CN102311434A - Evodiamine compounds, preparation method thereof and application thereof - Google Patents
Evodiamine compounds, preparation method thereof and application thereof Download PDFInfo
- Publication number
- CN102311434A CN102311434A CN 201110188588 CN201110188588A CN102311434A CN 102311434 A CN102311434 A CN 102311434A CN 201110188588 CN201110188588 CN 201110188588 CN 201110188588 A CN201110188588 A CN 201110188588A CN 102311434 A CN102311434 A CN 102311434A
- Authority
- CN
- China
- Prior art keywords
- evodiamine
- low
- alkyl
- grade
- rudimentary
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC(CI)C(N*1)N(C)C2=C1C=CIC=C2 Chemical compound CC(CI)C(N*1)N(C)C2=C1C=CIC=C2 0.000 description 4
Abstract
The invention relates to the technical field of medicines. The content of DNA topoisomerase I (TopoI) in tumor cells is substantially higher the content of the TopoI in normal tissues, and an inhibitor of the TopoI is listed as one of six types of antitumor drugs which are primarily researched by an American NCI (National Cancer Institute). The invention aims to obtain evodiamine derivatives with strong antitumor activities by modifying the structure of evodiamine. The evodiamine structure of the evodiamine compounds is represented by general formula (I) in the specification. The invention also provides an application of the evodiamine compounds and medicinal salts thereof in preparing topoisomerase inhibitors and antitumor drugs.
Description
Technical field
The present invention relates to medical technical field, be specifically related to evodiamine compounds and pharmaceutical salts thereof, and their preparation method and purposes.
Background technology
DNA topoisomerase I (topoisomeraseI; TopoI) be the indispensable enzyme that cell DNA duplicates, transcribes, recombinates and repairs; In tumour cell; Especially the TopoI content of colorectal carcinoma, cervical cancer, ovarian cancer etc. is much higher than healthy tissues, so such medicine has very high selectivity to tumour cell.The suppressor factor of this enzyme has been classified as one of six big series antineoplastic medicaments of primary study at present by U.S. NCI.
NSC 94600 is classical topoisomerase I suppressor factor, and existing at present three camptothecine compounds get into clinical use, is respectively that Rinotecan (Irinotecan), TPT (Topotecan) and shellfish Lip river are for health (Belotecan).Yet, the essential lactone structure of such compound activity too fast carboxylate salt that is hydrolyzed into non-activity in human body, and poorly water-soluble, toxicity are big.In order to overcome the defective of camptothecine compounds, successively obtain non-camptothecin topoisomerase I suppressor factor such as benzo phenanthridines compounds, indenoisoquinoline class, indolocarbazole class in recent years.
In early-stage Study; The inventor has launched virtual high flux screening research to the crystalline structure of topoisomerase I; Find that evodiamine (Evodiamine) has the activity that suppresses topoisomerase I; And in anti tumor activity in vitro, show medium anti-tumor activity (Guoqiang Dong; Chunquan Sheng.Selection of evodiamine as a novel topoisomerase I inhibitor by structure-based virtual screening and hit optimization of evodiamine derivatives as antitumor agents; J.Med.Chem.2010,53 (21): 7521-7531.Evodiamine structural formula: C
19H
17N
3O).
Summary of the invention
The objective of the invention is to through evodiamine is carried out structural modification, obtain one type of evodiamine verivate that has than powerful antitumor activity.
The invention provides one type of new evodiamine compounds (comprise its raceme, and d-type or l-type isomer) and pharmaceutical salts thereof, the structure of this compound is shown in general formula (I):
The female substitution in ring base of evodiamine can be single replacement, also can be polysubstituted, R
1To R
10Substituting group is explained as follows:
R
1, R
4Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, rudimentary hydroxyalkyl, lower alkoxy, low-grade alkenyl, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, diazanyl, rudimentary diazanyl alkyl, azido-;
Preferred R
1, R
4Represent following groups independently: hydrogen, halogen, low alkyl group, hydroxyl, lower alkoxy;
R
2, R
9Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, rudimentary hydroxyalkyl, lower alkoxy, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl;
Preferred R
2, R
9Represent following groups independently: hydrogen, halogen, hydroxyl, low alkyl group, lower alkoxy, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl;
R
3Expression following groups: hydrogen; Halogen; Low-grade halogenated alkyl; Low alkyl group; Hydroxyl; Rudimentary hydroxyalkyl; Lower alkoxy; Low-grade alkenyl; Alkynyl of low-grade chain; Amino; Low-grade alkyl amino; Low-grade halogenated alkyl is amino; Low-grade cycloalkyl is amino; Alkynyl of low-grade chain is amino; Nitro; Rudimentary 4-nitro alkyl; Cyanic acid; Rudimentary cyanic acid alkyl; Carboxamido-group; The low-grade cycloalkyl carboxamido-group; Rudimentary amido alkyl; Diazanyl; Rudimentary diazanyl alkyl; Azido-; Rudimentary azido-alkyl; NHR
11Or NHC (O) R
11, replacement or unsubstituted aralkyl or pyridyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy, piperazinyl;
Preferred R
3The expression following groups: hydrogen, halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade halogenated alkyl are amino, low-grade cycloalkyl is amino, alkynyl of low-grade chain is amino, nitro, carboxamido-group, low-grade cycloalkyl carboxamido-group, NHR
11Or NHC (O) R
11, replacement or unsubstituted aralkyl or pyridyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy, piperazinyl;
R
5Expression following groups: methylene radical, carbonyl, thiocarbonyl group;
R
6, R
8Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary hydroxyalkyl, low-grade alkenyl, alkynyl of low-grade chain, low alkyl group oxygen base, alkynyl of low-grade chain oxygen base, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, low-grade cycloalkyl carboxamido-group, diazanyl, rudimentary diazanyl alkyl, azido-, rudimentary azido-alkyl;
Preferred R
6, R
8Represent following groups independently: hydrogen, halogen, low alkyl group, lower alkoxy, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl;
R
7Expression following groups: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary hydroxyalkyl, low-grade alkenyl, alkynyl of low-grade chain, alkynyl of low-grade chain oxygen base, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, low-grade cycloalkyl carboxamido-group, diazanyl, rudimentary diazanyl alkyl, azido-, rudimentary azido-alkyl, OR
11Or OC (O) R
11
Preferred R
7Expression following groups: hydrogen, halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, nitro, carboxamido-group, low-grade cycloalkyl carboxamido-group, OR
11Or OC (O) R
11
R
10Expression hydrogen or to chlorobenzene formacyl;
R
11The expression following groups: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary epoxy alkyl, low-grade alkenyl, alkynyl of low-grade chain, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, rudimentary amido alkyl, diazanyl, rudimentary diazanyl alkyl, rudimentary azido-alkyl, low-grade cycloalkyl, replacement or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy, lower alkoxy low alkyl group;
Preferred R
11Expression following groups: low alkyl group, low-grade cycloalkyl, rudimentary aralkyl; Low-grade halogenated alkyl, rudimentary epoxy alkyl, low-grade alkenyl, alkynyl of low-grade chain;
The term " rudimentary " relevant with alkyl and alkoxyl group refers to contain the straight or branched saturated fatty hydrocarbyl group of 1 to 6 carbon atom among this paper; The term " rudimentary " relevant with alkenyl or alkynyl group refers to contain 2 to 6 carbon atoms and the one or more pairs of keys or triple-linked group; Naphthenic base is meant the ring that contains 3 to 7 carbon; Aryl refers to list, two or the tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring contains maximum 7 carbon atoms.
Above-mentioned replacement evodiamine compounds can be its raceme, also can be its d-type or l-type isomer.
Through the better compound R of test antitumous effect
1To R
10Concrete substituting group sees table 1 for details.
The chemical structure of table 1 preferred compound
Above-mentioned evodiamine compounds can be prepared into the form of pharmaceutical salts according to ordinary method.Comprise its organic acid salt and inorganic acid salt: mineral acid includes, but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, di-phosphate, Hydrogen bromide, nitric acid etc., and organic acid includes, but is not limited to acetate, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment, oxalic acid etc.
Compound general reaction flow process of the present invention is following:
General preparation process is:
1, the preparation of compound VI I
Replace tryptamines (Ia) with in ethyl formate 80 ℃ refluxed 12 hours, obtain substituted N-formyl radical tryptamines II.
Substituted N-formyl radical tryptamines (II) reacted 2 hours with POCl3 0-5 ℃, at room temperature reacted to obtain title product III in 2 hours again.
Substituted anthranilic acid (IV) obtained substituted pyridine red acid acid anhydride V in 3 hours with 70 ℃ of backflows of TRIPHOSGENE 99.5 in tetrahydrofuran solution.
