CN103193859B - Dehydroepiandrosterone D cyclobenzo-aminothiazole ring compounds as well as preparation method and application thereof - Google Patents

Dehydroepiandrosterone D cyclobenzo-aminothiazole ring compounds as well as preparation method and application thereof Download PDF

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CN103193859B
CN103193859B CN201310137636.6A CN201310137636A CN103193859B CN 103193859 B CN103193859 B CN 103193859B CN 201310137636 A CN201310137636 A CN 201310137636A CN 103193859 B CN103193859 B CN 103193859B
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phenyl
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replaces
sterone
dehydroepiandros
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CN103193859A (en
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刘宏民
张宝乐
张恩
郑甲信
庞露苹
李亚飞
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Zhengzhou University
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Abstract

The invention belongs to the field of medicinal chemistry and in particular relates to dehydroepiandrosterone D cyclobenzo-aminothiazole ring imine and imine reducing compounds as well as a preparation method and application thereof. The compounds are shown in a formula I in the specification. An in-vitro antineoplastic activity experiment indicates that the compounds have better broad-spectrum antineoplastic activity, have a favorable inhibition effect on multiple human cancer cells, such as EC109 and EC9706 and are suitable for research of antineoplastic lead compounds or preparation of novel antineoplastic medicaments. The preparation method is simple and convenient and suitable for industrial production.

Description

Dehydroepiandros-sterone D ring aminothiazole cyclics, its preparation method and application thereof
Technical field
The present invention relates to a class and there is the dehydroepiandros-sterone D ring of anti-tumor activity and thiazole ring imines class and imine reduction compounds, synthetic method and the application at anti-tumor aspect thereof, belong to medicinal chemistry art.
Background technology
According to World Health Organization's statistics, cancer is a global major causes of death, and the number of world wide internal cause cancer and death presents the situation increased year by year, and expect the year two thousand thirty, global number of cancer deaths will increase by 45%.But due to existing antitumor drug, to there is toxic side effect large, the shortcomings such as resistance, further investigation high-efficiency low-toxicity and the problem not having the new type antineoplastic medicine of resistance to become extremely important and urgent with existing antitumor drug.
Steroidal, as a class perhydrocyclopentanophenanthrene compounds, is prevalent in animal vegetable tissue, its sustaining life, adjusting sexual function, have clear and definite effect in body development, immunomodulatory, treating skin disease and Birth control.Along with the development of organic chemistry and medicinal chemistry art, modifying for chemical structure based on steroidal has become the focus of Recent study, its biological activity scope is also no longer confined to traditional hormones pharmacologically active as protein assimilation, anti-inflammatory, antagonism male sex hormone, contraception etc., show the physiologically actives such as anticancer, antibacterial gradually, as antitumor drug Abiraterone (Abiraterone) has been applied to the clinical treatment of refractory prostate cancer (see J. Med. Chem .2003, 46,2345-2351).
Thiazole structure unit, as active group, is extensively present in natural and synthetic and has in the compound of pharmacologically active, as Epothilone, Dasatinib have good antitumour activity (see Prog Heterocycl Chem:Elsevier; 2011. p.259-307; Expert Opinion on Investigational Drugs. 2005; 14:89-91), wherein TMC435350 is carrying out clinical study (see Antimicrob Agents Chemother. 2009 as antiviral; 53:1377-85.).
Utilize active fragments to integrate principle, thiazoles structural unit is introduced steroidal parent nucleus, synthesizes a class novel dehydroepiandros-sterone D ring and thiazole ring imines class and imine reduction compounds, and preliminary assessment is carried out to its biologic activity, have no bibliographical information at present.
Summary of the invention
Based on above-mentioned, one of the object of the invention is to provide the new dehydroepiandros-sterone D ring with anti-tumor activity of a class and thiazole ring imines class and imine reduction compounds; Two of object is to provide the preparation method of this compounds; Three of object is to provide this compounds and is preparing the application in antitumor drug.
For realizing the object of the invention, the present invention directly go for the D ring of epiandrosterone and on an aminothiazole ring, and utilize exposed amino and a series of aromatic aldehyde to be obtained by reacting imine compound 13, and its reduction compounds is obtained to carbon-to-nitrogen double bon reduction 14.
Described dehydroepiandros-sterone D ring thiazole ring imines class and imine reduction compounds have following general structure:
13 14
Wherein R is the C2-3 alkyl that phenyl replaces, phenyl, the phenyl that hydroxyl replaces, the phenyl that C 1-3 alkyl replaces, the phenyl that first cyanogen replaces, monosubstituted or polysubstituted p-methoxy-phenyl, monosubstituted or polysubstituted halogenophenyl, naphthyl, the heterocyclic aryl of heterocyclic aryl and replacement is as thienyl, pyrryl, pyridyl, furyl etc.
The C2-3 unsaturated alkyl that the preferred phenyl of R replaces, phenyl, the phenyl that hydroxyl replaces, aminomethyl phenyl, the phenyl that first cyanogen replaces, monosubstituted or polysubstituted p-methoxy-phenyl, monosubstituted or polysubstituted fluorine or chlorine or bromo phenyl, 2-thienyl, 2-pyrryl, 2-pyridyl, 2-furyl or 2-naphthyl etc.
