CN104230905A - Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs - Google Patents

Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs Download PDF

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CN104230905A
CN104230905A CN201410442746.8A CN201410442746A CN104230905A CN 104230905 A CN104230905 A CN 104230905A CN 201410442746 A CN201410442746 A CN 201410442746A CN 104230905 A CN104230905 A CN 104230905A
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benzodioxan
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dihydropyrazol
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朱海亮
严晓强
邱寒月
王鹏飞
王忠长
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Nanjing University
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Nanjing University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention relates to synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons. The synthesis is characterized by being provided with a general formula shown in descriptions. The dihydropyrazol sulfonamide derivatives containing the benzodioxane skeletons play an obvious role in inhibiting human mammary cancer cells (MCF-7), cervical carcinoma cells (HeLa), lung cancer cells (A549), liver cancer cells (HepG2) and matrix metalloproteinase-2 (MMP-2), and meanwhile, show cell toxicity, which is equivalent to or better than that of positive control drugs, to human kidney epithelial cells (293T). Thus, the dihydropyrazol sulfonamide derivatives containing the benzodioxane skeletons can be applied to the preparation of anti-tumor drugs. The invention discloses a preparation method and anti-tumor bioactivity of the dihydropyrazol sulfonamide derivatives containing the benzodioxane skeletons.

Description

One class is containing the synthesis of pyrazoline sulphone amide derivative of benzodioxan skeleton and the application in cancer therapy drug
Summary of the invention
The object of the present invention is to provide a class containing the synthesis of pyrazoline sulphone amide derivative of benzodioxan skeleton and the application in cancer therapy drug
Summary of the invention
Technical scheme of the present invention is as follows:
One class, containing the synthesis of the pyrazoline sulphone amide derivative of benzodioxan skeleton, is characterized in that it has following general formula:
A synthesis for the above-mentioned pyrazoline sulphone amide derivative containing benzodioxan skeleton, it is made up of the following step:
3.4 Dihydroxy benzaldehydes (50mmol) are dissolved in 250mL dry DMF by step 1., then add the glycol dibromide of 70mmol or the Anhydrous potassium carbonate of methylene bromide and 25mmol, 70 DEG C of 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) raw material 2-3, is obtained.
Step 2. under stirring at room temperature, the methyl phenyl ketone (10.0mmol) of different substituents, the 40%KOH aqueous solution, different benzodioxan formaldehyde (10.0mmol), ethanol (50mL) is added successively in the round-bottomed flask of 100mL, after maintaining this temperature continuation stirring reaction 4h, reaction solution is poured in 500mL beaker, 1mol/L hcl acidifying, filter, solid uses 1mol/L hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 4-38.
Step 3. is successively by different cinnamophenone 4-38 (4mmol), dehydrated alcohol (25mL), join in the round-bottomed flask of 50mL to Hydrazinobenzenesulfonamide (4.5mmol), acetic acid (1.0mL), after stirring at room temperature reaction 1h, still have fraction solids insoluble; Transferred to by reaction flask in oil bath pan, back flow reaction 6h, TLC follow the tracks of reaction (developping agent V acOEt: V pE=1: 2), after reaction terminates, filter, solid uses 1mol/L hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold washing with alcohol (3 × 50mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains lenticular target compound 39-73 by the solid crude product obtained.
Background technology
Sulfa drugs has multiple biological activity, it is the focus of medicinal chemistry art research always, be widely used in antibacterial, hypotensive, diuresis etc., but, such medicine is fungistat, and without germicidal action, easily generation resistance and frequent use can produce many untoward reactions, thus its range of application is greatly limited.But because it easily develops immunity to drugs, use range reduces gradually.But what document in recent years repeatedly reported its derivative has otherwise activity except antibacterial, is wherein anti-tumor activity the most significantly.
Pyrazoles is the important heterogeneous ring compound of a class, is extensively distributed in occurring in nature.Since having had since easing pain and diminishing inflammation and antipyretic effect be found containing the antipyrine of pyrazole ring, this compounds because of its have efficiently, low toxicity, and the multi-faceted conversion of its ring substituents and being used widely in pharmaceutical field.Research finds that pyrazole compound has the pharmacologically actives such as anti-inflammatory, pain relieving, antibacterial, sterilization, hyperglycemia, anticancer, anti-coagulant.In recent years, the commercialization in succession of many novel pyrazoles medicine, has become one of focus of current medicinal design study on the synthesis to the further investigation of pyrazole compound.
2H pyrazoles is very important nitrogenous five member ring heterocyclic compound, and it has stronger biological activity, such as antitumor, antibacterial, antiviral, antimycotic, tuberculosis, desinsection isoreactivity.It is a structural presence subunit with various pharmacological property, there is the active compound guide of general medicinal organism activity.A what is more important: because mostly 2H pyrazoles is chirality, causes the conformation of the replacement on ring and molecule to have larger polytropy, there is better biological activity potential quality! The application of 2H pyrazole compound in organic synthesis and other field is more and more extensive, and chirality 2H pyrazole compound has many biologies and pharmacological properties, facilitate the great development of medicine, for later drug development provides very large research space, development prospect is boundless, therefore building the heterocyclic system with 2H pyrrazole structure to have great importance, is the focus be concerned in recent years.
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 according to the literature, this, to the targeting important in inhibiting improving medicine, has larger development potentiality.In addition, as important active intermediate, benzodioxan skeleton is that one is extensively present in natural pharmacophoric group, has the multiple physiologically actives such as anticancer, antimycotic, antipsychotic.
Based on this, the present invention is by different sulfanilamide (SN) and have outstanding bioactive benzodioxan skeleton and be incorporated in pyrazoline derivative, the a series of pyrazoline sulphone amide derivative containing benzodioxan skeleton of design and synthesis, expects to have better biological activity, higher selectivity, lower toxicity, the longer or shorter longevity of residure etc.
Embodiment
The preparation of embodiment one: 4-(5-(1.3-benzodioxan)-3-phenyl-4,5-pyrazoline) benzsulfamide (compound 39)
Under agitation successively by 1,3-epoxy benzodioxan cinnamophenone (1.0g, 3.87mmol), ethanol (25mL), to Hydrazinobenzenesulfonamide (0.97g, 5.03mmol), acetic acid (1.0mL) joins in the round-bottomed flask of 50mL, still has fraction solids insoluble; Transferred to by flask in oil bath pan, back flow reaction 6h, TLC follow 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.
