CN100408578C - A class of 17-acyl diversine derivatives and its preparing method - Google Patents
A class of 17-acyl diversine derivatives and its preparing method Download PDFInfo
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- CN100408578C CN100408578C CNB2006100388629A CN200610038862A CN100408578C CN 100408578 C CN100408578 C CN 100408578C CN B2006100388629 A CNB2006100388629 A CN B2006100388629A CN 200610038862 A CN200610038862 A CN 200610038862A CN 100408578 C CN100408578 C CN 100408578C
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- tuduranine
- benzyloxy benzyl
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Abstract
The present invention discloses 17-acyl diversine derivative which has latent medicine application prospect. The structural formula of the 17-acyl diversine derivative is shown like the formula on the right, and in the structural formula I, R can be the chain hydrocarbon acyl, the cyclic hydrocarbon acyl and the replaced hydrocarbon acyl of C1-C15, such as acetyl, or propionyl, or butyryl, or benzene acetyl or ring abicin formyl; or R is aroyl group or aromatic heterocyclic acyl, such as benzoyl, or 3-5 lumichrome benzoyl, or salicyl, or fume acyl or furanformyl. In the synthetic process of the 17-acyl diversine derivative, the method of using benzyloxy-benzyl group to replace benzyl group as a protective group has the advantages of soft deprotection condition, high reaction speed, little side reaction and high yield.
Description
One, technical field
The present invention relates to a kind of chemical-biological alkali, specifically relate to class 17-acyl group Sinomenine derivate and preparation method thereof.
Two, background technology
Tuduranine (sinomenine) is morphine (morphine) Alkaloid that extracts from windproof own section plant Stem of Orientoine and hair sinomenium acutum rhizome.According to record, have pharmacologically actives such as anti-inflammatory, analgesia, step-down, anti-arrhythmia, clinical be mainly used in symptoms such as treatment rheumatoid arthritis, cerebral ischemia, maladjusted nervous system (Wang Naiqin, etc. Acta Pharmaceutica Sinica, 1992,23 (2): 81; Zhou Jinhuang waits the chief editor. the Pharmacology and Clinics of Chinese Materia Medica progress. and second. Beijing: China Science Tech Publishing House, 1993,66; Sun Xuguang, Huang Yuming, Chou Ping .CN 98120549, Chou Ping, the red .CN 1142946 of Qiu Sai, Chen Chong, Xu Haiqin, all good .CN 114945.).
Qin Guo-Wei etc. utilizes the reactive behavior of the carbonyl of C ring and enol ether to synthesize serial Sinomenine derivate and reported first tuduranine and derivative to have effects such as intelligence development, neuroprotective and (adopt mouse Morris water mazetest; Social recognition test, NaNO
2Induced anoxia test) (Qin Guo-Wei, etal.WO 2004/048340).Pang Zhigong etc. are in patent CN.1153171, and the tuduranine title complex of having reported blue or green network germanium-germanium metal is as broad-spectrum anti-cancer drug, have toxic side effect little, do not reduce immune function of human body, effectively press down the characteristics of knurl.
Up to the present, actually rare to the report of the preparation of Sinomenine derivate and pharmacologically active thereof, we replace 17 methyl of tuduranine will cause change its physiologically active and the mode of action with dissimilar functional groups at imagination.
Three, summary of the invention
The object of the present invention is to provide class 17-acyl group Sinomenine derivate and preparation method thereof; adopt the benzyloxy benzyl to replace the method for benzyl protection phenolic hydroxyl group, carry out mild condition with rare trifluoroacetic acid/dichloromethane solution room temperature during deprotection; speed of response is fast, and yield is higher.
The objective of the invention is to realize by following technical scheme:
One class 17-acyl group Sinomenine derivate, its structural formula is as follows:
Wherein R is C
1-C
15Chain hydrocarbon acyl group, cyclic hydrocarbon acyl group, replace the hydrocarbon acyl group, as: ethanoyl, propionyl, butyryl radicals,, phenylacetyl, cyclopropane carbonyl; Or aroyl, fragrant heterocyclic acyl, as: benzoyl, 3,5-dimethylbenzoyl, salicyloyl, nicotinoyl, furancarbonyl.
