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Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

a technology of hepatitis b virus and pyrimidine, which is applied in the field of organic compounds, can solve the problems of poor long-term response, debilitating side effects, and viral genotypes that do not show good responses to interferon therapy, and achieve the effects of improving the survival rate of hbv, improving the survival rate, and improving the survival ra

Inactive Publication Date: 2013-10-10
GUO LEI +8
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is related to new compounds (Formula I) and their manufacture, as well as the use of these compounds for the treatment or prevention of HBV infection. The technical effects of this patent include the discovery of novel compounds that can be used to develop new treatment options for HBV infection.

Problems solved by technology

HBV is a serious public health problem worldwide, with more than 400 million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus.
Interferon alpha is the other major therapy available for hepatitis B, but it is limited by a poor long-term response and debilitating side effects.
Some viral genotypes do not show good responses to interferon therapy.
The majority (around or more than 90%) of treated patients fail to achieve this goal.
This drawback is mainly due to the presence of a stable pool of viral cccDNA in nucleus that doesn't replicate itself, therefore, shows no accessibility to nucleoside (tide) analogs.

Method used

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  • Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
  • Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection
  • Novel 4-methyl-dihydropyrimidines for the treatment and prophylaxis of hepatitis b virus infection

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-(4-Fluoro-phenyl)-6-(1-methoxycarbonyl-1-methyl-ethoxymethyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

[0373]The title compound was prepared according to the general synthesis methods shown in Scheme 1 and Scheme 4. A detailed synthesis route is provided as shown in Scheme 5.

[0374]To a stirred suspension of NH4Cl in toluene (400 mL) was added Al(CH3)3 solution (1.0 M, 56 mL) at 0° C. over 30 minutes. After the mixture solution was stirred at rt for 30 minutes, the solution of thiazole-2-carbonitrile (5.24 g, 47.6 mmol) in toluene (10 mL) was added into the flask. The reaction mixture was stirred at 80° C. for 16 hours before cooling to rt and then the mixture was poured into a slurry of silica gel in DCM. After stirring for 20 minutes, the slurry was filtered and washed with MeOH three times and concentrated in vacuo to afford crude product of thiazole-2-carboxamidine XIX that was used in next step reaction without further purification. MS: calc...

example 2

6-(1-Carboxy-2,2,2-trifluoro-ethoxymethyl)-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

[0381]The title compound was prepared in analogy to Example 1 in Scheme 5 by using 3,3,3-trifluoro-2-hydroxy-propionic acid methyl ester instead of 2-hydroxy-2-methyl-propionic acid methyl ester, the so-obtained methyl ester was hydrolyzed by LiOH as indicated in Scheme 3. MS: calc'd 488 (MH+), exp 488 (MH+). 1H NMR (MeOD-d4, 400 MHz), 7.94 (d, 1H, J=2.8 Hz), 7.93 (d, 1H, J=2.8 Hz), 7.53-7.49 (m, 2H), 7.07-7.03 (m, 2H), 4.85-4.78 (m, 2H), 4.40-4.37 (m, 1H), 3.44 (s, 3H), 1.94 (s, 3H).

example 3

6-{[(1-Carboxy-cyclopropyl)-methyl-amino]-methyl}-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester

[0382]The title compound was prepared according to the synthesis method shown in Scheme 1 and Scheme 3. A detailed synthesis route is provided as shown in Scheme 6.

[0383]To a solution of 6-bromomethyl-4-(4-fluoro-phenyl)-4-methyl-2-thiazol-2-yl-4H-pyrimidine-1,5-dicarboxylic acid 1-tert-butyl ester 5-methyl ester XXIII (1.00 g, 1.90 mmol) and potassium carbonate in DMF was added 1-methylamino-cyclopropanecarboxylic acid methyl ester (258 mg, 2.00 mmol), the mixture was stirred at 40° C. for 3 hours and LC-MS indicated that the reaction was finished. The mixture was partitioned between water and ethyl acetate. The organic phase was dried and concentrated to afford the crude product used in the next step without further purification.

[0384]The crude product XXV from above step was dissolved in DCM and then TFA was added. The mixture was stir...

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Abstract

The invention provides novel compounds having the general formula:wherein R1, R2, R3, R4, R5, M and X are as described herein, compositions including the compounds and methods of using the compounds.

Description

CROSS-REFERENCE TO PRIOR APPLICATIONS[0001]This application claims the benefit of priority under 35 U.S.C. §119(a) to PCT / CN2012 / 073388 filed Mar. 31, 2012 the contents of which is herein incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to organic compounds useful for therapy and / or prophylaxis in a human, and in particular to Hepatitis B virus (HBV) inhibitors by targeting on HBV capsid useful for treating HBV infection.[0003]HBV is a species of the hepadnaviridae family of viruses. HBV is a serious public health problem worldwide, with more than 400 million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus. Although most individuals seem to resolve the infection following acute symptoms, 15-40% of HBV patients will finally develop clinical diseases during their lifespan, most notably, hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year 500,000 to 1 million people die ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D417/14C07D417/04
CPCC07D417/14C07D405/14C07D401/14C07D417/04C07D413/14
Inventor GUO, LEILIN, XIANFENGLIU, HAIXIAQIU, ZONGXINGSHENG, HONGTANG, GUOZHIWU, GUOLONGZHANG, WEIXINGZHU, WEI
Owner GUO LEI
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