White crystal, productive rate 66.4%.m.p.212～214℃； 1H?NMR(DMSO-d6，400MHz)δ：7.80(d，J＝7.4Hz，2H，ArH)，7.62(d，J＝8.6Hz，2H，ArH)，7.48～7.40(m，3H，ArH)，7.11(d，J＝8.6Hz，2H，ArH)，7.04(s，2H，NH 2)，6.87(d，J＝7.9Hz，1H，ArH)，6.78～6.75(m，2H，ArH)，5.90(s，2H，CH 2)，5.56(dd，J 1＝4.7，J 2＝4.7Hz，1H，5-H)，?3.91(dd，J 1＝12.4，J 2＝12.0Hz，1H，4-H b)，3.19(dd，J 1＝4.7，J 2＝4.6Hz，1H，4-Ha).ESI-MS：422.1[M+H] +.Anal.Calcd?for?C 22H 19N 3O 4S：C，H，N.
Embodiment two: the 4-(preparation of 5-(1.3-benzodioxan)-3-(m-aminomethyl phenyl-4,5-pyrazoline) benzsulfamide (compound 40)
Preparation method is with embodiment one.Obtain white crystal, productive rate 75.8%.m.p.187～188℃； 1H?NMR(DMSO-d6，400MHz)δ：7.64～7.56(m，4H，ArH)，7.34(t，J＝7.6Hz，1H，ArH)，7.23(d，J＝7.4Hz，1H，ArH)，6.10(d，J＝8.6Hz，2H，ArH)，7.04(s，2H，NH 2)，6.87(d，J＝7.8Hz，1H，ArH)，6.75(d，J＝9.9Hz，2H，ArH)，5.98(s，2H，CH 2)，5.55(dd，J 1＝4.7，J 2＝4.8Hz，1H，5-H)，3.91(dd，J 1＝12.1，J 2＝12.1Hz，1H，4-H b)，3.17(dd，J 1＝4.8，J 2＝4.7Hz，1H，4-Ha)，2.37(s，3H，CH 3)，.ESI-MS：436.1[M+H] +.Anal.Calcd?for?C 21H 23N 3O 4S：C，H，N.
Embodiment three: the 4-(preparation of 5-(1.3-benzodioxan)-3-(m-p-methoxy-phenyl-4,5-pyrazoline) benzsulfamide (compound 41)
Preparation method is with embodiment one.Obtain white crystal, productive rate 76.6%.m.p.219～221℃； 1H?NMR(DMSO-d6，400MHz)δ：7.61(d，J＝8.7Hz，2H，ArH)，7.37～6.99(m，8H，ArH)，6.87(d，J＝7.9Hz，1H，ArH)，6.76(s，2H，NH 2)，6.00(s，2H，CH 2)，5.56(dd，J 1＝4.9，J 2＝5.0Hz，1H，5-H)，3.91(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，3.82(s，3H，CH 3)，3.18(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha).ESI-MS：452.1[M+H] +.Anal.Calcd?for?C 21H 23N 3O 5S：C，H，N.
Embodiment four: the 4-(preparation of 5-(1.3-benzodioxan)-3-(o-fluorophenyl-4,5-pyrazoline) benzsulfamide (compound 42)
Preparation method is with embodiment one.Obtain white crystal, productive rate 66.5%.m.p.180～181℃； 1H?NMR(DMSO-d6，400MHz)δ：7.95(t，J＝7.6Hz，1H，ArH)，7.63(d，J＝8.6Hz，2H，ArH)，7.46(q，J＝7.2Hz，1H，ArH)，7.28(q，J＝8.1Hz，2H，ArH)，7.11(d，J＝8.5Hz，2H，ArH)，7.06(s，2H，NH 2)，6.87(d，J＝7.9Hz，1H，ArH)，6.77(t，J＝7.0Hz，2H，ArH)，5.99(s，2H，CH 2)，5.56(dd，J 1＝5.0，J 2＝5.0Hz，1H，5-H)，4.01(dd，J 1＝12.2，J 2＝12.2Hz，1H，4-H b)，3.20(dd，J 1＝4.6，J 2＝4.6Hz，1H，4-Ha).ESI-MS：440.1[M+H] +.Anal.Calcd?for?C 22H 18FN 3O 4S：C，H，N.
Embodiment five: the 4-(preparation of 5-(1.3-benzodioxan)-3-(m-fluorophenyl-4,5-pyrazoline) benzsulfamide (compound 43)
Preparation method is with embodiment one.Obtain white crystal, productive rate 69.8%.m.p.192～193℃； 1H?NMR(DMSO-d6，400MHz)δ：7.95(t，J＝7.6Hz，1H，ArH)，7.63(d，J＝8.6Hz，2H，ArH)，7.46(q，J＝7.2Hz，1H，ArH)，7.28(q，J＝8.1Hz，2H，ArH)，7.11(d，J＝8.5Hz，2H，ArH)，7.06(s，2H，NH 2)，6.87(d，J＝7.9Hz，1H，ArH)，6.77(t，J＝7.0Hz，2H，ArH)，5.99(s，2H，CH 2)，5.56(dd，J 1＝5.0，J 2＝5.0Hz，1H，5-H)，4.01(dd，J 1＝12.2，J 2＝12.2Hz，1H，4-H b)，3.20(dd，J 1＝4.6，J 2＝4.6Hz，1H，4-Ha).ESI-MS：440.1[M+H] +.Anal.Calcd?for?C 22H 18FN 3O 4S：C，H，N.
