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Nucleoside phosphoramidate derivatives and their applications
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A technology of alkyl and phenyl, applied in the field of medicinal chemistry, can solve the problem of high bioavailability
Active Publication Date: 2019-01-15
NANJING MAJOR BIOLOGICAL TECH
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Problems solved by technology
Despite these existing technologies, there is still an urgent clinical need for drugs with high bioavailability, good liver selectivity, and high efficacy for the treatment of HCV infection
Method used
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Embodiment 1
[0058] The synthesis of embodiment 1 MJ10803
[0059] (1) Synthesis of intermediate M811
[0060]
[0061] Dissolve the starting material 4-nitrophenyl dichlorophosphoric acid (S1, 25.6g, 0.1mol) in 150ml of anhydrous dichloromethane, cool down to -60°C, and slowly add deuterated phenol-d5 (9.9 g, 0.1mol) and triethylamine (15ml, 0.11mol) in 45ml of anhydrous dichloromethane solution, after the dropwise addition, the temperature was naturally raised to -5°C and reacted for 3h. Add isopropyl alanine hydrochloride (16.8g, 0.11mol) to the reaction solution, stir at 0°C for 30min, add triethylamine (28.6ml, 0.21mol) dropwise, react at 5°C for 3h, filter insoluble The reaction solution was concentrated to obtain an oily substance, and 13.7 g of a mixture of white solid M811 and M811D was obtained by silica gel column chromatography, and the yield of the mixture was 33.6%.
[0062] The mixture was dissolved in 50ml of diisopropyl ether, stirred and cooled to 5°C, stirred and ke...
Embodiment 2
[0073] Synthesis of Example 2 MJ10823
[0074] (1) Synthesis of intermediate M821
[0075]
[0076] Alanine deuterated isopropyl ester hydrochloride-d6 is prepared by acid-catalyzed reaction of alanine in deuterated isopropanol-d6.
[0077] Dissolve the starting material 4-nitrophenyl dichlorophosphoric acid (S1, 25.6g, 0.1mol) in 150ml of anhydrous dichloromethane, cool down to -60°C, and slowly add deuterated phenol-d5 (9.9 g, 0.1mol) and triethylamine (15ml, 0.11mol) in 45ml of anhydrous dichloromethane solution, after the dropwise addition, the temperature was naturally raised to -5°C and reacted for 3h. Alanine deuterated isopropyl ester hydrochloride-d6 (17.4g, 0.11mol) was added to the reaction solution, stirred at 0°C for 30min, triethylamine (28.6ml, 0.21mol) was added dropwise, and reacted at 5°C After 3 hours, the insoluble matter was filtered, and the reaction solution was concentrated to obtain an oily substance. Silica gel column chromatography gave 12.9 g o...
Embodiment 3
[0089] Synthesis of Example 3 MJ10863
[0090] Using alanine deuterated isopropyl ester hydrochloride-d7 as raw material, the target compound was obtained by the same method as in Example 2. MS(m / z): 641.3[M+1] + .
[0091]
[0092] Alanine deuterated isopropyl ester hydrochloride-d7 is prepared by acid-catalyzed reaction of alanine in deuterated isopropanol-d8.
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Abstract
Novel nucleoside phosphoramidate derivatives and applications thereof are disclosed. The derivatives are compounds as represented by formula (I) or pharmaceutically acceptable acidic salts, solvates or hydrates thereof, wherein R1 is C1-4 alkyl or deuterated C1-4 alkyl; R2 is optionally substituted phenyl or naphthyl, wherein the substituent is selected from deuterium, C1-4 alkyl, C1-4 alkoxy; R1 and R2 at least contain one deuterium substituent; and R3 is amino acid acyl or polypeptide acyl. The compounds of the present invention can be used for treating viral infection in mammals, especially for treating hepatitis C viral infection.
Description
technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a novel nucleoside phosphoramidate derivative, a pharmaceutically acceptable acid salt, a solvate or a hydrate, their preparation method, a pharmaceutical composition and their preparation for use in Use in mammalian infectious diseases, medicines for preventing or treating hepatitis C, liver cirrhosis, and liver cancer. Background technique [0002] Hepatitis C virus (HCV) infection is a worldwide health problem with various clinical manifestations ranging from inflammation to cirrhosis and liver cancer. There are more than 200 million infected individuals worldwide, and at least 3 to 4 million people are infected each year. Once infected, about 20% of people clear the virus, but the remainder may carry HCV for the rest of their lives. Ten to 20 percent of chronically infected individuals eventually develop destructive cirrhosis or cancer of the liver. ...
Claims
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