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Dihydropyrimidocyclic derivatives as hbv inhibitors

A compound and a selected technology, applied in the field of the compound represented by the formula or a pharmaceutically acceptable salt thereof, can solve the problems of rapid increase in drug resistance, rebound effect, high toxicity and side effects, etc.

Active Publication Date: 2018-10-30
QILU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, interferon has only moderate activity and high toxicity; although lamivudine (lamivudine) has good activity, its drug resistance increases rapidly during treatment and is often Rebound effect appears, IC of lamivudine (3-TC)> 50 Value is 300nM (Science, 299(2003), 893-896)

Method used

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  • Dihydropyrimidocyclic derivatives as hbv inhibitors
  • Dihydropyrimidocyclic derivatives as hbv inhibitors
  • Dihydropyrimidocyclic derivatives as hbv inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1，2

[0162]

[0163]

[0164] The first step (synthesis of compound 1-2)

[0165]Compound 1-1 (12.5g, 100mmol) was dissolved in methanol (30mL), THP (12.6g, 150mmol), p-TsOH (250mg, 1.3mmol) were added at room temperature, and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography with an eluent system (petroleum ether: ethyl acetate = 30:1) to obtain product 1-2 with a yield of 80%.

[0166] 1 H NMR (400MHz, CDCl 3 )δ: 4.68(t, J=3.6Hz, 1H), 4.03(td, J=6.4, 11.2Hz, 1H), 3.90(ddd, J=3.0, 8.4, 11.2Hz, 1H), 3.73-3.82(m ,1H),3.45-3.58(m,3H),1.80-1.91(m,1H),1.70-1.79(m,1H),1.51-1.63(m,4H).

[0167] The second step (synthesis of compound 1-4)

[0168] Sodium hydride (4.0 g, 100 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), 1-3 (9.4 g, 72 mmol) was added at -40°C, and stirred at -20°C for 30 minutes. Keeping the temperature constant, n-butyllithium (40 mL, 2.5N) solut...

Embodiment 3

[0190]

[0191] The first step (synthesis of compound 3-1)

[0192] Compound 2-1 (150 mg, 0.31 mmol) was dissolved in N,N-dimethylformamide (3 mL), sodium cyanide (54 mg, 2.2 mmol) was added, and stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate (10mL x 3), and the organic phases were combined, washed with water (10mL x 2) and saturated sodium chloride solution (10mL x 3) successively, dried over anhydrous sodium sulfate, filtered, and washed with a silica gel column Purification by chromatography with eluent system (petroleum ether: ethyl acetate = 10:1) gave the product 50 mg of compound 3-1, yield: 37%.

[0193] LCMS(ESI)m / z:430.9[M+H + ].

[0194] Second step (synthesis of embodiment 3)

[0195] Dissolve compound 3-1 (50mg, 0.11mmol) in absolute ethanol (0.8mL), add DMSO (0.2mL), sodium hydroxide solution (0.1mL, 5N), hydrogen peroxide (0.1mL), and stir at room temperature 3 hours. The reaction solution was concentrated...

Embodiment 4

[0199]

[0200] Example 4 was prepared as described in Example 1.

[0201] 1 H NMR (400MHz, CDCl 3 )δ: 7.79(d, J=3.2Hz, 1H), 7.35(d, J=3.2Hz, 1H), 7.30(dd, J=2.8, 8.4Hz, 1H), 7.26(d, J=6.4Hz, 1H), 6.95(dt, J=2.8, 8.4Hz, 1H), 6.15(s, 1H), 4.19-4.43(m, 2H), 3.97-4.10(m, 2H), 3.40(ddd, J=3.6, 8.4,18.0Hz,1H),3.06(td,J=9.2,18.0Hz,1H),1.97-2.21(m,2H),1.13(t,J=7.2Hz,3H).

[0202] LCMS(ESI)m / z:449.9[M+H + ].

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Abstract

The invention discloses a dihydropyrimidocyclic derivative taken as an HBV inhibitor, and particularly relates to a compound represented by formula (I) or a pharmaceutically acceptable salt of the compound.

Description

technical field [0001] The present invention relates to dihydropyrimidocyclic derivatives as HBV inhibitors, in particular to compounds represented by formula (I) or pharmaceutically acceptable salts thereof. Background technique [0002] Hepatitis B virus belongs to the Hepaviridae family. It can cause acute and or persistent / progressive chronic disease. Hepatitis B virus also causes many other clinical manifestations in the pathomorphology - especially chronic inflammation of the liver, cirrhosis and canceration of hepatocellular cells. In addition, co-infection with hepatitis D can have detrimental effects during the development of the disease. [0003] Conventional agents licensed for the treatment of chronic hepatitis are interferon and lamivudine. However, interferon has only moderate activity and high toxicity; although lamivudine (lamivudine) has good activity, its drug resistance increases rapidly during treatment and is often Rebound effect appears, IC of lamiv...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07D498/04C07D471/04C07D487/10A61K31/519A61K31/527A61K31/5377A61P31/20A61P1/16
Inventor 贺海鹰周凯覃华周跃东王校飞迟雪梅黎健陈曙辉
Owner QILU PHARMA CO LTD