Embodiment six: the 4-(preparation of 5-(1.3-benzodioxan)-3-(p-ethoxyl phenenyl-4,5-pyrazoline) benzsulfamide (compound 44)
Preparation method is with embodiment one.Obtain white crystal, productive rate 77.6%.m.p.182～184℃； 1H?NMR(DMSO-d6，400MHz)δ：7.71(d，J＝8.6Hz，2H，ArH)，7.60(d，J＝8.7Hz，2H，ArH)，7.08～6.98(m，6H，ArH)，6.86(d，J＝7.8Hz，1H，ArH)，6.74(s，2H，NH 2)，5.98(s，2H，CH 2)，5.50(dd，J 1＝4.9，J 2＝5.0Hz，1H，5-H)，4.05(q，J＝6.9Hz，2H，CH 2)，3.87(dd，J 1＝12.1，J 2＝11.8Hz，1H，4-H b)，3.13(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha)，1.34(t，J＝6.9Hz，3H，CH 3).ESI-MS：466.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 5S：C，H，N.
Embodiment seven: the 4-(preparation of 5-(1.3-benzodioxan)-3-(p-p-methoxy-phenyl-4,5-pyrazoline) benzsulfamide (compound 45)
Preparation method is with embodiment one.Obtain white crystal, productive rate 76.3%.m.p.200～201℃； 1H?NMR(DMSO-d6，400MHz)δ：7.73(d，J＝8.8Hz，2H，ArH)，7.59(d，J＝8.7Hz，2H，ArH)，7.08～7.01(m，6H，ArH?and?NH 2)，6.87(d，J＝7.9Hz，1H，ArH)，6.77～6.73(m，2H，ArH)，5.98(s，2H，CH 2)，5.51(dd，J 1＝5.0，J 2＝5.1Hz，1H，5-H)，3.88(dd，J 1＝12.0，J 2＝11.9Hz，1H，4-H b)，3.80(s，3H，OCH 3)，3.15(dd，J 1＝5.1，J 2＝5.0Hz，1H，4-Ha).ESI-MS：452.1[M+H] +.Anal.Calcd?for?C 23H 21N 3O 5S：C，H，N.
Embodiment eight: the 4-(preparation of 5-(1.3-benzodioxan)-3-(2.4-Dimethoxyphenyl-4,5-pyrazoline) benzsulfamide (compound 46)
Preparation method is with embodiment one.Obtain white crystal, productive rate 72.9%.m.p.180～182℃； 1H?NMR(DMSO-d6，400MHz)δ：7.60(d，J＝8.6Hz，2H，ArH)，7.35(d，J＝7.9Hz，1H，ArH)，7.17(s，1H，ArH)，7.10～7.03(m，5H，ArH?and?NH 2)，6.87(d，J＝7.7Hz，1H，ArH)，6.77～6.74(m，2H，ArH)，6.98(s，2H，CH 2)，5.48(dd，J 1＝4.8，J 2＝4.8Hz，1H，5-H)，3.98(dd，J 1＝12.0，J 2＝11.8Hz，1H，4-H b)，3.20(dd，J 1＝4.9，J 2＝4.8Hz，1H，4-Ha)，2.67(s，3H，CH 3)，2.31(s，3H，CH 3).ESI-MS：450.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 4S：C，H，N.
Embodiment nine: the 4-(preparation of 5-(1.3-benzodioxan)-3-(3.4-Dimethoxyphenyl-4,5-pyrazoline) benzsulfamide (compound 47)
Preparation method is with embodiment one.Obtain white crystal, productive rate 73.8%.m.p.179～180℃； 1H?NMR(DMSO-d6，400MHz)δ：7.60(d，J＝8.0Hz，3H，ArH)，7.49(d，J＝7.8Hz，1H，ArH)，7.21(d，J＝7.8Hz，1H，ArH)，7.08(d，J＝8.3Hz，2H，ArH)，7.02(s，2H，NH 2)，6.86(d，J＝7.8Hz，1H，ArH)，6.75(s，2H，ArH)，5.98(s，2H，CH 2)，5.53(dd，J 1＝4.4，J 2＝4.6Hz，1H，5-H)，3.88(dd，J 1＝12.1，J 2＝24.0Hz，1H，4-H b)，3.14(dd，J 1＝4.5，J 2＝4.4Hz，1H，4-Ha).ESI-MS：450.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 4S：C，H，N.
Embodiment ten: the 4-(preparation of 5-(1.3-benzodioxan)-3-(p-iodophenyl-4,5-pyrazoline) benzsulfamide (compound 48)
Preparation method is with embodiment one.Obtain white crystal, productive rate 58.9%.m.p.212～214℃； 1H?NMR(DMSO-d6，400MHz)δ：7.82(d，J＝7.9Hz，2H，ArH)，7.62～7.54(m，4H，ArH)，7.16(d，J＝8.5Hz，2H，ArH)，7.04(s，2H，NH 2)，6.86(d，J＝7.9Hz，1H，ArH)，6.54(d，J＝4.2Hz，2H，ArH)，5.98(s，2H，CH 2)，5.57(dd，J 1＝4.7，J 2＝5.1Hz，1H，5-H)，3.91(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，3.16(dd，J 1＝4.9，J 2＝5.0Hz，1H，4-Ha).ESI-MS：548.0[M+H] +.Anal.Calcd?for?C 22H 18IN 3O 4S：C，H，N.
Embodiment 11: the 4-(preparation of 5-(1.3-benzodioxan)-3-(p-chloro-phenyl--4,5-pyrazoline) benzsulfamide (compound 49)
Preparation method is with embodiment one.Obtain white crystal, productive rate 53.8%.m.p.168～170℃； 1H?NMR(DMSO-d6，400MHz)δ：7.78(d，J＝8.5Hz，2H，ArH)，7.63(d，J＝8.8Hz，2H，ArH)，?7.49(d，J＝8.6Hz，2H，ArH)，7.07～7.13(m，4H，ArH)，6.86(d，J＝7.8Hz，1H，ArH)，6.75(s，2H，NH 2)，5.98(s，2H，CH 2)，5.56(dd，J 1＝5.1，J 2＝5.3Hz，1H，5-H)，3.90(dd，J 1＝12.2，J 2＝12.1Hz，1H，4-H b)，3.17(dd，J 1＝5.3，J 2＝5-2Hz，1H，4-Ha).ESI-MS：456.9[M+H] +.Anal.Calcd?for?C 22H 18ClN 3O 4S：C，H，N.
