CN104230904A - Synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs - Google Patents
Synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs Download PDFInfo
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- CN104230904A CN104230904A CN201410442700.6A CN201410442700A CN104230904A CN 104230904 A CN104230904 A CN 104230904A CN 201410442700 A CN201410442700 A CN 201410442700A CN 104230904 A CN104230904 A CN 104230904A
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- dihydropyrazol
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- GUAQVFRUPZBRJQ-UHFFFAOYSA-N n-(3-aminopropyl)-2-methylprop-2-enamide Chemical compound CC(=C)C(=O)NCCCN GUAQVFRUPZBRJQ-UHFFFAOYSA-N 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960005222 phenazone Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003219 pyrazolines Chemical class 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons. The synthesis is characterized by being provided with a general formula shown in descriptions. The dihydropyrazol sulfonamide derivatives containing the naphthalene ring 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 naphthalene ring 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 naphthalene ring skeletons.
Description
Summary of the invention
The object of the present invention is to provide a class containing the synthesis of pyrazoline sulphone amide derivative of naphthalene nucleus 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 naphthalene nucleus skeleton, is characterized in that it has following general formula:
A synthesis for the above-mentioned pyrazoline sulphone amide derivative containing naphthalene nucleus skeleton, it is made up of the following step:
Step 1. under stirring at room temperature, the methyl phenyl ketone (10.0mmol) of different substituents, the 40%KOH aqueous solution, the naphthaldehyde (10.0mmol) of different substituents, ethanol (50mL) is added successively in the round-bottomed flask of 100mL, after continuing stirring reaction 4h, reaction solution is poured in 500mL beaker, 1mol/L hcl acidifying (pH=7.0), filter, solid uses distilled water (3 × 100mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 2-16.
Step 2. is successively by different cinnamophenone 2-16 (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 ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains lenticular target compound 17-31 by the solid crude product obtained.
Pyrazoline sulphone amide derivative containing naphthalene nucleus skeleton of the present invention has obvious restraining effect to human breast cancer cell (MCF-7), cervical cancer cell (HeLa), lung carcinoma cell (A549), liver cancer cell (HepG2) and MMP-2 (MMP-2), shows quite simultaneously or be better than the cytotoxicity of positive control medicine to people's renal epithelial cell (293T).Therefore the pyrazoline sulphone amide derivative containing naphthalene nucleus skeleton of the present invention can be applied to and prepare antitumor drug.
Background technology
Pyrazoles is the important heterogeneous ring compound of a class, is extensively distributed in occurring in nature.Since being found to have easing pain and diminishing inflammation and antipyretic effect containing the antipyrine of pyrazole ring, this compounds because of its have efficiently, low toxicity, and the character of 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 a lot of excellent 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.In addition, because mostly 2H pyrazoles is the conformation of the replacement on ring and molecule can be caused to have larger polytropy, thus, have chirality 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.
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.
The report of naphthalene nucleus skeleton on all kinds of International Periodicals is many, can be described as the large focus that compound structure modifies field.Except having outstanding anti-microbial activity, and there is outstanding anti-tumor activity.Along with the mechanism of tumor development is furtherd investigate gradually, naphthalene cycle compound is broadly applied in the exploitation of antitumor lead compound gradually.
Based on this, the present invention is by different sulfanilamide (SN) and have outstanding bioactive naphthalene nucleus skeleton and be incorporated in pyrazoline derivative, the a series of pyrazoline sulphone amide derivative containing naphthalene nucleus 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-(Alpha-Naphthyl)-3-(p-p-methoxy-phenyl)-4,5-pyrazolines) benzsulfamide (compound 17)
Under agitation successively by the cinnamophenone (1.0g of Alpha-Naphthyl, 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.
Obtain white crystal, productive rate 69.7%.m.p.194～196℃；
1H?NMR(DMSO-d6，300MHz)δ：8.33(s，1H，ArH)，8.02(d，J＝8.1Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.70～7.31(m，4H，ArH)，7.42～7.31(m，4H，ArH)，7.09～6.70(m，6H，ArH?and?NH
2)，?6.35(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.21(dd，J
1＝12.1，J
2＝11.8Hz，1H，4-H
b)，3.80(s，3H，OCH
3)，3.16(dd，J
1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：458.1[M+H]
+.Anal.Calcd?for?C
26H
23N
3O
3S：C，H，N.
