CN104945388A - Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs - Google Patents
Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs Download PDFInfo
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- CN104945388A CN104945388A CN201510407971.2A CN201510407971A CN104945388A CN 104945388 A CN104945388 A CN 104945388A CN 201510407971 A CN201510407971 A CN 201510407971A CN 104945388 A CN104945388 A CN 104945388A
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- acylhydrazone
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- 229950002839 clocoumarol Drugs 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title abstract description 4
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 title abstract 5
- 239000002246 antineoplastic agent Substances 0.000 title abstract 2
- 229940041181 antineoplastic drug Drugs 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 239000007787 solid Substances 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000012153 distilled water Substances 0.000 claims description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 10
- -1 filter Substances 0.000 claims description 10
- 229960004756 ethanol Drugs 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 238000011275 oncology therapy Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- CTEZEDIMFASQNI-UHFFFAOYSA-N 2-hydrazinylbenzenesulfonamide Chemical compound NNC1=CC=CC=C1S(N)(=O)=O CTEZEDIMFASQNI-UHFFFAOYSA-N 0.000 claims description 2
- OWBBAPRUYLEWRR-UHFFFAOYSA-N 4-hydroxycoumarin Chemical compound C1=CC=C2OC(O)=CC(=O)C2=C1 OWBBAPRUYLEWRR-UHFFFAOYSA-N 0.000 claims description 2
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 claims description 2
- VXIXUWQIVKSKSA-UHFFFAOYSA-N benzotetronic acid Natural products C1=CC=CC2=C1OC(=O)C=C2O VXIXUWQIVKSKSA-UHFFFAOYSA-N 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 210000004027 cell Anatomy 0.000 abstract description 23
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 230000004071 biological effect Effects 0.000 abstract description 5
- 239000013641 positive control Substances 0.000 abstract description 4
- 206010008342 Cervix carcinoma Diseases 0.000 abstract description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract description 3
- 201000010881 cervical cancer Diseases 0.000 abstract description 3
- 230000003013 cytotoxicity Effects 0.000 abstract description 3
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 3
- 201000001441 melanoma Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 201000009030 Carcinoma Diseases 0.000 abstract 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 abstract 1
- 210000001985 kidney epithelial cell Anatomy 0.000 abstract 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 20
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 10
- 235000015097 nutrients Nutrition 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 5
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- 238000011160 research Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 238000013016 damping Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
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- 208000001953 Hypotension Diseases 0.000 description 2
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000004142 Trypsin Human genes 0.000 description 2
- 108090000631 Trypsin Proteins 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 150000008331 benzenesulfonamides Chemical class 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
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- 239000012737 fresh medium Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
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- 230000036407 pain Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 150000003217 pyrazoles Chemical class 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 239000012588 trypsin Substances 0.000 description 2
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical group C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- OEDUIFSDODUDRK-UHFFFAOYSA-N 5-phenyl-1h-pyrazole Chemical compound N1N=CC=C1C1=CC=CC=C1 OEDUIFSDODUDRK-UHFFFAOYSA-N 0.000 description 1
- RLFWWDJHLFCNIJ-UHFFFAOYSA-N Aminoantipyrine Natural products CN1C(C)=C(N)C(=O)N1C1=CC=CC=C1 RLFWWDJHLFCNIJ-UHFFFAOYSA-N 0.000 description 1
- AIRAUYDAHZSVQQ-FJEPWZHXSA-N Cc(cc1)ccc1-c1cc(C(N/N=C/C(C(Oc2c3cccc2)=O)=C3Cl)=O)n[n]1-c(cc1)ccc1S(N)(=O)=O Chemical compound Cc(cc1)ccc1-c1cc(C(N/N=C/C(C(Oc2c3cccc2)=O)=C3Cl)=O)n[n]1-c(cc1)ccc1S(N)(=O)=O AIRAUYDAHZSVQQ-FJEPWZHXSA-N 0.000 description 1