Substituted pyridine red acid acid anhydride (V) generates substituted N-picoline red acid acid anhydride VI with iodomethane reaction under the NaH effect.
Compound III and VI with equimolar amount in methylene dichloride 45 ℃ refluxed 5 hours, obtain substituted evodiamine VII.
2, compound VI Ic preparation
Compound VI Ia is dissolved among the DMSO, is alkali and various halogenated alkane, halo naphthenic hydrocarbon, halo alkynes etc. with salt of wormwood, room temperature or 60 ℃ of compound VI Ic that reaction can be made in 2-7 hour.
3, compound VI Id preparation
Compound VI Ia is dissolved in an amount of methylene dichloride, adds acyl chlorides or acylbromide, and ice bath obtains title product VIId to 0-5 ℃ of reaction 3 hours under triethylamine catalysis.
4, compound VI Ie preparation
Compound VI Ib is dissolved in an amount of ethanol, is the compound VI Ie that 80 ℃ of reactions such as alkali and various halogenated alkane, halo naphthenic hydrocarbon, halo alkynes can be made in 4 hours with salt of wormwood.
5, compound VI If preparation
Compound VI Ib is dissolved in an amount of methylene dichloride, adds acyl chlorides or acylbromide, and room temperature reaction is 3 hours under triethylamine catalysis, obtains title product VIIf.
6, compound VIII preparation
Compound VI I is dissolved among an amount of DMF, is 80 ℃ of reactions of alkali and parachlorobenzoyl chloride 1 hour with NaH, the compound VIII of system.
7, compound I X preparation
Compound VI I is dissolved in an amount of toluene, obtains compound I X in 4 hours with 120 ℃ of reactions of lawesson reagent.
8, compounds X preparation
Compound VI I is dissolved in an amount of anhydrous tetrahydro furan, spends the night with the lithium aluminium hydride room temperature reaction, obtains compounds X.
Another purpose of the present invention provides above-mentioned evodiamine compounds and the application of pharmaceutical salts in the preparation topoisomerase enzyme inhibitor thereof, and the application in the preparation antitumor drug.
The compounds of this invention shows through experiment; Has good antineoplastic activity; The anti-tumor activity of majority of compounds is superior to TPT, and indivedual active outstanding antitumor activity of compound surpass NSC 94600, so The compounds of this invention and its esters can be used to prepare antitumor drug.
The pharmacologically active of The compounds of this invention makes it can be used to prepare antitumor drug.This pharmaceutical composition can be solid form or liquid form.
Embodiment
Combine embodiment and accompanying drawing that the present invention is described in detail, but enforcement of the present invention is not limited only to this at present.
Synthesizing of embodiment 1:1-methyl evodiamine
A, the preparation of N-formyl radical tryptamines
In the 50ml three-necked bottle, add 8g (50mmol) tryptamines and 25g ethyl formate, 80 ℃ were refluxed 12 hours, had reacted the back solvent evaporated, obtained brown oil, and room temperature was placed 2-3 days, and crystal slowly occurs, and suction filtration obtains product 7.3g, yield 87.1%.
B, 3,4-dihydro-β-Ka Lin preparation
In the 100ml three-necked bottle, add the 50ml methylene dichloride, under agitation condition; Add 5g (26mmol) N-formyl radical tryptamines, ice-water bath is cooled to about 5 ℃, then; Slowly add the 12.5ml POCl3, ice bath reacted 2 hours down, at room temperature reacted 2 hours again; After having reacted, methylene dichloride and unreacted POCl3 are reclaimed in underpressure distillation, and residual solid divides three extractions with the acetic acid aqueous solution of 120ml 10%.Combining extraction liquid is regulated pH to 9-10 with ammoniacal liquor, and suction filtration, washing, decompression oven dry obtain yellow powder 3,4-dihydro-β-Ka Lin 4.1g, yield 89.7%.
C, the preparation of 8-picoline red acid acid anhydride
In the 50ml three-necked bottle, add 1g (6.6mmol) 3-methyl anthranilic acid and 0.78g (2.6mmol) TRIPHOSGENE 99.5, add the dissolving of 30ml dry tetrahydrofuran; 70 ℃ were refluxed 3 hours; After having reacted, be cooled to room temperature, reaction solution is poured in the 100ml frozen water; Suction filtration, drying obtain white powder 8-picoline red acid acid anhydride 1g, yield 83.0%.
D, N-methyl-8-picoline red acid acid anhydride preparation
In the 50ml round-bottomed flask, add 1g (5.6mmol) 8-picoline red acid acid anhydride and NaH 0.2g (8.4mmol), add 20ml DMF; After the room temperature activation 30 minutes; Slowly drip methyl iodide 1g (6.7mmol), room temperature reaction 1 hour is poured in the frozen water after having reacted; Suction filtration, drying obtain grey powder N-methyl-8-picoline red acid acid anhydride 0.6g, yield 54.5%.
E, the preparation of 1-methyl evodiamine
In the 50ml round-bottomed flask, add 0.6g (3mmol) N-methyl-8-picoline red acid acid anhydride and 0.5g (3mmol) 3,4-dihydro-β-Ka Lin; Add the 20ml methylene dichloride; 45 ℃ were refluxed 5 hours, and after having reacted, reaction solution were cooled to room temperature; Suction filtration, drying obtain white powder 1-methyl evodiamine 0.78g, yield 82.1%.
Synthesizing of embodiment 2:4-fluorine evodiamine
Method according to embodiment 1; In step C with 6-fluorine o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 5-fluorine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-5-fluorine pyridine red acid acid anhydride with 5-fluorine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain grey powder 4-fluorine evodiamine 0.47g, total recovery 36.5% with N-methyl-5-fluorine pyridine red acid acid anhydride.
Synthesizing of embodiment 3:4-chlorine evodiamine
Method according to embodiment 1; In step C, replace 3-methyl anthranilic acid with the 6-chloro-o-amino benzoic acid; Obtain 5-chlorine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-5-chloro pyridine red acid acid anhydride with 5-chlorine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain grey powder 4-chlorine evodiamine 0.64g, total recovery 47.5% with N-methyl-5-chloro pyridine red acid acid anhydride.
Synthesizing of embodiment 4:4-methyl evodiamine
Method according to embodiment 1; In step C with 6-methyl o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 5-picoline red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-5-picoline red acid acid anhydride with 5-picoline red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain grey powder 4-methyl evodiamine 0.21g, total recovery 21.1% with N-methyl-5-picoline red acid acid anhydride.
Synthesizing of embodiment 5:4-Rhetsinine
In the 50ml three-necked bottle, add 4-methoxyl group evodiamine 0.2g (0.6mmol), add the dissolving of 20ml methylene dichloride; Nitrogen protection ,-78 ℃ add 0.22ml (2.4mmol) boron tribromide down, and-78 ℃ of reactions are after 4 hours; Room temperature reaction 3 hours has reacted the back and has added 40ml water, uses dichloromethane extraction; Organic layer merges, dry back evaporate to dryness, column chromatography (sherwood oil: ETHYLE ACETATE=3: 1) obtain white powder 4-Rhetsinine 0.15g, yield 78.9%.
Synthesizing of embodiment 6:4-methoxyl group evodiamine
Method according to embodiment 1; In step C with 6-methoxyl group o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 5-methoxyl group pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-5-methoxyl group pyridine red acid acid anhydride with 5-methoxyl group pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain grey powder 4-methoxyl group evodiamine 0.34g, total recovery 31.6% with N-methyl-5-methoxyl group pyridine red acid acid anhydride.
Synthesizing of embodiment 7:3-fluorine evodiamine
Method according to embodiment 1; In step C with 5-fluorine o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-fluorine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-fluorine pyridine red acid acid anhydride with 6-fluorine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain yellow powder 3-fluorine evodiamine 0.52g, total recovery 52.6% with N-methyl-6-fluorine pyridine red acid acid anhydride.
Synthesizing of embodiment 8:3-chlorine evodiamine
Method according to embodiment 1; In step C, replace 3-methyl anthranilic acid with the 5-chloro-o-amino benzoic acid; Obtain 6-chlorine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-chlorine pyridine red acid acid anhydride with 6-chlorine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain yellow powder 3-chlorine evodiamine 0.61g, total recovery 63.2% with N-methyl-6-chlorine pyridine red acid acid anhydride.
Synthesizing of embodiment 9:3-bromine evodiamine
Method according to embodiment 1; In step C with 5-bromine o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-bromine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-bromine pyridine red acid acid anhydride with 6-bromine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain pale yellow powder 3-bromine evodiamine 0.55g, total recovery 45.2% with N-methyl-6-bromine pyridine red acid acid anhydride.
