Hydroxylated indinavir, preparation method of hydroxylated indinavir, and application of hydroxylated indinavir in preparation of antimalarials

A hydroxyl and preparation process technology, applied to hydroxylated indinavir and its preparation and application in the preparation of antimalarial drugs, can solve problems such as death and malaria incidence, and achieve broad application prospects and good malaria parasite inhibition activity. Effect

Active Publication Date: 2009-09-30
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, malaria parasites have developed resistance to most traditional antimalarial drugs, and the cross-resistance of similar drugs has made this problem more serious, and has become the main cause of morbidity and death after malaria infection

Method used

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  • Hydroxylated indinavir, preparation method of hydroxylated indinavir, and application of hydroxylated indinavir in preparation of antimalarials
  • Hydroxylated indinavir, preparation method of hydroxylated indinavir, and application of hydroxylated indinavir in preparation of antimalarials
  • Hydroxylated indinavir, preparation method of hydroxylated indinavir, and application of hydroxylated indinavir in preparation of antimalarials

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Synthesis of compound 2

[0037] Add 150mL water and 150mL tert-butanol to a 500mL round bottom flask, 0.03gK 2 OSo 2 (OH) 4 , 0.33g (DHQD) 2 -PHAL, 42.47g K 3 Fe(CN) 6 and 17.82g K 2 CO 3 , the mixed system was fully stirred at room temperature, and then 4.09 g of methanesulfonamide was added, and the reaction system was stirred at 0° C., and salt precipitated out in the system. During stirring, 5.0 g of indene was slowly added dropwise, and the reaction system was stirred at 0°C for 12 hours. TLC (petroleum ether:ethyl acetate=10:4, v / v) showed that the raw material (indene) disappeared. Add 6g Na to the system 2 SO 3 and stirred at room temperature for 30 minutes, added 150 mL of ethyl acetate, separated the organic phase, extracted three times with ethyl acetate for the aqueous phase, washed the combined organic phase with 50 mL of 2.0N KOH solution, dried over anhydrous magnesium sulfate, and evaporated solvent to obtain 25.73 g of a white powdery solid w...

Embodiment 2

[0047] Synthesis of Compound 8

[0048] In a 250mL round bottom flask, add 4.5g indinavir, 120mL methanol, place the flask in an ice bath and stir, slowly add a preconfigured NaOH aqueous solution (6.6g NaOH is dissolved in 40mL water) dropwise through a constant pressure dropping funnel, During the dropwise addition, the solution gradually became white and turbid. After the dropwise addition, the ice bath was removed, heated to 40°C in a water bath and stirred for 24 hours. TLC (dichloromethane:methanol=10:1, v / v) showed that the raw materials disappeared. Under ice bath and vigorous stirring, slowly add 10% methanolic HCl solution dropwise until the pH of the system is 8, rotary evaporate and add anhydrous methanol several times to take out the moisture in the mixture, and dissolve the obtained solid with 80 mL of ethyl acetate and filter, The filter cake was washed three times with ethyl acetate, and the combined solution was dried over anhydrous sodium sulfate and rotary e...

Embodiment 3

[0057] Example 3 Evaluation of the antimalarial effect of hydroxylated indinavir in vitro

[0058] Taking the two stereoisomers of hydroxylated indinavir (hydroxylated indinavir A and hydroxylated indinavir B) as an example, hydroxylated indinavir is effective against human Plasmodium falciparum (P.falciparum) Both the sensitive strain 3D7 and the multidrug-resistant strain Dd2 had strong inhibitory effects.

[0059]

[0060] Hydroxylated Indinavir A Hydroxylated Indinavir B

[0061] The human P. falciparum (P. falciparum) sensitive strain 3D7 and the multi-drug resistant strain Dd2 were cultured in vitro with RMPI1640 medium + 10% human serum, and the hematocrit was about 5%. Synchronize Plasmodium parasites with 5% D-sorbitol, plate at their ring body stage, with an initial infection rate of 1% and a hematocrit of 5%. The drug is dissolved in DMSO to prepare a mother solution, and then diluted with a culture medium. When the activity is detected, the concentration gradi...

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Abstract

The present invention provides hydroxylated indinavir represented by general formula (12). The present invention further provides a preparation method of hydroxylated indinavir, which employs cheap and widely available indene as the raw material, and comprises the following steps: dihydroxylate and protect the indene, oxidize the benzyl to introduce carbonyl, and then transform the carbonyl into amido, to obtain the required reaction intermediate; prepare the other molecular block from indinavir, carry out hydrolytic reaction, and protect the hydroxyl; then, carry out acidamide condensation with the reaction intermediate, remove the protection, to obtain the target product. The present invention further provides an application of hydroxylated indinavir in preparation of antimalarials, especially combination with chloroquini phosphas to treat malaria. The hydroxylated indinavir provided in the present invention has favorable in-vivo and in-vitro activity in inhibition of malarial parasite; when used in combination with chloroquini phosphas, it can works with chloroquini phosphas to inhibit malarial parasite that is resistant or sensitive to chloroquini phosphas in vitro and in vivo. The hydroxylated indinavir can be used to develop antimalarials and compound antimalarials, sets a basis for reapplying the economical and practical chloroquini phosphas in treatment of malaria, andhas excellent application prospects.

Description

technical field [0001] The present invention relates to the fields of chemical synthesis and medicine, in particular to a class of novel medicine for treating malaria and its pharmaceutical composition, more specifically to hydroxylated indinavir, its stereoisomers and pharmaceutically acceptable salts, and Their preparation method, the present invention also relates to their application in the preparation of medicaments for treating malaria and their pharmaceutical composition plus chloroquine or another antimalarial drug with similar properties as compound application in malaria treatment. Background technique [0002] Malaria is widely distributed in the world, and it is the most serious insect-borne infectious disease that endangers human beings. It is one of the three major infectious diseases in the world. At present, there are still about 2.4 billion people living in malaria-endemic areas in the world, and 300-500 million people get sick every year, of which 1.5-2.7 m...

Claims

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Application Information

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IPC IPC(8): C07D401/06A61K31/496A61P33/06
CPCY02A50/30
Inventor 陈小平张健存邱发洋何正祥陈迁邓刚游剑岚梁文昌刘薇刘培均秦莉刘劲松陈凌
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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