CN102199186A - Diterpene lactone compound and applications thereof - Google Patents
Diterpene lactone compound and applications thereof Download PDFInfo
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- CN102199186A CN102199186A CN 201110074621 CN201110074621A CN102199186A CN 102199186 A CN102199186 A CN 102199186A CN 201110074621 CN201110074621 CN 201110074621 CN 201110074621 A CN201110074621 A CN 201110074621A CN 102199186 A CN102199186 A CN 102199186A
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Abstract
The invention relates to a diterpene lactone compound and applications thereof. The diterpene lactone compound is mainly prepared from andrographolide and sodium bisulfite through an addition/cyclization reaction. The diterpene lactone compound provided by the present invention can be applicable to prepare drugs for anti-bacterium, anti-viral, heat clearing and detoxification, and anti-inflammation, and the safety of the compound is superior to Lianbizhi (renal function impairment which appears with Lianbizhi injection does not appear with the compound).
Description
Technical field
The present invention relates to a kind of diterpene ginkgolide and uses thereof.
Background technology
Rographolide (its structure is suc as formula shown in the I) is the effective monomer of the pure Chinese medicine that extracts from herbal medicine Herba Andrographis, has characteristics such as easy absorption, consumption is little, evident in efficacy, security is good.
Lian Bizhi is the affixture of rographolide and sodium bisulfite, i.e. rographolidum Natrii Bisulfis (its structure is suc as formula shown in the II).Its function cures mainly and is clearing heat and detoxicating, antisepsis and anti-inflammation, is mainly used in treatment upper respiratory tract infection, malignant tumour, acute bacillary dysentery and children's's antral gastritis.But there is reported in literature Chinese medicine LIANBIZHI ZHUSHEYE to cause the case (Chinese combination of Chinese tradiational and Western medicine ephrosis magazine the 6th volume the 9th phase 529-531 September in 2005) of acute renal failure, and the careful use LIANBIZHI ZHUSHEYE of the public, hydroxyethylamyle 40,20 sodium chloride injection and KEYIN PIAN are reminded by national drug untoward reaction monitoring center in the 8th phase " adverse drug reaction communication " of issue, these three kinds of medicines may damage patient's liver, renal function.
Therefore, a kind of compound of rographolidum Natrii Bisulfis safely and effectively of development just becomes the technical issues that need to address of the present invention.
Summary of the invention
The present inventor's design has also been synthesized the novel rographolidum Natrii Bisulfis of a class.In-vitro antibacterial and antiviral experiment and the experiment of animal toxicity in vivo show: rographolidum Natrii Bisulfis compounds provided by the present invention not only has antibiotic and antiviral activity, and the generation of its renal dysfunction situation that toxic side effect is less, no LIANBIZHI ZHUSHEYE occurred.
Rographolidum Natrii Bisulfis compounds of the present invention, it has structure shown in the formula III:
In the formula III, R
1And R
2Independently be selected from respectively: hydrogen (H), C
1～C
6Direct-connected or side chain saturated alkyl is by phenyl or C
1～C
6The C direct-connected or branched alkoxy replaces
1～C
6Direct-connected or side chain saturated alkyl, the hexa-member heterocycle base, group shown in the formula IV, a kind of in the group shown in group shown in the formula V or the formula VI;
Wherein, the heteroatoms of described hexa-member heterocycle base is O, S or N, and the heteroatoms number is 1; R
3And R
4Independently be selected from respectively: C
1～C
6Direct-connected or side chain saturated alkyl, hexa-atomic aromatic ring yl or by C
1～C
6A kind of in the hexa-atomic aromatic ring yl that direct-connected or side chain saturated alkyl replaces; R
5, R
6And R
7Independently be selected from respectively: C
1～C
6A kind of in direct-connected or side chain saturated alkyl or the hexa-atomic aromatic ring yl.
In addition, the present invention also provides a kind of method for preparing rographolidum Natrii Bisulfis compounds of the present invention, its key step is: carry out the addition ring closure reaction by rographolide (compound shown in the formula I) and sodium bisulfite, obtain one of target compound (compound shown in the formula III, and R
1And R
2Be H), the gained compound again with reactions such as acid anhydrides or halogenide, can get other compound that formula III comprises.
Rographolidum Natrii Bisulfis compounds provided by the present invention can be used for preparing antibiotic and antiviral drug, and its toxic side effect is less.
