CN102952072A - Incarvillateine analogue, as well as preparation and application thereof in analgesics - Google Patents
Incarvillateine analogue, as well as preparation and application thereof in analgesics Download PDFInfo
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Abstract
The invention relates to an analogue of natural product incarvillateine with a novel structure of containing a cyclobutane dimer frame, including a compound with a general formula I, a compound with a general formula II and pharmaceutical salts thereof, as well as preparation methods of the compounds and application thereof in analgesics. In the general formula I, R1 is hydrogen or various alkyl substituent groups or various acyl substituent groups or various aryl groups, such as methyl, ethyl, propyl, butyl, allyl, benzyl, cyclopropyl methyl, acetyl, benzoyl and phenyl; R2 and R3 are respectively hydrogen or methyl, or R2 and R3 are methylene in common. In the general formula II, R4 is hydrogen or various alkyl substituent groups or various acyl substituent groups or various aryl groups, such as methyl, ethyl, propyl, butyl, allyl, benzyl, cyclopropyl methyl, acetyl, benzoyl and phenyl; and n is 0-4. The compounds have excellent pain relieving effect.
Description
Technical field
The present invention relates to novel structure, have analogue and the pharmaceutical salts thereof of the active natural product horned artemisia ester alkali of remarkable anti-injury, their preparation method and their purposes in analgesic.
Background technology
Pain (pain) a kind of offending reaction that to be body produce damaged tissue or potential damage is that a kind of Physiological Psychology of complexity is movable, is one of modal symptom clinically.It comprises that noxious stimulation acts on the caused pain of body and feels, and body is to pain reaction-somatic movement reaction and/or the internal organ vegetative reaction of noxious stimulation, and often with strong mood color.
The pain sensation can be used as a kind of warning that body comes to harm, and causes a series of egodefense reactions of body.But then, pain also has its limitation as alarm, cancer for example, often when the patient experiences pain, reach an advanced stage, simultaneously, some especially long-term having an intense pain that have an intense pain can become a kind of torment to body, cause the injury on the patients ' psychological, affect Quality of Life.Therefore, analgesia is the vital task that the medical personnel faces all the time.
Pharmacological agent is an indispensable measure of analgesia.The anodyne of present clinical use mainly contains NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) and opioid drug two classes.Although NSAID (non-steroidal anti-inflammatory drug) such as Asprin, Ibuprofen BP/EP, indomethacin etc. be widely used at present the treatment acute and chronic pain, its analgesic effect a little less than, and to gi tract stimulation is arranged, to side effects such as ulcer.Treat medium main force to severe pain and be undoubtedly opioid drug, wherein morphine has very important status, is separated from opium in 1806, has so far the history in more than 200 year for clinical in 1833.But because its some serious toxic side effect are used easily to produce tolerance and habituation especially continuously, seek toxic side effect anodyne few, that habituation is little is medicament research and development person's target all the time.Although by to the structural modification of morphine, simplify and transform the substitute that has developed a series of morphines, such as Pethidine etc., they still exist in various degree habituation and other toxic side effect, so that their clinical application is very restricted.Therefore, the few non-addicted analgesics of exploitation toxic side effect still is the drug research focus.
Natural product plays a part very important in drug discovery process, the medicine nearly 70% of using clinically now derives from the derivative of natural product or natural product, by to the biologically active native structural modification be transformed into an important channel of development medicine, and success ratio is very high.Opium kind analgesics just mainly by the natural product morphine and to its chemically modified and structure of modification and analogue form.Chinese Incarvilla Herb (Incarvillea sinensis LAM) is one of main source of Tuberculate Speranskia Herb, is called " goat's horn Tuberculate Speranskia Herb ", have dispel rheumatism, the effect of swelling and pain relieving.1999, trip day natural product chemistry man late beautiful bright grade isolated a kind of novel bimolecular monoterpene alkaloid with tetramethylene dimeric structure, called after horned artemisia ester alkali (Incarvillateine is abbreviated as INCA) from the herb of Chinese Incarvilla Herb.They find that this natural product shows the analgesic activities that is better than morphine in the formalin-induced model of mouse, and its mechanism of action is different from morphine, also find simultaneously at conditioned place preference (Conditioned Place Preference, CPP) the experiment small mouse has certain tendency of detesting on the contrary to its dependence effect that is a cup too low.Therefore, horned artemisia ester alkali has become the important lead compound of development of new non-narcotic analgesics thing.Horned artemisia ester alkali is carried out the novel non-narcotic analgesics that chemically modified or structure of modification are expected to find low toxicity, safety.
The structure of horned artemisia ester alkali is as follows:
Summary of the invention
The object of the present invention is to provide the analogue of the brand-new compound with good analgesic effect of a class formation-natural product horned artemisia ester alkali (Incarvillateine), contain the tetramethylene dimeric structure.
Another object of the present invention is to provide preparation method and the application of above-claimed cpd.
According to a first aspect of the invention, provide the compound of general formula I, or its steric isomer:
Wherein:
R
1Expression hydrogen or various alkyl substituent or various acyl substituent or various aryl are such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.;
R
2And R
3Represent separately hydrogen or methyl, or R
2And R
3Common expression methylene radical.
The compound of general formula I I is provided according to a second aspect of the invention:
Wherein:
R
4Expression hydrogen or various alkyl substituent or various acyl substituent or various aryl are such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.; N represents 0-4.
According to a third aspect of the present invention, provide the preparation method of compound of Formula I, synthetic route is as follows:
Reaction reagent and condition stub:
A:lewis acid, aqueous sodium hypochlorite solution, solvent, 0 ℃.Lewis acid in this condition can be Indium-111 chloride, cerous compounds or their hydrate; Methylene dichloride or chloroform and water form two-phase solvent.
B: hydrogen peroxide, aqueous sodium hydroxide solution, solvent, 0 ℃.Solvent is alcohol, can be methyl alcohol or ethanol.
C: acid, lithium chloride, tetrahydrofuran (THF), 0 ℃.Acid in this condition can be various inorganic acids or organic acid, preferred trifluoroacetic acid.
D: para-methylbenzenepyridinsulfonate sulfonate, 3,4-dihydropyrane, methylene dichloride.Reaction is at room temperature carried out.
