CN103254264B - Vitarrine aromatic aldehyde azine steroidal compounds and synthetic method thereof and preparing the application in antitumor drug - Google Patents
Vitarrine aromatic aldehyde azine steroidal compounds and synthetic method thereof and preparing the application in antitumor drug Download PDFInfo
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 35
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 title claims abstract description 31
- 150000001875 compounds Chemical class 0.000 title claims abstract description 30
- 230000003637 steroidlike Effects 0.000 title claims abstract description 26
- 150000003934 aromatic aldehydes Chemical class 0.000 title claims abstract description 25
- 239000002246 antineoplastic agent Substances 0.000 title claims description 9
- 229940041181 antineoplastic drug Drugs 0.000 title claims description 9
- 238000010189 synthetic method Methods 0.000 title description 5
- 239000000126 substance Substances 0.000 claims abstract 2
- -1 Vitarrine hydrazone Chemical class 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 210000004881 tumor cell Anatomy 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 201000011510 cancer Diseases 0.000 abstract description 4
- 230000000452 restraining effect Effects 0.000 abstract description 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 229960000935 dehydrated alcohol Drugs 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PFLUPZGCTVGDLV-UHFFFAOYSA-N acetone azine Chemical compound CC(C)=NN=C(C)C PFLUPZGCTVGDLV-UHFFFAOYSA-N 0.000 description 6
- CWLGEPSKQDNHIO-JOBJLJCHSA-N (e)-n-[(e)-benzylideneamino]-1-phenylmethanimine Chemical compound C=1C=CC=CC=1/C=N/N=C/C1=CC=CC=C1 CWLGEPSKQDNHIO-JOBJLJCHSA-N 0.000 description 5
- 229960004756 ethanol Drugs 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XIIAYQZJNBULGD-UHFFFAOYSA-N (5alpha)-cholestane Natural products C1CC2CCCCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XIIAYQZJNBULGD-UHFFFAOYSA-N 0.000 description 1
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical compound O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- 239000002775 capsule Substances 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- XIIAYQZJNBULGD-LDHZKLTISA-N cholestane Chemical compound C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XIIAYQZJNBULGD-LDHZKLTISA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
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- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
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- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
One class has the Vitarrine aromatic aldehyde azine steroidal compounds of azine structure, and chemical structural formula is as follows:
Description
One, technical field
The present invention relates to class Vitarrine aromatic aldehyde azine steroidal compounds and a synthetic method thereof, and it is preparing the application in antitumor drug.
Two, background technology
Azine and derivative thereof are the important compounds of a class.Bibliographical information, azines is in biological medicine and pesticide field extensive application, and they have researching value widely in the exploitation of antibacterial, desinsection and the medicine such as antitumor.In the study on the synthesis of azines, once reported that a class was used as the azine-Carbox amide (Chinese invention patent application number: CN200580028484.X) of cancer therapy drug.Simultaneously, in the synthesis of steroidal azines, once a class 6-carbonyl cholestane thiazolidone azines (SalmanAhmadKhan was reported, AbdullahM.Asiria, MohammedYusuf.Synthesisandbiologicalevaluationofsomethia zolidinonederivativesofsteroidasantibacterialagents, EuropeanJournalofMedicinalChemistry, 2009,44:2597 – 2600), this compounds has good anti-microbial activity.In the research of antitumor steroidal compounds, once reported courage steroid-4-alkene-B-cyclic lactam compound (Natalija
miraS.Bielakovi á,
synthesisofsomesteroidaloximes, lactams, thiolactamsandtheirantitumoractivities, Steroids, 2007,72:406 – 414), androstane-B cyclic lactam compounds (AnnaI.Koutsourea, MandisA.FthanasiosPapageorgiou, GeorgeNPairasPapagerous, GeorgeN.Pairas, SotirisS.Nikolaropoulos.Bioorganic & MedicalChemistry, 2008,16,5207-5212).Some in above-claimed cpd has cytotoxicity to some tumour cell in vitro.Chinese patent ZL201010107528.0 once provided a class " 6-replaces-4-azepine-A-homo-3-oxo steroidal compounds and preparing the application in antitumor drug ", and Chinese patent application 201110009124.2 provides another kind of " 3-replaces-B-Homo-steroidal-B-cyclic lactam compound and preparation method thereof and preparing the application in antitumor drug ".But, about Vitarrine aromatic aldehyde azine steroidal compounds and synthetic method thereof and its have no report preparing the application in antitumor drug.
