CN102040570B - Sulfo-taxane derivative and preparation method and application thereof - Google Patents
Sulfo-taxane derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a sulfo-taxane derivative and a preparation method and application thereof. The sulfo-taxane derivative has a structure shown in a formula (1) in the specification, wherein R is hydrogen, C1-18 alkyl, C1-18 substituent alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-6 cycloalkyl, C4-6 naphthenic base, aryl, substitutive aryl, heterocyclic radical or substituent heterocyclic radical; and the substituent group is selected from one or more of C1-8 alkyl, C1-8 alkoxy, C1-8 halogen alkyl, halogen, aryl, nitryl and azyl. The sulfo-taxane derivative in the invention can be used for preparing antitumor drugs.
Description
Technical field
The invention belongs to pharmaceutical chemistry and medical technical field, be specifically related to a kind of new thio-taxane derivatives with anti-tumor activity, its preparation method and pharmaceutical usage.
Background technology
Taxol (taxol) and Docetaxel (docetaxel) are two representational medicines in bearing taxanes family.(the J.Am.Chem.Soc.1971 such as Wall, 93,2325) from the bark of America Chinese yew genus plants yewtree (Taxus breviolia), extracted and separate the diterpene-kind compound obtaining first in 1971, be mainly used in treating ovarian cancer, mammary cancer and nonsmall-cell lung cancer.French Rhone-Poulenc Rorer in 1985 and French National Nature research establishment carry out the semi-synthetic Docetaxel that obtains by 10-DAB, it is water-soluble better than taxol, antitumor spectrum is wider, all effective to other solid tumors except kidney, knot, the rectum cancer.Under suitable toxicity dose, its antitumor action is higher 1 times than taxol.The Anticancer Effect and Mechanism of paclitaxel analog compound is by inducing and impelling tubulin polymerization to become microtubule, suppresses the depolymerization of the microtubule that forms simultaneously, produces stable microtubule fasolculus.The normal dynamic regeneration of microtubule fasolculus is obstructed, and cell can not form normal mitotic spindle in the time of mitotic division, thereby has suppressed cell fission and propagation.Research thinks, the reason that Docetaxel anti-tumor activity strengthens is that the tertbutyloxycarbonyl on C-13 side chain N has substituted benzoyl.
Summary of the invention
An object of the present invention is to provide the novel thio-taxane derivatives of high-efficiency low-toxicity.
Another object of the present invention is to provide the preparation method of this novel thio-taxane derivatives.
A further object of the present invention is to provide this novel thio-taxane derivatives in the application of preparing on antitumor drug.
Object of the present invention can reach by following measures:
Thio-taxane derivatives shown in formula (1):
Wherein,
R is hydrogen, C1～18 alkyl, C1～18 substituted alkyl, C2～10 thiazolinyl, C2～10 alkynyl, C3～6 cycloalkyl, C4～6 cycloalkenyl group, aryl, substituted aryl, heterocyclic radical or substituted heterocyclic radical, and described substituting group is selected from one or more in C1～8 alkyl, C1～8 alkoxyl group, C1～8 haloalkyl, halogen, aryl, nitro or amino; R is preferably hydrogen, C1～18 straight or branched alkyl, C1～18 straight or branched substituted alkyl, C2～6 straight or branched thiazolinyl, C2～6 straight or branched alkynyl, C3～6 cycloalkyl, C4～6 cycloalkenyl group, aryl, substituted aryl, C5～6 heterocyclic radical, and described substituting group is selected from one or more in C1～8 alkyl, C1～8 alkoxyl group, C1～8 haloalkyl, halogen, aryl, nitro or amino.
R more preferably C1～18 alkyl or benzene for C1～18 alkyl; R is further preferably C1～12 alkyl or benzene for C1～4 alkyl; R most preferably is C2～12 straight chained alkyl, C3～6 branched-chain alkyl or benzyl.
