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

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

Example Embodiment

[0071] Example 1 Synthesis of L-alanine ester of 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) with stirring, control the temperature at 25°C, and drop with stirring. Add 131.8ml (Boc) 2 O (1.1eq, 0.62mol), after the addition is complete, stir and react for 6h, evaporate the acetone under reduced pressure, extract the water layer with ether, then adjust the pH value of the water layer to 2~3 with dilute hydrochloric acid, and extract the water with ethyl acetate for 3 times Combine the organic layers, wash the organic layer with saturated brine, dry and concentrate with anhydrous sodium sulfate to obtain a crude product. Recrystallize with petroleum ether and ethyl acetate (2:1) to obtain Boc-L-alanine 95.4 g, yield Is 90%.

[0075] In step (2), the compound represented by formula II is prepa...

Example Embodiment

[0083] Example 2 Synthesis of L-phenylalanine ester of 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) with stirring, control the temperature at 25°C, and stir. Drop 70.6ml (Boc) 2 O (11eq, 0.33mol), after the addition is complete, stir and react 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 with ethyl acetate for 3 times Combine the organic layers, wash the organic layer with saturated brine, dry and concentrate with anhydrous sodium sulfate to obtain a crude product. Recrystallize with petroleum ether and ethyl acetate (2:1) to obtain 73.9 g of Boc-L-phenylalanine. The yield was 92%.

[0087] In step (2), the compound represented...

Example Embodiment

[0094] Example 3 Synthesis of 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) with stirring, control the temperature at 25°C, and drop with stirring. Add 100ml (Boc) 2 O (11eq, 0.47mol), after the addition is complete, the reaction is stirred for 6h, the acetone is evaporated under reduced pressure, the water layer is extracted with ether, and then the pH value of the water layer is adjusted to about 2-3 with dilute hydrochloric acid. Combine the organic layers, wash the organic layer with saturated brine, dry and concentrate with anhydrous sodium sulfate to obtain a crude product. Recrystallize with petroleum ether and ethyl acetate (2:1) to obtain 81.8 g of Boc-L-valine. The rate is 88.5%.

[0098] In step (2), the compound represented by formula II is prepared according to the ...

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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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