Embodiment
In optimized technical scheme of the present invention, R
1And R
2Independently be selected from respectively: H, C
1～C
3Direct-connected or side chain saturated alkyl is by phenyl or C
1～C
3The C direct-connected or branched alkoxy replaces
1～C
3Direct-connected or side chain saturated alkyl, THP trtrahydropyranyl, group shown in the formula IV, a kind of in the group shown in group shown in the formula V or the formula VI;
Wherein, R
3And R
4Independently be selected from respectively: C
1～C
5Direct-connected or side chain saturated alkyl, phenyl or by C
1～C
5A kind of in the phenyl that direct-connected or side chain saturated alkyl replaces; R
5, R
6And R
7Independently be selected from respectively: C
1～C
4A kind of in direct-connected or side chain saturated alkyl or the phenyl.
Preferred technical scheme is: R
1And R
2Independently be selected from respectively: H, methyl, benzyl, methoxyl methyl (CH
3OCH
2-), THP trtrahydropyranyl, ethanoyl, valeryl, benzoyl, methylsulfonyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, and is a kind of during the silica-based or tert-butyl diphenyl of tertiary butyl dimethyl is silica-based;
Best technical scheme is: R
1And R
2Independently be selected from respectively: H, methyl, ethanoyl, benzyl, a kind of during methylsulfonyl or tertiary butyl dimethyl are silica-based.
Below by embodiment the present invention is further elaborated.The cited case does not limit protection scope of the present invention.
Embodiment 1
The preparation of compound III-1:
3.5g rographolide (10mmol) is dissolved in 50mL Virahol/tetrahydrofuran (THF) (5: 1 (v/v)) solution, add 2.1g sodium bisulfite (20mmol), kept at least 36 hours at 40 ℃ of states, revolve to steam and remove organic solvent, recrystallization (Virahol/ethyl acetate), promptly get compound III-1 (white solid) 4.0g, productive rate 91.6%.
1H-NMR(400MH
z，DMSO-d
6)：δ6.65(s，1H)，4.94-4.89(t，J＝18.8Hz，1H)，4.23-4.20(t，J＝18.8Hz，1H)，3.89-3.87(d，J＝11.2Hz，1H)，3.17-3.12(m，2H)，2.90-2.81(m，3H)，2.36-2.34(d，J＝15.6Hz，1H)，2.23-2.17(m，1H)，2.04-1.90(m，2H)，1.65-1.63(m，1H)，1.56-1.53(m，2H)，1.43-1.40(m，1H)，1.24-1.20(m，1H)，1.04(s，3H)，0.98-0.97(m，1H)，0.94-0.93(m，1H)，0.90(s，3H)，0.88(m，1H)ppm，
13C-NMR(400MH
z，DMSO-d
6)：δ170.09，133.80，126.30，78.15，69.18，64.32，55.66，55.26，52.68，49.32，42.47，37.57，37.07，36.90，34.61，25.46，22.63，23.43，19.91，15.22ppm。
Embodiment 2
The preparation of compound III-2:
1.0g compound III-1 (2.3mmol) is dissolved in 25mL Virahol/tetrahydrofuran (THF) (5: 1 (v/v)) solution, add the 5mL diacetyl oxide, kept at least 12 hours in room temperature (20 ℃～30 ℃) state, organic solvent is removed in decompression, recrystallization (Virahol/ethyl acetate), promptly get compound III-2 (white solid) 0.8g, productive rate 66.8%.
1H-NMR(400MH
z，DMSO-d
6)：δ6.78(s，1H)，4.94-4.89(t，J＝18.8Hz，1H)，4.75-4.50(t，J＝18.8Hz，1H)，4.19-4.15(m，2H)，3.90-3.87(d，J＝11.2Hz，1H)，2.90-2.81(m，3H)，2.46-2.38(d，J＝15.6Hz，1H)，2.23-2.17(m，1H)，2.10(s，6H)2.04-1.82(m，2H)，1.67-1.65(m，1H)，1.56-1.53(m，2H)，1.43-1.39(m，1H)，1.24-1.20(m，1H)，1.04(s，3H)，0.98-0.97(m，1H)，0.94-0.93(m，1H)，0.91(s，3H)，0.81(m，1H)ppm，
13C-NMR(400MH
z，DMSO-d
6)：δ168.05，160.04，132.80，121.30，70.15，65.18，60.32，55.86，55.26，52.88，49.32，42.47，37.77，37.07，36.90，30.61，25.46，23.63，23.45，22.31，21.15，18.99，16.13ppm。
Embodiment 3
The preparation of compound III-3:
(2.3mmol) is dissolved in the 25mL methylene dichloride with 1.0g compound III-1, under 0 ℃, add 1.3mL triethylamine (9.2mmol) and 0.5mL methylsulfonyl chloride (6.9mmol) successively, and in 0 ℃ of state maintenance at least 5 hours, organic solvent is removed in decompression, recrystallization (Virahol/ethyl acetate), get compound III-3 (faint yellow solid) 1.2g, yield 88.0%.
