CN104744297A - Anti-hepatitis B virus (HBV) activity phenylpropanoid benzaldehyde oxime ester type compounds - Google Patents
Anti-hepatitis B virus (HBV) activity phenylpropanoid benzaldehyde oxime ester type compounds Download PDFInfo
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- CN104744297A CN104744297A CN201510177649.5A CN201510177649A CN104744297A CN 104744297 A CN104744297 A CN 104744297A CN 201510177649 A CN201510177649 A CN 201510177649A CN 104744297 A CN104744297 A CN 104744297A
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- benzaldoxime
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Abstract
The invention discloses anti-hepatitis B virus (HBV) activity phenylpropanoid benzaldehyde oxime ester type compounds, and in particular discloses phenylpropanoid benzaldehyde oxime ester type compounds which have a structural formula shown in the specification. The HepG2.2.15 cell experiment shows that the compounds have certain inhibitory action on HBV surface antigen (HBsAg) and e antigen (HBeAg), and are expected to be used for preparing medicaments for resisting HBV.
Description
Technical field
The present invention relates to a series of Phenylpropanoid Glycosides benzaldoxime ester compound, and the synthesis of this compounds and the application in anti-hepatitis B virus activities.Specifically anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound.
Background technology
Hepatitis B (viral hepatitis type B), be called for short hepatitis B, by hepatitis B virus (Hepatitis B virus, HBV) common transmittable that causes is sick, have infectivity strong, popular wide general, route of transmission is complicated, sickness rate comparatively high.Hepatitis B is a serious global hygienic issues, can cause chronic hepatopathy and chronic infection, and the risk that its patient dies from liver cirrhosis and liver cancer is very high.The whole world about 1/2 population lives is in HBV easy infection area, and about 2,000,000,000 people are proved to be and once infected HBV, and 3-4 hundred million people is HBV chronic infection, and about 780,000 people die from acute or chronic viral hepatitis B every year, causes in the world arranging residence the 10th in the dead cause of disease.China is that the whole world infects the maximum country of hepatitis B virus number, and the whole nation about 6.9 hundred million people once infected hepatitis B virus, wherein the long-term Hepatitis B carrier of 1.2 hundred million people.
The treatment of hepatitis B mainly comprises antiviral, immunomodulatory, anti-inflammatory protects the liver, anti-fibrosis etc., and wherein antiviral is crucial.At present, antiviral has two large class, Interferon, rabbit and nucleoside analogs.There is the problems such as expensive in Interferon, rabbit.The focus of antiviral research since nucleoside analog is the eighties in 20th century, become the choice drug of current treating hepatitis B, many have lamivudine, Entecavir, adefovir ester, Telbivudine etc., its competition take part in the synthesis of DNA in HBV, cause HBV DNA to synthesize be interfered and stop, but nucleoside medicine long-term taking causes general resistance and drug withdrawal knock-on.
Produce the problem such as resistance in order to improve current nucleoside analogue drugs at the HBV used, finding some novel drugs different from the mechanism of action nucleoside medicine structure is one of directions of developing of current Anti-HBV drugs.Some non-nucleosides are found like thing and are designed for and suppress HBV and help avoid resistance to produce.We design and have synthesized and have good anti-hepatitis B virus activities series Phenylpropanoid Glycosides benzaldoxime ester compound for this reason.
Summary of the invention
Object of the present invention provides a kind of anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound.
The technical scheme that the present invention solves the problems of the technologies described above is as follows
1. anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound, its general structure is as follows:
Wherein: R
1, R
2, R
3for H, OCH
3or-CH
2-(epidioxy propyl group);
R
4, R
5, R
6for H, OCH
3or-CH
2-(epidioxy propyl group).
2. the first Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of this first Phenylpropanoid Glycosides benzaldoxime ester compound is: 3,4-dimethoxy-cinnamic acid-3 ' and, 4 '-dimethoxy benzaldehyde oxime ester
Structural formula:
Molecular formula: molecular formula C
20h
21nO
6molecular weight: 371.38;
2) white crystal, fusing point 156.1-156.5 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic resonance data
1h NMR (400MHz, CDCl
3): δ 3.890 (12H, 4 × CH
3, s, H-17,18,19,20), 6.29 (1H, d, J=15.91Hz, H-8), 6.85 (1H, d, J=8.29, H-5), 6.88 (1H, d, J=8.34Hz, H-13), 7.05 (2H, dd, J=1.77,1.87Hz, H-2,16), 7.10 (1H, d, J=1.77,8.29Hz, H-6), 7.25 (1H, d, J=1.87,8.34Hz, H-12), 7.61 (1H, d, J=15.91Hz, H-7), 8.28 (1H, s, H-10).
13c NMR (100MHz, CDCl
3): δ 167.14 (C-9), 156.38 (C-10), 152.86 (C-14), 151.15 (C-15), 149.19 (C-3), 146.29 (C-7), 144.79 (C-4), 127.31 (C-1), 126.44 (C-11), 122.65 (C-12), 119.20 (C-6), 115.59 (C-13), 113.92 (C-8), 111.25 (C-5), 111.03 (C-16), 109.60 (C-2), 55.87,55.95,56.07,56.11 (C-17,18,19,20). mass-spectrometric data HRESIMS:m/z 372.126 [M+H]
+, 394.012 [M+Na]
+, 767.105 [2M+H+Na]
+.
