CN101265266A - Sinomenine derivative, preparation method and application thereof - Google Patents

Sinomenine derivative, preparation method and application thereof Download PDF

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CN101265266A
CN101265266A CNA2008100240512A CN200810024051A CN101265266A CN 101265266 A CN101265266 A CN 101265266A CN A2008100240512 A CNA2008100240512 A CN A2008100240512A CN 200810024051 A CN200810024051 A CN 200810024051A CN 101265266 A CN101265266 A CN 101265266A
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sinomenine derivate
sinomenine
preparation
tuduranine
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CN101265266B (en
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李建新
邓张双
刘珺
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Nanjing University
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Nanjing University
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Abstract

The invention aims at acid, alkali and heat labile features of sinomenine molecular structure, and provides an innovative structural reconstruction idea for new chemical synthesis of ring A, ring C, and ring D sinomenine derivatives. The chemical synthetic method includes amination and acylation of 1-position, C-C or C-O connection of 1 position, dicarbonylation and six-membered N heterocyclization of 3-position and 4-position, two molecule sinomenine adduction of connection of 4-hydroxyl and 1-amino, amination and acylation of 6-position, simultaneous amination and x-membered N heterocyclization of 6-position and 7-position, and opening of D ring and terminal amino group modification thereof. The method is novel and unique. The sinomenine derivatives have good antiinflammation activity and bioactivity evaluated by synovial membrane tumor cell (SW982), and can be used in drug and health products for resisting rheumatoid arthritis.

Description

Sinomenine derivate and its production and application
Technical field
The invention belongs to the macromolecular compound technical field, relate to the derivative of tuduranine, be specially Sinomenine derivate and its production and application.
Background technology
Tuduranine (sinomenine) be from menispermaceous plants Stem of Orientoine and hair sinomenium acutum rhizome, extract be applied to treating rheumatism and rheumatoid arthritis clinically, the most effective alkaloids medicament of diseases such as arthroncus has pharmacological actions such as significant anti-inflammatory, analgesia, step-down and anti-cerebral ischemia.
Transform by structure tuduranine, seek novel structure, active Sinomenine derivate more efficiently is present research focus, and to the structure of modification of tuduranine C ring research emphasis especially.(CN.1687070A CN.1687065A) synthesizes the Sinomenine derivate that the C ring is connected with pyrazine ring and five-membered ring to Yao Zhujun.(Acta Pharmaceutica Sinica such as Ye Xianrong, 2004,39 (3), 180-183) tuduranine C ring is carried out modification and obtained series compound, and adopt mouse acetic acid twisting method to carry out the active animal test, find that compound 7-methoxyl group-dihydro tuduranine analgesic activities is better than tuduranine.CN.1800164A modifies and obtains a series of derivatives equally to Kukoline C ring, this derivative has stronger anti-inflammatory and antalgic activity, can be used for preparing the medicine of treatment rheumatic arthritis and heart disorder aspect.
The Sinomenine structure-modified D ring that occurs in equally; patent CN.1785976A, CN.1785977A and CN1962638A have reported N-alkyl diversine and preparation method thereof respectively, and a class 17-sulfonyl diversine and preparation method thereof and a class have the tuduranine compound and the method for making of dextral C circle lacking of morphinan skeleton.
Up-to-date working out now to the modification of tuduranine A ring 1-position carbon, CN.1948291A has synthesized a class 1-substituted amine methyl diversine derivative, and patent CN.187634A introduces aldehyde radical and hydroxyethyl respectively on 1 on A ring.
Make a general survey of above-mentioned document, the structure of modification of tuduranine is mainly concentrated on C, D ring, new Sinomenine derivate is still waiting to discover.
Summary of the invention
The problem to be solved in the present invention is: transform by structure tuduranine, obtain novel structure, anti-inflammatory activity Sinomenine derivate more efficiently.