Its synthetic method comprises the following steps:
1, general formula 13preparation method
(1) in organic solvent, by dehydroepiandros-sterone 5with bromizating agent reaction, obtain compound 11.Bromizating agent used is N-bromo-succinimide (NBS), CuBr, CuBr 2wherein a kind of;
(2) by compound 11be dissolved in organic solvent, add alkali and thiocarbamide reaction, obtain compound 12;
(3) by compound 12be dissolved in organic solvent, add alkali and aromatic aldehyde obtains general formula 13.
Alkali used is the mineral alkalis such as organic bases or sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydroxide, potassium hydroxide such as pyridine, triethylamine, DMAP (DMAP), diisopropyl ethyl amine, organic solvent used be acetone, n, n-dimethyl formamide, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane one of them or wherein any two or three mixture.
The preferred 0-90 of above temperature of reaction 0c.
Selected aromatic aldehyde be following one of them: the C2-3 alkyl aldehyde that phenyl replaces, phenyl aldehyde, the phenyl aldehyde that hydroxyl replaces, the phenyl aldehyde that C 1-3 alkyl replaces, the phenyl aldehyde that first cyanogen replaces, monosubstituted or polysubstituted methoxybenzaldehyde, monosubstituted or polysubstituted halogenated benzaldehyde, naphthaldehyde, thienyl formaldehyde, pyrryl formaldehyde, pyridyl carboxylaldehyde, furyl formaldehyde.
Products therefrom is purified through column chromatography or recrystallization etc. and is obtained straight product.Recrystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, chloroform or the wherein mixture of two kinds.
In formula, R is same as above.
2, general formula 14preparation method:
By general formula 13in single compound be dissolved in alcohol organic solvent, add reductive agent, reduction carbon-to-nitrogen double bon obtain general formula 14compound.
Alcoholic solvent used comprises propyl carbinol, the trimethyl carbinol, Virahol, methyl alcohol or ethanol etc.; Reductive agent used is the mixing of lithium aluminum hydride, sodium borohydride, POTASSIUM BOROHYDRIDE a kind of or any two kinds.
Temperature of reaction is-10-60 preferably 0c, carries out in room temperature usually.Products therefrom is purified through column chromatography or recrystallization etc. and is obtained straight product.Recrystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, chloroform or the wherein mixture of two kinds.
In formula, R is same as above.
Compou nd synthesis method provided by the invention is easy, and be applicable to suitability for industrialized production, activity rating shows this compounds to various human cancer cells as EC109 has restraining effect well.Using its be active ingredient as a class antitumor compounds, can be used for the preparation of the cancer drugs such as prostate cancer, mammary cancer, the esophageal carcinoma.
Embodiment
By following embodiment, the present invention is further illustrated, but not as restriction.
Embodiment
1,16-bromo dehydroepiandros-sterone 11synthesis
Dehydroepiandros-sterone (0.01mol) dissolves in 100mL methyl alcohol, add cupric bromide (0.02mmol) room temperature reaction 10h, by system evaporate to dryness after question response is complete, use water, saturated common salt water washing 2 times more respectively with dichloromethane extraction, after organic layer anhydrous sodium sulfate drying, namely evaporate to dryness obtains faint yellow look solid 11 with quantitative yield and without the need to purifying.1H NMR (400 MHz, CDCl3) δ 5.37(d, 1H, J=5.42 Hz, 6-H), 4.54(t, 1H, 16-H), 3.54(m, 1H, 3α-H), 1.04(s, 3H, 18-Me), 0.93(s, 3H, 19-Me).。
2, dehydroepiandros-sterone D ring thiazoleamino compound 12synthesis
Compound 11(3.4g, 9.26 mmol), thiocarbamide (3.4g, 44.7mmol) and triethylamine (3.4g, 33.6mmol) dissolve in back flow reaction 10h in 150mL ethanol, the precipitation of adularescent solid is carried out along with what react in reaction system, suction filtration is placed in cooling, solid washing with alcohol can obtain compound 12 2 times, productive rate is 95%, mp > 250 DEG C. 1H NMR (400 MHz, DMSO) δ 6.75 (D2O exchangeable, s, 2H,-NH2), 5.30 (d, 1H, J=5.42 Hz, 6-H), 4.64 (D2O exchangeable, d, 1H, J=4.64 Hz, 3-OH), 3.26 (m, 1H, 3 α-H), 1.00 (s, 3H, 18-Me), 0.81 (s, 3H, 19-Me). 13C NMR (101 MHz, DMSO) δ 171.99, 165.65, 142.12, 120.58, 117.04, 70.45, 59.48, 50.79, 42.75, 42.32, 39.98, 37.26, 36.89, 34.67, 31.90, 31.17, 30.49, 27.75, 20.60, 19.55, 17.09. HRMS (ESI): m/z calcd for C22H31NaNO3 (M+H)+, 345.2001, found, 345.1996..
3, dehydroepiandros-sterone D ring the logical method of thiazole ring imine compound synthesis
Compound 12(200mg, 0.58 mmol) is dissolved in THF/EtOH [(1:1), 25 ml for each] and then adds aromatic aldehyde (1.16 mmol) and K 2cO 3/ Et 3n (1:2) (0.85 mmol total), backflow 3-15 hour, the completely rear evaporate to dryness system of question response, be extracted with ethyl acetate, water and saturated aqueous common salt respectively wash twice, organic phase with sodium sulfate is dry, evaporated under reduced pressure, and note chromatographic separation (petrol ether/ethyl acetate=4/1) obtains dehydroepiandros-sterone D ring and the synthesis of thiazole ring imine compound 13, productive rate is between 50%-90%.
