CN104557909A - 3-acyloxy substituted (+)-deoxytylophorinine derivatives, and preparation method, pharmaceutical composition and application thereof - Google Patents
3-acyloxy substituted (+)-deoxytylophorinine derivatives, and preparation method, pharmaceutical composition and application thereof Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
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Abstract
The invention relates to compounds represented by the general formula (I), a preparation method of the compounds, a pharmaceutical composition containing the compounds and an application of the compounds in preparation of drugs for preventing and/or treating cancer and/or inflammatory diseases.
Description
Technical field
The present invention relates to the compound shown in general formula (I), the preparation method of this compounds, preparing containing their pharmaceutical composition and this compounds the application prevented and/or treated in the medicine of cancer and/or inflammatory disease.
Background technology
Phenanthroindolizididerivative pyridine alkaloid is mainly distributed in Asclepiadaceae Tylophora plant, has multiple pharmacologically active, and antitumor action wherein and anti-inflammatory action attract people's attention.Find in National Cancer research institute (NCI) anti-tumor i n vitro test, this Alkaloid has significant effect for 60 kinds of tumor cell lines, half growth-inhibiting dosage (GI
50) 10
-8m level, and for malignant tumour, such as melanoma and lung carcinoma cell have good selectivity, effective for drug resistant cancer cells system, and there is no cross resistance with other anticarcinogen.
Wherein dextrorotation deoxidation tylophorinine is located away from Asclepiadaceae Tylophora plant three points of pellets (Tylophora atrofoculata) and Tylophora ovata (Tylophoro ovata), through Pharmacological Activity Screening, find that the compound screened is to the tumour cell of multiple different tissue sources, comprise human brain gliomas U251 and BT323 cell strain has significant activity, IC
5010
-8-10
-7the level of M, it is 70 ~ 80% that results from vivo experiments shows it to the inhibiting rate of mouse H22 growth of xenografted.The study on mechanism in early stage shows, this compound may be by playing a role between the intercalation of DNA and the AT base pair of RNA, being different from antitumor drug [Chemotherapy.2011,57:310-320] clinically.
Find through drug metabolism study, the main metabolites of this compound in experimental animals is 3-demethyl dextrorotation deoxidation tylophorinine [Anal.Chim.Acta.2012,731,60], synthesize it and screen active discovery, 3-demethyl dextrorotation deoxidation tylophorinine has cytotoxic activity [Synthesis.2012,44 of highly significant, A-H], this patent relates to and carries out composition optimizes to improve the work of its physico-chemical property and activity in vivo to this compound.
Summary of the invention
The technical problem to be solved in the present invention is to provide acceptable salt in general formula (I) compound and pharmacodynamics thereof.
The another technical problem that the present invention will solve is to provide prepares acceptable salt in general formula (I) compound and pharmacodynamics thereof.
The another technical problem that the present invention will solve is to provide a kind of pharmaceutical composition, and it comprises acceptable salt at least one general formula (I) compound and pharmacodynamics thereof.
The technical problem again that the present invention will solve to be to provide in general formula (I) compound and pharmacodynamics thereof acceptable salt for the preparation of the application prevented and/or treated in cancer and/or anti-inflammatory drugs.
For solving the problems of the technologies described above, the technical solution used in the present invention is:
The present invention relates to compound as Suo Shi general formula (I):
Wherein, R is selected from R
1cO-or R
2sO
2-;
When R is selected from R
1during CO-, R
1be selected from substituted or unsubstituted C
110the alkyl of straight chain and side chain, substituted or unsubstituted C
110the alkoxyl group of straight chain and side chain, the amido of substituted or unsubstituted formation five yuan, hexa-atomic or seven-membered ring;
When R is selected from R
2sO
2-time, R
2be selected from substituted or unsubstituted C
110alkyl and phenyl.
According to the present invention, preferred compound comprises:
According to the present invention, the compounds of this invention can the form of isomer exist, and usually described " the compounds of this invention " comprises the isomer of this compound.
According to embodiment of the present invention, described the compounds of this invention also comprises acceptable salt in its pharmacodynamics.