Technical scheme of the present invention is: Sinomenine derivate, and the tuduranine structural formula is as follows:
Figure A20081002405100091
After tuduranine A ring, C ring and D ring are by chemosynthesis, obtain Sinomenine derivate, comprising:
1) obtain the amino substituent Sinomenine derivate S1-S5 of connection by restore nitrification at 1:
Figure A20081002405100092
2) or the two molecule tuduranine adducts S6-S8 that form by 4 hydroxyls or 1 bit amino:
Figure A20081002405100093
3) or at 3,4 Sinomenine derivate S9-S14 that are connected with the pyrazine ring:
Figure A20081002405100094
4) or at 6 connect substituent Sinomenine derivate S15-S22 by amino/hydroxyl:
Figure A20081002405100101
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
5) or at 6,7 pass through the amino disinomenine molecule derivant S23-S24 that form the pyrazine ring:
Figure A20081002405100102
6) or the derivative S25-S26 that terminal amino group after the open loop of tuduranine D ring is transformed:
Figure A20081002405100103
R 1=H or CH 3, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H or CH 3, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.Perhaps
R 1=H or CH 3, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
7) or at tuduranine A encircle 1 Sinomenine derivate S32-S34 that is connected to form with C-C or C-O mode:
Figure A20081002405100111
R 1=Cl, Br, OMe, CO 2Me, CHO, CH 2CO 2CH 4, CH 2CN, NHCOCF 3, CH 3, COPh, NH 2, CN, CF 3, CH (OH) COOH etc.;
R 2=R 3=OH, NH 2, NO 2, perhaps R 2=OH, R 3=OCH 3, NO 2, Cl, Br, CH 3Deng, R 4=R 5=H;
R 3＝R 5＝NO 2，R 2＝R 4＝H。
The preparation method of Sinomenine derivate of the present invention is as follows:
Prepare Sinomenine derivate S1-S5, chemical formula by 1 bit aminoization and acylations thereof:
Figure A20081002405100112
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
Connect two molecule tuduranine adductions by 4 hydroxyls or 1 bit amino and prepare Sinomenine derivate S6-S8, chemical formula:
Prepare Sinomenine derivate S9-S14, chemical formula by 3,4 two carbonylations and six-membered heterocycleization:
Figure A20081002405100121
R 3, R 4, R 5, R 6=H, C 1-14Saturated and unsaturated alkyl, F, Cl, Br, I, OH, NH 2, OCH 3, OC 2H 5, NO 2, CN, CF 3, COOCH 3, COPh, COOH, Ph are phenyl.
Prepare Sinomenine derivate S15-S22 by 6 bit aminoizations and acylations thereof, prepare Sinomenine derivate S23-S24, chemical formula by 6,7 aminations simultaneously and six-membered heterocycleization:
Figure A20081002405100122
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
The chemical formula of preparation Sinomenine derivate S25-S26 is as follows, and S27-S31 is middle combination product:
R 1=H or CH 3, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H or CH 3, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H or CH 3, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
The method for preparing Sinomenine derivate S32-S34 comprises: (1): many substrates of microorganisms/enzymes catalysis cross-coupling, (2): Suzuki aryl cross-coupling;
By the preparation of many substrates of microorganisms/enzymes catalysis cross-coupling, its preparation process is as follows:
1) strains separation: specific habitat is taked in the field, and the dilution coating separates selective screening, 0 ℃ of preservation of strain inclined plane; Transform thick enzyme from above-mentioned bacterial strains, the protein separation method of saltouing is adopted in the separation of thick enzyme, and the enzyme of all the other uses is available from Sigma;
2) preparation of bioconversion product: activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product;
3) separation of bioconversion product: adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution;
By the preparation of Suzuki aryl cross-coupling reaction, its preparation process is as follows:
With 1-bromo tuduranine (0.5mmol), aryl boric acid (0.7mmol), Pd (OAc) 2(3mol%), DABCO (6mol%) and K 2CO 3(1.5mmol) mixture of Zu Chenging is suspended among the DMF of 3ml, and 80 ℃ of following stirring reactions after the TLC detection reaction finishes, filter, extraction, drying, post separate product.
Preparation process 1 by many substrates of microorganisms/enzymes catalysis cross-coupling) bioconversion strain or enzyme in comprise: fungal strain Antrodiella semisupina and belong to bacterial strain, monochromatic rainbow conk Coriolus unicolor together and belong to bacterial strain, peroxidase, lipase, laccase, lytic enzyme, cellulase, amylase, proteolytic enzyme together.
The present invention is directed to the tuduranine molecular structure to the heat-labile character of soda acid, propose the structure of modification thinking of novelty, prepared new tuduranine A ring, C ring and D ring Sinomenine derivate by chemosynthesis, the method novelty has uniqueness; Adopt synovial tumor cell (SW982) to estimate its anti-inflammatory activity, biological activity is good, can be applicable in resisting rheumatoid arthritis (RA) medicine and the healthcare products.
Description of drawings
Fig. 1 estimates the test result figure of its anti-inflammatory activity for Sinomenine derivate of the present invention adopts synovial tumor cell (SW982).
Embodiment
Below in conjunction with specific embodiment the present invention is described.
Embodiment 1
Synthesizing of 1,10 nitrogen sulphur hexa-member heterocycle
Figure A20081002405100141
As above-mentioned chemical formula, take by weighing the amino tuduranine 550mg (1.6mmol) of compound 1:1-, (632mg in glacial acetic acid solution 2.4mmol), slowly drips Br after the stirring and dissolving to add 4.0ml KSCN 2(96mg, glacial acetic acid solution 1.5ml 0.6mmol).Stirring at room 24h, ice bath drip 10%NaOH down and carry out cancellation, regulate pH value to 8.0, use CHCl 3Extraction, the organic layer that obtains is washed with saturated aqueous common salt, again by anhydrous Na SO 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 2, productive rate 59%.