3. the second Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of this second Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4,5-trimethoxy cinnamic acid-3 ' and, 4 '-dimethoxy benzaldehyde oxime ester;
Structural formula:
Molecular formula: C
21h
23nO
7molecular weight 401.41;
2) physico-chemical property: white crystal, fusing point 86.9-87.1 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic data
11h NMR (400MHz, CDCl
3): δ 3.94 (15H, 5 × CH
3, s, H-17,18,19,20,21), 6.47 (1H, d, J=15.9Hz, H-8), 6.91 (1H, d, J=8.29Hz, H-13), 6.82 (1H, s, H-6), 7.17 (1H, dd, J=1.74,8.29Hz, H-12), 7.28 (1H, s, H-2), 7.47 (1H, d, J=1.74, H-16), 7.79 (1H, d, J=15.9Hz, H-7), 8.39 (1H, s, H-10).
13c NMR (100MHz, CDCl
3): δ 164.77 (C-9), 156.22 (C-10), 153.47 (C-3,5), 152.30 (C-14), 149.45 (C-15), 146.22 (C-7), 140.40 (C-4), 129.73 (C-1), 124.14 (C-11), 122.87 (C-12), 114.70 (C-8), 110.58 (C-13), 108.69 (C-16), 105.38 (C-2,6), 61.02,60.41 (C-20,21), 56.18 (C-17,19), 56.00 (C-18). mass spectrum HRESIMS:m/z 401.923 [M
+], 424.196 [M+Na]
+, 827.466 [2M+H+Na]
+.
4. the third Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of this third Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4-((methylenedioxy)) styracin-3 ' and, 4 '-dimethoxy benzaldehyde oxime ester;
Structural formula:
Molecular formula: C
19h
17nO
6molecular weight: 355.34;
2) physico-chemical property: white crystal, fusing point 84.2-84.5 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.89 (6H, 2 × CH
3, s, H-18,19), 6.00 (2H, s, H-17), 6.44 (1H, d, J=15.90Hz, H-8), 6.84 (1H, d, J=8.25, H-5), 6.85 (1H, d, J=8.34Hz, H-13), 7.02 (1H, d, J=1.86,8.25Hz, H-6), 7.04 (1H, d, J=1.87,8.34Hz, H-12), 7.23 (1H, d, J=1.86Hz, H-2), 7.28 (1H, d, J=1.87Hz, H-16), 7.78 (1H, d, J=15.90Hz, H-7), 8.10 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.53 (C-9), 156.38 (C-10), 150.80 (C-14), 150.19 (C-15), 149.29 (C-3), 148.43 (C-4), 146.34 (C-7), 128.02 (C-1), 125.10 (C-11), 124.83 (C-12), 121.71 (C-6), 113.62 (C-8), 110.79 (C-13), 110.57 (C-5), 108.09 (C-16), 105.47 (C-2), 101.56 (C-17), 56.92,56.88 (C-18,19). mass-spectrometric data ESIMS:m/z 356.1 [M+H]
+, 378.2 [M+Na]
+.
5. the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 5-methoxyl group-3,4-((methylenedioxy)) styracin-3 ' and, 4 '-dimethoxy benzaldehyde oxime ester;
Structural formula:
Molecular formula: C
20h
19nO
7molecular weight: 385.37;
2) physico-chemical property: white crystal, fusing point 178.2-178.5 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.94 (9H, 3 × CH
3, s, H-18,19,20), 6.04 (2H, s, H-17), 6.38 (1H, d, J=15.86Hz, H-8), 6.89 (1H, d, J=8.25Hz, H-13), 6.75 (1H, d, J=1.32Hz, H-6), 7.16 (1H, dd, J=1.89,8.25Hz, H-12), 6.80 (1H, d, J=1.32Hz, H-2), 7.46 (1H, d, J=1.89, H-16), 7.74 (1H, d, J=15.86Hz, H-7), 8.37 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.91 (C-9), 156.14 (C-10), 152.30 (C-14), 149.49 (C-5), 149.45 (C-15), 146.01 (C-7), 143.74 (C-3), 137.72 (C-4), 129.09 (C-1), 124.07 (C-11), 122.95 (C-12), 113.90 (C-8), 110.63 (C-13), 109.64 (C-16), 108.81 (C-6), 101.35 (C-2), 102.09 (C-17), 56.67, 56.18, 55.99 (C-18, 19, 20). mass-spectrometric data ESIMS:m/z 386.4 [M+H]
+, 408.4 [M+Na]
+.
6. the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4-dimethoxy-cinnamic acid-5 ' methoxyl group-3 ', 4 '-((methylenedioxy)) benzaldoxime ester structural formula:
Molecular formula: molecular formula C
20h
19nO
7molecular weight: 385.37;
2) physico-chemical property: white crystal, fusing point 138.0-138.4 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic resonance data
1h NMR (400MHz, CDCl
3): δ 3.95 (9H, 3 × CH
3, s, H-17,18,20), 6.05 (2H, s, H-19), 6.41 (1H, d, J=15.91Hz, H-8), 6.89 (1H, d, J=8.29Hz, H-5), 6.96 (1H, d, J=1.48, H-16), 7.00 (1H, s, H-2), 7.16 (1H, d, J=8.29Hz, H-6), 7.10 (1H, d, J=1.48, H-12), 7.80 (1H, d, J=15.91Hz, H-7), 8.32 (1H, s, H-10).