Alkyl of the present invention is to comprise the alkyl of straight chain and the alkyl of side chain.Substituted alkyl refers to the alkyl that alkyl is replaced by one or more substituting groups.Aryl comprises monocyclic aryl, polyaromatic and non-benzene aryl.Heterocyclic radical is to contain one or more heteroatomic cyclic groups, comprise and have aromaticity group and nonaro-maticity group, and heteroatoms generally refers to N, O, S, P etc.Halogen comprises fluorine, chlorine, bromine and iodine.
Thio-taxane derivatives shown in formula provided by the invention (1) can adopt but be not limited to following method preparation:
Preparation method's of the present invention illustrations is as follows:
Step I: formula (2) compound 7,10-bis-(2,2,2-trichloro-ethoxycarbonyl)-3 '-N-goes tertbutyloxycarbonyl Docetaxel (compound 2) and sulfo-acyl chloride reaction to obtain compound 3;
Step II: compound 3 deprotections obtain the thio-taxane derivatives shown in formula (1).
In step I, compound 2, under the catalysis of alkali, is not having under solvent condition or in solvent and sulfo-acyl chloride reaction.Described alkali can be organic bases, as triethylamine, pyridine, N, N-diisopropylethylamine, DMAP, 1,8-diazabicyclo [5.4.0]-7-undecylene and 1,2,2,6,6-pentamethyl-piperidines etc. can be also mineral alkalis, as sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc.The solvent using in this preparation method can be any solvent, as long as this solvent is originally inertia in reaction, and can inhibited reaction.Described solvent comprises halogenated hydrocarbon solvent, as methylene dichloride, and chloroform, 1,2-ethylene dichloride etc.; Aromatic hydrocarbons solvent, as benzene and toluene etc.; Non-proton transitivity solvent, as acetone, acetonitrile, DMF, METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ring fourth sulfoxide and hexa-methylene phosphoryl triamide etc.; Esters solvent, as ethyl acetate and methyl acetate etc.; Ether solvent, as tetrahydrofuran (THF), ether and Isosorbide-5-Nitrae-dioxs etc.; Organic bases solvent, as pyridine, picoline etc.; Or the mixture of these solvents.Temperature of reaction can, between-80 DEG C to 50 DEG C, preferably adopt 0 DEG C to room temperature; Material molar ratio can be arbitrarily, preferably uses 1: 1.
In Step II, compound 3, having under acid exists, is not having under solvent condition or in solvent, to react the taxane derivatives shown in the formula of obtaining (1) with Metal Zn powder.The acid using in this preparation method comprises hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid etc.The solvent using in this preparation method can be any solvent, as long as this solvent is originally inertia in reaction, and can inhibited reaction.Described solvent comprises halogenated hydrocarbon solvent, as methylene dichloride, and chloroform, 1,2-ethylene dichloride etc.; Aromatic hydrocarbons solvent, as benzene and toluene etc.; Non-proton transitivity solvent, as acetone, acetonitrile, DMF, METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ring fourth sulfoxide and hexa-methylene phosphoryl triamide etc.; Esters solvent, as ethyl acetate and methyl acetate etc.; Ether solvent, as tetrahydrofuran (THF), ether and Isosorbide-5-Nitrae-dioxan etc.; Organic bases solvent, as pyridine, picoline etc.; Or the mixture of these solvents.This reaction is carried out-80 DEG C to 100 DEG C temperature ranges, preferably uses 0 DEG C to 100 DEG C, most preferably uses 50 DEG C.
Wherein in step I, compound 2 can be prepared by following steps, or with reference to publication CN101012210A:
1) 10-deacetylate Baccatine III (10-DAB) is with 2,2, hydroxyl in 7 and 10 of 2-trichloro-ethoxycarbonyl chlorine (TrocCl) protections, obtain intermediate 7,10-bis-(2,2,2-trichloro-ethoxycarbonyl)-10-deacetylate baccatin III (compound 4);
2) compound 4 and (4S, 5R)-N-tertbutyloxycarbonyl-2,2-dimethyl-4-phenyl-oxazolidines-5-formic acid is at condensing agent N, N '-dicyclohexylcarbodiimide (DCC), under DMAP (DMAP) catalysis, carry out esterification, obtain midbody compound 5;
3) midbody compound 5 reacts deprotection and obtains 7,10-bis-(2,2,2-trichloro-ethoxycarbonyl)-3 '-N-and remove tertbutyloxycarbonyl Docetaxel (compound 2) with anhydrous formic acid;
The illustrations of its preparation method is as follows:
Wherein in step I, sulfo-acyl chlorides can prepare by mercaptan and two (trichloromethyl) carbonic ether (be commonly called as solid phosgene, be designated hereinafter simply as BTC) reaction.