The e:Favorskii reaction.Sodium methylate, ether, 0 ℃.
F: sodium azide, solvent, 60-90 ℃.Solvent can be polar non-proton organic solvent in this condition, can be dimethyl sulfoxide (DMSO), DMF, tetrahydrofuran (THF), acetonitrile etc., preferred DMF; Temperature of reaction is 60-90 ℃, during with the solvent of boiling point in this scope, and reflux, preferred 70 ℃.
G: triphenylphosphine, water, tetrahydrofuran (THF) refluxes.The molecule lactamization reaction directly occurs after the Staudinger reaction.
H: catalytic hydrogenation.Catalyzer in this reaction can be heterogeneous catalyst, such as palladium/carbon, platinum dioxide, platinum oxide, Raney Ni, can also be homogeneous catalyst, such as the Wilkinson catalyzer; The pressure of hydrogen is 4atm, and solvent is alcohol.
I: alkali, R
1X, tetrahydrofuran (THF), 0 ℃-room temperature.Alkali can be sodium hydride in this reaction, can also be sodium methylate, potassium tert.-butoxide, butyllithium etc.
J: Lithium Aluminium Hydride, tetrahydrofuran (THF).Temperature of reaction is room temperature.
K: acid, solvent.Acid can also can be para-methylbenzenepyridinsulfonate sulfonate for strong acid in hydrochloric acid, acetic acid, tosic acid, the boric acid etc. or strong acid in this reaction, the lewis such as tindichloride acid; The solvent protonic solvent, such as methyl alcohol, ethanol, tetrahydrofuran (THF) and water as mixed solvent.
L: esterification has three kinds of methods:
Method 1:
With
In solvent, react under the existence of reagent and catalyzer, wherein condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., also can be triphenylphosphine and tetracol phenixin, iodate 1-methyl-2-chloropyridine, catalyzer is DMAP or pyridine, solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, and temperature of reaction is 25-60 ℃;
Method 2:
With
React in solvent under the existence of agent, wherein catalyzer is DMAP or pyridine, and solvent is methylene dichloride, 1, the 2-ethylene dichloride, and pyridine or tetrahydrofuran (THF), temperature of reaction is 25-85 ℃;
Method 3:
With
React in solvent under the existence of change agent, wherein catalyzer is DMAP or pyridine, and solvent is methylene dichloride, tetrahydrofuran (THF), normal heptane or acetonitrile, and temperature of reaction is room temperature.
Preferred method 3, the preferred DMAP of catalyzer wherein, the preferred acetonitrile of solvent.
M: sodium/anthracene, tetrahydrofuran (THF) ,-40 ℃.
In the synthetic route of compound of Formula I, R
1, R
2And R
3Described as defined above, X is Br, I, OMs, OTs, preferred I and OTs.
According to a fourth aspect of the present invention, provide the preparation method of general formula I I compound, synthetic route is as follows:
Reaction reagent and condition stub:
A: alkali, Wittig reagent, tetrahydrofuran (THF).In this condition, alkali can be sodium hydride, butyllithium, tert-butyl lithium, potassium hexamethyldisilazide, potassium tert.-butoxide etc.; Temperature of reaction is-78 ℃-room temperature, decides according to different Wittig reagent.
B: catalytic hydrogenation or hydrolysis.The condition of catalytic hydrogenation is that catalyzer can be heterogeneous catalyst, such as palladium/carbon, platinum dioxide, platinum oxide, Raney Ni, can also be homogeneous catalyst, such as the Wilkinson catalyzer; The pressure of hydrogen is 4atm, and solvent is alcohol.The condition of hydrolysis reaction is that acid can be Trace salt acid, trifluoroacetic acid or trichoroacetic acid(TCA), and solvent is protonic solvent, such as methyl alcohol, ethanol, or the mixed solvent of tetrahydrofuran (THF) and water formation.
C: reduction reaction.Reductive agent is sodium borohydride, lithium borohydride or diisobutyl aluminium hydride, and solvent is methyl alcohol, ether or tetrahydrofuran (THF), temperature of reaction be-20 ℃ to room temperature.
D: esterification.Condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., also can be triphenylphosphine and tetracol phenixin, iodate 1-methyl-2-chloropyridine, preferred 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride; Catalyzer is DMAP; Solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, preferred methylene dichloride; Temperature of reaction is 25-60 ℃, preferred 25 ℃.
E: trifluoroacetic acid, methylene dichloride reacts under the room temperature.
F: reduction amination.Reductive agent can be sodium borohydride, sodium cyanoborohydride, triethoxy sodium borohydride or palladium/carbon and hydrogen, preferred triethoxy sodium borohydride; Aldehyde can be various alkanoics, such as formaldehyde, acetaldehyde, propionic aldehyde, propenal, phenyl aldehyde etc.; Acid is as catalyzer, can formic acid, acetic acid, and perhaps lewis acid is such as zinc chloride; Solvent can be acetonitrile, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methylene dichloride, methyl alcohol etc., preferred acetonitrile.
G: sodium/anthracene, tetrahydrofuran (THF) ,-40 ℃.
In the synthetic route of general formula I I compound, R
4Described as defined above with n, R
5Expression methoxyl group or methyl carbonate or ethyl-carbonate, m represents 0-3.
Reagent among the present invention can be bought from commerce, does not need further processing, when solvent for use needs Non-aqueous processing, is and well known in the art different solvents is carried out the method for Non-aqueous processing, does not need to do other additional processing.Rare gas element conventional in this area all can be realized the present invention.In an embodiment of the present invention, described rare gas element is nitrogen or argon gas.
In an embodiment of the present invention, " concentrate " and refer generally to use under the water pump reduced pressure Rotary Evaporators solvent evaporated.The used device of the inventive method is the conventional equipment of this area.The purification of thick product can adopt according to the character of target product separation method well known in the art to carry out among the present invention, such as recrystallization, distillation or column chromatography etc.
The compound of above general formula I, II and salt form thereof, especially the salt of HX (X represents halogen atom) form has good analgesic activities, can be used as analgesic or is used for analgesic composition as analgesic bioactive substance.
