CN102850364A - Derivative of Dysosma versipellis, and composition, preparation method and use thereof - Google Patents

Derivative of Dysosma versipellis, and composition, preparation method and use thereof Download PDF

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CN102850364A
CN102850364A CN2011101845726A CN201110184572A CN102850364A CN 102850364 A CN102850364 A CN 102850364A CN 2011101845726 A CN2011101845726 A CN 2011101845726A CN 201110184572 A CN201110184572 A CN 201110184572A CN 102850364 A CN102850364 A CN 102850364A
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compound
hydroxyl
dmep
yls
naphtho
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CN102850364B (en
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肖旭华
孙文劼
闫琪
肖璘
吴学军
蔡立
张瑱
黄晓玲
刘珉宇
刘�英
邓轶方
陈仁海
汤生荣
刘全海
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Shanghai Institute of Pharmaceutical Industry
China State Institute of Pharmaceutical Industry
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Abstract

The invention discloses a derivative of Dysosma versipellis, and compositions, preparation methods and use thereof. The animal experiment proves that the derivative of Dysosma versipellis has good antitumor activity; can be used for the treatment of leukaemia, liver cancer, lung cancer and the similar diseases; has less toxicity; and can satisfy the clinical needs. The derivative of Dysosma versipellis is a compound of the following formula (I).

Description

Indian apple derivative and composition thereof, preparation method and application
Technical field
The present invention relates to indian apple derivative and composition thereof, preparation method and application, and the application of said composition in the preparation anti-tumor agents.
Background technology
Neoplastic disease is the multifactor malignant disease that causes, disturbs a certain (a bit) important step, just might stop tumor growth.
The application's project is the micromolecular indian apple derivative anti-tumor activity of research, for antitumor drug provides new selection.
Podophyllotoxin has significant anti-tumor activity, but greatly its application is restricted because of strong toxicity, side effect.Derivative etoposide (etoposid, vepesid, etoposide by podophyllotoxin structure of modification gained, the careless second glycosides of foot, VP16) and Vumon (teniposide, teniposide, Teniposide VM26) has become and has been applied to clinical anticancer representative medicine.They are effective to small cell lung cancer, carcinoma of testis, acute leukemia and malignant lymphoma etc.Podophyllotoxin energy and tubulin combine, and suppress microtubule polymerization, thereby destroy the formation of spindle fibre.But VP16 is then different from podophyllotoxin with VM26, mainly suppresses DNA topoisomerase 2, thereby disturbs copying of DNA.Belong to cell cycle nonspecific agent (CCNSA), Main Function is in S phase and G2 phase cell.Though VP16 is alone also effective, clinically normal and cisplatin combined lung cancer and the tumor of testis of being used for the treatment of, curative effect is better, also is used for lymphoma treating.VM26 is also effective to brain tumor.Untoward reaction has bone marrow depression and gastrointestinal reaction etc.
Therefore, the remarkable anti-tumor activity of indian apple derivative and composition thereof, develop its as novel cancer therapy drug or with other Anticancer drug combination new drug, will have very large market, also will produce larger Social benefit and economic benefit.
Summary of the invention
One of purpose of the present invention is to disclose a kind of indian apple derivative, and the defects that exists to overcome prior art satisfies clinical needs;
Two of purpose of the present invention is to disclose above-mentioned pharmaceutical composition;
Three of purpose of the present invention is the preparation methods that disclose described indian apple derivative;
Four of purpose of the present invention is to disclose the application of described indian apple derivative in the preparation anti-tumor agents.
Indian apple derivative of the present invention is for having following general structure (I) compound:
Wherein:
R 1Represent H, halogen, hydroxyl, C1～C4 alkoxyl group or C1～C4 alkoxyalkoxy group;
R 2Represent H, hydroxyl, C1～C3 haloalkyl or C1～C4 alkoxyl group;
R 3Represent H, hydroxyl, halogen, C1～C3 haloalkyl or C1～C4 alkoxyl group;
R 4Represent H, hydroxyl, halogen or C1～C4 alkoxyl group;
Wherein, as n=0, R 3During for C1～C4 alkoxyl group, R 1Be halogen, hydroxyl, C1～C4 alkoxyl group or C1～C4 alkoxyalkoxy group, R 2Be hydroxyl, halogen, C1～C3 haloalkyl or C1～C4 alkoxyl group simultaneously;
When n=0, R 1, R 2, R 3And R 4In, any three groups are arranged simultaneously
Figure BDA0000073252360000022
During for hydrogen, then remaining the 4th group is C1～C3 haloalkyl.
In the present invention, C1～C4 alkoxyl group, as a kind of group, mean to contain the side chain straight chain alkoxyl group of 1 to 4 carbon atom, it comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert.-butoxy, preferably, described C1～C4 alkoxyl group is OCH 3
Equally, C1～C3 haloalkyl refers to the C1 that replaced by one or more identical or different halo atoms～C3 alkyl, such as chloromethyl, methyl fluoride, trifluoromethyl, chloroethyl, two fluoro ethyls, chloropropyl etc., preferred, described C1～C3 haloalkyl is trifluoromethyl;
Described halogen is fluorine, chlorine, bromine or iodine, and is preferred, R 1The halogen of representative is fluorine or chlorine, R 3The halogen of representative is fluorine or bromine, R 4The halogen of representative is chlorine;
Among the present invention, R 1Preferred H, fluorine, chlorine, OH or OCH 3, OCH 2OCH 3
R 2Preferred H, OH, CF 3Or OCH 3
R 3Preferred H, OH, fluorine, bromine, CF 3Or OCH 3
R 4Preferred H, OH, Cl or OCH 3
Most preferred compound is:
(compound 1-6726-17-1) N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 3-trifluoromethyl benzamide,
(compound 2-6726-19-1) 2-chloro-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3,4-dimethoxy benzamide,
(compound 3-6726-20-1) N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls)-2,3, the 4-trimethoxy-benzamide,
(compound 4-6726-41-1) (4) 2-(2-fluorophenyl)-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls) ethanamide,
(compound 5-6726-33-1) 5-chlorine-2-hydroxyl-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-4-(methoxymethoxy) benzamide,
(compound 6-6726-43-1) 5-chloro-2,4-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls) benzamide,
(compound 7-6726-35-1) 4-bromo-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3,5-dimethoxy benzamide,
(compound 8-6726-36-1) N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 4-trifluoromethyl benzamide,
(compound 9-6726-37-1) 4-hydroxy-n-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 3-methyl benzamide,
(compound 10-6726-38-1) 4-bromo-3,5-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls)-benzamide,
(compound 11-6726-39-1) N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-2-(3-p-methoxy-phenyl) ethanamide or
(compound 12-6726-40-1) 2-(2,4 difluorobenzene base)-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls) ethanamide.