Compound 2:
1H?NMR(300MHz，CDCl 3)δppm?8.45(s，1H)，7.35(s，1H)，6.30(s，1H)，5.85(s，1H，OH)，5.50(s，1H)，4.24(d，1H，J＝15.9Hz)，3.82(s，3H)，3.29(m，4H)，3.08(s，1H)，2.56(m，1H)，2.44(s，3H)，2.40(s，1H)，2.07-1.90(m，4H).
13C?NMR(300MHz，CDCl 3)δ192.50，178.92，151.72，146.90，141.90，128.05，120.68，114.55，111.58，95.68，59.90，56.18，54.99，49.09，46.64，45.48，44.69，42.77，40.90，35.80.
Embodiment 2
1 bit amino sulfonylation
Figure A20081002405100151
As above-mentioned chemical formula, take by weighing the amino tuduranine 550mg (1.6mmol) of compound 1:1-, be dissolved in 3ml CH 2Cl 2, drip Et 3N 0.34ml (2.5mmol), ice bath add p-methyl benzene sulfonic chloride 381mg (2.0mmol) down, and ice bath stirs 5h down.Pour 30ml CH into 2Cl 2Middle extraction, organic layer is used anhydrous Na SO again with the saturated aqueous common salt washing 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 3, productive rate 52%.
Compound 3:
1H?NMR(300MHz，CDCl 3)δppm?7.58(d，2H，J＝6.6Hz)，7.25(d，2H，J＝6.6Hz)，6.39(s，1H)，5.85(s，1H，OH)，5.39(s，1H)，4.30(d，1H，J＝15.9Hz)，3.85(s，1H)，3.62(s，3H)，3.47(s，3H)，3.20(brd，1H)，3.01(brd，1H)，2.78(m，1H)，2.59-2.44(brd，1H)，2.40(s，3H)，2.36(s，1H)，2.19(brd，3H)，2.03-1.82(m，4H).
13C?NMR(300MHz，CDCl 3)δ193.50，152.66，144.80，143.81，129.80，129.71，127.41，126.98，126.90，123.93，114.09，108.15，63.20，60.93，56.18，55.89，54.89，48.92，46.71，42.22，40.46，35.43.
Embodiment 3
1 bit amino acylation reaction
As above-mentioned chemical formula, take by weighing the amino tuduranine 550mg (1.6mmol) of compound 1:1-, be dissolved in 3ml CH 2Cl 2, drip Et 3N 0.34ml (2.5mmol), ice bath add Benzoyl chloride 313mg (2.0mmol) down, and ice bath stirs 5h down.Pour 30ml CH into 2Cl 2Middle extraction, organic layer is washed with saturated aqueous common salt, uses anhydrous Na SO again 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 4, productive rate 73%.
Compound 4:
1H?NMR(300MHz，CDCl 3)δppm?7.95(d，2H，J＝7.2Hz)，7.54(d，1H，J＝9.3Hz)，7.53(dd，2H，J＝7.2，9.3Hz)，6.93(s，1H)，5.49(s，1H)，4.39(s，1H，J＝15.9Hz)，3.82(s，3H)，3.61(brd，1H)，3.51(s，3H)，3.40(brd，1H)，3.10-2.90(m，4H)，2.65(s，3H)，2.55-2.48(m，2H)，2.21-2.05(m，2H).
13C?NMR(300MHz，CDCl 3)δ193.63，152.68，145.79，143.77，134.17，132.14，128.80，127.45，126.03，123.55，121.34，113.03，108.84，57.38，56.20，55.07，49.97，49.70，49.41，49.13，48.01，47.56，43.15，41.54，39.69，33.83.
Embodiment 4
Form two molecule tuduranine adductss by 4-OH
Take by weighing tuduranine (sinomenine) 329mg (1mmol), be dissolved in 25ml CH 2Cl 2, drip Et 3N 1.1ml (8mmol), ice bath add glutaryl chlorine 169mg (1mmol) down, and ice bath stirs 5h down.Pour 30ml CH into 2Cl 2Middle extraction, organic layer is washed with saturated aqueous common salt, anhydrous Na SO 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=15: 1), get respective compound 5, productive rate 72%.
Compound 5:
1H?NMR(300MHz，CDCl 3)δppm?6.91(d，1H，J＝9Hz)，6.76(d，1H，J＝9Hz)，5.44(s，1H)，5.28(s，1H，OH)，3.82(d，1H，J＝15Hz)，3.74(s，3H)，3.46(s，3H)，3.27(s，1H)，3.10-3.01(m，2H)，2.89-2.70(m，3H)，2.6(d，1H，J＝12Hz)，2.54(s，1H)，2.47(s，3H)，2.18(td，1H，J＝6，12Hz)，2.24-2.13(m，1H)，1.95(td，1H，J＝6，12Hz)，1.6(d，1H，J＝12Hz).