Embodiment
In order to further describe the present invention; the below provides some embodiment; but these embodiment only are illustrative; protection scope of the present invention is not consisted of any restriction; one skilled in the art will appreciate that spirit is made according to the present invention replacement, modification etc. all fall within the scope of protection of the present invention.
Embodiment 1
Get the 500mL there-necked flask, R-Karvon (3g, 20mmol) is dissolved in the 150mL methylene dichloride, add CeCl
3H
2The water of O (8.2g, 22mmol) (100mL) solution, mechanical stirring, (8%, 160mL), 0 ℃ is continued to stir 3 hours until thin-layer chromatography detects raw material disappears the NaClO aqueous solution that dropwise adds with dropping funnel under 0 ℃.Thin up slowly adds saturated Na again
2S
2O
3Aqueous solution cancellation reaction, dichloromethane extraction three times merges organic phase, with saturated NaCl solution washing, anhydrous Na
2SO
4Drying concentrated obtain the pale yellow oily liquid body and is directly used in next step reaction.
The thick product of above-mentioned gained is dissolved in the 25mL methyl alcohol H that dropwise adds respectively under the ice bath
2O
2(35%, 10mL) with the NaOH aqueous solution (2.0M, 5mL), 0 ℃ of lower reaction rose to room temperature reaction 3 hours after 30 minutes to the aqueous solution.Thin up slowly adds saturated Na again under the ice bath
2S
2O
3Aqueous solution cancellation reaction, dichloromethane extraction three times merges organic phase, with saturated NaCl solution washing, anhydrous Na
2SO
4Drying concentrated obtain the pale yellow oily liquid body and is directly used in next step reaction.
Above-mentioned gained crude product and LiCl (8.5g, 0.2mmol) are dissolved in the 80mL tetrahydrofuran (THF), and 0 ℃ slowly added trifluoroacetic acid (4.6mL, 60mmol) afterreaction 2 hours down, dropwise adds saturated NaHCO with dropping funnel
3The aqueous solution is until no longer include Bubble formation.Extracted with diethyl ether three times merges organic phase, with saturated NaCl solution washing, anhydrous Na
2SO
4Drying, concentrated rear pillar chromatographic separation obtains colourless oil liquid 2.5g, three step overall yields 52%.
Get above-mentioned products therefrom (2.25g, 9.5mmol) and 3,4-dihydropyrane (3mL, 33.3mmol) is dissolved in the 10mL methylene dichloride, add PPTS (238mg, 0.95mmol), reaction is 24 hours under the room temperature.Add saturated NaHCO
3Aqueous solution cancellation reaction, ethyl acetate extraction three times, the gained organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying, concentrated rear pillar chromatographic separation obtains colourless oil liquid 2.7g, productive rate 89%.
Get above-mentioned products therefrom (2.5g, 7.8mmol) and be dissolved in the 30mL ether, 0 ℃ of lower methanol solution (1.0M, 37.5mL) that adds freshly prepd NaOMe reacted 1 hour.Add saturated NH
4The cancellation of the Cl aqueous solution, ethyl acetate extraction three times, the gained organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying, concentrated rear pillar chromatographic separation obtains compound 1, colourless oil liquid, 2.4g, productive rate 97%.
1H?NMR(400MHz,CDCl
3,1:1mixture?of?epimeric?acetals,data?for?both?epimeric?acetals?given)δ5.20(s,1H),5.19(s,1H),4.96(s,1H),4.95(s,1H),4.65(m,1H),4.57(m,1H),4.20(t,J=4.0Hz,1H),4.09(t,J=4.3Hz,1H),4.04(d,J=12.0Hz,2H),4.00(d,J=12.0Hz,2H),3.70-3.56(m,1H),3.53(brs,6H),3.46(m,2H),3.38(dt,J=10.8,6.8Hz,1H),3.28(dt,J=11.0,6.6Hz,1H),2.84(dd,J=10.0,8.0Hz,1H),2.80(dd,J=10.0,8.0Hz,1H),2.60-2.50(m,2H),1.06(dd,J=13.1,6.6Hz,1H),1.98-1.91(m,2H),1.83-1.73(m,3H),1.68-1.60(m,3H),1.57-1.45(m,8H),1.08(d,J=7.0Hz,3H),0.98(d,J=7.0Hz,3H).
13C?NMR(100MHz,CDCl
3,1:1mixture?ofepimeric?acetals,data?for?both?epimeric?acetals?given)δ174.5(2×C),145.60,145.55,115.0,114.7,100.2,94.7,81.4,76.6,62.6,61.7,53.5(2×C),51.2(2×C),48.4,48.3,42.4,42.2,42.03,41.98,38.9,36.1,30.9,30.7,25.5,25.4,19.7,19.1,14.0,13.9.
Embodiment 2
Compound 2: compound 1 (1.6g, 5.0mmol) is dissolved among the DMF (30mL), adds NaN
3(650mg, 10mmol).Mixture heating up to 70 ℃ reaction 15 hours.Concentrated, then the thin up residue uses ethyl acetate extraction three times, and the gained organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying concentrated obtain yellow oily liquid and is directly used in next step reaction.
Above-mentioned products therefrom is dissolved in the 30mL tetrahydrofuran (THF), adds triphenylphosphine (1.6g, 6.0mmol) and water (0.9mL, 50mmol).Reflux 12 hours.Concentrated rear pillar chromatographic separation obtains compound 2, white solid, 1.2g, two step overall yields 90%.
1H?NMR(400MHz,CDCl
3,1:1mixture?of?epimeric?acetals,data?for?both?epimeric?acetals?given)δ6.83(brs,2H),4.89(brs,3H),4.86(s,1H),4.73(m,1H),4.58(m,1H),4.12(m,1H),4.03(m,1H),3.90-3.84(m,4H),3.71(m,1H),3.67(m,1H),3.51-3.47(m,2H),3.28(dd,J=18.3,9.3Hz,1H),3.19(dd,J=18.3,9.6Hz,1H),2.57(t,J=9.9Hz,1H),2.52(t,J=9.6Hz,1H),2.24(m,2H),2.17(ddd,J=13.6,8.2,2.0Hz,1H),2.07(dd,J=13.7,7.8Hz,1H),1.94(m,1H),1.85-1.76(m,3H),1.74-1.65(m,2H),1.62-0.51(m,8H),1.29(d,J=6.8Hz,3H),1.18(d,J=6.8Hz,3H).
