CN103232467A - Kukoline structurally-reconstructed compound and preparation method thereof - Google Patents
Kukoline structurally-reconstructed compound and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kukoline structurally-reconstructed compound and a preparation method thereof. The kukoline structurally-reconstructed compound takes kukoline as a parent substance, and is a derivative which is prepared through a chemical synthesis method and contains new substituent groups on A, C and D rings or C and D rings. The kukoline structurally-reconstructed compound disclosed by the invention has certain activity in drug effect experiments on anti-inflammation, immunization, analgesia, anaphylactic reaction and the like.
Description
Patent application of the present invention is for dividing an application, and the original bill application number is 200710111253.6, and the applying date is on June 19th, 2007, and denomination of invention is a kind of Sinomenine structure-modified compound and preparation method thereof.
Technical field
The present invention relates to a kind of compound and preparation method thereof, particularly a kind of Sinomenine structure-modified compound and preparation method thereof.
Background technology
Tuduranine is the most effective treatment rheumatism extracted from the Stem of Orientoine plant and the alkaloids medicament of rheumatoid arthritis disease, has significant analgesia, calmness, anti-inflammatory, immunosuppression, effect such as hypotensive.It can act on the central nervous system endocrine system of unifying, and by two-ways regulation, improves immunity and anti-inflammatory mechanisms, eliminates paathogenic factor in the body, the repair tissue damage.If the sinomenium acutum alkali salt drug main of widespread use now is bulk drug with the sinomenine hydrochloride, make various types of tablets, capsule, injection liquid etc.In the medication process, find to have only a few patient appearance untoward reaction to a certain degree, as muscle redness, itch etc.The present invention is intended to develop the Sinomenine structure-modified new compound than curative effect and the more excellent performance of sinomenine hydrochloride or blue or green Teng alkali.
Summary of the invention
First purpose of the present invention is to disclose a kind of compound; Second purpose of the present invention is to disclose the preparation method of this compound; The 3rd purpose of the present invention is to disclose the new pharmaceutical use of this compound.
The present invention seeks to be achieved through the following technical solutions:
Sinomenine structure-modified compound of the present invention is to be parent with the tuduranine, be prepared from by chemical synthesis process, comprise upward new substituting group derivative of each ring, for example: a class A encircles the new substituent Sinomenine derivate of connection, class C ring connects new substituent Sinomenine derivate or a class D ring or C, D and encircles the new substituent Sinomenine derivate of connection.
The chemical structural formula of described tuduranine parent is:
Above-mentioned class A ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
Above-mentioned class C ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
An above-mentioned class D ring or C, D ring connect new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
The preparation method of all kinds of Sinomenine structure-modified compounds of the present invention is: in the organic solvent of water or 2000-3000 milliliter/mole, under room temperature-reflux conditions, tuduranine and reagent reacted 1-48 hour with the ratio of 1:1.0-2.0, product separates with the method for recrystallization or the method that uses column chromatography is separated, and obtains Sinomenine structure-modified compound.
The preparation method of all kinds of Sinomenine structure-modified compounds of the present invention is preferably: in the organic solvent of water or 2500 milliliters/mole, under room temperature-reflux conditions, tuduranine and reagent reacted 24 hours with the ratio of 1:1.5, product separates with the method for recrystallization or the method that uses column chromatography is separated, and obtains Sinomenine structure-modified compound.
Organic solvent of the present invention includes but not limited to methyl alcohol, ethanol, propyl alcohol, butanols, Virahol, the trimethyl carbinol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ethyl acetate, ether, tetrahydrofuran (THF), 1,4-dioxy six alkane, benzene, toluene, acetone, second cyanogen, methyl-sulphoxide or N, dinethylformamide.
Reagent of the present invention can be selected conventional reagent for use according to the constructional feature of compound.
Sinomenine structure-modified compound of the present invention is for the preparation of anti-inflammatory, analgesia, calmness or immunoregulatory medicine.