Three, summary of the invention
The object of this invention is to provide a class Vitarrine aromatic aldehyde azine steroidal compounds.
Another object of the present invention is to provide the synthetic method of above-claimed cpd.
A further object of the present invention is to provide above-claimed cpd and is preparing the application in antitumor drug.
The present invention is achieved through the following technical solutions above-mentioned purpose:
Vitarrine aromatic aldehyde azine steroidal compounds structural formula of the present invention is as follows:
Vitarrine acetone azine (1) Vitarrine benzaldehyde azine (2)
Vitarrine-3-pyridinecarboxaldehyde azine (3) Vitarrine-3-thiophenecarboxaldehyde azine (4)
Vitarrine-3-hydroxy benzaldehyde azine (5) Vitarrine-2-naphthaldehyde azine (6)
Vitarrine-4-quinoline aldehyde azine (7) Vitarrine-6-methoxy naphthyl aldehyde azine (8)
Vitarrine aromatic aldehyde azine steroidal compounds of the present invention, is reacted by natural steroid compound Vitarrine and hydrazine hydrate, generates Vitarrine hydrazone.Vitarrine hydrazone further from different aromatic aldehydes or heteroaromatic aldehyde reaction, obtain Vitarrine aromatic aldehyde azine steroidal compounds.
The reaction preparing Vitarrine aromatic aldehyde azine steroidal compounds is as follows:
Vitarrine Vitarrine hydrazone
By cancer cell in vitro inhibit activities test show, Vitarrine aromatic aldehyde azine steroidal compounds of the present invention to various tumor cell strains as the tumor cell lines such as liver cancer, cancer of the stomach, cervical cancer, colorectal carcinoma have significant restraining effect.Therefore Vitarrine aromatic aldehyde azine steroidal compounds of the present invention can be used for the medicine preparing Therapeutic cancer.
The present invention also provides a kind of medicine being used for the treatment of cancer, and it contains above-mentioned Vitarrine aromatic aldehyde azine steroidal compounds and pharmaceutically acceptable auxiliary.The form that this medicine can make injection, tablet, pill, capsule, suspension agent or emulsion uses, 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.
The preparation of embodiment 1 Vitarrine acetone azine (1)
Step 1: the preparation of Vitarrine hydrazone
Take Vitarrine 3.0g, be placed in 100mL round-bottomed flask, add 30mL dehydrated alcohol, after 75 DEG C of stirrings make it dissolve completely, add 4mL85% hydrazine hydrate, stir 1 hour, a large amount of white crystal is had to separate out, TLC follows the tracks of reaction process, stops heating after the completely dissolve of raw material point, and ice bath cools, suction filtration, thick product dichloromethane methanol mixed solvent recrystallization, obtains target product 2.3g, productive rate: 73% after suction filtration, oven dry.M.p:207-209 DEG C. product structure is analyzed through IR, NMR and MS and is determined.
Step 2: the preparation of Vitarrine acetone azine (1)
Take Vitarrine hydrazone 120mg and be placed in 100mL round-bottomed flask, add 30mL dehydrated alcohol, stir, after dissolving completely, add 1mL acetone, stirring reaction 5 hours at 50 DEG C, TLC follows the tracks of, without termination reaction after raw material point, and underpressure distillation, with ether to its recrystallization, obtain colourless granules shape crystal 110mg, productive rate: 83%, m.p:187-189 DEG C.Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 2 Vitarrine benzaldehyde azine (2)
Take Vitarrine hydrazone 100mg, be placed in 100mL round-bottomed flask, add 15mL dehydrated alcohol, stir after dissolving completely and add 45mg phenyl aldehyde, stir 2h under 50C °, TLC follows the tracks of reaction process, without termination reaction after raw material point, plate layer chromatography is separated (chromatographic solution: ethyl acetate: sherwood oil=1:1.6), obtains 107mg white powder, productive rate: 89%.m.p:187-189℃。Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 3 Vitarrine-3-pyridinecarboxaldehyde azine (3)
Take Vitarrine hydrazone 100mg and be placed in 100mL round-bottomed flask; add 15mL dehydrated alcohol, be warming up to 75 DEG C, stir after making it dissolve completely and add 41mg3-pyridylaldehyde; react 1 hour; TLC follows the tracks of reaction, without stopped reaction after raw material point, and underpressure distillation; obtain yellow oil; add sherwood oil mixed system to its recrystallization with ethanol, obtain light yellow crystal, repeat crystallization and obtain target product 56mg. productive rate three times: 42%; M.p:207-210 DEG C.Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 4 Vitarrine-3-thiophenecarboxaldehyde azine (4)