Selected aromatic aldehyde is: the C2-3 unsaturated alkyl aldehyde that phenyl replaces, phenyl aldehyde, the phenyl aldehyde that hydroxyl replaces, tolyl aldehyde, monosubstituted or polysubstituted methoxybenzaldehyde, monosubstituted or polysubstituted fluorine or chlorine or bromobenzene formaldehyde, 2 thiophene carboxaldehyde, 2-pyrrole aldehyde, 2-pyridylaldehyde, 2 furan carboxyaldehyde or 2-naphthaldehyde etc.
4, dehydroepiandros-sterone D ring the logical method of thiazole ring imine reduction compounds synthesis
Compound 13(200mg) be dissolved in methyl alcohol and then add sodium borohydride (1.5eq), room temperature reaction 30 minutes, the completely rear evaporate to dryness system of question response, be extracted with ethyl acetate, water and saturated aqueous common salt respectively wash twice, organic phase with sodium sulfate is dry, and namely evaporated under reduced pressure obtains dehydroepiandros-sterone D ring and thiazole ring imine reduction compounds 14, productive rate is between 95%-100%.
Series compound has been synthesized in this enforcement 13a-lwith 14a-l,as following table:
In table 1, the nuclear magnetic data of compound is expressed as follows:
Compound 13a
Yellow solid, fusing point 177.5-178.5 DEG C. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H, imine olefinic – N=CH-), 7.98 (d, 2H,-Ph), 7.49 (m, 3H,-Ph), 5.41 (d, 1H, J=5.42 Hz, 6-H), 3.56 (m, 1H, 3 α-H), 1.11 (s, 3H, 18-Me), 1.04 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.28, 169.03, 161.05, 141.38, 135.26, 132.28, 131.13, 129.60 (C), 128.86 (2C), 120.93, 71.63, 59.95, 50.72, 42.73, 42.29, 37.15, 36.87, 34.21, 31.63, 31.27, 30.57, 28.31, 20.55, 19.39, 17.13. HRMS (ESI): m/z calcd for C 27h 33n 2oS (M+H) +, 433.2314, found, 433.2310..
Compound 13b
Yellow solid, fusing point 232.5-233.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H, imine olefinic – N=CH-), 7.91 (d, 2H,-Ph), 7.48 (m, 3H,-Ph), 5.42 (d, 1H, J=5.42 Hz, 6-H), 3.58 (m, 1H, 3 α-H), 1.12 (s, 3H, 18-Me), 1.05 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 159.32, 141.35, 138.34, 133.803, 131.66, 130.64 (2C), 129.24 (2C), 129.02, 120.96, 99.99, 71.69, 59.96, 50.72, 42.74, 42.29, 37.14, 36.87, 34.21, 31.64, 31.27, 30.58, 28.33, 20.55, 19.39, 17.14. HRMS (ESI): m/z calcd for C 27h 32clN 2oS (M+H) +, 467.1924, found, 467.1926..
Compound 13c
Pink solid, fusing point 96.7-97.7 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H, imine olefinic – N=CH-), 7.65 (d, 1H, 5-H of furan), 7.09 (d, 1H, 3-H of furan), 6.58 (d d, 1H, 4-H of furan), 5.39 (d, 1H, J=5.42 Hz, 6-H), 3.55 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 1.01 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.09, 168.90, 151.71, 147.25, 146.75, 141.35, 132.15, 120.91, 118.66, 112.83, 71.59, 59.90, 50.70, 42.70, 42.28, 37.14, 36.85, 34.21, 31.61, 31.25, 30.56, 28.24, 20.53, 19.37, 17.15. HRMS (ESI): m/z calcd for C 25h 30n 2o 2sNa (M+Na) +, 445.2016, found, 445.2020..
Compound 13d
Yellow solid, fusing point 226.5-227.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H, imine olefinic – N=CH-), 7.97 (m, 2H,-Ph), 7.16 (m, 2H,-Ph), 5.40 (d, 1H, J=5.42 Hz, 6-H), 3.55 (m, 1H, 3 α-H), 1.10 (s, 3H, 18-Me), 1.02 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.05, 169.01, 166.50, 163.97, 159.43, 141.40, 131.70, 131.61, 131.24, 120.89, 116.26, 116.04, 71.59, 59.94, 50.71, 42.72, 42.29, 37.14, 36.86, 34.20, 31.62, 31.26, 30.56, 28.29, 20.53, 19.38, 17.13. HRMS (ESI): m/z calcd for C 27h 32fN 2oS (M+H)+, 451.2214, found, 451.2222..
Compound 13e
Brown solid, fusing point 109.5-110.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.82 (d, 1H, imine olefinic – N=CH-), 7.56 (d, 2H,-Ph), 7.41 (m, 3H,-Ph), 7.32 (s, 1H), 7.11 (d d, 1H), 5.43 (d, 1H, J=5.42 Hz, 6-H), 3.57 (m, 1H, 3 α-H), 1.12 (s, 3H, 18-Me), 1.03 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.45, 169.19, 161.93, 146.45, 141.35, 135.49, 131.67, 130.07, 128.99 (2C), 127.85, 127.82 (2C), 120.96, 71.66, 59.92, 50.72, 42.71, 42.30, 37.15, 36.87, 34.21, 31.64, 31.27, 30.58, 28.29, 20.55, 19.39, 17.14. HRMS (ESI): m/z calcd for C 29h 35n 2oS (M+H) +, 459.2470, found, 459.2478..