- HAYNMANUJNGMAK-FJEPWZHXSA-N Cc1cc(-c2cc(C(N/N=C/C(C(Oc3c4cccc3)=O)=C4Cl)=O)n[n]2-c(cc2)ccc2S(N)(=O)=O)ccc1 Chemical compound Cc1cc(-c2cc(C(N/N=C/C(C(Oc3c4cccc3)=O)=C4Cl)=O)n[n]2-c(cc2)ccc2S(N)(=O)=O)ccc1 HAYNMANUJNGMAK-FJEPWZHXSA-N 0.000 description 1
- 244000124209 Crocus sativus Species 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
- DAUUYZZSBTWCKJ-IPPBACCNSA-N NS(c(cc1)ccc1-[n](c(-c(cc1)ccc1O)c1)nc1C(N/N=C/C(C(Oc1c2cccc1)=O)=C2Cl)=O)(=O)=O Chemical compound NS(c(cc1)ccc1-[n](c(-c(cc1)ccc1O)c1)nc1C(N/N=C/C(C(Oc1c2cccc1)=O)=C2Cl)=O)(=O)=O DAUUYZZSBTWCKJ-IPPBACCNSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-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-YZTFXSNBSA-N 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
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- 230000036592 analgesia Effects 0.000 description 1
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- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- VEQOALNAAJBPNY-UHFFFAOYSA-N antipyrine Chemical compound CN1C(C)=CC(=O)N1C1=CC=CC=C1 VEQOALNAAJBPNY-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
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- 230000035619 diuresis Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000003255 drug test Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940089256 fungistat Drugs 0.000 description 1
- 230000002070 germicidal effect Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-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
- 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
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride 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
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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
- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides synthesis for a 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate. The synthesis is characterized by being implemented according to the general formula (please see the formula in specification). The 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate has the obvious inhibiting effect on culture of cervical cancer cells (Hela), human melanoma cells (F10) and hepatoma carcinoma cells (HepG2) and has cytotoxicity equivalent to or better than that of positive control drugs for human kidney epithelial cells (293T). Accordingly, the 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate can be used for preparing anti-tumor drugs. The invention discloses a preparing method of the benzene sulfonamide derivate and anti-tumor biological activity.
Description
Summary of the invention
The object of the present invention is to provide 4-(3-(3-(4-Clocoumarol)-the acylhydrazone)-5-phenyl-pyrazole) preparation method of benzsulfamide analog derivative and the application in cancer therapy drug
Summary of the invention
Technical scheme of the present invention is as follows:
The synthesis of 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative, is characterized in that it has following general formula:
A synthesis for above-mentioned 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative, it is made up of the following step:
6mL phosphorus oxychloride is added drop-wise in 12mL dimethyl formamide by step 1. under 0 DEG C of ice bath, then the 4 hydroxy coumarin being dissolved in dimethyl formamide (6mL) is dropwise joined in above-mentioned mixed solution, allow reaction be raised to stirring at room temperature 2h gradually, then reaction flask is transferred in 60 DEG C of oil bath pans and reacts 6h.After reaction terminates, reaction solution is poured in frozen water, is neutralized to pH=7 with sodium carbonate, filter, solid successively with cold ethanol (3 × 50mL), distilled water (3 × 200mL) washing, dry raw material 2
Sodium methylate (80mmol) is dissolved in 40mL anhydrous methanol by step 2. at 0 DEG C, then each substituent methyl phenyl ketone 3-22 (20mmol) and dimethyl oxalate (40mmol) are dissolved in 40mL anhydrous methanol, dropwise join in the methanol solution of sodium methylate, reaction flask is transferred 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, reaction mixture is added in frozen water, 1mol/L hcl acidifying, filters, solid successively with cold ethanol (3 × 50mL), distilled water (3 × 200mL) washing, dry raw material 23-42.
