CN102286055B - B-drop-3, 6-disubstituted cholestane compound and preparation method and application thereof to preparation of antitumor drug - Google Patents
B-drop-3, 6-disubstituted cholestane compound and preparation method and application thereof to preparation of antitumor drug Download PDFInfo
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- CN102286055B CN102286055B CN 201110179146 CN201110179146A CN102286055B CN 102286055 B CN102286055 B CN 102286055B CN 201110179146 CN201110179146 CN 201110179146 CN 201110179146 A CN201110179146 A CN 201110179146A CN 102286055 B CN102286055 B CN 102286055B
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Abstract
The invention relates to a B-drop-3, 6-disubstituted cholestane compound which has the following chemical structural formula in the formula I or II, wherein R represents different substituent groups in -OH, =NOH, -OSO3Na, =O, =NNHC(=S)NH2, =NNHC(=O)NH2, =NOCH2Ph, =NOCH3, =NOCH2CH3, -OCH2CH2N(CH3)2, -OCH2CH2N(CH2CH3)2, -OCH2CH2N(CH2CH2Cl)2 and -N(CH2CH2Cl)2; R1 represents different substituent groups in =NOH, -OSO3Na, =NNHC(=S)NH2, =NNHC(=O)NH2, =NOCH2Ph, =NOCH3, =NOCH2CH3, -OCH2CH2N(CH3)2, -OCH2CH2N(CH2CH3)2, -OCH2CH2N(CH2CH2Cl)2 and -N(CH2CH2Cl)2; and in the formula, the R and the R1 can be the same and can also be different. The B-drop-3, 6-disubstituted cholestane compound disclosed by the invention can be prepared from cholesterol through carrying out transformation by a chemical method of functional group protection, ozonization, cyclization, condensation, de-protection, oxidization and addition. A test shows that the B-drop-3,6-disubstituted cholestane compound disclosed by the invention has obvious inhibition effect on various tumor cell lines and can have application to preparation of a medicament for treating cancer.
Description
(1) technical field
The present invention relates to a class B-and fall-3,6-two replaces cholestane compound and synthetic method thereof, and the application in the preparation antitumor drug.
(2) background technology
Cancer is a kind of malignant tumour, is one of disease to human health and quality of life harm maximum.Seeking efficient, highly selective and the little antitumor drug of side effect is the main direction of medicament research and development.
In antitumor drug, the medicine Finasteride that is used for the treatment of hyperplasia of prostate that Merck in 1992 lists a company belongs to the steroidal amides.In recent years in the research of antitumor drug, occurred many to the report of steroidal compounds as antitumor drug, courage steroid-4-alkene-B-cyclic lactam steroidal compounds (Natalija M. for example
Mira S.Bielakovi á,
Synthesis of some steroidal oximes, lactams, thiolactams and their antitumoractivities, 2007, steroids, 72:406-414), androstane-B-cyclic lactam class steroidal compounds (Anna I.Koutsourea, Mandis A.Fthanasios Papageorgiou, George N Pairas Papagerous, George N.Pairas and Sotiris S.Nikolaropoulos.Rational design, synthesis, and in vivo evaluation of the antileukemic activity ofsix new alkylating steroidal esters, Bioorganic ﹠amp; Medical Chemistry, 2008 (16): 5207-5212), 4-alkene-6-oxime steroidal compounds (Krstic ' a, N.M.; Bjelakovic ', M.S.; Ziz ˇ akb, Z.; Pavlovic, M.D.; Jurani ' c, Z.D.; Pavlovi ' c, V.D.Synthesis of some steroidal oximes, lactams, thiolactams and their antitumoractivities, 2007, steroids, 72:406-414), some above-mentioned compound growth increment to some tumour cell in external or body has remarkable restraining effect.