Take Vitarrine hydrazone 100mg, add 15mL dehydrated alcohol and dissolve completely, add 35mg3-thiazole carboxaldehyde.40 degree of lower stir about 12h, TLC follow the tracks of, and stopped reaction after the completely dissolve of raw material point, obtain faint yellow solid after underpressure distillation, thick product ethanol adds petroleum ether system recrystallization, obtains light yellow crystal 109mg, productive rate 80%.M.p:181-183 DEG C; Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 5 Vitarrine-3-hydroxy benzaldehyde azine (5)
Take Vitarrine hydrazone 100mg, be placed in 100mL round-bottomed flask, add 15mL dehydrated alcohol, stirred at ambient temperature adds 37mg3-hydroxy benzaldehyde after making it dissolve completely, 40C ° of stirring reaction 3 hours, and TLC follows the tracks of without termination reaction after raw material point, petroleum ether system recrystallization is added with dehydrated alcohol after underpressure distillation, obtain light yellow crystal 76mg, productive rate 60%.Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 6 Vitarrine-2-naphthaldehyde azine (6)
Take Vitarrine hydrazone 100mg and be placed in 100mL round-bottomed flask, add 25mL dehydrated alcohol, stirred at ambient temperature, after dissolving completely, add 65mg1-naphthaldehyde, be warming up to 75C ° and react about 1h, TLC tracking, termination reaction after the completely dissolve of raw material point, underpressure distillation.Thick product ethanol adds petroleum ether system recrystallization twice, obtains light yellow crystal 90mg, productive rate 64%.m.p:200-202℃。Product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 7 Vitarrine-4-quinoline aldehyde azine (7)
Take Vitarrine hydrazone 100mg, be placed in 100mL round-bottomed flask, add 15mL dehydrated alcohol, stirred at ambient temperature adds 47mg4-quinoline aldehyde after making it dissolve completely, in 40 degree of lower stirring reaction 12h, solution gradually becomes green, TLC follows the tracks of reaction process, and without termination reaction after raw material point, after underpressure distillation, thick product ethanol adds petroleum ether system recrystallization, obtain pale green crystals 115mg, productive rate 81%.M.p:202-204 DEG C. product structure is analyzed through IR, NMR and MS and is determined.
The preparation of embodiment 8 Vitarrine-6-methoxy naphthyl aldehyde azine (8)
Take Vitarrine hydrazone 100mg, move in 100mL round-bottomed flask, stir after dissolving completely and add 57mg6-methoxy-2-naphthaldehyde, 75C ° of stirring is spent the night, and adularescent precipitation generates, and TLC follows the tracks of, termination reaction after the completely dissolve of raw material point.After underpressure distillation, thick product re-crystallizing in ethyl acetate, obtains tip-like clear crystal 100mg, productive rate 66.6%, m.p:183-184 DEG C.Product structure is analyzed through IR, NMR and MS and is determined.
Embodiment 9
The present embodiment is the test result adopting Vitarrine aromatic aldehyde azine steroidal compounds of the present invention some tumour cell to be carried out to cell toxicity test.
Adopt MTT method, to human cervical carcinoma cell lines (HeLa), colon cancer cell line (HT-29), hepatoma cell strain (Bel-7404) and stomach cancer cell line (SGC-7901), the test of growth and proliferation of cell inhibit activities is carried out to Vitarrine aromatic aldehyde azine steroidal compounds of the present invention.The Vitarrine aromatic aldehyde azine steroidal compounds of the present invention of different concns is added in the logarithmic phase cell cultivated in 96 orifice plates, carry out 3 parallel tests simultaneously, compare with control group, cultivate after 72 hours, add MTT, measure its absorbancy, calculate the concentration of compound when inhibition tumor cell grows into 50% respectively, with IC
50value represents, result is as shown in table 1:
Table 1 synthetic compound extracorporeal suppression tumor cell growing multiplication activity (MTT method) (IC
50, μm ol/L)
Data from table, this type of Vitarrine aromatic aldehyde azine steroidal compounds has obvious growing multiplication restraining effect to above-mentioned tumour cell.
