CN104311621B - Steroidal beta-lactam compound, its preparation method and application thereof that D ring is modified - Google Patents

Steroidal beta-lactam compound, its preparation method and application thereof that D ring is modified Download PDF

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CN104311621B
CN104311621B CN201410662272.8A CN201410662272A CN104311621B CN 104311621 B CN104311621 B CN 104311621B CN 201410662272 A CN201410662272 A CN 201410662272A CN 104311621 B CN104311621 B CN 104311621B
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CN104311621A (en
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刘宏民
亓萍萍
余斌
石晓静
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Zhengzhou University
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    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/006—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton spiro-condensed

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Abstract

The invention belongs to pharmaceutical chemistry and medical technical field, disclose steroidal beta-lactam compound, its preparation method and application thereof<b>.</b>This compounds is suc as formula shown in I, and anti tumor activity in vitro experiment shows, this compounds has the antitumor activity of wide spectrum, and various human cancer cell is had to inhibitory action well as EC-109, MGC-803, GES-1 and U-87 etc.; Be applicable to the research of antitumor lead compound or prepare new type antineoplastic medicine. Its simple synthetic method, is applicable to suitability for industrialized production.

Description

Steroidal beta-lactam compound, its preparation method and application thereof that D ring is modified
Technical field
The present invention relates to steroidal beta-lactam noval chemical compound that a class has antitumor activity, synthetic method and anti-The application of tumour aspect, belongs to pharmaceutical chemistry field.
Background technology
According to World Health Organization's statistics, cancer is a global major causes of death, world wide internal cause cancerAnd dead number presents the situation increasing year by year, expect the year two thousand thirty, global cancer mortality number will increase by 45%. But due toIt is large that existing antineoplastic exists toxic and side effect, the shortcomings such as drug resistance, further investigation high-efficiency low-toxicity and with existing antineoplasticThing does not have the new type antineoplastic medicine of drug resistance to become extremely important and urgent problem.
Steroidal, as a class cyclopentanoperhy drophenanthrene compounds, is prevalent in animal vegetable tissue, its sustaining life,Adjusting sexual function, there is to clear and definite effect body development, immunological regulation, treating skin disease and birth control aspect. Along withThe development in organic chemistry and pharmaceutical chemistry field, the chemical constitution based on steroidal is modified the focus that has become Recent study, itsBiologically active scope be also no longer confined to traditional steroids pharmacology active as protein assimilation, anti-inflammatory, antagonism androgen, keep awayPregnant etc., show gradually the physiologically actives such as anticancer, antibacterial, as antineoplastic abiraterone (Abiraterone) is applied toThe clinical treatment (referring to J.Med.Chem.2003,46,2345-2351) of refractory prostate cancer.
Traditional beta-lactam compound generally uses as antibacterials, in the antibacterial infection for the treatment of, has important workWith. In recent years, the compound that contains this group is found to have antitumor activity, and the people such as DiChen find N-mercaptan-β-NeiAmides compound can inducing cancer cell DNA damage and apoptosis, and wherein, compound beta-lactam L-1 has significantly breast cancerInhibitory action (referring to CancerLett.2008,268,63-69).
Utilize active fragment to integrate principle, quaternary lactams construction unit is introduced to steroidal parent nucleus, the synthetic novel steroid of a classBody beta-lactam compound, and its BA is carried out to preliminary assessment, have no at present bibliographical information.
Summary of the invention
Based on above-mentioned, one of the object of the invention is to provide the steroidal beta-lactam with antitumor activity that a class is newCompound; Two of object is to provide a kind of preparation method who simply efficiently has no this compounds of bibliographical information; Three of object isProvide this compounds in the application of preparing aspect antineoplastic.
Steroidal beta-lactam compound of the present invention has following general structure:
Wherein, R is phenyl, by the mono-substituted phenyl of nitro, by the mono-substituted phenyl of methylsulfonyl, by halogen atom monosubstituted orPolysubstituted phenyl.
The preferred phenyl of R, by the mono-substituted phenyl of nitro, by the mono-substituted phenyl of methylsulfonyl, monosubstituted by fluorine or chlorine or bromineOr polysubstituted phenyl.
Its synthetic method: under alkali condition, utilize the Isosorbide-5-Nitrae-azepine that carries out that diene amide group on steroidal D ring selectsMichael reaction generates beta-lactam nucleus, and it is further by airborne O2Oxidation, at the upper introducing hydroxyl base of beta-lactam nucleusGroup. Comprise the following steps:
Compound 4 is dissolved in organic solvent, adds organic base or inorganic base compound, under ice bath, reaction obtains targetThing.