The preparation method's of the 17-acyl group Sinomenine derivate that the present invention relates to reaction process is as follows:
The preparation method of one class 17-acyl group Sinomenine derivate, its preparation process is as follows:
(1) preparation of 4-benzyloxy benzyl tuduranine (III): get tuduranine (II), triphenylphosphine, 4-benzyloxy benzylalcohol dissolution with solvents with q.s, 0-20 ℃ drips diethyl azodiformate down, 0.5-2hr in add, continue to be stirred to reaction and finish to obtain 4-benzyloxy benzyl tuduranine, yield 80.0-99.0%; Wherein the consumption of triphenylphosphine, 4-benzyloxy benzylalcohol, diethyl azodiformate is all 1.5-5.0 times (mol) that green grass or young crops rises alkali (II) consumption, described solvent is tetrahydrofuran (THF), toluene or both mixtures, and its total consumption is 5-100 a times of tuduranine (II) quality.
(2) preparation of 17-demethyl-4-benzyloxy benzyl tuduranine (IV): 4-benzyloxy benzyl tuduranine (III) is used dissolution with solvents, in the presence of acid binding agent, react then, obtain N-(1-chloroethene oxygen formyl radical)-4-benzyloxy benzyl tuduranine with chloroformate-1-chloro-ethyl ester; The residuum of reaction is directly joined in the absolute methyl alcohol of q.s, reflux obtains 17-demethyl-4-benzyloxy benzyl tuduranine and hydrochloride mixture thereof under the nitrogen protection, this mixture disperses with chloroform, the sodium hydrogen carbonate solution neutralization obtains 17-demethyl-4-benzyloxy benzyl tuduranine (IV), wherein solvent for use is 1, aprotic solvent such as 2-ethylene dichloride, chloroform, methylene dichloride, acetone, toluene, its consumption are 3-15 times (quality) of 4-benzyloxy benzyl tuduranine; Described acid binding agent is an alkaline carbonate, and as sodium bicarbonate, yellow soda ash, salt of wormwood, its consumption is 1.0-60 times (quality) of 4-benzyloxy benzyl tuduranine; The chloroformate-1-chloro-ethyl ester consumption is 0.1-3.0 times (quality) of 4-benzyloxy benzyl tuduranine;
(3), the preparation of 17-acyl group-4-benzyloxy benzyl tuduranine (V): get above-mentioned 17-demethyl-4-benzyloxy benzyl tuduranine (IV); after dissolution with solvents; in the presence of acid binding agent with acyl chlorides or acid anhydrides generation acylation reaction; or in the presence of DCC (dicyclohexyl charing diimine), obtain 17-acyl group-4-benzyloxy benzyl tuduranine (V) with the direct condensation of carboxylic acid; described acid binding agent is organic bases, as triethylamine, pyridine; or mineral alkali, as yellow soda ash, salt of wormwood, sodium bicarbonate, the 1-10 that its consumption is 17-demethyl-4-benzyloxy benzyl tuduranine is (mol) doubly.
(4), the preparation of 17-acyl group-4-benzyloxy benzyl tuduranine (I): get 17-acyl group-4-benzyloxy benzyl tuduranine at room temperature with 2-20% trifluoroacetic acid/dichloromethane solution-treated, with NaHCO
3Neutralization, drying, precipitation obtain 17-acyl group tuduranine (I).