The preparation of embodiment two: 4-(5-(Alpha-Naphthyl)-3-(m-aminomethyl phenyl)-4,5-pyrazolines) benzsulfamide (compound 18)
Preparation method is with embodiment one.Obtain white crystal, productive rate 70.4%.m.p.229～230℃；
1H?NMR(DMSO-d6，300MHz)δ：8.33(s，1H，ArH)，8.03(d，J＝8.1Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.70～7.58(m，6H，ArH)，7.42～7.21(m，3H，ArH)，7.03(s，4H，ArH?and?NH
2)，6.36(dd，J
1＝5.4，J
2＝5.5Hz，1H，5-H)，4.23(dd，J
1＝12.4，J
2＝12.2Hz，1H，4-H
b)，3.16(dd，J
1＝3.8，J
2＝5.3Hz，1H，4-Ha)，2.34(s，3H，CH
3).ESI-MS：442.1[M+H]
+.Anal.Calcd?for?C
26H
23N
3O
2S：C，H，N.
The preparation of embodiment three: 4-(5-(Alpha-Naphthyl)-3-(o-aminomethyl phenyl)-4,5-pyrazolines) benzsulfamide (compound 19)
Preparation method is with embodiment one.Obtain white crystal, productive rate 67.3%.n.p.232～235℃；
1H?NMR(DMSO-d6，300MHz)δ：7.92～7.84(m，4H，ArH)，7.68(s，1H，ArH)，7.59(t，J＝6.8Hz，3H，ArH)，7.53～7.48(m，2H，ArH)，7.37～7.33(m，2H，ArH)，7.14(d，J＝8.9Hz，2H，ArH)，7.00(s，2H，NH
2)，5.81(dd，J
1＝5.2，J
2＝5.2Hz，1H，5-H)，4.05(dd，J
1＝12.3，J
2＝12.1Hz，1H，4-H
b)，3.28(dd，J
1＝5.3，J
2＝5.2Hz，1H，4-Ha)，2.37(s，3H，CH
3).ESI-MS：442.1[M+H]
+.Anal.Calcd?for?C
26H
23N
3O
2S：C，H，N.
The preparation of embodiment four: 4-(5-(Alpha-Naphthyl)-3-(m-iodo phenyl)-4,5-pyrazolines) benzsulfamide (compound 20)
Preparation method is with embodiment one.Obtain white crystal, productive rate 78.5%.m.p.218～220℃；
1H?NMR(DMSO-d6，300MHz)δ：8.31(s，1H，ArH)，8.02(d，J＝8.0Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.77(d，J＝8.1Hz，2H，ArH)，7.70～7.55(m，6H，ArH)，7.39(d，J＝6.9Hz，1H，ArH)，7.08(s，2H，NH
2)，7.04(d，J＝8.4Hz，3H，ArH)，6.34(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.21(dd，J
1＝12.8，J
2＝12.5Hz，1H，4-H
b)，3.13(dd，J
1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：554.1[M+H]
+.Anal.Calcd?for?C
25H
20IN
3O
2S：C，H，N.
The preparation of embodiment five: 4-(5-(Alpha-Naphthyl)-3-(o-chloro-phenyl-)-4,5-pyrazolines) benzsulfamide (compound 21)
Preparation method is with embodiment one.Obtain white crystal, productive rate 59.8.5%.m.p.190～191℃；
1H?NMR(DMSO-d6，300MHz)δ：8.33(s，1H，ArH)，8.02(d，J＝8.0Hz，1H，ArH)，7.88～7.80(m，2H，ArH)，7.77～7.61(m，5H，ArH)，7.54～7.38(m，3H，ArH)，7.01(s，2H，NH
2)，7.04(d，J＝9.9Hz，1H，ArH)，6.39(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.39(dd，J
1＝12.7，J
2＝12.4Hz，1H，4-H
b)，3.24(dd，J1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：462.1[M+H]
+.Anal.Calcd?for?C
25H
20C1N
3O
2S：C，H，N.
The preparation of embodiment six: 4-(5-(Alpha-Naphthyl)-3-(2,4 difluorobenzene base)-4,5-pyrazolines) benzsulfamide (compound 22)
Preparation method is with embodiment one.Obtain white crystal, productive rate 73.4%.m.p.250～252℃；
1H?NMR(DMSO-d6，300MHz)δ：8.03(q，J＝8.7Hz，1H，ArH)，7.93～7.85(m，4H，ArH)，7.59(d，J＝8.9Hz，2H，ArH)，7.53～7.35(m，4H，ArH)，7.24～7.20(m，1H，ArH)，7.14(d，J＝8.8Hz，2H，ArH)，7.03(s，2H，NH
2)，5.80(dd，J
1＝5.5，J
2＝5.6Hz，1H，5-H)，4.12(dd，J
1＝12.4，J
2＝12.4Hz，1H，4-H
b)，3.29(dd，J
1＝4.4，J
2＝5.2Hz，1H，4-Ha).ESI-MS：464.1[M+H]
+.Anal.Calcd?for?C
25H
19F
2N
3O
2S：C，H，N.