13c NMR (100MHz, CDCl
3): δ 164.92 (C-9), 155.76 (C-10), 151.45 (C-15), 149.22 (C-13), 149.19 (C-3), 146.30 (C-7), 143.92 (C-4), 138.47 (C-14), 127.20 (C-1), 124.55 (C-11), 122.95 (C-6), 112.91 (C-8), 111.02 (C-5), 109.74 (C-2), 108.44 (C-16), 102.67 (C-12), 102.21 (C-19), 56.78, 56.01, 55.91 (C-17, 18, 20). mass-spectrometric data HRESIMS:m/z 386.435 [M+H]
+, 408.327 [M+Na]
+, 795.124 [2M+H+Na]
+.
7. the 6th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 6th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4,5-trimethoxy cinnamic acid-5 ' methoxyl group-3 ' and, 4 '-((methylenedioxy)) benzaldoxime ester;
Structural formula:
Molecular formula: C
21h
21nO
8molecular weight 415.39;
2) physico-chemical property: white crystal, fusing point 139.6-140.1 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.93 (12H, 4 × CH
3, s, H-17,18,19,21), 6.04 (2H, s, H-20), 6.44 (1H, d, J=15.93Hz, H-8), 6.80 (2H, s, H-2,6), 6.95 (1H, d, J=1.33Hz, H-16), 6.98 (1H, d, J=1.33, H-12), 7.77 (1H, d, J=15.93Hz, H-7), 8.31 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.58 (C-9), 155.88 (C-10), 153.46 (C-15), 149.22 (C-13), 146.29 (C-7), 143.92 (C-3,5), 140.48 (C-14), 138.54 (C-4), 129.67 (C-1), 124.47 (C-11), 114.56 (C-8), 108.59 (C-16), 105.45 (C-2,6), 102.62 (C-12), 102.20 (C-20), 60.98 (C-21), 56.77,56.17 (C-17,18,19). mass-spectrometric data ESIMS:m/z 415.9 [M
+].
8. the 7th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 7th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4-((methylenedioxy)) styracin-5 '-methoxyl group-3 ' and, 4 '-((methylenedioxy)) benzaldoxime ester;
Structural formula:
Molecular formula: C
19h
15nO
7molecular weight: 369.32;
2) physico-chemical property: white crystal, fusing point 172.3-172.8 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water;
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.92 (3H, s, H-19), 5.75 (2H, s, H-18), 6.02 (2H, s, H-17), 6.29 (1H, d, J=15.57Hz, H-8), 6.82 (1H, d, J=7.95, H-5), 7.01 (1H, dd, J=1.51,7.95, H-6), 7.03 (1H, d, J=1.51, H-2), 7.21 (1H, s, H-16), 7.27 (1H, s, H-12), 7.57 (1H, d, J=15.57Hz, H-7), 8.13 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 167.66 (C-9), 156.70 (C-10), 151.99 (C-15), 149.10 (C-13), 148.87 (C-3), 148.08 (C-4), 146.35 (C-7), 142.42 (C-14), 128.91 (C-1), 124.20 (C-11), 117.31 (C-6), 113.86 (C-8), 110.89 (C-5), 108.59 (C-2), 106.44 (C-16), 105.50 (C-12), 102.35,101.52 (C-17,18), 56.85 (C-19). mass-spectrometric data ESIMS:m/z 370.1636 [M+H]
+, 392.1478 [M+Na]
+.
9. the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 5-methoxyl group-3,4-((methylenedioxy)) styracin-5 '-methoxyl group-3 ' and, 4 '-((methylenedioxy)) benzaldoxime ester;
Structural formula:
Molecular formula: C
20h
17nO
8molecular weight: 399.35;
2) physico-chemical property: white crystal, fusing point 146.5-146.9 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.94,3.95 (6H, 2 × CH
3, s, H-18,20), 6.04,6.05 (4H, each 2H, s, H-17,19), 6.38 (1H, d, J=15.85Hz, H-8), 6.75 (1H, d, J=1.41Hz, H-6), 6.80 (1H, d, J=1.41Hz, H-2), 6.96 (1H, d, J=1.32Hz, H-12), 6.99 (1H, d, J=1.32, H-16), 7.73 (1H, d, J=15.85Hz, H-7), 8.31 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.77 (C-9), 155.83 (C-10), 149.46 (C-15), 149.24 (C-5), 146.15 (C-7), 143.97 (C-13), 143.74 (C-3), 141.99 (C-14), 138.55 (C-4), 129.07 (C-1), 124.55 (C-11), 113.78 (C-8), 109.68 (C-16), 108.56 (C-12), 102.70 (C-6), 101.35 (C-2), 102.21, 102.10 (C-17, 19), 56.81, 56.68 (C-18, 20). mass-spectrometric data ESIMS:m/z 422.1 [M+Na]
+.
10. the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester compound in anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound:
1) chemical name of the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4-dimethoxy-cinnamic acid-3 ' and, 4 ', 5 '-TMB oxime ester;
Structural formula:
Molecular formula: C
16h
15nO
4s molecular weight: 317.36;
2) physico-chemical property: white crystal, fusing point 137.7-137.9 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (400MHz, CDCl
3): δ 3.91 (15H, 5 × CH
3, s, H-17,18,19,20,21), 6.40 (1H, d, J=15.90Hz, H-8), 6.88 (1H, d, J=8.28Hz, H-5), 6.98 (2H, s, H-12,16), 7.08 (1H, d, J=1.62Hz, H-2), 7.16 (1H, dd, J=1.62,8.28, Hz, H-6), 7.79 (1H, d, J=15.90Hz, H-7), 8.35 (1H, s, H-10).
