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Purine ketone compound, preparation method thereof and application of purine ketone compound in medicine

A compound and general formula technology, applied in the directions of active ingredients of heterocyclic compounds, organic chemistry, anti-tumor drugs, etc., can solve the problem of unmet medical needs of the patient population

Active Publication Date: 2022-06-24
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are currently no approved DNA-PK inhibitor drugs, so there is a significant unmet medical need in this patient population

Method used

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  • Purine ketone compound, preparation method thereof and application of purine ketone compound in medicine
  • Purine ketone compound, preparation method thereof and application of purine ketone compound in medicine
  • Purine ketone compound, preparation method thereof and application of purine ketone compound in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] 7-Methyl-2-((6-methyl-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-7-yl)amino)-9-(tetrakis Hydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 1

[0200]

[0201]

[0202] first step

[0203] 1-(4-Methyl-2-nitrophenyl)pyrrole 1b

[0204] Dissolve 1-bromo-4-methyl-2-nitrobenzene 1a (5.00g, 25.5mmol, prepared by the method disclosed in patent application "CN107325002A, P10") and tetrahydropyrrole (9.08g, 127.4mmol) In 25 mL of absolute ethanol, the mixture was stirred at reflux for 96 hours. Concentrated under reduced pressure, added 100 mL of water, extracted with ethyl acetate (50 mL×3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was used a CombiFlash rapid prep as eluent system Purification of B gave the title product 1b (4.9 g), yield: 95.1%.

[0205] MS m / z (ESI): 207.1 [M+1].

[0206] second step

[0207] N-(5-Methyl-2-(pyrrolidin-1-yl)phenyl)acetamide 1...

Embodiment 2

[0228] 7-Methyl-2-((7-methyl-2,3-dihydrobenzo[4,5]imidazo[2,1-b]thiazol-6-yl)amino)-9-(tetrahydro -2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one 2

[0229]

[0230] first step

[0231] 2-((4-Methyl-2-nitrophenyl)amino)ethyl-1-ol 2b

[0232] 1-Chloro-4-methyl-2-nitrobenzene 2a (5.00g, 29.1mmol, prepared by the method disclosed in patent application "CN107325002A, P91") and 2-aminoethanol (5.34g, 87.4mmol, adamas) was dissolved in 25 mL of absolute ethanol and stirred at reflux for 96 hours. Concentrated under reduced pressure, added 100 mL of water, extracted with ethyl acetate (50 mL × 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was used a CombiFlash rapid prep as the eluent system Purification of B gave the title product 2b (1.7 g), yield: 29.7%. MS m / z (ESI): 197.0 [M+1].

[0233] second step

[0234] 2-((2-Amino-4-methylphenyl)amino)ethyl-1-ol 2c

[0235] Compou...

Embodiment 3

[0263] 7-Methyl-2-((7-methylbenzo[4,5]imidazo[2,1-b]thiazol-6-yl)amino)-9-(tetrahydro-2H-pyran-4 -yl)-7,9-dihydro-8H-purin-8-one 3

[0264]

[0265] first step

[0266] Methyl 4-amino-2-methyl-5-nitrobenzoate 3b

[0267] Methyl 4-fluoro-2-methyl-5-nitrobenzoate 3a (5.0 g, 23.5 mmol, prepared by the method disclosed in the patent application "US20120277224A1, P61") was dissolved in 20 mL of 1,4-dioxane To the hexacyclic ring, 118 mL of ammonia in 1,4-dioxane solution (0.4 M) was added and stirred overnight. 20 mL of water was added, concentrated under reduced pressure to remove the organic solvent, filtered, washed with water once, and air-dried to obtain the title product 3b (4.5 g), yield: 91.3%. MS m / z (ESI): 211.0 [M+1].

[0268] second step

[0269] Methyl 4,5-diamino-2-methylbenzoate 3c

[0270]Compound 3b (1.1 g, 5.23 mmol) was dissolved in 30 mL of methanol, 10% palladium on carbon (wet) (400 mg, 0.37 mmol) was added, hydrogen was replaced three times, and the ...

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Abstract

The invention relates to a purine ketone compound, a preparation method thereof and application of the purine ketone compound in medicine. Specifically, the invention relates to a purine ketone compound as shown in a general formula (IG), a preparation method thereof, a pharmaceutical composition containing the compound and application of the purine ketone compound as a therapeutic agent, especially application of the purine ketone compound as a DNA-PK inhibitor and application of the purine ketone compound in preparation of drugs for treating and / or preventing cancers. Wherein each group in the general formula (IG) is defined in the specification.

Description

technical field [0001] The present disclosure belongs to the field of medicine, and relates to a purinone compound, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to a purinone compound represented by the general formula (IG), a preparation method thereof, and a pharmaceutical composition containing the compound, as well as its use as a DNA-PK inhibitor and its preparation for treatment and / or use or use in medicines to prevent cancer. Background technique [0002] DNA-dependent protein kinase (DNA-PK) is a serine / hydroxybutyrine protein kinase complex composed of a heterodimer of catalytic subunit DNA-PKcs and Ku protein (Ku70 / Ku80), which is involved in the repair of DNA damage. It also plays an important role in maintaining the stability of telomerase, participating in innate immunity and V(D)J recombination, and transcriptional regulation (Curr Opin Allergy Clin Immunol, 2009, 9, 503-509). [0003] There are...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00C07D487/04C07D513/04A61P35/00A61P35/02A61K31/522
CPCC07D519/00C07D487/04C07D513/04A61P35/00A61P35/02
Inventor 陆标沈晓冬贺峰陶维康
Owner JIANGSU HENGRUI MEDICINE CO LTD
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