Step 3. under stirring at room temperature, 23-42 (15mmol) is added successively, to Hydrazinobenzenesulfonamide (15mmol), anhydrous methanol (50mL) in the round-bottomed flask of 100mL, reaction flask is transferred in oil bath pan, back flow reaction 6h, reaction solution is poured in 500mL beaker, filter, solid uses 1mol/L hydrochloric acid (3 × 50mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 43-62.
Step 4. successively by 43-62 (8mmol), dehydrated alcohol (20mL), hydrazine hydrate (120mmol), join in the round-bottomed flask of 50mL, reaction flask is transferred 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, dry, will obtain intermediate 63-82.
Step 5. under stirring at room temperature, successively 63-82 (0.5mmol), 2 (0.6mmol), dehydrated alcohol (20mL), glacial acetic acid (1mL) are joined in the round-bottomed flask of 50mL, after stirring at room temperature 12h, reaction mixture is joined in frozen water, filter, solid is successively with cold ethanol (3 × 50mL), distilled water (3 × 150mL) washing, drying, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains Powdered target compound 83-102.
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.
Coumarin kind compound is the important organic heterocyclic molecule of a class, has antibacterial, sterilization, anti-freezing and the multiple physiologically active such as antitumor, is widely used in pharmaceutical industries.Structural modification is carried out on the basis of tonka bean camphor basic framework, and the derivative of gained can be used as analgesia, desinsection, hypotensive, antithrombotic and the medicine such as anticancer.
Based on this, the present invention is by sulfanilamide (SN) and have outstanding bioactive coumarin skeleton and be incorporated in pyrazoline derivative, design and synthesis a series of 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative, 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-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide
Under agitation 5-phenylpyrazole hydrazides benzsulfamide (0.27g successively, 0.5mmol), ethanol (15mL), the chloro-1-chromen-2-one (0.12g, 0.6mmol) of 4-, acetic acid (0.5mL) join in the round-bottomed flask of 50mL; Stirring at room temperature reaction 12h, TLC follow the tracks of reaction (developping agent V
acOEt: V
normal hexane=1: 2), after reaction terminates, reaction mixture is joined in frozen water, filter, solid distilled water wash, last vacuum-drying, the solid obtained is dissolved in the purification of dehydrated alcohol recrystallization and obtains Powdered target compound.
Yellow solid, productive rate 80.4%, m.p.243 ~ 248 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.25 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.79 ~ 7.75 (m, 1H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.53 (t, J=7.5Hz, 4H, ArH and SO
2nH
2), 7.44 (t, J=2.4Hz, 3H, ArH), 7.36 (d, J=2.7Hz, 2H, ArH), 7.23 (s, 1H, CH) .ESI-MS:549.1 [M+H]
+.Anal.Calcd for C
26h
18clN
5o
5s:C, H, N.
The preparation of embodiment two: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-aminomethyl phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain brown solid, productive rate 66.8%.m.p.238 ~ 241 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.23 (s, 1H, CONH), 8.73 (s, 1H, CHN), 8.03 (d, J=6.0Hz, 1H, ArH), 7.89 (d, J=6.4Hz, 2H, ArH), 7.78 ~ 7.74 (m, 1H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.52 (d, J=6.0Hz, 4H, ArH and SO
2nH
2), 7.23 (s, 4H, ArH), 7.17 (s, 1H, CH), 2.32 (s, 3H, CH
3) .ESI-MS:563.1 [M+H]
+.Anal.Calcd for C
27h
20clN
5o
5s:C, H, N.
The preparation of embodiment three: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3-aminomethyl phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 76.6%.m.p.214 ~ 217 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.23 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.61 (d, J=6.4 Hz, 2H, ArH), 7.51 (d, J=6.0Hz, 4H, ArH and SO
2nH
2), 7.25 (t, J=6.0Hz, 3H, ArH), 7.20 (s, 1H, CH), 7.03 (d, J=6.0Hz, 1H, ArH), 2.30 (s, 3H, CH
3) .ESI-MS:563.1 [M+H]
+.Anal.Calcd for C
27h
20clN
5o
5s:C, H, N.
