CN103044518A - 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester, and application of 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester in preparing antineoplastic drug - Google Patents
3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester, and application of 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester in preparing antineoplastic drug Download PDFInfo
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Abstract
The invention discloses 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester. A chemical structural formula of 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester is as follows as shown in the specification. A chemical structural formula of 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester is as follows as shown in the specification. An experiment proves that 3-oxo-7-oximido-4-aza-A-homo-chenodeoxycholic acid methyl ester and 3-O-benzyl oximido-7-aza-7a-oxo-B-homo-chenodeoxycholic acid methyl ester have obvious inhibition effects on various tumor cell strains, and can be applied in preparing a drug for treating a cancer.
Description
One, technical field
The present invention relates to 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl compound and synthetic method thereof, with and application in preparation treatment cancer drug.
Two, background technology
Cancer medically calls cancer to the malignant tumour that derives from epithelium, is to one of human health and the dangerous maximum disease of quality of life.Seeking efficient, highly selective and the little cancer therapy drug of side effect is the main direction of cancer therapy drug exploitation.
In the research of antitumor drug, once reported courage steroid-4-alkene-B-cyclic lactam compound (Natalija
Mira S.Bielakovi á,
Synthesis of some steroidal oximes, lactams, thiolactams and their antitumor activities, 2007, steroids, 72:406 – 414), androstane-B-cyclic lactam compounds (Anna I.Koutsourea, Mandis A.Fthanasios Papageorgiou, George N Pairas Papagerous, George N.Pairas and Sotiris S.Nikolaropoulos.Bioorganic ﹠amp; Medical Chemistry, 2008 (16), 5207-5212), androstane-D-cyclic lactam compounds (Dimitrios T.P.Trafalis, George D.Geromichalos, Catherine Koukoulitsa, Athannasios Papageorogiou, Panagiotis Karamanakos, and Charalambos Camoutsis, Breast Cancer Reaearch and Treatment.2006,97:17-31), courage steroid-A-cyclic lactam compound (Yanmin HUANG, Jianguo CUI, Sijing CHEN, Chunfang GAN, Aimin ZHOU, Synthesis and antiproliferative activity of some steroidal lactams.Steroids2011,76:1346 – 1350), cholic acid and 7-Septochol-A-cyclic lactam compound (Yanmin Huang, Sijing Chen, Jianguo Cui, Chunfang Gan, Zhiping Liu, Yingliang Wei, Huachan Song.Synthesis and cytotoxicity of A-homo-lactam derivatives of cholic acid and7-deoxycholic acid.Steroids2011,76:690 – 694).In the above-claimed cpd some has cytotoxicity to some tumour cell in external or body.But about 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds, have not yet to see report.
Three, summary of the invention
The purpose of this invention is to provide compound 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters.
Another object of the present invention provides the synthetic method of above-claimed cpd.
Further purpose of the present invention provides the application of above-claimed cpd in the preparation antitumor drug.
The present invention is achieved through the following technical solutions above-mentioned purpose: 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters has following structural:
3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters (6)
3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters (11)
3-oxo of the present invention-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters, be 3 by gallodesoxycholic acid (1) through over-churning, Jones reagent oxidation, 7-dioxo gallodesoxycholic acid methyl esters (3), then with 3-position carbonyl oximate, further obtain 3 by Beckmann rearrangement, 7-dioxo-4-azepine-A-homo-gallodesoxycholic acid methyl esters (5), 7-position carbonyl oximate with 3,7-dioxo-4-azepine-A-homo-gallodesoxycholic acid methyl esters obtains 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters (6) at last.
From gallodesoxycholic acid, press following chemical equation synthesising target compound 6:
Reagent and condition: a:MeOH/HCl; B:Jones, 0-5 ° of C; C:NH
2OHHCl, 95%EtOH/NaOAc3H
2O; D:SOCl
2/ THF, 0-5 ° of C; E:NH
2OHHCl, 95%EtOH/NaOAc3H
2O.