Part of compounds title numbering and physico-chemical constant thereof that 17 1 acyl group Sinomenine derivates such as structural formula I are comprised see the following form:
Four, embodiment
The preparation embodiment of compound involved in the present invention is provided below:
The preparation of preparation example one 17-ethanoyl tuduranine (compound 1):
(1) preparation of 4-benzyloxy benzyl tuduranine (III):
In the 100ml there-necked flask, add 1.65g tuduranine (II) successively, 4g PPh
3, 3.17g4-benzyloxy benzylalcohol and 40ml absolute thf, start stirring, ice bath is cooled to 0 ℃ and drips 2.65gDEAD down, adds in the 30min, remove ice bath, continue to stir with TLC detection reaction progress, about 10hr afterreaction finishes, and decompression is revolved and desolvated, with silica gel chromatographic column dress post, use ethyl acetate successively, reach 6: 1 chloroform/methanol drip washing, obtain pale yellow product, the ether recrystallization obtains 2.2g white solid 4-benzyloxy benzyl tuduranine;
(2) preparation of N-demethyl-4-benzyloxy benzyl tuduranine (IV):
1.0g4-benzyloxy benzyl tuduranine III dissolves with ethylene dichloride, add sodium bicarbonate 4.0g, be cooled to 0 ℃ under stirring, drip the 1.0ml chloroformate-1-chloro-ethyl ester, insulation 1-2hr, remove ice-water bath, be warming up to little backflow 0.5-1hr, TLC (ethyl acetate expansion) detection reaction is extremely complete, cool to room temperature, filter, revolve and desolvate;
The gained intermediate product directly joins in the absolute methyl alcohol of 20ml without refining, reflux 15min under the nitrogen protection, and the TLC detection reaction is complete, and decompression is revolved and is desolvated, and products obtained therefrom is N-demethyl-4-benzyloxy benzyl tuduranine (IV) and hydrochloride mixture thereof; This mixture disperses with the 20ml chloroform, adds the 10ml depth of water liquid of 2g sodium bicarbonate, stirs 5 minutes, tells organic layer, anhydrous magnesium sulfate drying, and solvent is sloughed in decompression, obtains N-demethyl-4-benzyloxy benzyl tuduranine (IV);
(3) 17-ethanoyl-4-benzyloxy benzyl tuduranine (V, preparation R=Ac):
100mgN-demethyl-4-benzyloxy benzyl tuduranine (III), methylene dichloride 15ml, 0.1ml triethylamine, Dropwise 5 0mg Acetyl Chloride 98Min. under the ice-water bath, TLC are followed the tracks of reaction to fully, wash, with anhydrous magnesium sulfate drying, decompression is revolved to desolvate and is made with extra care with silica gel column chromatography, gets 98mg white solid 17-ethanoyl-4-benzyloxy benzyl tuduranine, yield 88.8%;
(4) preparation of 17-ethanoyl tuduranine (compound 1):
50mg17-ethanoyl-4-benzyloxy benzyl tuduranine 5%TFA/CH
2Cl
2The 5ml stirring at room was handled 30 minutes, and with the neutralization of 5ml saturated sodium bicarbonate aqueous solution, branch vibration layer with anhydrous magnesium sulfate drying, is sloughed solvent, preparation silica-gel plate layer chromatography separate 36mg compound 4, yield 89.0%.
The preparation (compound 8) of preparation example two 17-benzoyl tuduranines
(1) preparation of 4-benzyloxy benzyl tuduranine (III) [with step (1) in the preparation example one];
(2) preparation of N-demethyl-4-benzyloxy benzyl tuduranine (IV) [with step (2) in the preparation example one];
(3) preparation of 17-benzoyl-4-benzyloxy benzyl tuduranine:
Add phenylformic acid (70mg) and DCC (100mg) in methylene dichloride (10ml) solution of 100mg benzyloxy benzyl tuduranine, TLC follows the tracks of reaction to fully, filters the not purified the next step that is directly used in of gained filtrate; (4) preparation of 17-benzoyl tuduranine:
In the solution of step (1) gained, add 5ml 5% trifluoroacetic acid/dichloromethane solution room temperature treatment 5min, washing, drying, the pressure reducing and steaming solvent, product obtains compound 8, yield: 80% with the silica gel column chromatography separation.
The preparation of preparation example two 17-cyclopropane carbonyl tuduranines (compound 4)
(1) preparation of 4-benzyloxy benzyl tuduranine (III) [with step (1) in the preparation example one];
(2) preparation of N-demethyl-4-benzyloxy benzyl tuduranine (IV) [with step (2) in the preparation example one];
(3) preparation of 17-cyclopropane carbonyl-4-benzyloxy benzyl tuduranine:
In trichloromethane (10ml) solution of 100mg 17-demethyl-4-benzyloxy benzyl tuduranine, add cyclopropanecarboxylic acid (30mg) and DCC (100mg), TLC follows the tracks of reaction to fully, filters the not purified the next step that is directly used in of gained filtrate.
(4) in the solution of step (3) gained, add 5ml 5% trifluoroacetic acid/dichloromethane solution room temperature treatment 5min, washing, drying, the pressure reducing and steaming solvent, product obtains compound 4, yield: 80% with the silica gel column chromatography separation.
The preparation (compound 16) of preparation example four 17-salicyloyl tuduranines
(1) preparation of 4-benzyloxy benzyl tuduranine (III) [with step (1) in the preparation example one];
(2) preparation of N-demethyl-4-benzyloxy benzyl tuduranine (IV) [with step (2) in the preparation example one];
(3) preparation of 17-salicyloyl-4-benzyloxy benzyl tuduranine:
In trichloromethane (10ml) solution of 100mg 17-demethyl-4-benzyloxy benzyl tuduranine, add acetylsalicylic acid (50mg) and DCC (100mg), TLC follows the tracks of reaction to fully, filters the not purified the next step that is directly used in of gained filtrate.