13C?NMR(100MHz,CDCl
3,1:1mixture?of?epimeric?acetals,data?for?both?epimeric?acetals?given)δ174.5(2×C),143.7(2×C),113.7,113.4,100.3,94.6,81.4,76.5,62.7,61.6,56.0,55.9,53.54,53.50,51.2(2×C),42.9,42.7,42.2,41.9,38.5,35.6,30.9,30.6,25.4,25.3,19.7,19.1,13.95,13.87.
Embodiment 3
Compound 3: compound 2 (5.7g, 21.6mmol) is dissolved in the 70mL methyl alcohol, under argon shield, adds palladium/carbon (10%, 1.1g, 1.1mmol).Fill the hydrogen exchange argon gas and be placed on hydrogenation instrument (4atm H
2) the middle reaction 15 hours.With diatomite filtering palladium/carbon, concentrated filtrate rear pillar chromatographic separation obtains compound 3, white solid, 3.86g, productive rate 67%.
1H?NMR(400MHz,CDCl
3,1:1mixture?of?epimeric?acetals,data?for?both?epimeric?acetals?given)δ6.62(brs,2H),4.69(m,1H),4.56(m,1H),4.09(m,1H),4.00(m,1H),3.90-3.83(m,2H),3.50-3.45(m,2H),3.06-2.98(m,3H),2.74-2.66(m,1H),2.64-2.55(m,1H),2.44(m,2H),2.15-2.01(m,5H),1.89-1.75(m,4H),1.73-1.64(m,2H),1.59-1.48(m,9H),1.41-1.34(m,1H),1.27(d,J=6.9Hz,3H),1.14(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H),0.88(d,J=6.9Hz,3H).
Compound 4: above-mentioned reaction can obtain the steric isomer compound 4 of compound 3, white solid, 1.88g, productive rate 33% simultaneously.
1H?NMR(400MHz,CDCl
3,1.3:1mixture?of?epimeric?acetals,data?for?both?epimeric?acetals?given)δ5.87(brs,1.6H),4.72(m,1H),4.58(m,0.8H),4.06(m,1H),3.97-3.95(m,0.8H),3.93-3.86(m,1.9H),3.52-3.48(m,1.9H),3.20-3.15(m,1.7H),2.95(m,1.7H),2.53(t,J=10.3Hz,1H),2.48(t,J=10.0Hz,0.8H),2.27-2.07(m,5.7H),1.85-1.78(m,1.9H),1.75-1.68(m,2.7H),1.59-1.48(m,10H),1.34(d,J=6.7Hz,3H),1.23(d,J=6.7Hz,2.5H),0.98(d,J=6.9Hz,5.4H).
Embodiment 4
Compound 5: compound 3 (209mg, 0.78mmol) is dissolved in the 1mL tetrahydrofuran (THF), is cooled to 0 ℃ under the argon shield; add sodium hydride (60%in oil, 47mg, 1.2mmol); stir and add iodopropane after 15 minutes, rise to room temperature and continue reaction 24 hours.Add saturated NH under the ice bath
4Cl aqueous solution cancellation reaction, ethyl acetate extraction three times, the gained organic phase is with saturated NaCl solution washing, anhydrous Na
2SO
4Drying, concentrated rear pillar chromatographic separation obtains colourless oil liquid, 148mg, productive rate 61%.
Above-mentioned products therefrom is dissolved in the 2mL tetrahydrofuran (THF) 0 ℃ of lower LiAlH that adds
4(72.8mg, 1.9mmol), reaction is 1 hour under the room temperature.Reaction mixture is cooled to 0 ℃, adds the cancellation of several NaOH solution, the filtering solid, and wash with ethyl acetate.Be directly used in next step reaction after the concentrated gained filtrate.
Above-mentioned gained crude product is dissolved in the 1mL methyl alcohol, adds PTSA (91mg, 0.5mmol), reaction is 4 hours under the room temperature.Concentrated, add 0.2N NaOH solution dilution residue, dichloromethane extraction, gained organic phase anhydrous Na
2SO
4Drying, concentrated rear pillar chromatographic separation obtains compound 5, white solid, 92mg, two step productive rates 91%.
1H?NMR(400MHz,CDCl
3)δ4.29(m,1H),2.76-2.72(m,1H),2.60-2.57(m,1H),2.46-2.38(m,1H),2.28-2.24(t,J=7.5Hz,2H),2.09-2.06(m,1H),1.92-1.89(m,1H),1.85-1.77(m,2H),1.68(t,J=11.5Hz,1H),1.61-1.47(m,5H),1.01(d,J=7.3Hz,3H),0.88(t,J=7.3Hz,3H),0.85(d,J=4.0Hz,3H).
Embodiment 5
Compound 6: the preparation method is with embodiment 4.Take compound 3 as starting raw material, the positive butyl ester of tosic acid is alkylating agent, and the experience three-step reaction obtains compound 6, oily liquids, 102mg with 90% overall yield.
1H?NMR(400MHz,CDCl
3)δ4.28(t,J=6.4,1.6Hz,1H),2.74(ddd,J=11.2,5.6,1.6Hz,1H),2.58(ddd,J=11.2,4.4,1.6Hz,1H),2.42(td,J=12.8,6.4Hz,1H),2.29(dd,J=8.8,6.8Hz,2H),2.07(m,1H),1.90(m,.1H),1.79(td,J=12.8,6.4Hz,2H),1.68(t,J=11.2Hz,1H),1.55(t,J=11.6Hz,1H),1.52-1.44(m,3H),1.34-1.22(m,3H),1.01(d,J=7.6Hz,3H),0.91(t,J=7.6Hz,3H),0.87(d,J=6.8Hz,3H);
13C?NMR(100MHz,CDCl
3)δ72.5,58.1,55.16,55.10,44.8,42.2,37.6,32.3,29.5,27.9,20.5,17.1,14.0,13.7;
HRMS(ESI)calcd?for?C
14H
28NO[M+H]
+?226.2171;found?226.2167.
