Cyclosporine A derivative as well as preparation method and application thereof

A technology for cyclosporine and derivatives, which is applied in the field of cyclosporine A derivatives and their preparation, can solve the problems of unsatisfactory yield of hydroxyl modification process, unfavorable industrial production and application, inability to obtain target substances, etc. Overcome harsh preparation conditions, high accuracy and good crystal state

Pending Publication Date: 2022-03-01
AUTOBIO DIAGNOSTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, due to the large steric hindrance of the free hydroxyl group, the yield of the hydroxyl group modification process is not ideal, and even the target product cannot be obtained; the preparation scheme for extending the carbon chain at the end of the double bond has harsh conditions and high technical difficulty, which is not conducive to the industry. Chemical production application and other defects

Method used

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  • Cyclosporine A derivative as well as preparation method and application thereof
  • Cyclosporine A derivative as well as preparation method and application thereof
  • Cyclosporine A derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1 Preparation of CsA ethylene oxide product

[0041]

[0042] Add CsA raw material (5.00g, 4.16mmol) into a 500mL eggplant-shaped bottle, dissolve it in 150mL of dichloromethane, add potassium peroxymonosulfonate (the molar ratio of addition to CsA is 1:1~1:15), at room temperature Stir overnight. Wash the reaction mother liquor twice with 200mL of 20% sodium sulfite solution, and wash twice with 200mL of 10% sodium carbonate aqueous solution. The organic layer was then dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 4.83 g of a white solid product with a purity of 96.8% and a yield of 92.2%.

[0043] Gained CsA epoxidation product mass spectrum and proton nuclear magnetic spectrum data are as follows:

[0044] MS-ESI(m / z):1240.73[M+Na] + ;

[0045] 1 H NMR (400MHz, DMSO-d 6 )δ:7.43-7.48(m,4H,-NH-CO-),5.28(s,1H,-OH),4.61-4.36(m,11H,-CH),4.05(s,2H,-CH 2 ),3.32-2.94(m,21H,-CH3 ),2.73-2.46(m,4H,-CH),2.30-2.17(m,10H,-CH 2 )...

Embodiment 2

[0046] Embodiment 2: Preparation of CsA aminated derivative 1

[0047]

[0048] Under the protection of argon, add CsA epoxide (500.0mg, 0.41mmol) to 50ml of anhydrous tetrahydrofuran, then add ethylenediamine (the molar ratio of addition to CsA epoxide is 1:2~1:50), heat to reflux 8h~40h. After the reaction was stopped, the solvent was concentrated by a rotary evaporator under reduced pressure, then ethyl acetate was added to dissolve the remaining solid, and then washed with 0.01M dilute hydrochloric acid solution for 1 to 5 times, and 0.1M ammonia water for 1 to 3 times. The organic phase was dried with a desiccant, concentrated under reduced pressure by a rotary evaporator to remove the solvent, then added a small amount of methanol, and then added a certain amount of purified water (the volume ratio of purified water to methanol was 1:10 to 1:100) for recrystallization and purification. After filtration and drying, 468.3 mg of the white crystal derivative was obtained...

Embodiment 3

[0052] Embodiment 3: Preparation of CsA aminated derivative 2

[0053]

[0054] Under the protection of argon, add CsA epoxide (500.0mg, 0.41mmol) to 50ml of anhydrous tetrahydrofuran, and then add 1,7-heptanediamine (the molar ratio of addition to CsA epoxide is 1:2~1:50 ), heated to reflux for 8h to 40h. After the reaction was stopped, the solvent was concentrated by a rotary evaporator under reduced pressure, then ethyl acetate was added to dissolve the remaining solid, and then washed with 0.01M dilute hydrochloric acid solution for 1 to 5 times, and 0.1M ammonia water for 1 to 3 times. The organic phase was dried with a desiccant, concentrated under reduced pressure by a rotary evaporator to remove the solvent, then added a small amount of methanol, and then added a certain amount of purified water (the volume ratio of purified water to methanol was 1:10 to 1:100) for recrystallization and purification. After filtration and drying, 376.9 mg of the white crystal deriva...

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Abstract

The invention relates to the technical field of biology, in particular to a cyclosporine A derivative as well as a preparation method and application thereof. The cyclosporine A derivative has a structure as shown in a formula I, is high in immunogenicity, can meet the quantitative detection requirement of a full-automatic chemiluminescence detection platform, and does not have cross reaction with common interference drugs; and a CsA detection reagent prepared by taking the hapten derivative as an antigen is strong in specificity, high in precision, high in accuracy and good in stability.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to a cyclosporine A derivative and its preparation method and application. Background technique [0002] Cyclosporin A (cyclosporin, CsA) is a cyclic polypeptide compound containing 11 amino acids, which has a relatively high selective inhibitory effect on cellular and humoral immunity, and is a lymphocyte activation inhibitor. It is mainly used for various organ transplants and some autoimmune diseases, blood system diseases, etc. However, due to the large individual differences in the process of CsA in the body and the narrow therapeutic window, its high blood concentration will cause toxic and side effects, especially the toxicity to the liver and kidney; if the concentration is too low, the therapeutic effect will be low or ineffective, and even cause organ transplant rejection. occur. Therefore, it is very necessary to monitor the plasma concentration of CsA in whole blood and ad...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/02C07K1/14G01N33/68G01N33/543G01N33/58G01N21/76
CPCC07K7/64G01N33/68G01N33/54326G01N33/581G01N21/76
Inventor 杨书彬朱宇皇马建军渠海
Owner AUTOBIO DIAGNOSTICS CO LTD
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