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Preparation and application of beta-D-(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine derivatives

A R2-C, R3-C technology, applied in the field of hepatitis C virus infection, can solve complex multidisciplinary tasks, a large number of experiments and other problems

Inactive Publication Date: 2012-11-14
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While envisioning prodrug candidates is deceptively simple, identifying compounds with appropriate physicochemical and pharmacokinetic properties, in vivo transformation, and safety profiles is a complex multidisciplinary task that requires extensive experimentation

Method used

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  • Preparation and application of beta-D-(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine derivatives
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  • Preparation and application of beta-D-(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0107] The following specific examples are preferred embodiments of the present invention, which should not be construed as constituting any limitation to the present invention.

[0108] The melting point of the compound was determined by RY-1 melting point apparatus, and the thermometer was not corrected. Mass spectra were determined by a Micromass ZabSpec high-resolution mass spectrometer (resolution 1000). 1 H-NMR is measured by JNM-ECA-400 superconducting NMR instrument, working frequency 1 H-NMR 400MHz.

[0109] Abbreviations or symbols used in this application have the following meanings:

[0110] DAST: Diethylaminosulfur trifluoride

[0111] TIPDSCl 2 : 1,3-dichloro-1,1,3,3-tetraisopropyl disiloxane

[0112] TBAF: Tetrabutylammonium fluoride

[0113] HOBt: 1-Hydroxybenzotriazole

[0114] DCC: Dicyclohexylcarbodiimide

[0115]DMAP: 4-Dimethylaminopyridine

[0116] TFAA: Trifluoroacetic anhydride

[0117] Bz: benzoyl

preparation example

[0119] Preparation of compound 9

[0120] Preparation of β-D-4-N-benzoylcytidine (2)

[0121] Dissolve 2.5g of cytidine (1) (10mmol), 2.5g of benzoic anhydride (11mmol) in 50ml of anhydrous pyridine to form a suspension, and stir at room temperature for 48h. The solvent was distilled off under reduced pressure. A small amount of ether was added to the residue and filtered. The filter cake was washed with ethyl acetate, water and acetone. The obtained white solid was recrystallized from ethanol-water (3:1) to obtain 2.7 g of a white solid. Yield 77%. mp: 232-233°C. 1 H-NMR (400MHz, DMSO) δ (ppm): 3.69 (2H, m, 5'-CH2), 3.90 (3H, m, 2', 3', 4'-CH), 5.07 (1H, d, J =5.6Hz, OH), 5.20 (1H, t, J=4.8, 5′-OH), 5.53 (1H, d, J=4.4Hz, OH), 5.81 (1H, d, J=2.8, 1′- CH), 7.35(1H, d, J=7.2Hz), 7.52(2H, t, J=7.6Hz), 7.63(1H, t, J=7.2Hz), 8.01(2H, d, J=7.2Hz) , 8.51 (1H, d, J=7.6Hz), 11.26 (1H, s, NH).

[0122] Preparation of β-D-4-N-benzoyl-3',5'-O-(tetraisopropyldisiloxane-1,3-diether...

Embodiment 14

[0138] Example 14-N-valyl-2'-methyl-2'-fluorocytidine hydrochloride (compound 12)

[0139]

[0140] Under nitrogen protection, 380mg (1.75mmol) N-tert-butoxycarbonyl valine, 473mg (3.5mmol) 1-hydroxybenzotriazole (HOBt) and 90mg (0.35mmol) 2′-methanol were added to a 10mL three-necked flask. base-2'-flucytidine. Add 5 mL of a mixed solution of anhydrous tetrahydrofuran and anhydrous N,N-dimethylformamide. At an internal temperature of 0° C., 360 mg (1.75 mmol) of dicyclohexylcarbodiimide (DCC) was added dropwise, and reacted for 1 hour, then reacted overnight at room temperature. The solvent was distilled off under reduced pressure, and 100 mL of ethyl acetate was added for dissolution, followed by washing with 50 mL of water. The organic layer was washed with 50 mL each of saturated sodium bicarbonate and saturated sodium chloride solutions. The organic layer was dried over anhydrous sodium sulfate overnight. Filtration, the mother liquor was evaporated to remove the s...

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Abstract

The invention relates to compounds as represented by the general formula (A) or their hydrates, solvates or medicinal salts formed with acids, a preparation method thereof, compositions containing the same and application of the same in treating flavivirus infections (such as hepatitis c, West Nile disease and Dengue fever), especially in treating hepatitis c virus (HCV) infected disease. X, Y and Z in the general formula (A) are defined by the specification.

Description

field of invention [0001] The present invention relates to β-D-(2'R)-2'-deoxy-2'-fluoro-2'-C-methylcytidine derivatives, processes for preparing these derivatives and these derivatives and / or their derivatives The medicinal composition is used for treating infectious diseases of Flaviviridae (such as hepatitis C, West Nile disease and dengue fever), especially hepatitis C virus (HCV) infectious diseases. Background technique [0002] Hepatitis C virus belongs to the flaviviridae family, and infection with this virus is one of the main causes of chronic liver diseases, such as cirrhosis and hepatocellular carcinoma. Hepatitis C is a global infectious disease with an incidence ranging from 1% to 10%, with an average of about 3%. According to the World Health Organization, there are more than 200 million infected people in the world, and at least 3-4 million people are infected every year. The infection rate of hepatitis C in China is more than 3%, and there are about 38 mill...

Claims

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Application Information

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IPC IPC(8): C07H19/09C07H1/00A61K31/7068A61P31/14
CPCY02A50/30
Inventor 聂爱华张明顾为张振清张天宏
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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