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Apocynin water-soluble prodrug, preparation method and pharmaceutical composition thereof, and application of apocynin water-soluble prodrug and pharmaceutical composition thereof

A compound and halogen technology, applied in the design and preparation of prodrugs, can solve the problems of limiting the development and utilization of oral drugs, unsatisfactory bioavailability, and poor water solubility

Inactive Publication Date: 2017-11-21
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although apocynin has good physiological activity, its poor water solubility leads to unsatisfactory bioavailability in animals, which greatly limits its development and utilization as an oral drug

Method used

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  • Apocynin water-soluble prodrug, preparation method and pharmaceutical composition thereof, and application of apocynin water-soluble prodrug and pharmaceutical composition thereof
  • Apocynin water-soluble prodrug, preparation method and pharmaceutical composition thereof, and application of apocynin water-soluble prodrug and pharmaceutical composition thereof
  • Apocynin water-soluble prodrug, preparation method and pharmaceutical composition thereof, and application of apocynin water-soluble prodrug and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Embodiment 1: Preparation of N-tert-butoxycarbonyl-L-methionine ester:

[0090]

[0091] Specific steps:

[0092] Weigh apocynin (1.2mmol, 200mg) and dissolve it in dichloromethane (15ml), add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.6mmol, 300mg), 1-hydroxybenzotriazole (HOBT) (1.6mmol, 216mg) and N-Boc-L-methionine (1.5mmol, 375mg), stirred at room temperature overnight. After the reaction was complete, add water to quench, extract 3 times with ethyl acetate, combine the organic phases, wash with water and saturated brine successively, anhydrous Na 2 SO 4 After drying, the solvent was evaporated under reduced pressure, separated and purified on a silica gel column (solvent ratio PE / EA=1:3) to obtain the white solid product 2aa (465 mg), and the yield was 97%.

[0093] The specific characterization data of this product 2aa are:

[0094] 1 H NMR (400MHz, Chloroform-d) δ7.59(s,1H),7.56(d,J=8.1Hz,1H),7.16(d,J=8.0Hz,1H),5.29(d,J=9.5Hz ...

Embodiment 2

[0095] The preparation of embodiment 2.N-BOC-O-benzyl-L-serine ester:

[0096]

[0097] N-Boc-O-benzyl-L-serine (1.5mmol, 443mg) was used as starting material, and the white solid product 2ab (507mg) was prepared by the same method as compound 2aa, with a yield of 95%.

[0098] The specific characterization data of product 2ab are:

[0099] 1 H NMR (400MHz, Chloroform-d) δ7.60(s, 1H), 7.55(dd, J=1.6, 8.2Hz, 1H), 7.39–7.25(m, 5H), 7.13(d, J=8.2Hz, 1H), 5.55(d, J=8.8Hz, 1H), 4.78(d, J=8.9Hz, 1H), 4.64(s, 2H), 4.11(dd, J=9.3, 3.2Hz, 1H), 3.87( dd,J=9.5,3.1Hz,1H),3.82(s,3H),2.61(s,3H),1.48(s,9H); LRMS(ESI)m / z:C 24 h 29 NO 7 ,found 466.1[M+Na] + .

Embodiment 3

[0100] Example 3. Preparation of (S)-2,6-di-tert-butoxycarbonylaminocaproate:

[0101]

[0102] (S)-2,6-Di-tert-butoxycarbonylaminocaproic acid (1.5mmol, 521mg) was used as starting material, and the white solid product 2ac (565mg) was prepared by the same method as compound 2aa, with a yield of 95%.

[0103] The specific characterization data of product 2ac are:

[0104] 1 H NMR (400MHz, Chloroform-d) δ7.60(s, 1H), 7.56(d, J=8.3Hz, 1H), 7.15(d, J=8.1Hz, 1H), 5.23(d, J=7.7Hz ,1H),4.62(dd,J=6.8,41.0Hz,2H),3.87(s,3H),3.17(d,J=5.7Hz,2H),2.61(d,J=4.9Hz,3H),2.12 –1.76(m,3H),1.66–1.50(m,3H),1.47(s,9H),1.44(s,9H); LRMS(ESI)m / z:C 25 h 38 N 2 o 8 ,found 517.1[M+Na] + .

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Abstract

The invention discloses an apocynin water-soluble prodrug having a structure in a general formula I as shown below in the specification, a preparation method and application thereof in preparation of drugs for preventing and / or treating retinal degenerative diseases. The apocynin prodrug disclosed by the invention has favorable water solubility, higher oral bioavailability and remarkable activity of in vivo preventing light injury to retinal photoreceptor cells. The general formula I is shown in the specification.

Description

technical field [0001] The present invention relates to the field of prodrug preparation and drug therapeutics of active natural products, in particular to the design, preparation method, pharmaceutical composition and application of the prodrug of natural product apocynin. The compounds can be used to prepare medicines for preventing and / or treating retinal degeneration. Background technique [0002] Apocynin, also known as Apocynin, vanilla ethyl ketone, is a natural phenolic compound extracted and isolated from plants such as Scrophulariaceae plant Huhuanglian root, Apocynaceae plant Canadian hemp root, etc. The specific structure of the product is the following formula V. [0003] [0004] Studies have found that apocynin has a good protective effect on retinal photoreceptor cells from light damage, and also has a significant cardiovascular protective effect. Apocynin can be a selective inhibitor of phagocytic NADPH oxidase NOX2, acting on the respiratory, nervous, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/59C07C271/22C07D209/20C07D233/64C07D207/16C07C323/58C07C229/22C07C237/06C07C229/08C07C229/24C07C229/26C07D295/205C07D211/60C07D205/04C07D333/20C07C271/48C07C271/52C07C271/54C07C69/96C07C307/02C07D487/04C07D413/04C07D309/10C07F9/09C07F9/12A61K31/27A61K31/405A61K31/4172A61K31/401A61K31/223A61K31/225A61K31/495A61K31/445A61K31/397A61K31/381A61K31/4985A61K31/454A61K31/265A61K31/351A61K31/661A61P27/02
CPCC07C69/96C07C229/08C07C229/22C07C229/24C07C229/26C07C237/06C07C271/22C07C271/48C07C271/52C07C271/54C07C307/02C07C323/58C07C323/59C07D205/04C07D207/16C07D209/20C07D211/60C07D233/64C07D295/205C07D309/10C07D333/20C07D413/04C07D487/04C07F9/091C07F9/12
Inventor 朱维良陈瑜冯佳卞敏娟李波张勇杜宵烨唐晓婷徐志建丁李立强蔡婷婷于心同张腾陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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