The preparation of embodiment seven: 4-(5-(betanaphthyl)-3-(o-aminomethyl phenyl)-4,5-pyrazolines) benzsulfamide (compound 23)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 68.8% with the cinnamophenone of betanaphthyl.m.p.228～229℃；
1H?NMR(DMSO-d6，300MHz)δ：7.92～7.87(m，4H，ArH)，7.59(d，J＝8.9Hz，2H，ArH)，7.53～7.47(m，3H，ArH)，7.38～7.25(m，4H，ArH)，7.10(d，J＝8.7Hz，2H，ArH)，7.01(s，2H，NH
2)，5.75(dd，J
1＝5.3，J
2＝5.4Hz，1H，5-H)，4.13(dd，J
1＝12.2，J
2＝12.1Hz，1H，4-H
b)，3.34(dd，J
1＝4.4，J
2＝5.2Hz，1H，4-Ha)，2.76(s，3H，CH
3).ESI-MS：442.1[M+H]
+.Anal.Calcd?for?C
26H
23N
3O
2S：C，H，N.
The preparation of embodiment eight: 4-(5-(betanaphthyl)-3-(m-p-methoxy-phenyl)-4,5-pyrazolines) benzsulfamide (compound 24)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 72.8% with the cinnamophenone of betanaphthyl.m.p.215～217℃；
1H?NMR(DMSO-d6，300MHz)δ：8.33(s，1H，ArH)，8.02(d，J＝8.1Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.70～7.31(m，4H，ArH)，7.42～7.31(m，4H，ArH)，7.09～6.70(m，6H，ArH?and?NH
2)，6.35(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.21(dd，J
1＝12.1，J
2＝11.8Hz，1H，4-H
b)，3.80(s，3H，OCH
3)，3.16(dd，J
1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：458.1[M+H]
+.Anal.Calcd?for?C26H23N3O3S：C，H，N.
The preparation of embodiment nine: 4-(5-(betanaphthyl)-3-(m-aminomethyl phenyl)-4,5-pyrazolines) benzsulfamide (compound 25)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 71.3% with the cinnamophenone of betanaphthyl.m.p.206～207℃；
1H?NMR(DMSO-d6，300MHz)δ：7.92～7.84(m，4H，ArH)，7.68(s，1H，ArH)，7.59(t，J＝6.8Hz，3H，ArH)，7.53～7.48(m，2H，ArH)，7.37～7.33(m，2H，ArH)，7.14(d，J＝8.9Hz，2H，ArH)，7.00(s，2H，NH
2)，5.81(dd，J
1＝5.2，J
2＝5.2Hz，1H，5-H)，4.05(dd，J
1＝12.3，J
2＝12.1Hz，1H，4-H
b)，3.28(dd，J
1＝5.3，J
2＝5.2Hz，1H，4-Ha)，2.37(s，3H，CH
3).ESI-MS：442.1[M+H]
+.Anal.Calcd?for?C
26H
23N
3O
2S：C，H，N.
The preparation of embodiment ten: 4-(5-(betanaphthyl)-3-(m-chloro-phenyl-)-4,5-pyrazolines) benzsulfamide (compound 26)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 69.2% with the cinnamophenone of betanaphthyl.n.p.165～167℃；
1H?NMR(DMSO-d6，300MHz)δ：8.33(s，1H，ArH)，8.02(d，J＝8.0Hz，1H，ArH)，7.88～7.80(m，2H，ArH)，7.77～7.61(m，5H，ArH)，7.54～7.38(m，3H，ArH)，7.01(s，2H，NH
2)，7.04(d，J＝9.9Hz，1H，ArH)，6.39(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.39(dd，J
1＝12.7，J
2＝12.4Hz，1H，4-H
b)，3.24(dd，J
1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：462.1[M+H]
+.Anal.Calcd?for?C
25H
20IN
3O
2S：C，H，N.