According to present invention also offers the method preparing the compounds of this invention.
The invention still further relates to a kind of containing the compound as described in general formula I of medicine effective dose and the pharmaceutical composition of pharmaceutically acceptable carrier.
Further aspect of the present invention also relates to the pharmaceutical composition using the compounds of this invention as active ingredient.This pharmaceutical composition can be prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration can be enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention first particle or micropill be can be made with thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, can with water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, the Suitable dosage ranges of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, is more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
The invention still further relates to the application of compound of the present invention in the medicine preparing Therapeutic cancer and/or inflammatory disease, the application particularly in the cancers such as human glioma, people's marrow neuroblastoma, human colon carcinoma, people's cancer of the stomach, human ovarian cancer, cervical cancer, liver cancer, lung cancer, carcinoma of the pancreas.
Accompanying drawing explanation
Fig. 1 each treated animal body weight record
The each treated animal knurl of Fig. 2 heavily record
Embodiment
Initial compounds used in the embodiment of the present invention, can prepare according to the ordinary method of this area and/or method well known to those skilled in the art, and can by the preparation of following citing preparation example.
The following examples are used for further illustrating the present invention, but this and do not mean that any limitation of the invention.
Embodiment 1:(13aS) synthesis of-3-benzyloxy acyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (1)
Methylene dichloride 50mL is added in 100mL dry reaction bottle, 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, adds triethylamine 60 μ L, then chloroformic acid benzyl ester 49 μ L is added, react 2 hours, reaction solution saturated ammonium chloride is washed, dry, be separated through silica gel column chromatography after evaporate to dryness, eluent dichloromethane/methyl alcohol (50/1), obtains product 0.11g, yield 79%.
1H-NMR(500MHz,C
5D
5N):8.93(1H,d,J=2.5Hz),7.65(1H,dd,J=9.0Hz,2.5Hz),8.07(1H,d,J=9.0Hz),8.29(1H,s),7.44(1H,s),7.53(2H,m),7.36(3H,m),3.95(3H,s,MeO),3.94(3H,s,MeO),5.41(2H,s),4.81(1H,d,J=15.0Hz),3.69(1H,d,J=15.0Hz),3.35(2H,m),2.93(1H,m),2.40(1H,m),2.31(1H,m),2.08(1H,m),1.87(1H,m),1.71(2H,m)。
Embodiment 2:(13aS) synthesis of-3-ethoxy acyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (2)
Methylene dichloride 50mL is added in 100mL dry reaction bottle, 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, adds triethylamine 60 μ L, then Vinyl chloroformate 33 μ L is added, react 2 hours, reaction solution saturated ammonium chloride is washed, dry, be separated through silica gel column chromatography after evaporate to dryness, eluent dichloromethane/methyl alcohol (50/1), obtains product 0.09g, yield 75%.
1H-NMR(500MHz,C
5D
5N):8.92(1H,d,J=2.0Hz),7.67(1H,dd,J=9.0Hz,2.0Hz),8.06(1H,d,J=9.0Hz),8.28(1H,s),7.41(1H,s),3.96(3H,s,MeO),3.94(3H,s,MeO),4.78(1H,d,J=15.0Hz),3.67(1H,d,J=15.0Hz),4.29(2H,q),1.22(3H,t),3.35(2H,m),2.92(1H,m), 2.38(1H,m),2.31(1H,m),2.08(1H,m),1.87(1H,m),1.71(2H,m)。
Embodiment 3:(13aS) synthesis of-3-new pentane acyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (3)
Methylene dichloride 50mL is added in 100mL dry reaction bottle, 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, adds triethylamine 60 μ L, then pivalyl chloride 42 μ L is added, react 2 hours, reaction solution saturated ammonium chloride is washed, dry, be separated through silica gel column chromatography after evaporate to dryness, eluent dichloromethane/methyl alcohol (50/1), obtains product 0.09g, yield 72%.