The system back of the body of embodiment 12: 4-(5-(1.4-benzodioxan)-3-phenyl-4,5-pyrazoline) benzsulfamide (compound 50)
Preparation method is with embodiment one.To replace the cinnamophenone of 1.3-benzodioxan skeleton to obtain white crystal, productive rate 73.5% containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.156～157℃； 1H?NMR(DMSO-d6，400MHz)δ：7.79(d，J＝6.8Hz，2H，ArH)，7.61(d，J＝8.9Hz，2H，ArH)，7.47～7.40(m，3H，ArH)，7.09(t，J＝8.9Hz，2H，ArH)，6.99(s，2H，NH 2)，6.82(d，J＝8.4Hz，1H，ArH)，6.72～6.99(m，2H，ArH)，5.54(dd，J 1＝4.8，J 2＝4.8Hz，1H，5-H)，4.18(s，4H，CH 2)，3.91(dd，J 1＝12.1，J 2＝12.0Hz，1H，4-H b)，3.17(dd，J 1＝4.9，J 2＝3.6Hz，1H，4-Ha).ESI-MS：435.1[M+H] +.Anal.Calcd?for?C 23H 21N 3O 4S：C，H，N.
The preparation of embodiment 13: 4-(5-(1.4-benzodioxan)-3-(m-bromophenyl)-4,5-pyrazolines) benzsulfamide (compound 51)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 86.8% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.196～197℃； 1H?NMR(DMSO-d6，400MHz)δ：7.96(s，1H，ArH)，7.74(d，J＝7.9Hz，1H，ArH)，7.76～7.57(m，3H，ArH)，7.39(t，J＝7.9Hz，1H，ArH)，7.1(d，J＝8.9Hz，2H，ArH)，7.06(s，2H，NH 2)，5.56(dd，J 1＝4.88，J 2＝5.0Hz，1H，5-H)，4.19(s，4H，CH 2)，3.88(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，，3.18(dd，J 1＝5.1，J 2＝4.9Hz，1H，4-Ha).ESI-MS：515.4[M+H] +.Anal.Calcd?for?C 23H 20BrN 3O 4S：C，H，N.
The preparation of embodiment 14: 4-(5-(1.4-benzodioxan)-3-(m-p-methoxy-phenyl)-4,5-pyrazolines) benzsulfamide (compound 52)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 70.1% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.146～147℃； 1H?NMR(DMSO-d6，400MHz)δ：7.60(d，J＝8.9Hz，2H，ArH)，7.34(d，J＝4.9Hz，2H，ArH)，7.11～7.00(m，3H，ArH)，6.99(s，2H，NH 2)，6.82(2，J＝8.4Hz，2H，ArH)，6.71～6.69(m，2H，ArH)，5.54(dd，J 1＝4.7，J 2＝4.9Hz，1H，5-H)，4.19(s，4H，CH 2)，3.89(dd，J 1＝12.1，J 2＝12.0Hz，1H，4-H b)，3.80(s，3H，OCH 3)，3.17(dd，J 1＝4.9，J 2＝4.8Hz，1H，4-Ha).ESI-MS：466.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 5S：C，H，N.
The preparation of embodiment 15: 4-(5-(1.4-benzodioxan)-3-(o-fluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 53)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 69.4% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.191～192℃； 1H?NMR(DMSO-d6，300MHz)δ：7.94(t，J＝7.6Hz，1H，ArH)，7.63(d，J＝8.6Hz，2H，ArH)，7.45(q，J＝7.1Hz，1H，ArH)，7.27(q，J＝8.7Hz，2H，ArH)，7.11(2，J＝9.0Hz，4H，ArH)，7.82(d，J＝8.1Hz，4H，ArH)，6.72(s，2H，NH 2)，5.53(dd，J 1＝4.7，J 2＝4.8Hz，1H，5-H)，4.19(s，4H，CH 2)，3.99(dd，J 1＝12.1，J 2＝12.1Hz，1H，4-H b)，3.17(dd，J 1＝2.5，J 2＝2.2Hz，1H，4-Ha).ESI-MS：454.1[M+H] +.Anal.Calcd?for?C 23H 20FN 3O 4S：C，H，N.
The preparation of embodiment 16: 4-(5-(1.4-benzodioxan)-3-(m-fluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 54)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 68.7% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.200～201℃； 1H?NMR(DMSO-d6，300MHz)δ：7.84(q，J＝5.6Hz，2H，ArH)，7.60(d，J＝8.9Hz，2H，ArH)，7.29(t，J＝8.8Hz，2H，ArH)，7.08(t，J＝8.9Hz，2H，ArH)，6.99(s，2H，NH 2)，6.82(q，2，J＝8.1Hz，2H，ArH)，6.70(t，J＝8.0Hz，2H，ArH)，5.54(dd，J 1＝4.8，J 2＝4.8Hz，1H，5-H)，4.19(s，4H，CH 2)，3.91(dd，J 1＝12.1，J 2＝11.9Hz，1H，4-H b)，3.16(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha).ESI-MS：454.1[M+H] +.Anal.Calcd?for?C 23H 20FN 3O 4S：C，H，N.
The preparation of embodiment 17: 4-(5-(1.4-benzodioxan)-3-(3.5-difluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 55)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 63.4% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.182～183℃； 1H?NMR(DMSO-d6，300MHz)δ：7.62(q，J＝8.9Hz，2H，ArH)，7.50～7.47(m，2H，ArH)，7.31～7.26(m，1H，ArH)，7.15(t，J＝8.9Hz，2H，ArH)，7.10(s，2H，NH 2)，6.82(t，J＝8.2Hz，2H，ArH)，6.72～6.69(m，2H，ArH)，5.60(dd，J 1＝4.9，J 2＝5.4Hz，1H，5-H)，4.19(s，4H，CH 2)，3.88(dd，J 1＝12.1，J 2＝11.9Hz，1H，4-H b)，3.19(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha).ESI-MS：472.1[M+H] +.Anal.Calcd?for?C 23H 19F 2N 3O 4S：C，H，N.