The tabulation of table one preferred compound structural formula
Figure BDA0000073252360000051
No. n R1 R2 R3 R4 Molecular formula
1 0 H CF 3 H H C 29H 24F 3NO 8
2 0 Cl OCH 3 OCH 3 H C 30H 28ClNO 10
3 0 OCH 3 OCH 3 OCH 3 H C 31H 31NO 11
4 1 F H H H C 29H 26FNO 8
5 0 OCH 2OCH 3 H OH Cl C 30H 28ClNO 11
6 0 OH H OH Cl C 28H 24ClNO 10
7 0 H OCH 3 Br OCH 3 C 30H 28BrNO 10
8 0 H H CF 3 H C 29H 24F 3NO 8
9 0 H OCH 3 OH H C 29H 27NO 9
10 0 H OH Br OH C 28H 24BrNO 10
11 1 H OCH 3 H H C 30H 29NO 9
12 1 F H F H C 29H 25F 2NO 8
Above-mentioned compound can adopt following reaction scheme to be prepared: the synthetic route general formula:
Formula (II) formula (III) formula (I)
R1, R2, R3 and R4's is described as defined above.
In organic solvent, condensing agent exists under the effect of lower and alkali and reacts with formula II compound and formula III compound.Temperature of reaction is-15-100 ℃, and the reaction times is 1-120 hour, then collection type (I) target product from reaction product;
Concrete, comprise the steps:
In organic solvent, condensing agent exists under the effect of lower and alkali and reacts with formula II compound and formula III compound.Reaction conditions is that temperature of reaction is-15～100 ℃, preferred 10～50 ℃; Reaction times is 1～120 hour, preferred 2～48 hours; The molar ratio of formula II compound and formula III compound is 1: 1～1: 5, preferred 1: 1～1: 3.
Described organic solvent is selected from one or more in tetrahydrofuran (THF), pyridine, acetonitrile, methylene dichloride, trichloromethane, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone and the methyl-sulphoxide; Preferred methylene dichloride, DMF.
Described alkali is selected from more than one in organic bases or the mineral alkali.Organic bases such as pyridine, triethylamine, N, one or more in N dimethylamine yl pyridines and the diisopropylethylamine (DIEA), one or more in mineral alkali such as sodium hydroxide, potassium hydroxide, yellow soda ash and the sodium bicarbonate; Preferred organic bases.
Described condensing agent is selected from general dewatering agent, preferably dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt), N, N '-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), the methylphosphine acid anhydrides, the ethylphosphonic acid acid anhydride, the n-propyl phosphonic acid anhydride, a kind of or several in propyl-phosphine acid cyclic acid anhydride (T3P) and the benzotriazole base diethyl phosphoric acid.
Formula II compound (4 beta-aminos-4 '-O-demethyl epipodophyllotoxin) can adopt document Journal of Natural Products, 1989, Vol52, and No3, the method for 606-613 bibliographical information is prepared;
Sour commercial (Aldrich) that formula III compound 1-4 and 7-14 are corresponding, among the preparation reference WO2006/117669 (2006) of the acid of compound 5 correspondences " example 153 ", among the preparation reference WO2006/117669 (2006) of the acid of compound 6 correspondences " G10compound C ", Journal ofthe American Chemical Society, the method of 1935,1077-1078 bibliographical information is prepared;
The invention still further relates to a kind of composition, the compound and the pharmaceutically acceptable carrier that comprise the formula (1) for the treatment of significant quantity, described carrier refers to the pharmaceutical carrier of pharmaceutical field routine, as: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc., tackiness agent such as derivatived cellulose, gelatin and polyvinylpyrrolidone etc., wetting agent such as glycerine etc., tensio-active agent such as cetyl alcohol etc., disintegrating agent such as calcium carbonate etc., lubricant such as talcum powder, calcium stearate and magnesium etc.;
Can adopt method well known in the art, the compound of the present invention for the treatment of significant quantity is mixed mutually with one or more pharmaceutically acceptable carriers, be prepared into conventional solid preparation such as tablet, pulvis, capsule or injection etc.
According to the present invention, in tablet, pulvis, capsule or the injection, the weight percent content of compound of the present invention is 0.1%-99.5%, preferred 0.5%-19.5%.
Indian apple derivative of the present invention has obvious result for the treatment of for tumour, in particular for treatment leukemia, colorectal carcinoma, lung cancer, mammary cancer, cancer of the stomach, human oral cavity epithelial cancer or lung cancer, and can be for the preparation of the treatment anti-tumor drug;
Compound of the present invention can be applied to the patient who needs this treatment by modes such as oral, injections.Be used for it to be prepared into conventional solid preparation such as tablet, pulvis or capsule etc. when oral; When being used for injection, it can be prepared into injection liquid.Amount of application of the present invention can change according to the type of age of route of administration, patient, body weight, the disease for the treatment of and severity etc., and its per daily dose can be 2-50mg/kg body weight (po) or 1-20mg/kg (iv).
Animal experiment proves, indian apple derivative of the present invention has good anti-tumor activity, can be used for treating the diseases such as leukemia, liver cancer, lung cancer, and toxicity is very little, can satisfy clinical needs.