The preparation of embodiment four: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(2,4-3,5-dimethylphenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 80.8%.m.p.224 ~ 227 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.24 (s, 1H, CONH), 8.75 (s, 1H, CHN), 8.05 (d, J=6.0Hz, 1H, ArH), 7.83 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.4Hz, 1H, ArH), 7.53 (d, J=6.4Hz, 4H, ArH), 7.48 (s, 2H, SO
2nH
2), 7.15 (t, J=6.0Hz, 2H, ArH and CH), 7.08 (d, J=5.1Hz, 2H, ArH), 2.31 (s, 3H, CH
3), 2.02 (s, 3H, CH
3) .ESI-MS:577.1 [M+H]
+.Anal.Calcd for C
28h
22clN
5o
5s:C, H, N.
The preparation of embodiment five: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3,4-3,5-dimethylphenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 79.2%.m.p.218 ~ 220 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.19 (s, 1H, CONH), 8.73 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.52 (t, J=7.2Hz, 4H, ArH and SO
2nH
2), 7.24 (s, 1H, CH), 7.15 (d, J=4.2Hz, 2H, ArH), 6.93 (d, J=6.0Hz, 1H, ArH), 2.24 (s, 3H, CH
3), 2.21 (s, 3H, CH
3) .ESI-MS:577.1 [M+H]
+.Anal.Calcd for C
28h
22clN
5o
5s:C, H, N.
The preparation of embodiment six: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-p-methoxy-phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 77.6%.m.p.224 ~ 226 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.22 (s, 1H, CONH), 8.73 (s, 1H, CHN), 8.03 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.78 ~ 7.74 (m, 1H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.51 (t, J=6.4Hz, 4H, ArH and SO
2nH
2), 7.27 (d, J=6.4Hz, 2H, ArH), 7.14 (s, 1H, CH), 6.98 (d, J=6.4Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:579.1 [M+H]
+.Anal.Calcd for C
27h
20clN
5o
6s:C, H, N.
The preparation of embodiment seven: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3-p-methoxy-phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 76.3%.m.p.216 ~ 217 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.26 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.91 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.63 (d, J=6.4Hz, 2H, ArH), 7.54 ~ 7.50 (m, 4H, ArH and SO
2nH
2), 7.32 (t, J=6.0Hz, 1H, ArH), 7.26 (s, 1H, CH), 7.00 ~ 6.94 (m, 2H, ArH), 6.85 (d, J=6.0Hz, 1H, ArH), 3.70 (s, 3H, OCH
3) .ESI-MS:579.1 [M+H]
+.Aral.Calcd for C
27h
20clN
5o
6s:C, H, N.
The preparation of embodiment eight: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3,4-Dimethoxyphenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 72.9%.m.p.241 ~ 242 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.23 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.92 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.63 (d, J=6.4Hz, 2H, ArH), 7.52 (t, J=6.0Hz, 4H, ArH and SO
2nH
2), 7.21 (s, 1H, CH), 6.99 ~ 6.83 (m, 3H, ArH), 3.77 (s, 3H, OCH
3), 3.63 (s, 3H, OCH
3) .ESI-MS:609.1 [M+H]
+.Anal.Calcd for C
28h
22clN
5o
7s:C, H, N.
The preparation of embodiment nine: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3,4,5-trimethoxyphenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 73.8%.m.p.221 ~ 223 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.27 (s, 1H, CONH), 8.75 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.95 (d, J=6.4Hz, 2H, ArH), 7.79 ~ 7.75 (m, 1H, ArH), 7.66 (d, J=6.4Hz, 2H, ArH), 7.54 ~ 7.50 (m, 4H, ArH and SO
2nH
2), 7.30 (s, 1H, CH), 6.60 (s, 2H, ArH), 3.69 (s, 3H, OCH
3), 3.62 (s, 6H, OCH
3) .ESI-MS:639.1 [M+H]
+.Anal.Calcd for C
29h
24clN
5o
8s:C, H, N.
