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Adefovir thio L-amino acid ester and mono bile acid ester derivatives and preparation method thereof

A technology of propyl monocholate and amino acids, which can be used in drug combinations, steroids, and the digestive system, and can solve the problems of high toxicity and side effects and low oral bioavailability

Inactive Publication Date: 2016-11-16
GUIZHOU MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In view of this, the technical problem to be solved in this application is that the adefovir drugs in the prior art have relatively large toxic and side effects and low oral bioavailability

Method used

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  • Adefovir thio L-amino acid ester and mono bile acid ester derivatives and preparation method thereof
  • Adefovir thio L-amino acid ester and mono bile acid ester derivatives and preparation method thereof
  • Adefovir thio L-amino acid ester and mono bile acid ester derivatives and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Preparation of 9-[2-(phosphonomethoxy)ethyl]adenine monothio-L-alanine propyl ester and monoursodeoxycholic acid propyl ester (compound 1)

[0067] (1) Preparation of N-tert-butoxycarbonylthio L-alanine-3-bromo-1-propyl ester

[0068] Dissolve N-tert-butoxycarbonyl-L-alanine (5 g, 0.031 mol) in 40 mL of dry tetrahydrofuran, cool to -20°C in an ice-salt bath, add N-methylmorpholine (22 g, 0.15 mol) And isobutyl chloroformate (3.1 g, 0.025 mol), the system was kept warm and stirred for 30 minutes. Keep the internal temperature of the reaction system below -15°C, feed self-made hydrogen sulfide gas for 1.5-2 hours, until the hydrogen sulfide gas in the system is absorbed to saturation, then keep the temperature for another 2 hours to complete the reaction. Add 40 mL of anhydrous ether, adjust the pH of the system to 3 with 0.1 mol / L hydrochloric acid, separate the organic layer, wash with 2×20 mL of water, 2×20 mL of saturated brine, dry over anhydrous sodium sulfate, fil...

Embodiment 2

[0080] Preparation of 9-[2-(phosphonomethoxy)ethyl]adenine monothiol-valine propyl ester and monoursodeoxy propyl ester (compound 2)

[0081] Using adefovir, N-tert-butoxycarbonylthio L-valine-3-bromo-1-propyl ester and ursodeoxycholic acid-3-bromo-1-propyl ester as reaction substrates, Prepared according to a method similar to Example 1, the target compound 9-[2-(phosphonomethoxy)ethyl]adenine monothio L-valine propyl ester, monoursodeoxycholic acid propyl Esters, yield 19.5%.

[0082] 1 H-NMR (400MH, CDCl 3 ): δ8.31(s,1H,2-H),7.99(s,1H,8-H),6.60(brs,2H,NH 2 ), 4.43(t, J=4.4Hz, 2H, NCH 2 ),4.20-4.08(m,6H,CH 2 OCO,2×P(O)OCH 2 ),4.04-4.00(m,1H,CHNH 2 ),3.95-3.92(m,2H,NCH 2 CH 2 ), 3.82 (d, J=8.0Hz, 2H, OCH 2 P),3.66-3.59(m,2H,2×CHOH),2.87-2.85(m,2H,CH 2SCO),2.36-2.32(m,1H),2.28-2.24(m,1H),2.01-1.93(m,4H,OCH 2 CH 2 ,SCH 2 CH 2 ),1.85-1.04(m,28H),1.03-0.96(m,9H,3×CH 3 ),0.92-0.89(m,6H,2×CH 3 ); 13 C NMR (100MHz, CDCl 3 ):δ175.29,174.25,155.64,152.84,149.59,141....

Embodiment 3

[0084] Preparation of 9-[2-(phosphonomethoxy)ethyl]adenine monothiol-isoleucine propyl ester, monoursodeoxy propyl ester (compound 3)

[0085] Using adefovir, N-tert-butoxycarbonylthio L-isoleucine-3-bromo-1-propyl ester and ursodeoxycholic acid-3-bromo-1-propyl ester as reaction substrates , prepared according to a method similar to Example 1, to obtain the target compound 9-[2-(phosphonomethoxy)ethyl]adenine monothio L-isoleucine propyl ester, monoursodeoxycholic acid Propyl ester, yield 14.7%.

[0086] 1 H-NMR (400MH, CD 3 OD): δ8.29(s,1H,2-H),7.92(s,1H,8-H),6.08(brs,2H,NH 2 ), 4.40(t, J=5.6Hz, 2H, NCH 2 ),4.18-4.05(m,7H,2×P(O)OCH 2 ,CH 2 OCO,CHNH 2 ), 3.91(t, J=4.0Hz, 2H, NCH 2 CH 2 ), 3.78 (d, J=8.0Hz, 2H, OCH 2 P),3.55-3.45(m,2H,2×CHOH),2.87-2.84(m,2H,CH 2 SCO),2.39-2.30(m,1H),2.23-2.16(m,1H),2.07-1.97(m,4H,OCH 2 CH 2 ,SCH 2 CH 2 ),1.97-0.96(m,32H),0.93-0.86(m,12H,4×CH 3 ); 13 C NMR (100MHz, CD 3 OD):δ175.01,174.16,155.47,152.92,149.76,141.34,119.12,71....

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Abstract

The invention discloses a compound with a chemical structure as described in the specification, and pharmaceutically acceptable salts, salt crystalline hydrates and salt crystalline solvents thereof. In the chemical structure, R1 is H or OH; R2 is H or OH; and R3 is an alkyl group with 1 to 4 carbon atoms. Antiviral activity and primary hepatocyte uptaking experiment results show that the compound has better antiviral activity and liver cell transfer specificity than adefovir dipivoxil, and can be used for preparation of drugs treating hepatitis B virus infection.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to an adefovir monothio L-amino acid ester monocholate derivative and a preparation method thereof. Background technique [0002] Hepatitis B virus (HBV) belongs to the Hepadnaviridae family and is one of the viruses most likely to infect humans. WHO reports that there are about 350-400 million HBV-infected people in the world, and nearly 30% of them may develop liver cirrhosis and primary liver cancer. These two lesions cause about 500,000-1,000,000 chronic hepatitis B patients to die each year (Dienstag J.L. et al. N. Engl. J. Med. 2008, 359, 1486-1500). [0003] Adefovir dipivoxil (Adefovir dipivoxil) is the first acyclic nucleoside phosphonate anti-HBV drug developed by Gilead Science Company approved by FDA in 2002. Clinical studies have shown that the advantages of adefovir dipivoxil are: significantly improving the liver histological properties of patients wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61P1/16A61P31/20
CPCC07J9/005
Inventor 傅晓钟王永林苏航兰燕宇李勇军王爱民黄勇陈雅罗敏张文政
Owner GUIZHOU MEDICAL UNIV
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