CN104530021A - Compounds and preparation method thereof, application of compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds - Google Patents

Compounds and preparation method thereof, application of compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds Download PDF

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CN104530021A
CN104530021A CN201510059392.3A CN201510059392A CN104530021A CN 104530021 A CN104530021 A CN 104530021A CN 201510059392 A CN201510059392 A CN 201510059392A CN 104530021 A CN104530021 A CN 104530021A
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formula
structure
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reaction
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CN201510059392.3A
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朱海亮
严晓强
俞海荣
钟飞
杨永安
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江苏耐雀生物工程技术有限公司
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J71/00Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005Oxygen-containing hetero ring
    • C07J71/001Oxiranes

Abstract

The invention discloses compounds disclosed as Formula VIII and a preparation method thereof, application of the compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds. In the Formula VIII, R1 is selected from H, CH3 and CF3, R2 is selected from H, CH3 and Br, and n is 1 or 2. Compared with the prior art, the compounds have the advantages of high bioactivity, high selectivity and lower toxicity, and have obvious inhibiting actions on human mammary cancer cells, cervical carcinoma cells, lung cancer cells and liver cancer cells.

Description

Compound, its preparation method, its antitumor drug in the application prepared in antitumor drug and preparation thereof

Technical field

The present invention relates to field of pharmaceutical chemistry technology, especially a kind of compound, its preparation method, its antitumor drug in the application prepared in antitumor drug and preparation thereof.

Background technology

C 21steroidal saponin is through the steroidal saponin constituents that extraction separation and purification obtains from Chinese medicine Caulis Marsdeniae Tenacissimae, and its aglycon is by unique steroidal saponin structure of 21 C atomic buildings, is therefore called C 21steroidal saponin.There is C 21the pharmacologically active such as the compound of steroidal saponin parent nucleus has immunomodulatory, relieving asthma, has obtained clinically as the index activeconstituents of medicine clinically and has applied more widely.

Applicant is through repeatedly studying discovery: C 21steroidal saponin may have good anti-tumor activity.Current to this type of C 21the research contents of steroidal saponin mainly contains: carry out separation and purification and analyzing and testing research according to its physico-chemical property to it, carry out structural modification research for its parent nucleus, carry out pharmacology activity research etc. for its constitutional features.

But also there is biological activity and the shortcoming such as selectivity is lower, toxicity is higher in existing product.

Summary of the invention

Goal of the invention a: object is to provide a kind of compound, at least to solve the subproblem that prior art exists.Further object is to provide a kind of preparation method of compound.Further object is to provide the application of a kind of compound in antitumor drug, and provides a kind of antitumor drug.

Technical scheme: a kind of compound with structure shown in formula VIII,

Wherein, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2.

Structure such as formula a preparation method for compound shown in VIII,

Wherein, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2;

Comprise the steps:

Step 1: structure is dissolved in dry DMF such as formula the compound shown in I, adds glycol dibromide or methylene bromide, Anhydrous potassium carbonate successively, and obtained structure is such as formula the compound shown in II;

Step 2: by the converting compounds of structure as shown in formula III for structure is such as formula the compound shown in V;

Step 3: add structure successively such as formula the compound shown in V, the KOH aqueous solution, structure such as formula the compound shown in II and ethanol in reaction vessel, obtained structure is such as formula the compound shown in VI;

Step 4: be the compound shown in formula VII such as formula the converting compounds shown in VI by structure;

Step 5: structure is added in reaction vessel successively such as formula the compound shown in VII, methylene dichloride and boron tribromide, reaction obtains structure such as formula the compound shown in VIII;

Wherein, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2.

Preferably, described step 1 is further:

Structure is dissolved in dry DMF such as formula the compound shown in I, add 1 successively, 2-ethylene dibromide or methylene bromide, Anhydrous potassium carbonate, at 80 ± 10 DEG C of reacting by heating 30 ± 5min, then reaction mixture is added in frozen water, use distilled water wash solid after filtering, then carry out column chromatography, obtained structure is such as formula the compound shown in II.

Preferred, in step 1, the mol ratio of each reactant is for structure is such as formula the compound shown in I: glycol dibromide (or methylene bromide): Anhydrous potassium carbonate=1:2 ~ 3:4 ~ 6, and further preferably, ratio is 1:2.5:5 or 1:3:4.

Preferably, described step 2 is further:

In room temperature (herein, room temperature refers to 15 DEG C ~ 25 DEG C) stir under, in round-bottomed flask, add the compound of structure as shown in formula III, dilute hydrochloric acid and dehydrated alcohol successively, stir after 2 ~ 3h, reaction flask is transferred in the oil bath pan of 78 ~ 80 DEG C, back flow reaction 7 ~ 9h; TLC follows the tracks of reaction, and reaction terminates rear filtration; The solid obtained uses dilute hydrochloric acid, distilled water, cold ethanol, distilled water wash, drying successively, and the solid crude product obtained is dissolved in dehydrated alcohol, and recrystallization obtains the structure of the lenticular of partial reduction such as formula the compound shown in IV.