Compound 13f
Yellow solid, fusing point 94.2-95.2 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H, imine olefinic – N=CH-), 7.60 (s, 1H,-Ph), 7.45 (d, 1H,-Ph), 7.36 (t, 1H,-Ph), 7.08 (d d, 1H,-Ph), 5.39 (d, 1H, J=5.42 Hz, 6-H), 3.87 (s, 3H,-OMe), 3.55 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 1.02 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.14, 169.05, 160.97, 159.99, 141.40, 136.63, 131.05, 129.77, 123.52, 120.88, 119.70, 111.79, 71.57, 59.93, 55.47, 50.71, 42.72, 42.28, 37.14, 36.86, 34.20, 31.61, 31.26, 30.56, 28.32, 20.53, 19.38, 17.12. HRMS (ESI): m/z calcd for C 28h 35n 2o 2s (M+H) +, 463.2419, found, 463.2415..
Compound 13g
Yellow solid, fusing point 213.5-214.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H, imine olefinic – N=CH-), 8.00 (s, 1H, 2-Ph), 7.79 (d, 1H, 6-Ph), 7.46 (d, 1H, 4-Ph), 7.41 (t, 1H, 5-Ph), 5.42 (d, 1H, J=5.42 Hz, 6-H), 3.56 (m, 1H, 3 α-H), 1.11 (s, 3H, 18-Me), 1.04 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.56, 169.30, 159.01, 141.37, 137.08, 135.09, 132.08, 132.03, 130.09, 128.85, 127.89, 120.91, 71.64, 59.95, 50.70, 42.73, 42.29, 37.14, 36.87, 34.19, 31.63, 31.26, 30.58, 28.32, 20.54, 19.39, 17.17. HRMS (ESI): m/z calcd for C 27h 32clN 2oS (M+H)+, 467.1918, found, 467.1920..
Compound 13h
Yellow solid, fusing point 211.5-212.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H, imine olefinic – N=CH-), 8.33 (d, 1H,-Ph), 7.42 (m, 2H,-Ph), 7.35 (m, 1H,-Ph), 5.39 (d, 1H, J=5.42 Hz, 6-H), 3.59 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 1.03 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.88, 169.42, 157.43, 141.41, 136.79, 133.00, 132.42, 131.79, 130.10, 129.04, 127.18, 120.87, 71.58, 59.96, 50.70, 42.73, 42.28, 37.14, 36.86, 34.18, 31.61, 31.26, 30.57, 28.34, 20.53, 19.39, 17.14. HRMS (ESI): m/z calcd for C 27h 32clN 2oS (M+H)+, 467.1918, found, 467.1920..
Compound 13i
Yellow solid, fusing point 131.9-132.9 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H, imine olefinic – N=CH-), 7.08 (s, 1H, H of pyrrole), 6.82 (s, 1H, H of pyrrole), 6.36 (s, 1H, H of pyrrole), 5.42 (d, 1H, J=5.42 Hz, 6-H), 3.58 (m, 1H, 3 α-H), 1.11 (s, 3H, 18-Me), 1.02 (s, 3H, 19-Me) 13C NMR (101 MHz, CDCl3) δ 174.74, 168.48, 149.68, 141.37, 130.06, 129.07, 124.76, 120.98, 119.13, 111.46, 71.68, 59.90, 50.76, 42.68, 42.31, 37.15, 36.88, 34.22, 31.65, 31.29, 30.56, 28.31, 20.55, 19.39, 17.06. HRMS (ESI): m/z calcd for C 25h 32n 3oS (M+H) +, 422.2266, found, 422,2263..
compound 13j
Yellow solid, fusing point 113.1-114.1 DEG C, 1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H, imine olefinic – N=CH-), 8.73 (d, 1H, H of pyridine), 8.29 (d, 1H, H of pyridine), 7.81 (t, 1H, H of pyridine), 7.39 (t, 1H, H of pyridine), 5.39 (d, 1H, J=5.42 Hz, 6-H), 3.55 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 1.03 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.11, 169.60, 161.26, 153.78, 149.93, 141.41, 136.75, 132.27, 125.63, 122.74, 120.84, 71.56, 59.98, 50.71, 42.69, 42.28, 37.14, 36.86, 34.14, 31.62, 31.25, 30.57, 28.37, 20.51, 19.38, 17.13. HRMS (ESI): m/z calcd for C 26h 32n 3oS (M+H) +, 434.2266, found, 434.2262..
Compound 13k
Yellow solid, fusing point 234.9-235.9 DEG C, 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H, imine olefinic – N=CH-), 7.60 (s, 1H, H of thiophene), 7.59 (s, 1H, H of thiophene), 7.16 (s, 1H, H of thiophene), 5.41 (d, 1H, J=5.42 Hz, 6-H), 3.56 (m, 1H, 3 α-H), 1.11 (s, 3H, 18-Me), 1.02 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.89, 168.92, 153.40, 141.90, 141.36, 134.18, 132.18, 131.14, 128.17, 120.95, 71.64, 59.91, 50.72, 42.72, 42.30, 37.15, 36.87, 34.22, 31.63, 31.27, 30.57, 28.30, 20.55, 19.39, 17.12. HRMS (ESI): m/z calcd for C 25h 31n 2oS 2(M+H) +, 439.1878, found, 439.1869..