We once provided application for a patent for invention (Chinese invention patent, the application number: 200810073497.4 of a class " 3,6-di-substituted sterides oxime compounds is as antitumor drug "; Publication number: CN 101245090A), the while has also been done relevant report (JianguoCui, Liliang Huang, Lei Fan, Aimin Zhou, steroids, 2008,73 (3): 252-256; Jian-Guo Cui, Lei Fan, Li-Liang Huang, Hong-Li Liu, Ai-Min Zhou.Steroids, 2009,74 (1), 62-72; Jianguo Cui, Lei Fan, Yanmin Huang, Yi Xin, Aimin Zhou, Steroids.2009,74 (12), 989-995).In addition, we also provide application for a patent for invention (Chinese invention patent, the application number: 201010107528.0 of a class " 6-replacement-4-azepine-A-homo-3-oxo steroidal compounds and the application in the preparation antitumor drug thereof "; CN 101845075A) and the application for a patent for invention (Chinese patent of another kind of " 3-replacement-B-Homo-steroidal-B-cyclic lactam compound and preparation method thereof and in the application of preparation in the antitumor drug " publication number:, application number: 201110009124.2.), delivered simultaneously relevant report (Yanmin Huang, SijingChen, Jianguo Cui, Chunfang Gan, Zhiping Liu, Yingliang Wei, Huachan Song.Steroids 2011, doi:10.1016/j.steroids.2011.03.009; Yanmin HUANG, Jianguo CUI, Zhengguo ZHONG, ChunfangGAN, Wenyan ZHANG, Huacan SONG, Bioorg.Med.Chem.Lett.2011, DOI:10.1016/j.bmcl.2011.04.093).
(3) summary of the invention
The purpose of this invention is to provide a class B-and fall-3,6-two replaces the cholestane compound, the synthetic method of this compounds and the application in preparation treatment antitumor drug thereof.
B-of the present invention falls-3, and 6-two replaces the cholestane compound, has following general formula:
Wherein, R be-OH ,=NOH ,-OSO
3Na ,=O ,=NNHC (=S) NH
2,=NNHC (=O) NH
2,=NOCH
2Ph ,=NOCH
3,=NOCH
2CH
3,-OCH
2CH
2N (CH
3)
2,-OCH
2CH
2N (CH
2CH
3)
2,-OCH
2CH
2N (CH
2CH
2Cl)
2,-N (CH
2CH
2Cl)
2Middle different substituting group
R
1For=NOH ,-OSO
3Na ,=NNHC (=S) NH
2,=NNHC (=O) NH
2,=NOCH
2Ph ,=NOCH
3,=NOCH
2CH
3,-OCH
2CH
2N (CH
3)
2,-OCH
2CH
2N (CH
2CH
3)
2,-OCH
2CH
2N (CH
2CH
2Cl)
2,-N (CH
2CH
2Cl)
2Middle different substituting group.
R and R in the formula
1Can be identical, also can be different.
B-of the present invention falls-3, and 6-two replaces the cholestane compounds, can be from cholesterol, through protective group, ozonize, cyclisation, condensation, go to protect, the chemical process of oxidation, addition is transformed.
Prepare B-of the present invention and fall-3, the reaction formula of following some compound in the 6-two replacement cholestane compounds is as follows:
B-falls-3, and 5-dihydroxyl-6-replaces the syntheti c route of cholestane
From the above-claimed cpd 4s, from different reagent (example hydrochloric acid azanol, thiosemicarbazide, Urea,amino-, amino methyl ether, amino benzyl oxide etc.) reaction, perhaps will react again after the 6-position aldehyde radical reduction in 4, perhaps further the 3-position hydroxyl in 4 is carried out functional group's conversion, can obtain listed different product in the general formula I.
B-falls-and 3 beta-hydroxies-6-replaces the syntheti c route of courage steroid-5-alkene
From the above-claimed cpd 11s, carry out condensation reaction from different reagent (example hydrochloric acid azanol, thiosemicarbazide, Urea,amino-, amino methyl ether, amino benzyl oxide etc.), perhaps the 6-position hydroxyl in 13 is carried out functional group's conversion, perhaps further the 3-position hydroxyl in 11 is carried out functional group's conversion, can obtain listed different product among the general formula I I.
Show by vitro inhibition growth of cancer cells increment activity test, B-of the present invention falls-3, and 6-two replaces the cholestane compounds cancer cell strains such as various tumor cell strains such as liver cancer, lung cancer, cancer of the stomach, cervical cancer, prostate cancer, colorectal carcinoma are had significant restraining effect.Therefore, B-of the present invention falls-3, and 6-two replaces the cholestane compound and can be used for preparing the medicine for the treatment of cancer.
It is a kind of for anti-tumor drug that the present invention also provides, and it contains above-mentioned B-and falls-3, and 6-two replaces cholestane compound 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.
(4) embodiment
The invention will be further described by the following examples.
