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Hydrazides as Inhibitors of Coagulation Factor Xa

A compound, formamide technology, applied in the field of new hydrazide compounds, can solve problems such as high risk

Active Publication Date: 2019-02-01
NORTH CHINA PHARMA COMPANY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patients treated with apixaban are at high risk for concomitant therapy with strong inhibitors of CYP3A4

Method used

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  • Hydrazides as Inhibitors of Coagulation Factor Xa
  • Hydrazides as Inhibitors of Coagulation Factor Xa
  • Hydrazides as Inhibitors of Coagulation Factor Xa

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0151] 4-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4-c ] Pyridin-6(7H)-yl)piperidin-1-yl)morpholin-3-one

[0152]

[0153] Reaction flow:

[0154]

[0155] Step A: Dissolve (4-methoxyphenyl)hydrazine hydrochloride (4.83 g, 27.7 mmol) in ethanol (50 mL) and add 1-ethoxy-2,2,2-trifluoroethanol (4.8 g, 33.3 mmol), then the mixture was refluxed for 16 hours. The reaction was concentrated, then the residue was dissolved in DMF (50 mL) and cooled to 0 °C. NBS (6.1 g, 27.7 mmol) was slowly added to the solution. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (PE to PE:EA=20:1) to give (Z)-2,2,2-trifluoro-N'-(4-methoxyphenyl)bromoacetyl Hydrazine (3.3 g, 39%) as a ye...

Embodiment 2

[0165] 1-(4-methoxyphenyl)-6-(2'-oxo-[1,1'-dipiperidinyl]-4-yl)-3-(trifluoromethyl)-5,6 -two Hydrogen-1H-pyrazolo[3,4-c]pyridin-7(4H)-one

[0166]

[0167] Step A: 6-(1-aminopiperidin-4-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazole And[3,4-c]pyridin-7(4H)-one (500 mg, 1.22 mmol) was dissolved in DMF (8 mL), and DIEA (315 mg, 2.44 mmol) and 5-bromopentyl Acid chloride (267 mg, 1.34 mmol). The mixture was stirred at 25°C for 3 hours, poured into water (30 mL), extracted with EA (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified by thin layer chromatography (EA) to give 5-bromo-N-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4 , 5-Dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)piperidin-1-yl)pentanamide (180 mg, 25%) as a yellow solid. LCMS(ESI)m / z:528.2(M+1),530.2(M+3).

[0168] Step B: Add 5-bromo-N-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyridin...

Embodiment 3

[0170] 1-(4-methoxyphenyl)-6-(1-(2-oxopyrrolidin-1-yl)-piperidinyl-4-yl)-3-(trifluoromethyl)- 5,6-Dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one

[0171]

[0172] Step A: To 6-(1-aminopiperidin-4-yl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-5,6-dihydro-1H-pyrazole To [3,4-c]pyridin-7(4H)-one (250 mg, 0.611 mmol) in DCM (8 mL) was added Et 3 N (62 mg, 0.611 mmol) and 4-chlorobutyryl chloride (86 mg, 0.611 mmol). The mixture was stirred at 25 °C for 16 hours, the resulting mixture was poured into water (30 mL), extracted with DCM (30 mL×2), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by TLC (EA) to give 4- Chloro-N-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazolo[3,4 -c] pyridin-6(7H)-yl)piperidin-1-yl)butanamide (100 mg, 32%) as a yellow solid. LCMS(ESI)m / z:514.2(M+1),516.2(M+3).

[0173] Step B: At 0°C, to 4-chloro-N-(4-(1-(4-methoxyphenyl)-7-oxo-3-(trifluoromethyl)-4,5-di Hydrogen-1H-pyrazolo[3,4-c]pyri...

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Abstract

The invention relates to a new compound represented by formula (I) or a pharmaceutically acceptable salt thereof. In the formula (I), X is selected from a 3-9-membered carbon ring or a benzo ring thereof and a 4-10-membered heterocyclic ring or a benzo ring thereof; Y and Z are respectively independently selected from 4-9-membered saturated heterocyclic rings; and R1-3 are respectively independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2, CHO and COOH, or are selected from R01 substituted C1-10 alkyl or heteroalkyl groups, C3-C10 cycloalkyl or heterocycloalkyl groups, and C3-10 cycloalkyl or heterocycloalkyl group substituted C1-10 alkyl or heteroalkyl groups. The compound can be used as an anticoagulant for treating and preventing thrombus abnormity diseases. The strong blood coagulation factor Xa inhibitor is provided to meet practical demands of selectivity and the strong inhibitor of the blood coagulation factor Xa.

Description

technical field [0001] The present invention relates to a new hydrazide compound, especially a compound represented by formula (I), its preparation method, pharmaceutical composition and its use as an anticoagulant in the treatment and prevention of thromboembolic diseases. Background technique [0002] Cardiovascular disease is the leading cause of morbidity and mortality in the developed world population, with the majority of cardiovascular events primarily attributable to thrombosis. Warfarin is the first oral anticoagulant approved for marketing, and its application suffers from slow vitamin K-dependent antagonism, drug-drug interactions, and drug-food interactions, which lead to Continuous monitoring is required for accurate dosing. Other anticoagulants such as heparin and fondaparinux are only suitable for parenteral administration. The above-mentioned defects of existing anticoagulants have promoted the in-depth research of new anticoagulant drugs. [0003] In the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D413/14A61K31/5377A61K31/4545A61P7/02A61P9/10A61P11/00A61P13/12
CPCC07D413/14C07D471/04
Inventor 丁照中赖光华陈曙辉颜小兵
Owner NORTH CHINA PHARMA COMPANY
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