Sinomenine structure-modified compound of the present invention confirms through pharmacodynamics test: have analgesia, calmness, anti-inflammatory and the immunosuppressive action similar to sinomenine hydrochloride or blue or green Teng alkali, Sinomenine structure-modified compound has toxicity and the more significant drug action lower than tuduranine.Sinomenine structure-modified compound building-up reactions method of the present invention is simple, reaction conditions is gentle, easy operation, suitable industrial production.
Following experiment and embodiment are used for further specifying but are not limited to the present invention.
1 pair of mouse ear of experimental example Oleum Tiglii inhibition of inflammation
To mouselet subcutaneous injection Sinos 50mg/kg, left ear is coated with 2% crotons fluid 50ul and causes inflammation behind the 0.5h, and auricle under the 4h backlash is weighed, about two auricle weight differences be the swelling degree, represent anti-inflammatory action intensity with inhibitory rate of intumesce, the results are shown in Table 1.
The mouse of table 1 Sinos ear Oleum Tiglii inhibition of inflammation
In 40 compounds of experiment, there are 12 new compounds that mouse ear Oleum Tiglii inflammation is had stronger restraining effect, wherein the strongest with Sino-14, Sino-30, Sino-23, Sino-31 takes second place.
The restraining effect of 2 pairs of rat carrageenan foot swellings of experimental example
To big rat subcutaneous injection Sinos50mg/kg, 0.5h the carrageenin 100ul of the left back sufficient stone intradermal injection 1% in back causes inflammation, measures a Guo joint girth, continuous 6 hours every 1h later on, with about Guo joint, back girth difference be the swelling degree, inhibitory rate of intumesce is represented anti-inflammatory action intensity.The results are shown in Table-2
The restraining effect of the rat carrageenan foot swelling of table 2Sinos
The result shows: compound S ino-14, and 26,29,25 pairs of rat carrageenan foot swellings have stronger restraining effect, Sino-14 wherein, 26 is more remarkable than Sino-0 effect.
Experimental example 3 analgesic activities
Mouse subcutaneous injection Sinos50 or 25mg/kg, 0.5h pneumoretroperitoneum is injected 7% acetic acid 10ml/kg, observe and record mouselet immediately and turn round for the first time in body time (turn round body latent period) and the 15min and turn round the body number of times, with the prolongation of latency rate with turn round the analgesic activities that body number of times decrement is represented compound.The results are shown in Table 3
The rat analgesic activity of table 3Sinos
The result shows: 18 new compounds listing in the above-mentioned table all have certain effect to rat analgesia, compound S ino-28, and 25,14,30 analgesic activity is stronger, Sino-28 wherein, 25,14 is more remarkable than Sino-0 effect.
4 pairs of rat abdominal cavity mast cell degranulations of experimental example
Get big rat abdominal cavity white corpuscle, add Sinos, final concentration is 10-5mol/L, 37 ℃ of 2min, and toluylene red dyeing is observed under the mirror and numeration mast cell degranulation percentage, represents to take off granule strength partly to take off particle and to take off particle percentage sum entirely.The results are shown in Table 4.
Table-4Sinos, to the rat abdominal cavity mast cell degranulation,
The result shows: 30 new compounds going up in the table all have certain effect to the rat abdominal cavity mast cell degranulation, compound S ino-31, and 46,3,33 mast cell degranulation is stronger, and wherein Sino-33 is more remarkable than Sino-0 effect.