Compound 13l
Yellow solid, fusing point 187.2-188.2 DEG C, 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H, imine olefinic – N=CH-), 9.16 (d, 1H, H of naphthalene), 8.24 (d, 1H, H of naphthalene), 8.04 (d, 1H, H of naphthalene), 7.95 (d, 1H, H of naphthalene), 7.68 (t, 1H, H of naphthalene), 7.59 (t, 2H, H of naphthalene), 5.43 (d, 1H, J=5.42 Hz, 6-H), 3.58 (m, 1H, 3 α-H), 1.13 (s, 3H, 18-Me), 1.08 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 174.83, 169.17, 160.67, 141.36, 133.92, 133.12, 131.67, 131.47, 131.14, 130.45, 128.82, 127.85, 126.43, 125.32, 124.56, 120.98, 71.68, 59.98, 50.73, 42.81, 42.31, 37.15, 36.88, 34.28, 31.65, 31.29, 30.60, 28.35, 20.58, 19.40, 17.17. HRMS (ESI): m/z calcd for C 31h 35n 2oS (M+H) +, 483.2470, found, 483.2468..
Compound 13m
Yellow solid, fusing point 225.5-226.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H, imine olefinic – N=CH-), 7.97 (d, 1H,-Ph), 7.88 (d, 1H,-Ph), 7.71 (m, 2H,-Ph), 5.40 (d, 1H, J=5.42 Hz, 6-H), 3.56 (m, 1H, 3 α-H), 1.11 (s, 3H, 18-Me), 1.01 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 172.51, 168.88, 168.72, 150.00, 141.38, 136.71, 133.49, 132.26, 131.83, 130.69, 123.81, 122.57, 120.88, 71.64, 59.82, 50.68, 42.88, 42.26, 37.14, 36.86, 34.25, 31.62, 31.24, 30.54, 28.23, 20.52, 19.40, 17.18. HRMS (ESI): m/z calcd for C 28h 32n 3oS (M+H)+, 458.2261, found, 458.2264..
Compound 14a
White-yellowish solid, fusing point 101.1-102.1 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.38 (m, 5H ,-Ph), 5.57 (s, 1H ,-NH-), 5.40 (d, 1H, J=5.42 Hz, 6-H), 4.43 (s, 2H ,-CH 2-next to amino), 3.56 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 0.95 (s, 3H, 18-Me). 13C NMR (101 MHz, CDCl3) δ 173.06,165.90,141.28,137.70,128.71,127.70,127.61,121.13,118.35,71.70,59.83,50.77,49.84,42.56,42.31,37.14,36.86,34.28,31.65,31.30,30.46,27.79,20.58,19.37,16.70. HRMS (ESI): m/z calcd for C 27h 35n 2oS (M+H) +, 435.2470; Found, 435.2473..
Compound 14b
White solid, fusing point 95.1-96.1 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 1H, 5-H of furan), 6.35 (d, 1H, 3-H of furan), 6.31 (d d, 1H, 4-H of furan), 5.41 (d, 1H, J=5.42 Hz, 6-H), 5.36 (s, 1H ,-NH-), 4.44 (s, 2H ,-CH 2-next to amino), 3.56 (m, 1H, 3 α-H), 1.09 (s, 3H, 18-Me), 0.95 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 172.37,165.92,151.07,142.32,141.30,121.10,118.75,110.39,107.77,71.68,59.84,50.78,42.73,42.57,42.31,37.15,36.86,34.27,31.64,31.29,30.47,27.77,20.57,19.37,16.66. HRMS (ESI): m/z calcd for C 25h 33n 2o 2s (M+H) +, 424.2263; Found, 2267..
Compound 14c
White solid, fusing point 54.7-55.7 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H ,-Ph), 7.21 (d, 2H ,-Ph), 6.03 (s, 1H ,-NH-), 5.38 (d, 1H, J=5.42 Hz, 6-H), 4.38 (s, 2H ,-CH 2-next to amino), 3.533.29 (m, 1H, 3 α-H), 3.38 (t, 1H,-C (-Ph) H-), 1.25 (s, 3H,-CH3 of isopropyl), 1.24 (s, 3H,-CH3 of isopropyl), 1.07 (s, 3H, 18-Me), 0.93 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.46, 165.57, 148.31, 141.43, 135.06, 127.60, 126.70, 120.96, 117.89, 71.48, 59.82, 50.77, 49.57, 49.47, 42.56, 42.28, 37.17, 36.86, 34.28, 33.79, 31.59, 31.29, 30.45, 27.77, 24.00, 20.56, 19.36, 16.66. HRMS (ESI): m/z calcd for C 30h 41n 2oS (M+H) +, 477.2940, found, 477.2935..