1H-NMR(400MH
z，DMSO-d
6)：δ6.58(s，1H)，4.84-4.79(t，J＝18.8Hz，1H)，4.23-4.18(t，J＝18.8Hz，1H)，3.80-3.72(d，J＝11.2Hz，1H)，3.55-3.35(m，6H)，3.10-3.05(m，2H)，2.91-2.84(m，3H)，2.32-2.30(d，J＝15.6Hz，1H)，2.17-2.06(m，1H)，2.00-1.81(m，2H)，1.65-1.63(m，1H)，1.59-1.55(m，2H)，1.43-1.38(m，1H)，1.26-1.22(m，1H)，1.00(s，3H)，0.96-0.95(m，1H)，0.94-0.93(m，1H)，0.91(s，3H)，0.86(m，1H)ppm
13C-NMR(100MH
z，DMSO-d
6)：δ168.04，132.80，127.30，78.15，68.17，64.30，55.88，55.20，52.00，49.22，42.35，39.58，38.55，37.67，37.28，36.93，34.61，26.41，23.85，23.55，19.91，15.23ppm。
Embodiment 4
The preparation of compound III-4:
(1.2mmol) is dissolved in the 15mL acetonitrile with 0.5g compound III-1, under 0 ℃, add 1.0mL triethylamine (7.2mmol) and 0.2mL methyl iodide (3.0mmol) successively, and in 0 ℃ of state maintenance at least 5 hours, organic solvent is removed in decompression, recrystallization (Virahol/ethyl acetate), get compound III-4 (faint yellow solid) 0.5g, yield 90.0%.
1H-NMR(400MH
z，DMSO-d
6)：δ6.67(s，1H)，4.92-4.88(t，J＝18.8Hz，1H)，4.25-4.20(t，J＝18.8Hz，1H)，3.83-3.80(d，J＝11.2Hz，1H)，3.25(s，6H)，3.16-3.12(m，2H)，2.89-2.81(m，3H)，2.32-2.28(d，J＝15.6Hz，1H)，2.22-2.16(m，1H)，2.03-1.91(m，2H)，1.62-1.60(m，1H)，1.55-1.50(m，2H)，1.41-1.38(m，1H)，1.22-1.18(m，1H)，1.00(s，3H)，0.97-0.95(m，1H)，0.94-0.93(m，1H)，0.90(s，3H)，0.88(m，1H)ppm。
Embodiment 5
The preparation of compound III-5:
0.5g compound III-1 (1.2mmol) is dissolved in the anhydrous N of 10mL, dinethylformamide, add 0.33 sodium hydride (4.8mmol), (20 ℃～30 ℃) kept 1 hour under room temperature, dripped 0.43mL cylite (3.6mmol) then, and kept at least 5 hours in room temperature (20 ℃～30 ℃) state, organic solvent is removed in decompression, recrystallization (Virahol/ethyl acetate) gets compound III-5 (faint yellow solid) 0.6g, yield 85.0%.
1H-NMR(400MH
z，DMSO-d
6)：δ7.32-7.25(m，10H)，6.62(s，1H)，4.95-4.88(t，J＝18.8Hz，1H)，4.67(s，4H)，4.29-4.23(t，J＝18.8Hz，1H)，3.85-3.81(d，J＝11.2Hz，1H)，3.24(s，6H)，3.16-3.12(m，2H)，2.89-2.81(m，3H)，2.31-2.28(d，J＝15.6Hz，1H)，2.23-2.16(m，1H)，2.03-1.93(m，2H)，1.64-1.60(m，1H)，1.53-1.50(m，2H)，1.42-1.38(m，1H)，1.23-1.18(m，1H)，1.00(s，3H)，0.97-0.88(m，6H)ppm。
Embodiment 6
The preparation of compound III-6:
(1.2mmol) is dissolved in the 25m methylene dichloride with 0.5g compound III-1, add 0.65g imidazoles (9.6mmol), the silica-based chlorine of 1.3g tertiary butyl dimethyl (8.4mmol) is dissolved in the 10mL methylene dichloride, be transferred in the reaction solution then, (20 ℃～30 ℃) kept 10 hours under room temperature, and organic solvent, recrystallization (Virahol/ethyl acetate) are removed in decompression, get compound III-6 (faint yellow solid) 0.7g, yield 92.0%.