1H-NMR(500MHz,C
5D
5N):8.96(1H,d,J=1.5Hz),7.60(1H,dd,J=8.5Hz,1.5Hz),8.14(1H,d,J=8.5Hz),8.36(1H,s),7.43(1H,s),3.92(3H,s,MeO),3.85(3H,s,MeO),4.81(1H,d,J=15.0Hz),3.69(1H,d,J=15.0Hz),3.35(2H,m),2.94(1H,m),2.40(1H,m),2.33(1H,m),2.08(1H,m),1.87(1H,m),1.69(2H,m)，1.35(9H,s)。
Embodiment 4:(13aS) synthesis of-3-mesyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (4)
Methylene dichloride 50mL is added in 100mL dry reaction bottle, 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, adds triethylamine 60 μ L, then pivalyl chloride 27 μ L is added, react 2 hours, reaction solution saturated ammonium chloride is washed, dry, be separated through silica gel column chromatography after evaporate to dryness, eluent dichloromethane/methyl alcohol (50/1), obtains product 0.08g, yield 66%.
1H-NMR(500MHz,C
5D
5N):8.96(1H,d,J=2.0Hz),7.78(1H,dd,J=9.0Hz, 2.0Hz),8.06(1H,d,J=9.0Hz),8.26(1H,s),7.43(1H,s),3.94(3H,s,MeO),3.90(3H,s,MeO),4.84(1H,d,J=15.0Hz),3.74(1H,d,J=15.0Hz),3.53(3H,s),3.36(2H,m),2.97(1H,m),2.47(1H,m),2.37(1H,m),2.10(1H,m),1.91(1H,m),1.74(2H,m)。
Embodiment 5:(13aS)-3-(4 '-piperidyl) synthesis of piperidines acyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (5)
Methylene dichloride 50mL is added in 100mL dry reaction bottle, 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, adds triethylamine 60 μ L, then pivalyl chloride 90mg is added, react 2 hours, reaction solution saturated ammonium chloride is washed, dry, be separated through silica gel column chromatography after evaporate to dryness, eluent dichloromethane/methyl alcohol (50/1), obtains product 0.12g, yield 77%.
1H-NMR(500MHz,C
5D
5N):8.98(1H,d,J=2.0Hz),7.73(1H,dd,J=9.0Hz,2.0Hz),8.11(1H,d,J=9.0Hz),8.34(1H,s),7.44(1H,s),3.93(3H,s,MeO),3.88(3H,s,MeO),4.82(1H,d,J=15.0Hz),3.70(1H,d,J=15.0Hz),4.51(1H,m),4.42(2H,m),3.49(1H,m),3.37(2H,m),2.95(1H,m),2.78(2H,m),2.37(5H,m),2.09(1H,m),1.87(1H,m),1.70(2H,m),1.64(1H,m),1.49(5H,m),1.27(4H,m)。
Embodiment 6:(13aS)-3-(2 '-S-t-butoxycarbonyl amino) synthesis of propionyloxy-6,7-dimethoxy-9-luxuriant and rich with fragrance a pair of horses going side by side [9,10-b]-Indolizidine (6)
Methylene dichloride 50mL is added in 100mL dry reaction bottle; 100mg reactant 3-hydroxyl-6,7-dimethoxy phenanthrene-9-methyl alcohol (PF403) is dissolved in wherein, under ice bath, adds the L-Ala 0.11g of Boc protection; then the EDCI of 0.11g is added; react and rise to room temperature after 0.5 hour, then react 2 hours, reaction solution is washed; dry; be separated through silica gel column chromatography after evaporate to dryness, obtain product 85mg, yield 57%.
1H-NMR(500MHz,C
5D
5N):8.83(1H,d,J=2.0Hz),7.61(1H,dd,J=8.5Hz,2.0Hz),8.05(1H,d,J=8.5Hz),8.22(1H,s),7.40(1H,s),3.90(3H,s,MeO),3.87(3H,s,MeO),4.78(1H,d,J=14.5Hz),3.67(1H,d,J=14.5Hz),4.90(1H,m),3.33(2H,m),2.91(1H,m),2.39(1H,m),2.30(1H,m),2.05(1H,m),1.85(1H,m),1.70(1H,m),1.66(2H,d),1.63(1H,m),1.52(9H,s)。
Pharmacological testing
Experimental example 1: the mensuration (mtt assay) of anti tumor activity in vitro
In order to measure the anti tumor activity in vitro of the compounds of this invention, measure the compound prepared in the embodiment of the present invention, its experimental procedure is:
1. cultivate the tumour cell of normal growth, with 1 × 10
4cell/mL is inoculated into (every hole 100 μ L) in 96 orifice plates, at 37 DEG C, and 5%CO
2cultivate 24 hours in incubator.