Compound 14d
White solid, fusing point 99.5-100.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.32 (s, 4H ,-Ph), 6.05 (s, 1H ,-NH-), 5.40 (d, 1H, J=5.42 Hz, 6-H), 4.41 (s, 2H ,-CH 2-next to amino), 3.55 (m, 1H, 3 α-H), 1.08 (s, 3H, 18-Me), 0.93 (s, 3H, 18-Me). 13C NMR (101 MHz, CDCl3) δ 173.51,165.63,141.40,136.50,133.26,128.84,128.75,120.94,118.01,71.43,59.77,50.74,48.97,42.54,42.29,37.16,36.84,34.29,31.59,31.27,30.43,27.73,20.54,19.36,16.71.HRMS (ESI): m/z calcd for C 27h 34clN 2oS (M+H) +, 469.2080; Found, 469.2078..
Compound 14e
White solid, fusing point 68.1-69.1 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.25 (m, 1H, H of Ph), 6.94 (m, 2H, H of Ph), 6.83 (d d, 1H, H of Ph), 5.37 (d, 1H, J=5.42 Hz, 6-H), 4.37 (s, 2H ,-CH 2-next to amino), 3.78 (s, 3H,-CH3), 3.52 (m, 1H, 3 α-H), 1.06 (s, 3H, 18-Me), 0.92 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.69, 165.31, 159.86, 141.39, 139.36, 129.65, 120.97, 119.78, 117.90, 113.13, 112.98, 71.51, 59.80, 55.20, 50.76, 49.72, 42.56, 41.96, 37.16, 36.85, 34.24, 31.59, 30.44, 27.77, 27.00, 24.97, 19.35, 16.67. HRMS (ESI): m/z calcd for C 28h 37n 2o 2s (M+H) +, 465.2576, found, 465.2572..
Compound 14f
White solid, fusing point 124.9-125.9 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.30-7.45 (m, 5H, H of-Ph), 6.68 (m, 1H,-CH=CH-), 6.31 (d, 1H ,-CH=CH-), 5.42 (d, 1H, J=5.42 Hz, 6-H), 5.28 (s, 1H ,-NH-), 4.05 (s, 2H ,-CH 2-next to amino), 3.56 (m, 1H, 3 α-H), 1.10 (s, 3H, 18-Me), 0.96 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 171.92, 165.40, 141.66, 136.55, 130.67, 128.61, 127.43, 126.72, 126.15, 120.08, 116.15, 69.98, 59.09, 50.30, 46.23, 42.27, 41.98, 36.80, 36.41, 34.17, 31.44, 30.70, 30.02, 27.22, 20.15, 19.08, 16.61. HRMS (ESI): m/z calcd for C 29h 37n 2oS (M+H) +, 461.2627, found, 461.2628..
Compound 14g
White solid, fusing point 127.8-128.8 DEG C, 1H NMR (400 MHz, DMSO) δ 8.13 (d, 1H, H of naphthalene), 7.93 (t, 2H, H of naphthalene), 7.878.04 (d, 1H, H of naphthalene), 7.55 (m, 3H, H of naphthalene), 7.47 (s, 1H ,-NH-), 5.31 (d, 1H, J=5.42 Hz, 6-H), 4.87 (s, 2H ,-CH 2-next to amino), 4.64 (d, 1H, 3-OH), 3.29 (m, 1H, 3 α-H), 1.00 (s, 3H, 18-Me), 0.85 (s, 3H, 19-Me). 13C NMR (101 MHz, DMSO) δ 171.85, 165.31, 141.63, 134.35, 133.33, 131.07, 128.45, 127.65, 126.13, 125.75, 125.72, 125.35, 123.72, 120.08, 116.14, 70.00, 59.09, 50.30, 45.90, 42.29, 42.00, 39.52, 36.80, 36.40, 34.18, 31.45, 30.71, 30.02, 27.22, 20.16, 19.06, 16.59. HRMS (ESI): m/z calcd for C 31h 37n 2oS (M+H) +, 485.2627, found, 485.2622..
Compound 14h
White solid, fusing point 218.9-219.9 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.22 (t, 1H, H of Ph), 7.17 (d, 1H, H of Ph), 6.98 (d, 1H, H of Ph), 6.87 (t, 1H, H of Ph), 5.39 (d, 1H, J=5.42 Hz, 6-H), 4.51 (m, 2H ,-CH 2-next to amino), 3.56 (m, 1H, 3 α-H), 1.10 (s, 3H, 18-Me), 0.96 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 172.58, 164.37, 155.34, 141.67, 129.42, 128.28, 125.39, 120.08, 118.97, 116.24, 115.99, 69.99, 59.04, 50.27, 43.20, 42.28, 41.98, 36.79, 36.42, 34.08, 31.44, 30.69, 30.00, 27.30, 20.10, 19.08, 16.56. HRMS (ESI): m/z calcd for C 27h 35n 2o 2s (M+H) +, 451.2419, found, 451.2411..
Compound 14i
White solid, fusing point 113.7-114.7 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.19 (m, 3H ,-Ph), 5.39 (d, 1H, J=5.42 Hz, 6-H), 4.39 (d, 2H ,-CH 2-next to amino), 3.54 (m, 1H, 3 α-H), 1.08 (s, 3H, 18-Me), 0.92 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.03, 165.70, (151.59 d d), (149.12 d d), 141.30, 135.01, 123.34 (q), 121.05, 118.44, 117.46 (d), 116.52 (d), 71.63, 59.81, 50.74, 48.66, 42.56, 42.28, 37.14, 36.84, 34.25, 31.61, 31.27, 30.44, 27.75, 20.53, 19.35, 16.69. HRMS (ESI): m/z calcd for C 27h 33f 2n 2oS (M+H)+, 471.2282, found, 471.2276..