The preparation of embodiment ten: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-ethoxyl phenenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 78.9%.m.p.204 ~ 207 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.23 (s, 1H, CONH), 8.73 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.79 ~ 7.75 (m, 1H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.52 (t, J=6.4Hz, 4H, ArH and SO
2nH
2), 7.25 (d, J=6.4Hz, 2H, ArH), 7.14 (s, 1H, CH), 6.96 (d, J=6.4Hz, 2H, ArH), 4.07 ~ 4.02 (m, 2H, CH
2), 1.33 (t, J=5.2Hz, 3H, CH
3) .ESI-MS:593.1 [M+H]
+.Anal.Calcd for C
28h
22clN
5o
6s:C, H, N.
The preparation of embodiment 11: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(2-chloro-phenyl-)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 73.8%.m.p.214 ~ 217 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.28 (s, 1H, CONH), 8.75 (s, 1H, CHN), 8.05 (d, J=6.0Hz, 1H, ArH), 7.86 (t, J=6.4Hz, 2H, ArH), 7.78 (t, J=6.0Hz, 1H, ArH), 7.63 (d, J=6.0Hz, 2H, ArH), 7.56 ~ 7.52 (m, 6H, ArH), 7.49 (s, 3H, ArH and SO
2nH
2), 7.19 (s, 1H, CH) .ESI-MS:583.0 [M+H]
+.Anal.Calcd for C
26h
17cl
2n
5o
5s:C, H, N.
The preparation of embodiment 12: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3-chloro-phenyl-)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 73.5%.m.p.231 ~ 233 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.25 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.92 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.65 (t, J=6.4Hz, 4H, ArH), 7.53 ~ 7.50 (m, 5H, ArH and SO
2nH
2), 7.36 (t, J=6.0Hz, 1H, ArH), 7.31 (s, 1H, CH), 7.26 (d, J=6.0Hz, 1H, ArH) .ESI-MS:583.0 [M+H]
+.Anal.Calcd for C
26h
17cl
2n
5o
5s:C, H, N.
The preparation of embodiment 13: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3,4-dichlorophenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain safran solid, productive rate 86.8%.m.p.203 ~ 205 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.27 (s, 1H, CONH), 8.75 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.93 (d, J=6.4Hz, 2H, ArH), 7.82 ~ 7.76 (m, 2H, ArH), 7.67 (t, J=6.4Hz, 3H, ArH), 7.54 ~ 7.50 (m, 4H, ArH and SO
2nH
2), 7.36 (s, 1H, CH), 7.23 (d, J=6.4Hz, 1H, ArH) .ESI-MS:616.9 [M+H]
+.Anal.Calcd for C
26h
16cl
3n
5o
5s:C, H, N.
The preparation of embodiment 14: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(2-fluorophenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 70.1%.m.p.214 ~ 216 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.30 (s, 1H, CONH), 8.76 (s, 1H, CHN), 8.05 (d, J=6.0Hz, 1H, ArH), 7.88 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.56 ~ 7.50 (m, 6H, ArH and SO
2nH
2), 7.36 (d, J=6.0Hz, 1H, ArH), 7.31 (d, J=7.5Hz, 1H, ArH), 7.26 (s, 1H, CH) .ESI-MS:567.1 [M+H]
+.Anal.Calcd for C
26h
17clFN
5o
5s:C, H, N.
