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Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof

A technology of pyridine pyrimidine amine and pyridine pyridine amine, applied in the field of medicinal chemistry, can solve the problems of termination of clinical research, toxic and side effects, lack of selectivity of CDK subtype inhibition, etc.

Active Publication Date: 2015-12-16
GUANGZHOU BEBETTER MEDICINE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Clinical studies of CDK inhibitors AG-24322, ZK-304709, SNS-032, R547, Seliciclib and AZD5438 were terminated due to efficacy and toxicity
However, after analyzing the causes of severe toxic side effects, it was found that these drugs lack selectivity for CDK subtype inhibition, thus producing serious toxic side effects

Method used

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  • Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof
  • Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof
  • Pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0107] Example 1: N 2 -(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-N 5 -(piperidine-4-methyl)pyridine-2,5-diamine (N 2 -(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)-N 5 -(piperidin-4-ylmethyl)pyridine-2,5-diamine) (compound 1) preparation

[0108] Step 1a: Preparation of N-isopropylacetamide (N-Isopropyl-acetamide) (compound 102-1)

[0109] Isopropylamine (10 g, 0.169 mol, 1.0 eq) and triethylamine (23.58 mL, 0.338 mol, 2.0 eq) were premixed in 100 mL of dichloromethane. Cool to 0°C, slowly add acetic anhydride (16.15 ml, 0.338 mol, 2.0 equiv) dropwise to the reaction solution, and react at room temperature overnight. Concentrate under reduced pressure, extract the concentrate with ethyl acetate, and dry the organic phase over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain compound N-isopropylacetamide (15.05 g, yield: 88%). 1 HNMR (500MHz, CDCl ...

Embodiment 2

[0128] Example 2: 2-[4-({6-[5-fluoro-4-(7-fluoro-2-methyl-3-propyl-3H-benzimidazol-5-yl)-pyrimidine-2- Amino]-pyridin-3-ylamino}-methyl)-piperidin-1-yl]-ethanol (2-[4-({6-[5-Fluoro-4-(7-fluoro-2-methyl -3-propyl-3H-benzoimidazol-5-yl)-pyrimidin-2-ylamino]-pyridin-3-ylamino}-methyl)-piperidin-1-yl]-ethanol) (compound 2)

[0129] Step 2a: Preparation of N-n-propylacetamide (N-propylacetamide) (compound 102-2)

[0130] Dissolve n-propylamine (5 grams, 0.085 moles, 1.0 equivalents) and triethylamine (11.79 milliliters, 0.169 moles, 2.0 equivalents) in 100 milliliters of dichloromethane, cool to 0 degrees, and add acetic anhydride (8.67 grams , 0.085 mol, 1.0 equivalent). After reacting overnight at room temperature, the solvent was spin-dried, and the concentrate was purified by alumina column chromatography (eluent: ethyl acetate) to obtain N-n-propylacetamide (7.5 g, yield: 88%) as a colorless oily liquid. LCMS(ESI):m / z102[M+H] + .

[0131] Step 2b: N'-(4-bromo-2,6-difluoro...

Embodiment 3

[0142] Example 3: N 5 -(1-Benzylpiperidin-4-ylmethyl)-N 2 -[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzimidazol-5-yl)-pyrimidin-2-yl]-pyridine-2,5-diamine (N 5 -(1-Benzyl-piperidin-4-ylmethyl)-N 2 -[5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-pyridine-2,5-diamine) (Compound 3) preparation

[0143] Compound 4-((tert-butoxycarbonyl)(6-(5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzimidazol-6-yl)pyrimidine-2 -yl)aminopyridin-3-yl))aminomethylpiperidine-1-carboxylic acid tert-butyl ester (109-1) (217 mg, 0.313 mmol, 1.0 equiv) was dissolved in dichloromethane (50 mL) , slowly dropwise into methanolic hydrochloric acid solution (8 ml), and stirred for 4 hours. The reaction solution was directly concentrated in vacuo to obtain a brown solid. The obtained solid and potassium carbonate (56 mg, 0.406 mmol, 1.4 eq) were added to a reaction flask equipped with acetonitrile (30 mL), followed by benzyl chloride (31 mg, 0.244 mmol, 0.8 eq...

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Abstract

The invention discloses pyridylpyrimidyl amine compounds or pyridylpyridyl amine compounds disclosed as Formula I and application thereof in preparing antineoplastic drugs, belonging to the technical field of drugs. The compounds can selectively inhibit CDK4 and CDK6, enable G1-period tumor cells to stop growth and G1-period tumor cells to reduce, can effectively lower the phosphorylation of the tumor inhibiting protein Rb in the Ser780 site, and thus, can be used for various diseases caused by cell cycle control maladjustment participated by CDK4 and CDK6. The compounds are especially suitable for treating malignant tumors, and have the characteristics of high selectivity, high activity and high tumor cell proliferation resistance.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a pyridine pyrimidine amine compound and a pyridine pyridine amine compound and a preparation method and application thereof. Background technique [0002] Cyclin-dependent protein kinase (cyclin-dependent kinase, CDK) and cyclin (cyclin) are important factors in cell cycle regulation. CDK can combine with cyclin to form a heterodimer, in which CDK is the catalytic subunit and cyclin is the regulatory subunit, forming various cyclin-CDK complexes, phosphorylating different substrates, and promoting and promoting different phases of the cell cycle. Transformation. [0003] There are at least nine CDKs in mammals. Cell transition from G1 phase to S phase is mainly controlled by CDK kinases in G1 phase. CDK kinases that bind to cyclins in the G1 phase mainly include CDK2, CDK4 and CDK6. CyclinD mainly binds to CDK4 and CDK6 and regulates the activity of the latter; C...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D405/14C07D487/08A61K31/506A61K31/4545A61P35/00A61P35/04
CPCA61K31/506C07D401/14C07D405/14C07D487/08
Inventor 蔡雄钱长庚刘斌李军旗林明生卿远辉翁运幄王艳艳薛伟才游华金周石清
Owner GUANGZHOU BEBETTER MEDICINE TECH CO LTD
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