The present invention further provides thio-taxane derivatives in the application of preparing on antitumor drug, wherein part of compounds has the anti-tumor activity stronger than Docetaxel.Thio-taxane derivatives shown in pharmacological research display type (1) has obvious antitumor action and good dose-dependence.In to human hepatoma cell strain (BEL-7402), human breast cancer cell strain (MDA-MB-231), human stomach cancer cell line (SGC-7901), human oophoroma cell line (SKOV-3), the test of human lung carcinoma cell line (A549) cytotoxic activity, discovery is quite active with Docetaxel, is even better than Docetaxel.
Therefore, thio-taxane derivatives of the present invention can be made into the various preparations that comprise safe and effective amount thio-taxane derivatives and pharmaceutical carrier.
" safe and effective amount " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Safe and effective amount is according to determining the age for the treatment of target, the state of an illness, the course for the treatment of etc.
" pharmaceutical carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for people's use, and must have enough purity and enough low toxicity." consistency " referred to herein as each component energy and compound of the present invention and blending mutually between them in composition, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable carrier part example has sugar (as glucose, sucrose, lactose etc.), starch (as W-Gum, yam starch etc.), Mierocrystalline cellulose and derivative thereof (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.), gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent is (as tween
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these embodiment are never any limitation of the invention.
Embodiment 1
Get 100mL there-necked flask, dryout, logical nitrogen, at 0 DEG C of temperature, adds after BTC (3.82g), adds dry CH
2cl
2(40mL), BTC complete molten after, add ethanethio (2.41mL), slowly drip Et
3n (4.48mL), adularescent precipitation produces, and after dropwising, room temperature is crossed liquid, and reaction solution elimination insolubles obtains the solution of sulfo-acyl chlorides without any processing, is directly used in next step reaction.Get a 100mL there-necked flask, add taxol midbody compound 2 (500mg), use CH
2cl
2(10mL) dissolve, in ice-water bath, slowly drip excessive acyl chlorides, dropwise, under room temperature, stirred liquid, stopped reaction, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, except desolventizing, column chromatography (elutriant: petrol ether/ethyl acetate=2/1).Obtaining midbody compound 3 is 0.165g, yield 30.6%.Get a 10mL single necked round bottom flask, dry, rush nitrogen, add midbody compound 3 (135mg), Zn (270mg), then add CH
3oH, drip ice HOAc (3mL), reaction at 50 DEG C, TLC detects (developping agent: petrol ether/ethyl acetate=2/1), after 2 hours, raw material disappears, remove methyl alcohol, add ethyl acetate, wash respectively with saturated sodium bicarbonate solution and saturated aqueous common salt, anhydrous sodium sulfate drying, except desolventizing, it is 67mg that column chromatography (elutriant: sherwood oil/acetone=2/1) obtains product 6, yield 70.1%.