1H-NMR(400MH
z，DMSO-d
6)：δ6.69(s，1H)，4.89-4.85(t，J＝18.8Hz，1H)，4.25-4.20(t，J＝18.8Hz，1H)，3.84-3.80(d，J＝11.2Hz，1H)，3.26(s，6H)，3.15-3.10(m，2H)，2.88-2.80(m，3H)，2.31-2.26(d，J＝15.6Hz，1H)，2.24-2.19(m，1H)，2.03-1.96(m，2H)，1.62-1.59(m，1H)，1.56-1.51(m，2H)，1.40-1.36(m，1H)，1.25-1.20(m，1H)，1.00(s，3H)，0.97-0.80(m，24H)ppm。
Embodiment 7
Bacteriostatic experiment
With above-claimed cpd III-1 of the present invention, compound III-2, compound III-3, carry out the antibacterial activity in vitro contrast experiment with the Lian Bizhi and the rographolide of equivalent.Wherein the Lian Bizhi of medicine and rographolide adopt the Lian Bizhi and the rographolide sheet of same medicine total amount respectively in contrast, are formulated as the experimental drug matter sample of same concentrations behind porphyrize.Experimental result sees Table 1:
Table 1
Table 1 is as can be known: medicine of the present invention all shows certain bacteriostatic activity to common gram-positive microorganism and negative pathogenic bacterium.Pseudomonas aeruginosa, bacillus cloacae, bloodthirsty influenza bacterium, Hemolytic streptococcus there are bacteriostatic activity preferably, stronger to golden staphylococci and streptococcus pneumoniae bacteriostatic activity, and all be better than the bacteriostatic activity of Lian Bizhi and rographolide.Illustrate that medicine of the present invention has stronger bacteriostatic activity.
Embodiment 8
Antiviral experiment
With Hep-2 cell (5 * 10
5/ L, every hole 0.1mL) placing 96 orifice plates, DMEM respectively is substratum, cultivates in 37 ℃, 5% CO2gas incubator, and nutrient solution in the hole of inclining next day is with 100TCID
50Adenovirus ADV
3, ADV
7And respiratory syncytial virus (RSV) is inoculated respectively in 96 orifice plates that the Hep-2 cell grows into monolayer cell, in 37 ℃, 5% CO2gas incubator, cultivate, hatch 1 little, the time after remove supernatant liquor, PBS washes flush away virus twice, and DMEM is a substratum, adds The compounds of this invention III-1～compound III-6 of 5mg/mL respectively, every kind of compound 5 holes, Lian Bizhi and viral Cuo control group and blank group are set simultaneously, under 37 ℃ of constant temperatures, observation of cell pathology effect day by day.Experimental result sees Table 2:
Table 2
Annotate: no pathology in "-" expression cell; How much "+" represents lesion degree in the cell.
As shown in Table 2: compound III-1～compound III-6 couple ADV
3, ADV
7, RSV restraining effect all be better than Lian Bizhi and viral Cuo.
Embodiment 9
Long term toxicity test
Give the rat medication with compound III-1～compound III-6, rat every day is by 1.667g/kg (calculating 200 times that are equivalent to clinical 60kg Coming-of-Age Day consumption 0.5g by kg body weight), get blood after two weeks of drug withdrawal in two months for the continuous gastric infusion of rat and carry out the relevant item inspection, the result show between medication and drug withdrawal after the heart of rat, liver, spleen, internal organs such as lung or kidney official function does not have considerable change, illustrate that medicine of the present invention is lower to rat long-term prescription toxicity, medication is than safety and do not have a generation of the renal dysfunction situation that LIANBIZHI ZHUSHEYE occurs.
Claims (6)
1. rographolidum Natrii Bisulfis compounds, it has structure shown in the formula III:
In the formula III, R
1And R
2Independently be selected from respectively: hydrogen, C
1～C
6Direct-connected or side chain saturated alkyl is by phenyl or C
1～C
6The C direct-connected or branched alkoxy replaces
1～C
6Direct-connected or side chain saturated alkyl, the hexa-member heterocycle base, group shown in the formula IV, a kind of in the group shown in group shown in the formula V or the formula VI;
Wherein, the heteroatoms of described hexa-member heterocycle base is O, S or N, and the heteroatoms number is 1;
R
3And R
4Independently be selected from respectively: C
1～C
6Direct-connected or side chain saturated alkyl, hexa-atomic aromatic ring yl or by C
1～C
6A kind of in the hexa-atomic aromatic ring yl that direct-connected or side chain saturated alkyl replaces;
R
5, R
6And R
7Independently be selected from respectively: C
1～C
6A kind of in direct-connected or side chain saturated alkyl or the hexa-atomic aromatic ring yl.