The preparation of embodiment 18: 4-(5-(1.4-benzodioxan)-3-(p-ethoxyl phenenyl)-4,5-pyrazolines) benzsulfamide (compound 56)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 59.8% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.193～194℃； 1H?NMR(DMSO-d6，400MHz)δ：7.71(d，J＝8.6Hz，2H，ArH)，7.60(d，J＝8.7Hz，2H，ArH)，7.07～6.98(m，6H，ArH)，6.81(d，J＝8.0Hz，1H，ArH)，6.70(s，2H，NH 2)，5.48(dd，J 1＝5.0，J 2＝4.7Hz，1H，5-H)，4.18(s，4H，CH 2)，4.05(q，J＝6.8Hz，2H，CH 2)，3.86(dd，J 1＝12.0，J 2＝11.7Hz，1H，4-H b)，3.12(dd，J 1＝4.7，J 2＝4.6Hz，1H，4-Ha)，1.34(t，J＝6.9Hz，3H，CH 3).ESI-MS：480.1[M+H] +.Anal.Calcd?for?C 25H 25N 3O 5S：C，H，N.
The preparation of embodiment 19: 4-(5-(1.4-benzodioxan)-3-(p-p-methoxy-phenyl)-4,5-pyrazolines) benzsulfamide (compound 57)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 75.6% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.207～208℃； 1H?NMR(DMSO-d6，400MHz)δ：7.73(d，J＝8.8Hz，2H，ArH)，7.59(d，J＝8.7Hz，2H，ArH)，7.08～7.01(m，6H，ArH?and?NH 2)，6.87(d，J＝7.9Hz，1H，ArH)，6.77～6.73(m，2H，ArH)，5.49(dd，J 1＝5.0，J 2＝5.1Hz，1H，5-H)，4.19(s，4H，CH 2)，3.87(dd，J 1＝12.0，J 2＝11.9Hz，1H，4-H b)，3.81(s，3H，OCH 3)，3.13(dd，J 1＝5.1，J 2＝5.0Hz，1H，4-Ha).ESI-MS：466.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 5S：C，H，N.
The preparation of embodiment 20: 4-(5-(1.4-benzodioxan)-3-(p-aminomethyl phenyl)-4,5-pyrazolines) benzsulfamide (compound 58)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 75.6% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.153～154℃； 1H?NMR(DMSO-d6，400MHz)δ：7.68(d，J＝8.1Hz，2H，ArH)，7.59(d，J＝8.9Hz，2H，ArH)，7.26(d，J＝8.0Hz，2H，ArH)，7.06(t，J＝8.9Hz，1H，ArH)，6.99(s，2H，NH 2)，6.82(d，J＝8.6Hz，1H，ArH)，6.70～6.68(m，2H，ArH)，5.51(dd，J 1＝4.7，J 2＝4.7Hz，1H，5-H)，4.18(s，4H，CH 2)，3.88(dd，J 1＝12.0，J 2＝11.8Hz，1H，4-H b)，3.13(dd，J 1＝4.9，J 2＝4.8Hz，1H，4-Ha)，2.34(s，3H，CH 3).ESI-MS：450.1[M+H] +.Anal.Calcd?for?C 24H 23N 3O 4S：C，H，N.
The preparation of embodiment 21: 4-(5-(1.4-benzodioxan)-3-(3.4-3,5-dimethylphenyl)-4,5-pyrazolines) benzsulfamide (compound 59)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 72.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.166～168℃； 1H?NMR(DMSO-d6，400MHz)δ：7.60(d，J＝8.7Hz，3H，ArH)，7.48(d，J＝7.8Hz，2H，ArH)，7.20(d，J＝7.9Hz，1H，ArH)，7.07(t，J＝8.7Hz，3H，ArH)，6.81(d，J＝8.4Hz，1H，ArH)，6.90(s，2H，NH 2)，5.50(dd，J 1＝4.5，J 2＝4.6Hz，1H，5-H)，4.19(s，4H，CH 2)，3.86(dd，J 1＝12.0，J 2＝11.8Hz，1H，4-H b)，3.12(dd，J 1＝4.6，J 2＝4.5Hz，1H，4-Ha)，2.27(s，3H，CH 3)，2.26(s，3H，CH 3).ESI-MS：464.1[M+H] +.Anal.Calcd?for?C 25H 25N 3O 4S：C，H，N.
The preparation of embodiment 22: 4-(5-(1.4-benzodioxan)-3-(3-methyl-4-chloro-phenyl-)-4,5-pyrazolines) benzsulfamide (compound 60)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 71.4% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.159～161℃； 1H?NMR(DMSO-d6，300MHz)δ：7.78(q，J＝8.9Hz，1H，ArH)，7.64～7.60(m，3H，ArH)，7.48～7.40(m，1H，ArH)，7.11(t，J＝8.9Hz，2H，ArH)，7.09(s，2H，NH 2)，6.82(t，J＝8.2Hz，2H，ArH)，6.72～6.69(m，2H，ArH)，5.54(dd，J 1＝4.9，J 2＝5.4Hz，1H，5-H)，4.19(s，4H，CH 2)，3.86(dd，J 1＝12.1，J 2＝11.9Hz，1H，4-H b)，3.15(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha)，2.35(s，3H，CH 3)，.ESI-MS：468.1[M+H] +.Anal.Calcd?for?C 24H 22ClN 3O 4S：C，H.N.
The preparation of embodiment 23: 4-(5-(1.4-benzodioxan)-3-(p-chloro-phenyl-)-4,5-pyrazolines) benzsulfamide (compound 61)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 73.9% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.146～148℃； 1H?NMR(DMSO-d6，400MHz)δ：7.79(d，J＝8.6Hz，2H，ArH)，7.61(d，J＝8.8Hz，2H，ArH)，7.50(d，J＝8.6Hz，2H，ArH)，7.11～7.08(m，3H，ArH)，6.82(2，J＝8.0Hz，2H，ArH)，6.99(s，2H，NH 2)，5.55(dd，J 1＝4.8，J 2＝4.8Hz，1H，5-H)，4.19(s，4H，CH 2)，3.89(dd，J 1＝7.0，J 2＝12.0Hz，1H，4-H b)，3.16(dd，J 1＝5.0，J 2＝4.9Hz，1H，4-Ha).ESI-MS：470.1[M+H] +.Anal.Calcd?for?C 23H 20ClN 3O 4S：C，H，N.
