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Derivatives of ticagerlor, and preparation method and pharmaceutical application thereof

A technology of ticagrelor and its derivatives, applied in the field of medicine, can solve the problem of inability to accurately control the relative dosage and effect of ticagrelor and aspirin

Active Publication Date: 2012-10-17
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the above-mentioned combined administration method or the method of making a compound preparation cannot accurately control the relative doses of ticagrelor and aspirin, which will have an adverse effect on the effect of the combination drug

Method used

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  • Derivatives of ticagerlor, and preparation method and pharmaceutical application thereof
  • Derivatives of ticagerlor, and preparation method and pharmaceutical application thereof
  • Derivatives of ticagerlor, and preparation method and pharmaceutical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] The synthesis of the L-alanine ester of embodiment 1 ticagrelor

[0072] Step (1), Boc protects the amino group of L-alanine

[0073]

[0074] Dissolve 50g of L-alanine (1.0eq, 0.56mol) in a mixed solution of 100ml of water and 200ml of acetone, add 121.5ml of triethylamine (1.5eq, 0.84mol) under stirring, control the temperature at 25°C, and drop while stirring Add 131.8ml (Boc) 2 O (1.1eq, 0.62mol), stir the reaction for 6h after the dropwise addition, evaporate the acetone under reduced pressure, extract the water layer with diethyl ether, then adjust the pH value of the water layer to 2~3 with dilute hydrochloric acid, and extract the water layer 3 times with ethyl acetate layers, the organic layers were combined, the organic layer was washed with saturated brine, dried and concentrated over anhydrous sodium sulfate to obtain the crude product and recrystallized with petroleum ether and ethyl acetate (2: 1) to obtain 95.4 g of Boc-L-alanine, the yield 90%.

...

Embodiment 2

[0083] The synthesis of the L-phenylalanine ester of embodiment 2 ticagrelor

[0084] Step (1), Boc protects the amino group of L-phenylalanine

[0085]

[0086] Dissolve 50g of L-phenylalanine (1.0eq, 0.30mol) in a mixed solution of 100ml of water and 200ml of acetone, add 65.1ml of triethylamine (1.5eq, 0.45mol) under stirring, control the temperature at 25°C, and stir Add 70.6ml (Boc) dropwise 2O (11eq, 0.33mol), after the dropwise addition, stir the reaction for 6h, evaporate the acetone under reduced pressure, extract the water layer with ether, then adjust the pH value of the water layer to about 2-3 with dilute hydrochloric acid, and extract the water layer 3 times with ethyl acetate Layers, the organic layer was combined, the organic layer was washed with saturated brine, dried and concentrated over anhydrous sodium sulfate to obtain the crude product and recrystallized with petroleum ether and ethyl acetate (2: 1) to obtain 73.9g of Boc-L-phenylalanine, Yield 9...

Embodiment 3

[0094] The synthesis of embodiment 3 ticagrelor L-valine ester

[0095] Step (1), Boc protects the amino group of L-valine

[0096]

[0097] Dissolve 50g of L-valine (1.0eq, 0.426mol) in a mixed solution of 100ml of water and 200ml of acetone, add 92.4ml of triethylamine (1.5eq, 0.64mol) under stirring, control the temperature at 25°C, and drop while stirring Add 100ml (Boc) 2 O (11eq, 0.47mol), after the dropwise addition, stir the reaction for 6h, evaporate the acetone under reduced pressure, extract the water layer with ether, then adjust the pH value of the water layer to about 2-3 with dilute hydrochloric acid, and extract the water layer 3 times with ethyl acetate The organic layer was combined, and the organic layer was washed with saturated brine, dried and concentrated over anhydrous sodium sulfate to obtain the crude product, which was recrystallized with petroleum ether and ethyl acetate (2: 1) to obtain 81.8g of Boc-L-valine. The rate is 88.5%.

[0098] Ste...

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PUM

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Abstract

The invention provides derivatives of ticagerlor or pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 in a formula representing the derivatives or the pharmaceutically acceptable salts thereof can be selected from amino acid residues or acetylsalicyloyl groups. The invention also provides a preparation method for the derivatives of ticagerlor or the pharmaceutically acceptable salts thereof and further provides application of the derivatives of ticagerlor or the pharmaceutically acceptable salts thereof in preparation of drugs used for treating blood coagulation-related diseases. The derivatives provided in the invention can improve bioavailability of ticagerlor or enhance the drug combination effect of ticagerlor and aspirin.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to derivatives or salts thereof of the small-molecule anticoagulant drug ticagrelor, methods for preparing the derivatives or the salts thereof, and the pharmaceutical use of the derivatives or the salts thereof. Background technique [0002] Ticagrelor (former code: ADZ6140, ARC126532) is a new type of selective small molecule anticoagulant drug developed by AstraZeneca, which can reversibly act on The Purinoceptor 2 (P2) subtype P2Y12 on vascular smooth muscle cells (VSMC) has obvious inhibitory effect on ADP-induced platelet aggregation, so it can effectively improve the symptoms of patients with acute coronary heart disease. On July 20, 2011, the US FDA approved ticagrelor for reducing cardiovascular death and heart attack in patients with acute coronary syndrome (ACS), with a trade name of Brilinta. [0003] British Astra Pharmaceutical Co., Ltd. disclosed the chemical struct...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/625A61K31/519A61P7/02A61P9/10
CPCY02P20/55
Inventor 袁建栋
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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