5 pairs of sensitization big rats of experimental example abdominal cavity mastocyte discharges the influence of histamine
Big rat is with variola powder antiserum(antisera) sensitization, get the abdominal cavity mastocyte, adjusting concentration is 106 cells/mL, get enchylema 0.1mL, add testing compound (final concentration 10-5mol/L) and Snakegourd Root liquid, cumulative volume 1mL, cultivate 10min for 37 ℃, discharge histamine successively with alkali-propyl carbinol and acid extraction purifying, o-phthalaldehyde(OPA) derivatize, measure fluorescence intensity (excitation wavelength 355nm, emission wavelength 440nm), reflect the histamine release level with this, calculate the percentage that the testing compound fluorescence intensity accounts for full threshing pipe fluorescence intensity, judge that testing compound discharges the influence of histamine to mastocyte, and discharge the histamine degree with Sinos and compare, the results are shown in Table-5
The sensitization big rat of table-5 Sinos abdominal cavity mastocyte discharges the influence of histamine
The result shows: 11 new compounds going up in the table all have certain effect to the effect that sensitization big rat abdominal cavity mastocyte discharges histamine, and the mast cell degranulation of compound S ino-28 is stronger, and wherein Sino-28 is more remarkable than Sino-0 effect.
6 pairs of big rat splenocytes of experimental example discharge the influence of IL-2
Get the big rat splenocyte, remove red corpuscle, regulating cell concn is 5 * 10
6/ ml gets 1 milliliter in enchylema, and (final concentration is 10 to add ConA10ul (final concentration is 10ul/ml) and testing compound
-5Mol/L) cultivated 24 hours for 37 ℃, survey IL-2 level in the supernatant.The results are shown in Table-6:
Show the influence that-6 pairs of big rat splenocytes discharge IL-2
The result shows: 4 new compounds going up in the table all have certain effect to the influence that the big rat splenocyte discharges IL-2, compound S ino-34, and 26,14,30 effects are stronger, Sino-26 wherein, 30 is more remarkable than Sino-0 effect.
Following embodiment all can realize the effect of above-mentioned experimental example
Embodiment
Embodiment 1:
The Sino-14 compound is prepared by following method:
The protection of A, phenolic hydroxyl group: take by weighing the 10mmol tuduranine; join in 250 milliliter of three neck round-bottomed flask; add KOH10% ethanol (containing KOH11mmol); add 150 milliliters of ethanol again and make solvent, heating is stirred simultaneously; reaction is 30 minutes under the reflux conditions; drip the 20mmol chloromethyl ether, after adding, under refluxad reacted again 2 hours; follow the tracks of with thin-layer chromatography in the reaction process; reaction in about 2 hours is finished, and stops heating, cooling; in the flask in material impouring 150 ml waters; divide 3 extractions with 150 milliliters of chloroforms, merge the chloroformic solution of extraction, with anhydrous Na
2SO
4Drying, the evaporating solvent chloroform gets solid mixture to doing, and by column chromatography for separation, with the hexanaphthene of 8:1 volume ratio: ethyl acetate is developping agent, and the rare bismuth potassium iodide of developer gets tuduranine protection product 3.35 grams, yield 90%, fusing point 92-93 ℃;
B; formylation reaction: measure 1 milliliter of POCl3 and join in 100 milliliter of three neck round-bottomed flask; flask places ice bath to be cooled to 0 ℃, slowly splashes into 10 milliliters of DMF, and the recession deicing was bathed in 10 minutes; under drying conditions, stirred 30 minutes; add 40 milliliters of DMF solvents again, take by weighing 10mmol tuduranine protection product, join in the flask; stir simultaneously; react more violent, heat release was reacted 4 hours under 60 ℃ of conditions then; follow the tracks of with thin-layer chromatography in the reaction process; reaction in about 4 hours is finished, and stops heating, cooling; in the flask in 150 milliliters of 2N sodium acetate solns of material impouring; divide 3 extractions with 150 milliliters of chloroforms, merge the chloroformic solution of extraction, with anhydrous Na
2SO
4Drying, the evaporating solvent chloroform gets solid mixture to doing, by column chromatography for separation, with the hexanaphthene of 8:1 volume ratio: ethyl acetate is developping agent, the rare bismuth potassium iodide of developer, get tuduranine formylation product 3.08 grams of hydroxyl protection, yield 77%., fusing point 114-116 ℃;
C, deprotection reaction: the tuduranine formylation product that takes by weighing the 10mmol hydroxyl protection; join in 250 milliliter of three neck round-bottomed flask; the methyl alcohol that adds the 3:1 volume ratio: 150 milliliters of methylene dichloride mixed solvents; add 10 milliliters of concentrated hydrochloric acids again; stirring reaction is 24 hours at ambient temperature; follow the tracks of with thin-layer chromatography in the reaction process; reaction in about 24 hours is finished; in the flask in material impouring 150 ml waters; being neutralized to pH value with 1moL/LNaOH solution is 9-10, filters solid product, and filtrate is divided 3 extractions with 150 milliliters of chloroforms; the chloroformic solution that merges extraction is with anhydrous Na
2SO
4Drying, the evaporating solvent chloroform gets solid mixture to doing, and by column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, and the rare bismuth potassium iodide of developer gets Sino-14 compound products 2.28 grams, yield 64%. fusing point 102-104 ℃.