Preferred, in step 2, the compound 10mmol of structure as shown in formula III is dissolved in the hydrochloric acid 5ml that dehydrated alcohol 50ml. drips 1mol/L.

Under ice-water bath stirring action, diazomethane ether mixed solution, boron trifluoride-ether complex, structure is added successively such as formula the compound shown in IV in round-bottomed flask, after reaction 20 ~ 40min, back flow reaction 5 ~ 7h again, TLC follows the tracks of reaction, reaction terminates rear filtration, and the solid obtained uses dilute hydrochloric acid, distilled water, cold ethanol, distilled water wash, drying successively, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains the structure of lenticular such as formula the compound shown in V.

Preferred, each reactant molar ratio in above-mentioned steps: structure is such as formula the compound shown in IV: diazomethane: boron tribromide=1:1.2 ~ 1.5:1.5 ~ 2.0.Preferred further, ratio is 1:1.3:1.8,1:1.5:1.5.

Under stirring at room temperature, compound that structural formula is V, the KOH aqueous solution, structure is added successively such as formula the compound shown in II, ethanol in round-bottomed flask, after continuing stirring reaction 3 ~ 6h, dilute hydrochloric acid acidifying regulates pH, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, dry, obtains structure such as formula the compound shown in VI.

Preferred: the compound that each reactant molar ratio is V for structural formula in above-mentioned steps: structure is such as formula the compound shown in II: boron tribromide=1:1:1 ~ 1.5.Preferred further, 1:1:1.3.

Preferably, described step 4 further for: successively by structure such as formula the compound shown in VI, dehydrated alcohol, join in round-bottomed flask to Hydrazinobenzenesulfonamide, acetic acid, after stirring at room temperature reaction 20 ~ 40min, still have fraction solids insoluble; Back flow reaction 5 ~ 8h, TLC follow the tracks of reaction, after reaction terminates, filter, solid uses dilute hydrochloric acid, distilled water, cold ethanol, distilled water wash successively, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains the structure of lenticular such as formula the compound shown in VII.

Preferred: in above-mentioned steps each reactant mol ratio for: structure is such as formula the compound shown in VI: to Hydrazinobenzenesulfonamide: acetic acid=1:1.2 ~ 1.5:0.5.Preferred further, ratio is 1:1.2:1.5,1:1.5:0.5.

Preferably, described step 5 is further:

Under stirring at-20 ± 5 DEG C, in round-bottomed flask, add structure successively such as formula the compound shown in VII, methylene dichloride, and progressively drip boron tribromide, continue stirring reaction 20 ~ 40min, room temperature continues reaction 10 ~ 14h, and TLC follows the tracks of reaction, after reaction terminates, filter, solid distilled water wash, last vacuum-drying, is dissolved in dehydrated alcohol by the solid obtained, recrystallization is purified, and obtains the structure of lenticular such as formula the compound shown in VIII.

Preferred: in above-mentioned steps each reactant mol ratio for: structure is such as formula the compound shown in VII: boron tribromide=1:0.5.

Present method is transformed for saponin(e aglycon, has effectively integrated sulfonamide backbones, benzodioxan skeleton, pyrazoline skeleton, assay reproducibility is strong, good stability, and the required condition of experiment reaction is simpler, and experimental situation is gentle, productive rate is better, can produce in a large number in less input situation.

The compound with structure shown in formula VIII is preparing the application in antitumor drug,

Wherein, R 1, be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2;

Described antitumor drug comprises the medicine being used for the treatment of human breast cancer cell, cervical cancer cell, lung carcinoma cell and liver cancer cell.

A kind of antitumor drug, comprises structure such as formula the compound shown in VIII and medically acceptable auxiliary material.

Beneficial effect: compared with prior art, biological activity of the present invention and selectivity is high, toxicity is lower, has obvious restraining effect to human breast cancer cell, cervical cancer cell, lung carcinoma cell and liver cancer cell.

Embodiment

One class is containing the pyrazoline sulfanilamide (SN) C of benzodioxan skeleton 21the synthesis of steroidal saponin aglycone derivative, the structural formula of related raw material, intermediate product and target product is as follows:

In certain preferred embodiment, its preparation method is specially:

3, the 4-Dihydroxy benzaldehyde 1-6 containing different substituents are dissolved in dry DMF by step 1., then add glycol dibromide or methylene bromide, Anhydrous potassium carbonate successively, 70 DEG C of about reacting by heating 30min.Then be added in frozen water by reaction mixture, filter, solid distilled water (3 × 200mL) washing, (elutriant is V to column chromatography ethyl acetate: V sherwood oil=1:8), obtain compound 7-18.