3-O-benzaldoxime base of the present invention-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters, can be from obtained above 3,7-dioxo gallodesoxycholic acid methyl esters (3) sets out, obtain 3-hydroxyl-7-carbonyl gallodesoxycholic acid methyl esters (7) through selective reduction, then oximate obtains 3-hydroxyl-7-oximido gallodesoxycholic acid methyl esters (8), 8 further obtain 3-hydroxyl-7a-oxo-7-azepine-B-homo-gallodesoxycholic acid methyl esters (9) by Beckmann rearrangement, then be that carbonyl obtains 3 with 3-position hydroxyl oxidize, 7a-dioxo-7-azepine-B-homo-gallodesoxycholic acid methyl esters (10) obtains 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters (11) with 10 3-position carbonyl benzaldoxime etherificate at last.
Press following chemical equation synthesising target compound 11:
Reagents?and?conditions:a:NaBH
4/COCl
2·6H
2O;b:NH
2OH·HCl,95%EtOH/NaOAc．3H
2O;c:SOCl
2/THF，0-5°C;d:Jones,0-5°C;e:PhCH
2ONOH·HCl,EtOH/CH
3COOH,55°C.
Suppress activity test by cancer cell in vitro and show, 3-oxo of the present invention-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters has significant restraining effect to cancer cell strains such as various tumor cell strains such as liver cancer, cancer of the stomach, mammary cancer, ovarian cancers.3-oxo of the present invention-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters can be used in the medicine of preparation treatment cancer.
The present invention also provides a kind of medicine that is used for the treatment of cancer, and it contains above-mentioned 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds and pharmaceutically acceptable auxiliary.This medicine can be made the form of injection, tablet, pill, capsule, suspension agent or emulsion and use, and its route of administration can be oral, or through subcutaneous, vein or intramuscular injection.
Four, embodiment
The invention will be further described by the following examples.
Embodiment 1
The preparation of 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters (6)
Synthesizing of 7-Deoxycholic Acid methyl esters (2)
338mg compound 1 is dissolved in an amount of methyl alcohol, then is added dropwise to the 0.25mL concentrated hydrochloric acid, stirring reaction at normal temperatures, TLC monitoring reaction process, developping agent V
Ethyl acetate: V
Sherwood oil=1:2 is behind the reaction 3h, without raw material point, stopped reaction.The most of methyl alcohol of pressure reducing and steaming adds suitable quantity of water, uses first ethyl acetate extraction, and ethyl acetate is respectively washed once respectively anhydrous sodium sulfate drying, pressure reducing and steaming solvent, column chromatography for separation, moving phase: V mutually again with saturated sodium bicarbonate solution, water, saturated aqueous common salt
Ethyl acetate: V
Sherwood oil=1:3 obtains white solid 2320mg, productive rate 91.6%, m.p.75～77 ° C.The spectroscopic data of compound 2: IR (KBr) ν/cm
-1: 3395,2933,2868,1744,1429,1376,1335,1164,1078;
1H NMR (δ, ppm, CDCl
3, 300MHz): 0.608 (s, 3H, 19-CH
3), 0.854 (s, 6H, 19-CH
3And 21-CH
3), 3.369(s, 1H, 7-CH) 3.609(s, 3H ,-OCH
3), 3.776 (s, 1H, 3-CH);
13C NMR (δ, ppm, CDCl
3, 75MHz): 174.6,71.6,68.1,55.8,51.4,50.3,42.5,41.5,39.6,39.5,39.3,35.4,35.2,34.9,34.7,32.8,30.9,30.5,28.1,23.5,22.8,20.6,18.2,11.7; LRESIMS(m/z): 429.3(M
++ 23).
Synthesizing of 3,7-dioxo Chenodiol methyl esters (3)
356mg compound 2 is dissolved in the proper amount of acetone, and stirring makes temperature reduce to 0 ~ 5 ° of C under ice bath, slowly drips Jones reagent, until no longer produce blackish green precipitation, TLC monitoring reaction process, developping agent: V
Ethyl acetate: V
Sherwood oil=1:3 is without the raw material point, with the frozen water stopped reaction.Decompress filter removes most of precipitation.The most of solvent of pressure reducing and steaming adds suitable quantity of water, uses first ethyl acetate extraction, and ethyl acetate is respectively washed once respectively anhydrous sodium sulfate drying mutually again with saturated sodium bicarbonate solution, water, saturated aqueous common salt.The pressure reducing and steaming solvent, column chromatography for separation, moving phase: V
Ethyl acetate: V
Sherwood oil=1:4 obtains white solid 3338mg, productive rate 96%, m.p.164～165 ° C.The spectroscopic data of compound 3: IR (KB) ν/cm
-1: 3395,2945,2864,1740,1707,1450,1429,1168;
1H NMR (CDCl
3, 300M); 0.669 (s, 3H, 18-CH
3), 0.908 (d, 3H, J=3.6,21-CH
3), 1.281 (s, 3H, 19-CH
3), 2.857 (d, 1H, J=6.0), 3.634 (s, 3H ,-OCH
3);
13C NMR (δ, ppm, CDCl
3, 75MHz): 211.1,210.2,174.5,54.7,51.4,49.5,48.8,47.7,44.9,42.9,42.7,42.6,38.8,36.7,35.4,35.1,31.0,30.9,28.2,24.7,22.4,22.1,18.2,12.1; LRESIMS m/z): 425.3 (M
++ 23).