Embodiment 2:
Synthesizing of Sino-1 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, be solvent with toluene, drip equimolar to fluorobenzoyl chloride, after dripping, under 80 degree temperature condition, continuously stirring reaction 4 hours, cooling reactant, sodium hydroxide solution with 5% is regulated pH value, and solid product is separated out fully, cross filter solid, ethyl alcohol recrystallization obtains the Sino-1 compound products, fusing point 96-100 ℃, yield 54%.
Embodiment 3:
Sino-2, Sino-3, Sino-9 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, with methanol solvate, at room temperature drip bromine water, after dripping, continuously stirring reaction 2 hours, the sodium hydroxide solution with 5%, regulate pH value, solid product is separated out fully, cross filter solid, pass through column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer gets compound products Sino-2 and Sino-3, and yield is respectively 77% and 64%. fusing points and is respectively 130-135 ℃ and 144-143 ℃; After Sino-3 handled with saturated sodium carbonate solution, obtain new compound Sino-9 in another, fusing point is 129-131 ℃, yield 27%.
Embodiment 4:
Sino-4, Sino-5, Sino-6 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 50 milliliter of 40% Hydrogen bromide, equal 9, mistake filter solid with 5% the sodium hydroxide pH value that neutralizes in 80 ℃ of reactions after 6 hours, ethyl alcohol recrystallization, obtain compound products Sino-6, fusing point 121-122 ℃, yield 84%; Sino-6 is joined in the diacetyl oxide pyridine solvent, the DMPA that adds catalytic amount simultaneously, spend stirring reactions 3 hours 80, regulating pH value separates out solid, by column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer, get compound products Sino-4 and Sino-5, yield is respectively 53% and 73%. fusing points and is respectively 85-87 ℃ and 61-64 ℃.
Embodiment 5:
Synthesizing of Sino-7 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, is solvent with toluene, drips equimolar (C
2H
5) NSF
3, under 80 degree temperature condition, continuously stirring reaction 4 hours, the cooling reactant, the sodium hydroxide solution with 5% is regulated pH value, and solid product is separated out fully, crosses filter solid, and ethyl alcohol recrystallization obtains compound products Sino-7, and fusing point 152-153 ℃, yield 33%.
Embodiment 6:
Synthesizing of Sino-8 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, be solvent with toluene, drip equimolarly to diacetyl oxide, add the DMPA of triethylamine and catalytic amount, after dripping, under 80 degree temperature condition, continuously stirring reaction 4 hours, the cooling reactant, the sodium hydroxide solution with 5% is regulated pH value, solid product is separated out fully, cross filter solid, ethyl alcohol recrystallization, obtain compound products Sino-8, fusing point 82-84 ℃, yield 83%.