Synthesizing of embodiment 10:N-(4-chlorobenzene formacyl)-3-bromine evodiamine
In the 50ml round-bottomed flask, add 0.3g (0.78mmol) 3-bromine evodiamine and 0.21g NaH, add 20ml DMF dissolving; Stirring at room 30 minutes adds parachlorobenzoyl chloride 1.3g (7.8mmol), and 80 ℃ were reacted 1 hour; After having reacted, reaction solution adds 50ml 2% sodium hydroxide solution, uses ethyl acetate extraction; Organic phase merging, drying, evaporate to dryness, column chromatography (sherwood oil: ETHYLE ACETATE=10: 1), obtain yellow solid 0.12g, yield 30.7%.
Synthesizing of embodiment 11:3-iodine evodiamine
Method according to embodiment 1; In step C with 5-iodine o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-iodine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-iodine pyridine red acid acid anhydride with 6-iodine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain pale yellow powder 3-iodine evodiamine 0.52g, total recovery 43.2% with N-methyl-6-iodine pyridine red acid acid anhydride.
Synthesizing of embodiment 12:3-methyl evodiamine
Method according to embodiment 1; In step C with 5-methyl o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-picoline red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-picoline red acid acid anhydride with 6-picoline red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain pale yellow powder 3-methyl evodiamine 0.41g, total recovery 33.1% with N-methyl-6-picoline red acid acid anhydride.
Synthesizing of embodiment 13:3-Rhetsinine
According to the method for embodiment 5, replace 4-methoxyl group evodiamine with 3-methoxyl group evodiamine, obtain white powder 3-Rhetsinine 0.10g, yield 52.4%.
Synthesizing of embodiment 14:3-methoxyl group evodiamine
Method according to embodiment 1; In step C with 5-methoxyl group o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-methoxyl group pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-methoxyl group pyridine red acid acid anhydride with 6-methoxyl group pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain pale yellow powder 3-methoxyl group evodiamine 0.43g, total recovery 34.5% with N-methyl-6-methoxyl group pyridine red acid acid anhydride.
Synthesizing of embodiment 15:N-(4-chlorobenzene formacyl)-3-methoxyl group evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 3-methoxyl group evodiamine, obtain yellow powder N-(4-chlorobenzene formacyl)-3-methoxyl group evodiamine 0.11g, yield 35.6%
Synthesizing of embodiment 16:3-nitro evodiamine
Method according to embodiment 1; In step C with 5-nitro o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6-nitro pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-nitro pyridine red acid acid anhydride with 6-nitro pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain yellow powder 3-nitro evodiamine 0.63g, total recovery 65.4% with N-methyl-6-nitro pyridine red acid acid anhydride.
Synthesizing of the amino evodiamine of embodiment 17:3-
In the 100ml round-bottomed flask, add 3-nitro evodiamine 1.2g (3.4mmol), add the 50mlDMF dissolving; Add 0.12g Pd/C (1%) again, reaction system hydrogen emptying 6 times, room temperature reaction spends the night; After having reacted; Use the oil pump solvent evaporated, column chromatography (methylene dichloride: methyl alcohol=100: 2) obtain the amino evodiamine 1.0g of yellow powder 3-, yield 90.1%.
Synthesizing of embodiment 18:3-(bromopropyl is amino) evodiamine
In the 50ml round-bottomed flask, add amino evodiamine 0.5g (1.5mmol) of 3-and salt of wormwood 0.4g (3mmol), add 10ml DMSO dissolving; Slowly drip 1,3-dibromopropane 0.35g (1.7mmol), room temperature reaction is after 2 hours; 60 ℃ were reacted 3 hours, added water 40ml after having reacted, and used ethyl acetate extraction; Organic phase merging, drying, evaporate to dryness, column chromatography (sherwood oil: ETHYLE ACETATE=5: 1) separate, obtain yellow powder 3-(bromopropyl is amino) evodiamine 0.1g, yield 16.7%.
Synthesizing of embodiment 19:3-(the ring fourth is amino) evodiamine
According to the method for embodiment 18,60 ℃ were reacted 7 hours, obtained yellow powder 3-(the ring fourth is amino) evodiamine 0.24g, yield 37.7%.
Synthesizing of embodiment 20:3-kharophen evodiamine
In the 50ml round-bottomed flask, add the amino evodiamine 0.5g (1.5mmol) of 3-, add the dissolving of 20ml methylene dichloride; Ice bath adds 5 triethylamines to 0-5 ℃, slowly drips diacetyl oxide 0.25g (2mmol) then; Ice bath reaction 3 hours has been reacted the back suction filtration, drying; Obtain white powder 3-kharophen evodiamine 0.46g, yield 82.3%.
Synthesizing of embodiment 21:3-ring propyl formamide base evodiamine
According to the method for embodiment 20, replace diacetyl oxide with ring third formyl chloride, obtain white powder 3-ring propyl formamide base evodiamine 0.46g, yield 78.9%.
Synthesizing of embodiment 22:3-(acetobrom is amino) evodiamine
Method according to embodiment 20 replaces diacetyl oxide with bromoacetyl bromide, obtains yellow powder 3-(acetobrom is amino) evodiamine 0.55g, yield 84.6%.
Synthesizing of embodiment 23:3-(sulfydryl kharophen) evodiamine
In the 50ml round-bottomed flask, add 3-(acetobrom is amino) evodiamine 0.5g (1.1mmol), add 10ml DMF dissolving,, add 2.7g (11mmol) Na
2S9H
2O, room temperature reaction spends the night, and has reacted solvent evaporated, column chromatography (methylene dichloride: methyl alcohol=100: 3), obtain yellow powder 0.1g, yield 23.2%.
Synthesizing of embodiment 24:3-(2-(piperazine-1-yl) pyridin-4-yl) evodiamine
In the 50ml round-bottomed flask, add 3-iodine evodiamine 0.43g (1mmol), add 8ml solvent (DMF: dissolving water=5: 1); Add yellow soda ash 0.17g (1.5mmol) and triphenyl phosphorus palladium 0.17g (0.15mmol), add 0.44g (1.5mmol) 2-piperazine-4-pyridine boric acid then, nitrogen protection; 120 ℃ were reacted 3.5 hours; Reacted the back solvent evaporated, column chromatography (methylene dichloride: methyl alcohol=10: 1) obtain yellow powder 0.33g, yield 71.7%.
Synthesizing of embodiment 25:3-fluoro-10-Rhetsinine
According to the method for embodiment 5, replace 4-methoxyl group evodiamine with 3-fluoro-10-methoxyl group evodiamine, obtain white powder 3-fluoro-10-Rhetsinine 0.11g, yield 51.4%.
Synthesizing of embodiment 26:3-fluoro-10-methoxyl group evodiamine
According to the method for embodiment 1, in steps A, replace tryptamines with the 5-methoxytryptamine, obtain 6-methoxyl group-N-formyl radical tryptamines; In step B, replace N-formyl radical tryptamines to obtain 6-methoxyl group-3 with 6-methoxyl group-N-formyl radical tryptamines; 4-dihydro-β-Ka Lin with 5-fluorine o-amino benzoyl acid substitution 3-methyl anthranilic acid, obtains 6-fluorine pyridine red acid acid anhydride in step C; Replace 8-picoline red acid acid anhydride to obtain N-methyl-6-fluorine pyridine red acid acid anhydride with 6-fluorine pyridine red acid acid anhydride among the step D; In step e, replace N-methyl-8-picoline red acid acid anhydride with N-methyl-6-fluorine pyridine red acid acid anhydride, with 6-methoxyl group-3,4-dihydro-β-Ka Lin replaces 3; 4-dihydro-β-Ka Lin obtains yellow powder 3-fluoro-10-methoxyl group evodiamine 0.43g, total recovery 35.4%.
Synthesizing of embodiment 27:3-(N-propine-3-base is amino) evodiamine
According to the method for embodiment 18, replace 1 with propargyl bromide, the 3-dibromopropane obtains 3-(N-propine-3-base is amino) evodiamine 0.1g, yield 21.3%.
Synthesizing of embodiment 28:3-(N, N-two propine-3-base is amino) evodiamine
According to the method for embodiment 19, replace 1 with propargyl bromide, the 3-dibromopropane obtains 3-(N-propine-3-base is amino) evodiamine 0.4g, yield 66.5%.
Synthesizing of embodiment 29:2-chlorine evodiamine
Method according to embodiment 1; In step C, replace 3-methyl anthranilic acid with the 4-chloro-o-amino benzoic acid; Obtain 7-chlorine pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-7-chlorine pyridine red acid acid anhydride with 7-chlorine pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain white powder 2-chlorine evodiamine 0.53g, total recovery 55.4% with N-methyl-7-chlorine pyridine red acid acid anhydride.