Synthesizing of 7-oxo-3-oximido Chenodiol methyl esters (4)
Compound 3238mg, heating is dissolved in 20mL95% ethanol, adds 88mg (0.65mmol) CH
3COONa3H
2O adds 45mg (0.65mmol) NH after the dissolving fully in batches
2OH.HCl continues reaction 30min at 60 ℃.The most of ethanol of pressure reducing and steaming adds suitable quantity of water, uses ethyl acetate extraction, merges organic phase, and saturated common salt is washed to neutrality, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, thick product column chromatography for separation, moving phase: V
Ethyl acetate: V
Sherwood oil=1:2 obtains white solid 4230mg, productive rate 93%.M.p.89 ~ 90 ℃; 4 be one by (Z) and (E)-mixture that the 3-oximido consists of, wherein (Z)-Shi: (E)-like=1:1.3.IR(KB)ν/cm
-1:3382,2958,2941,2872,2843,1732,1687,1560,1446,1384,1274,1200,?1172.
Synthesizing of 3,7-dioxo-4-azepine-A-homo Chenodiol methyl esters (5)
479mg compound 4 is added in the reaction flask, pass into the argon shield reaction system, the THF that adds the 19mL drying under ice bath makes its dissolving.With the 2.2mL SOCl that newly steams
2Be dissolved among the THF of 4mL drying, slowly be added dropwise in the reaction system, mixture is at 0 ~ 10 ℃ of stirring reaction, TLC detection reaction process, developping agent: V
Methyl alcohol: V
Methylene dichloride=1:20.Without the raw material point, add freezing distilled water termination reaction in the mixture behind the reaction 60min, with ammonia neutralization to PH ≈ 7.Use CH
2Cl
2Extraction merges organic phase, through washing, and saturated common salt washing, anhydrous Na
2SO
4Dry.The pressure reducing and steaming solvent, thick product uses column chromatography developping agent: V
Ethyl acetate: V
Sherwood oil=1:1 obtains white solid 5143mg, productive rate 30%.m.p.227～230℃。The spectroscopic data of compound 5: IR(KBr) ν/cm
-1: 3199,2941,2904,2851,1732,1703,1683,1625,1446,1339,1298,1249,1094,1004;
1H NMR (CDCl
3, 300MHz) δ: 0.673 (s, 3H, 19-CH
3), 0.922 (d, 3H, J=6.3Hz, 21-CH
3), 1.278 (s, 3H, 18-CH
3), 2.663 (dd, 1H, J=12.3Hz, 4
β-C
βH), 2.936 (dd, 1H, J=5.7Hz, 4a-C
αH), 3.677 (s, 3H ,-OCH
3), 6.495 (s, 1H ,-NH);
13C N MR (δ, ppm, CDCl
3, 75MHz): 210.9,176.2,174.6,54.8,51.5,49.6,48.7,46.8,44.9,44.1,42.5,39.5,38.9,38.5,38.0,36.5,35.1,31.0,30.9,28.2,24.6,22.0,18.3,12.0; LRESIMS(m/z): 418.3(M
++ 1).
