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Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof

A compound and hydrate technology, applied in the field of pyrazolo[3,4-c]pyridin-7-one compounds as factor Xa inhibitors, for the preparation of drugs for the treatment and/or prevention of thromboembolic diseases, capable of Solve problems such as inconvenient administration, narrow therapeutic index, and safety

Active Publication Date: 2015-04-15
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The oral anticoagulant drug warfarin can inhibit post-transcriptional mature coagulation factors VII, IX, X and prothrombin, and is effective for both venous and arterial thromboembolism, but has a narrow therapeutic index and slow onset of action, and it is not compatible with many foods and drugs Interactions exist, requiring drug monitoring and dose adjustments, limiting its use
Low-molecular-weight heparin and fondaparinux sodium are administered by injection, and there are problems such as safety and inconvenient administration. Therefore, it is particularly necessary to develop a class of safe and effective oral anticoagulant drugs

Method used

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  • Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof
  • Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof
  • Pyrazolo[3, 4-c]pyridine-7-one compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0239] Step 1 3,3-Dichloro-piperidin-2-one (2)

[0240] At room temperature, 100 g (1.01 mol) of raw material (1) was dissolved in 500 ml of chloroform to prepare solution A. Dissolve 632 g (3.03 mol) of phosphorus pentachloride in 500 ml of chloroform to prepare solution B. Slowly drip solution A into solution B, control the temperature during the dripping process at 0~-15℃, after dripping, heat up to 25℃, add 277ml (3.03mol) phosphorus oxychloride, after addition, react at 70℃ for 4h. The solvent was evaporated under reduced pressure to obtain a dark brown liquid. Pour the liquid slowly into 800g of crushed ice with stirring, use K 2 CO 3 Adjust the pH to 8, stirring at room temperature for 1 hour, and suction filtration to obtain 155.2 g of a light gray solid (theoretical yield is 168.7 g), which is recrystallized with 1400 ml of absolute ethanol to obtain 136.6 g of white needle-like crystals. The total yield is 81%.

[0241] Step 2 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-o...

Embodiment 2

[0268] 1-(4-Methoxyphenyl)-6-[4-(3-oxo-4-morpholinyl)phenyl]-3-(1-methyl-1H-1,2,4-tri (Azazol-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one

[0269] ESI-MS m / z:500.5[M+H] + ;

Embodiment 3

[0271] 1-(4-Methoxyphenyl)-6-[4-(3-oxo-4-morpholinyl)phenyl]-3-[4-methylamino-ethyl-4H-1,2 ,4-Triazol-3-yl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-7-one

[0272] ESI-MS m / z:500.5[M+H] + ;

[0273] Step 14 N-((Dimethylamino)methylene)1-(4-methoxyphenyl-7-oxo-6-(4-(3-morpholinonyl)phenyl)-4,5, 6,7-Tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-amide (18)

[0274] Suspend carboxylic acid (5g, 0.01mol) and dissolve in 50mL ethyl acetate, add 2mL triethylamine dropwise, stir for 20min, add (1.85mL, 0.013mol) tert-butyl chloroformate dropwise, and react at 30℃ for 2h ; Evaporate the reaction solution to dryness to obtain a brown-yellow solid; dissolve the above-mentioned brown-yellow solid in a minimum amount of methanol (if there is insoluble matter, add a small amount of dichloromethane to dissolve), put the dissolved methanol solution slowly under ice Add dropwise to 50mL hydrazine hydrate. With the dropwise addition, a large amount of white solid is gradually precipitated. After the...

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PUM

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Abstract

Belonging to the technical field of medicine, the invention relates to a 4, 5-dihydro-1H-pyrazolo[3, 4-c]pyridine-7-one containing derivative shown as general formula I, and pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein the substituents A, R1 and R2 have meanings given in the specification. The preparation also relates to a preparation method of the general formula I compound and its pharmaceutically acceptable salt or prodrug, medicinal compositions containing the compound and application of the compound as an Xa factor inhibitor, especially application in preparation of drugs for treatment and / or prevention of thromboembolic diseases. (formula I).

Description

Technical field [0001] The present invention relates to a novel pyrazolo[3,4-c]pyridine-7-one compound and pharmaceutically acceptable salts, hydrates or prodrugs thereof, their preparation methods and pharmaceutical combinations containing the compounds Things. The present invention also relates to the use of pyrazolo[3,4-c]pyridine-7-one compounds as factor Xa inhibitors, especially in the preparation of drugs for the treatment and / or prevention of thromboembolic diseases. Background technique [0002] Thrombosis, the formation of local blood clots, is the main cause of arterial diseases such as myocardial infarction and stroke, as well as venous thromboembolic diseases. Traditional anticoagulant drugs mainly include warfarin, heparin and low molecular weight heparin. Oral anticoagulant drug warfarin can inhibit the post-transcriptional mature coagulation factors VII, IX, X and prothrombin. It is effective for venous and arterial thromboembolism, but has a narrow therapeutic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61P7/02
CPCC07D471/04
Inventor 宫平刘亚婧赵燕芳翟鑫廖伟科
Owner SHENYANG PHARMA UNIVERSITY
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