Embodiment
Below in conjunction with embodiment the present invention is further elaborated, but these embodiment rather than any limitation of the invention.The fusing point of compound is measured with SGW X-4 micro-meldometer among all embodiment, and thermometer is not proofreaied and correct. 1HNMR is by Varian AM-400 type nmr determination, and take TMS as interior mark, chemical shift represents with δ (ppm); Mass spectrum is measured with Q-TOF type mass spectrograph; The column chromatography used silica gel is Chemical Reagent Co., Ltd., Sinopharm Group's (silica gel 100-200 order), and thin layer chromatography board is that Yantai Zhifu experiment chemical industry produces HSGF 254 types that produce.
Embodiment 1
N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-preparation (compound 1) of 3-trifluoromethyl benzamide
With 3-trifluoromethylbenzoic acid (475mg, 2.5mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (525mg, 2.76mmol), I-hydroxybenzotriazole (350mg, 2.6mmol), join in the methylene dichloride (10ml), stir 30min, add again compound I I (1.0g, 2.5mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 1 (728mg) to the crude product of gained through column chromatography purification.Fusing point: 168.9～173.3 ℃.ESI-MS：572(M ++H)，594(M ++Na)，610(M ++K)。 1HNMR/ (CDCl 3) δ ppm:8.051 (1H, s, Ar-H), 7.979 (1H, d, J=7.6Hz, Ar-H), 7.831 (1H, d, J=7.6Hz, Ar-H), 7.602-7.641 (1H, m, Ar-H), 6.836 (1H, s, DMEP-H, H5), 6.596 (1H, s, DMEP-H, H8), 6.351 (2H, s, DMEP-H, H-2 ', 6 '), 6.286 (1H, d, J=6.8Hz, NH), 6.006 (2H, d, J=6.4Hz, DMEP-H, H13), 5.460-5.488 (1H, m, DMEP-H, H4), (5.418 1H, s, OH, heavy water exchange), 4.655 (1H, d, J=5.2Hz, DMEP-H, H1), 4.490-4.532 (1H, m, DMEP-H, H11a), 3.871-3.921 (1H, m, DMEP-H, H11b), 3.816 (6H, s, OCH 3, H-7 ', 8 '), 3.064-3.102 (1H, m, DMEP-H, H3), 2.922-2.970 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 2
2-chloro-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3, the preparation of 4-dimethoxy benzamide (compound 2)
With 2-chloro-3,4-dimethoxybenzoic acid (216mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 2h, add again compound I I (399mg, 1mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 2 (308mg) to the crude product of gained through column chromatography purification.Fusing point: 132.1～136.2 ℃.ESI-MS：598(M ++H)，620(M ++Na)，1217(2M ++Na)。 1HNMR/ (CDCl 3) δ ppm:7.490 (1H, d, J=8.4Hz, Ar-H), 6.893 (1H, d, J=8.8Hz, Ar-H), 6.872 (1H, s, DMEP-H, H5), 6.533 (1H, s, DMEP-H, H8), 6.470 (1H, d, J=6.8Hz, NH), 6.325 (2H, s, DMEP-H, H-2 ', 6 '), 5.958-5.981 (2H, dd, J 1=1.2Hz, J 2=8.4Hz, DMEP-H, H13), 5.416-5.445 (1H, m, DMEP-H, H4), 5.394 (1H, s, OH, the heavy water exchange), 4.600 (1H, d, J=4.8Hz, DMEP-H, H1), 4.474-4.516 (1H, m, DMEP-H, H11a), 3.995-4.045 (1H, m, DMEP-H, H11b), 3.908 (3H, s, OCH 3), 3.848 (3H, s, OCH 3), 3.789 (6H, s, OCH 3, H-7 ', 8 '), 3.002-3.047 (1H, m, DMEP-H, H3), 2.879-2.926 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 3
N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-2,3, the preparation of 4-trimethoxy-benzamide (compound 3)
With 2,3,4 trimethoxybenzoic acid (212mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 2h, add again compound I I (399mg, 1mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 3 (298mg) to the crude product of gained through column chromatography purification.Fusing point: 137.4～141.9 ℃.ESI-MS：594(M ++H)，616(M ++Na)，632(M ++K)。 1HNMR/ (CDCl 3) δ ppm:8.078 (1H, d, J=6.8Hz, NH), 7.868 (1H, d, J=9.2Hz, Ar-H), 6.846 (1H, s, DMEP-H, H5), 6.800 (1H, d, J=8.8Hz, Ar-H), 6.558 (1H, s, DMEP-H, H8), (6.344 2H, s, DMEP-H, H-2 ', 6 '), (5.969 2H, s, DMEP-H, H13), 5.428-5.457 (1H, m, DMEP-H, H4), 5.392 (1H, s, OH, the heavy water exchange), 4.630 (1H, d, J=5.2Hz, DMEP-H, H1), 4.454-4.495 (1H, m, DMEP-H, H11a), 3.918 (3H, s, OCH 3), 3.864-3.898 (1H, m, DMEP-H, H11b), 3.846 (3H, s, OCH 3), 3.827 (3H, s, OCH 3), 3.794 (6H, s, OCH 3, H-7 ', 8 '), 3.007-3.051 (1H, m, DMEP-H, H3), 2.878-2.925 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 4
2-(2-fluorophenyl)-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls) ethanamide (compound 4)
With 2-difluorophenyl acetic acid (160mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5mL).Stir 30min, add again compound I I (399mg, 1mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 13 (366mg) to the crude product of gained through column chromatography purification.Fusing point: 154.5～157.8 ℃.ESI-MS：536(M ++H)，553(M ++NH 4)，558(M ++Na)，574(M ++K)。 1HNMR/ (CDCl 3) δ ppm:7.066-7.326 (4H, m, Ar-H), 6.688 (1H, s, DMEP-H, H5), 6.499 (1H, s, DMEP-H, H8), 6.279 (2H, s, DMEP-H, H-2 ', 6 '), 5.967 (2H, s, DMEP-H, H13), (5.641 1H, d, J=7.6Hz, NH), (5.374 1H, s, OH, heavy water exchange), (5.191-5.220 1H, m, DMEP-H, H4), 4.540 (1H, d, J=4.8Hz, DMEP-H, H1), 4.333-4.374 (1H, m, DMEP-H, H11a), 3.763 (6H, s, OCH 3, H-7 ', 8 '), 3.695-3.746 (1H, m, DMEP-H, H11b), 3.621 (2H, s, CH 2), 2.897-2.932 (1H, m, DMEP-H, H3), 2.679-2.727 (1H, dd, J 1=5.2Hz, J 2=14.4Hz, DMEP-H, H2).