Synthesizing of 3-dioxo-7-oximido-4-azepine-A-homo-Methyl cholate (6)
With 100mg, compound 5 is dissolved in the 30mL95% ethanol in being connected with the reaction flask of spherical condensation tube, is warming up to 60 ℃.Add 32.6mg NaAc3H
2O adds 16.7mg NH after the dissolving fully in batches
2OHHCl keeps 60 ℃ of temperature of reaction, and TLC detects, developping agent: V
Methyl alcohol: V
Methylene dichloride=1:20, the reaction 40min after without the raw material point.The most of ethanol of pressure reducing and steaming adds suitable quantity of water, uses ethyl acetate extraction, merges organic phase.Water, saturated common salt are washed to neutrality successively, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, thick product column chromatography for separation, moving phase: V
Methyl alcohol: V
Methylene dichloride=1:40 obtains white solid 693mg, productive rate 90%; M.p.218 ~ 219 ℃.The spectroscopic data of compound 6: IR(KBr) ν/cm
-1: 3280,2937,2872,1736,1654,1442,1384,1164,967;
1H NMR (δ, ppm, 300MHz, CDCl
3): 0.686 (s, 3H, 18-CH
3), 0.932 (s, 3H, 21-CH
3), 1.142 (s, 3H, 19-CH
3), 3.665 (s, 3H, OCH
3), 6.966 (s, 1H, CONH), 9.224 (s, 1H, NOH);
13C NMR (δ, ppm, CDCl
3, 75MHz): 177.9,174.7,159.1,54.7,51.5,49.2,45.2,42.7,42.3,39.7,38.9,38.4,37.4,36.6,35.8,31.0,30.9,29.4,28.0,25.1,23.5,21.4,18.3,12.0; LRESIMS(m/z): 455.3(M
++ 23).
Embodiment 2
The preparation of 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters (11)
Synthesizing of 3 beta-hydroxies-7-oxo Chenodiol methyl esters (7)
200mg compound 3 is dissolved in 15mL methyl alcohol, behind the dissolve complete, adds 118mg CoCl
26H
2O, solution be by the colourless lilac red that becomes, and adds gradually 56mg (1488mmol) NaBH after at room temperature stirring 20min
4, TLC follows the tracks of reaction, developping agent: V
Ethyl acetate: V
Sherwood oil=1:2 without the raw material point, makes reaction terminating with the hydrochloric acid neutralization reaction liquid of 1mol/L behind the 30min.The most of methyl alcohol of pressure reducing and steaming adds suitable quantity of water, has immediately a large amount of white opacities to generate, and uses ethyl acetate extraction, merges organic layer, respectively washes once with saturated sodium bicarbonate solution, water, saturated aqueous common salt respectively, uses at last anhydrous sodium sulfate drying.Removal of solvent under reduced pressure gets a white solid, column chromatography for separation, moving phase: V
Ethyl acetate: V
Sherwood oil=1:2 gets white crystals 7130mg, productive rate 65.0%.M.p.67-68 ℃; The spectroscopic data of compound 7: IR (KBr) ν/cm
-1: 3517,2921,2868,1707,1638,1425,1376,1294,1254,1200,1155,1070,1004,980,898;
1H NMR (δ, ppm, CDCl
3, 300Mz): 0.644 (s, 3H, 18-CH
3), 0.912 (d, 3H, J=6.3,21-CH
3), 1.188 (s, 3H, 19-CH
3), 3.536 ~ 3.623 (m, 1H, 3-CH), 2.849 (dd, 1H, J=12.6,6.0Hz, 8-CH), 3.657 (s, 3H ,-OCH
3);
13C NMR (δ, ppm, CDCl
3, 75MHz): 212.3,174.7,70.7,54.7,51.49,51.48,49.5,48.9,46.1,45.4,42.7,42.6,38.9,37.3,35.2,35.1,34.1,31.0,29.8,28.3,24.8,23.0,21.7,18.4,12.0.
Synthesizing of 3 beta-hydroxies-7-oximido Chenodiol methyl esters (8)
174mg compound 7 is dissolved in the 20mL95% ethanol, is warming up to 55 ℃.Add 146mg NaAc3H
2O adds 74mgNH fully after the dissolving
2OH.HCl keeps 55 ℃ of temperature of reaction, and TLC detects, developping agent: V
Ethyl acetate: V
Sherwood oil=1:4, the reaction 3h after without the raw material point.Stopped reaction, the most of ethanol of pressure reducing and steaming adds suitable quantity of water, uses ethyl acetate extraction.Merge organic phase, water and saturated common salt are washed to neutrality according to this, anhydrous sodium sulfate drying.The pressure reducing and steaming solvent, thick product column chromatography for separation moving phase: V
Ethyl acetate: V
Sherwood oil=1:5 obtains white solid 8165mg, productive rate 92%.M.p.49 ~ 50 ° C; The spectroscopic data of compound 8: IR (KBr) ν/cm
-1: 3387,2933,2868,1797,1740,1650,1446,1372,1298,1262,1196,1057,1004,967;
1H NMR (δ, ppm, CDCl
3, 300MHz): 0.664 (s, 3H, 18-CH
3); 0.920 (d, 3H, J=6.3Hz, 21-CH
3); 1.106 (s, 3H, 19-CH
3); 2.930-3.001(s, 1H, OH), 3.127 (d, 1H, J=9.0Hz, 8-CH), 3.535-3.606 (m, 1H, 3-CH), 3.657 (s, 3H ,-OCH
3), 8.801 (s, 1H, N-OH).