13c NMR (100MHz, CDCl
3): δ 164.90 (C-9), 156.10 (C-10), 153.50 (C-13,15), 151.47 (C-3), 149.21 (C-4), 146.37 (C-7), 141.06 (C-14), 127.14 (C-1), 125.47 (C-11), 122.97 (C-6), 112.85 (C-8), 111.02 (C-5), 109.73 (C-2), 105.56 (C-12,16), 60.97 (C-20), 56.32,55.99,55.89 (C-17,18,19,21). mass-spectrometric data HRESIMS:m/z 402.443 [M+H]
+, 424.245 [M+Na]
+, 826.792 [2M+H+Na]
+.
Tenth kind of Phenylpropanoid Glycosides benzaldoxime ester compound in 11. anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compounds:
1) chemical name of the tenth kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4,5-trimethoxy cinnamic acid-3 ' and, 4 ' 5 '-TMB oxime ester;
Structural formula:
Molecular formula: C
22h
25nO
8molecular weight 431.44;
2) physico-chemical property: white crystal, fusing point 112.5-112.8 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.90 (18H, 6 × CH
3, s, H-17,18,19,20,21,22), 6.45 (1H, d, J=15.93Hz, H-8), 6.81 (2H, s, H-2,6), 7.00 (2H, s, H-12,16), 7.79 (1H, d, J=15.93Hz, H-7), 8.36 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.64 (C-9), 156.25 (C-10), 153.59 (C-13,15), 153.52 (C-3,5), 146.44 (C-7), 141.30 (C-14), 140.58 (C-4), 129.69 (C-1), 125.39 (C-11), 114.58 (C-8), 105.72 (C-12,16), 105.53 (C-2,6), 61.01,61.02 (C-18,21), 56.40,56.22 (C-17,19,20,22). mass-spectrometric data ESIMS:m/z 432.1 [M+H]
+, 454.2 [M+Na]
+.
11 kind of Phenylpropanoid Glycosides benzaldoxime ester compound in 12. anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compounds:
1) chemical name of the 11 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 3,4-((methylenedioxy)) styracin-3 ' and, 4 ' 5 '-TMB oxime ester;
Structural formula:
Molecular formula: C
20h
19nO
7molecular weight: 385.37;
2) physico-chemical property: white crystal, fusing point 148.8-149.1 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.91 (9H, 3 × CH
3, s, H-18,19,20), 6.03 (2H, s, H-17), 6.37 (1H, d, J=15.91Hz, H-8), 6.84 (1H, d, J=7.94Hz, H-5), 7.00 (2H, s, H-12,16), 7.07 (1H, dd, J=1.46,7.94Hz, H-6), 7.09 (1H, d, J=1.46Hz, H-2), 7.78 (1H, d, J=15.91Hz, H-7), 8.36 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.85 (C-9), 156.14 (C-10), 153.57 (C-13,15), 150.02 (C-3), 148.46 (C-4), 146.15 (C-7), 141.22 (C-14), 128.71 (C-1), 125.48 (C-11), 124.94 (C-6), 113.19 (C-8), 108.65 (C-5), 106.57 (C-2), 105.69 (C-12,16), 101.68 (C-17), 61.00 (C-19), 56.40 (C-18,20). mass-spectrometric data HRESIMS:m/z 386.1252 [M+H]
+, 408.1065 [M+Na]
+.
12 kind of Phenylpropanoid Glycosides benzaldoxime ester compound in 13. 1 class Phenylpropanoid Glycosides benzaldoxime ester compounds:
1) chemical name of the 12 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds is: 5-methoxyl group-3,4-((methylenedioxy)) styracin-3 ' and, 4 ' 5 '-TMB oxime ester;
Structural formula:
Molecular formula: C
21h
21nO
8molecular weight: 415.39;
2) physico-chemical property: white crystal, fusing point 155.0-155.3 DEG C.Be dissolved in chloroform, ethyl acetate, acetone, methyl alcohol and ethanol, be insoluble in water.
Nuclear magnetic resonance data
1h NMR (500MHz, CDCl
3): δ 3.92 (12H, 3 × CH
3, s, H-18,19,20,21), 6.04 (2H, s, H-17), 6.38 (1H, d, J=15.87Hz, H-8), 6.76 (1H, d, J=1.36Hz, H-6), 6.81 (1H, d, J=1.36Hz, H-2), 7.00 (2H, s, H-12,16), 7.75 (1H, d, J=15.87Hz, H-7), 8.36 (1H, s, H-10).
13c NMR (125MHz, CDCl
3): δ 164.75 (C-9), 156.18 (C-10), 153.58 (C-13,15), 149.48 (C-5), 146.22 (C-7), 143.76 (C-3), 141.03 (C-14), 137.34 (C-4), 129.05 (C-1), 125.44 (C-11), 113.75 (C-8), 105.70 (C-12,16), 109.73 (C-6), 101.35 (C-2), 102.10 (C-17), 61.00 (C-18), 56.69,56.40 (C-19,20,21). mass-spectrometric data ESIMS:m/z 416.1315 [M+H]
+, 438.1139 [M+Na]
+.