Embodiment 7:
Synthesizing of Sino-10 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, with CH
2Cl
2Be solvent, drip equimolar CH
3COONO
2, the control temperature is-78 ℃, continuously stirring reaction 1 hour, and the sodium hydroxide solution with 5% is regulated pH value, and solid product is separated out fully, crosses filter solid, and ethyl alcohol recrystallization obtains compound products Sino-10, and fusing point 136-138 ℃, yield 30%.
Embodiment 8:
Sino-11, Sino-12, Sino-13, Sino-17, Sino-18 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, the Paraformaldehyde 96 that adds equivalent, the 2N hydrochloric acid that adds 10 milliliters again, in 60 ℃ of reactions 2 hours, cooling back is with 10% sodium hydroxide solution neutralizing acid, regulate pH value and equal 9-10, cross filter solid, pass through column chromatography for separation, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, the rare bismuth potassium iodide of developer gets compound products Sino-12 and Sino-13, and yield is respectively 58% and 44%. fusing points and is respectively 247 ℃ (decomposition) and 263 ℃ (decomposition); Sino-12 is dissolved in the dichloromethane solvent, adds reagent D EAD and PPh3, reaction is 2 hours under the room temperature, obtain new compound Sino-11, separate by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, fusing point is 120-123 ℃, yield 81%; Sino-12 is dissolved in the acetone solvent, adds 2N sodium hydroxide, drip 30% hydrogen peroxide, reaction is 2 hours under the room temperature, obtains new compound Sino-17, separates by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, and fusing point is 122-124 ℃, yield 43%; Sino-12 is dissolved in the acetone solvent, solution is used nitroso-group N, the accelerine oxidation, add oxammonium hydrochloride then, room temperature reaction 2 hours, product separates by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, obtain compound product Sino-18, fusing point is 233-236 ℃, yield 39%.
Embodiment 9:
Sino-16, Sino-15 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of flasks to the stupid basic weight nitrogen salt of methoxyl group that now prepare, maintain the temperature at 0-5 ℃, stirring reaction 1 hour is crossed filter solid, ethyl alcohol recrystallization, obtain new compound Sino-15, fusing point is 114-118 ℃, yield 79%; Sino-15 is dissolved in the acetone solvent, add the diacetyl oxide of equivalent and the DMPA of triethylamine and catalytic amount, 60 ℃ were reacted 2 hours, product separates by column chromatography purification, the methylene dichloride of 8:1 volume ratio: methyl alcohol is developping agent, obtain compound product Sino-16, fusing point is 105-108 ℃, yield 81%.
Embodiment 10:
Synthesizing of Sino-22, Sino-21 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder adds the oxammonium hydrochloride and the sodium acetate soln that contain equivalent, and room temperature reaction 1 hour obtains new compound Sino-21, crosses filter solid, and ethyl alcohol recrystallization, new compound fusing point are 238 ℃, yield 99%; Under the similarity condition, with 2,4-dinitraniline/acetic acid and tuduranine reaction, obtain new compound Sino-22.
Embodiment 11:
Synthesizing of Sino-23 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 ml flasks, add methyl alcohol and make solvent, Pd/C is catalyzer, feeds hydrogen, adds p-Chlorobenzoic acid amide then, continue to feed hydrogen, thoroughly reaction obtains new compound Sino-23, ethyl alcohol recrystallization, the new compound fusing point is 124-127 ℃, yield 28%.
Embodiment 12:
Synthesizing of Sino-20 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 ml flasks, adds methyl alcohol and makes solvent, Pd/C is catalyzer, feed hydrogen, add oxammonium hydrochloride and the sodium acetate soln of equivalent then, react half an hour under the room temperature, get compound S ino-20, ethyl alcohol recrystallization, new compound fusing point are 244-246 ℃, yield 54%.
Embodiment 13:
Synthesizing of Sino-19 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 ml flasks, adds methyl alcohol and makes solvent, the ethylene glycol of equivalent feeds dry hydrogen chloride gas, reacts 4 hours, gets new compound Sino-19, ethyl alcohol recrystallization, new compound fusing point are 87 ℃, yield 64%.