Step 2. under stirring at room temperature, adds Tenacissoside A (a kind of C successively in round-bottomed flask 21steroidal saponin) 19, dilute hydrochloric acid, dehydrated alcohol, stir after 1h, reaction flask transferred in oil bath pan, back flow reaction 7-9h.TLC follows the tracks of reaction (developping agent V acOEt: V pE=1:2), after reaction terminates, filter, the solid obtained uses dilute hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, drying, is dissolved in the lenticular C that dehydrated alcohol recrystallization obtains partial reduction by the solid crude product obtained 21steroidal saponin aglycon 20.

Step 3., under ice-water bath stirring action, adds diazomethane ether mixed solution, boron trifluoride-ether complex, C successively in round-bottomed flask 21steroidal saponin aglycon 20, reaction about 0.5h, then back flow reaction 5-7h.TLC follows the tracks of reaction (developping agent V acOEt: V pE=1:2), after reaction terminates, filter, obtaining solid uses dilute hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization by the solid crude product obtained and obtains lenticular intermediate 21.

Step 4. under stirring at room temperature, intermediate 21, the KOH aqueous solution, corresponding compound 7-18, ethanol is added successively in round-bottomed flask, after continuing stirring reaction 4h, pH is regulated with dilute hydrochloric acid acidifying, filter, the solid obtained uses distilled water (3 × 100mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 22-33.

Step 5., successively by the compound 22-33 of correspondence, dehydrated alcohol, join in round-bottomed flask to Hydrazinobenzenesulfonamide, acetic acid, after stirring at room temperature reaction 1h, still has fraction solids insoluble; Back flow reaction 5h, TLC follow the tracks of reaction (developping agent V acOEt: V pE=1:2), after reaction terminates, filter, solid uses dilute hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains lenticular intermediate 34-45 by the solid crude product obtained.

Step 6. adds corresponding intermediate 8-11, methylene dichloride successively, and progressively drips boron tribromide under stirring at-20 ± 5 DEG C in round-bottomed flask, and after continuing stirring reaction about 1h, room temperature continues reaction about 12h.TLC follows the tracks of reaction (developping agent V acOEt: V normal hexane=1:2), after reaction terminates, filter, solid distilled water wash, last vacuum-drying, is dissolved in dehydrated alcohol by the solid obtained, and recrystallization is purified, and obtains lenticular target compound 46-57.

Embodiment one:

4-(5-(1,3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 46)

Under stirring at-20 DEG C, corresponding intermediate 34 (10.0mmol), methylene dichloride (25mL) that step 5 obtains is added successively in the round-bottomed flask of 50mL, and progressively drip after boron tribromide (5mmol) continues stirring reaction 1h, reaction flask is transferred to room temperature, continues reaction 12h.TLC follows the tracks of reaction (developping agent V acOEt: V normal hexane=1:2), after reaction terminates, filter, solid distilled water wash, last vacuum-drying, the solid obtained is dissolved in the purification of dehydrated alcohol recrystallization and obtains lenticular target compound.

Obtain white crystal, productive rate 54.3%.m.p.234~236℃; 1H NMR(DMSO-d 6,300MHz)δ:8.01(d,J=7.7Hz,2H,ArH),7.74(d,J=7.5Hz,2H,ArH),6.89(s,2H,NH 2),5.90(d,J=4.7Hz,1H,ArH),5.80~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.8Hz,J 2=11.4Hz,1H,CH 2),5.37(s,2H,OH),4.49(s,1H,OH),4.15(d,J=10.3Hz,1H,CH),3.58~3.29(m,5H,CH and CH 2),2.24~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.83~1.11(m,16H,CHand CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:668.8[M+H] +.Anal.Calcd forC 35H 45N 3O 8S:C,H,N.

Embodiment two:

4-(5-(4-methyl isophthalic acid, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 47)

Preparation method's reference example one.Obtain white crystal, productive rate 46.2%.m.p.219~220℃; 1H NMR(DMSO-d 6,300MHz)δ:8.00(d,J=7.5Hz,2H,ArH),7.76(d,J=7.5Hz,2H,ArH),6.89(s,2H,NH 2),5.91(d,J=4.7Hz,1H,ArH),5.82~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.3Hz,J 2=11.1Hz,1H,CH 2),5.39(s,2H,OH),4.48(s,1H,OH),4.15(d,J=10.1Hz,1H,CH),3.54~3.29(m,5H,CH and CH 2),2.24~2.15(m,2H,CH 2),2.01(t,J=4.5Hz,1H,CH),1.80~1.10(m,18H,CH and CH 2),0.88(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:682.9[M+H] +.Anal.Calcd for C 36H 47N 3O 8S:C,H,N.