Compound 6:
1h NMR (300MHz, CDCl
3): δ 1.11 (s, 3H, 17-CH
3), 1.11 (t, 3H, J=6.9Hz, 2 " CH
3), 1.23 (s, 3H, 16-CH
3), 1.73 (s, 3H, 19-CH
3), 1.83 (s, 3H, 18-CH
3), 2.24 (m, 2H, 14-CH
2), 2.36 (s, 3H, OAc), 1.83 and 2.54 (2m, 2H, 6-CH
2), 2.77 (q, 2H, J=6.9Hz), 3.87 (d, 1H, J=6.9Hz, 3-CH), 4.18 and 4.30 (2d, 2H, J=8.7Hz, 20-CH
2), 4.23 (m, 1H, 7-CH), 4.70 (br s, 1H, 2 '-CH), 4.93 (d, 1H, J=9.0Hz, 5-CH), 5.27 (s, 1H, 10-CH), 5.60 (d, 1H, J=7.2Hz, 3 '-CH), 5.65 (d, 1H, J=6.9Hz, 2-CH), 6.24 (t, 1H, J=8.7Hz, 13-CH), 6.55 (d, 1H, J=7.5Hz,-CONH-), 7.34 (m, 1H, p-Ph), 7.39 (m, 4H, o-Ph and m-Ph), 7.51 (t, 2H, J=7.5Hz, m-OBz), 7.62 (t, 1H, J=7.5Hz, p-OBz), 8.11 (d, 2H, J=7.5Hz, o-OBz), ESIMS m/z 818.2[M+Na
+].
Embodiment 2
7：R＝(CH
2)
2CH
3
8：R＝(CH
2)
3CH
3
9：R＝(CH
2)
4CH
3
10：R＝(CH
2)
5CH
3
11：R＝(CH
2)
11CH
3
Except ethanethio is replaced with respectively propyl group mercaptan, additive method is with embodiment 1, obtains compound 7, ESIMS m/z 832.1[M+Na
+].
Except ethanethio is replaced with respectively butanethiol, additive method is with embodiment 1, obtains compound 8, ESIMS m/z 846.2[M+Na
+].
Except ethanethio is replaced with respectively amyl mercaptan, additive method is with embodiment 1, obtains compound 9, ESIMS m/z 860.2[M+Na
+].
Except ethanethio is replaced with respectively hexyl mercaptans, additive method is with embodiment 1, obtains compound 10, ESIMS m/z 874.2[M+Na
+].
Except ethanethio is replaced with respectively lauryl mercaptan, additive method is with embodiment 1, obtains compound 11, ESIMS m/z 958.4[M+Na
+].
Embodiment 3
Get 100ml there-necked flask, dryout, logical nitrogen, at 0 DEG C of temperature, adds after BTC (0.86g), adds dry CH
2cl
2(15mL), BTC complete molten after, add isopropyl mercaptan (0.73mL), slowly drip Et
3n (1.10mL), adularescent precipitation produces, and after dropwising, room temperature is crossed liquid, and reaction solution elimination insolubles obtains the solution of acyl chlorides without any processing, is directly used in next step reaction.Get a 100mL there-necked flask, add taxol midbody compound 2 (500mg), use CH
2cl
2(10mL) dissolve, in ice-water bath, slowly drip excessive acyl chlorides, dropwise, under room temperature, stirred liquid, stopped reaction, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, except desolventizing, column chromatography (elutriant: petrol ether/ethyl acetate=2/1).Obtaining compound intermediate compound 3 is 0.18g, yield 33.0%.Get a 10mL single necked round bottom flask, dry, rush nitrogen, add midbody compound 3 (144mg), Zn (288mg), then add CH
3oH, drip ice HOAc (3.0mL), reaction at 40 DEG C, TLC detects (developping agent: petrol ether/ethyl acetate=2/1), after 2 hours, raw material disappears, remove methyl alcohol, add ethyl acetate, wash respectively with saturated sodium bicarbonate solution and saturated aqueous common salt, anhydrous sodium sulfate drying, except desolventizing, it is 62mg that column chromatography (elutriant: sherwood oil/acetone=2/1) obtains product 12, yield 61.7%.