2. add tested compound respectively, at 5%CO
2, cultivate 5 days in humidified incubator completely.
3. reject nutrient solution, every hole adds 0.04%MTT100 μ L, cultivates 4 hours under similarity condition.
4. reject nutrient solution, adds DMSO(every hole 150 μ L), in mensuration wavelength 570nm after mixing, reference wavelength 450nm, colorimetric recording light optical density, computerized compound is to the inhibiting rate of growth of tumour cell.
Table 1PF403 and prodrug thereof are to the growth-inhibiting effect (72h) of the tumour cell of vitro culture
HepG2: human liver cancer cell; Mia-PaCa2: human pancreatic cancer cell; SHSY-5Y: people's marrow neuroblastoma cell; SKOV3: Proliferation of Human Ovarian Cell; TJ905: human glioma cell
From result, 1 ~ No. 6 compound all has certain extracorporeal anti-tumor cell growth inhibition, but will be weaker than its prototype compound PF403.
Experimental example 2: the mensuration of anti-tumor in vivo activity
1, laboratory animal and grouping: ICR mouse, SPF level, female, body weight 18-20g.Purchased from: Beijing Vital River Experimental Animals Technology Co., Ltd., behind oxter inoculation G422 mouse glioblastoma multiforme (knurl liquid: stroke-physiological saline solution=1:3), next day, random packet, weighed and administration.Be divided into blank group, positive controls (endoxan), administration group (1,2,3,4,5, No. 6 compound 10mg/kg and 5mg/kg oral administration group, PF40310mg/kg, 5mg/kg, 2.5mg/kg intraperitoneal injection group) at random.
2, Pharmaceutical formulations and administering mode: Cyclophosphamide for injection is dissolved in stroke-physiological saline solution (concentration 10mg/ml, every 20g mouse peritoneal injection 0.2ml) before use, and first day intraperitoneal injection once after inoculation.Test-compound 1,2,3,4,5,6 with being dissolved in distilled water (concentration 5mg/ml, 2.5mg/ml, every 20g mouse stomach 0.4ml) after tween 80 hydrotropy, the next day gastric infusion; Stroke-physiological saline solution (polyoxyethylene glycol final concentration 25%) is dissolved in, intraperitoneal injection after PF403 poly(oxyethylene glycol) 400 hydrotropy; Test-compound and the equal matching while using of PF403, keep in Dark Place.
3, animal process: record body weight every other day, and draw body weight change curve, in latter 15th day of inoculation, cervical dislocation put to death animal, strips tumour, took a picture, and record knurl weighs and calculates tumour inhibiting rate.
Table 2PF403 prodrug is to G422 mouse glioblastoma multiforme Anticancer effect in vivo the selection result
+: prodrug oral administration, administration in the 2nd, 4,6,7,9,11,13 day after inoculation, altogether administration 7 times; PF403 injected dose is total dosage, high dose group the 2nd, 5 days 10mg/kg, 7,10,12 days 15mg/kg, 13,14 days 20mg/kg, altogether administration 7 times; The same high dose group of middle dosage group administration time, dosage reduces by half; The same high dose group of low dose group administration time, dosage is middle dosage group half.
#p < 0.05; ##p < 0.01; ###p < 0.001; * p < 0.05; * p < 0.01; * * p < 0.001, compares with negative control group.
From result, 1 ~ No. 6 compound all has the activity of stronger suppression G422 tumour, and wherein 2,3,5, No. 6 compound restraining effect are better than prototype compound PF403, and dose-effect relationship is better, and body weight reduction degree is few compared with other compounds.