Embodiment 6
Compound 7: the preparation method is with embodiment 4.Take compound 4 as starting raw material, methyl iodide is alkylating agent, and the experience three-step reaction obtains compound 7, white solid, 170mg with 93% overall yield.
1H?NMR(400MHz,CDCl
3)δ4.19(m,1H),3.73(m,1H),2.81(d,J=12.0Hz,1H),2.65(ddd,J=11.0,3.0,1.2Hz,1H),2.22(s,3H),2.10-2.01(m,2H),1.92(ddd,J=14.6,6.6,1.2Hz,1H),1.84(td,J=6.6,3.2Hz,1H),1.77(m,1H),1.72(ddd,J=14.6,8.0,2.5Hz,1H),1.48(t,J=11.0Hz,1H),1.47(m,1H),1.40-1.32(m,1H),0.98(d,J=6.8Hz,3H),0.80(d,J=6.3Hz,3H);
13C?NMR(100MHz,CDCl
3)δ74.9,63.4,55.4,46.8,43.6,42.1,39.4,38.8,34.5,17.7,11.8.
Embodiment 7
Compound 8: the preparation method is with embodiment 4.Take compound 2 as starting raw material, methyl iodide is alkylating agent, and the experience three-step reaction obtains compound 7,130mg with 81% overall yield.
1H?NMR(400MHz,CDCl
3)δ4.85(s,1H),4.81(s,1H),4.22(m,1H),3.00(d,J=12.3Hz,1H),2.78(q,J=6.6Hz,1H),2.72(d,J=12.3Hz,1H),2.44(dd,J=11.8,4.4Hz,1H),2.37(dd,J=11.8,4.8Hz,1H),2.24(dt,J=13.8,6.3Hz,1H),2.24(s,3H),1.89(dt,J=13.6,5.2Hz,1H),1.91-1.82(m,1H),1.70(dd,J=13.8,2.8Hz,1H),1.68(dd,J=13.8,2.8Hz,1H),0.98(d,J=6.6Hz,3H);
13C?NMR(100MHz,CDCl
3)δ145.9,109.6,74.1,61.4,56.8,46.3,45.0,40.4,40.1,38.4,12.6.
Embodiment 8
Compound 9: with compound 5 (72mg, 0.34mmol), DMAP (4.2mg, 0.034mmol) and 3,3 '-dimethoxy-4 ', 4 '-two tosic acid ester group-α-soil former times acid two trimethylacetic acid acid anhydrides (147.4mg, 0.17mmol) are dissolved in the 1mL acetonitrile, and reaction is 3 days under the room temperature.Add 20mL CH
2Cl
2Dilution, (0.2N) transfers to 11~12 with reaction system PH with NaOH solution.Water CH
2Cl
2Extraction merges organic phase and uses anhydrous Na
2SO
4Drying, obtain the white powder solid, 104mg, productive rate 56% concentrated the separation by column chromatography.
With above-mentioned product (87mg; 0.083mmol) be dissolved in the 5mL tetrahydrofuran (THF), be cooled to-40 ℃ under the argon shield, add the tetrahydrofuran solution (0.49mL of freshly prepd Na/Anthracene; 0.25mmol) ,-40 ℃ of lower reactions 3 hours until raw material disappears.Add saturated NaHCO
3Cancellation.Use dichloromethane extraction, merge organic phase and use anhydrous Na
2SO
4Drying, obtain compound 8 white solids, 54mg, productive rate 84% concentrated the separation by column chromatography.
1H?NMR(400MHz,CDCl
3)δ6.80-6.76(m,6H,4.89(m,2H),4.33(m,2H),3.86(s,3H),3.85(s,3H),3.84(m,2H),2.66(m,2H),2.54(m,2H),2.29-2.16(m,4H),2.16-2.07(m,1H),1.96(m,3H),1.83(m,3H),1.76-1.67(m,2H),1.64-1.56(m,3H),1.53-1.42(m,4H),1.04(m,1H),0.83(t,J=7.4Hz,6H),0.79(d,J=7.4Hz,3H),0.74(d,J=6.8Hz,3H),0.58(d,J=7.2Hz,3H),0.66-0.46(m,1H).
13C?NMR(100MHz,CDCl
3)δ171.9,171.7,146.7,146.6,145.2,145.1,130.7,130.5,120.4,119.9,114.49,114.45,110.9,110.8,76.6,76.4,60.7(2×C),55.8,55.7,55.5(2×C),55.2,55.1,47.9,47.3,45.63,45.58,41.8,41.2,40.52,40.49,37.92,37.86,30.0,29.9,29.8,29.3,19.53,19.50,17.1,16.9,14.8,14.4,12.0(2×C).
Embodiment 9
Compound 10: the preparation method is with embodiment 8.By compound 6 and 3,3 '-dimethoxy-4 ' obtains white amorphous solid, two step overall yields 64% after 4 '-two tosic acid ester group-α-soil former times acid two trimethylacetic acid acid anhydride condensations remove the p-toluenesulfonyl protecting group afterwards.
1H?NMR(400MHz,CDCl
3)δ6.87-6.78(m,6H),5.72(brs,2H),4.94-4.84(m,2H),4.39-4.29(m,2H),3.91(s,3H),3.89(s,3H),3.87-3.80(m,2H),2.62(m,2H),2.51(m,2H),2.23(m,4H),2.18-2.10(m,1H),1.97(m,3H),1.87-1.78(m,3H),1.76-1.52(m,5H),1.43(m,5H),1.31-1.22(m,5H),1.06(m,1H),0.88(t,J=7.3Hz,6H),0.81(d,J=7.3Hz,3H),0.75(d,J=6.9Hz,3H),0.70(d,J=6.8Hz,3H),0.60(d,J=7.3Hz,3H),0.58-0.53(m,1H);
13C?NMR(100MHz,CDCl
3)δ171.9,171.7,146.7,146.6,145.2,145.1,130.6,130.4,120.3,119.8,114.54,114.50,110.8,110.7,76.6,76.4,58.6(2×C),55.7(2×C),55.5(2×C),55.2,55.1,47.9,47.2,45.7,45.6,42.0,41.7,40.5(2×C),37.9,37.8,29.99,29.95,29.8,29.2,28.5,28.4,20.7(2×C),17.1,16.9,14.8,14.4,13.9(2×C);
Embodiment 10
Compound 11: the preparation method is with embodiment 8.By compound 7 and 3,3 '-dimethoxy-4 ' obtains white powder solid, two step overall yields 88% after 4 '-two tosic acid ester group-α-soil former times acid two trimethylacetic acid acid anhydride condensations remove the p-toluenesulfonyl protecting group afterwards.