Compound 14j
White solid, fusing point 104.7-105.7 DEG C, 1H NMR (400 MHz, CDCl3) δ 6.57 (s, 2H ,-Ph), 5.33 (d, 1H, J=5.42 Hz, 6-H), 4.32 (d, 2H ,-CH 2-next to amino), 3.79 (s, 9H, H of – OCH3), 3.50 (m, 1H, 3 α-H), 1.04 (s, 3H, 18-Me), 0.90 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.60, 165.55, 153.34, 141.36, 137.17, 133.58, 120.94, 118.07, 104.38, 71.45, 60.82, 59.79, 56.04, 49.97, 42.55, 42.25, 37.15, 36.83, 34.27, 31.55, 31.25, 30.43, 27.76, 19.34, 16.69. HRMS (ESI): m/z calcd for C 30h 41n 2o 4s (M+H)+, 525.2787, found, 525.2784..
Compound 14k
White solid, fusing point 97.3-98.3 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.34 (m, 2H ,-Ph), 7.03 (m, 2H ,-Ph), 5.37 (d, 1H, J=5.42 Hz, 6-H), 4.38 (d, 2H ,-CH 2-next to amino), 3.54 (m, 1H, 3 α-H), 1.07 (s, 3H, 18-Me), 0.92 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 173.25,165.65,163.47,161.03,141.32,133.52,129.27,121.03,118.18,115.62,115.41,71.59,59.81,50.75,49.02,42.55,42.28,37.14,36.85,34.26,31.60,31.27,30.44,27.76,19.35,16.69. HRMS (ESI): m/z calcd for C 27h 34fN 2oS (M+H)+, 453.2376; Found, 453.2370..
Compound 14l
White solid, fusing point 74.4-75.4 DEG C, 1H NMR (400 MHz, DMSO) δ 7.18 (m, C27H34FN2OSH ,-Ph), 5.30 (d, 1H, J=5.42 Hz, 6-H), 4.31 (d, 2H ,-CH 2-next to amino), 3.45 (m, 1H, 3 α-H), 0.98 (s, 3H, 18-Me), 0.83 (s, 3H, 19-Me). 13C NMR (101 MHz, DMSO) δ 168.33, 161.02, 136.53, 135.22, 129.80, 125.19, 123.06, 122.89, 120.87, 116.33, 113.73, 66.90, 55.05, 45.99, 44.40, 37.81, 37.53, 32.39, 32.10, 29.52, 26.86, 26.52, 25.69, 24.96, 23.01, 15.80, 14.61. HRMS (ESI): m/z calcd for C 27h 34clN 2oS (M+H)+, 469.2080, found, 469.2079..
Compound 14m
White solid, fusing point 85.5-86.5 DEG C, 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H ,-Ph), 7.39 (s, 1H ,-Ph), 7.25 (m, 2H ,-Ph), 5.39 (d, 1H, J=5.42 Hz, 6-H), 4.53 (d, 2H ,-CH 2-next to amino), 3.55 (m, 1H, 3 α-H), 1.08 (s, 3H, 18-Me), 0.94 (s, 3H, 19-Me). 13C NMR (101 MHz, CDCl3) δ 172.99, 165.88, 141.31, 135.24, 133.54, 129.63, 129.40, 128.93, 126.96, 121.08, 118.32, 71.67, 59.81, 50.77, 47.52, 42.57, 42.30, 37.14, 36.86, 34.26, 31.63, 31.29, 30.46, 27.77, 20.56, 19.36, 16.68. HRMS (ESI): m/z calcd for C 27h 34clN 2oS (M+H)+, 469.2080, found, 469.2077..
Antitumor activity evaluation method:
In the present invention, antitumor activity evaluation method adopts mtt assay, and concrete operations are as follows: the human carcinoma cell line of phase growth of taking the logarithm, counts after refinement.3 × 10 3(190 μ L) is inoculated in 96 porocyte culture plates in individual/hole.24h adds the testing sample solution of 10 μ L different concns after cell attachment, testing sample is made to be respectively 1 μ L, 2 μ L, 5 μ L, 10 μ L, 20 μ L and 50 μ L often organizing the ultimate density in hole, often group has three parallel holes at least, and process cell is to the fixed time.Before measuring, every hole adds 20 μ LMTT solution (MTT sterile PBS buffer is made into the solution of 5mg/mL), 37 DEG C hatch 4h after, careful sucking-off supernatant liquor, every hole adds the DMSO of 200 μ L, concussion 15min, crystallisate is fully dissolved, evenly.570nm place absorbance is measured by microplate reader.The OD value of each test hole is deducted background OD value (perfect medium adds MTT, acellular), the OD value of each parallel hole is averaged.Cell survival rate %=(dosing cell OD value-background OD value)/(compared with control cells OD value-background OD value) × 100%.Each check point gets the mean value of three parallel holes, draws and suppresses curve, calculates IC 50value.