The preparation of 14. Phenylpropanoid Glycosides benzaldoxime ester compounds, step is as follows:
1) by 3 of 1 equivalent (10mmol), 4-dimethoxy formaldehyde, 3,4,5-trimethoxy formaldehyde or 5 '-3, the oxammonium hydrochloride of 4-(methylene-dioxy) phenyl aldehyde, 1.2 equivalents (12mmol), the sodium acetate trihydrate of 1.2 equivalents (12mmol) are dissolved in 50ml ethanol, stirring reaction 2 hours at 60 DEG C.Concentratedly after stopped reaction obtain enriched material, then dense enriched material is dissolved in 50 milliliters of methylene dichloride, through 1mol/L 70 milliliters of salt acid elutions three times, separates upper solution, obtains lower floor's dichloromethane solution.After pickling, dichloromethane solution 70 ml waters wash three times, then separate lower floor's dichloromethane solution.Dichloromethane solution after washing finally washes 3 times with 70 milliliters, saturated sodium-chloride water, separates lower floor and will obtain dichloromethane solution.The dichloromethane solution that obtains will be washed through 10 grams of anhydrous Na through sodium chloride solution
2sO
4drying, concentrates and obtains 3,4-dimethoxy formoxime, 3,4,5-trimethoxy formoximes or 5 '-methoxyl group-3,4-(methylene-dioxy) benzaldoxime.
2) by 3 of 1 equivalent (10mmol), 4-dimethoxy-cinnamic acid, 3,4,5-trimethoxy cinnamic acid, 3,4-(methylene-dioxy) styracin or 5-methoxyl group-3,4-(methylene-dioxy) styracin is dissolved in 10ml methylene dichloride, adds the thionyl chloride of 5 equivalents (50mmol), and at 65 DEG C, stirring and refluxing reacts 5 hours.Concentrate after stopped reaction and obtain 3,4-(methylene-dioxy) cinnamyl chloride, 3,4-dimethoxycinnamoyl chlorine, 3,4,5-trimethoxy cinnamyl chlorides or 5-methoxyl group-3,4-(methylene-dioxy) cinnamyl chloride.
3) by step 1) obtained 3,4-dimethoxy formoxime is dissolved in 15 milliliters of methylene dichloride, add the step 2 of 1.2 eq of triethylamine (12mmol) and 1.2 equivalents (12mmol)) obtained 3,4-dimethoxycinnamoyl chlorine, 3,4,5-trimethoxy cinnamyl chloride, 3,4-(methylene-dioxy) cinnamyl chloride or 5-methoxyl group-3,4-(methylene-dioxy) cinnamyl chloride, react at 0 DEG C after 30 minutes, then continue reaction 12 hours at normal temperatures.Concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the first Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-3 ', 4 '-dimethoxy benzaldehyde oxime ester, the second Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-3 ', 4 '-dimethoxy benzaldehyde oxime ester, the third Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-(methylene-dioxy) styracin-3 ', 4 '-dimethoxy benzaldehyde oxime ester and the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-(methylene-dioxy) styracin-3 ', 4 '-dimethoxy benzaldehyde oxime ester.
4) by step 1) obtained 3,4,5-trimethoxy formoxime is dissolved in 15 milliliters of methylene dichloride, add the step 2 of 1.2 eq of triethylamine (12mmol) and 1.2 equivalents (12mmol)) obtained 3,4-dimethoxycinnamoyl chlorine, 3,4,5-trimethoxy cinnamyl chloride, 3,4-(methylene-dioxy) cinnamyl chloride or 5-methoxyl group-3,4-(methylene-dioxy) cinnamyl chloride, react at 0 DEG C after 30 minutes, then continue reaction 12 hours at normal temperatures.Concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-3 ', 4 ', 5 '-TMB oxime ester, 6th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-3 ', 4 ', 5 '-TMB oxime ester, 7th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-(methylene-dioxy) styracin-3 ', 4 ', 5 '-TMB oxime ester and the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-(methylene-dioxy) styracin-3 ', 4 ', 5 '-TMB oxime ester.
5) by step 1) obtained 5-methoxyl group-3,4-(methylene-dioxy) benzaldoxime is dissolved in 15 milliliters of methylene dichloride, add the step 2 of 1.2 eq of triethylamine (12mmol) and 1.2 equivalents (12mmol)) obtained 3,4-dimethoxycinnamoyl chlorine, 3,4,5-trimethoxy cinnamyl chloride, 3,4-(methylene-dioxy) cinnamyl chloride or 5-methoxyl group-3,4-(methylene-dioxy) cinnamyl chloride, react at 0 DEG C after 30 minutes, then continue reaction 12 hours at normal temperatures.Concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-5 '-methoxyl group-3 ', 4 '-(methylene-dioxy) benzaldoxime, tenth kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-5 '-methoxyl group-3 ', 4 '-(methylene-dioxy) benzaldoxime, 11 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-(methylene-dioxy) styracin-5 '-methoxyl group-3 ', 4 '-(methylene-dioxy) benzaldoxime and the 12 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-(methylene-dioxy) styracin-5 '-methoxyl group-3 ', 4 '-(methylene-dioxy) benzaldoxime.
15. Phenylpropanoid Glycosides benzaldoxime ester compounds are for the preparation of the medicine of hepatitis B virus resisting, and in vitro tests compound is to the toxicity of HepG2 2.2.15 cell and the suppression to HBsAg and HBeAg.Cultivating HepG22.2.15 cell DMEM substratum used is the solution containing 10% foetal calf serum, 0.03% glutamine, G418 380 μ g/ml and kantlex 50 μ g/ml.Culture condition is 37 DEG C, 5%CO
2, within 2-3 days, change a nutrient solution, within 4-5 days, go down to posterity once.Phenylpropanoid Glycosides benzaldoxime ester compound is made into mother liquor with methyl-sulphoxide respectively, 4 DEG C of preservations, faces the used time to be made into desired concn with DMEM substratum.