Embodiment 5
5-chlorine-2-hydroxyl-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-4-(methoxymethoxy) benzamide (compound 5)
With 5-chloro-2,4-two (methoxymethoxy) phenylformic acid (830mg, 3mmol) (among the WO2006/117669 (2006) " example 153 "), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (606mg, 3.2mmol), I-hydroxybenzotriazole (431mg, 3.2mmol) joins in the methylene dichloride (10ml).Stir 3h, add compound I I (1273mg, 3.2mmol) again, 25-30 ℃ of lower reaction spent the night.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 5 (405mg) to the crude product of gained through column chromatography purification.Fusing point: 160.9～165.4 ℃.ESI-MS：614(M ++H)，631(M ++NH 4)，636(M ++Na)，652(M ++K)。 1HNMR/ (CDCl 3) δ ppm:12.124 (1H, s, OH, heavy water exchange), 7.398 (1H, s,, Ar-H), 6.802 (1H, s, Ar-H), 6.789 (1H, s, DMEP-H, H5), 6.557 (1H, s, DMEP-H, H8) 6.404 (1H, d, J=6.4Hz, NH, the heavy water exchange), 6.327 (2H, s, DMEP-H, H-2 ', 6 '), 5.996 (2H, d, J=4.0Hz, DMEP-H, H13), 5.409-5.437 (2H, m, DMEP-H, H4, OH, the heavy water exchange), 5.275 (2H, s, CH 2), 4.587 (1H, d, J=4.8Hz, DMEP-H, H1), 4.436-4.477 (1H, m, DMEP-H, H11a), 3.836-3.885 (1H, m, DMEP-H, H11b), 3.790 (6H, s, OCH 3, H-7 ', 8 '), 3.516 (3H, s, OCH 3), 3.031-3.059 (1H, m, DMEP-H, H3), 2.919-2.967 (1H, dd, J 1=5.2Hz, J 2=14.4Hz, DMEP-H, H2).
Embodiment 6
5-chloro-2,4-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3, the 5-Dimethoxyphenyl)-and 8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-s [2,3-d] [1,3] dioxy 5 ring-5-yls also) benzamide (compound 6)
Method one:
With 5-chloro-2,4-resorcylic acid (188mg, 1mmol) (Journal of the American Chemical Society, 1935,1077-1078), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 3h, add compound I I (399mg, 1mmol) again, 25-30 ℃ of lower reaction spent the night.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 6 (138mg) to the crude product of gained through column chromatography purification.
Method two:
Compound 5 (70mg) is dissolved in (5ml) in the Virahol, adds again zirconium chloride (13mg) reflux and spend the night.Remove solvent under reduced pressure, residue acetic acid ethyl dissolution, washing, anhydrous sodium sulfate drying; Filter and remove anhydrous sodium sulphate, remove solvent under reduced pressure, get compound 6.(58mg)。Fusing point: 174.5～179.7 ℃.ESI-MS：570(M ++H)，592(M ++Na)，608(M ++K)。 1HNMR/ (CDCl 3) δ ppm:12.024 (1H, s, OH, heavy water exchange), 7.298 (1H, s, Ar-H), 6.792 (1H, s, DMEP-H, H5), 6.688 (1H, s, Ar-H), 6.613 (1H, s, DMEP-H, H8), 6.324 (2H, s, DMEP-H, H-2 ', 6 '), 6.138 (1H, d, J=6.8Hz, NH), 5.997 (2H, d, J=4.8Hz, DMEP-H, H13), 5.900 (1H, s, OH, the heavy water exchange), 5.390-5.417 (2H, m, DMEP-H, H4, OH, the heavy water exchange), 4.634 (1H, d, J=4.4Hz, DMEP-H, H1), 4.433-4.474 (1H, m, DMEP-H, H11a), 3.829-3.880 (1H, m, DMEP-H, H11b), 3.793 (6H, s, OCH 3, H-7 ', 8 '), 3.028-3.055 (1H, m, DMEP-H, H3), 2.893-2.941 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 7
4-bromo-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3,5-dimethoxy benzamide (compound 7)
With 4-bromo-2,5-dimethoxybenzoic acid (65mg, 0.25mmol) and 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU) (114mg, 0.3mmol), DIPEA (65mg, 0.5mmol) is dissolved in N, after stirring in the dinethylformamide (5ml), add compound I I (100mg, 0.25mmol), 25-30 ℃ of lower reaction 5h.Remove most of solvent under reduced pressure, dichloromethane extraction is used in washing; Merge organic layer, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 7 (99.2mg) to the crude product of gained through column chromatography purification.Fusing point: 208.3～211.3 ℃.ESI-MS：644(M ++H)，661(M ++NH 4)，666(M ++Na)，682(M ++K)。 1HNMR/ (CDCl 3) δ ppm:6.939 (1H, s, Ar-H), 6.847 (1H, s, DMEP-H, H5), 6.661 (1H, s, DMEP-H, H8), 6.356 (2H, s, DMEP-H, H-2 ', 6 '), 6.133 (1H, d, J=6.8Hz, NH, the heavy water exchange), 6.014 (2H, d, J=3.6Hz, DMEP-H, H13), 5.433-5.462 (1H, m, DMEP-H, H4), (5.424 1H, s, OH, heavy water exchange), 4.667 (1H, d, J=4.8Hz, DMEP-H, H1), 4.496-4.539 (1H, m, DMEP-H, H11a), 3.886-3.936 (1H, m, DMEP-H, H11b), 3.980 (6H, s, Ar-OCH 3), 3.825 (6H, s, OCH 3, H-7 ', 8 '), 3.060-3.099 (1H, m, DMEP-H, H3), 2.922-2.970 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 8