Synthesizing of embodiment 30:N-(4-chlorobenzene formacyl)-2-chlorine evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 2-chlorine evodiamine, obtain white solid N-(4-chlorobenzene formacyl)-2-chlorine evodiamine 0.21g, yield 65.3%
Synthesizing of embodiment 31:2-methoxyl group evodiamine
Method according to embodiment 1; In step C with 4-methoxyl group o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 7-methoxyl group pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-7-methoxyl group pyridine red acid acid anhydride with 7-methoxyl group pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain white powder 2-methoxyl group evodiamine 0.23g, total recovery 12.5% with N-methyl-7-methoxyl group pyridine red acid acid anhydride.
Synthesizing of embodiment 32:N-(4-chlorobenzene formacyl)-2-methoxyl group evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 2-methoxyl group evodiamine, obtain white solid N-(4-chlorobenzene formacyl)-2-methoxyl group evodiamine 0.24g, yield 85.7%
Synthesizing of the amino evodiamine of embodiment 33:2-chloro-3-
According to the method for embodiment 17, replace 3-nitro evodiamine with 2-chloro-3-nitro evodiamine, obtain the amino evodiamine 0.09g of yellow powder 2-chloro-3-, yield 10.9%.
Embodiment 34:2,3-dimethoxy evodiamine synthetic
According to the method for embodiment 1, in step C with 4,5-dimethoxy o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 6,7-dimethoxy pyridine red acid acid anhydride, among the step D with 6; 7-dimethoxy pyridine red acid acid anhydride replaces 8-picoline red acid acid anhydride to obtain N-methyl-6,7-dimethoxy pyridine red acid acid anhydride, in step e with N-methyl-6; 7-dimethoxy pyridine red acid acid anhydride replaces N-methyl-8-picoline red acid acid anhydride to obtain white powder 2,3-dimethoxy evodiamine 0.43g, total recovery 45.6%.
Embodiment 35:N-(4-chlorobenzene formacyl)-2,3-dimethoxy evodiamine synthetic
According to the method for embodiment 10, with 2,3-dimethoxy evodiamine replaces 3-bromine evodiamine, obtains white solid N-(4-chlorobenzene formacyl)-2,3-dimethoxy evodiamine 0.27g, yield 55.7%
Synthesizing of embodiment 36:2-chloro-3-nitro evodiamine
Method according to embodiment 1; In step C with 4-chloro-5-nitro o-amino benzoyl acid substitution 3-methyl anthranilic acid; Obtain 7-chloro-6-nitro pyridine red acid acid anhydride; Replace 8-picoline red acid acid anhydride to obtain N-methyl-7-chloro-6-nitro pyridine red acid acid anhydride with 7-chloro-6-nitro pyridine red acid acid anhydride among the step D, in step e, replace N-methyl-8-picoline red acid acid anhydride to obtain white powder 2-chloro-3-nitro evodiamine 0.33g, total recovery 50.1% with N-methyl-7-chloro-6-nitro pyridine red acid acid anhydride.
Synthesizing of embodiment 37:12-chlorine evodiamine
A, N-formyl radical-7-chlorine tryptamines preparation
In the 50ml three-necked bottle, add 2g (10mmol) 7-chlorine tryptamines and 5g ethyl formate, 80 ℃ were refluxed 12 hours, had reacted the back solvent evaporated, obtained brown oil, and room temperature was placed 2-3 days, and crystal slowly occurs, and suction filtration obtains product 1.4g, yield 63.6%.
B, 8-chloro-3,4-dihydro-β-Ka Lin preparation
In the 50ml three-necked bottle, add the 20ml methylene dichloride, under agitation condition; Add 1g (4.4mmol) N-formyl radical-7-chlorine tryptamines, ice-water bath is cooled to about 5 ℃, then; Slowly add the 3ml POCl3, ice bath reacted 2 hours down, at room temperature reacted 2 hours again; After having reacted, methylene dichloride and unreacted POCl3 are reclaimed in underpressure distillation, and residual solid divides three extractions with the acetic acid aqueous solution of 60ml 10%.Combining extraction liquid is regulated pH to 9-10 with ammoniacal liquor, and suction filtration, washing, decompression oven dry obtain yellow powder 8-chloro-3,4-dihydro-β-Ka Lin 0.8g, yield 88.9%.
C, the preparation of 12-chlorine evodiamine
In the 50ml round-bottomed flask, add 0.55g (3mmol) N-picoline red acid acid anhydride and 0.60g (3mmol) 8-chloro-3,4-dihydro-β-Ka Lin; Add the 20ml methylene dichloride; 45 ℃ were refluxed 5 hours, and after having reacted, reaction solution were cooled to room temperature; Suction filtration, drying obtain yellow powder 12-chlorine evodiamine 0.58g, yield 58.2%.
Synthesizing of embodiment 38:10-fluorine evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-fluorine tryptamines, obtain N-formyl radical-5-fluorine tryptamines; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-fluoro-3 with N-formyl radical-5-fluorine tryptamines among the step B; 4-dihydro-β-Ka Lin, with 6-fluoro-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-fluorine evodiamine 0.33g, total recovery 17.1%.
Synthesizing of embodiment 39:N-(4-chlorobenzene formacyl)-10-fluorine evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 10-fluorine evodiamine, obtain yellow oily solid N-(4-chlorobenzene formacyl)-10-fluorine evodiamine 0.27g, yield 77.1%
Synthesizing of embodiment 40:10-chlorine evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-chlorine tryptamines, obtain N-formyl radical-5-chlorine tryptamines; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-chloro-3 with N-formyl radical-5-chlorine tryptamines among the step B; 4-dihydro-β-Ka Lin, with 6-chloro-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-chlorine evodiamine 0.45g, total recovery 21.0%.
Synthesizing of embodiment 41:N-(4-chlorobenzene formacyl)-10-chlorine evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 10-chlorine evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-10-chlorine evodiamine 0.24g, yield 64.9%
Synthesizing of embodiment 42:10-bromine evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-bromine tryptamines, obtain N-formyl radical-5-bromine tryptamines; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-bromo-3 with N-formyl radical-5-bromine tryptamines among the step B; 4-dihydro-β-Ka Lin, with 6-bromo-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-bromine evodiamine 0.55g, total recovery 24.2%.
Synthesizing of embodiment 43:N-(4-chlorobenzene formacyl)-10-bromine evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 10-bromine evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-10-bromine evodiamine 0.30g, yield 73.2%
Synthesizing of embodiment 44:10-iodine evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-iodine tryptamines, obtain N-formyl radical-5-iodine tryptamines; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-iodo-3 with N-formyl radical-5-iodine tryptamines among the step B; 4-dihydro-β-Ka Lin, with 6-iodo-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-iodine evodiamine 0.60g, total recovery 22.9%.
Synthesizing of embodiment 45:10-methyl evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-methyltryptamine, obtain N-formyl radical-5-methyltryptamine; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-methyl-3 with N-formyl radical-5-methyltryptamine among the step B; 4-dihydro-β-Ka Lin, with 6-methyl-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-methyl evodiamine 0.47g, total recovery 24.2%.
Synthesizing of embodiment 46:N-(4-chlorobenzene formacyl)-10-methyl evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 10-methyl evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-10-methyl evodiamine 0.28g, yield 78.8%
Synthesizing of embodiment 47:10-methoxyl group evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with the 5-methoxytryptamine, obtain N-formyl radical-5-methoxytryptamine; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-methoxyl group-3 with N-formyl radical-5-methoxytryptamine among the step B; 4-dihydro-β-Ka Lin, with 6-methoxyl group-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-methoxyl group evodiamine 0.41g, total recovery 20.1%.
Synthesizing of embodiment 48:N-(4-chlorobenzene formacyl)-10-methoxyl group evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 10-methoxyl group evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-10-methoxyl group evodiamine 0.31g, yield 83.8%
Synthesizing of embodiment 49:10-nitro evodiamine
According to the method for embodiment 37, in steps A, replace 7-chlorine tryptamines with 5-nitro tryptamines, obtain N-formyl radical-5-nitro tryptamines; Replace N-formyl radical-7-chlorine tryptamines to obtain 6-nitro-3 with N-formyl radical-5-nitro tryptamines among the step B; 4-dihydro-β-Ka Lin, with 6-nitro-3,4-dihydro-β-Ka Lin replaces 8-chloro-3 in step C; 4-dihydro-β-Ka Lin obtains yellow solid 10-nitro evodiamine 0.54g, total recovery 24.1%.