Compound 12:
1h NMR (300MHz, CDCl
3): δ 1.11 (s, 3H, 17-CH
3), 1.14 (d, 3H, J=7.2Hz, 1 " CH
3), 1.19 (d, 3H, J=7.2Hz, 3 " CH
3), 1.24 (s, 3H, 16-CH
3), 1.72 (s, 3H, 19-CH
3), 1.83 (s, 3H, 18-CH
3), 2.25 (d, 2H, J=7.5Hz, 14-CH
2), 2.35 (s, 3H, OAc), 1.83 and 2.53 (2m, 2H, 6-CH
2), 3.49 (m, 1H, 2 " CH), 3.86 (d, 1H, J=6.6Hz, 3-CH), 4.17 and 4.30 (2d, 2H, J=8.7Hz, 20-CH
2), 4.21 (m, 1H, 7-CH), 4.45 (s, 1H, 2 '-OH), 4.72 (br s, 1H, 2 '-CH), 4.93 (d, 1H, J=9.0Hz, 5-CH), 5.30 (s, 1H, 10-CH), 5.59 (d, 1H, J=9.0Hz, 3 '-CH), 5.65 (d, 1H, J=6.6Hz, 2-CH), 6.24 (t, 1H, J=8.7Hz, 13-CH), 6.52 (d, 1H, J=8.7Hz,-CONH-), 7.33 (m, 1H, p-Ph), 7.39 (m, 4H, o-Ph and m-Ph), 7.50 (t, 2H, J=7.5Hz, m-OBz), 7.62 (t, 1H, J=7.5Hz, p-OBz), 8.11 (d, 2H, J=7.5Hz, o-OBz), ESIMS m/z 832.1[M+Na
+].
Embodiment 4
Except isopropyl mercaptan is replaced with respectively corresponding mercaptan, additive method is with embodiment 3.
Compound 13:
1h NMR (300MHz, CDCl
3): δ 1.11 (s, 3H, 17-CH
3), 1.24 (s, 3H, 16-CH
3), 1.35 (s, 9H, t-Bu), 1.71 (s, 3H, 19-CH
3), 1.85 (s, 3H, 18-CH
3), 2.29 (d, 2H, J=8.7Hz, 14-CH
2), 2.34 (s, 3H, OAc), 1.85 and 2.51 (2m, 2H, 6-CH
2), 2.84 (d, 1H, J=6.0Hz, 1-OH), 3.85 (d, 1H, J=6.9Hz, 3-CH), 4.16 and 4.30 (2d, 2H, J=8.7Hz, 20-CH
2), 4.21 (m, 1H, 7-CH), 4.41 (br s, 1H, 2 '-OH), 4.54 (s, 1H, 10-OH), 4.74 (br s, 1H, 2 '-CH), 4.94 (d, 1H, J=9.3Hz, 5-CH), 5.35 (s, 1H, 10-CH), 5.57 (d, 1H, J=8.4Hz, 3 '-CH), 5.65 (d, 1H, J=6.6Hz, 2-CH), 6.22 (t, 1H, J=8.7Hz, 13-CH), 6.49 (d, 1H, J=9.0Hz,-CONH-), 7.33 (m, 1H, p-Ph), 7.41 (m, 4H, o-Ph and m-Ph), 7.49 (t, 2H, J=7.5Hz, m-OBz), 7.61 (t, 1H, J=7.5Hz, p-OBz), 8.10 (d, 2H, J=7.5Hz, o-OBz), ESIMS m/z 846.2[M+Na
+].
Compound 14, ESIMS m/z 846.2[M+Na
+].
Compound 15, ESIMS m/z 860.2[M+Na
+].
Compound 16, ESIMS m/z 846.2[M+Na
+].
Compound 17, ESIMS m/z 860.2[M+Na
+].