1H?NMR(400MHz,CDCl
3)δ6.85(brs,2H),6.75-6.70(m,6H),4.77(m,1H),4.65(m,1H),4.29(m,2H),3.85(s,3H),3.83(s,3H),3.79-3.71(m,2H),2.76(t,J=12.7Hz,2H),2.59(t,J=12.2Hz,2H),2.15(s,3H),2.14(s,3H),2.02(dd,J=12.2,4.6Hz,2H),1.97(dd,J=11.9,4.6Hz,2H),1.74(dd,J=14.8,6.2Hz,1H),1.60(m,1H),1.49-1.20(m,9H),1.07-1.01(m,1H),0.76(d,J=6.5Hz,3H),0.70(d,J=5.2Hz,3H),0.66(d,J=6.3Hz,3H),0.48(d,J=6.6Hz,3H);
13C?NMR(100MHz,CDCl
3)δ171.8,171.7,146.8,146.5,145.3,145.1,130.6(2×C),120.3,120.1,114.8,114.5,110.84,110.77,79.0,78.6,63.04,62.97,55.72,55.66,54.8,54.6,47.8,47.5,46.6,46.5,44.1,44.0,41.70,41.66,41.4,41.2,37.3(2×C),37.0,36.5,34.2,34.0,17.54,17.51,11.8,11.3.
Embodiment 11
Compound 12: the preparation method is with embodiment 8.By compound 8 and 3,3 '-dimethoxy-4 ' obtains white amorphous solid, two step overall yields 43% after 4 '-two tosic acid ester group-α-soil former times acid two trimethylacetic acid acid anhydride condensations remove the p-toluenesulfonyl protecting group afterwards.
1H?NMR(400MHz,CDCl
3)δ6.84-6.78(m,6H),5.68(brs,2H),4.86(m,2H),4.82(s,1H),4.81(s,1H),4.80(m,2H),4.38-4.29(m,2H),3.88(s,3H),3.86(s,3H),3.81(m,2H),2.94(d,J=12.2Hz,2H),2.68(t,J=11.9Hz,2H),2.55(m,1H),2.39-2.26(m,5H),2.20(brs,6H),2.11(dt,J=14.4,6.2Hz,1H),1.90(dd,J=14.4,6.2Hz,1H),1.86(dd,J=14.4,7.8Hz,1H),1.82-1.66(m,3H),1.31(dd,J=14.4,8.0Hz,1H),0.88-0.75(m,1H),0.79(d,J=6.7Hz,3H),0.51(d,J=5.5Hz,3H);
13C?NMR(100MHz,CDCl
3)δ171.8,171.7,146.55,146.47,145.02,144.96,144.81,144.75,130.9,130.8,120.5,120.0,114.4(2×C),110.8,110.6,110.2,110.1,77.7,77.4,61.0(2×C),56.14,56.08,55.9(2×C),48.0,47.4,46.0(2×C),45.2(2×C),41.7,41.3,40.0(2×C),38.70,38.66,35.7,35.1,12.8,12.3.
Embodiment 12
Compound 13: NaH (60%in oil, 500mg, 12.5mmol) is added in the 10mL tetrahydrofuran (THF), and the ice bath cooling adds phosphine acyl acetic acid three ethyl (2.2mL, 12.5mmol) under the argon shield, removes ice bath, and reaction is 1 hour under the room temperature.Reaction mixture is cooled to 0 ℃ with ice bath again, and N-Boc-piperidone (997mg, 5mmol) slowly is added dropwise to reaction system after being dissolved in the 1mL tetrahydrofuran (THF), removes ice bath, reacts 18 hours under the room temperature until react completely.Add saturated NH
4The cancellation of Cl solution, ethyl acetate extraction three times.Merge organic phase, use successively saturated NaHCO
3Solution, saturated NaCl solution washing, anhydrous Na
2SO
4Dry.Concentrated by column chromatography separation white solid 1.3g, productive rate 97%.
Above-mentioned products therefrom (639mg, 2.4mmol) is dissolved in the 6mL methyl alcohol, adds Pd/C (10w%, 200mg) under the argon gas.Fill the hydrogen exchange argon gas three times, at hydrogenation instrument (4atm H
2) in the reaction spend the night.The reaction solution diatomite filtration, the ethyl acetate washing.Filtrate obtains white solid, 722mg, productive rate 100% concentrated the separation by column chromatography.
Above-mentioned products therefrom (506mg, 1.9mmol) is dissolved in the 10mL ether, is cooled to-20 ℃, add diisobutyl aluminium hydride (1.0M, 5mL, 5mmol), react and disappeared to raw material in 10 minutes.Pour saturated sodium tartrate potassium solution into, stir 3 hours under the room temperature to the reaction mixture clarification, water extracted with diethyl ether three times merge organic phase, with saturated NaCl solution washing, anhydrous Na
2SO
4Dry.Obtain white solid, 368mg, productive rate 86% concentrated the separation by column chromatography.
With above-mentioned products therefrom (367mg, 1.6mmol), 3,3 '-dimethoxy-4 ', 4 '-two tosic acid ester group-α-soil former times acid (522mg, 0.75mmol) and DMAP (183mg, 1.5mmol) add in the 5mL methylene dichloride, stirred 10 minutes under the room temperature until solid dissolves fully, add EDCI (432mg, 2.3mmol), reaction is spent the night under the room temperature.Then add saturated NaHCO
3Solution dilution, water ethyl acetate extraction three times merge organic phase, with saturated NaCl solution washing, anhydrous Na
2SO
4Dry.Obtain white unsetting solid, 707mg, productive rate 84% concentrated the separation by column chromatography.