Embodiment three:

4-(5-(4,7-dimethyl-1,3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 48)

Preparation method's reference example one.Obtain white crystal, productive rate 48.2%.m.p.199~200℃; 1H NMR(DMSO-d 6,300MHz)δ:8.04(d,J=7.2Hz,2H,ArH),7.75(d,J=7.1Hz,2H,ArH),6.88(s,2H,NH 2),5.92(d,J=4.7Hz,1H,ArH),5.80~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.2Hz,J 2=11.4Hz,1H,CH 2),5.37(s,2H,OH),4.49(s,1H,OH),4.12(d,J=9.5Hz,1H,CH),3.53~3.29(m,5H,CH and CH 2),2.28~2.16(m,2H,CH 2),2.01(t,J=4.2Hz,1H,CH),1.81~1.05(m,20H,CH and CH 2),0.89(s,3H,CH 3),0.85(s,3H,CH 3).ESI-MS:696.9[M+H] +.Anal.Calcd for C 37H 49N 3O 8S:C,H,N.

Embodiment four:

4-(5-(the bromo-4-methyl isophthalic acid of 7-, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 49)

Preparation method's reference example one.Obtain white crystal, productive rate 48.7%.m.p.196~198℃; 1H NMR(DMSO-d 6,300MHz)δ:7.93(d,J=7.2Hz,2H,ArH),7.78(d,J=7.8Hz,2H,ArH),6.89(s,2H,NH 2),5.80(d,J=4.7Hz,1H,ArH),5.74~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.8Hz,J 2=11.4Hz,1H,CH 2),5.36(s,2H,OH),4.49(s,1H,OH),4.15(d,J=10.3Hz,1H,CH),3.58~3.29(m,5H,CH and CH 2),2.24~2.12(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.67~1.11(m,17H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:761.7[M+H] +.Anal.Calcd for C 36H 46BrN 3O 8S:C,H,N.

Embodiment five:

4-(5-(4-Trifluoromethyl-1,3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 50)

Preparation method's reference example one.Obtain white crystal, productive rate 42.8%.m.p.229~230℃; 1H NMR(DMSO-d 6,300MHz)δ:8.05(d,J=7.7Hz,2H,ArH),7.74(d,J=7.5Hz,2H,ArH),6.89(s,2H,NH 2),5.91(d,J=4.7Hz,1H,ArH),5.82~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=10.5Hz,J 2=10.1Hz,1H,CH 2),5.37(s,2H,OH),4.46(s,1H,OH),4.18(d,J=10.6Hz,1H,CH),3.58~3.29(m,5H,CH and CH 2),2.20~2.12(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.73~1.15(m,15H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:736.8[M+H] +.Anal.Calcd for C 36H 44F 3N 3O 8S:C,H,N.

Embodiment six:

4-(5-(7-methyl isophthalic acid, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 51)

Preparation method's reference example one.Obtain white crystal, productive rate 49.7%.m.p.211~212℃; 1H NMR(DMSO-d 6,300MHz)δ:7.95(d,J=7.2Hz,2H,ArH),7.75(d,J=6.8Hz,2H,ArH),6.80(s,2H,NH 2),5.97(d,J=4.7Hz,1H,ArH),5.82~5.61(m,2H,ArH),5.40(s,1H,CH 2),5.36(dd,J 1=11.8Hz,J 2=11.4Hz,1H,CH 2),5.32(s,2H,OH),4.59(s,1H,OH),4.15(d,J=10.3Hz,1H,CH),3.58~3.29(m,5H,CH and CH 2),2.28~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.83~1.11(m,18H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:682.9[M+H] +.Anal.Calcd for C 36H 47N 3O 8S:C,H,N.

Embodiment seven:

4-(5-(Isosorbide-5-Nitrae-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 52)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 48.1%.m.p.223~224℃; 1H NMR(DMSO-d 6,300MHz)δ:8.07(d,J=7.7Hz,2H,ArH),7.82(d,J=7.8Hz,2H,ArH),6.85(s,2H,NH 2),5.92(d,J=4.7Hz,1H,ArH),5.86~5.61(m,2H,ArH),5.55(s,1H,CH 2),5.44(dd,J 1=8.8Hz,J 2=9.7Hz,1H,CH 2),5.35(s,2H,OH),4.49(s,1H,OH),4.38(d,J=9.2Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.29~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.91~1.24(m,16H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:682.9[M+H] +.Anal.Calcd forC 36H 47N 3O 8S:C,H,N.