Embodiment 14:
Sino-24, Sino-25, Sino-26, Sino-27, Sino-28, Sino-29, Sino-30, Sino-31 compound synthetic
The reduction of A, carbonyl: take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, and adding 200 ml methanol is solvent, stirs tuduranine is all dissolved, and other takes by weighing 180mmolNaBH
4Crystal is placed on crystal in one small beaker, is positioned in the moisture eliminator, slowly adds NaBH with the gradation of little spoon
4Crystal is in reaction flask, and a large amount of heat is emitted in reaction, the cooling of flask external application cold water, and temperature control is being advisable below 10 ℃, adds NaBH
4Speed be advisable not emit a large amount of gases, big can be with NaBH in 1.5-2 hour time
4Add, add NaBH
4After, remove water cooling, continued reaction stirred 2 hours, it is fully reacted completely, slowly drip the hydrochloric acid of 1mol/L then, make unreacted NaBH
4React completely, material in the flask is evaporated most of solvent methanol with Rotary Evaporators, be evaporated to into till the thickness state, thick material poured into while hot in the beaker of 200 ml waters, and then add 100 ml waters, vigorous stirring makes thick material thoroughly be dissolved in the water, solution becomes light yellow, and static several minutes is separated out the thick shape crystal of white immediately, regulate pH value to 9-11 with the hydrochloric acid of 1mol/L, stir half an hour, filter crystal, wash crystal 2-3 with water, drain to such an extent that solid 17.84 restrains, vacuum-drying gets solid 13.3 grams, and mother liquor is placed and separated out crystal 2 .0 gram after 2 hours, and the mother liquor after the filtration is placed in the refrigerator and spends the night, separate out crystal 1.2 grams, obtain dry thick product 16.5 grams altogether, productive rate 83%, crude product recrystallizing methanol, get crystalline substance, fusing point 216-217 ℃;
B, chlorination: the crystalline substance for preparing is previously got 30mmol be dissolved in 250 milliliters of there-necked flasks, add 50 milliliters of pyridine dissolvings, behind the connection gas absorbing device, in flask, slowly drip the 33mmol sulfur oxychloride, after dripping, be heated to 45 ℃, react half an hour, filter solid is crossed in the frozen water cooling, after filtrate decompression boils off solvent, residue adds 10% sodium bicarbonate again and fully stirs in 10 minutes, filters, dry 7.7 gram white solids, be chloro-product, fusing point 134-136 ℃;
C, get the chloro-product 10mmol for preparing above and be dissolved in 250 milliliters of there-necked flasks, add 100 milliliters of acetonitrile dissolvings, the para-bromoaniline that adds 10.1mmol again, under refluxad successive reaction is 6 hours, boils off to add 5% sodium hydrogen carbonate solution behind the solvent, fully with reactant, cross filter solid, the solid recrystallizing methanol obtains 6.6 gram white crystal Sino-24, fusing point 155-157 ℃; Under same reaction conditions, respectively with para-fluoroaniline, p-Chlorobenzoic acid amide, p-trifluoromethylaniline, aniline, P-nethoxyaniline, replace para-bromoaniline to react to trifluoro-methoxyaniline, m-chloro aniline, obtain Sino-25 respectively, Sino-26, Sino-27, Sino-28, Sino-29, Sino-30, seven new compounds of Sino-31, its fusing point is respectively: 115-120 ℃, and 120-123 ℃, 143-147 ℃, 155-160 ℃, 93-97 ℃, 126-130 ℃, 137-140 ℃.