In compound 4, R is the same; Inorganic base used is: Li2CO3、LiBr、CaCO3、Na2CO3、NaHCO3、K2CO3、KHCO3、NaOAC、NaOH、NaH、Al2O3、KOH、Na3PO4Or KF/Al2O3One of them; Organic base is sodium methoxide, sodium methoxidePotassium, caustic alcohol, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, piperidines, morpholine, pyridine, triethylamine, methylamine, diethylamine, 1,8-phenodiazineAssorted two ring [5.4.0] 11 carbon-7-alkene, DMAP, imidazoles, lithium diisopropyl amido or n-BuLi wherein itOne; Organic solvent used be carrene, acetone, toluene, oxolane, methyl alcohol, ethanol, dioxane one of them.
Compou nd synthesis method provided by the invention is easy, and yield is high, reaches more than 67.5%, is applicable to suitability for industrialized production, livesProperty evaluation show that such compound presses down as EC-109, MGC-803, GES-1 and U-87 etc. have well various human cancer cellMake and use. Using it as active ingredient as a class antitumor compounds, can be used for the system of the cancer drug such as breast cancer, the cancer of the esophagusStandby.
Detailed description of the invention
By following embodiment, the present invention is further illustrated, but not as restriction.
Embodiment 1
1, synthesizing of 3 β-acetoxyl group dehydroepiandros-sterone (2)
Dehydroepiandros-sterone (4mmol) dissolves in 50mL carrene, adds acetic anhydride (4.4mmol), triethylamine(8.0mmol) with the rear room temperature reaction 5h of DMAP (0.02mmol), question response completely rear water, saturated common salt water washing respectively 2 times,After organic layer anhydrous sodium sulfate drying, evaporate to dryness obtains white solid 2 with quantitative yield and without purifying. Mp169.4-170.6℃.1HNMR(400MHz,CDCl3):δ5.43(d,J＝5.1Hz,1H,H-6),4.63(m,1H,3α-H),2.06(s,3H,-OCOCH3),1.07(s,3H,H-18),0.91(s,3H,H-19).HRMS(ESI):m/zcalcdforC21H30NaO3(M+Na)+,353.2093；found,353.2094.
2, synthesizing of 3 β-acetoxyl group steroidal-17-thiazolinyl malononitrile (3)
Compound 2 (3.0mmol), ammonium acetate (0.5g) and malononitrile (4.5mmol) dissolve in back flow reaction in 10mL ethanol3h, reaction system is cooled to that adularescent solid after room temperature is separated out, suction filtration, and solid can obtain compound 32 times with ethanol washing,Productive rate is 95%, mp187.9-188.9 DEG C.1HNMR(400MHz,CDCl3):δ5.38(d,J＝5.1Hz,1H,6-H),4.74–4.45(m,1H,3α-H),3.04–2.86(m,1H,16α-H),2.74(m,1H,16β-H),2.04(s,3H,-OCOCH3),1.05(s,6H,H-18andH-19).13CNMR(100MHz,CDCl3):δ196.08,170.50,139.93,121.58,112.26,111.16,79.73,73.58,55.22,49.34,48.91,37.99,36.83,36.56,34.73,33.61,31.39,31.37,27.63,23.56,21.40,20.78,19.27,16.24.HRMS(ESI):m/zcalcdforC24H30N2NaO2(M+Na)+,401.2205；found,401.2229.
3, the synthetic logical method of steroidal diene amide (4)
Compound 3 (1.0mmol) dissolves in 10mL ethanol with aldehyde (1.0mmol), and adds NaOAc (2.0mmol) heatingBack flow reaction 3-7h, removes by filter sodium acetate after question response is complete, and filter residue washs with DCM, after organic phase drying under reduced pressure, adds DCMDissolve, water and saturated common salt water washing respectively, organic phase dried over sodium sulfate, evaporated under reduced pressure, note chromatography (benzinum/Ethyl acetate=2/1) obtain steroidal diene amide 4, productive rate is between 50%-90%.