Embodiment 50:10,12-dinitrobenzene evodiamine synthetic
In the 50ml round-bottomed flask, add 0.3g (1mmol) evodiamine, add the 15ml concentrated sulfuric acid dissolution; Ice bath is dissolved in 0.12g (1.2mmol) saltpetre in the 5ml vitriol oil to 0-5 ℃, slowly drips in the reaction solution; Ice bath reaction 2 hours is poured reaction solution in the ice into after having reacted, and obtains yellow powder 10; 12-dinitrobenzene evodiamine 0.23g, yield 58.1%.
Synthesizing of embodiment 51:10-Rhetsinine
According to the method for embodiment 5, replace 4-methoxyl group evodiamine with 10-methoxyl group evodiamine, obtain white powder 10-Rhetsinine 0.12g, yield 63.2%.
Synthesizing of embodiment 52:N-(4-chlorobenzene formacyl)-10-Rhetsinine
According to the method for embodiment 10, replace 3-bromine evodiamine with the 10-Rhetsinine, obtain yellow solid N-(4-chlorobenzene formacyl)-10-Rhetsinine 0.21g, yield 58.3%.
Synthesizing of embodiment 53:10-oxyethyl group evodiamine
In the 50ml round-bottomed flask; Add 0.32g (1mmol) 10-Rhetsinine and 0.16g (1.2mmol) salt of wormwood, add the 20ml dissolve with ethanol, add monobromethane 0.13g (1.2mmol) then; 80 ℃ were refluxed 4 hours; Reacted the back solvent evaporated, column chromatography (sherwood oil: ETHYLE ACETATE=4: 1) obtain yellow powder 10-oxyethyl group evodiamine 0.28g, yield 79.9%.
Synthesizing of embodiment 54:10-propoxy-evodiamine
According to the method for embodiment 53, replace monobromethane with the 1-N-PROPYLE BROMIDE, obtain yellow solid 10-propoxy-evodiamine 0.31g, yield 86.1%.
Synthesizing of embodiment 55:10-glycidoxy evodiamine
According to the method for embodiment 53, replace monobromethane with epoxy chloropropane, obtain yellow solid 10-glycidoxy evodiamine 0.30g, yield 78.9%.
Synthesizing of the embodiment 56:10-third alkynyloxy group evodiamine
According to the method for embodiment 53, replace monobromethane with propargyl bromide, obtain the yellow solid 10-third alkynyloxy group evodiamine 0.32g, yield 88.8%.
Synthesizing of embodiment 57:10-benzyloxy evodiamine
According to the method for embodiment 53, replace monobromethane with bromobenzyl, obtain yellow solid 10-benzyloxy evodiamine 0.34g, yield 82.9%.
Synthesizing of embodiment 58:10-(cyclopropyl methoxycarbonyl) evodiamine
In the 50ml round-bottomed flask; Add 0.32g (1mmol) 10-Rhetsinine, add the dissolving of 20ml methylene dichloride, drip 4 triethylamines and make catalyzer; Add 0.15g (1.5mmol) cyclopropyl formyl chloride then; Room temperature reaction 3 hours, suction filtration, drying obtain white powder 10-(cyclopropyl methoxycarbonyl) evodiamine 0.29g, yield 76.3% after having reacted.
Synthesizing of embodiment 59:5-thiocarbonyl group evodiamine
In the 50ml round-bottomed flask; Add 0.3g (1mmol) evodiamine, add the dissolving of 20ml toluene, add 0.61g (1.5mmol) lawesson reagent; 120 ℃ were refluxed 4 hours; Reacted the back solvent evaporated, column chromatography (sherwood oil: ETHYLE ACETATE=4: 1) obtain 5-thiocarbonyl group evodiamine 0.21g, yield 65.6%.
Synthesizing of embodiment 60:N-(4-chlorobenzene formacyl)-5-thiocarbonyl group evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 5-thiocarbonyl group evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-5-thiocarbonyl group evodiamine 0.32g, yield 69.5%.
Synthesizing of embodiment 61:10-methoxyl group-5-thiocarbonyl group evodiamine
According to the method for embodiment 59, replace evodiamine with 10-methoxyl group evodiamine, obtain yellow powder 10-methoxyl group-5-thiocarbonyl group evodiamine 0.28g, yield 80.0%.
Synthesizing of embodiment 62:5-methylene radical evodiamine
In the 50ml round-bottomed flask, add 0.3g (1mmol) evodiamine, add the dissolving of 20ml anhydrous tetrahydro furan; Add 0.11g (3mmol) lithium aluminium hydride, stirred overnight at room temperature, the adding saltcake is urged and being gone out after having reacted; Add water 80ml, use the 200ml ethyl acetate extraction, merge organic phase; Drying, evaporate to dryness, column chromatography (sherwood oil: ETHYLE ACETATE=5: 1) obtain 5-methylene radical evodiamine 0.17g, yield 58.6%.
Synthesizing of embodiment 63:N-(4-chlorobenzene formacyl)-5-methylene radical evodiamine
According to the method for embodiment 10, replace 3-bromine evodiamine with 5-methylene radical evodiamine, obtain yellow solid N-(4-chlorobenzene formacyl)-5-methylene radical evodiamine 0.33g, yield 70.2%.
Synthesizing of embodiment 64:3-fluorine evodiamine hydrochloride
In the 50ml round-bottomed flask; Add 0.32g (1mmol) 3-fluorine evodiamine, add the ethyl acetate solution 30ml dissolving of saturated hydrogenchloride, room temperature reaction 3 hours; Suction filtration, washing, drying obtain 3-fluorine evodiamine hydrochloride 0.21g, yield 58.3% after having reacted.
The preparation of embodiment 65:d-3-fluoro-10-Rhetsinine and l-3-fluoro-10-Rhetsinine
Instrument: Agilent 1100 and Daicel chirality semipreparative column (CHIRAPAK AD-H).Sample: 3-fluoro-10-Rhetsinine; Preparation condition: moving phase: Virahol: normal hexane=20: 80-30: 70; Flow velocity: 0.8ml/min; RT: d-3-fluoro-10-Rhetsinine R
d=13.818,1-3-fluoro-10-Rhetsinine R
l=16.013; Detect wavelength: 254nm; Ee value: d-3-fluoro-10-Rhetsinine ee 99%, l-3-fluoro-10-Rhetsinine ee 98%; Specific rotation: d-3-fluoro-10-Rhetsinine [α]
D+ 334 ° of (CH
3OH), l-3-fluoro-10-Rhetsinine [α]
D-393 ° of (CH
3OH).
The corresponding general formula (I) of the related compound of above embodiment
1HNMR and MS data see table 2 for details.Wherein sequence number 1-63 distinguishes 1-63 compound and embodiment 1-63 in the correspondence table 1.
Table 2 preferred compound
1HNMR and MS data
Embodiment 66: the anti-tumor activity test of The compounds of this invention
Compound of the present invention has been carried out the tumor cell proliferation inhibition test, and TP adopts conventional mtt assay (like Lv Qiujun chief editor " developmental pharmacology research method ", 2007:242-243)
Cell strain is selected A549 (human lung carcinoma cell), HCT116 (people's colon-cancer cell), MDA-MB-435 (human breast cancer cell) for use.Nutrient solution is that DMEM+15%NBS+ is two anti-.
Sample liquid preparation: after DMSO (Merck) dissolving; Adding PBS (-) is made into solution or the uniform suspension of 100 μ g/mL; Use PBS (-) dilution of DMSO then, ultimate density is respectively 10 μ g/mL, 1 μ g/mL, 0.1 μ g/mL, 0.01 μ g/mL, 0.001 μ g/mL, 0.0001 μ g/mL.
Antitumor drug TPT, the NSC 94600 of listing are made into reference substance solution with same condition.
It is the cell suspension 100 μ L of 3 * 104/mL that the every hole of 96 orifice plates adds concentration, i.e. 3000 cells/well are put in 37 ℃, 5%CO2 incubator.After 24 hours, add sample liquid and reference substance liquid respectively, 10 μ L/ holes, 37 ℃ act on 72 hours.Every hole adds MTT (3-(4,5-dimethylthiazole-2-yl)-2,5-phenylbenzene tetrazolium father-in-law bromide) the solution 20 μ L of 5mg/mL; Act on and add lysate DMSO after 4 hours; Put in the incubator in 100 μ L/ holes, and the full-automatic ELIASA of inferior daily MK-2 is surveyed 570nm OD value.Calculation of half inhibitory concentration IC50.
Test-results sees table 3 for details, and wherein, sample is meant the evodiamine compounds for preparing among the corresponding embodiment, is illustrated in resulting evodiamine compounds among the embodiment 1 like compound 1, in like manner analogizes.