Embodiment 15:
Sino-33, Sino-34, Sino-35, Sino-36 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, adding 200 ml methanol is solvent, stirs tuduranine is all dissolved, add the 60mmol cyanogen bromide, add 8.4 gram powdered sodium carbonates after 2 hours in 60 ℃ of reactions, continue under this temperature, to react 4 hours evaporating solvent methyl alcohol, separate out compound S ino-33, fusing point 171-172 ℃; Sino-33 is joined in the hydrochloric acid of 2N, boiled 1 hour, the pH value that neutralizes of the sodium hydroxide with 5% equals 9, crosses filter solid, and ethyl alcohol recrystallization obtains 8.7 and digests compound product Sino-34, fusing point 121-123 ℃; Take by weighing the dry refined Sino-34 compound of 10mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add the 15mmol sodium bicarbonate powder again, add 100 ml methanol and make solvent, add 10mmol2-methyl isophthalic acid-n-butyl bromide, under refluxad stir, successive reaction 3 hours, boil off methyl alcohol, residue cold water washing, ethyl alcohol recrystallization, obtain 3.1 and digest compound product Sino-36, fusing point 171-172 ℃; Other takes by weighing the dry refined Sino-34 compound of 10mmol, and grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add the 15mmol powdered sodium carbonate again, add 100 ml methanol and make solvent, drip the 10mmol Acetyl Chloride 98Min., under refluxad stir then, successive reaction 3 hours, boil off methyl alcohol, residue cold water washing, ethyl alcohol recrystallization, obtain 3.3 and digest compound product Sino-35, fusing point 150-153 ℃.
Embodiment 16:
Synthesizing of Sino-32 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder joins in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stirring is all dissolved tuduranine, adds oxygenant mCPBA then, reaction is 48 hours under room temperature condition, obtains new compound Sino-32.
Embodiment 17:
Synthesizing of Sino-37 compound:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stirring is all dissolved tuduranine, adds diacetyl oxide and Acetyl Chloride 98Min. then, and reaction is 8 hours under 90 ℃ of conditions, obtain new compound Sino-37, fusing point 72-74 ℃ with 30% hydrogen peroxide oxidation then.
Embodiment 18:
Sino-38, Sino-39, Sino-40 compound synthetic:
Take by weighing the dry refined tuduranine of 60mmol, grinding powder, join in 250 milliliters of three mouthfuls of round-bottomed flasks, add 200 milliliters of carbon tetrachloride solvents, stirring is all dissolved tuduranine, adds reagent N BS then, reaction is 12 hours under room temperature condition, obtain new compound Sino-38,84 ℃ of fusing points, yield 69.6%; Under the same terms, replace the NBS reaction to obtain new compound Sino-39 with NCS, 92 ℃ of fusing points, yield 50% is put in Sino-38 and boiled in the 2N sulfuric acid 1 hour, obtains new compound Sino-40, fusing point 150-153 ℃.
Claims (5)
1. compound is characterized in that being is that each ring of parent is gone up new substituent derivative with the tuduranine, and the C ring connects new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
2. compound is characterized in that being is that each ring of parent is gone up new substituent derivative with the tuduranine, and D ring or C, D ring connect new substituent Sinomenine derivate, and its structural formula is optional following a kind of:
3. as the preparation method of the arbitrary described compound of claim 1-2, it is characterized in that this method is: in the organic solvent of water or 2000-3000 milliliter/mole, under room temperature-reflux conditions, tuduranine and reagent reacted 1-48 hour with the ratio of 1:1.0-2.0, product separates with the method for recrystallization or the method that uses column chromatography is separated, and obtains Sinomenine structure-modified compound; Wherein said organic solvent is methyl alcohol, ethanol, propyl alcohol, butanols, Virahol, the trimethyl carbinol, methylene dichloride, chloroform, 1,2-ethylene dichloride, tetracol phenixin, ethyl acetate, ether, tetrahydrofuran (THF), 1,4-dioxy six alkane, benzene, toluene, acetone, second cyanogen, methyl-sulphoxide or N, dinethylformamide; Wherein said reagent is selected conventional reagent for use according to the constructional feature of compound.