Embodiment 1
B-falls-3, the preparation of 5-dihydroxyl-6-hydroxyl imido grpup cholestane (6)
Step 1: the preparation of intermediate product (2)
5.018g (13mmol) cholesterol is dissolved in the 40mL pyridine, behind the dissolve complete, slowly drips the 4.0mL diacetyl oxide, after diacetyl oxide adds, continues to stir 0.5 hour, then reactant is left standstill under room temperature 24 hours.Adding distil water 15mL with 10mL * 3 ethyl acetate extractions, washes respectively saturated NaHCO again with 1N dilute hydrochloric acid
3Wash, wash 2 times, be washed to neutrality with saturated common salt at last.Anhydrous sodium sulfate drying filters, and decompression steams solvent, when having relatively large solid to separate out, stops distillation, and the solid that heating for dissolving is separated out leaves standstill and allows its crystallization.Obtain white plates crystal 2 5.308g after suction filtration and the drying, productive rate 96%.Product structure is through IR, NMR and MS Analysis deterrmination.
Step 2: the preparation of intermediate product (3)
110mg compound 2 is packed in the reaction flask, adds 16mL methylene dichloride and 4mL methyl alcohol.Place the ethyl acetate vacuum flask of cooled with liquid nitrogen, when treating that system temperature is cooled to-78 ℃, pass into and be rich in O
3Oxygen Flow, after reaction is finished, add the 2mL dimethyl sulphide, be warming up to stirred overnight at room temperature.Decompression extracts most of solvent and obtains oily matter, and this oily matter adds the layering of 10mL distilled water with the dissolving of 50mL methylene dichloride, tells the organic layer anhydrous sodium sulfate drying.Decompression extracts solvent, obtains water white oily matter, drying.Rapid column chromatography separates (eluent: V
Sherwood oil: V
Ethyl acetate=4: 1) obtain oily compound 3108mg, productive rate 91%.Product structure is through IR, NMR and MS Analysis deterrmination.
Step 3: the preparation of intermediate product (4)
Fill and add 22mL benzene and neutral alumina 4.78g in the 100mL round-bottomed flask of 478mg compound 3, stirring reaction is 24 hours under the room temperature, and TLC follows the tracks of reaction, does not have afterwards stopped reaction of raw material point, in this mixture impouring silica gel short column, with a large amount of CH
2Cl
2Flushing is until without the product point, extract solvent and obtain transparent oily matter 445mg.The silica gel column chromatography separation obtains white solid compound 4 377mg, productive rate 85%.Product structure is through IR, NMR and MS Analysis deterrmination.
Step 4: the preparation of intermediate product (5)
184mg (0.4mmol) compound 4 places reaction flask, adds the ethanol of 15mL 95%, stirring and dissolving under 60 ℃ water bath condition, the sodium acetate trihydrate of adding 55mg, disposable adding 32mg oxammonium hydrochloride after the dissolving.TLC follows the tracks of reaction, is stopped reaction without the raw material point, removes most ethanol under reduced pressure, adds a little distilled water, white solid occurs.With ethyl acetate extraction 3 times, merge the organic layer washing once, saturated common salt is washed once, anhydrous sodium sulfate drying.Column chromatography for separation obtains pure compound 5166mg, productive rate 87.4%.Product structure is through IR, NMR and MS Analysis deterrmination.
Step 5: the preparation of product (6)
117mg compound 5 is dissolved in the KOH/CH of 10mL
3Among the OH (5: 95), stirring reaction at room temperature, TLC are followed the tracks of reaction to without the rear stopped reaction of raw material point.The pressure reducing and steaming solvent obtains white solid, adds the frozen water of 10mL, uses ethyl acetate extraction 3 times, washes with water once behind the merging organic layer, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, remove solvent under reduced pressure and obtain oily matter.Column chromatography for separation obtains white solid product 683mg, productive rate 78%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 2
B-falls-preparation of 3 beta-acetoxyl group-5s-hydroxyl-6-contracting ammonia sulfonyl hydrazone group cholestane (7)
114mg (0.248mmol) compound 4 places the 100mL reaction flask, adds the 15mL dehydrated alcohol, and stirring and dissolving under 60 ℃ water bath condition splashes into 2-3 and drips Glacial acetic acid control pH value of solution ≈ 4, subsequently disposable adding 52mg thiosemicarbazide.TLC follows the tracks of reaction to being stopped reaction without the raw material point, removes most of ethanol under reduced pressure, obtains oily matter.Column chromatography for separation obtains solid product 7120mg, productive rate 91%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 3
B-falls-3, the preparation of 5-dihydroxyl-6-contracting ammonia sulfonyl hydrazone group cholestane (8)
63mg compound 7 is dissolved in the KOH/CH of 8mL