Compound 13a-lantitumour activity data (IC 50, μ g/mL)
Compound EC109 EC-9706
13a 63.109±1.800 54.398±1.736
13b 55.517±1.744 106.889±2.029
13c 60.221±1.780 61.075±1.786
13d 49.247±1.692 >128
13e 28.239±1.451 29.439±1.469
13f 36.735±1.565 29.647±1.472
13g 20.995±1.322 48.216±1.683
13h 29.052±1.463 46.839±1.671
13i 32.266±1.509 119.985±2.079
13j 52.026±1.716 38.289±1.583
13k 24.712±1.393 84.087±1.925
13l 16.326±1.213 18.477±1.267
13m 12.036±1.080 39.245±1.594
Compound 14a-lantitumour activity data (IC 50, μ g/mL)
Compound EC109 EC-9706
14a 7.526±0.884 16.287±1.200
14b 10.453±1.019 37.485±1.547
14c 11.938±1.077 24.336±1.386
14d 0.092±0.068 18.421±1.265
14e 8.359±0.922 35.497 ±1.550
14f 12.882±1.110 23.677±1.374
14g 7.341±0.866 82.843±1.918
14h 2.034±0.308 21.703±1.312
14i 3.247±0.389 15.880±1.194
14j 1.464±0.165 11.710±1.107
14k 2.609±0.416 17.564±1.243
14l 0.974±0.107 14.227±1.117
14m 0.679±0.084 10.227±1.007
As can be seen from table, this series compound 13a-lwith 14a-lall anti-tumor activity is demonstrated to 2 kinds of cancer cells of test, wherein 14a-lto the IC of test Ec109 50mostly be less than 10 μ g/mL.

Claims (6)

1. dehydroepiandros-sterone D ring thiazole ring imines class and imine reduction compounds, is characterized in that having following general structure:
Wherein R is the C2-3 alkyl that phenyl replaces, phenyl, the phenyl that hydroxyl replaces, the phenyl that C 1-3 alkyl replaces, the phenyl that first cyanogen replaces, the monosubstituted or polysubstituted phenyl by methoxyl group, the monosubstituted or polysubstituted phenyl by halogen atom, naphthyl, thienyl, pyrryl, pyridyl, furyl.
2. dehydroepiandros-sterone D ring as claimed in claim 1 thiazole ring imines class and imine reduction compounds, it is characterized in that, the C2-3 unsaturated alkyl that the preferred phenyl of R replaces, phenyl, the phenyl that hydroxyl replaces, aminomethyl phenyl, the phenyl that first cyanogen replaces, monosubstituted or the polysubstituted phenyl by methoxyl group, the monosubstituted or polysubstituted phenyl by halogen atom ,2-thienyl, 2-pyrryl, 2-pyridyl, 2-furyl or 2-naphthyl.
3. dehydroepiandros-sterone D ring according to claim 1 thiazole ring imines class and imine reduction compounds, is characterized in that preferably having one of compound of following structural formula:
。
4. prepare dehydroepiandros-sterone D ring according to claim 1 and the method for thiazole ring imine compound, it is characterized in that, realized by following steps:
(1) in organic solvent, by dehydroepiandros-sterone 5with bromizating agent reaction, obtain compound 11; Bromizating agent used is N-bromo-succinimide, CuBr, CuBr 2wherein a kind of;
(2) by compound 11be dissolved in organic solvent, add alkali and thiocarbamide reaction, obtain compound 12;
(3) by compound 12be dissolved in organic solvent, add alkali and aromatic aldehyde obtains general formula 13;
Alkali used be organic bases pyridine, triethylamine, DMAP, diisopropyl ethyl amine one of them or inorganic bases sodium carbonate, salt of wormwood, sodium bicarbonate, sodium hydroxide, potassium hydroxide one of them; Organic solvent used be acetone, n, n-dimethyl formamide, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane one of them or wherein any two or three mixture;
Selected aromatic aldehyde be following one of them: the C2-3 alkyl aldehyde that phenyl replaces, phenyl aldehyde, the phenyl aldehyde that hydroxyl replaces, the phenyl aldehyde that C 1-3 alkyl replaces, the phenyl aldehyde that first cyanogen replaces, the monosubstituted or polysubstituted phenyl aldehyde by methoxyl group, the monosubstituted or polysubstituted phenyl aldehyde by halogen atom, naphthaldehyde, thienyl formaldehyde, pyrryl formaldehyde, pyridyl carboxylaldehyde, furyl formaldehyde.
5. prepare dehydroepiandros-sterone D ring according to claim 1 and the synthetic method of thiazole ring imine reduction compounds, it is characterized in that, realized by following steps:
By general formula 13in single compound be dissolved in alcohol organic solvent, add reductive agent, reduction carbon-to-nitrogen double bon obtain general formula 14compound;
Alcoholic solvent used is propyl carbinol, the trimethyl carbinol, Virahol, methyl alcohol or ethanol; Reductive agent used is the mixing of lithium aluminum hydride, sodium borohydride, POTASSIUM BOROHYDRIDE a kind of or any two kinds.
6. according to the dehydroepiandros-sterone D ring of claim 1-3 described in one of them and thiazole ring imines class and the application of imine reduction compounds in medicine preparation, it is characterized in that, with it for active ingredient, use it in preparation mammary cancer, the esophageal carcinoma, cancer of the stomach, prostate cancer, uterus carcinoma, ovarian cancer, cervical cancer, colon and rectum carcinoma, thyroid carcinoma, lung cancer, liver cancer, carcinoma of testis, kidney, bladder cancer, carcinoma of small intestine, carcinoma of the pancreas or leukemia medicament.
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