4, the synthetic logical method of steroidal beta-lactam compound (5)
Compound 4 (0.4mmol) is dissolved in 10ml oxolane, and adds NaH or sodium methoxide (1.2mmol) in ice bathReaction 0.5-2h, after question response is complete, adds ethyl acetate diluting reaction system, and water, saturated common salt water washing 3 respectivelyInferior, organic phase anhydrous sodium sulfate drying, evaporated under reduced pressure, column chromatography for separation (petrol ether/ethyl acetate=2/1) obtain steroidal β-Lactam analog compound 5a-j, productive rate is between 20-70%.
Serial steroidal beta-lactam compound 5a--j has been synthesized in this enforcement, as following table:
In table 1, the characterization data of compound is as follows:
5a: white solid, productive rate 23.0%, fusing point 162.1-163.5 DEG C,1HNMR(400MHz,DMSO-d6)δ8.44(s,1H),8.23(s,1H),7.44–7.29(m,2H),7.23(t,J＝8.6Hz,2H),6.62(s,1H),5.36(s,1H),4.45(d,J＝7.9Hz,1H),1.99(s,3H),1.19(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.21,163.19,162.82,160.74,140.03,136.11,132.85,131.49,131.40,128.11,122.13,116.98,116.08,115.87,79.33,73.60,55.41,52.73,49.24,42.24,38.09,36.77,36.64,32.36,31.85,31.10,27.78,21.52,20.18,19.40,14.90.
5b: white solid, productive rate 51.0%, fusing point 200.2-201.9 DEG C,1HNMR(400MHz,DMSO-d6)δ8.49(s,1H),8.25(s,1H),7.49(dd,J＝12.5,4.6Hz,2H),7.44–7.30(m,2H),6.85(s,1H),5.33(d,J＝3.5Hz,1H),4.55–4.36(m,1H),1.99(s,3H),1.21(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.20,162.58,139.99,138.90,134.26,133.40,130.62,130.13,129.88,127.62,125.76,122.12,116.92,78.96,73.58,55.41,52.60,49.19,42.39,38.08,36.76,36.63,32.29,31.88,31.10,31.00,27.78,21.52,20.17,19.40,14.87.
5c: white solid, productive rate 67.5%, fusing point 195.1-196.4 DEG C,1HNMR(400MHz,DMSO-d6)δ8.42(s,1H),8.24(s,1H),7.65(d,J＝8.4Hz,1H),7.50(d,J＝1.8Hz,1H),7.30(dd,J＝8.4,1.8Hz,1H),6.59(s,1H),5.35(d,J＝3.8Hz,1H),4.53–4.36(m,1H),1.99(s,3H),1.19(s,3H),1.02(s,3H).13CNMR(100MHz,DMSO-d6)δ170.19,162.62,140.02,139.21,136.97,131.77,131.20,130.89,130.84,129.33,126.84,122.07,116.83,79.09,73.58,55.41,52.73,50.48,49.22,39.37,38.09,36.76,36.64,32.36,31.82,31.19,31.07,30.27,27.77,26.89,22.93,21.52,20.15,19.40,14.87.
5d: white solid, productive rate 45.5%, fusing point 186.5-188.2 DEG C,1HNMR(400MHz,DMSO-d6)δ8.44(s,1H),8.24(s,1H),7.59(d,J＝8.4Hz,2H),7.25(d,J＝8.4Hz,2H),6.59(s,1H),5.35(d,J＝3.6Hz,1H),4.56–4.32(m,1H),1.99(s,3H),1.19(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.21,162.76,140.03,137.49,135.49,131.98,131.34,128.08,122.11,121.60,116.92,79.26,73.60,55.40,52.72,49.23,42.22,38.09,36.77,36.64,32.47,31.85,31.09,27.78,21.53,20.17,19.40,14.89.
5e: faint yellow solid, productive rate 27.5%, fusing point 194.3-195.9 DEG C,1HNMR(400MHz,DMSO-d6)δ8.50(s,1H),8.29(s,1H),8.24(d,J＝8.3Hz,2H),7.57(d,J＝8.3Hz,2H),6.73(s,1H),5.35(s,1H),4.44(d,J＝7.4Hz,1H),1.99(s,3H),1.22(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.19,162.53,146.84,142.78,141.49,140.04,130.40,127.35,124.22,122.05,116.77,79.02,73.57,55.47,52.79,49.22,42.13,38.08,36.77,36.64,32.70,31.86,31.09,31.03,30.27,27.77,21.51,20.14,19.39,14.90.