3Among the OH (5: 95), stirring reaction under the room temperature (20 ℃), TLC are followed the tracks of reaction extremely without raw material point stopped reaction.Decompression extracts solvent and obtains white solid, adds the frozen water of 8mL, uses ethyl acetate extraction 3 times, washes with water once behind the merging organic layer, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains oily matter.Column chromatography for separation obtains white solid compound 853mg, productive rate 91%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 4
B-falls-preparation of 3 beta-acetoxyl group-5s-hydroxyl-6-hydrazone group cholestane (9)
115mg (0.25mmol) compound 4 places the 50mL reaction flask, adds the 15mL dehydrated alcohol, and stirring and dissolving under 65 ℃ oil bath condition splashes into 2 Glacial acetic acid control pH value of solution ≈ 4, subsequently disposable adding 25 μ L hydrazine hydrates (80%).TLC follows the tracks of reaction to without raw material point stopped reaction, removes most of ethanol under reduced pressure, obtains oily matter.Then add a little distilled water, with ethyl acetate extraction 3 times (10mL*3), merge organic layer, wash once, saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains white solid matter.This crude product obtains pure compound 996mg through column chromatography for separation, productive rate 78%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 5
B-falls-3, the preparation of 5-dihydroxyl-6-hydrazone group cholestane (10)
66mg (0.14mmol) compound 9 is dissolved in the KOH/CH of 8mL
3Among the OH (5: 95), stirring reaction (20 ℃) at room temperature, TLC are followed the tracks of reaction to without raw material point stopped reaction.Decompression extracts solvent and obtains white solid, adds the frozen water of 8mL, uses ethyl acetate extraction 3 times, washes with water once behind the merging organic layer, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains oily matter.Column chromatography for separation obtains faint yellow solid compound 1050mg, productive rate: 83%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 6
B-falls-preparation of 3 beta-hydroxies-6-hydroxyl imido grpup courage steroid-5-alkene (12)
Step 1: the preparation of intermediate product (11)
460mg (0.4mmol) compound 4 is dissolved in the KOH/CH of 15mL
3Among the OH (5: 95), stirring reaction under 45 ℃ of water bath condition, TLC are followed the tracks of reaction extremely without stopped reaction behind the raw material point.Decompression extracts solvent and obtains yellow oil, adds the 8mL frozen water, uses ethyl acetate extraction 3 times, washes with water once behind the merging organic layer, and saturated common salt is washed once, anhydrous sodium sulfate drying.Filter, the pressure reducing and steaming solvent obtains oily matter.Column chromatography for separation obtains oily compound 11284mg, productive rate 87.4%.Product structure is through IR, NMR and MS Analysis deterrmination.
Step 2: the preparation of product (12)
106mg (0.25mmol) compound 11 places the 50mL reaction flask, adds the ethanol of 15mL 95%, and stirring and dissolving under 60 ℃ of water bath condition adds the 35mg sodium acetate trihydrate, disposable adding 22mg (0.30mmol) oxammonium hydrochloride after the dissolving.TLC follows the tracks of reaction, is stopped reaction without the raw material point, removes most ethanol under reduced pressure, obtains faint yellow solid.Add a little distilled water, use ethyl acetate extraction 3 times, merge the organic layer washing once, saturated common salt is washed once, anhydrous sodium sulfate drying.Column chromatography for separation obtains faint yellow solid product 1290mg, productive rate 82.0%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 7
B-falls-3, the preparation of 6-dihydroxyl courage steroid-5-alkene (13)
418mg (0.9mmol) compound 11 is dissolved in 20mL CH
3Among the OH, disposable adding sodium borohydride 44mg after the stirring and dissolving at room temperature, TLC follow the tracks of reaction to without raw material point stopped reaction.Decompression extracts solvent and obtains white solid.Use CH
2Cl
2Dissolve this solid, 60-100 order silica gel mixed sample, column chromatography for separation (eluent: V
Sherwood oil: V
Ethyl acetate=2: 1) obtain white solid 13314mg, productive rate 78%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 8
B-falls-preparation of 3 beta-hydroxies-5-alkene-6-contracting ammonia sulfonyl hydrazone group cholestane (14)
160mg (0.38mmol) compound 11 places the 100mL reaction flask, adds the 15mL dehydrated alcohol, and stirring and dissolving under 70 ℃ of oil baths splashes into 2 Glacial acetic acid control pH value of solution ≈ 4, disposable adding 86mg thiosemicarbazide.TLC follows the tracks of reaction (V
Sherwood oil: V
Ethyl acetate=2: 1) to without raw material point stopped reaction, remove most of ethanol under reduced pressure, obtain white solid.Column chromatography for separation obtains solid product 14143mg, productive rate 76%.Product structure is through IR, NMR and MS Analysis deterrmination.