The preparation of embodiment 24: 4-(5-(1.4-benzodioxan)-3-(3.4-dichlorophenyl)-4,5-pyrazolines) benzsulfamide (compound 62)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 73.5% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.171～173℃； 1H?NMR(DMSO-d6，400MHz)δ：7.7.97(d，J＝1.9Hz，2H，ArH)，7.76～7.61(m，5H，ArH)，7.24～7.06(m，4H，hrH)，6.82～6.68(m，3H，ArH?and?NH 2)，5.59(dd，J 1＝4.8，J 2＝5.0Hz，1H，5-H)，4.19(s，4H，CH 2)，3.89(dd，J 1＝12.0，J 2＝24.0Hz，1H，4-H b)，3.19(dd，J 1＝5.0，J 2＝4.9Hz，1H，4-Ha).ESI-MS：504.1[M+H] +.Anal.Calcd?for?C 23H 19C1 2N 3O 4S：C，H，N.
The preparation of embodiment 25: 4-(5-(1.4-benzodioxan)-3-(p-bromophenyl)-4,5-pyrazolines) benzsulfamide (compound 63)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 63.5% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.153～154℃； 1H?NMR(DMSO-d6，300MHz)δ：7.72(d，J＝8.6Hz，2H，ArH)，7.61(q，J＝8.8Hz，2H，ArH)，7.09(t，J＝8.8Hz，2H，ArH)，6.99(s，2H，NH 2)，6.81(2，J＝8.0Hz，2H，ArH)，5.55(dd，J 1＝4.9，J 2＝4.9Hz，1H，5-H)，4.19(s，4H，CH 2)，3.91(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，3.16(dd，J 1＝5.0，J 2＝4.9Hz，1H，4-Ha).ESI-MS：514.0[M+H] +.Anal.Calcd?for?C 23H 20BrN 3O 4S：C，H，N.
The preparation of embodiment 26: 4-(5-(1.4-benzodioxan)-3-(p-fluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 64)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 67.8% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.195～196℃； 1H?NMR(DMSO-d6，300MHz)δ：7.84(q，J＝5.6Hz，2H，ArH)，7.60(d，J＝8.9Hz，2H，ArH)，7.29(t，J＝8.8Hz，2H，ArH)，7.08(t，J＝8.9Hz，2H，ArH)，6.99(s，2H，NH 2)，6.82(q，2，J＝8.1Hz，2H，ArH)，6.70(t，J＝8.0Hz，2H，ArH)，5.54(dd，J 1＝4.8，J 2＝4.8Hz，1H，5-H)，4.19(s，4H，CH 2)，3.91(dd，J 1＝12.1，J 2＝11.9Hz，1H，4-H b)，3.16(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha).ESI-MS：454.1[M+H] +.Anal.Calcd?for?C 23H 20FN 3O 4S：C，H，N.
The preparation of embodiment 27: 4-(5-(1.4-benzodioxan)-3-(2.4-difluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 65)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 65.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.168～169℃； 1H?NMR(DMSO-d6，300MHz)δ：7.97(q，J＝7.6Hz，1H，ArH)，7.61(d，J＝7.9Hz，2H，ArH)，7.36(q，J＝9.7Hz，1H，ArH)，7.20(t，J＝8.4Hz，2H，ArH)，7.10(d，J＝9.0Hz，2H，ArH)，7.08(s，2H，NH 2)，6.81(d，J＝8.4Hz，1H，ArH)，6.70(d，J＝10.0Hz，2H，ArH)，5.53(dd，J 1＝4.5，J 2＝4.7Hz，1H，5-H)，4.19(s，4H，CH 2)，3.98(dd，J 1＝12.3，J 2＝12.2Hz，1H，5-H)，3.44(dd，J 1＝6.8，J 2＝7.4Hz，1H，4-H b)，3.14(dd，J 1＝2.5，J 2＝4.3Hz，1H，4-Ha).ESI-MS：472.1[M+H] +.Anal.Calcd?for?C 23H 19F 2N 3O 4S：C，H，N.
The preparation of embodiment 28: 4-(5-(1.4-benzodioxan)-3-(p-iodophenyl)-4,5-pyrazolines) benzsulfamide (compound 66)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 72.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.187～189℃； 1H?NMR(DMSO-d6，300MHz)δ：7.79(d，J＝8.1Hz，2H，ArH)，7.63(d，J＝7.6Hz，2H，ArH)，7.55(d，J＝8.0Hz，2H，ArH)，7.11(d，J＝8.6Hz，2H，ArH)，6.82(2，J＝8.1Hz，2H，ArH)，6.70(s，2H，NH 2)，5.53(dd，J 1＝4.6，J 2＝4.7Hz，1H，5-H)，4.18(s，4H，CH 2)，3.87(dd，J 1＝12.4，J 2＝12.0Hz，1H，4-H b)，3.13(dd，J 1＝4.7，J 2＝4.5Hz，1H，4-Ha).ESI-MS：562.0[M+H] +.Anal.Calcd?for?C 23H 20IN 3O 4S：C，H，N.
The preparation of embodiment 29: 4-(5-(1.4-benzodioxan)-3-(the fluoro-4-p-methoxy-phenyl of 2-)-4,5-pyrazolines) benzsulfamide (compound 67)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 89.5% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.211～212℃； 1H?NMR(DMSO-d6，400MHz)δ：7.85(t，J＝8.8Hz，1H，ArH)，7.60(d，J＝8.9Hz，2H，ArH)，7.06(d，J＝8.9Hz，3H，ArH)，6.69～6.93(m，5H，ArH?and?NH 2)，5.47(dd，J 1＝4.9，J 2＝5.0Hz，1H，5-H)，4.09(s，4H，CH 2)，3.94(dd，J 1＝12.0，J 2＝11.5Hz，1H，4-H b)，3.82(s，3H，CH 3)，3.12(dd，J 1＝3.6，J 2＝2.64Hz，1H，4-Ha).ESI-MS：484.5[M+H] +.Anal.Calcd?for?C 24H 22FN 3O 5S：C，H，N.