Claims (8)
1. the compound represented by following general formula (I), and acceptable salt in pharmacodynamics:
Wherein, R is selected from R
1cO-or R
2sO
2-;
When R is selected from R
1during CO-, R
1be selected from substituted or unsubstituted C
110the alkyl of straight chain and side chain, substituted or unsubstituted C
110the alkoxyl group of straight chain and side chain, the amido of substituted or unsubstituted formation five yuan, hexa-atomic or seven-membered ring;
When R is selected from R
2sO
2-time, R
2be selected from substituted or unsubstituted C
110alkyl and phenyl.
2. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IA), and acceptable salt in pharmacodynamics:
Wherein, R
1be selected from substituted or unsubstituted C
110the alkyl of straight chain and side chain, substituted or unsubstituted C
110the alkoxyl group of straight chain and side chain, the amido of substituted or unsubstituted formation five yuan, hexa-atomic or seven-membered ring.
3. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IB), and acceptable salt in pharmacodynamics:
Wherein, R
2be selected from substituted or unsubstituted C
110alkyl and phenyl.
4. according to the compound of claims 1 to 3, it is characterized in that, described compound is selected from:
5. a pharmaceutical composition, is characterized in that, the arbitrary compound according to any one of claim 1-4 containing effective dose and pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is selected from tablet, capsule, pill, injection, sustained release preparation, controlled release preparation and various particulate delivery system.
7. the compound according to any one of claim 1-4 is preparing the application prevented and/or treated in the medicine of cancer and/or inflammatory disease.
8. application according to claim 7, is characterized in that, described cancer is selected from human glioma, people's marrow neuroblastoma, human colon carcinoma, people's cancer of the stomach, human ovarian cancer, cervical cancer, liver cancer, lung cancer, carcinoma of the pancreas.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016161538A1 (en) * | 2015-04-09 | 2016-10-13 | 中国医学科学院药物研究所 | 3-acyloxy substituted (+)-deoxytylophorinine derivatives, and preparation method, pharmaceutical composition and use thereof |
| CN110117280A (en) * | 2018-02-05 | 2019-08-13 | 中国医学科学院药物研究所 | The crystal type A of (13aS) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
| CN110117279A (en) * | 2018-02-05 | 2019-08-13 | 中国医学科学院药物研究所 | The crystal B-type of (13aS) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
| CN110294752A (en) * | 2018-03-21 | 2019-10-01 | 中国医学科学院药物研究所 | The preparation of optical voidness (S) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
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| CN102186850A (en) * | 2008-10-23 | 2011-09-14 | 株式会社益力多本社 | Phenanthroindolizidine derivative and nfkb inhibitor containing same as active ingredient |
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| CN102186850A (en) * | 2008-10-23 | 2011-09-14 | 株式会社益力多本社 | Phenanthroindolizidine derivative and nfkb inhibitor containing same as active ingredient |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016161538A1 (en) * | 2015-04-09 | 2016-10-13 | 中国医学科学院药物研究所 | 3-acyloxy substituted (+)-deoxytylophorinine derivatives, and preparation method, pharmaceutical composition and use thereof |
| CN110117280A (en) * | 2018-02-05 | 2019-08-13 | 中国医学科学院药物研究所 | The crystal type A of (13aS) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
| CN110117279A (en) * | 2018-02-05 | 2019-08-13 | 中国医学科学院药物研究所 | The crystal B-type of (13aS) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
| CN110117279B (en) * | 2018-02-05 | 2021-05-11 | 中国医学科学院药物研究所 | Crystal form B of (13aS) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine |
| CN110294752A (en) * | 2018-03-21 | 2019-10-01 | 中国医学科学院药物研究所 | The preparation of optical voidness (S) -3- new pentane acyloxy -6,7- dimethoxy phenanthroindolizididerivative pyridine |
| CN110294752B (en) * | 2018-03-21 | 2022-01-11 | 中国医学科学院药物研究所 | Preparation of optically pure (S) -3-pivaloyloxy-6, 7-dimethoxyphenanthroindolizidine |
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| Publication number | Publication date |
|---|---|
| CN104557909B (en) | 2019-01-01 |
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