Above-mentioned products therefrom (655mg, 0.58mmol) is dissolved in the 3mL methylene dichloride, adds the 1mL trifluoroacetic acid, reacted 15 minutes.Concentrated, the methylene dichloride dilution adds saturated Na
2CO
3Solution is to without Bubble formation, water CH
2Cl
2Extract three times, merge organic phase, use anhydrous Na
2SO
4Dry.Remaining oily matter is dissolved in the 40mL acetonitrile after concentrated, and ice bath is cooled to 0 ℃, adds successively NaCNBH
3(443mg, 7.0mmol) and formalin solution (1.5mL) remove ice bath, and reaction is spent the night until raw material disappears under the room temperature, adds 1.5mL AcOH cancellation.NaOH solution modulation PH=11~12 with 10%, dichloromethane extraction, gained organic phase anhydrous K
2CO
3Dry.Obtain white unsetting solid, 332mg, productive rate 60% concentrated the separation by column chromatography.
With above-mentioned product (301mg; 0.32mmol) be dissolved in the 80mL tetrahydrofuran (THF), be cooled to-40 ℃ under the argon shield, add the tetrahydrofuran solution (2.9mL of freshly prepd Na/Anthracene; 1.44mmol) ,-40 ℃ of lower reactions 1 hour until raw material disappears.Add saturated NaHCO
3Cancellation.Use dichloromethane extraction, gained organic phase anhydrous Na
2SO
4Drying, obtain compound 13, white solid, 205mg, productive rate 100% concentrated the separation by column chromatography.
1H?NMR(400MHz,MeOD)δ6.89(s,2H),6.75(m,4H),4.32(dd,J=10.4,7.6Hz,2H),3.91-3.74(m,4H),3.87(s,6H),3.82(dd,J=10.4,7.6Hz,2H),2.83(d,J=11.2Hz,4H),2.30.(s,6H),1.99(t,J=13.0Hz,4H),1.49(q,J=13.2Hz,4H),1.17(m,4H),1.09(t,J=13.0Hz,4H),0.90(m,2H);
13C?NMR(100MHz,MeOD)δ173.9,148.8,146.9,132.0,121.3,116.2,112.7,63.1,56.5,56.2,48.9,46.0,42.8,35.9,32.2,32.1.
Embodiment 13
Compound 14: the preparation method is with embodiment 8.Take the N-Boc-piperidone as starting raw material, experience Wittig reaction, hydrolysis alkene ether becomes aldehyde, reduction reaction, esterification removes tertbutyloxycarbonyl, reduction amination and remove p-toluenesulfonyl 7 step reaction and obtain.White solid, 210mg, 7 step overall yields 43%.
1H?NMR(400MHz,DMSO-d
6)δ8.84(brs?2H),6.85(s,2H),6.67(m,4H),4.23(dd,J=10.4,7.6Hz,2H),3.75(dd,J=10.4,7.6Hz,2H),3.73(s,6H),3.53(m,4H),2.60(d,J=10.8Hz,4H),2.08(s,6H),1.66(t,J=10.8Hz,4H),1.22(m,4H),1.10(m,2H),0.90(m,J=12.0,3.2Hz,4H);
13C?NMR(100MHz,DMSO-d
6)δ171.6,147.3,145.6,129.8,119.8,115.1,112.1,68.2,55.6,54.6,46.8,46.1,40.8,34.0,28.2,28.1.
The biological activity test example:
Embodiment horned artemisia ester alkali analogue is prepared into its corresponding hydrochloride carries out analgesic test in the Mice Body, the result is as shown in table 1:
Test mice: male ICR mouse
Testing method: hot plate method in mice, hot plate temperature are set as 55 ℃, and thermal stimulus dead line is 60s, are the threshold of pain index latent period of licking metapedes or hopping response take mouse.Intraperitoneal injection, each compound amount are 40 μ mol/kg.As positive control drug, consumption is 10mg/kg with Srm-Rhotaard, is about 27 μ mol/kg.
Evaluation of result:
Calculate as follows maximum analgesic effect percentage (MPE%), evaluation analgesia intensity:
Table 1: the analgesic activities result of representative horned artemisia ester alkali analogue
Data representation mean value ± SEM; Vehicle represents the solvent for dissolved compound and positive drug, is DMSO (dimethyl sulfoxide (DMSO))+saline (physiological saline) 1: 99; * represent to compare P<0.01 with the solvent control group; * represents to compare P<0.001 with the solvent control group.
Conclusion (of pressure testing):
Above test-results shows that in hot plate method animal pain model, each embodiment horned artemisia ester alkali analogue all demonstrates stronger analgesic activities.Wherein the activity of INCAD-4 and INCAD-6 is better than natural product horned artemisia ester alkali (INCA), especially INCAD-6, and is under the dosage of 40 μ mol/kg, suitable when its analgesic effect and morphine 27 μ mol/kg.
Claims (10)
1. the represented compound of general formula I, or its steric isomer:
R
1Expression hydrogen or various alkyl substituent or various acyl substituent or various aryl are such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.;
R
2And R
3Represent separately hydrogen or methyl, or R
2And R
3Common expression methylene radical.
2. the represented compound of general formula I I:
Wherein:
R
4Expression hydrogen or various alkyl substituent or various acyl substituent or various aryl are such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.; N represents 0-4.
3. the compound of the claim 1 of salt form or hydrate forms.
4. the compound of the claim 2 of salt form or hydrate forms.
5. according to claim 1 compound, its corresponding pharmaceutical salts is formula I compound 2HX, X represents halogen;
According to claim 2, compound, its corresponding pharmaceutical salts are formula II compound 2HX, and X represents halogen.