HepG2 2.2.15 cell is inoculated in the DMEM substratum in 96 orifice plates, adds Phenylpropanoid Glycosides benzaldoxime ester compound process 9 days respectively.DMEM substratum is added after 9th day removing supernatant liquor, every hole adds 20 μ L MTT (5mg/mL), cultivate 4h again for 37 DEG C, experiment terminates, discard supernatant liquor, every hole adds 150 μ L DMSO and dissolves the MTT-first a ceremonial jade-ladle, used in libation generated in hole, by microplate reader at 490nm wavelength detecting each hole absorbance, carries out quantitatively the first a ceremonial jade-ladle, used in libation that each porocyte generates.Compare with control group (cell survival rate 100%), calculate each porocyte survival rate, to judge the cytotoxicity of medicine.
HepG2 2.2.15 cell is with 1 × 10
4/ mL is inoculated in the nutrient solution of 96 orifice plates, cultivates the various Phenylpropanoid Glycosides benzaldoxime ester compound dimethyl sulfoxide solutions adding different concns after 24 hours respectively.If serum free medium group is negative control group, lamivudine group is positive controls.Experimental design is time dependent, within after adding Phenylpropanoid Glycosides benzaldoxime ester compound every 3 days, collects supernatant liquor once, then adds the DMEM substratum containing Phenylpropanoid Glycosides benzaldoxime ester compound, hatch 9 days altogether.The the 3rd, the 6th, the 9th day supernatant liquor collected, detects HBsAg and HBeAg in HepG2 2.2.15 cell conditioned medium liquid by ELISA method.
Benefit effect of the present invention:
1. novel Phenylpropanoid Glycosides benzaldoxime ester compound provided by the present invention is Nonnucleoside anti-hepatitis B virus activities molecule, is expected to the newtype drug becoming hepatitis B virus resisting.
2. Phenylpropanoid Glycosides benzaldoxime ester compound provided by the present invention all has certain restraining effect to HBsAg and HBeAg.Lamivudine under the same terms 55.86% is only had to HBsAg inhibiting rate, and Phenylpropanoid Glycosides benzaldoxime ester compound 90.99% be can reach to HBsAg inhibiting rate, and there is the low feature of toxicity.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but can not limit protection content of the present invention.
Embodiment 1
The preparation method of the first Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) 3, the 4-dimethoxy formaldehyde of 10mmol, the oxammonium hydrochloride of 12mmol, the sodium acetate trihydrate of 12mmol are dissolved in 50ml ethanol, stirring reaction 2 hours at 60 DEG C.Concentratedly after stopped reaction obtain enriched material, then dense enriched material is dissolved in 50 milliliters of methylene dichloride, through 1mol/L 70 milliliters of salt acid elutions three times, separates upper solution, obtains lower floor's dichloromethane solution.After pickling, dichloromethane solution 70 ml waters wash three times, then separate lower floor's dichloromethane solution.Dichloromethane solution after washing finally washes 3 times with 70 milliliters, saturated sodium-chloride water, separates lower floor and will obtain dichloromethane solution.The dichloromethane solution that obtains will be washed through 10 grams of anhydrous Na through sodium chloride solution
2sO
4drying, concentrates and obtains 3,4-dimethoxy formoxime;
(2) 3, the 4-dimethoxy-cinnamic acids of 10mmol are dissolved in 10ml methylene dichloride, add the thionyl chloride of 50mmol, under 65 DEG C of conditions, stirring and refluxing reacts 5 hours, concentrates and obtain 3,4-dimethoxycinnamoyl chlorine after stopped reaction;
(3) by obtained for embodiment step (1) 3, 4-dimethoxy formoxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-dimethoxycinnamoyl chlorine, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the first Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-3 ', 4 '-dimethoxy formoxime ester.
Embodiment 2
The preparation method of the second Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with the step (1) of embodiment 1.
(2) 3,4, the 5-trimethoxy cinnamic acids of 10mmol are dissolved in 10ml methylene dichloride, add the thionyl chloride of 50mmol, under 65 DEG C of conditions, stirring and refluxing reacts 5 hours, concentrates and obtain 3,4,5-trimethoxy cinnamyl chloride after stopped reaction;
(3) by obtained for step (1) 3, 4-dimethoxy benzaldehyde oxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4, 5-trimethoxy cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the second Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-3 ', 4 '-dimethoxy benzaldehyde oxime ester.
Embodiment 3
The preparation method of the third Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with the step (1) of embodiment 1.
(2) by 3 of 10mmol, 4-(methylene-dioxy) styracin is dissolved in 10ml methylene dichloride, adds the thionyl chloride of 50mmol, and under 65 DEG C of conditions, stirring and refluxing reacts 5 hours, concentrate after stopped reaction and obtain 3,4-(methylene-dioxy) cinnamyl chloride;
(3) by obtained for step (1) 3, 4-dimethoxy benzaldehyde oxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-dimethoxycinnamoyl chlorine, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the third Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-((methylenedioxy)) styracin-3 ', 4 '-dimethoxy benzaldehyde oxime ester.
Embodiment 4
The preparation method of the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with the step (1) of embodiment 1.
