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Entecavir fatty acid derivatives and pharmaceutical composition thereof

A fatty acid derivative, entecavir technology, applied in the field of medicine, can solve the problems of high solubility adverse reactions, hindering transmembrane transport, and low bioavailability

Active Publication Date: 2016-05-18
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Entecavir belongs to Class III drugs in the Biopharmaceutical Classification System (BCS), that is, high solubility and low permeability drugs. The low permeability of Entecavir hinders its transmembrane transport in the human gastrointestinal tract, resulting in low bioavailability; Entecavir The high solubility leads to its adverse reactions, mainly including: headache, upper respiratory tract infection, nasopharyngitis, epigastric pain, fatigue, fever, nausea, etc. The adverse reactions involve multiple organs and tissues throughout the body

Method used

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  • Entecavir fatty acid derivatives and pharmaceutical composition thereof
  • Entecavir fatty acid derivatives and pharmaceutical composition thereof
  • Entecavir fatty acid derivatives and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: N-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-6H-purine-6- The preparation of keto-2-octanoamide (formula I-1, entecavir-2-octanoamide)

[0034]

[0035] 1.0 g of entecavir was dissolved in 20 mL of dichloromethane, and 587 mg of caprylic acid chloride was added in an equimolar amount. After mixing, 0.5 mL of pyridine was added, and the reaction was carried out at 30° C. for 8 hours. After the reaction, dichloromethane was distilled off, 10mL of water was added to the obtained crude product, and reacted at 30°C for 0.5 hours to eliminate unreacted caprylic acid chloride, then 100mL of water was added, after mixing, extracted with dichloromethane, and the organic phase was washed with anhydrous Sodium sulfate to remove residual moisture, filter, and distill methylene chloride under reduced pressure to obtain N-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxyl-3-hydroxymethyl-2- Methylenepentyl]-6H-purin-6-one-2-octanamide (1.17 g, 74%). ...

Embodiment 2

[0037] Example 2: N-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-6H-purine-6- The preparation of ketone-2-lauroylamide (formula I-2, entecavir-2-lauroylamide)

[0038]

[0039] 1.0 g of entecavir was dissolved in 20 mL of dichloromethane, and 790 mg of lauric acid chloride was added in an equimolar amount. After mixing, 0.5 mL of pyridine was added and reacted at 50°C for 8 hours. After the reaction, dichloromethane was distilled off, 10mL of water was added to the resultant, and reacted at 30°C for 0.5 hours to eliminate unreacted lauric acid chloride, then 100mL of water was added, after mixing, extracted with dichloromethane, and the organic phase was Use anhydrous sodium sulfate to remove residual moisture, filter, and distill off dichloromethane under reduced pressure to obtain N-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl -2-Methylenepentyl]-6H-purin-6-one-2-lauramide (1.22 g, 68%).

[0040] MS(ES):460.34(M+H + )

Embodiment 3

[0041] Embodiment 3: the preparation of entecavir-2-octanoamide tablet (1000)

[0042]

[0043] The above materials were crushed separately, sieved with 8 meshes, after entecavir-2-octylamide, microcrystalline cellulose and starch were fully mixed, an appropriate amount of starch slurry was added to make a soft material, sieved with 12 meshes, dried at 50°C for 2 hours, and added Sodium carboxymethyl starch and magnesium stearate are mixed evenly, and pressed into tablets to obtain the product.

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Abstract

The invention provides entecavir fatty acid derivatives and pharmaceutical composition thereof and further relates to preparation methods of the entecavir fatty acid derivatives. The entecavir fatty acid derivatives had higher bioavailability and smaller toxic and side effects, and the pharmaceutical composition of the entecavir fatty acid derivatives is safer and more efficient when used for treating hepatitis B virus infection.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to an entecavir fatty acid derivative and a pharmaceutical composition thereof. Background technique [0002] Entecavir is a cyclopentanoylguanosine analogue, mainly used for oral treatment of chronic hepatitis B in adults with active viral replication, persistently elevated serum transaminases, or active liver lesions. It was first listed in the United States by Bristol-Myers Squibb in 2005. [0003] The chemical name of Entecavir is: 2-amino-1,9-dihydro-9-[(1S,3R,4S)-4-hydroxy-3-hydroxymethyl-2-methylenecyclopentyl]-6H- Purin-6-one, the structural formula is: [0004] [0005] Entecavir belongs to Class III drugs in the Biopharmaceutical Classification System (BCS), that is, drugs with high solubility and low permeability. The low permeability of Entecavir hinders its transmembrane transport in the human gastrointestinal tract, resulting in low bioavailability; Entecavir Th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D473/18A61K31/522A61P31/20
CPCC07D473/18
Inventor 王善春张喜全顾红梅郭利刚王祥建张来芳耿文军
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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