13C?NMR(300MHz，CDCl 3)δ192.18，172.14，152.56，149.98，139.59，129.73，129.03，125.59，114.34，110.98，56.73，56.02，54.97，49.92，46.88，45.36，42.53，40.46，36.80，33.29，24.35，20.18.
Embodiment 5
6 bit amino sulfonylations
Figure A20081002405100171
As above-mentioned chemical formula, take by weighing compound 6:6-amino-7,8 dihydro tuduranine 260mg (0.78mmol), be dissolved in 20ml CH 2Cl 2, drip Et 3N 0.16ml (1.17mmol), ice bath add Tosyl chloride 179mg (0.94mmol) down, and ice bath stirs 6h down.Pour 30ml CH into 2Cl 2Middle extraction, organic layer is washed with saturated aqueous common salt, anhydrous Na SO 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 7, productive rate 98%.
Compound 7:
1H?NMR(300MHz，CDCl 3)δppm?7.62(d，2H，J＝6.0Hz)，7.23(d，2H，J＝6.0Hz)，6.71(d，1H，J＝9.0Hz)，6.60(d，1H，J＝9.0Hz)，4.11(d，1H，J＝9.0Hz)，3.86(brd，1H)，3.84(s，3H)，3.77(dd，1H，J＝3.0，15.0Hz)，3.27(s，1H)，3.20(dd，1H，J＝3.0，12.0Hz)，2.92(s，3H)，2.86(s，1H)，2.77-2.67(m，1H)，2.48-2.39(m，1H)，2.36(s，3H)，2.34(s，3H)，1.97(dt，1H，J＝6.0，12.0Hz)，1.81(dt，1H，J＝6.0，12.0Hz)，1.59-1.47(m，2H)，1.37(d，1H，J＝12.0Hz)，1.28(d，1H，J＝12.0Hz).
13C?NMR(300MHz，CDCl 3)δ145.21，144.63，142.60，138.86，129.52，129.16，127.03，126.96，124.13，119.34，109.91，79.13，57.41，56.52，55.85，51.03，47.28，44.12，42.29，37.50，37.32，35.20，32.50，28.79，23.86，21.52.
Embodiment 6
6 bit amino acylation reactions
Figure A20081002405100181
As above-mentioned chemical formula, take by weighing compound 6:6-amino-7,8 dihydro tuduranine 150mg (0.45mmol), be dissolved in 10ml CH 2Cl 2, drip Et 3N 0.1ml (0.68mmol), ice bath add Benzoyl chloride 62 μ L (0.54mmol) down, and ice bath stirs 6h down.Pour 30ml CH into 2Cl 2Middle extraction, organic layer is washed with saturated aqueous common salt, anhydrous Na SO 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 8, productive rate 90%.
Compound 8:
1H?NMR(300MHz，CDCl 3)δppm?7.62-7.24(m，5H)，6.76(d，1H，J＝9.0Hz)，6.67(d，1H，J＝9.0Hz)，5.92(d，1H，J＝9.0Hz)，4.94-4.90(m，1H)，4.03(dd，1H，J＝3.0，15.0Hz)，3.59-3.53(m，1H)，3.51(s，1H)，3.38(s，1H)，3.07-2.85(m，3H)，2.58-2.53(m，1H)，2.45(s，3H)，2.10-1.95(m，3H)，1.98(d，1H，J＝12.0Hz)，1.67-1.58(m，2H)，1.43(dd，1H，J＝15.0，3.0Hz)，1.31(t，1H，J＝6.0Hz).
13C?NMR(300MHz，CDCl 3)δ166.51，144.90，144.87，134.47，130.98，130.31，127.99(2C)，126.89(2C)，125.07，119.26，108.66，78.86，57.50，56.12，55.57，47.44，46.13，44.50，42.56，37.88，36.82，35.60，29.75，24.05.
Embodiment 7
6 hydroxyl reduction
Take by weighing tuduranine (sinomenine) 3.6g and be dissolved in 30ml methyl alcohol, slowly add 10g NaBH under the ice bath in batches 4, reaction 24h, ice bath drips the acetone termination reaction down, and concentrating under reduced pressure becomes solid, adds rare HCl dissolving, and strong aqua is regulated pH value to 9.0, uses CH 2Cl 2(50ml) carry out 3 extractions, organic layer is washed with saturated aqueous common salt, anhydrous Na SO 4Drying, concentrating under reduced pressure, silicagel column separates (CH 3Cl: CH 3OH=15: 1), get compound 9, productive rate 55%, and compound 10, productive rate 30%.