The preparation of embodiment 30: 4-(5-(1.4-benzodioxan)-3-(p-methylthio group phenyl)-4,5-pyrazolines) benzsulfamide (compound 68)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 87.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.202～203℃； 1H?NMR(DMSO-d6，400MHz)δ：7.71(d，J＝8.4Hz，2H，ArH)，7.60(d，J＝9.0Hz，2H，ArH)，7.32(d，J＝8.5Hz，2H，ArH)，6.69～7.09(m，7H，ArH?and?NH 2)，5.52(dd，J 1＝4.8，J 2＝5.0Hz，1H，5-H)，4.19(s，4H，CH 2)，3.88(dd，J 1＝12.0，J 2＝11.9Hz，1H，4-H b)，3.15(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha)，2.52(s，3H，CH 3).ESI-MS：482.6[M+H] +.Anal.Calcd?for?C 24H 23N 3O 4S 2：C，H，N.
The preparation of embodiment 31: 4-(5-(1.4-benzodioxan)-3-(m-iodophenyl)-4,5-pyrazolines) benzsulfamide (compound 69)
Preparation method is with embodiment one.To replace obtaining tawny crystal, productive rate 87.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.209～210℃； 1H?NMR(DMSO-d6，400MHz)δ：8.13(s，H，ArH)，7.75(d，J＝8.9Hz，2H，ArH)，7.61(d，J＝8.8Hz，2H，ArH)，7.23(t，J＝7.8Hz，H，ArH)，7.11(d，J＝8.9Hz，2H，ArH)，7.06(s，2H，NH 2)，6.81(d，J＝8.1Hz，H，ArH)，6.68～6.70(m，2H，ArH)，5.55(dd，J 1＝4.8，J 2＝4.9Hz，1H，5-H)，4.18(s，4H，CH 2)，3.87(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，3.16(dd，J 1＝5.0，J 2＝4.8Hz，1H，4-Ha).ESI-MS：562.4[M+H] +.Anal.Calcd?for?C 23H 20IN 3O 4S：C，H，N.
The preparation of embodiment 32: 4-(5-(1.4-benzodioxan)-3-(p-trifluoromethyl)-4,5-pyrazolines) benzsulfamide (compound 70)
Preparation method is with embodiment one.To replace obtaining yellow crystals, 63.3% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.216～218℃； 1H?NMR(DMSO-d6，400MHz)δ：7.97(d，J＝8.1Hz，2H，ArH)，7.79(d，J＝8.4Hz，2H，ArH)，7.63(d，J＝8.9Hz，2H，ArH)，7.14(d，J＝8.9Hz，2H，ArH)，6.70～6.83(m，3H，ArH?and?NH 2)，5.61(dd，J 1＝5.0，J 2＝5.1Hz，1H，5-H)，4.19(s，4H，CH 2)，3.91～4.03(m，2H，ArH?and?4-H b)，3.21(dd，J 1＝5.1，J 2＝5.0Hz，1H，4-Ha).ESI-MS：504.5[M+H] +.Anal.Calcd?for?C 24H 20F 3N 3O 4S：C，H，N.
The preparation of embodiment 33: 4-(5-(1.4-benzodioxan)-3-(p-nitrophenyl)-4,5-pyrazolines) benzsulfamide (compound 71)
Preparation method is with embodiment one.To replace obtaining red crystals, productive rate 89.6% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.219～220℃； 1H?NMR(DMSO-d6，400MHz)δ：8.27(d，J＝9.0Hz，2H，ArH)，7.99(d，J＝8.0Hz，2H，ArH)，7.65(d，J＝9.9Hz，2H，ArH)，7.18(d，J＝8.9Hz，2H，ArH)，7.09(s，2H，NH 2)，6.82(d，J＝8.24Hz，H，ArH)，6.70～6.74(m，2H，ArH)，5.65(dd，J 1＝5.0，J 2＝5.2Hz，1H，5-H)，4.19(s，4H，CH 2)，3.96(dd，J 1＝12.4，J 2＝12.2Hz，1H，4-H b)，3.23(dd，J 1＝5.2，J 2＝5.1Hz，1H，4-Ha).ESI-MS：481.5[M+H] +.Anal.Calcd?for?C 23H 20IN 3O 4S：C，H，N.Anal.Calcd?for?C 23H 20N 4O 6S：C，H，N.
The preparation of embodiment 34: 4-(3.5-(1.3-benzodioxan)-4,5-pyrazolines) benzsulfamide (compound 72)
Preparation method is with embodiment one.Obtain white crystal, productive rate 48.6%.m.p.196～198℃； 1HNMR(DMSO-d6，400MHz)δ：7.60(d，J＝8.5Hz，2H，ArH)，7.43(s，1H，ArH)，7.20(d，J＝8.1Hz，1H，ArH)，7.08(d，J＝8.4Hz，2H，ArH)，7.04(s，2H，NH 2)，6.97(d，J＝8.0Hz，1H，ArH)，6.86(d，J＝7.9Hz，1H，ArH)，6.74(d，J＝8.12Hz，2H，ArH)，6.09(s，2H，CH 2)，5.98(s，2H，CH 2)，5.51(dd，J 1＝4.6，J 2＝4.8Hz，1H，5-H)，3.86(dd，J 1＝12.2，J 2＝12.0Hz，1H，4-H b)，3.13(dd，J 1＝4.6，J 2＝4.5Hz，1H，4-Ha).ESI-MS：465.1[M+H] +.Anal.Calcd?for?C 23H 19N 3O 6S：C，H，N.
The preparation of embodiment 35: 4-(3.5-(1.3-benzodioxan)-5-(1.4-benzodioxan)-4,5-pyrazolines) benzsulfamide (compound 73)
Preparation method is with embodiment one.To replace obtaining white crystal, productive rate 58.4% containing the cinnamophenone of 1.3-benzodioxan skeleton containing the cinnamophenone of 1.4-benzodioxan skeleton.m.p.186～188℃； 1H?NMR(DMSO-d6，300MHz)δ：7.58(d，J＝8.9Hz，2H，ArH)，7.41(s，1H，ArH)，7.20(q，J＝1.2Hz，1H，ArH)，7.05(q，J＝2.8Hz，4H，ArH)，6.98(d，J＝8.1Hz，1H，ArH)，7.81(d，J＝8.0Hz，1H，ArH)，6.70(s，2H，NH 2)，6.10(s，2H，CH 2)，5.50(dd，J 1＝4.7，J 2＝4.8Hz，1H，5-H)，4.19(s，4H，CH 2)，3.84(dd，J 1＝12.1，J 2＝11.8Hz，1H，4-H b)，3.12(dd，J 1＝4.9，J 2＝4.7Hz，1H，4-Ha).ESI-MS：480.1[M+H] +.Anal.Calcd?for?C 24H 21N 3O 6S：C，H，N.