13C NMR (δ, ppm, CDCl
3, 75MHz): 174.81,160.95,71.01,54.80,51.52,49.4,44.9,43.3,42.8,42.3,39.16,36.44,35.44,35.2,34.5,30.9,30.0,28.1,27.7,26.8,25.2,23.3,21.1,18.4,12.0.
Synthesizing of 3 beta-hydroxies-7-oxo-7a-azepine-B-homo-Chenodiol methyl esters (9)
120mg compound 8 adds in the reaction flask, uses the argon shield reaction system, and the THF that adds the 4mL drying makes its dissolving, with the 0.6mL SOCl that newly steams
2Be dissolved among the THF of 3.1mL drying, slowly add in the reaction system, at 0 ℃ of stirring reaction, TLC detection reaction process, developping agent: V
Methylene dichloride: V
Methyl alcohol=20:1.Without the raw material point, add freezing distilled water termination reaction in the mixture behind the reaction 3h, with ammonia neutralization to PH ≈ 7.Use CH
2Cl
2Extraction merges organic phase, through washing, and saturated common salt washing, anhydrous Na
2SO
4Dry.The pressure reducing and steaming solvent, thick product column chromatography for separation, moving phase: V
Ethyl acetate: V
Sherwood oil=1:2 obtains white solid 983mg, productive rate 70.5%, m.p.:89-91 ℃.The spectroscopic data of compound 9: IR (KBr) ν/cm
-1: 3403,2945,2864,1736,1658,1437,1380,1245,1196,1164;
1H NMR (δ, ppm, CDCl
3, 300MHz): 0.633 (s, 3H, 18-CH
3), 0.887 (d, 3H, J=6.0Hz, 21-CH
3), 1.019 (s, 3H, 19-CH
3), 2.810-2.913 (t, 2H), 3.229-3.307 (m, 2H), 3.632 (s, 3H, OCH
3), 5,890 (s, 1H, CONH);
13C NMR (δ, ppm, CDCl
3, 75MHz): 176.3,174.5,70.6,55.4,54.1,52.0,51.5,42.5,41.6,40.4,38.6,38.3,36.5,36.4,35.3,35.0,30.9,30.7,29.8,27.5,25.0,23.1,21.7,18.7,11.45.
Synthesizing of 3,7-dioxo-7a-azepine-B-homo Chenodiol methyl esters (10)
200mg compound 9 is dissolved in an amount of acetone, and stirring makes temperature reduce to 0-5 ° of C in ice bath, slowly drips Jones reagent, until no longer produce cyan precipitation, TLC monitoring reaction process, developping agent: V
Methylene dichloride: V
Methyl alcohol=20:1 without the raw material point, with the frozen water stopped reaction, regulates pH value with NaOH solution and approximates 7.Decompress filter removes most of precipitation.The most of solvent of pressure reducing and steaming adds suitable quantity of water, uses first dichloromethane extraction, the pressure reducing and steaming extraction agent.Column chromatography for separation, moving phase: V
Methylene dichloride: V
Methyl alcohol=30:1 obtains white solid 10139mg, productive rate 69.5%.M.p.166-167 ℃; The spectroscopic data of compound 10: IR (KBr) ν/cm
-1: 3244,3084,2966,2876,1711,1740,1662,1470,1433,1380,1168;
1H NMR (δ, ppm, CDCl
3, 300MHz): 0.657 (s, 3H, 18-CH
3), 0.883 (d, 3H, J=6.0Hz, 21-CH
3), 1.129 (s, 3H, 19-CH
3), 2.943 (d, 1H, J=14.4Hz, 6-C
αH), 3.309-3.362 (t, 1H, 6-C
βH), 3.362 (s, 3H ,-OCH
3), 6.090 (s, 1H ,-NH);
13C NMR (δ, ppm, CDCl
3, 75MHz): 210.1,175.0,174.4,55.3,54.0,51.8,51.5,43.3,42.5,41.7,40.4,38.5,38.4,37.5,37.0,36.9,35.0,30.8,30.6,27.5,24.9,22.6,22.0,18.16,11.5.