(4) preparation of 17-salicyloyl tuduranine:
In the solution of step (1) gained, add 5ml 5% trifluoroacetic acid/dichloromethane solution room temperature treatment 5min, washing, drying, the pressure reducing and steaming solvent, product obtains compound 16, yield: 60% with the silica gel column chromatography separation.
Claims (6)
1. a class 17-acyl group Sinomenine derivate, its structural formula is as follows:
Wherein R is any one in the following acyl group: ethanoyl, propionyl, butyryl radicals, cyclopropane carbonyl, phenylacetyl, α-(2-methylenedioxy phenoxy) ethanoyl, 2-phenyl propionyl, benzoyl, 3; 5-dimethylbenzoyl, 3,4-difluoro benzoyl, α-(6-methoxyl group-naphthalene-2-yl) propionyl, (furans-2-yl) formyl radical, (pyridin-3-yl) formyl radical, 3-chlorobenzene formacyl, 4-methyl benzoyl, salicyloyl.
2. method for preparing the described class 17-acyl group Sinomenine derivate of claim 1, its preparation process is as follows:
(1) preparation of 4-benzyloxy benzyl tuduranine: get tuduranine, triphenylphosphine, 4-benzyloxy benzylalcohol dissolution with solvents, 0-20 ℃ drips diethyl azodiformate down, 0.5-2hr in add, continue to be stirred to reaction and finish to obtain 4-benzyloxy benzyl tuduranine, yield 80.0-99.0%;
(2) preparation of 17-demethyl-4-benzyloxy benzyl tuduranine: with 4-benzyloxy benzyl tuduranine dissolution with solvents, in the presence of acid binding agent, react then, obtain N-(1-chloroethene oxygen formyl radical)-4-benzyloxy benzyl tuduranine with chloroformate-1-chloro-ethyl ester; Products therefrom is directly joined in the methyl alcohol, and reflux obtains 17-demethyl-4-benzyloxy benzyl tuduranine and hydrochloride mixture thereof under the nitrogen protection, and this mixture disperses with chloroform, and the sodium hydrogen carbonate solution neutralization obtains 17-demethyl-4-benzyloxy benzyl tuduranine; The solvent that 4-benzyloxy benzyl tuduranine uses is a kind of in methylene dichloride, trichloromethane, the trifluoroacetic acid, and its concentration is between 1-20%, and the mass ratio of the consumption of solvent and 4-benzyloxy benzyl tuduranine is 5-100 times;
(3) preparation of 17-acyl group-4-benzyloxy benzyl tuduranine: get above-mentioned 17-demethyl-4-benzyloxy benzyl tuduranine, after dissolution with solvents, in the presence of acid binding agent with acyl chlorides or acid anhydrides generation acylation reaction, or in the presence of dicyclohexyl charing diimine with the direct condensation of carboxylic acid, obtain 17-acyl group-4-benzyloxy benzyl tuduranine;
(4) preparation of 17-acyl group tuduranine: get 17-acyl group-4-benzyloxy benzyl tuduranine, with the dichloromethane solution room temperature treatment of the trifluoroacetic acid of concentration 2-20%, with NaHCO
3Neutralization, drying, precipitation obtain 17-acyl group tuduranine.
3. the preparation method of a class 17-acyl group Sinomenine derivate according to claim 2; it is characterized in that the consumption of triphenylphosphine, 4-benzyloxy benzylalcohol, diethyl azodiformate in step (1) is all 1.5-5.0 times (mol) of tuduranine consumption; described solvent is tetrahydrofuran (THF), benzene or both mixtures, and the total consumption of solvent is 5-100 a times of tuduranine quality.
4. the preparation method of a class 17-acyl group Sinomenine derivate according to claim 2, it is characterized in that at the solvent described in the step (2) be 1, a kind of in 2-ethylene dichloride, chloroform, methylene dichloride, acetone or the toluene, its consumption is the 3-15 doubly (quality) of 4-benzyloxy benzyl tuduranine; Described acid binding agent is a kind of in sodium bicarbonate, yellow soda ash or the salt of wormwood, and its consumption is the 1.0-6.0 doubly (quality) of 4-benzyloxy benzyl tuduranine; The chloroformate-1-chloro-ethyl ester consumption is 0.1-3.0 times (quality) of 4-benzyloxy benzyl tuduranine.
