino acid residues of the substrate, phosphorylate proteins, and exert their physiological and biochemical functions. Protein kinase is an important class of kinases. It has two main functions in signal transduction: one is to regulate the activity of proteins through phosphorylation; cellular response. [0003] The abnormality of protein kinase activity is not only closely related to tumor proliferation, apoptosis, metastasis, etc., but also to the abnormality of a certain link in a series of signal transduction pathway...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P35/00A61P17/06A61P1/16A61P11/00A61P29/00A61P19/02A61P3/10A61P37/02A61P9/00A61P25/08A61P25/28A61P25/14A61P25/16A61P35/02
CPCA61K31/675C07F9/6561
Inventor 吕慧敏
Owner SHANDONG HUIRUIDI BIOTECH
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