Embodiment eight:

4-(5-(5-methyl isophthalic acid, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 53)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 56.2%.m.p.218~219℃; 1H NMR(DMSO-d 6,300MHz)δ:8.00(d,J=7.3Hz,2H,ArH),7.75(d,J=6.8Hz,2H,ArH),6.89(s,2H,NH 2),5.90(d,J=4.7Hz,1H,ArH),5.80~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.6Hz,J 2=10.9Hz,1H,CH 2),5.37(s,2H,OH),4.49(s,1H,OH),4.42(d,J=9.2Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.34~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.83~1.11(m,18H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:696.9[M+H] +.Anal.Calcd for C 37H 49N 3O 8S:C,H,N.

Embodiment nine:

4-(5-(5,8-dimethyl-1,3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 54)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 46.3%.m.p.228~229℃; 1H NMR(DMSO-d 6,300MHz)δ:8.02(d,J=7.2Hz,2H,ArH),7.71(d,J=7.7Hz,2H,ArH),6.80(s,2H,NH 2),5.96(d,J=4.2Hz,1H,ArH),5.77~5.67(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.8Hz,J 2=11.2Hz,1H,CH 2),5.27(s,2H,OH),4.69(s,1H,OH),4.52(d,J=9.2Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.34~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.83~1.11(m,20H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:710.9[M+H] +.Anal.Calcd for C 38H 51N 3O 8S:C,H,N.

Embodiment ten:

4-(5-(the bromo-5-methyl isophthalic acid of 8-, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 55)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 55.8%.m.p.246~248℃; 1H NMR(DMSO-d 6,300MHz)δ:8.03(d,J=7.4Hz,2H,ArH),7.68(d,J=7.2Hz,2H,ArH),6.89(s,2H,NH 2),5.93(d,J=4.7Hz,1H,ArH),5.74~5.62(m,2H,ArH),5.48(s,1H,CH 2),5.42(dd,J 1=11.2Hz,J 2=9.8Hz,1H,CH 2),5.35(s,2H,OH),4.49(s,1H,OH),4.35(d,J=9.2Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.34~2.15(m,2H,CH 2),2.01(t,J=4.2Hz,1H,CH),1.81~1.11(m,17H,CH and CH 2),0.89(s,3H,CH 3),0.84(s,3H,CH 3).ESI-MS:775.8[M+H] +.Anal.Calcd forC 37H 48BrN 3O 8S:C,H,N.

Embodiment 11:

4-(5-(5-Trifluoromethyl-1,3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 56)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 53.7%.m.p.253~254℃; 1H NMR(DMSO-d 6,300MHz)δ:7.91(d,J=7.7Hz,2H,ArH),7.84(d,J=7.5Hz,2H,ArH),6.88(s,2H,NH 2),5.97(d,J=3.9Hz,1H,ArH),5.80~5.65(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=8.8Hz,J 2=9.2Hz,1H,CH 2),5.37(s,2H,OH),4.49(s,1H,OH),4.42(d,J=9.2Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.34~2.15(m,2H,CH 2),2.01(t,J=4.8Hz,1H,CH),1.83~1.11(m,15H,CH and CH 2),0.92(s,3H,CH 3),0.85(s,3H,CH 3).ESI-MS:750.8[M+H] +.Anal.Calcd forC 37H 46F 3N 3O 8S:C,H,N.

Embodiment 12:

4-(5-(8-methyl isophthalic acid, 3-benzodioxan)-((3aR, 4aS, 8S, 10aS, 11S, 12S, 12aS)-(8,11,12-trihydroxy-)-(10a, 12a-dimethyl)-(1,2-pentamethylene base)-1,10a-b-epoxy n-tetradecane base)-(4,5-pyrazoline)) preparation of benzsulfamide (compound 57)

Preparation method's reference example one.To replace the compound containing 1.3-benzodioxan skeleton containing the compound of 1.4-benzodioxan skeleton, obtain white crystal, productive rate 52.8%.m.p.248~249℃; 1H NMR(DMSO-d 6,300MHz)δ:7.88(d,J=7.2Hz,2H,ArH),7.67(d,J=7.8Hz,2H,ArH),6.94(s,2H,NH 2),5.90(d,J=4.7Hz,1H,ArH),5.76~5.59(m,2H,ArH),5.50(s,1H,CH 2),5.40(dd,J 1=11.8Hz,J 2=11.4Hz,1H,CH 2),5.37(s,2H,OH),4.49(s,1H,OH),4.42(d,J=9.5Hz,2H,CH),3.79~3.41(m,6H,CH and CH 2),2.44~2.13(m,2H,CH 2),2.01(t,J=4.9Hz,1H,CH),1.83~1.11(m,18H,CH and CH 2),0.88(s,3H,CH 3),0.86(s,3H,CH 3).ESI-MS:696.9[M+H] +.Anal.Calcd for C 37H 49N 3O 8S:C,H,N.