6. the synthetic route for preparing compound of Formula I:
A:lewis acid, aqueous sodium hypochlorite solution, solvent, 0 ℃, the lewis acid in this condition can be Indium-111 chloride, cerous compounds or their hydrate, methylene dichloride or chloroform and water form two-phase solvent;
B: hydrogen peroxide, aqueous sodium hydroxide solution, solvent, 0 ℃, solvent are alcohol, can be methyl alcohol or ethanol;
C: acid, lithium chloride, tetrahydrofuran (THF), 0 ℃, the acid in this condition can be various inorganic acids or organic acid, preferred trifluoroacetic acid;
D: para-methylbenzenepyridinsulfonate sulfonate, 3,4-dihydropyrane, methylene dichloride, temperature of reaction is room temperature;
E: sodium methylate, ether, 0 ℃;
F: sodium azide, solvent, 60-90 ℃, solvent can be polar non-proton organic solvent in this condition, can be dimethyl sulfoxide (DMSO), N, dinethylformamide, tetrahydrofuran (THF), acetonitrile etc., preferred DMF, temperature of reaction is 60-90 ℃, during with the solvent of boiling point in this scope, reflux, preferred 70 ℃;
G: triphenylphosphine, water, tetrahydrofuran (THF), backflow;
H: catalytic hydrogenation.Catalyzer in this reaction can be heterogeneous catalyst, such as palladium/carbon, platinum dioxide, platinum oxide, Raney Ni, can also be homogeneous catalyst, and such as the Wilkinson catalyzer, the pressure of hydrogen is 4atm, and solvent is alcohol;
I: alkali, R
1X, tetrahydrofuran (THF), 0 ℃-room temperature, alkali can be sodium hydride in this reaction, can also be sodium methylate, potassium tert.-butoxide, butyllithium etc.;
J: Lithium Aluminium Hydride, tetrahydrofuran (THF), temperature of reaction are room temperature;
K: acid, solvent, acid can also can be para-methylbenzenepyridinsulfonate sulfonate for strong acid in hydrochloric acid, acetic acid, tosic acid, the boric acid etc. or strong acid in this reaction, the lewis such as tindichloride acid, solvent is protonic solvent, such as methyl alcohol, ethanol or tetrahydrofuran (THF) and water as mixed solvent;
L: esterification has three kinds of methods:
Method 1:
With
In solvent, react under the existence of reagent and catalyzer, wherein condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., also can be triphenylphosphine and tetracol phenixin, iodate 1-methyl-2-chloropyridine, catalyzer is DMAP or pyridine, solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, and temperature of reaction is 25-60 ℃;
Method 2:
With
React in solvent under the existence of agent, wherein catalyzer is DMAP or pyridine, and solvent is methylene dichloride, 1, the 2-ethylene dichloride, and pyridine or tetrahydrofuran (THF), temperature of reaction is 25-85 ℃;
Method 3:
With
React in solvent under the existence of change agent, wherein catalyzer is DMAP or pyridine, and solvent is methylene dichloride, tetrahydrofuran (THF), normal heptane or acetonitrile, and temperature of reaction is room temperature;
Preferred method 3, the preferred DMAP of catalyzer wherein, the preferred acetonitrile of solvent;
M: sodium/anthracene, tetrahydrofuran (THF) ,-40 ℃.
7. claim
Synthetic route, R wherein
1For hydrogen or various alkyl substituent or various acyl substituent or various aryl, such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.; R
2And R
3Represent separately hydrogen or methyl, or R
2And R
3Common expression methylene radical; X is Br, I, OMs, OTs, preferred I and OTs.
8. the synthetic route for preparing general formula I I compound:
A: alkali, Wittig reagent, tetrahydrofuran (THF), in this condition, alkali can be sodium hydride, butyllithium, tert-butyl lithium, potassium hexamethyldisilazide, potassium tert.-butoxide etc., temperature of reaction is-78 ℃-room temperature, decides according to different Wittig reagent;
B: catalytic hydrogenation or hydrolysis, the catalyzer of catalytic hydrogenation can be heterogeneous catalyst, such as palladium/carbon, platinum dioxide, platinum oxide, Raney Ni, can also be homogeneous catalysts, and such as the Wilkinson catalyzer, the pressure of hydrogen is 4atm, and solvent is alcohol; The condition of hydrolysis reaction is that acid can be Trace salt acid, trifluoroacetic acid or trichoroacetic acid(TCA), and solvent is protonic solvent, and such as methyl alcohol, ethanol, or tetrahydrofuran (THF) and water are as mixed solvent;
C: reduction reaction, reductive agent are sodium borohydride, lithium borohydride or diisobutyl aluminium hydride, and solvent is methyl alcohol, ether or tetrahydrofuran (THF), temperature of reaction be-20 ℃ to room temperature;
D: esterification, condensation reagent can be N, N '-dicyclohexylcarbodiimide, N, N '-DIC, 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride etc., also can be triphenylphosphine and tetracol phenixin, iodate 1-methyl-2-chloropyridine, preferred 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, catalyzer is DMAP, solvent is methylene dichloride, tetrahydrofuran (THF) or acetonitrile, preferred methylene dichloride, temperature of reaction is 25-60 ℃, preferred 25 ℃;
E: react under trifluoroacetic acid, methylene dichloride, the room temperature;
F: reduction amination, reductive agent can be sodium borohydride, sodium cyanoborohydride, triethoxy sodium borohydride or palladium/carbon and hydrogen, preferred triethoxy sodium borohydride, and aldehyde can be various alkanoics, such as formaldehyde, acetaldehyde, propionic aldehyde, propenal, phenyl aldehyde etc., acid is as catalyzer, can formic acid, acetic acid, and perhaps lewis acid is such as zinc chloride, solvent can be acetonitrile, tetrahydrofuran (THF), 1,4-dioxane, methylene dichloride, methyl alcohol etc., preferred acetonitrile;
G: sodium/anthracene, tetrahydrofuran (THF) ,-40 ℃.
9. claim
Synthetic route, R wherein
4For hydrogen or various alkyl substituent or various acyl substituent or various aryl, such as methyl, ethyl, propyl group, butyl, allyl group, benzyl, cyclopropyl methyl, cyclobutylmethyl, ethanoyl, benzoyl, phenyl etc.; R
5Expression methoxyl group or methyl carbonate or ethyl-carbonate; M represents 0-3; N represents 0-4.
Among the claim 1-6 each compound as analgesic or as the purposes of the composition in the analgesic composition.
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CN103655559A (en) * | 2013-12-25 | 2014-03-26 | 华东理工大学 | Application of incarvillateine compounds in preparation of anti-breast cancer drugs |
CN103655559B (en) * | 2013-12-25 | 2016-04-20 | 华东理工大学 | Horned artemisia ester alkali compounds is preparing the application in anti-breast cancer medicines |
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