Claims (4)
1. a class Vitarrine aromatic aldehyde azine steroidal compounds, chemical structural formula is as follows:
2. prepare the method for Vitarrine aromatic aldehyde azine steroidal compounds as claimed in claim 1 for one kind, it is characterized in that, comprise the steps: from Vitarrine, first react with hydrazine hydrate, generate Vitarrine hydrazone, Vitarrine hydrazone further from different aromatic aldehydes or heteroaromatic aldehyde reaction, obtain Vitarrine aromatic aldehyde azine steroidal compounds 1-7.
3. Vitarrine aromatic aldehyde azine steroidal compounds as claimed in claim 1 is preparing the application in antitumor drug.
4. the medicinal compositions being activeconstituents with Vitarrine aromatic aldehyde azine steroidal compounds according to claim 1 is preparing the application in antitumor drug.
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| CN105254699B (en) * | 2015-10-29 | 2017-05-17 | 广西师范学院 | 4-(4 minute-trifluoromethyl) phenyl-2-dehydroepiandrosterone-17 minute-hydrazone thiazole as well as preparation method and application thereof |
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Citations (3)
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| US3232960A (en) * | 1959-10-08 | 1966-02-01 | Upjohn Co | 3-keto-4-fluoro- and 3-keto-4,4-difluorosteroids and process |
| US3268520A (en) * | 1963-01-23 | 1966-08-23 | Bayer Ag | Steroid guanylhydrazones and production thereof |
| CN102816198A (en) * | 2012-09-08 | 2012-12-12 | 广西师范学院 | Preparation method of 3-hydroxy-5-alkenesteroid compounds with ammonia derivative branched chain structure and application thereof in antineoplastic drugs |
-
2013
- 2013-05-19 CN CN201310184358.XA patent/CN103254264B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3232960A (en) * | 1959-10-08 | 1966-02-01 | Upjohn Co | 3-keto-4-fluoro- and 3-keto-4,4-difluorosteroids and process |
| US3268520A (en) * | 1963-01-23 | 1966-08-23 | Bayer Ag | Steroid guanylhydrazones and production thereof |
| CN102816198A (en) * | 2012-09-08 | 2012-12-12 | 广西师范学院 | Preparation method of 3-hydroxy-5-alkenesteroid compounds with ammonia derivative branched chain structure and application thereof in antineoplastic drugs |
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| Title |
|---|
| Reaction of pregnenolone with cyanoacetylhydrazine: Novel synthesis of hydrazide–hydrazone, pyrazole, pyridine, thiazole, thiophene derivatives and their cytotoxicity evaluations;Rafat M. Mohareb，Fatima Al-Omran;《Steroids》;20121231;第77卷(第14期);第1551-1559页 * |
| Synthesis and Evaluation of Pregnane Derivatives as Inhibitors of Human Testicular 17r-Hydroxylase/C17，20-Lyase;Ji-song Li等;《J. Med. Chem.》;19961011;第39卷;第4335-4339页 * |
| 具有生物活性氮杂甾体化合物的研究进展;范良华等;《化学研究与应用》;20120131;第24卷(第1期);第8-15页 * |
| 具有生理活性甾体腙类化合物的研究进展;陈思静等;《有机化学》;20110215;第31卷(第2期);第187-192页 * |
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Effective date of registration: 20171227 Address after: 401220 No. 16 group 30 of Yantan village, Changshou District, Chongqing Patentee after: Li Yizhong Address before: 518000 Guangdong Province, Shenzhen New District of Longhua City, Dalang street, Longsheng Gold Dragon Road community e-commerce incubator exhibition Tao Commercial Plaza E block 706 Patentee before: Shenzhen step Technology Transfer Center Co., Ltd. |
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Effective date of registration: 20180820 Address after: 518000 Guangdong Shenzhen Longhua New District big wave street Longsheng community Tenglong road gold rush e-commerce incubation base exhibition hall E commercial block 706 Patentee after: Shenzhen step Technology Transfer Center Co., Ltd. Address before: 401220 No. 16 group 30 of Yantan village, Changshou District, Chongqing Patentee before: Li Yizhong |
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Effective date of registration: 20181019 Address after: 401120 Chongqing Yubei District Shuangfeng Bridge Street Airport Development Zone Xiangyu Road 15, 1 1 stories. Patentee after: CHONGQING TIANYI HENGHUA TECHNOLOGY CO., LTD. Address before: 518000 Guangdong Shenzhen Longhua New District big wave street Longsheng community Tenglong road gold rush e-commerce incubation base exhibition hall E commercial block 706 Patentee before: Shenzhen step Technology Transfer Center Co., Ltd. |
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Granted publication date: 20160406 Termination date: 20190519 |