(2) by the 5-methoxyl group-3 of 10mmol, 4-(methylene-dioxy) styracin is dissolved in 10ml methylene dichloride, add the thionyl chloride of 50mmol, under 65 DEG C of conditions, stirring and refluxing reacts 5 hours, concentrate after stopped reaction and obtain 5-methoxyl group-3,4-(methylene-dioxy) cinnamyl chloride;
(3) by obtained for step (1) 3, 4-dimethoxy benzaldehyde oxime is dissolved in 15 milliliters of methylene dichloride, add the 5-methoxyl group-3 that the step (2) of 12mmol triethylamine and 12mmol is obtained, 4-(methylene-dioxy) cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-((methylenedioxy)) styracin-3 ', 4 '-dimethoxy benzaldehyde oxime ester.
Embodiment 5
The preparation method of the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) 5-methoxyl group-3,4-((methylenedioxy)) phenyl aldehyde of 10mmol, the oxammonium hydrochloride of 12mmol, the sodium acetate trihydrate of 12mmol are dissolved in 50ml ethanol, stirring reaction 2 hours at 60 DEG C.Concentratedly after stopped reaction obtain enriched material, then dense enriched material is dissolved in 50 milliliters of methylene dichloride, through 1mol/L70 milliliter salt acid elution three times, separates upper solution, obtains lower floor's dichloromethane solution.After pickling, dichloromethane solution 70 ml waters wash three times, then separate lower floor's dichloromethane solution.Dichloromethane solution after washing finally washes 3 times with 70 milliliters, saturated sodium-chloride water, separates lower floor and will obtain dichloromethane solution.The dichloromethane solution that obtains will be washed through 10 grams of anhydrous Na through sodium chloride solution
2sO
4drying, concentrates and obtains 5-methoxyl group-3,4-((methylenedioxy)) benzaldoxime;
(2) identical with embodiment 1 step (2).
(3) by 5-methoxyl group-3 obtained for step (1), 4-(methylene-dioxy) benzaldoxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-dimethoxycinnamoyl chlorine, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-5 ' methoxyl group-3 ', 4 '-((methylenedioxy)) benzaldoxime ester.
Embodiment 6
The preparation method of the 6th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 5 step (1).
(2) identical with embodiment 2 step (2).
(3) by 5-methoxyl group-3 obtained for step (1), 4-((methylenedioxy)) benzaldoxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4, 5-trimethoxy cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 6th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-5 ' methoxyl group-3 ', 4 '-((methylenedioxy)) benzaldoxime ester.
Embodiment 7
The preparation method of the 7th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 5 step (1).
(2) identical with embodiment 3 step (2).
(3) by 5-methoxyl group-3 obtained for step (1), 4-(methylene-dioxy) benzaldoxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-(methylene-dioxy) cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 7th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-((methylenedioxy)) styracin-5 '-methoxyl group-3 ', 4 '-((methylenedioxy)) benzaldoxime ester.
Embodiment 8
The preparation method of the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 5 step (1).
(2) identical with embodiment 4 step (2).
(3) by obtained for step (1) 3, 4-((methylenedioxy)) benzaldoxime is dissolved in 15 milliliters of methylene dichloride, add the 5-methoxyl group-3 that the step (2) of 12mmol triethylamine and 12mmol is obtained, 4-(methylene-dioxy) cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-((methylenedioxy)) styracin-5 '-methoxyl group-3 ', 4 '-((methylenedioxy)) benzaldoxime ester.
Embodiment 9
The preparation method of the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) oxammonium hydrochloride of the 3,4,5-Trimethoxybenzaldehyde of 10mmol, 12mmol, the sodium acetate trihydrate of 12mmol are dissolved in 50ml ethanol, stirring reaction 2 hours at 60 DEG C.Concentratedly after stopped reaction obtain enriched material, then dense enriched material is dissolved in 50 milliliters of methylene dichloride, through 1mol/L 70 milliliters of salt acid elutions three times, separates upper solution, obtains lower floor's dichloromethane solution.After pickling, dichloromethane solution 70 ml waters wash three times, then separate lower floor's dichloromethane solution.Dichloromethane solution after washing finally washes 3 times with 70 milliliters, saturated sodium-chloride water, separates lower floor and will obtain dichloromethane solution.The dichloromethane solution that obtains will be washed through 10 grams of anhydrous Na through sodium chloride solution
2sO
4drying, concentrates and obtains 3,4,5-Trimethoxybenzaldehyde oxime;
(2) identical with embodiment 1 step (2).
(3) by obtained for step (1) 3, 4, 5-TMB oxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-dimethoxycinnamoyl chlorine, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-dimethoxy-cinnamic acid-3 ', 4 ', 5 '-TMB oxime ester.
Embodiment 10
The preparation method of the tenth kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 9 step (1).
(2) identical with embodiment 2 step (2).
(3) by obtained for step (1) 3, 4, 5-TMB oxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4, 5-trimethoxy cinnamyl chloride, react at 0 DEG C after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the tenth kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4, 5-trimethoxy cinnamic acid-3 ', 4 ' 5 '-TMB oxime ester.
Embodiment 11
The preparation method of the 11 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 9 step (1).
(2) identical with embodiment 3 step (2).
(3) by obtained for step (1) 4, 5-TMB oxime is dissolved in 15 milliliters of methylene dichloride, add the step (2) of 12mmol triethylamine and 12mmol obtained 3, 4-(methylene-dioxy) cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 11 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 3, 4-((methylenedioxy)) styracin-3 ', 4 ' 5 '-TMB oxime ester.
Embodiment 12
The preparation method of the 12 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds, step is as follows:
(1) identical with embodiment 9 step (1).
(2) identical with embodiment 4 step (2).