Table 3 compound is to the half-inhibition concentration IC of tumour cell
50(unit: μ g/mL)
Above experimental result shows; Compound of the present invention has good antineoplastic activity; The anti-tumor activity of compound 1,3,5,7,8,13,14,25,26,37,44,51,52 is superior to TPT (TPT); The anti-tumor activity of compound 7,8,13,25,26,37,51,52 is superior to NSC 94600 (CPT), so The compounds of this invention and its esters can be used to prepare antitumor drug.
Claims (13)
1. one type of evodiamine compounds and pharmaceutical salts thereof, the structure of this evodiamine compounds is shown in general formula (I):
The female substitution in ring base of evodiamine is single replacement or polysubstituted, R
1To R
10Substituting group is explained as follows:
R
1, R
4Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, rudimentary hydroxyalkyl, lower alkoxy, low-grade alkenyl, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, diazanyl, rudimentary diazanyl alkyl or azido-;
R
2, R
9Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, hydroxyl, rudimentary hydroxyalkyl, lower alkoxy, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group or rudimentary amido alkyl;
R
3Expression following groups: hydrogen; Halogen; Low-grade halogenated alkyl; Low alkyl group; Hydroxyl; Rudimentary hydroxyalkyl; Lower alkoxy; Low-grade alkenyl; Alkynyl of low-grade chain; Amino; Low-grade alkyl amino; Low-grade halogenated alkyl is amino; Low-grade cycloalkyl is amino; Alkynyl of low-grade chain is amino; Nitro; Rudimentary 4-nitro alkyl; Cyanic acid; Rudimentary cyanic acid alkyl; Carboxamido-group; The low-grade cycloalkyl carboxamido-group; Rudimentary amido alkyl; Diazanyl; Rudimentary diazanyl alkyl; Azido-; Rudimentary azido-alkyl; NHR
11Or NHC (O) R
11, replacement or unsubstituted aralkyl or pyridyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or piperazinyl;
R
5Expression following groups: methylene radical, carbonyl or thiocarbonyl group;
R
6, R
8Represent following groups independently: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary hydroxyalkyl, low-grade alkenyl, alkynyl of low-grade chain, low alkyl group oxygen base, alkynyl of low-grade chain oxygen base, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, low-grade cycloalkyl carboxamido-group, diazanyl, rudimentary diazanyl alkyl, azido-or rudimentary azido-alkyl;
R
7Expression following groups: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary hydroxyalkyl, low-grade alkenyl, alkynyl of low-grade chain, alkynyl of low-grade chain oxygen base, amino, low-grade alkyl amino, nitro, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, carboxamido-group, rudimentary amido alkyl, low-grade cycloalkyl carboxamido-group, diazanyl, rudimentary diazanyl alkyl, azido-, rudimentary azido-alkyl, OR
11Or OC (O) R
11
R
10Expression hydrogen or to chlorobenzene formacyl;
R
11The expression following groups: hydrogen, halogen, low-grade halogenated alkyl, low alkyl group, rudimentary epoxy alkyl, low-grade alkenyl, alkynyl of low-grade chain, rudimentary 4-nitro alkyl, cyanic acid, rudimentary cyanic acid alkyl, rudimentary amido alkyl, diazanyl, rudimentary diazanyl alkyl, rudimentary azido-alkyl, low-grade cycloalkyl, replacement or unsubstituted rudimentary aralkyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy, lower alkoxy low alkyl group;
" rudimentary " relevant with alkyl and alkoxyl group refers to contain the straight or branched saturated fatty hydrocarbyl group of 1 to 6 carbon atom;
" rudimentary " relevant with alkenyl or alkynyl group refers to contain 2 to 6 carbon atoms and the one or more pairs of keys or triple-linked group;
Naphthenic base is meant the ring that contains 3 to 7 carbon;
Aryl refers to list, two or the tricyclic hydrocarbon compound, and wherein at least one ring is aromatic nucleus, and each ring contains maximum 7 carbon atoms.
2. evodiamine compounds according to claim 1 and pharmaceutical salts thereof is characterized in that R wherein
1, R
4Represent following groups independently: hydrogen, halogen, low alkyl group, hydroxyl or lower alkoxy.
3. evodiamine compounds according to claim 1 and 2 and pharmaceutical salts thereof is characterized in that R wherein
2, R
9Represent following groups independently: hydrogen, halogen, hydroxyl, low alkyl group, lower alkoxy, nitro, amino, low-grade alkyl amino or low-grade halogenated alkyl.
4. evodiamine compounds according to claim 1 and 2 and pharmaceutical salts thereof is characterized in that R wherein
3The expression following groups: hydrogen, halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, low-grade halogenated alkyl are amino, low-grade cycloalkyl is amino, alkynyl of low-grade chain is amino, nitro, carboxamido-group, low-grade cycloalkyl carboxamido-group, NHR
11Or NHC (O) R
11, replacement or unsubstituted aralkyl or pyridyl, wherein substituting group is low alkyl group, hydroxyl, halogen, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxy or piperazinyl.
5. evodiamine compounds according to claim 1 and 2 and pharmaceutical salts thereof is characterized in that R wherein
6, R
8Represent following groups independently: hydrogen, halogen, low alkyl group, lower alkoxy, nitro, amino, low-grade alkyl amino, low-grade halogenated alkyl or rudimentary hydroxyalkyl.
6. evodiamine compounds according to claim 1 and 2 and pharmaceutical salts thereof is characterized in that R wherein
7Expression following groups: hydrogen, halogen, low alkyl group, hydroxyl, lower alkoxy, amino, low-grade alkyl amino, nitro, carboxamido-group, low-grade cycloalkyl carboxamido-group, OR
11Or OC (O) R
11
7. evodiamine compounds according to claim 1 and 2 and pharmaceutical salts thereof is characterized in that R wherein
11Expression following groups: low alkyl group, low-grade cycloalkyl, rudimentary aralkyl; Low-grade halogenated alkyl, rudimentary epoxy alkyl, low-grade alkenyl or alkynyl of low-grade chain.
8. evodiamine compounds according to claim 1 and pharmaceutical salts thereof is characterized in that this evodiamine compounds is:
1-methyl evodiamine,
4-fluorine evodiamine,
4-chlorine evodiamine,
4-methyl evodiamine,
The 4-Rhetsinine,
4-methoxyl group evodiamine,
3-fluorine evodiamine,
3-chlorine evodiamine,
3-bromine evodiamine,
N-(4-chlorobenzene formacyl)-3-bromine evodiamine,
3-iodine evodiamine,
3-methyl evodiamine,
The 3-Rhetsinine,
3-methoxyl group evodiamine,
N-(4-chlorobenzene formacyl)-3-methoxyl group evodiamine,
3-nitro evodiamine,
The amino evodiamine of 3-,
3-(bromopropyl is amino) evodiamine,
3-(the ring fourth is amino) evodiamine,
3-kharophen evodiamine,
3-ring propyl formamide base evodiamine,
3-(acetobrom is amino) evodiamine,
3-(sulfydryl kharophen) evodiamine,
3-(2-(piperazine-1-yl) pyridin-4-yl) evodiamine,
3-fluoro-10-Rhetsinine,
3-fluoro-10-methoxyl group evodiamine,
3-(N-propine-3-base is amino) evodiamine,
3-(N, N-two propine-3-base is amino) evodiamine,
2-chlorine evodiamine,
N-(4-chlorobenzene formacyl)-2-chlorine evodiamine,
2-methoxyl group evodiamine,
N-(4-chlorobenzene formacyl)-2-methoxyl group evodiamine,
The amino evodiamine of 2-chloro-3-,
2,3-dimethoxy evodiamine,
N-(4-chlorobenzene formacyl)-2,3-dimethoxy evodiamine,
2-chloro-3-nitro evodiamine,
12-chlorine evodiamine,
10-fluorine evodiamine,
N-(4-chlorobenzene formacyl)-10-fluorine evodiamine,
10-chlorine evodiamine,
N-(4-chlorobenzene formacyl)-10-chlorine evodiamine,
10-bromine evodiamine,
N-(4-chlorobenzene formacyl)-10-bromine evodiamine,
10-iodine evodiamine,
10-methyl evodiamine,
N-(4-chlorobenzene formacyl)-10-methyl evodiamine,
10-methoxyl group evodiamine,
N-(4-chlorobenzene formacyl)-10-methoxyl group evodiamine,
10-nitro evodiamine,
10,12-dinitrobenzene evodiamine,
The 10-Rhetsinine,
N-(4-chlorobenzene formacyl)-10-Rhetsinine,
10-oxyethyl group evodiamine,
10-propoxy-evodiamine,
10-glycidoxy evodiamine,
The 10-third alkynyloxy group evodiamine,
10-benzyloxy evodiamine,
10-(cyclopropyl methoxycarbonyl) evodiamine,
5-thiocarbonyl group evodiamine,
N-(4-chlorobenzene formacyl)-5-thiocarbonyl group evodiamine,
10-methoxyl group-5-thiocarbonyl group evodiamine,
5-methylene radical evodiamine,
N-(4-chlorobenzene formacyl)-5-methylene radical evodiamine,
3-fluorine evodiamine hydrochloride,
D-3-fluoro-10-Rhetsinine, or
L-3-fluoro-10-Rhetsinine.