Compound 9:
1H?NMR(300MHz，CDCl 3)δppm?6.65(s，1H，J＝9.0Hz)，6.57(s，1H，J＝9.0Hz)，5.29(s，1H，OH)，4.49(s，1H)，4.17(d，1H，J＝6.0Hz)，3.80(s，3H)，3.68(d，1H，J＝15.0Hz)，3.48(s，3H)，3.03(s，1H)，2.90(d，1H，J＝18.0Hz)，2.75(dd，1H，J＝6.0，18.0Hz)，2.50(brd，2H)，2.40(s，3H)，2.01(td，1H，J＝3.0，12.0Hz)，1.89(d，1H，J＝12.0Hz)，1.72(dd，1H，J＝3.0，15.0Hz)，1.63(dd，1H，J＝6.0，15.0Hz).
13C?NMR(300MHz，CDCl 3)δ156.68，144.87，144.44，131.32，125.28，119.04，108.90，97.23，66.95，57.94，56.19，54.47，48.10，45.36，42.78，40.07，36.68，34.40，24.61.
Compound 10:
1H?NMR(300MHz，CDCl 3)δppm?6.62(d，1H，J＝9.0Hz)，6.53(d，1H，J＝9.0Hz)，4.39(s，1H)，4.20-4.26(m，1H)，3.83(s，3H)，3.66(dd，1H，J＝6.0，12.0Hz)，3.44(s，3H)，3.01(s，1H)，2.89(d，1H，J＝12.0Hz)，2.75-2.67(m，2H)，2.53(d，1H，J＝3.0Hz)，2.41(s，3H)，2.06(td，1H，J＝3.0，12.0Hz)，1.82-1.74(m，2H)，1.59(t，1H，J＝12.0Hz).
13C?NMR(300MHz，CDCl 3)δ156.53，144.63(2C)，131.47，124.52，118.21，108.21，96.62，66.95，57.46，56.21，54.48，47.86，45.36，42.84，41.13，37.42，36.05，24.13.
Embodiment 8
1 on tuduranine A ring is connected to form Sinomenine derivate with C-C or C-O mode:
Figure A20081002405100191
Adopt the common micro-organisms separation method from specific habitat, to separate and obtain tuduranine (sinomenine) conversion bacterial strain mould Antrodiella semisupina.Activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate methyl catechol of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value to 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product, and adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution.Separate compound 11, productive rate 13%, and compound 12, productive rate 5%.
Compound 11:
1H?NMR(300MHz，CDCl 3)δppm?6.94(d，1H，J＝8.4Hz)，6.68(brs，1H)，6.67(dd，1H，J＝8.4，1.8Hz)，6.56(s，1H)，5.46(d，1H，J＝1.9Hz)，4.42(d，1H，J＝15.6Hz)，3.89(s，1H)，3.80(s，3H)，3.52(s，3H)，3.12(brt，J＝4.0Hz)，3.01(dd，1H，J＝4.0，1.9Hz)，2.75(brd，1H，J＝18.6Hz)，2.75(dd，1H，J＝18.6，4.0Hz)，2.57(ddd，1H，J＝12.2，4.4，1.5Hz)，2.49(d，1H，J＝15.6Hz)，2.31(s，3H)，2.10(td，J＝12.2，3.2Hz)，2.02(dt，1H，J＝12.4，3.2Hz)，1.89(td，1H，J＝12.4，4.4Hz).
13C?NMR(300MHz，CDCl 3)δ194.2，152.3，143.8，146.3，144.6，144.5，134.3，131.8，127.7，122.5，121.9，115.2，114.3，111.7，111.0，56.6，56.0，55.9，54.9，49.1，47.4，45.6，43.8，40.8，35.8，23.4.
Compound 12:
1H?NMR(300MHz，CDCl 3)δppm?7.00-6.96(overlapped，2H)，6.75(m，1H)，6.44(s，1H)，6.36(dd，1H，J＝8.5，1.1Hz)，5.39(d，1H，J＝1.8Hz)，4.37(d，1H，J＝15.7Hz)，3.95(s，3H)，3.73(s，3H)，3.49(s，3H)，3.19(brt，1H，J＝5.8Hz)，3.03(brd，1H，J＝5.8Hz)，3.00(d，1H，J＝18.5Hz)，2.58(ddd，1H，J＝12.0，4.4，1.8Hz)，2.47(d，1H，J＝15.7Hz)，2.36(s，3H)，2.36(dd，1H，J＝18.5，5.8Hz)，2.14(td，1H，J＝12.0，3.4Hz)，2.00(dt，1H，J＝12.4，3.4Hz)，1.93(td，1H，J＝12.4，4.4Hz).
13C?NMR(300MHz，CDCl 3)δ193.7，152.4，149.1，147.5(2C)，141.7，144.1，122.3，120.7，114.8，114.6，123.4，122.5，112.2，103.1，56.1，56.0，55.8，54.8，49.0，47.0，45.6，42.7，40.4，35.6，18.5.