Embodiment 13:

Employing MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures the pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton 21steroidal saponin aglycone derivative is to the half-inhibition concentration (IC of human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2) 50).

(1) preparation of nutrient solution (/L): 1. suspension cell: DMEM cultivates one bag, powder (10.4g), new-born calf serum 100mL, penicillin solution (2 × 10 -5u/mL) 0.5mL, Streptomycin Solution (2 × 10 -5u/mL) 0.5mL, after adding tri-distilled water dissolving, with the NaHCO of 5.6% 3solution adjust pH, to 7.2-7.4, is finally settled to 1000mL.Filtration sterilization.2. attached cell: the same, then add NaHCO 32.00g, HEPES 2.38g.

(2) preparation of D-Hanks damping fluid (often liter): NaCl 8.00g, KCl 0.40g, Na 2hPO 412H 2o 0.06g, KH 2pO 40.06g, NaHCO 30.35g.Autoclaving.

(3) preparation of trypsin solution: utilizing D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.

(4) preparation of liquid is tested: dissolved by a small amount of tri-distilled water of test sample and be made into storing solution, i.e. 10 times of preparation storing solutions of empirically maximum concentration.Different according to compound dissolution, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, then adds tri-distilled water and dissolve.Storing solution is stored in-20 DEG C of refrigerators for subsequent use.

(5) cultivation of human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2): be adherent growth cell, cellar culture is (containing 10% calf serum, 100U/mL Streptomycin sulphate) in DMEM nutrient solution, is placed in 37 DEG C, 5%CO 2cultivate in incubator, go down to posterity once every 3-4d.When going down to posterity, nutrient solution in former bottle is transferred in centrifuge tube, the centrifugal 5min of 1000rpm, discard original fluid, add equivalent fresh medium, piping and druming evenly, pipette appropriate in fresh culture bottle, then supplement fresh medium to original volume (nutrient solution volume is about 1/10 of culturing bottle capacity).

(6) cell incubation: the tumour cell in vegetative period of taking the logarithm, tune concentration of cell suspension is 1-1.5 × 10 5individual/mL.In 96 well culture plates, every hole adds cell suspension 100 μ L, puts 37 DEG C, 5%CO 224h is cultivated in incubator.After cultivating 24h, add liquid by design respectively.

(7) dosing: join in each hole by test liquid respectively according to the concentration gradient of ultimate density, each concentration establishes 6 parallel holes.Experiment is divided into drug test group (adding the test medicine of different concns respectively), control group (only add nutrient solution and cell, do not add test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after dosing are placed in 37 DEG C, 5%CO 248h is cultivated in incubator.The activity of positive control medicine measures according to the method for test sample.

(8) mensuration of survivaling cell: in 96 orifice plates after having cultivated 48h, every hole adds MTT 40 μ L (being made into 4mg/mL with D-Hanks damping fluid).After placing 4h at 37 DEG C, remove supernatant liquor.Every hole adds 150 μ L DMSO, and vibration 5min, makes formazan dissolving crystallized.Finally, automatic microplate reader is utilized to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.

Half-inhibition concentration (IC 50) be defined as drug level when the tumor cell survival of 50%.According to the optical density(OD) (OD value) measured, make the typical curve of inhibitory rate of cell growth, typical curve is tried to achieve the drug level of its correspondence.

The IC recorded 50be shown in Table 1.

The listed pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of table 1 the present invention 21steroidal saponin aglycone derivative is to the suppression IC of tumour cell 50value (μm ol/mL)

a6 parallel tests, experimental result is averaged, and error is between 5-10%

From above-mentioned experiment: the pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of the present invention 21steroidal saponin aglycone derivative has obvious restraining effect to human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549) and liver cancer cell (HepG2), especially best to A549 cell, the inhibit activities of contrast Tenacissoside A is significantly improved, and contrast positive control drug then shows quite or is better than the inhibit activities of positive control medicine.Therefore the pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of the present invention 21steroidal saponin aglycone derivative can be applied to prepares antitumor drug.

Embodiment 14:

Containing the pyrazoline sulfanilamide (SN) C of benzodioxan skeleton 21steroidal saponin aglycone derivative anti tumor activity in vitro is about Cytotoxic research

The present invention tests new synthetic compound 46-57 to the cytotoxicity of people's renal epithelial cell (293T), cytotoxicity result as table 2, using Celecoxib as positive control.The toxicity suppressor T cell survival rate of each compound to 50% time concentration (CC 50) represent.