5. the preparation method of a class 17-acyl group Sinomenine derivate according to claim 2; it is characterized in that at the acylting agent described in the step (3) be a kind of in acyl chlorides, acid anhydrides, carboxylic acid or the dicyclohexyl charing diimine; reagent dosage is 1-10 times (mol) of 17-demethyl-4-benzyloxy benzyl tuduranine; described acid binding agent is an organic bases; or mineral alkali, the consumption of alkali is 1-10 times (mol) of 17-demethyl-4-benzyloxy benzyl tuduranine.
6. the preparation method of a class 17-acyl group Sinomenine derivate according to claim 5 is characterized in that described organic bases is triethylamine or pyridine; Described mineral alkali is a kind of in sodium bicarbonate, yellow soda ash or the salt of wormwood.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100388629A CN100408578C (en) | 2006-03-15 | 2006-03-15 | A class of 17-acyl diversine derivatives and its preparing method |
| JP2008545875A JP2009519960A (en) | 2005-12-15 | 2006-12-15 | Preparation and use of sinomenine derivatives |
| PCT/US2006/048086 WO2007070703A2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| EP06847694A EP1959956A2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| CN2006800474181A CN101578101B (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
| US12/096,543 US7932264B2 (en) | 2005-12-15 | 2006-12-15 | Sinomenine derivatives and preparation and uses thereof |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101578101B (en) * | 2005-12-15 | 2012-05-23 | 自然医学公司 | Sinomenine derivatives and preparation and uses thereof |
| CN1876634A (en) * | 2006-06-19 | 2006-12-13 | 湖南正清制药集团股份有限公司 | Sinomenine structure-modified compound and its preparation method |
| 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 |
| CN103387579A (en) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | Synthesis of 4-benzyloxy-17-benzenesulfonylmorphinan-6-one |
| CN103387539A (en) * | 2012-05-08 | 2013-11-13 | 长沙理工大学 | Synthesis of 4-benzyloxy-17-acetylmorphinan-6-one |
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| CN1153171A (en) * | 1995-12-29 | 1997-07-02 | 西安医科大学 | Anticancer preparation |
| WO2004048340A1 (en) * | 2002-11-28 | 2004-06-10 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Sinomenine and sinomenine compounds, synthesis and use |
| CN1687065A (en) * | 2005-03-18 | 2005-10-26 | 中国科学院上海有机化学研究所 | Derivative of sinomenine with pyrazinc cyclc being connected to C cycle, synthetic method and application |
| CN1687070A (en) * | 2005-03-18 | 2005-10-26 | 中国科学院上海有机化学研究所 | Sinomenine derivative with C cycle connected to penetabasic heterocycle and synthesizing method |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1153171A (en) * | 1995-12-29 | 1997-07-02 | 西安医科大学 | Anticancer preparation |
| WO2004048340A1 (en) * | 2002-11-28 | 2004-06-10 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Sinomenine and sinomenine compounds, synthesis and use |
| CN1687065A (en) * | 2005-03-18 | 2005-10-26 | 中国科学院上海有机化学研究所 | Derivative of sinomenine with pyrazinc cyclc being connected to C cycle, synthetic method and application |
| CN1687070A (en) * | 2005-03-18 | 2005-10-26 | 中国科学院上海有机化学研究所 | Sinomenine derivative with C cycle connected to penetabasic heterocycle and synthesizing method |
Non-Patent Citations (4)
| Title |
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| Morphinane Alkaloids with Cell Protective Effects fromSinomenium acutum. Bao, Guan-Hu et al.Journal of Natural Products68,Vol.68 No.7. 2005 |
| Morphinane Alkaloids with Cell Protective Effects fromSinomenium acutum. Bao, Guan-Hu et al.Journal of Natural Products68,Vol.68 No.7. 2005 * |
| Suppressive effects of JCICM-6, the extract of an anti-arthriticherbal formula, on the experimental inflammatory and iceptivemodels in rodents. Zhou, Hua, et al.Biological & Pharmaceutical Bulletin,Vol.29 No.2. 2006 |
| Suppressive effects of JCICM-6, the extract of an anti-arthriticherbal formula, on the experimental inflammatory and iceptivemodels in rodents. Zhou, Hua, et al.Biological & Pharmaceutical Bulletin,Vol.29 No.2. 2006 * |
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