5f: white solid, productive rate 47.3%, fusing point 179.3-180.9 DEG C,1HNMR(400MHz,DMSO-d6)δ8.48(s,1H),8.27(s,1H),7.94(d,J＝8.3Hz,2H),7.55(d,J＝8.3Hz,2H),6.71(s,1H),5.35(d,J＝3.2Hz,1H),4.54–4.34(m,1H),3.23(s,3H),1.99(s,3H),1.22(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.20,162.58,141.16,140.38,140.13,140.03,130.01,127.71,122.08,116.83,79.07,73.59,55.47,52.82,49.23,43.97,42.16,38.09,36.77,36.65,32.62,31.88,31.08,27.77,21.51,20.16,19.40,14.92.
5g: white solid, productive rate 33.0%, fusing point 172.5-174.4 DEG C,1HNMR(400MHz,DMSO-d6)δ8.45(s,1H),8.24(s,1H),7.40(t,J＝7.4Hz,2H),7.31(t,J＝8.2Hz,3H),6.65(s,1H),5.35(d,J＝3.2Hz,1H),4.55–4.35(m,1H),1.99(s,3H),1.20(s,3H),1.03(s,3H).13CNMR(100MHz,DMSO-d6)δ170.20,162.85,140.02,136.31,136.24,129.36,129.29,129.01,128.41,122.14,117.01,79.37,73.60,55.43,52.76,49.24,42.23,38.10,36.77,36.64,32.49,31.87,31.10,27.78,21.52,19.40,14.92.
5h: faint yellow solid, productive rate 52.5%, fusing point 179.8-181.3 DEG C,1HNMR(400MHz,DMSO-d6)δ8.42(s,1H),8.24(s,1H),7.65(d,J＝8.4Hz,1H),7.50(d,J＝1.8Hz,1H),7.30(dd,J＝8.4,1.8Hz,1H),6.59(s,1H),5.35(d,J＝3.8Hz,1H),4.54–4.35(m,1H),1.99(s,3H),1.19(s,3H),1.02(s,3H).13CNMR(100MHz,DMSO-d6)δ170.19,162.62,140.02,139.21,136.97,131.77,131.20,130.89,130.84,129.33,126.84,122.07,116.83,79.09,73.58,55.41,52.73,50.48,49.22,39.37,38.09,36.76,36.64,32.36,31.82,31.19,31.07,30.27,27.77,26.89,22.93,21.52,20.15,19.40,14.87.
5i: white solid, productive rate 40.5%, fusing point 162.5-164.4 DEG C,1HNMR(400MHz,DMSO-d6)δ8.39(s,1H),8.23(s,1H),8.10(dd,J＝8.1,1.3Hz,1H),7.99(s,1H),7.73(d,J＝7.8Hz,1H),7.65(t,J＝7.9Hz,1H),6.69(s,1H),5.28(d,J＝3.4Hz,1H),4.50–4.26(m,1H),1.93(s,3H),1.17(s,3H),0.94(s,3H).13CNMR(100MHz,DMSO-d6)δ170.16,162.63,148.36,140.05,139.87,137.81,135.37,130.64,127.17,123.57,122.95,121.99,116.79,79.05,73.56,55.45,52.80,49.24,42.21,38.08,36.76,36.64,32.41,31.85,31.07,27.76,21.47,20.15,19.37,14.87.
5j: white solid, productive rate 21.5%, fusing point 173.8-175.1 DEG C,1HNMR(400MHz,DMSO-d6)δ8.45(s,1H),8.25(s,1H),7.45(d,J＝8.5Hz,2H),7.31(d,J＝8.5Hz,2H),6.61(s,1H),5.35(d,J＝4.0Hz,1H),4.57–4.33(m,1H),1.99(s,3H),1.18(s,3H),1.02(s,3H).13CNMR(100MHz,DMSO-d6)δ170.24,162.78,140.03,137.36,135.14,132.93,131.07,129.06,128.00,122.11,116.92,99.99,79.26,73.60,55.40,52.72,49.23,42.21,38.08,36.76,36.63,32.45,31.85,31.09,27.77,21.52,20.16,19.39,14.89.