2. rographolidum Natrii Bisulfis compounds as claimed in claim 1 is characterized in that, wherein R
1And R
2Independently be selected from respectively: H, C
1～C
3Direct-connected or side chain saturated alkyl is by phenyl or C
1～C
3The C direct-connected or branched alkoxy replaces
1～C
3Direct-connected or side chain saturated alkyl, THP trtrahydropyranyl, group shown in the formula IV, a kind of in the group shown in group shown in the formula V or the formula VI;
Wherein, R
3And R
4Independently be selected from respectively: C
1～C
5Direct-connected or side chain saturated alkyl, phenyl or by C
1～C
5A kind of in the phenyl that direct-connected or side chain saturated alkyl replaces; R
5, R
6And R
7Independently be selected from respectively: C
1～C
4A kind of in direct-connected or side chain saturated alkyl or the phenyl.
3. rographolidum Natrii Bisulfis compounds as claimed in claim 2 is characterized in that, wherein R
1And R
2Independently be selected from respectively: H, methyl, benzyl, methoxyl methyl, THP trtrahydropyranyl, ethanoyl, valeryl, benzoyl, methylsulfonyl, p-toluenesulfonyl, trimethyl silicon based, triethyl is silica-based, and is a kind of during the silica-based or tert-butyl diphenyl of tertiary butyl dimethyl is silica-based.
4. rographolidum Natrii Bisulfis compounds as claimed in claim 3 is characterized in that, wherein R
1And R
2Independently be selected from respectively: H, methyl, benzyl, ethanoyl, a kind of during methylsulfonyl or tertiary butyl dimethyl are silica-based.
5. rographolidum Natrii Bisulfis compounds as claimed in claim 4 is characterized in that, described rographolidum Natrii Bisulfis compounds is a compound shown in formula III-1, formula III-2, formula III-3, formula III-4, formula III-5 or the formula III-6:
Wherein: Ac is an ethanoyl, and Ms is a methylsulfonyl, and Me is a methyl, and Bn is a benzyl, and TBS is that tertiary butyl dimethyl is silica-based.
6. antibiotic or/and the application in the antiviral in preparation as any described rographolidum Natrii Bisulfis compounds in the claim 1～5.
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|---|---|---|---|
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|---|---|---|---|
| CN 201110074621 CN102199186B (en) | 2011-03-25 | 2011-03-25 | Diterpene lactone compound and applications thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145665A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydro-14,17-cyclo-andrographolide-19-sulphate and its preparation method and use in drug preparation |
| CN114940667A (en) * | 2022-04-28 | 2022-08-26 | 宁波大学 | Diterpenoid compound and preparation method and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100999542A (en) * | 2006-12-31 | 2007-07-18 | 沈阳陶普农化有限公司 | Green synthesizing process of rape cin lactone and its analogue |
-
2011
- 2011-03-25 CN CN 201110074621 patent/CN102199186B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100999542A (en) * | 2006-12-31 | 2007-07-18 | 沈阳陶普农化有限公司 | Green synthesizing process of rape cin lactone and its analogue |
Non-Patent Citations (1)
| Title |
|---|
| 《安徽医药》 20050430 朱仁发 等 穿心莲内酯亚硫酸钠的新合成方法 249-250 1-6 第9卷, 第4期 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145665A (en) * | 2012-04-12 | 2013-06-12 | 江西青峰药业有限公司 | 17-hydro-9-dehydro-14,17-cyclo-andrographolide-19-sulphate and its preparation method and use in drug preparation |
| CN103145665B (en) * | 2012-04-12 | 2014-12-31 | 江西青峰药业有限公司 | 17-hydro-9-dehydro-14,17-cyclo-andrographolide-19-sulphate and its preparation method and use in drug preparation |
| CN114940667A (en) * | 2022-04-28 | 2022-08-26 | 宁波大学 | Diterpenoid compound and preparation method and application thereof |
| CN114940667B (en) * | 2022-04-28 | 2023-06-13 | 宁波大学 | Diterpenoid compound and preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
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