Embodiment 9
Tuduranine A encircles 1 Sinomenine derivate that is connected to form in the C-C mode:
Figure A20081002405100201
Adopt the common micro-organisms separation method from specific habitat, to separate and obtain tuduranine (sinomenine) conversion bacterial strain mould Coriolus unicolor.Activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate pyrocatechol of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value to 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product, and adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution.Separate compound 13, productive rate 15%.
Compound 13:
1H?NMR(300MHz，CDCl 3)δppm?6.81(d，1H，J＝9.0Hz)，6.61(s，1H)，6.52(s，1H)，6.48(d，1H，J＝9.0Hz)，5.43(s，1H)，4.37(d，1H，J＝15.0Hz)，3.74(s，3H)，3.47(s，3H)，3.38(brd，1H)，2.75-2.53(m，3H)，2.45(d，1H，J＝15.0Hz)，2.34(s，3H)，2.21-2.13(m，1H，)，2.02-1.89(m，3H).
13C?NMR(300MHz，CDCl 3)δ194.53，152.41，144.97，144.28，143.76，143.58，133.97，132.26，126.06，121.53，120.83，116.11，115.09，114.58，111.53，56.96，56.00，54.96，47.52，44.24，42.05，40.40，34.64，29.72，23.81.
Embodiment 10
Form two molecule tuduranine adductss by 4 hydroxyls:
Figure A20081002405100211
Take by weighing tuduranine (sinomenine) 1.5g (4.56mmol), be dissolved in 20ml EtOH, add K 2CO 33.15g (22.8mmol), drip 1,3-dibromopropane 232 μ L (2.28mmol), backflow 5h.After reacting completely, regulate pH value to 3, stir 10min, use dense NH again with rare HCl 4OH regulates pH value to 8～9, and methylene dichloride repeatedly extracts, combined dichloromethane extraction liquid, anhydrous Na SO 4Drying, the rotation solvent evaporated, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 14, productive rate 53%.
Compound 14:
1H?NMR(300MHz，CDCl 3)δppm?6.99-6.66(m，2H)，5.46(s，1H)，4.35-4.14(m，3H)，3.78(s，3H)，3.47(s，3H)，3.16-3.14(m，1H)，2.95-2.76(m，2H)，2.72(dd，1H，J＝6.0，12.0Hz)，2.53-2.45(m，3H)，2.41(s，3H)，2.07-1.87(m，4H).
13C?NMR(300MHz，CDCl 3)δ193.71，152.57，151.53，148.26，130.02，129.98，122.54，115.28，111.54，69.69，56.68，55.90，54.89，50.01，47.26，46.18，42.83，40.91，37.46，31.55，24.65.
Embodiment 11
Terminal amino group after the open loop of tuduranine D ring is transformed:
Figure A20081002405100221
Take by weighing tuduranine (sinomenine) 1.5g (4.56mmol), be dissolved in the 200ml 15%NaOH solution, boil 8min, the flowing water cooling is regulated pH value to 4 with dense HCl, filters again, and filtrate is used dense NH 4OH makes the pH value be adjusted to 8, repeatedly extracts with methylene dichloride, and the combined dichloromethane extraction liquid is used anhydrous Na SO 4Drying, the rotation solvent evaporated, silicagel column separates (CH 3Cl: CH 3OH=9: 1), get respective compound 15, productive rate 33%.
Compound 15:
1H?NMR(300MHz，CDCl 3)δppm?6.73(d，1H，J＝9.0Hz)，6.66(d，1H，J＝9.0Hz)，6.0(s，1H)，5.76(s，1H)，4.23(dd，1H，J＝18.0Hz)，3.86(s，3H)，3.70(s，3H)，3.17-3.11(m，2H)，2.97(s，1H)，2.84(dd，1H，J＝6.0，18.0Hz)，2.66(d，1H，J＝18.0Hz)，2.42(dd，1H，J＝3.0，12.0Hz)，2.36(s，3H)，2.19(dt，1H，J＝12.0，12.0，3.0Hz)，2.06(dt，1H，J＝12.0，12.0，3.0Hz)，1.56(dd，1H，J＝12.0Hz)
13C?NMR(300MHz，CDCl 3)δ194.84，151.21，144.79，143.85，130.67，127.08，119.80，118.77，109.07，58.10，56.29，54.97，48.37，47.26，43.30，42.09，38.28，28.25，27.59.