9. according to arbitrary described evodiamine compounds of claim 1 to 8 and pharmaceutical salts thereof; It is characterized in that pharmaceutical salts wherein is organic acid salt or inorganic acid salt; Mineral acid comprises hydrochloric acid, sulfuric acid, phosphoric acid, di-phosphate, Hydrogen bromide or nitric acid, and organic acid comprises acetate, toxilic acid, fumaric acid, tartrate, succsinic acid, lactic acid, tosic acid, Whitfield's ointment or oxalic acid.
10. according to the arbitrary described evodiamine compounds raceme of claim 1 to 8, d-type or l-type isomer and pharmaceutical salts thereof.
11. the preparation method of evodiamine compounds as claimed in claim 1 and pharmaceutical salts thereof, its reaction process is following:
Concrete steps are:
A. the preparation of compound VI I
I. replace tryptamines (Ia) with in ethyl formate 80 ℃ refluxed 12 hours, obtain substituted N-formyl radical tryptamines II;
The substituted N-formyl radical of ii tryptamines (II) reacted 2 hours with POCl3 0-5 ℃, at room temperature reacted to obtain title product III in 2 hours again;
Iii. substituted anthranilic acid (IV) obtained substituted pyridine red acid acid anhydride V in 3 hours with 70 ℃ of backflows of TRIPHOSGENE 99.5 in tetrahydrofuran solution;
Iv. substituted pyridine red acid acid anhydride (V) generates substituted N-picoline red acid acid anhydride VI with iodomethane reaction under the NaH effect;
V. compound III and VI with equimolar amount in methylene dichloride 45 ℃ refluxed 5 hours, obtain substituted evodiamine VII;
B. compound VI Ic preparation
Compound VI Ia is dissolved among the DMSO, is alkali and various halogenated alkane, halo naphthenic hydrocarbon, halo alkynes etc. with salt of wormwood, room temperature or 60 ℃ of compound VI Ic that reaction can be made in 2-7 hour;
C. compound VI Id preparation
Compound VI Ia is dissolved in an amount of methylene dichloride, adds acyl chlorides or acylbromide, and ice bath obtains title product VIId to 0-5 ℃ of reaction 3 hours under triethylamine catalysis;
D. compound VI Ie preparation
Compound VI Ib is dissolved in an amount of ethanol, is the compound VI Ie that 80 ℃ of reactions such as alkali and various halogenated alkane, halo naphthenic hydrocarbon, halo alkynes can be made in 4 hours with salt of wormwood;
E. compound VI If preparation
Compound VI Ib is dissolved in an amount of methylene dichloride, adds acyl chlorides or acylbromide, and room temperature reaction is 3 hours under triethylamine catalysis, obtains title product VIIf;
F. compound VIII preparation
Compound VI I is dissolved among an amount of DMF, is 80 ℃ of reactions of alkali and parachlorobenzoyl chloride 1 hour with NaH, the compound VIII of system;
G. compound I X preparation
Compound VI I is dissolved in an amount of toluene, obtains compound I X in 4 hours with 120 ℃ of reactions of lawesson reagent;
H. compounds X preparation
Compound VI I is dissolved in an amount of anhydrous tetrahydro furan, spends the night with the lithium aluminium hydride room temperature reaction, obtains compounds X.
12. like arbitrary described evodiamine compounds of claim 1 to 8 and the application of pharmaceutical salts in the preparation topoisomerase enzyme inhibitor thereof.
13. like arbitrary described evodiamine compounds of claim 1 to 8 and the application of pharmaceutical salts in the preparation antitumor drug thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110188588 CN102311434B (en) | 2011-07-07 | 2011-07-07 | Evodiamine compounds, preparation method thereof and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110188588 CN102311434B (en) | 2011-07-07 | 2011-07-07 | Evodiamine compounds, preparation method thereof and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102311434A true CN102311434A (en) | 2012-01-11 |
| CN102311434B CN102311434B (en) | 2013-08-21 |
Family
ID=45425034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110188588 Expired - Fee Related CN102311434B (en) | 2011-07-07 | 2011-07-07 | Evodiamine compounds, preparation method thereof and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102311434B (en) |
Cited By (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659782A (en) * | 2012-04-26 | 2012-09-12 | 中国人民解放军第三军医大学第三附属医院 | Evodiamine derivative, preparation method and application thereof |
| CN102885819A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885701A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885704A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885702A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885705A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885703A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN103992326A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indol-hexahydropyrazine-quinazolinone anti-tumour compounds and preparation method thereof |
| CN103992336A (en) * | 2014-05-19 | 2014-08-20 | 中国人民解放军第二军医大学 | Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof |
| CN105418610A (en) * | 2015-12-16 | 2016-03-23 | 中国人民解放军第二军医大学 | 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof |
| CN105622608A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Nitrate NO donor type evodiamine derivatives with anti-tumor activity |
| CN105622607A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
| CN106265704A (en) * | 2016-07-26 | 2017-01-04 | 河南大学 | The Traditional Chinese Herb combination of a kind of target tumor hypoxia microenvironment application in oncotherapy |
| CN107141288A (en) * | 2017-04-14 | 2017-09-08 | 中山大学 | One class evodia rutaecarpa alkaloid compound and preparation method and application |
| CN108794474A (en) * | 2018-07-26 | 2018-11-13 | 中国人民解放军第二军医大学 | Rutaecarpin derivative and its preparation method and application with multiple target point antitumor activity |
| CN110066281A (en) * | 2019-06-06 | 2019-07-30 | 中国人民解放军第二军医大学 | Rutaecarpin derivative of multiple target point anti-tumor activity and the preparation method and application thereof |
| CN110156817A (en) * | 2019-06-06 | 2019-08-23 | 中国人民解放军第二军医大学 | Dievodiamine molecule antitumor derivative and its preparation and application |
| CN110483550A (en) * | 2019-09-04 | 2019-11-22 | 南华大学 | One kind derivative of rutaecarpin containing trimethoxyphenyl and its application |
| CN111620871A (en) * | 2020-06-30 | 2020-09-04 | 陕西中医药大学 | Aminoevodiamine derivative and preparation method and application thereof |
| CN111686077A (en) * | 2020-06-30 | 2020-09-22 | 陕西中医药大学 | Amino evodiamine polymer micelle and preparation method and application thereof |
| CN112390798A (en) * | 2020-11-16 | 2021-02-23 | 张家港威胜生物医药有限公司 | Production process of evodiamine and method for recycling solvent used in production |
| CN112438272A (en) * | 2020-12-03 | 2021-03-05 | 兰州大学 | Evodiamine analog and application thereof in preventing and treating plant pathogenic fungi |
| CN112500412A (en) * | 2020-12-14 | 2021-03-16 | 中国人民解放军空军军医大学 | Penamine A alkaloid structure simplification compound and application thereof |
| CN113321655A (en) * | 2021-06-29 | 2021-08-31 | 天津农学院 | Preparation and application of evodia rutaecarpa botanical insecticide |
| CN114133397A (en) * | 2021-11-08 | 2022-03-04 | 海南大学 | Evodiamine compound and preparation method and application thereof |
| CN114539267A (en) * | 2022-02-07 | 2022-05-27 | 中国人民解放军海军军医大学 | Evodiamine derivative and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110790762B (en) * | 2019-10-08 | 2021-06-15 | 中国医学科学院医药生物技术研究所 | Tetrahydroindole quinazoline compound and application thereof |
-
2011
- 2011-07-07 CN CN 201110188588 patent/CN102311434B/en not_active Expired - Fee Related
Non-Patent Citations (4)
| Title |
|---|
| 《Bioorg. Med. Chem.》 20041231 Bipul Baruah, et al. Synthesis and cytotoxic activity of novel quinazolino-beta-carboline-beta-one derivatives 1991-1994 1-10、12-13 第12卷, * |
| 《J. Med. Chem.》 20101013 Guoqiang Dong, et al. Selection of Evodiamine as a Novel Topoisomerase I Inhibitor by Structure-Based Virtual Screening and Hit Optimization of Evodiamine Derivatives as Antitumor Agents 7521-7531 1-13 第53卷, 第21期 * |
| 《Journal of the American Chemical Society》 19610205 IRWINJ. PACHTE, et al. The Chemistry of Hortiamine and 6-Methoxyrhetsinine 635-642 1-10 第83卷, * |
| 《STN Columbus》 20091201 Registry database 70553-68-3，1194762-84-9，920265-63-0，155158-85-3，133347-96-3，116976-07-9，112659-10-6，90823-51-1，75853-61-1，70553-69-4，13058-31-6，5956-87-6，518-18-3，518-17-2 1-10 , * |