Experimental technique:

(1) cultivator renal epithelial cell (293T) is tending towards fusion until reach its logarithmic growth end of term cell, digests cell dispersion, be mixed with 1 × 10 with cell culture fluid with cell dissociation buffer 4the cell suspension of individual/mL.Get 96 well culture plates, in every hole, add the cell suspension of 100 μ L.Horizontally rotating culture plate gently makes cell be evenly dispersed in the surface in ware hole.

(2) be placed in containing 5%CO 2in cell culture incubator, at 37 ± 2 DEG C of temperature, cultivate 24h.Discard original fluid, every hole adds the blank liquid of 100 μ L, negative controls, positive control solution, the test sample vat liquor of 100% and 50% concentration.Often organize and at least establish 8 holes.Note: lixiviate stoste or make the serial lixiviate diluent of thinner with substratum.When adopting 0.9% sodium chloride injection lixiviate, use 2 times of concentrated substratum when diluting lixiviate.

(3) be placed in containing 5%CO 2in incubator, cultivate at 37 ± 2 DEG C of temperature.Cultivate 48h.

(4) after date between each cultivation, every hole adds MTT solution 20 μ L, is placed in containing 5%CO 2in incubator, at 37 ± 2 DEG C of temperature, cultivate 5h.

(5) discard liquid in hole, every hole adds 200 μ L DMSO respectively, and culture plate is placed 10min, and level is rocked and made solution colour in hole even.

(6) measure absorbancy by microplate reader, wavelength adopts 570nm.

The CC recorded 50be shown in Table 2.

The listed pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of table 2 the present invention 21steroidal saponin aglycone derivative is to the suppression CC of 293T cell 50value (μm ol/mL)

a6 parallel tests, experimental result is averaged, and error is between 5-10%.

Can learn from above experiment: the pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of the present invention 21steroidal saponin aglycone derivative is to showing quite people's renal epithelial cell (293T) or being better than the cytotoxicity of positive control medicine, and compare with Tenacissoside A, cytotoxicity also almost maintains an equal level.Therefore the pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of the present invention 21steroidal saponin aglycone derivative can be applied to prepares antitumor drug.

In a word, containing 2 Sauerstoffatoms in benzodioxan skeleton, the multiple non-covalent interaction of easy generation, as hydrogen bond and metallic ion coordination etc., these two Sauerstoffatoms play an important role to combining closely of ligand-receptor, and therefore, it is to the targeting important in inhibiting improving medicine, as important active intermediate, there is antitumour activity.Mostly pyrazoline is chirality, and the conformation of the replacement on ring and molecule can be caused to have larger polytropy, thus has better biological activity potential quality.

By above-described embodiment and experimental data known, the benzodioxan skeleton and sulfanilamide (SN) group with superior bio activity are incorporated in pyrazoline derivative by the present invention, combine simultaneously and have very well active C 21steroidal saponin aglycon skeleton, a series of pyrazoline sulfanilamide (SN) C containing benzodioxan skeleton of design and synthesis 21through experiment, steroidal saponin aglycone derivative, finds that it has better biological activity, higher selectivity and lower toxicity etc.

More than describe the preferred embodiment of the present invention in detail; but the present invention is not limited to the detail in above-mentioned embodiment, within the scope of technical conceive of the present invention; can carry out multiple equivalents to technical scheme of the present invention, these equivalents all belong to protection scope of the present invention.It should be noted that in addition, each the concrete technical characteristic described in above-mentioned embodiment, in reconcilable situation, can be combined by any suitable mode, the order of such as step 1 and step 2 can adjust.In order to avoid unnecessary repetition, the present invention illustrates no longer separately to various possible array mode.In addition, also can carry out arbitrary combination between various different embodiment of the present invention, as long as it is without prejudice to thought of the present invention, it should be considered as content disclosed in this invention equally.

Claims (9)