The preparation of embodiment 15: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(3-fluorophenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 69.4%.m.p.234 ~ 236 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.28 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.92 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.64 (d, J=6.4Hz, 2H, ArH), 7.55 ~ 7.47 (m, 5H, ArH and SO
2nH
2), 7.35 ~ 7.25 (m, 3H, CH and ArH), 7.14 (d, J=6.0Hz, 1H, ArH) .ESI-MS:567.1 [M+H]
+.Anal.Calcd for C
26h
17clFN
5o
5s:C, H, N.
The preparation of embodiment 16: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-fluorophenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 68.7%.m.p.251 ~ 253 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.25 (s, 1H, CONH), 8.73 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.51 (t, J=5.1Hz, 4H, ArH and SO
2nH
2), 7.43 ~ 7.39 (m, 2H, ArH), 7.29 (t, J=6.6Hz, 2H, ArH), 7.23 (s, 1H, CH) .ESI-MS:567.1 [M+H]
+.Anal.Calcd for C
26h
17clFN
5o
5s:C, H, N.
The preparation of embodiment 17: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-nitrophenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 63.4%.m.p.260 ~ 262 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.29 (s, 1H, CONH), 8.75 (s, 1H, CHN), 8.27 (d, J=6.4Hz, 2H, ArH), 8.04 (d, J=6.0Hz, 2H, ArH), 7.92 (d, J=6.4Hz, 2H, ArH), 7.77 (t, J=6.0Hz, 1H, ArH), 7.65 (t, J=6.4Hz, 4H, ArH), 7.53 ~ 7.50 (m, 4H, ArH and SO
2nH
2), 7.43 (s, 1H, CH) .ESI-MS:594.1 [M+H]
+.Anal.Calcd for C
26h
17clN
6o
7s:C, H, N.
The preparation of embodiment 18: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(2-hydroxy phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain red solid, productive rate 69.6%.m.p.214 ~ 216 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.26 (s, 1H, CONH), 10.50 (s, 1H, OH), 8.82 (s, 1H, CHN), 8.13 ~ 7.98 (m, 2H, ArH), 7.80 ~ 7.68 (m, 4H, ArH), 7.53 (d, J=6.0Hz, 3H, ArH and SO
2nH
2), 7.43 ~ 7.35 (m, 4H, ArH), 7.16 ~ 7.07 (m, 2H, ArH and CH) .ESI-MS:565.1 [M+H]
+.Anal.Calcd for C
26h
18clN
5o
6s:C, H, N.
The preparation of embodiment 19: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-hydroxy phenyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 75.6%.m.p.234 ~ 236 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.21 (s, 1H, CONH), 9.90 (s, 1H, OH), 8.73 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.79 ~ 7.75 (m, 1H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.52 (t, J=6.0Hz, 4H, ArH and SO
2nH
2), 7.14 (d, J=6.4Hz, 2H, ArH), 7.09 (s, 1H, CH), 6.79 (d, J=6.4Hz, 2H, ArH) .ESI-MS:565.1 [M+H]
+.Anal.Calcd for C
26h
18clN
5o
6s:C, H, N.
The preparation of embodiment 20: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-(4-trifluoromethyl)-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 65.3%.m.p.244 ~ 245 DEG C;
1h NMR (DMSO-d
6, 300MHz) and δ: 12.27 (s, 1H, CONH), 8.74 (s, 1H, CHN), 8.04 (d, J=6.0Hz, 1H, ArH), 7.92 (d, J=6.4Hz, 2H, ArH), 7.82 ~ 7.75 (m, 3H, ArH), 7.65 ~ 7.58 (m, 4H, ArH), 7.51 (d, J=6.0Hz, 4H, ArH and SO
2nH
2), 7.36 (s, 1H, CH) .ESI-MS:617.1 [M+H]
+.Anal.Calcd for C
27h
17clF
3n
5o
5s:C, H, N.
Implement 21: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzene sulfonamide derivatives antitumor activity
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 cervical cancer cell (Hela), lung carcinoma cell (A549), melanoma cell (F10) and liver cancer cell (HepG2)
50).