Cited By (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102885819B (en) * | 2012-04-20 | 2014-09-17 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885702A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885705B (en) * | 2012-04-20 | 2014-09-17 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885704A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885701B (en) * | 2012-04-20 | 2014-09-17 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885705A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885703A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885702B (en) * | 2012-04-20 | 2014-09-17 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885701A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102885819A (en) * | 2012-04-20 | 2013-01-23 | 朱丹 | Application of evodiamine to preparation of anti-ultraviolet composition |
| CN102659782A (en) * | 2012-04-26 | 2012-09-12 | 中国人民解放军第三军医大学第三附属医院 | Evodiamine derivative, preparation method and application thereof |
| CN103992336A (en) * | 2014-05-19 | 2014-08-20 | 中国人民解放军第二军医大学 | Oxa- or thio-evodiamine anti-tumor derivatives and preparation method thereof |
| CN103992336B (en) * | 2014-05-19 | 2017-01-04 | 中国人民解放军第二军医大学 | Oxa-or thia evodiamine anti-tumor derivant and preparation method thereof |
| CN103992326A (en) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | Indol-hexahydropyrazine-quinazolinone anti-tumour compounds and preparation method thereof |
| CN103992326B (en) * | 2014-05-29 | 2016-09-28 | 中国人民解放军第二军医大学 | Indole hexahydropyrazine quinazolinone anti-tumor compounds and preparation method thereof |
| CN105418610A (en) * | 2015-12-16 | 2016-03-23 | 中国人民解放军第二军医大学 | 10-hydroxyevodiamine type anti-tumor compounds as well as preparation method and application thereof |
| CN105418610B (en) * | 2015-12-16 | 2017-07-28 | 中国人民解放军第二军医大学 | A kind of 10 hydroxyevodiamine anti-tumor compounds and its preparation method and application |
| CN105622607B (en) * | 2016-01-12 | 2017-04-26 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
| CN105622608B (en) * | 2016-01-12 | 2017-04-26 | 沈阳药科大学 | Nitrate NO donor type evodiamine derivatives with anti-tumor activity |
| CN105622607A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Furazan NO donor type evodiamine derivatives with anti-tumor activity |
| CN105622608A (en) * | 2016-01-12 | 2016-06-01 | 沈阳药科大学 | Nitrate NO donor type evodiamine derivatives with anti-tumor activity |
| CN106265704A (en) * | 2016-07-26 | 2017-01-04 | 河南大学 | The Traditional Chinese Herb combination of a kind of target tumor hypoxia microenvironment application in oncotherapy |
| CN107141288B (en) * | 2017-04-14 | 2019-12-27 | 中山大学 | Evodiamine compounds and preparation method and application thereof |
| CN107141288A (en) * | 2017-04-14 | 2017-09-08 | 中山大学 | One class evodia rutaecarpa alkaloid compound and preparation method and application |
| WO2018188446A1 (en) * | 2017-04-14 | 2018-10-18 | 中山大学 | Evodiamine compounds, preparation method therefor and application thereof |
| CN108794474B (en) * | 2018-07-26 | 2022-03-18 | 中国人民解放军第二军医大学 | Evodiamine derivative with multi-target antitumor activity and preparation method and application thereof |
| CN108794474A (en) * | 2018-07-26 | 2018-11-13 | 中国人民解放军第二军医大学 | Rutaecarpin derivative and its preparation method and application with multiple target point antitumor activity |
| CN110066281A (en) * | 2019-06-06 | 2019-07-30 | 中国人民解放军第二军医大学 | Rutaecarpin derivative of multiple target point anti-tumor activity and the preparation method and application thereof |
| CN110156817B (en) * | 2019-06-06 | 2024-02-27 | 中国人民解放军第二军医大学 | Anti-tumor derivative of bi-evodiamine molecule and preparation and application thereof |
| CN110066281B (en) * | 2019-06-06 | 2024-01-30 | 中国人民解放军第二军医大学 | Multi-target anti-tumor activity evodiamine derivative, and preparation method and application thereof |
| CN110156817A (en) * | 2019-06-06 | 2019-08-23 | 中国人民解放军第二军医大学 | Dievodiamine molecule antitumor derivative and its preparation and application |
| CN110483550A (en) * | 2019-09-04 | 2019-11-22 | 南华大学 | One kind derivative of rutaecarpin containing trimethoxyphenyl and its application |
| CN111686077B (en) * | 2020-06-30 | 2022-08-02 | 陕西中医药大学 | Amino evodiamine polymer micelle and preparation method and application thereof |
| CN111620871B (en) * | 2020-06-30 | 2023-12-08 | 陕西中医药大学 | Aminoevodiamine derivative, and preparation method and application thereof |
| CN111686077A (en) * | 2020-06-30 | 2020-09-22 | 陕西中医药大学 | Amino evodiamine polymer micelle and preparation method and application thereof |
| CN111620871A (en) * | 2020-06-30 | 2020-09-04 | 陕西中医药大学 | Aminoevodiamine derivative and preparation method and application thereof |
| CN112390798A (en) * | 2020-11-16 | 2021-02-23 | 张家港威胜生物医药有限公司 | Production process of evodiamine and method for recycling solvent used in production |
| CN112438272A (en) * | 2020-12-03 | 2021-03-05 | 兰州大学 | Evodiamine analog and application thereof in preventing and treating plant pathogenic fungi |
| CN112500412A (en) * | 2020-12-14 | 2021-03-16 | 中国人民解放军空军军医大学 | Penamine A alkaloid structure simplification compound and application thereof |
| CN113321655A (en) * | 2021-06-29 | 2021-08-31 | 天津农学院 | Preparation and application of evodia rutaecarpa botanical insecticide |
| CN114133397A (en) * | 2021-11-08 | 2022-03-04 | 海南大学 | Evodiamine compound and preparation method and application thereof |
| CN114133397B (en) * | 2021-11-08 | 2024-04-12 | 海南大学 | Evodiamine compound and preparation method and application thereof |
| CN114539267A (en) * | 2022-02-07 | 2022-05-27 | 中国人民解放军海军军医大学 | Evodiamine derivative and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102311434B (en) | 2013-08-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102311434B (en) | Evodiamine compounds, preparation method thereof and application thereof | |
| CN103992336B (en) | Oxa-or thia evodiamine anti-tumor derivant and preparation method thereof | |
| CN102887895B (en) | Pyridopyrimidine class mTOR inhibitors | |
| CN1807413B (en) | Carbazole sulfonamide derivative and its preparation method | |
| CN102070595A (en) | Substituted benzoxanthone type compound and application thereof | |
| CN102947273A (en) | Indenoquinolone compound, preparation method and use thereof | |
| CN103755595A (en) | Hydroxamic acid derivative and application thereof | |
| CN103601670A (en) | Piplartine analogue, and preparation method and application thereof | |
| CN103992326A (en) | Indol-hexahydropyrazine-quinazolinone anti-tumour compounds and preparation method thereof | |
| CN107573327B (en) | Indazole-formamide-pyridone derivative and preparation method and application thereof | |
| CN106946868B (en) | Nitric oxide donator type coumarin derivative, preparation method and medical usage | |
| CN110156822B (en) | Naphthol-phenylboronic acid compound and preparation method and application thereof | |
| CN111875582A (en) | Quinoline hydroxamic acid derivative and preparation method and application thereof | |
| CN103450176A (en) | Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof | |
| CN101899051B (en) | 1-azaxanthone-3-formamide compounds as well as preparation method and antitumor application thereof | |
| CN106117182B (en) | Quinazoline-N- phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN101684094A (en) | 3-substituted-1, 8-naphthalimide compound and synthesis method and medical application thereof | |
| CN101475574B (en) | Camptothecin derivative, and preparation and use thereof | |
| CN102985407A (en) | 8-hydroxy-quinoline derivatives | |
| CN112390781B (en) | Diaryl-substituted 1,1-ethylene compound, preparation method and application | |
| CN100465175C (en) | 7-bit substituted comptothecine kind compound and pharmaceutical use thereof | |
| CN103864680A (en) | Chloroxoquinoline derivatives with anti-tumor activity | |
| CN110172058B (en) | 7-azaspiro [5.6] dodecane-10-one compound and preparation method and application thereof | |
| CN100408582C (en) | Homocamptoth-ecine compounds, their preparation process and use | |
| CN102351870B (en) | Method for preparing benzacridine derivative and application of benzacridine derivative as anti-cancer medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130821 Termination date: 20160707 |