1. there is a compound for structure shown in formula VIII,
Wherein, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2.
2. structure is such as formula a preparation method for compound shown in VIII,
Wherein, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2;
It is characterized in that, comprise the steps:
Step 1: structure is dissolved in dry DMF such as formula the compound shown in I, adds glycol dibromide or methylene bromide, Anhydrous potassium carbonate successively, and obtained structure is such as formula the compound shown in II;
Step 2: by the converting compounds of structure as shown in formula III for structure is such as formula the compound shown in V;
Step 3: add structure successively such as formula the compound shown in V, the KOH aqueous solution, structure such as formula the compound shown in II and ethanol in reaction vessel, obtained structure is such as formula the compound shown in VI;
Step 4: be the compound shown in formula VII such as formula the converting compounds shown in VI by structure;
Step 5: structure is added in reaction vessel successively such as formula the compound shown in VII, methylene dichloride and boron tribromide, reaction obtains structure such as formula the compound shown in VIII;
In formula I, II and formula VI, VII, R 1be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2.
3. the preparation method of compound as claimed in claim 2, it is characterized in that, described step 1 is further:
Structure is dissolved in dry DMF such as formula the compound shown in I, add 1 successively, 2-ethylene dibromide or methylene bromide, Anhydrous potassium carbonate, at 80 ± 10 DEG C of reacting by heating 30 ± 5min, then reaction mixture is added in frozen water, filters, use distilled water wash solid, then carry out column chromatography, obtained structure is such as formula the compound shown in II.
4. the preparation method of compound as claimed in claim 2, it is characterized in that, described step 2 is further:
Under stirring at room temperature, in round-bottomed flask, add the compound of structure as shown in formula III, aqueous hydrochloric acid and dehydrated alcohol successively, after stirring 2 ~ 3h, reaction flask is transferred in the oil bath pan of 78 ~ 80 DEG C, back flow reaction 7 ~ 9h; TLC follows the tracks of reaction, and reaction terminates rear filtration; The solid obtained uses aqueous hydrochloric acid, distilled water, cold ethanol, distilled water wash, drying successively, and the solid product obtained is dissolved in dehydrated alcohol, and recrystallization obtains the structure of the lenticular of partial reduction such as formula the compound shown in IV;
Under ice-water bath stirring action, diazomethane ether mixed solution, boron trifluoride-ether complex, structure is added successively such as formula the compound shown in IV in round-bottomed flask, after reaction 20 ~ 40min, back flow reaction 5 ~ 7h again, TLC follows the tracks of reaction, and reaction terminates rear filtration, and the solid obtained uses aqueous hydrochloric acid, distilled water, cold ethanol, distilled water wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains the structure of lenticular such as formula the compound shown in V by the solid crude product obtained.
5. the preparation method of compound as claimed in claim 2, it is characterized in that, described step 3 is further:
Under stirring at room temperature, structure is added successively such as formula the compound shown in V, the KOH aqueous solution, structure such as formula the compound shown in II, ethanol in round-bottomed flask, continue stirring reaction 3 ~ 6h, use salt acid for adjusting pH, filter, the solid obtained uses distilled water, cold ethanol, distilled water wash successively, dry, obtains structure such as formula the compound shown in VI.
6. the preparation method of compound as claimed in claim 2, it is characterized in that, described step 4 further for: successively by structure such as formula the compound shown in VI, dehydrated alcohol, join in round-bottomed flask to Hydrazinobenzenesulfonamide, acetic acid, stirring at room temperature reaction 20 ~ 40min, still has fraction solids insoluble; Back flow reaction 5 ~ 8h, TLC follow the tracks of reaction, after reaction terminates, filter, solid uses aqueous hydrochloric acid, distilled water, cold ethanol, distilled water wash successively, dry, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains the structure of lenticular such as formula the compound shown in VII.
7. the preparation method of compound as claimed in claim 2, it is characterized in that, described step 5 is further:
Under stirring at-20 ± 5 DEG C, in round-bottomed flask, add structure successively such as formula the compound shown in VII, methylene dichloride, and progressively drip boron tribromide, continue stirring reaction 20 ~ 40min, room temperature continues reaction 10 ~ 14h, and TLC follows the tracks of reaction, after reaction terminates, filter, solid distilled water wash, last vacuum-drying, is dissolved in dehydrated alcohol by the solid obtained, recrystallization is purified, and obtains the structure of lenticular such as formula the compound shown in VIII.
8. the compound with structure shown in formula VIII is preparing the application in antitumor drug,
Wherein, R 1, be selected from H, CH 3, CF 3, R 2be selected from H, CH 3, Br, n be 1,2.
9. an antitumor drug, is characterized in that, comprises compound according to claim 1 and medically acceptable auxiliary material.
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CN105130808A (en) * 2015-08-13 2015-12-09 上海瑞博化学有限公司 High purity 2,5-dimethyl-3,4-dihydroxy methylbenzoate synthesis method

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CN104788531A (en) * 2015-04-29 2015-07-22 江苏耐雀生物工程技术有限公司 Dihydro pyrazol piperazine C21 steroid saponin aglycone derivative containing thiophene backbone as well as preparation method and application thereof
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CN104829685A (en) * 2015-04-30 2015-08-12 江苏耐雀生物工程技术有限公司 Furan skeleton-containing dihydropyrazolsulfanilamide C21 steroid sapogenin derivative, and preparation method and application thereof
CN105130808A (en) * 2015-08-13 2015-12-09 上海瑞博化学有限公司 High purity 2,5-dimethyl-3,4-dihydroxy methylbenzoate synthesis method

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