Synthesizing of 8-oxo-3-benzyloxy oxime ether-7-azepine-B-homo Chenodiol methyl esters (11)
In being connected with the reaction flask of spherical condensation tube, 230mg compound 10 is dissolved in the 40mL95% ethanol, is warming up to 55 ℃.Add 154mg NaAc3H
2O, the fully PhCH of disposable adding 264mg after the dissolving
2ONH
2HCl keeps 55 ℃ of temperature of reaction, and TLC detects, developping agent: V
Methyl alcohol: V
Methylene dichloride=1:20, the reaction 1h after without the raw material point.The most of ethanol of pressure reducing and steaming adds suitable quantity of water, uses ethyl acetate extraction, merges organic phase.Water, saturated common salt are washed to neutrality successively, anhydrous sodium sulfate drying, pressure reducing and steaming solvent, thick product column chromatography for separation, moving phase: V
Ethyl acetate: V
Sherwood oil=1:2 obtains the spectroscopic data IR(KBr of two kinds of white solids, 11. compounds 11) ν/cm
-1: 3235,3092,2945,2876,1736,1654,1433,1376,1339,1266,1164,1102,988,939;
1H NMR (δ, ppm, CDCl
3, 300MHz): 0.677(s, 3H, 18-CH
3), 0.913 (d, 3H, J=3.0Hz, 21CH
3), 1.099 (s, 3H, 19-CH
3), 3.668 (s, 3H ,-OCH
3), 5.026 (s, 2H, NOCH
2), 5.789 (s, 1H, CONH), 7.326 (s, 5H ,-C
6H
5);
13C NMR (δ, ppm, CDCl
3, 75MHz): 175.4,174.5,158.9,137.9,128.3,128.0,127.6,75.2,55.4,54.2,51.8,51.5,42.5,42.4,40.3,39.1,38.5,38.1,36.6,35.0,30.9,30.7,27.6,26.8,25.4,25.0,23.0,21.92,18.1,11.5.
Embodiment 3
The present embodiment is to adopt 3-oxo of the present invention-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds that some tumour cell is carried out cell toxicity test.
Adopt 3-oxo of the present invention-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters that human prostate cancer cell line PC-3, lung cancer cell line H-292, breast carcinoma cell strain SKBR3 and Ovarian Cancer Cells Hey-1B are carried out cell toxicity test.Adopt the MTT method, carry out vitro cytotoxicity and measure.The 3-oxo of adding different concns-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters in the logarithmic phase cell of in 96 orifice plates, cultivating, carry out simultaneously 3 parallel tests, compare with control group, cultivate after 72 hours, add MTT, measure its absorbancy, the concentration of compound when calculating respectively inhibition tumor cell and growing into 50% is with IC
50Value representation, the result is as shown in table 1:
Table 13-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters anti-tumor activity test result (MTT method, IC
50, μ mol/mL)
Compound 6,11 is carried out the experiment of cell growth inhibition type, and the dead mode that proves cell is to be undertaken by apoptotic mode.Simultaneously, the anti-tumor activity experiment shows in the animal body, and compound 6,11 pairs of ovarian cancers have obvious restraining effect.
Claims (5)
1. 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters steroidal compounds (6) is characterized in that, this structural formula of compound is:
2. 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds (11) is characterized in that, this structural formula of compound is:
3. the preparation method of 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds as claimed in claim 1 or 2, it is characterized in that, described method is from gallodesoxycholic acid, and is synthetic through the method for over-churning, oxidation, oximate, rearrangement, oximate and esterification, oxidation, selective reduction, oximate, rearrangement, benzyl.
4. the application of 3-oxo as claimed in claim 1 or 2-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds in the preparation antitumor drug.
5. the application of medicinal compositions in the preparation antitumor drug take claim 1 or 2 described 3-oxo-7-oximido-4-azepine-A-homo-gallodesoxycholic acid methyl esters and 3-O-benzaldoxime base-7-azepine-7a-oxo-B-homo-gallodesoxycholic acid methyl esters steroidal compounds as activeconstituents.
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