N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-4-trifluoromethyl benzamide (compound 8)
With 4-trifluoromethylbenzoic acid (190mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 30min, add again compound I I (399mg, 1mmol).25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 8 (330mg) to the crude product of gained through column chromatography purification.Fusing point: 181.5～183.2 ℃.ESI-MS：572(M ++H)，589(M ++NH 4)，594(M ++Na)，610(M ++K)。 1HNMR/ (CDCl 3) δ ppm:7.912 (2H, d, J=7.6Hz, Ar-H), 7.748 (2H, d, J=7.6Hz, Ar-H), 6.838 (1H, s, DMEP-H, H5), 6.598 (1H, s, DMEP-H, H8), 6.352 (2H, s, DMEP-H, H-2 ', 6 '), 6.276 (1H, d, J=6.8Hz, NH, the heavy water exchange), 6.010 (2H, d, J=7.2Hz, DMEP-H, H13), 5.454-5.482 (1H, m, DMEP-H, H4), (5.426 1H, s, OH, heavy water exchange), 4.655 (1H, d, J=4.8Hz, DMEP-H, H1), 4.498-4.539 (1H, m, DMEP-H, H11a), 3.875-3.925 (1H, m, DMEP-H, H11b), 3.820 (6H, s, OCH 3, H-7 ', 8 '), 3.066-3.103 (1H, m, DMEP-H, H3), 2.909-2.958 (1H, dd, J 1=5.2Hz, J 2=14.4Hz, DMEP-H, H2).
Embodiment 9
4-hydroxy-n-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3-methyl benzamide (compound 9)
With 4-hydroxy-3-methyl phenylformic acid (152mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 30min, add again compound I I (399mg, 1mmol).25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 9 (107mg) to the crude product of gained through column chromatography purification.Fusing point: 135.5～137.4 mend ℃.ESI-MS：534(M ++H)，551(M ++NH 4)，556(M ++Na)，572(M ++K)。 1HNMR/ (CDCl 3) δ ppm:7.560 (1H, d, J=2.0Hz, Ar-H), 7.464-7.491 (1H, dd, J 1=2.4Hz, J 2=8.4Hz, Ar-H), 6.770 (1H, d, J=8.8Hz, Ar-H), 6.804 (1H, s, DMEP-H, H5), (6.533 1H, s, DMEP-H, H8), 6.222 (1H, d, J=6.8Hz, NH), 6.317 (2H, s, DMEP-H, H-2 ', 6 '), 5.962 (2H, d, J=6.0Hz, DMEP-H, H13), 5.389-5.417 (2H, m, DMEP-H, H4, OH, the heavy water exchange), 4.587 (1H, d, J=4.8Hz, DMEP-H, H1), 4.433-4.473 (1H, m, DMEP-H, H11a), 3.853-3.902 (1H, m, DMEP-H, H11b), 3.770 (6H, s, OCH 3, H-7 ', 8 '), 2.915-3.029 (2H, m, DMEP-H, H2, H3), 2.259 (3H, s, CH 3).
Embodiment 10
4-bromo-3,5-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3, the 5-Dimethoxyphenyl)-and 8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-s [2,3-d] [1,3] dioxy 5 ring-5-yls also)-benzamide (compound 10)
With 4-bromo-2,5-resorcylic acid (233mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (210mg, 1.1mmol), I-hydroxybenzotriazole (150mg, 1.1mmol), be dissolved in the DMF (5ml).Stir 3h, add compound I I (399mg, 1mmol) again, 25-30 ℃ of lower reaction spent the night.Remove most of solvent under reduced pressure, dichloromethane extraction is used in washing.Merge organic layer, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 10 (275mg) to the crude product of gained through column chromatography purification.Fusing point: 207.9～210.7 ℃.ESI-MS：612(M +-H)，614(M ++H)。 1HNMR/ (CDCl 3) δ ppm: 7.032 (2H, s, Ar-H), 6.819 (1H, s, DMEP-H, H5), 6.578 (1H, s, DMEP-H, H8), 6.350 (2H, s, DMEP-H, H-2 ', 6 '), 6.253 (1H, s, NH), (6.012 2H, d, J=6.8Hz, DMEP-H, H13), 5.401-5.429 (2H, m, DMEP-H, H4, OH, the heavy water exchange), 4.637 (1H, d, J=4.8Hz, DMEP-H, H1), 4.461-4.501 (1H, m, DMEP-H, H11a), 3.845-3.895 (1H, m, DMEP-H, H11b), 3.823 (6H, s, OCH 3, H-7 ', 8 '), 3.639 (1H, s, OH), 2.942-3.079 (2H, m, DMEP-H, H2, H3).