Embodiment 36: the pyrazoline sulphone amide derivative anti tumor activity in vitro containing benzodioxan skeleton is studied
Adopt MTT [3-(4,5)-bis-methyl-2-thiazole-(2,5)-phenyl bromination tetrazole is blue] method measures the half-inhibition concentration (IC of pyrazoline sulphone amide derivative to 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 (often liter): 1. suspension cell: DMEM cultivates one bag, powder (10.4g), new-born calf serum 100mL, penicillin solution (200,000 U/mL) 0.5mL, Streptomycin Solution (200,000 U/mL) 0.5mL, after adding tri-distilled water dissolving, with the NaHCO of 5.6% 3solution adjusts pH value 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 2o0.06g, 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, generally 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.The concentration of DMSO in nutrient solution is unsuitable excessive, and in the every porocyte suspension after dosing, the final concentration of DMSO is generally no more than 0.05-0.1%.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, went down to posterity once every 3-4 days.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, adjusts concentration of cell suspension to be (1-1.5) × 10 5individual mL -1.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 LDMSO, 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 sulphone amide derivative containing benzodioxan skeleton of table 1 the present invention is to the suppression IC of tumour cell 50value (μm ol/mL)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 37: containing the pyrazoline sulphone amide derivative anti tumor activity in vitro of benzodioxan skeleton about the research suppressing MMP-2 (MMP-2) active
1. experiment material
Reagent: MMP-2 proteolytic enzyme rhMMP2,10082-HNAH, Sino Biological Inc.; Mca-PLGL-Dpa-AR-NH 2(AnaSpec, Catalog#27076), Shanghai gill biochemistry corporation,Ltd..P-aminophenylmercuric acetate (APMA) (Genmed Scientifics Inc.U.S.A, Catalog#GMS12197v.A), Sigma company produces.Other conventional chemical reagent is domestic analytical pure.
Instrument: TECAN A-5882 microplate reader (Switzerland), Other Instruments is the same.
2. experimental technique
(1) with containing the Assay Buffer of 1mM APMA by rhMMP2 protein activation, its ultimate density is made to be 100 μ g/mL.
(2) rhMMP2 albumen is hatched 1h at 37 DEG C.
(3) with Assay Buffer, the rhMMP2 albumen after activation is diluted to 0.2 μ g/mL.
(4) with Assay Buffer, substrate is diluted to 40 μMs.
(5) in 96 orifice plates, add the rhMMP2 after 50 μ L dilutions, and add the liquid 25 μ L of different concns, act on and add 25 μ L at low temperatures after 10 minutes, the substrate Mca-PLGL-Dpa-AR-NH of 40 μMs 2.
(6) fluorescence is surveyed in Ex320nm, EM450nm place, kinetic measurement 5min.
Active calculating: inhibiting rate=[(Ke-Kc)-(Ks-Kc)]/(Ke-Kc) × 100%
Ke: enzyme activity contrast Kc: blank Background control Ks: experimental value
The IC recorded 50be shown in Table 2.
The listed pyrazoline sulphone amide derivative containing benzodioxan skeleton of table 2 the present invention is to the suppression IC of matrix metalloproteinase 50value (μm ol/mL)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 38: containing the pyrazoline sulphone amide derivative anti tumor activity in vitro of benzodioxan skeleton about Cytotoxic research
The present invention tests new synthetic compound 39-73 to the cytotoxicity of people's renal epithelial cell (293T), cytotoxicity result as table 3, 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 horizontal jolting makes solution colour in hole even.
(6) measure absorbancy by microplate reader, wavelength adopts 570nm.
The CC recorded 50be shown in Table 3.
The listed pyrazoline sulphone amide derivative containing benzodioxan skeleton of table 3 the present invention is to the suppression CC of 293T cell 50value (μm ol/mL)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%.

Claims (2)

1. a class is containing the synthesis of the pyrazoline sulphone amide derivative of benzodioxan skeleton, it is characterized in that it has following general formula:
A synthesis for the above-mentioned pyrazoline sulphone amide derivative containing benzodioxan skeleton, it is made up of the following step:
3,4 Dihydroxy benzaldehydes (50mmol) are dissolved in 250mL dry DMF by step 1., then add the glycol dibromide of 70mmol or the Anhydrous potassium carbonate of methylene bromide and 25mmol, 70 DEG C of 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) raw material 2-3, is obtained.
Step 2. under stirring at room temperature, the methyl phenyl ketone (10.0mmol) of different substituents, the 40%KOH aqueous solution, different benzodioxan formaldehyde (10.0mmol), ethanol (50mL) is added successively in the round-bottomed flask of 100mL, after maintaining this temperature continuation stirring reaction 4h, reaction solution is poured in 500mL beaker, 1mol/L hcl acidifying, filter, solid uses 1mol/L hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 4-38.
Step 3. is successively by different cinnamophenone 4-38 (4mmol), dehydrated alcohol (25mL), join in the round-bottomed flask of 50mL to Hydrazinobenzenesulfonamide (4.5mmol), acetic acid (1.0mL), after stirring at room temperature reaction 1h, still have fraction solids insoluble; Transferred to by reaction flask in oil bath pan, back flow reaction 6h, TLC follow the tracks of reaction (developping agent V acOEt: V pE=1: 2), after reaction terminates, filter, solid uses 1mol/L hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold washing with alcohol (3 × 50mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains lenticular target compound 39-73 by the solid crude product obtained.
2. according to claim containing the synthesis of pyrazoline sulphone amide derivative of benzodioxan skeleton and the application in cancer therapy drug.
CN201410442746.8A 2014-08-29 2014-08-29 Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs Pending CN104230905A (en)

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