Embodiment 12
By Suzuki aryl cross-coupling reaction, preparation encircles 1 Sinomenine derivate S32-S34 that is connected to form with C-C or C-O mode at tuduranine A:
Figure A20081002405100231
R 1=Cl, Br, OMe, CO 2Me, CHO, CH 2CO 2CH 4, CH 2CN, NHCOCF 3, CH 3, COPh, NH 2, CN, CF 3, CH (OH) COOH etc.;
R 2=R 3=OH, NH 2, NO 2, perhaps R 2=OH, R 3=OCH 3, NO 2, Cl, Br, CH 3Deng, R 4=R 5=H;
R 3＝R 5＝NO 2，R 2＝R 4＝H
Its preparation process is as follows:
1-bromo tuduranine (0.5mmol), aryl boric acid (0.7mmol), Pd (OAc) 2(3mol%), DABCO (6mol%) and K 2CO 3(1.5mmol) mixture of Zu Chenging is suspended among the dimethyl formamide DMF of 3ml, and 80 ℃ of following stirring reactions after the TLC detection reaction finishes, filter, extraction, drying, post separate product.
Embodiment 13
The anti-inflammatory action of Sinomenine derivate: get synovial tumor cell SW982 and cultivate culture density 1 * 10 in 24 porose discs 4/ hole, (final concentration is 10% foetal calf serum with the perfect medium CGM of L-15 behind the 24h, the penicillin of 100U/ml and Streptomycin sulphate, the L-glutamine of 2mM, pH=7.40) displacement nutrient solution, replace foetal calf serum (FBS) with 0.2% bovine serum albumin (BSA) among the CGM, again behind the 24h, substratum displacement nutrient solution with 1ng/ml 1L-1 β, substratum contains 0.2% BSA and final concentration and is respectively 200 μ mol/L, 100 μ mol/L, the testing drug of 50 μ mol/L, Sinomenine derivate promptly of the present invention; After continuing to cultivate 48h, get cell conditioned medium liquid, detect, the results are shown in Figure 1 with Human IL-6 test kit.
As can be seen from Figure 1, compound 13,14 under three kinds of concentration all pair cell inflammatory factor IL-6 show strong restraining effect, compound 11 has shown certain restraining effect under three kinds of concentration, compound 5,7,8 under high density (200 μ M) IL-6 is had certain restraining effect, and chemical combination 3 (50 μ M) under lower concentration has certain restraining effect, and 15 of compounds under intermediate concentration (100 μ M) have restraining effect to IL-6.Other compounds have strong promoter action as 4,6 couples of IL-6, and compound 10,12 also has certain promoter action.Compound 9 restraining effect maintain an equal level with tuduranine basically.
The organic solvent that uses in the embodiment of the invention includes but not limited to methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the trimethyl carbinol, Pentyl alcohol, primary isoamyl alcohol, hexalin, Bian alcohol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ether, tetrahydrofuran (THF), benzene,toluene,xylene, acetone, butanone, second cyanogen, N, dinethylformamide, ethyl acetate etc.

Claims (9)

1, Sinomenine derivate, the tuduranine structural formula is as follows:
Figure A20081002405100021
It is characterized in that after tuduranine A ring, C ring and D ring are by chemosynthesis, obtaining Sinomenine derivate, comprising:
1) obtain the amino substituent Sinomenine derivate S1-S5 of connection by restore nitrification at 1:
Figure A20081002405100022
2) or the two molecule tuduranine adducts S6-S8 that form by 4 hydroxyls or 1 bit amino:
Figure A20081002405100023
3) or at 3,4 Sinomenine derivate S9-S14 that are connected with the pyrazine ring:
Figure A20081002405100024
4) or at 6 connect substituent Sinomenine derivate S15-S22 by amino/hydroxyl:
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng
5) or at 6,7 pass through the amino disinomenine molecule derivant S23-S24 that form the pyrazine ring:
Figure A20081002405100032
6) or the derivative S25-S26 that terminal amino group after the open loop of tuduranine D ring is transformed:
Figure A20081002405100033
R 1=H or CH 3, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H or CH 3, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H or CH 3, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
7) or at tuduranine A encircle 1 Sinomenine derivate S32-S34 that is connected to form with C-C or C-O mode:
Figure A20081002405100041
R 1=Cl, Br, OMe, CO 2Me, CHO, CH 2CO 2CH 4, CH 2CN, NHCOCF 3, CH 3, COPh, NH 2, CN, CF 3, CH (OH) COOH etc.;
R 2=R 3=OH, NH 2, NO 2, perhaps R 2=OH, R 3=OCH 3, NO 2, Cl, Br, CH 3Deng, R 4=R 5=H;
R 3＝R 5＝NO 2，R 2＝R 4＝H。
2,, the preparation method of Sinomenine derivate according to claim 1, it is characterized in that preparing Sinomenine derivate S1-S5 by 1 bit aminoization and acylations thereof, chemical formula is as follows:
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
3, the preparation method of Sinomenine derivate according to claim 1 is characterized in that connecting two molecule tuduranine adductions by 4 hydroxyls or 1 bit amino prepares Sinomenine derivate S6-S8, and chemical formula is as follows:
Figure A20081002405100043
4, the preparation method of Sinomenine derivate according to claim 1 is characterized in that preparing Sinomenine derivate S9-S14 by 3,4 two carbonylations and six-membered heterocycleization, and chemical formula is as follows:
Figure A20081002405100051
R 3, R 4, R 5, R 6=H, C 1-14Saturated and unsaturated alkyl, F, Cl, Br, I, OH, NH 2, OCH 3, OC 2H 5, NO 2, CN, CF 3, COOCH 3, COPh, COOH, Ph are phenyl.