Embodiment 5
Get 100ml there-necked flask, dryout, logical nitrogen, at 0 DEG C of temperature, adds after BTC (0.724g), adds dry CH
2cl
2(10mL), BTC complete molten after, add benzyl mercaptan (0.75mL), slowly drip Et
3n (0.926mL), adularescent precipitation produces, and after dropwising, room temperature is crossed liquid, and reaction solution elimination insolubles obtains the solution of compound acyl chlorides without any processing, is directly used in next step reaction.Get a 100mL there-necked flask, add taxol midbody compound 2 (500mg), use CH
2cl
2(10mL) dissolve, in ice-water bath, slowly drip excessive acyl chlorides, dropwise, under room temperature, stirred liquid, stopped reaction, ethyl acetate extraction, saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, except desolventizing, column chromatography (elutriant: petrol ether/ethyl acetate=2/1).Obtaining midbody compound 3 is 0.189g, yield 34%.Get a 10mL single necked round bottom flask, dry, rush nitrogen, add midbody compound 3 (146mg), Zn (292mg), then add CH
3oH, drip ice HOAc (3mL), reaction at 60 DEG C, TLC detects (developping agent: petrol ether/ethyl acetate=2/1), after 2 hours, raw material disappears, remove methyl alcohol, add ethyl acetate, wash respectively with saturated sodium bicarbonate solution and saturated aqueous common salt, anhydrous sodium sulfate drying, except desolventizing, it is 67mg that column chromatography (elutriant: sherwood oil/acetone=2/1) obtains product 18, yield 60.7%.ESIMS m/z 880.3[M+Na
+]。
Embodiment 6
Anti tumor activity in vitro experiment
1) material
1.1 cell strains: human hepatoma cell strain (BEL-7402), human breast cancer cell strain (MDA-MB-231), human stomach cancer cell line (SGC-7901), human oophoroma cell line (SKOV-3), human lung carcinoma cell line (A549).
1.2 positive controls: Docetaxel.
1.3 reagent: HyQR modified form RPMI 1640 substratum, DMEN substratum, GIBCO; MTT; Pancreatin; Three solubilising reagents;
The configuration of 1.4 3 joint-trial agent: 20%SDS, 10% isopropylcarbinol, 0.024mol/LHCL, distilled water dissolves.
1.5 equipment: CO2 incubator, aseptic operating platform, microplate reader, whizzer etc., liquid-transfering gun, transfer pipet, centrifuge tube, 96 orifice plates etc.
2) experimental technique step
2.1 cell cultures: human hepatoma cell strain (BEL-7402), human stomach cancer cell line (SGC-7901), human breast cancer cell strain (MDA-MB-231): with RPMI 1640 substratum containing 10% foetal calf serum, in 37 DEG C, in the incubator of 5%CO2, cultivate.Non-small cell lung carcinoma cell strain (A549): with F-12Kaighn ' the S substratum of 10% foetal calf serum, in 37 DEG C, cultivate in the incubator of 5%CO2.Human oophoroma cell line (SKOV-3): with McCoy ' the s 5A substratum containing 10% foetal calf serum, in 37 DEG C, cultivate in the incubator of 5%CO2.
2.2 cell processing: get in exponential phase of growth, cell in good condition, adds appropriate trypsin digestion cell, and collecting cell is centrifugal, abandons supernatant.With the nutrient solution suspendible cell again containing serum, then counting, and cell density is diluted to 2 × 104/ml density.
2.3 cell inoculations: obtained cell suspension is inoculated on 96 orifice plates, 150ul/ hole (containing 3000/hole of tumour cell).Culture plate is proceeded in constant temperature CO2 incubator, at 37 DEG C, under 5%CO2 and saturated humidity condition, cultivate 24 hours.
2.4 compounds configurations: planted experimentally compound and be first mixed with DMSO the storage liquid of 0.01M, then dilute sample as required.The screening concentration of BEL-7402 cell and MDA-MB-231 cell strain is: 100,50,25,10,5,2.5,1,0.5,0.25,0.1 μ M; 1000,200,40,8,1.6,0.32,0.064,0.0128,0.00256,0.000512mM the screening concentration of A549, SKOV-3, SGC-7901 cell strain is:.
2.5 add test-compound: 50ul/ hole, cultivate 72 hours, and establish 3 parallel holes for every group, and repeat experiment.
2.6 results are measured: compound effects, after 72 hours, adds the MTT of 5mg/ml in 96 orifice plates, and 20 μ L/ holes are placed in incubator and hatch 4 hours, then add three joint-trial agent, and light absorption value is surveyed in 50 μ L/ holes at 570nm place after spending the night.