The preparation of embodiment 11: 4-(5-(betanaphthyl)-3-(m-iodo phenyl)-4,5-pyrazolines) benzsulfamide (compound 27)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 71.5% with the cinnamophenone of betanaphthyl.m.p.216～218℃；
1H?NMR(DMSO-d6，300MHz)δ：8.31(s，1H，ArH)，8.02(d，J＝8.0Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.77(d，J＝8.1Hz，2H，ArH)，7.70～7.55(m，6H，ArH)，7.39(d，J＝6.9Hz，1H，ArH)，7.08(s，2H，NH
2)，7.04(d，J＝8.4Hz，3H，ArH)，6.34(dd，J
1＝4.7，J
2＝4.8Hz，1H，5-H)，4.21(dd，J
1＝12.8，J
2＝12.5Hz，1H，4-H
b)，3.13(dd，J
1＝4.9，J
2＝4.7Hz，1H，4-Ha).ESI-MS：554.1[M+H]
+.Anal.Calcd?for?C
25H
20ClN
3O
2S：C，H，N.
The preparation of embodiment 12: 4-(5-(betanaphthyl)-3-(m-fluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 28)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 69.2% with the cinnamophenone of betanaphthyl.m.p.229～230℃；
1H?NMR(DMSO-d6，300MHz)δ：8.00(t，J＝7.4Hz，1H，ArH)，7.93～7.85(m，4H，ArH)，7.59(d，J＝8.8Hz，2H，ArH)，7.53～7.44(m，3H，ArH)，7.40～7.28(m，3H，ArH)，7.15(d，J＝8.8Hz，2H，ArH)，7.03(s，2H，NH
2)，5.81(dd，J
1＝5.4，J
2＝5.5Hz，1H，5-H)，4.14(dd，J
1＝12.3，J
2＝12.3Hz，1H，4-H
b)，3.30(dd，J
1＝3.8，J
2＝5.3Hz，1H，4-Ha).ESI-MS：446.1[M+H]
+.Anal.Calcd?for?C
25H
20FN
3O
2S：C，H，N.
The preparation of embodiment 13: 4-(5-(betanaphthyl)-3-(2.4-difluorophenyl)-4,5-pyrazolines) benzsulfamide (compound 29)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 68.3% with the cinnamophenone of betanaphthyl.m.p.225～227℃；
1H?NMR(DMSO-d6，300MHz)δ：8.03(q，J＝8.7Hz，1H，ArH)，7.93～7.85(m，4H，ArH)，7.59(d，J＝8.9Hz，2H，ArH)，7.53～7.35(m，4H，ArH)，7.24～7.20(m，1H，ArH)，7.14(d，J＝８.8Hz，2H，ArH)，7.03(s，2H，NH
2)，5.80(dd，J
1＝5.5，J
2＝5.6Hz，1H，5-H)，4.12(dd，J
1＝12.4，J
2＝12.4Hz，1H，4-H
b)，3.29(dd，J
1＝4.4，J
2＝5.2Hz，1H，4-Ha).ESI-MS：464.1[M+H]
+.Anal.Calcd?forC
25H
19F
2N
3O
2S：C，H，N.
Embodiment 14: 4-(5-(1.3-benzodioxan)-5-(α-naphthalene nucleus)-4,5-pyrazolines) preparation of benzsulfamide (compound 30)
Preparation method is with embodiment one.White crystal, productive rate 68.2%.m.o.212～213C；
1H?NMR(DMSO-d6，300MHz)δ：8.31(s，1H，ArH)，8.02(d，J＝8.1Hz，1H，ArH)，7.87(d，J＝8.2Hz，1H，ArH)，7.70～7.56(m，4H，ArH)，7.45～7.39(m，2H，ArH)，7.20(d，J＝8.0Hz，1H，ArH)，7.04(s，2H，NH
2)，7.02～6.94(m，4H，ArH)，6.31(dd，J
1＝5.4，J
2＝5.5Hz，1H，5-H)，6.09(s，2H，CH
2)，4.18(dd，J
1＝12.4，J
2＝12.2Hz，1H，4-H
b)，3.13(dd，J
1＝3.8，J
2＝5.3Hz，1H，4-Ha).ESI-MS：472.1[M+H]
+.Anal.Calcd?for?C
26H
21N
3O
4S：C，H，N.