Embodiment 11
N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-2-(3-p-methoxy-phenyl) ethanamide (compound 11)
With 4-methoxyphenylacetic acid (166mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol) joins in the methylene dichloride (5ml).Stir 30min, add again compound I I (399mg, 1mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 11 (353mg) to the crude product of gained through column chromatography purification.Fusing point: 138.5～143.4 ℃.ESI-MS：548(M ++H)，565(M ++NH 4)，570(M ++Na)。 1HNMR/ (CDCl 3) δ ppm:6.772-7.273 (4H, m, Ar-H), 6.638 (1H, s, DMEP-H, H5), 6.468 (1H, s, DMEP-H, H8), 6.257 (2H, s, DMEP-H, H-2 ', 6 '), 5.946 (2H, d, J=4.4Hz, DMEP-H, H13), 5.497 (1H, d, J=7.2Hz, NH), (5.362 1H, s, OH, heavy water exchange), (5.179-5.208 1H, m, DMEP-H, H4), 4.498 (1H, d, J=5.2Hz, DMEP-H, H1), 4.345-4.386 (1H, m, DMEP-H, H11a), 3.783 (3H, s, OCH 3), 3.755 (6H, s, OCH 3, H-7 ', 8 '), 3.691-3.741 (1H, m, DMEP-H, H11b), 3.577 (2H, s, CH 2), 2.880-2.908 (1H, m, DMEP-H, H3), 2.581-2.628 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 12
2-(2,4 difluorobenzene base)-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3, the 5-Dimethoxyphenyl)-and 8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-s [2,3-d] [1,3] dioxy 5 ring-5-yls also) ethanamide (compound 12)
With 2,4 difluorobenzene acetic acid (177mg, 1mmol), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI) (191mg, 1mmol), I-hydroxybenzotriazole (135mg, 1mmol), join in the methylene dichloride (5mL).Stir 30min, add again compound I I (399mg, 1mmol), 25-30 ℃ of lower reaction 4h.The reaction solution washing, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure, (eluent: methylene dichloride/acetone gradient elution) purifying gets white solid compound 12 (196mg) to the crude product of gained through column chromatography purification.Fusing point: 159.6～162.3 ℃.ESI-MS：554(M ++H)，571(M ++NH 4)，576(M ++Na)，592(M ++K)。 1HNMR/ (CDCl 3) δ ppm:6.825-7.308 (3H, m, Ar-H), 6.673 (1H, s, DMEP-H, H5), 6.502 (1H, s, DMEP-H, H8), 6.273 (2H, s, DMEP-H, H-2 ', 6 '), 5.980 (2H, d, J=0.8Hz, DMEP-H, H13), 5.600 (1H, d, J=7.6Hz, NH), (5.367 1H, s, OH, heavy water exchange), (5.176-5.205 1H, m, DMEP-H, H4), 4.548 (1H, d, J=4.8Hz, DMEP-H, H1), 4.333-4.374 (1H, m, DMEP-H, H11a), 3.763 (6H, s, OCH 3, H-7 ', 8 '), 3.697-3.747 (1H, m, DMEP-H, H11b), 3.561 (2H, s, CH 2), 2.900-2.929 (1H, m, DMEP-H, H3), 2.699-2.748 (1H, dd, J 1=4.8Hz, J 2=14.0Hz, DMEP-H, H2).
Embodiment 13
Mtt assay is measured each compound to the susceptibility of different tumour cells
Results logarithmic phase cell is adjusted concentration to 20 * 10 behind the counting 4/ ml, 96 orifice plates, every hole adds 90 μ l cell suspensions.10 μ l/ hole application of samples after medicine dilutes in proportion calculate final concentration.37 ℃, 5%CO behind the mixing 2Cultivate after 48 hours in the incubator, add 5mg/ml MTT (PBS) solution 20 μ l/ holes, 37 ℃, 5%CO 2After cultivating again 4 hours in the incubator, add lysate (10%SDS, 5% isopropylcarbinol, 0.02M HCl) 100 μ l/ holes, 37 ℃, 5%CO 2Place in the incubator and spend the night.Observe next day in each hole precipitation fully dissolving be that available microplate reader is measured the OD value at 570nm.
Interpretation of result: inhibiting rate %=(control wells OD-test hole OD)/control wells OD * 100%
Return with the concentration logarithm, calculate IC 50
Each compound is to the susceptibility of different tumour cells
Figure BDA0000073252360000151
Embodiment 14
Mtt assay is measured compound 2, compound 5, compound 6, to the susceptibility of different tumour cells
Results logarithmic phase cell is adjusted concentration to 20 * 10 behind the counting 4/ ml, 96 orifice plates, every hole adds 90 μ l cell suspensions.10 μ l/ hole application of samples after compound dilutes in proportion calculate final concentration.37 ℃, 5%CO behind the mixing 2Cultivate after 48 hours in the incubator, add 5mg/ml MTT (PBS) solution 20 μ l/ holes, 37 ℃, 5%CO 2After cultivating again 4 hours in the incubator, add lysate (10%SDS, 5% isopropylcarbinol, 0.02M HCl) 100 μ l/ holes, 37 ℃, 5%CO 2Place in the incubator and spend the night.Observe next day in each hole precipitation fully dissolving be that available microplate reader is measured the OD value at 570nm.
Interpretation of result: inhibiting rate %=(control wells OD-test hole OD)/control wells OD * 100%
Return with the concentration logarithm, calculate IC 50
Compound 2, compound 5, the susceptibility of 6 pairs of different tumour cells of compound
Figure BDA0000073252360000161
Embodiment 15
The pharmacodynamic study of compound 1 and 2 pairs of ICR mouse of compound S180 transplanted tumor
Get 3 of the mouse S180 ascites sarcomas of growth animated period, extract ascites under the aseptic condition, with normal saline dilution to 2 * 10 7, press 0.2ml/ only to the subcutaneous vaccination of mouse armpit.At random be divided into 11 group with mouse next day, 6 every group.
Be respectively blank group, compound 1 1.5mg/kg group, 3mg/kg group, 6mg/kg group; Compound 21.5mg/kg group, 3mg/kg group, 6mg/kg group; The VP-163mg/kg group.
Each is organized mouse and is the tail vein injection administration, and administration volume 0.5ml/20 restrains, and inoculates to rise next day to be administered once every day.And execution dissection in the 10th day is peeled off tumour and is weighed after inoculation, calculates tumour inhibiting rate.
Figure BDA0000073252360000171
The pharmacodynamic study of compound 1 and compound 2ICR mouse S180 transplanted tumor
The overt toxicity reaction appears in compound 26mg/kg group successive administration after 5 days, the 7th day dead 2, the residue the weight of animals obviously alleviates.