Antitumor activity evaluation method:
In the present invention, antitumor activity evaluation method adopts mtt assay, and concrete operations are as follows: people's cancer of the phase growth of taking the logarithm is thinBorn of the same parents system, counts after refinement. 3 × 103(190 μ L) is inoculated in 96 porocyte culture plates in individual/hole. 24h adds after cell attachmentThe testing sample solution of 10 μ L variable concentrations, makes the ultimate density of testing sample in every group of hole be respectively 1 μ L, 2 μ L, 5 μ L, 10μ L, 20 μ L and 50 μ L, every group has three parallel holes at least, processes cell to the fixed time. Before measuring, every hole adds 20 μ LMTT moltenLiquid (MTT is made into the solution of 5mg/mL with aseptic PBS buffer solution), hatches after 4h for 37 DEG C, careful sucking-off supernatant, and every hole addsThe DMSO of 200 μ L, concussion 15min, fully dissolves, evenly crystal. With ELIASA mensuration 570nm place absorbance. Will be eachThe OD value of instrument connection deducts background OD value (complete medium adds MTT, acellular), and the OD value of each parallel hole is averaged. CellSurvival rate %=(dosing cell OD value-background OD value)/(control cells OD value-background OD value) × 100%. Each test point is gotThe mean value of three parallel holes, draws and suppresses curve, calculates IC50Value.
Anti tumor activity in vitro data (the IC of compound 5a-j50,μM)
Compound GES-1 MGC-803 EC-109 U-87
5a 5.275±0.722 0.460±0.030 5.563±1.097 8.669±0.824
5b 11.338±1.055 5.999±0.778 6.041±0.781 24.302±1.386
5c 7.632±0.883 1.653±0.218 9.411±0.974 3.542±0.549
5d 2.227±0.348 3.579±0.554 6.352±0.803 4.922±0.692
5e 134.58±2.129 7.300±0.863 25.868±1.413 609.172±2.785 6 -->
5f 51.931±1.715 10.478±1.020 29.324±1.467 3.432±0.536
5g 5.805±0.764 3.592±0.555 9.411±0.974 5.321±0.726
5h 3.17±0.507 3.024±0.481 16.971±1.230 14.975±1.175
5i 27.99±1.447 4.676±0.670 47.079±1.673 1.626±0.211
5j 5.655±0.752 1.395±0.144 6.901±0.839 4.988±0.698
Can be found out by table, in this series compound 5a-j, most 4 kinds of cancer cells to test demonstrate goodAntitumor activity, the IC of the cancerous cell line of most these compounds to test50All be less than 10 μ M.

Claims (5)

1. steroidal beta-lactam compound, is characterized in that, has following general structure:
Wherein, R is phenyl, by the mono-substituted phenyl of nitro, by the mono-substituted phenyl of methylsulfonyl, monosubstituted or get by halogen atom moreThe phenyl in generation.
2. steroidal beta-lactam compound according to claim 1, is characterized in that, R selects phenyl, monosubstituted by nitroPhenyl, by the mono-substituted phenyl of methylsulfonyl, by fluorine or chlorine or bromine is monosubstituted or polysubstituted phenyl.
3. steroidal beta-lactam compound according to claim 2, is characterized in that, preferably has following structural formulaOne of compound
4. the method for the steroidal beta-lactam compound described in preparation claim 1, is characterized in that, comprises following stepRapid:
R is phenyl, by the mono-substituted phenyl of nitro, by the mono-substituted phenyl of methylsulfonyl, monosubstituted or polysubstituted by halogen atomPhenyl;
Compound 4 is dissolved in organic solvent, adds organic base or inorganic base compound, under ice bath, reaction obtains object;
Inorganic base used selects Li2CO3、LiBr、CaCO3、Na2CO3、NaHCO3、K2CO3、KHCO3、NaOAC、NaOH、NaH、Al2O3、KOH、Na3PO4Or KF/Al2O3One of them; Organic base selects sodium methoxide, caustic alcohol, potassium ethoxide, potassium tert-butoxide, the tert-butyl alcoholSodium, piperidines, morpholine, pyridine, triethylamine, methylamine, diethylamine, 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene, 4-diformazanAminopyridine, imidazoles, lithium diisopropyl amido or n-BuLi one of them; Organic solvent used select carrene, acetone,Toluene, oxolane, methyl alcohol, ethanol, dioxane one of them.
According to claim 1-3 the steroidal beta-lactam compound described in one of them in the application of preparing in medicine, itsBe characterised in that, as active ingredient, use it for preparation breast cancer, the cancer of the esophagus, cancer of the stomach, prostate cancer, the cancer of the uterus, oophoroma,Cervix cancer, colon and rectum carcinoma, lung cancer, liver cancer, thyroid cancer, carcinoma of testis, kidney, carcinoma of urinary bladder, carcinoma of small intestine, cancer of pancreas orIn leukemia medicament.
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