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Hydroximic acid derivative and application thereof

A technology of compounds and hydrates, applied in the field of biomedicine, can solve problems such as drug interactions, toxic side effects, complex pharmacokinetics, etc., and achieve the effects of improving therapeutic effects, reducing adverse reactions, and good application prospects

Pending Publication Date: 2021-12-03
CHENGDU ZIHAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the combined drug has the disadvantages of complex pharmacokinetics, possible drug interactions, and more toxic and side effects.

Method used

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  • Hydroximic acid derivative and application thereof
  • Hydroximic acid derivative and application thereof
  • Hydroximic acid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0316] Example 1, 2-(4-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzamide)methyl)piperidine- 1-yl)-N-hydroxypyrimidine-5-carboxamide (compound 1)

[0317]

[0318] A: 4-Aminomethylpiperidin-1-yl-pyrimidine-5-carboxylic acid methyl ester

[0319] In a 500ml three-necked flask, add 200 milliliters of N,N-dimethylacetamide, 34.3 grams (0.3mol) of compound 4-aminomethylpiperidine and 65.5 milliliters (0.375mol) of N,N-diisopropylethyl Amine, at room temperature, add 25.9 g (0.15 mol) of methyl 4-chloropyrimidine-5-carboxylate dropwise while stirring in 100 ml of N,N-dimethylacetamide solution, after 3 hours, the reaction solution was slowly Pour into the stirred ice-water mixture, then extract three times with 300 ml ethyl acetate respectively, combine the organic phases, wash twice with an appropriate amount of saturated saline, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain light yellow Waxy. Then recrystallized wi...

Embodiment 2

[0332] Example 2, 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-N-hydroxypyrimidine-5-carboxamide (compound 2)

[0333]

[0334] A: Methyl 2-(4-((2H-indazole-7-carboxamide)methyl)piperidin-1-yl)-5-carboxylate

[0335] Into a 250ml one-necked flask, add 8.1 grams (50mmol) of the compound 2H-indazole-7-carboxylic acid, 100ml of N,N-dimethylformamide, stir at room temperature, and then add 8.1 grams of N,N-carbonyldiimidazole (50mmol), there was gas evolution, and after 2 hours, 12.5 g (50mmol) of 4-aminomethylpiperidin-1-yl-pyrimidine-5-carboxylic acid methyl ester was added. Stir overnight, and the next day, slowly pour the reaction solution into the stirred ice-water mixture, and a light yellow solid precipitates out. After standing for 3 hours, filter, wash with water, and dry to obtain a light yellow powder product, which is the target compound 17.2 g was directly used in the next reaction without further purification. ESI-MS: m / z 395.2.

[0336] B: 2-(4-((2H-i...

Embodiment 3

[0346] Example 3, 2-((1-((2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidine-4- base) methylamino)-N-hydroxypyrimidine-5-carboxamide (compound 3)

[0347]

[0348] A: Methyl 2-(piperidin-4-ylmethylamino)pyrimidine-5-carboxylate

[0349] In a 100ml single-necked bottle, add 4.0g of 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)methylaminopyrimidine-5-carboxylic acid methyl ester, and 40ml of ethyl acetate hydrochloric acid gas solution, room temperature Under stirring reaction, TLC monitors the reaction process, after the reaction is complete, the precipitated solid is filtered to obtain 2.8 g of the target product.

[0350] B: 2-((1-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)piperidin-4-yl)methanol Amino)pyrimidine-5-carboxylic acid methyl ester

[0351] In a three-necked flask, add 5.96 grams of 2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid, 100ml of N,N-dimethylformamide, At room temperature, under stirring, add 8...

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Abstract

The invention provides a hydroximic acid derivative and application thereof, and relates to the field of biological medicine. The hydroximic acid derivative is a compound represented by formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a hydrate thereof, or a prodrug thereof. The invention provides a compound with good inhibitory activity on HDAC and PARP, and the compound has a good inhibitory effect on HDAC and PARP, can be used for preparing a PARP / HDAC double-target inhibitor, and can be used for preventing and / or treating diseases, such as tumors, ischemic diseases, diabetes mellitus, inflammatory diseases and the like, which are improved due to PARP and / or HDAC activity inhibition. Meanwhile, the compound disclosed by the invention has a synthetic lethal effect, can be used as a chemotherapy drug sensitizer and a radiotherapy sensitizer, and can be combined with other antitumor drugs for use, so that the treatment effect is improved, and the adverse reaction is relieved. In addition, the compound provided by the invention improves the compliance of patients, has more pharmacoeconomics advantages, and has a good application prospect.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of hydroxamic acid derivatives and applications thereof. Background technique [0002] Polyadenosine diphosphate-ribose polymerase (PARP) is an important DNA repair enzyme that exists in eukaryotic cells and has a protease that catalyzes the ribosylation of polyadenosine diphosphate (poly ADP). It recognizes DNA single-strand breaks and initiates repair. This repair acts on many proteins, involving chromosome stability, DNA damage repair, gene transcription, cell growth, death and apoptosis, and is closely related to inflammation, tumors, aging and other diseases in terms of physiology and pathology. [0003] PARP inhibitors can inhibit PARP activity, enhance the effect of radiotherapy and DNA damage chemotherapy drugs, and can also selectively kill tumor cells with DNA repair defects when used alone. The application of PARP inhibitors in tumor therapy is mainly based on two ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P35/00A61P9/10A61P29/00A61P3/10A61K31/506
CPCC07D401/14A61P35/00A61P9/10A61P29/00A61P3/10
Inventor 周鑫叶兵
Owner CHENGDU ZIHAO PHARMA
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