4. the preparation method of compound as claimed in claim 3, it is characterized in that this method is: in the organic solvent of water or 2500 milliliters/mole, under room temperature-reflux conditions, tuduranine and reagent reacted 24 hours with the ratio of 1:1.5, product separates with the method for recrystallization or the method that uses column chromatography is separated, and obtains Sinomenine structure-modified compound.
5. has application in the medicine of anti-inflammatory, analgesia, calmness or immunoregulation effect as the arbitrary described compound of claim 1-2 in preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310158361.4A CN103232467B (en) | 2006-06-19 | 2007-06-19 | A kind of Sinomenine structure-modified compound and preparation method thereof |
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| CN 200610086423 CN1876634A (en) | 2006-06-19 | 2006-06-19 | Sinomenine structure-modified compound and its preparation method |
| CN200610086423.5 | 2006-06-19 | ||
| CN201310158361.4A CN103232467B (en) | 2006-06-19 | 2007-06-19 | A kind of Sinomenine structure-modified compound and preparation method thereof |
| CN2007101112536A CN101092397B (en) | 2006-06-19 | 2007-06-19 | Structure modified compound of sinomenine, and prepartion method |
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| CN103232467B CN103232467B (en) | 2015-11-18 |
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| CN116283773A (en) * | 2023-02-03 | 2023-06-23 | 安徽农业大学 | Sinomenine amide derivative, and preparation method and application thereof |
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| CN101798285B (en) | 2010-02-10 | 2012-05-23 | 中国科学院上海有机化学研究所 | Sinomenine derivate, synthesis method and application thereof |
| CN101899004A (en) * | 2010-06-24 | 2010-12-01 | 江苏大学 | Sinomenine derivatives and preparation method and medical application thereof |
| CN101948430A (en) * | 2010-09-01 | 2011-01-19 | 南京大学 | Sinomenine derivative and preparation method and applications thereof |
| CN102250003A (en) * | 2011-05-13 | 2011-11-23 | 湖南省药品检验所 | Sinomenine sulfonic acid compound and its preparation and application |
| CN102532024B (en) * | 2011-12-28 | 2016-08-03 | 赵爱国 | Sinomenine derivate |
| CN102964303A (en) * | 2012-11-28 | 2013-03-13 | 湖南大学 | Sinomenine derivate and preparation method and application thereof |
| CN106986826A (en) * | 2016-01-20 | 2017-07-28 | 苏州工业园区南华生物科技有限公司 | A kind of 1 substitutive derivative of cucoline and its preparation method and application |
| CN114409597B (en) * | 2022-01-04 | 2023-10-03 | 广东克冠达医药科技有限公司 | Sinomenine derivative and preparation method and application thereof |
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| WO1999042105A1 (en) * | 1998-02-20 | 1999-08-26 | Avmax, Inc. | Epimorphian compound and its use |
| CN1328280C (en) * | 2002-11-28 | 2007-07-25 | 中国科学院上海药物研究所 | Tetrandrine and tetrandrine compound, synthesis and uses thereof |
| CN100408578C (en) * | 2006-03-15 | 2008-08-06 | 南京大学 | A class of 17-acyl diversine derivatives and its preparing method |
| CN1785976A (en) * | 2005-12-15 | 2006-06-14 | 南京大学 | N-alkyl diversine and its preparation method |
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| CN116283773A (en) * | 2023-02-03 | 2023-06-23 | 安徽农业大学 | Sinomenine amide derivative, and preparation method and application thereof |
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Denomination of invention: Structure modified compound of sinomenine, and prepartion method Effective date of registration: 20180823 Granted publication date: 20151118 Pledgee: Bank of Changsha, Limited by Share Ltd, Huaihua branch Pledgor: Zhengqing Pharmaceutical Group Corp., Ltd., Hunan Prov. Registration number: 2018430000059 |
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