5, the preparation method of Sinomenine derivate according to claim 1; it is characterized in that preparing Sinomenine derivate S15-S22 by 6 bit aminoizations and acylations thereof; prepare Sinomenine derivate S23-S24 by 6,7 aminations simultaneously and six-membered heterocycleization, chemical formula is as follows:
Figure A20081002405100052
R 1=H, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
6, the preparation method of Sinomenine derivate according to claim 1, the chemical formula that it is characterized in that preparing Sinomenine derivate S25-S26 is as follows, and S27-S31 is middle combination product:
Figure A20081002405100061
R 1=H or CH 3, R 2=SO 2R 3R wherein 3=CH 3Ph; 2-OH-3,5-Cl 2C 6H 22,4-Cl 2-5-COOHC 6H 2Deng.
Perhaps
R 1=H or CH 3, R 2=COR 3R wherein 3=Ph; 4-Cl-C 6H 43,4-Cl 2-C 6H 34-CH 3-C 6H 44-OCH 3-C 6H 4Deng.
Perhaps
R 1=H or CH 3, R 2=-COC (R 3) NHR 4R wherein 3=CH 3, PhCH 2, (CH 3) 2CHCH 2CH 3SCH 2CH 2Deng, R 4=H; SO 2Ph; CONHC 6H 5Deng.
7, the preparation method of Sinomenine derivate according to claim 1 is characterized in that the method for preparing Sinomenine derivate S32-S34 comprises: many substrates of (1) microorganisms/enzymes catalysis cross-coupling, (2) Suzuki aryl cross-coupling;
By the preparation of many substrates of microorganisms/enzymes catalysis cross-coupling, its preparation process is as follows:
1) strains separation: specific habitat is taked in the field, and the dilution coating separates selective screening, 0 ℃ of preservation of strain inclined plane;
Transform thick enzyme from above-mentioned bacterial strains, the protein separation method of saltouing is adopted in the separation of thick enzyme, and the enzyme of all the other uses is available from Sigma;
2) preparation of bioconversion product: activate 7 days slant strains, be transferred in the fermention medium, at 25 ℃, cultivated 4 days on the shaking table of 150r/min, add the tuduranine hydrochloride, final concentration≤400 μ g/ml, similarity condition continues to cultivate second kind of substrate of adding after 1 day down, final concentration≤400 μ g/ml, the same terms continue down to cultivate 4 days, stop to cultivate; With filtering fermentation liquor, filtrate is used NH 4OH regulates pH value 8～9, repeatedly extracts combined dichloromethane extraction liquid, anhydrous Na SO with methylene dichloride 4Drying is filtered, and the rotation solvent evaporated gets converted product;
3) separation of bioconversion product: adopting the chromatography column of filling is silicagel column, and chromatographic solution is 100: 0～50: 50V/V chloroform-methanol mixed solution;
By the preparation of Suzuki aryl cross-coupling reaction, its preparation process is as follows:
1-bromo tuduranine (0.5mmol), aryl boric acid (0.7mmol), Pd (OAc) 2(3mol%), DABCO (6mol%) and K 2CO 3(1.5mmol) mixture of Zu Chenging is suspended among the dimethyl formamide DMF of 3ml, and 80 ℃ of following stirring reactions after the TLC detection reaction finishes, filter, extraction, drying, post separate product.
8, the preparation method of Sinomenine derivate according to claim 7 is characterized in that the preparation process 1 by many substrates of microorganisms/enzymes catalysis cross-coupling) in bioconversion strain or enzyme comprise: fungal strain Antrodiellasemisupina and belong to bacterial strain, monochromatic rainbow conk Coriolus unicolor together and belong to bacterial strain, peroxidase, lipase, laccase, lytic enzyme, cellulase, amylase, proteolytic enzyme together.
9, the described Sinomenine derivate of claim 1 is in the anti-inflammatory drug of preparation rheumatoid arthritis and the application in the healthcare products.
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CN108863932A (en) * 2018-06-08 2018-11-23 无锡市太湖医院 Sinomenine derivate, its esters and its preparation method and application
CN108863932B (en) * 2018-06-08 2022-01-11 无锡市太湖医院 Sinomenine derivative, its salt, preparation method and application thereof
CN113880764A (en) * 2020-07-01 2022-01-04 北京师范大学 Sinomenine derivative and preparation method and application thereof
CN113880764B (en) * 2020-07-01 2023-04-18 北京师范大学 Sinomenine derivative and preparation method and application thereof

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