(3) by obtained for step (1) 3, 4, 5-TMB oxime is dissolved in 15 milliliters of methylene dichloride, add the 5-methoxyl group-3 that the step (2) of 12mmol triethylamine and 12mmol is obtained, 4-(methylene-dioxy) cinnamyl chloride, react under 0 DEG C of condition after 30 minutes, then reaction 12 hours is continued at normal temperatures, concentrating under reduced pressure after stopped reaction, be separated by silica gel column chromatography, moving phase consists of: the sherwood oil of boiling point 60-90 DEG C: the volume ratio of ethyl acetate tapers to the solvent of 1:1 from 3:1, carry out gradient elution, obtain the 12 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds 5-methoxyl group-3, 4-((methylenedioxy)) styracin-3 ', 4 ' 5 '-TMB oxime ester.
Embodiment 13
External Anti-HBV activity experiment
Phenylpropanoid Glycosides benzaldoxime ester compound is for the preparation of the medicine of hepatitis B virus resisting, and in vitro tests compound is to the toxicity of HepG2 2.2.15 cell and the suppression to HBsAg and HBeAg.Cultivating HepG2 2.2.15 cell DMEM substratum used is the solution containing 10% foetal calf serum, 0.03% glutamine, G418 380 μ g/ml and kantlex 50 μ g/ml.Culture condition is 37 DEG C, 5%CO
2, within 2-3 days, change a nutrient solution, within 4-5 days, go down to posterity once.Phenylpropanoid Glycosides benzaldoxime ester compound is made into mother liquor with methyl-sulphoxide respectively, 4 DEG C of preservations, faces the used time to be made into desired concn with DMEM substratum.
HepG2 2.2.15 cell is inoculated in the DMEM substratum in 96 orifice plates, adds Phenylpropanoid Glycosides benzaldoxime ester compound process 9 days respectively.DMEM substratum is added after 9th day removing supernatant liquor, every hole adds 20 μ L MTT (5mg/mL), cultivate 4h again for 37 DEG C, experiment terminates, discard supernatant liquor, every hole adds 150 μ L DMSO and dissolves the MTT-first a ceremonial jade-ladle, used in libation generated in hole, by microplate reader at 490nm wavelength detecting each hole absorbance, carries out quantitatively the first a ceremonial jade-ladle, used in libation that each porocyte generates.Compare with control group (cell survival rate 100%), calculate each porocyte survival rate, to judge the cytotoxicity of medicine.
HepG2 2.2.15 cell is with 1 × 10
4/ mL is inoculated in the nutrient solution of 96 orifice plates, cultivates the dimethyl sulfoxide solution of the various Phenylpropanoid Glycosides benzaldoxime ester compounds adding different concns after 24 hours respectively.If serum free medium group is negative control group, lamivudine group is positive controls.Experimental design is time dependent, within after adding Phenylpropanoid Glycosides benzaldoxime ester compound every 3 days, collects supernatant liquor once, then adds the DMEM substratum containing Phenylpropanoid Glycosides benzaldoxime ester compound, hatch 9 days altogether.The the 3rd, the 6th, the 9th day supernatant liquor collected, detects HBsAg and HBeAg in HepG2 2.2.15 cell conditioned medium liquid by ELISA method.
Phenylpropanoid Glycosides benzaldoxime ester compound all shows hypotoxicity.Table one is the inhibition of compound to HBsAg.Table two is compound inhibitions to HBeAg.
Table one
Note: in table, compound number corresponds to claims compound number according to claim 2.Table two is same.
Table two
Claims (3)
1. anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound, is characterized in that, its general structure is as follows:
Wherein, R
1, R
2, R
3can be H, OCH
3or-CH
2-(epidioxy propyl group);
R
4, R
5, R
6can be H, OCH
3or-CH
2-(epidioxy propyl group).
2. anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound as claimed in claim 1, is characterized in that described anti-hepatitis B virus activities Phenylpropanoid Glycosides benzaldoxime ester compound has following structural formula:
1) structural formula of this first Phenylpropanoid Glycosides benzaldoxime ester cpds:
2) structural formula of the second Phenylpropanoid Glycosides benzaldoxime ester cpds:
3) structural formula of the third Phenylpropanoid Glycosides benzaldoxime ester cpds:
4) structural formula of the 4th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
5) structural formula of the 5th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
6) structural formula of the 6th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
7) structural formula of the 7th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
8) structural formula of the 8th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
9) structural formula of the 9th kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
10) structural formula of the tenth kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
11) structural formula of the 11 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
12) structural formula of the 12 kind of Phenylpropanoid Glycosides benzaldoxime ester cpds:
3. Phenylpropanoid Glycosides benzaldoxime ester compound as claimed in claim 1 is for the preparation of the medicine of hepatitis B virus resisting.
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| CN (1) | CN104744297A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213311A (en) * | 2021-12-27 | 2022-03-22 | 浙江工业大学 | Substituted benzaldehyde oxime ester compound and preparation method and application thereof |
-
2015
- 2015-04-15 CN CN201510177649.5A patent/CN104744297A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| E. A. DIKUSAR. ET AL.: "Preparative Synthesis of Veratraldehyde and Citral Oxime Esters", 《RUSSIAN JOURNAL OF APPLIED CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114213311A (en) * | 2021-12-27 | 2022-03-22 | 浙江工业大学 | Substituted benzaldehyde oxime ester compound and preparation method and application thereof |
| CN114213311B (en) * | 2021-12-27 | 2023-10-31 | 浙江工业大学 | Substituted benzaldehyde oxime ester compound and preparation method and application thereof |
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