Figure BDA0000073252360000172
Embodiment 16
The pharmacodynamic study of 5 pairs of ICR mouse of compound S180 transplanted tumor
Get 3 of the mouse S180 ascites sarcomas of growth animated period, extract ascites under the aseptic condition, with normal saline dilution to 2 * 10 7, press 0.2ml/ only to the subcutaneous vaccination of mouse armpit.At random be divided into 8 group with mouse next day, 6 every group.
Be respectively the blank group, compound 5 15mg/kg group, 30mg/kg group, 60mg/kg group; VP-16 10mg/kg group.
Each is organized mouse and is the tail vein injection administration, and administration volume 0.5ml/20 restrains, and inoculates to rise next day to be administered once every day.And execution dissection in the 10th day is peeled off tumour and is weighed after inoculation, calculates tumour inhibiting rate.
Figure BDA0000073252360000181
The pharmacodynamic study of 5 pairs of ICR mouse of compound S180 transplanted tumor:
The overt toxicity reaction appears after the 5th day after the VP-16 10mg/kg group beginning administration, the 6th day dead 3, remain 3 all death in the 7th day.
Figure BDA0000073252360000182
Embodiment 17
The pharmacodynamic study of compound 2 and 5 pairs of ICR mouse of compound S180 transplanted tumor
Get be in logarithmic phase the K111 cell, be diluted to 25 * 10 4Individual/ml, every mouse (C57BL/6 mouse) intravenous injection 0.2mL, random packet is established coordinative solvent control group and endoxan positive controls (30mg/kg/d, ip * 7d), sample I-1 administration group is 40mg/kg, play administration next day, continuous intravenous injection 14 days took off cervical vertebra and puts to death on the 21st day, get lungs, branch on count kitchen range number.
The overt toxicity reaction appears after the 5th day after the VP-16 10mg/kg group beginning administration, the 6th day dead 3, remain 3 all death in the 7th day.
Figure BDA0000073252360000184
Figure BDA0000073252360000191
Embodiment 18
The pharmacodynamic study of 5 pairs of F1 mouse of compound C26 transplanted tumor
Get 3 of the F1 mouse C26 solid tumors of growth animated period, dissect under the aseptic condition and get the knurl piece, homogenate is cell suspension, with normal saline dilution to 2 * 10 7, press 0.2ml/ only to the subcutaneous vaccination of mouse armpit.At random be divided into 11 group with mouse next day, 6 every group.
Be respectively blank group, compound 5 15mg/kg group, 30mg/kg group, 60mg/kg group; VP-16 3mg/kg group.
Each is organized mouse and is the tail vein injection administration, and administration volume 0.5ml/20 restrains, and inoculates to rise next day to be administered once every day.And execution dissection in the 10th day is peeled off tumour and is weighed after inoculation, calculates tumour inhibiting rate.
Figure BDA0000073252360000192
The pharmacodynamic study of 5 pairs of F1 mouse of compound C26 transplanted tumor
Embodiment 19
Compound 5 mouse mainline acute toxicity tests
The test of mouse preliminary survey poison
Experimental technique:
Get each 15 of the female and male KM mouse of 18-20g, adapt to a week after, be divided at random 5 groups, be respectively the 1g/kg of compound 5,500mg/kg, 250mg/kg, 125mg/kg, 62.5mg/kg, by labelled amount abdominal cavity single-dose, observe its death condition and body weight change and survival condition etc. respectively.
Calculate the LD50 value through the bliss method and be 222mg/kg.
Embodiment 20
Tablet:
Figure BDA0000073252360000201
The preparation method:
Compound of the present invention and starch, Icing Sugar are fully mixed, granulate with 10% starch slurry is mixed, air seasoning below 60 ℃ adds Magnesium Stearate, whole grain, and mixing, compressing tablet, and get final product.
Embodiment 21
Tablet:
Figure BDA0000073252360000202
The preparation method is with embodiment 20.
Embodiment 22
Tablet:
Figure BDA0000073252360000203
The preparation method is with embodiment 20.
Embodiment 23
Tablet:
Figure BDA0000073252360000204
The preparation method is with embodiment 20.
Embodiment 24
Injection:
The preparation method:
Get and boil in right amount logical nitrogen and be cooled to water for injection about 50 ℃, add recipe quantity sodium-chlor stirring and dissolving, add again 0.1% gac (W/V) decarbonization filtering.Recipe quantity compound of the present invention and soybean phospholipid in above-mentioned filtrate after the adding PEG400 dissolving are regulated about pH value to 4.0, inject water to amount of preparation, mixing, and to clarification, can is led to the nitrogen sealing by fusing in the 2ml ampoule through 0.45 μ m filtering with microporous membrane.Put 100 ℃ of flowing steam sterilizations 30 minutes, and get final product.
Embodiment 25
Injection:
Figure BDA0000073252360000212
The preparation method is with embodiment 24.
Embodiment 26
Injection:
Figure BDA0000073252360000213
The preparation method is with embodiment 24.

Claims (17)

1. indian apple derivative is characterized in that, for having the compound of following general structure (I):
Figure FDA0000073252350000011
Wherein:
R 1Represent H, halogen, hydroxyl, C1～C4 alkoxyl group or C1～C4 alkoxyalkoxy group;
R 2Represent H, hydroxyl, C1～C3 haloalkyl or C1～C4 alkoxyl group;
R 3Represent H, hydroxyl, halogen, C1～C3 haloalkyl or C1～C4 alkoxyl group;
R 4Represent H, hydroxyl, halogen or C1～C4 alkoxyl group;
Wherein, as n=0, R 3During for C1～C4 alkoxyl group, R 1Be halogen, hydroxyl, C1～C4 alkoxyl group or C1～C4 alkoxyalkoxy group, R 2Be hydroxyl, halogen, C1～C3 haloalkyl or C1～C4 alkoxyl group simultaneously;
When n=0, R 1, R 2, R 3And R 4In, when any three groups were arranged simultaneously for hydrogen, then remaining the 4th group was C1～C3 haloalkyl.