2.7 try to achieve according to the following formula inhibiting rate:
2.8IC
50calculating: inhibiting rate is higher than 50% compound, with SPSS computed in software IC
50value.
3) experimental result
Restraining effect (the IC of table 1 compound to different cell proliferations
50average, μ M), (n > 3)
| Compound number | MDA-MB-231 | BEL-7402 | A-549 | SGC-7901 | SKOV-3 |
| 6 7 11 12 13 14 15 16 17 18 Docetaxel | / 8.56±7.75 5.14±1.41 26.33±10.55 7.46±8.24 1.53±2.09 4.91±4.72 2.06±2.84 2.52±2.08 26.31±17.82 9.08±10.04 | / / 6.7±3.28 102.4±5.24 59.84±32.74 27.48±16.17 23±14.59 16.66±6.95 11.18±3.36 / / | 0.34±0.36 0.12±0.049 8.92±0.75 0.56±0.81 0.051±0.034 0.19±0.24 0.048±0.027 0.063±0.023 0.38±0.25 11.74±2.29 0.041±0.033 | 0.086±0.04 0.061±0.025 8.1±2.03 0.037±0.028 0.039±0.027 0.051±0.026 0.073±0.07 0.045±0.02 0.025±0.03 2.9±1.71 0.033±0.0045 | 0.82±0.3 0.6±0.11 11.74±0.43 0.44±0.39 0.16±0.2 0.8±0.54 0.33±0.39 0.44±0.22 0.29±0.24 68.69 0.36±0.28 |
Claims (8)
1. the thio-taxane derivatives shown in formula (1),
Wherein, R is C3～6 branched-chain alkyl.
2. thio-taxane derivatives according to claim 1, wherein R is (CH
3)
3c-, CH
3cH
2(CH
3) CH-, CH
3cH
2(CH
3)
2c-, (CH
3)
2cHCH
2-, (CH
3)
2cH (CH
3) CH-.
3. the thio-taxane derivatives shown in formula (1),
Wherein, R is CH
3(CH
2)
11-or (CH
3)
2cH-.
4. the preparation method of thio-taxane derivatives claimed in claim 1, is characterized in that comprising the steps:
Step I: formula (2) compound 7,10-bis-(2,2,2-trichloro-ethoxycarbonyl)-3 '-N-goes tertbutyloxycarbonyl Docetaxel under the catalysis of alkali, there is no to obtain formula (3) compound with sulfo-acyl chloride reaction under solvent condition or in solvent;
Step II: formula (3) compound, having under acid exists, obtains formula (1) thio-taxane derivatives there is no to react deprotection with Zn powder under solvent condition or in solvent;
Reaction equation is as follows:
5. the preparation method of thio-taxane derivatives according to claim 4, it is characterized in that described alkali is triethylamine, pyridine, N, N-diisopropylethylamine, DMAP, 1,8-diazabicyclo [5.4.0]-7-undecylene, 1,2,2,6,6-pentamethyl-piperidines, sodium carbonate, salt of wormwood, sodium bicarbonate or saleratus; Described acid is hydrochloric acid, phosphoric acid, acetic acid or sulfuric acid.
6. the preparation method of thio-taxane derivatives according to claim 4, it is characterized in that the solvent described in step I or II is selected from methylene dichloride, chloroform, 1,2-ethylene dichloride, benzene, toluene, acetone, acetonitrile, N, one or more in dinethylformamide, METHYLPYRROLIDONE, dimethyl sulfoxide (DMSO), tetramethylene sulfone, ring fourth sulfoxide, hexa-methylene phosphoryl triamide, ethyl acetate, methyl acetate, tetrahydrofuran (THF), ether, Isosorbide-5-Nitrae-dioxan, pyridine or picoline.
7. the preparation method of thio-taxane derivatives according to claim 4, the temperature of reaction that it is characterized in that step I is 0 DEG C～25 DEG C, the temperature of reaction of Step II is 0 DEG C～100 DEG C.
In claim 1～3 arbitrary described thio-taxane derivatives in the purposes of preparing in antitumor drug.
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