(1) preparation of nutrient solution (often liter): 1. suspension cell: RPMI-1640 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
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, 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 cervical cancer cell (Hela), lung carcinoma cell (A549), melanoma cell (F10) and liver cancer cell (HepG2): be suspension growth cell, cellar culture is (containing 10% calf serum, 100U/mL Streptomycin sulphate) in RPMI-1640 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.
(8) 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.
(9) 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.
Table 1 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative is to the suppression IC of tumour cell
50value (μM)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 22: 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzene sulfonamide derivatives anti-tumor activity is about Cytotoxic research
The present invention tests new synthetic compound 83-102 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) until reach its logarithmic growth end of term cell be tending towards merge, digest cell dispersion with cell dissociation buffer, with cell culture fluid be mixed with × 10
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 2.
4-listed by table 2 the present invention (3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative is to the suppression CC of 293T cell
50value (μM)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%.
Claims (2)
- Technical scheme of the present invention is as follows:The synthesis of 1.4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative, is characterized in that it has following general formula:A synthesis for above-mentioned 4-(3-(3-(4-Clocoumarol)-acylhydrazone)-5-phenyl-pyrazole) benzsulfamide analog derivative, it is made up of the following step:6mL phosphorus oxychloride is added drop-wise in 12mL dimethyl formamide by step 1. under 0 DEG C of ice bath, then the 4 hydroxy coumarin being dissolved in dimethyl formamide (6mL) is dropwise joined in above-mentioned mixed solution, allow reaction be raised to stirring at room temperature 2h gradually, then reaction flask is transferred in 60 DEG C of oil bath pans and reacts 6h.After reaction terminates, reaction solution is poured in frozen water, is neutralized to pH=7 with sodium carbonate, filter, solid successively with cold ethanol (3 × 50mL), distilled water (3 × 200mL) washing, dry raw material 2Sodium methylate (80mmol) is dissolved in 40mL anhydrous methanol by step 2. at 0 DEG C, then each substituent methyl phenyl ketone 3-22 (20mmol) and dimethyl oxalate (40mmol) are dissolved in 40mL anhydrous methanol, dropwise join in the methanol solution of sodium methylate, reaction flask is transferred 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, reaction mixture is added in frozen water, 1mol/L hcl acidifying, filters, solid successively with cold ethanol (3 × 50mL), distilled water (3 × 200mL) washing, dry raw material 23-42.Step 3. under stirring at room temperature, 23-42 (15mmol) is added successively, to Hydrazinobenzenesulfonamide (15mmol), anhydrous methanol (50mL) in the round-bottomed flask of 100mL, reaction flask is transferred in oil bath pan, back flow reaction 6h, reaction solution is poured in 500mL beaker, filter, solid uses 1mol/L hydrochloric acid (3 × 50mL), distilled water (3 × 150mL), cold ethanol (3 × 50mL), distilled water (3 × 100mL) to wash successively, dry intermediate 43-62.Step 4. successively by 43-62 (8mmol), dehydrated alcohol (20mL), hydrazine hydrate (120mmol), join in the round-bottomed flask of 50mL, reaction flask is transferred 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, dry, will obtain intermediate 63-82.Step 5. under stirring at room temperature, successively 63-82 (0.5mmol), 2 (0.6mmol), dehydrated alcohol (20mL), glacial acetic acid (1mL) are joined in the round-bottomed flask of 50mL, after stirring at room temperature 12h, reaction mixture is joined in frozen water, filter, solid is successively with cold ethanol (3 × 50mL), distilled water (3 × 150mL) washing, drying, the solid crude product obtained is dissolved in dehydrated alcohol recrystallization and obtains Powdered target compound 83-102.
- 2. 4-(3-(3-(4-Clocoumarol)-the acylhydrazone)-5-phenyl-pyrazole) preparation method of benzsulfamide analog derivative according to claim and the application in cancer therapy drug.
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