2. indian apple derivative according to claim 1 is characterized in that, described C1～C4 alkoxyl group is side chain or the straight chain alkoxyl group that contains 1 to 4 carbon atom.
3. indian apple derivative according to claim 2 is characterized in that, described C1～C4 alkoxyl group is OCH 3
4. indian apple derivative according to claim 1 is characterized in that, described C1～C3 haloalkyl is trifluoromethyl.
5. indian apple derivative according to claim 3 is characterized in that, described C1～C3 haloalkyl is trifluoromethyl.
6. indian apple derivative according to claim 1 is characterized in that, described halogen is fluorine, chlorine, bromine or iodine.
7. indian apple derivative according to claim 1 is characterized in that, R 1The halogen of representative is fluorine or chlorine, R 3The halogen of representative is fluorine or bromine, R 4The halogen of representative is chlorine.
8. each described indian apple derivative is characterized in that R according to claim 1～7 1Represent H, fluorine, chlorine, OH or OCH 3, OCH 2OCH 3
R 2Represent H, OH, CF 3Or OCH 3
R 3Represent H, OH, fluorine, bromine, CF 3Or OCH 3
R 4Represent H, OH, Cl or OCH 3
9. indian apple derivative is characterized in that, comprising:
(compound 1-6726-17-1) N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 3-trifluoromethyl benzamide,
(compound 2-6726-19-1) 2-chloro-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3,4-dimethoxy benzamide,
(compound 3-6726-20-1) N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls)-2,3, the 4-trimethoxy-benzamide,
(compound 4-6726-41-1) (4) 2-(2-fluorophenyl)-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls) ethanamide,
(compound 5-6726-33-1) 5-chlorine-2-hydroxyl-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-4-(methoxymethoxy) benzamide,
(compound 6-6726-43-1) 5-chloro-2,4-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls) benzamide,
(compound 7-6726-35-1) 4-bromo-N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-3,5-dimethoxy benzamide,
(compound 8-6726-36-1) N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 4-trifluoromethyl benzamide,
(compound 9-6726-37-1) 4-hydroxy-n-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-the 3-methyl benzamide,
(compound 10-6726-38-1) 4-bromo-3,5-dihydroxyl-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls)-benzamide,
(compound 11-6726-39-1) N-((5S, 5aS, 8aR, 9R)-and 9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, 9-hexahydro furyl also [3 ', 4 ': 6,7] naphtho-[2,3-d] [1,3] dioxy 5 ring-5-yls)-2-(3-p-methoxy-phenyl) ethanamide or
(compound 12-6726-40-1) 2-(2,4 difluorobenzene base)-N-((5S, 5aS, 8aR, 9R)-9-(4-hydroxyl-3,5-Dimethoxyphenyl)-8-oxo-5,5a, 6,8,8a, the 9-hexahydro furyl is [3 ', 4 ': 6,7] naphtho-[2 also, 3-d] [1,3] dioxy 5 ring-5-yls) ethanamide.
10. the preparation method of each described indian apple derivative is characterized in that according to claim 1～9, and the synthetic route general formula is:
Figure FDA0000073252350000041
Formula (II) formula (III) formula (I)
R1, R2, R3 and R4's is described as defined above.
11. method according to claim 10 is characterized in that, comprises the steps: formula II compound and formula III compound in organic solvent, condensing agent exists under the effect of lower and alkali and reacts.Temperature of reaction is-15-100 ℃, and the reaction times is 1-120 hour, then collection type (I) target product from reaction product.
12. method according to claim 11 is characterized in that, temperature of reaction is-15～100 ℃, and the reaction times is 1～120 hour, and the molar ratio of formula II compound and formula III compound is 1: 1～1: 5, preferred 1: 1～1: 3.
13. method according to claim 11, it is characterized in that, described organic solvent is selected from one or more in tetrahydrofuran (THF), pyridine, acetonitrile, methylene dichloride, trichloromethane, DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone and the methyl-sulphoxide.
14. method according to claim 11, it is characterized in that, described alkali is selected from more than one in organic bases or the organic bases, described condensing agent is selected from dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(dimethylin) propyl group] carbodiimide hydrochloride (EDCI), I-hydroxybenzotriazole (HOBt), N, N '-carbonyl dimidazoles (CDI), 2-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU), the methylphosphine acid anhydrides, the ethylphosphonic acid acid anhydride, the n-propyl phosphonic acid anhydride, in propyl-phosphine acid cyclic acid anhydride (T3P) and the benzotriazole base diethyl phosphoric acid one or more.
15. a composition comprises each described compound of claim 1～9 and the pharmaceutically acceptable carrier for the treatment of significant quantity.
16. the application of each described compound of claim 1～9 in preparation medicine for treating tumor thing.
17. application according to claim 16 is characterized in that, described tumour is leukemia, colorectal carcinoma, lung cancer, mammary cancer, cancer of the stomach, human oral cavity epithelial cancer or lung cancer.
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WO2015161745A1 (en) * 2014-04-25 2015-10-29 中国医药工业研究总院 Podophyllotoxin derivative, and preparation method, pharmaceutical composition and use thereof
CN107652300A (en) * 2017-09-20 2018-02-02 辽宁大学 Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015161745A1 (en) * 2014-04-25 2015-10-29 中国医药工业研究总院 Podophyllotoxin derivative, and preparation method, pharmaceutical composition and use thereof
CN105037379B (en) * 2014-04-25 2017-12-19 上海医药工业研究院 Podophyllotoxin derivative, its preparation method, pharmaceutical composition and application
CN107652300A (en) * 2017-09-20 2018-02-02 辽宁大学 Podophyllotoxin analogue and its application containing 1,2,4 triazinone structures
CN107652300B (en) * 2017-09-20 2019-08-09 辽宁大学 The podophyllotoxin analogue of the structure of triazinone containing 1,2,4- and its application

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