Embodiment 9
Present embodiment is to adopt B-of the present invention to fall-3, and 6-two replaces the cholestane compound carries out inhibition tumor cell growth increment activity test to some tumour cell test result.
Select part B-of the present invention to fall-3,6-two replace the cholestane compound tests its to human hepatoma cell strain (7404), the cytotoxicity of stomach cancer cell line (7901).Adopt the MTT method, carry out vitro cytotoxicity and measure.The B-that adds different concns in the logarithmic phase cell of cultivating in 96 orifice plates falls-3, and 6-two replaces the cholestane compound, carries out simultaneously 3 parallel tests, compares with control group.Cultivate after 72 hours, add MTT, measure its absorbancy, calculate respectively the concentration of inhibition tumor cell growth increment compound to 50% time, with IC
50Value representation, the result is as shown in table 1:
Table 1B-falls-3, and 6-two replaces cholestane antitumor activity of compound test result (MTT method, IC
50, μ mol/L)
Listed compound is to human hepatoma cell, the inhibiting IC of stomach cancer cell from table 1
50Value can find out that B-of the present invention falls-3, and 6-two replaces the cholestane compound these 2 kinds of tumour cells are had good restraining effect, such as the inhibition IC of 8 pairs of human hepatoma cell strains of compound (7404)
50Value is 8.6 μ mol/L, to the inhibition IC of stomach cancer cell line (7901)
50Value is 8.4 μ mol/L.
Claims (4)
1. a class B-falls-3, and 6-two replaces the cholestane compound, it is characterized in that this structural formula of compound is as follows:
2. the described B-of preparation claim 1 falls-3, and 6-two replaces the method for cholestane compound, it is characterized in that B-falls-3, and the syntheti c route of 5-dihydroxyl-6-replacement cholestane is as follows:
B-falls-and that 3 beta-hydroxies-6-replaces the syntheti c route of courage steroid-5-alkene is as follows:
。
3. B-falls-3 as claimed in claim 1, and 6-two replaces the application of cholestane compound in the preparation antitumor drug.
4. B-falls-3 as claimed in claim 1, and 6-two replaces the application of medicinal compositions in the preparation antitumor drug that the cholestane compound is activeconstituents.
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| CN103214542A (en) * | 2013-04-18 | 2013-07-24 | 广西师范学院 | B-nor-6-(4'-alkyl) aminothizone cholestane compound, and preparation method and application thereof in anticancer drugs |
| CN103204892A (en) * | 2013-04-18 | 2013-07-17 | 广西师范学院 | Beta-norcholest-6-(4'-phenyl)-aminothizone compound and synthesis method and application thereof in preparing antitumor drug |
| CN104447937B (en) * | 2014-12-17 | 2016-06-08 | 广西师范学院 | Cholestane benzimidazoles compound and its production and use drops in a kind of B- |
| CN106866774B (en) * | 2016-12-23 | 2018-12-04 | 广西师范学院 | For antitumor compound and its preparation method and application |
| CN109824748A (en) * | 2019-03-26 | 2019-05-31 | 广西万德药业有限公司 | B- norcholesterol oxidized derivatives and its synthetic method and application |
| CN115322240B (en) * | 2022-08-17 | 2023-09-12 | 南宁师范大学 | Cholesterol selenocyanate compound, and preparation method and application thereof |
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| CN101245090A (en) * | 2008-03-14 | 2008-08-20 | 广西师范学院 | 3,6-di-substituted sterides oximes compound as antineoplastic medicament |
| CN101292162A (en) * | 2005-08-15 | 2008-10-22 | 斯克利普斯研究院 | Methods to identify therapeutic agents |
| CN101508717A (en) * | 2009-04-03 | 2009-08-19 | 中国人民解放军第三军医大学 | Synthesis of tuberculosis resistant compound of arguesterol |
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| CN101292162A (en) * | 2005-08-15 | 2008-10-22 | 斯克利普斯研究院 | Methods to identify therapeutic agents |
| CN101245090A (en) * | 2008-03-14 | 2008-08-20 | 广西师范学院 | 3,6-di-substituted sterides oximes compound as antineoplastic medicament |
| CN101508717A (en) * | 2009-04-03 | 2009-08-19 | 中国人民解放军第三军医大学 | Synthesis of tuberculosis resistant compound of arguesterol |
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