The preparation of embodiment 15: 4-(5-(1.3 benzodioxan)-5-(β-naphthalene nucleus)-4,5-pyrazolines) benzsulfamide (compound 31)
Preparation method is with embodiment one.The cinnamophenone of Alpha-Naphthyl is replaced to obtain white crystal, productive rate 64.1% with the cinnamophenone of betanaphthyl.m.p.236～238℃；
1H?NMR(DMSO-d6，300MHz)δ：8.35～7.7.83(m，4H，ArH)，7.7.60～7.47(m，6H，ArH)，7.37～7.35(m，2H，ArH)，7.14～6.98(m，4H，ArH?and?NH
2)，6.10(s，2H，CH
2)，5.77(dd，J
1＝5.3，J
2＝5.5Hz，1H，5-H)，4.00(dd，J
1＝12.2，J
2＝12.0Hz，1H，4-H
b)，3.25(dd，J
1＝5.4，J
2＝5.3Hz，1H，4-Ha).ESI-MS：472.1[M+H]
+.Anal.Calcd?for?C
26H
21N
3O
4S：C，H，N.
Embodiment 16: containing the pyrazoline sulphone amide derivative anti tumor activity in vitro of naphthalene nucleus skeleton about the research of anti-tumour cell proliferative
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): NaCl8.00g, 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, tune concentration of cell suspension is 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 naphthalene nucleus skeleton of table 1 the present invention is to the suppression IC of tumour cell
50value (μm ol/mL)
α3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 17: containing the pyrazoline sulphone amide derivative anti tumor activity in vitro of naphthalene nucleus 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: TECANA-5882 microplate reader (Switzerland), Other Instruments is the same.
2. experimental technique
(1) with containing the Assay Buffer of 1mMAPMA 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 25TL 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 naphthalene nucleus skeleton of table 2 the present invention is to the suppression IC of matrix metalloproteinase
50value (μm ol/mL)
α3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 18: containing the pyrazoline sulphone amide derivative anti tumor activity in vitro of naphthalene nucleus skeleton about Cytotoxic research
The present invention tests new synthetic compound 15-27 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 ± 2C 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 570nn.
The CC recorded
50be shown in Table 3.
The listed pyrazoline sulphone amide derivative containing naphthalene nucleus skeleton of table 3 the present invention is to the suppression CC of 293T cell
50value (μm ol/mL)
α3 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 naphthalene nucleus skeleton, it is characterized in that it has following general formula:
A synthesis for above-mentioned pyrazoline sulphone amide derivative, it is made up of the following step:
Step 1. under stirring at room temperature, the methyl phenyl ketone (10.0mmol) of different substituents, the 40%KOH aqueous solution, the naphthaldehyde (10.0mmol) of different substituents, ethanol (50mL) is added successively in the round-bottomed flask of 100mL, after continuing stirring reaction 4h, reaction solution is poured in 500mL beaker, 1mol/L hcl acidifying (pH=7.0), filter, solid uses distilled water (3 × 100mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 2-16.
Step 2. is successively by different cinnamophenone 2-16 (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 ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, drying, is dissolved in dehydrated alcohol recrystallization and obtains lenticular target compound 17-31 by the solid crude product obtained.
2. the class according to claim is containing the synthesis of pyrazoline sulphone amide derivative of naphthalene nucleus skeleton and the application in cancer therapy drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829534A (en) * | 2015-05-20 | 2015-08-12 | 南京大学 | Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs |
| CN104961683A (en) * | 2015-07-10 | 2015-10-07 | 南京大学 | Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs |
| CN106146399A (en) * | 2016-06-27 | 2016-11-23 | 南京大学 | One class benzoyl hydrazine derivant containing pyrazoline structure and preparation method thereof |
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| CN1942446A (en) * | 2004-02-16 | 2007-04-04 | 埃斯特韦实验室有限公司 | Pyrazoline derivatives useful for the treatment of cancer |
| CN103664786A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Synthesis method of dihydro-pyrazole sulfonamide derivatives of salicylaldehydes and application of dihydro-pyrazole sulfonamide derivatives to preparation of anticancer drugs |
| CN103664785A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug |
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| CN1942446A (en) * | 2004-02-16 | 2007-04-04 | 埃斯特韦实验室有限公司 | Pyrazoline derivatives useful for the treatment of cancer |
| CN103664786A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Synthesis method of dihydro-pyrazole sulfonamide derivatives of salicylaldehydes and application of dihydro-pyrazole sulfonamide derivatives to preparation of anticancer drugs |
| CN103664785A (en) * | 2013-11-04 | 2014-03-26 | 南京大学 | Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104829534A (en) * | 2015-05-20 | 2015-08-12 | 南京大学 | Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs |
| CN104961683A (en) * | 2015-07-10 | 2015-10-07 | 南京大学 | Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs |
| CN106146399A (en) * | 2016-06-27 | 2016-11-23 | 南京大学 | One class benzoyl hydrazine derivant containing pyrazoline structure and preparation method thereof |
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