CN105037268A - Synthesis for sulfaphenazole acylhydrazone derivatives and application of sulfaphenazole acylhydrazone derivatives in anti-cancer drugs - Google Patents
Synthesis for sulfaphenazole acylhydrazone derivatives and application of sulfaphenazole acylhydrazone derivatives in anti-cancer drugs Download PDFInfo
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- 229960004818 sulfaphenazole Drugs 0.000 title claims abstract description 18
- QWCJHSGMANYXCW-UHFFFAOYSA-N sulfaphenazole Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NN1C1=CC=CC=C1 QWCJHSGMANYXCW-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 11
- 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 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000007787 solid Substances 0.000 claims description 55
- 238000006243 chemical reaction Methods 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- -1 sulfaphenazole acyl hydrazone derivative Chemical class 0.000 claims description 17
- 239000012153 distilled water Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 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
- 229960004756 ethanol Drugs 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001424 substituent group Chemical group 0.000 claims description 5
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- 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
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- 239000012043 crude product Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
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- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
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- QUSABYOAMXPMQH-UHFFFAOYSA-N 5-(4-methoxyphenyl)-1h-pyrazole Chemical class C1=CC(OC)=CC=C1C1=CC=NN1 QUSABYOAMXPMQH-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
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- LPXVFOGDBRACCG-MUFRIFMGSA-N Cc(cc1)ccc1-c1cc(C(N/N=C/c(cc2OC)cc(OC)c2OC)=O)n[n]1-c(cc1)ccc1S(N)(=O)=O Chemical compound Cc(cc1)ccc1-c1cc(C(N/N=C/c(cc2OC)cc(OC)c2OC)=O)n[n]1-c(cc1)ccc1S(N)(=O)=O LPXVFOGDBRACCG-MUFRIFMGSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
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- 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
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
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- 239000003430 antimalarial agent Substances 0.000 description 1
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- 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
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- 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
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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
- 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
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- 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
- 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
- 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
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses synthesis for sulfaphenazole acylhydrazone derivatives which are characterized by having the following general formula: FORMULA as shown in the specification. The sulfaphenazole acylhydrazone derivatives have obvious inhibiting effect on lung cancer cells (A549), especially have certain inhibiting effect on liver cancer cells (HepG2) by virtue of part of compounds 46 and 48, and show cell toxicity, which is equivalent to or superior to that of a positive control drug, on human kidney epithelial cells (293T). And therefore, the sulfaphenazole acylhydrazone derivatives disclosed by the invention can be applied in preparing anti-tumor drugs. The invention further discloses a preparation method and anti-tumor biological activity of the sulfaphenazole acylhydrazone derivatives.
Description
Summary of the invention
The object of the present invention is to provide the synthesis of a class sulfaphenazole acyl hydrazone derivative and the application in cancer therapy drug
Summary of the invention
Technical scheme of the present invention is as follows:
The synthesis of one class sulfaphenazole acyl hydrazone derivative, is characterized in that it has following general formula:
A synthesis for above-mentioned sulfaphenazole acylhydrazone, it is made up of the following step:
Sodium methylate (80mmol) is dissolved in 40mL anhydrous methanol by step 1. at 0 DEG C, then each substituent methyl phenyl ketone 1-5 (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 6-10.
Step 2. under stirring at room temperature, 6-10 (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 11-15.
Step 3. successively by 11-15 (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 16-20.
Step 4. under stirring at room temperature, successively the phenyl aldehyde (0.6mmol) of 16-20 (0.5mmol), different substituents, 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 21-64.
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.
Acylhydrazone shows good antibacterial, anticonvulsion, antimalarial, pain relieving, anti-obesity, tuberculosis, the pharmacologically active such as antitumor because of its special chemical structure, get more and more people's extensive concerning for many years always, become one of emphasis problem that Pharmaceutical Chemists further investigate, especially concerned especially containing the fragrant hydrazone compound of pyrimidine, indoles and heterocycle structure, many pyrazoles acylhydrazones have been in the news research.
Based on this, the present invention is by different sulfanilamide (SN) and have outstanding bioactive benzene sulfonyl hydrazone skeleton and be incorporated in pyrazoline derivative, the a series of sulfaphenazole sulphonyl hydrazone class 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-(3-(benzoyl hydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Under agitation successively by 5-(4-methoxyphenyl) pyrazoles hydrazides benzsulfamide (0.1g, 0.25mmol), ethanol (10mL), phenyl aldehyde (0.039g, 0.375mmol), acetic acid (0.5mL) joins in the round-bottomed flask of 50mL, normal-temperature reaction 12h, TLC follow the tracks of reaction (developping agent V
acOEt: V
pE=1: 2), after reaction terminates, filter, solid is cold ethanol, distilled water wash successively, last vacuum-drying, the solid obtained is dissolved in the purification of dehydrated alcohol recrystallization and obtains Powdered target compound.
Obtain white solid, productive rate 60%.m.p.251 ~ 253 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.81 (s, 1H, CONH), 8.55 (s, 1H, CHN), 7.90 (d, J=6.3Hz, 2H, ArH), 7.72 (d, J=5.1Hz, 2H, ArH), 7.60 (d, J=6.3Hz, 2H, ArH), 7.48 (t, J=6.3Hz, 5H, ArHandSO
2nH
2), 7.27 (d, J=6.5Hz, 2H, ArH), 7.12 (s, 1H, CH), 6.98 (d, J=6.4Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:476.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
4s:C, H, N.
The preparation of embodiment two: 4-(3-(4-anisole acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.White solid, productive rate 41%, m.p.169 ~ 171 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.66 (s, 1H, CONH), 8.48 (s, 1H, CHN), 7.89 (t, J=6.4Hz, 2H, ArH), 7.66 (d, J=6.5Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.49 (s, 2H, SO
2nH
2), 7.26 (d, J=6.5Hz, 2H, ArH), 7.10 (s, 1H, CH), 7.03 (d, J=6.5Hz, 2H, ArH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.82 (s, 3H, OCH
3), 3.78 (s, 3H, OCH
3) .ESI-MS:506.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
5s:C, H, N.
The preparation of embodiment three: 4-(3-(2-anisole acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 58.6%.m.p.157 ~ 160 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.86 (s, 1H, CONH), 8.89 (s, 1H, CHN), 7.89 (t, J=6.4Hz, 3H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.43 (t, J=6.4Hz, 1H, ArH), 7.27 (d, J=6.5Hz, 2H, ArH), 7.12 (d, 2H, CHandArH), 7.04 (t, J=5.6Hz, 1H, ArH), 6.99 (d, J=6.5Hz, 2H, ArH), 3.87 (s, 3H, OCH
3), 3.79 (s, 3H, OCH
3) .ESI-MS:506.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
5s:C, H, N.
The preparation of embodiment four: 4-(3-(3-anisole acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 78%.m.p.150 ~ 152 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.81 (s, 1H, CONH), 8.52 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.39 (t, J=6.0Hz, 1H, ArH), 7.27 (d, J=6.3Hz, 4H, ArH), 7.11 (s, 1H, CH), 7.04 ~ 7.01 (m, 1H, ArH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.82 (s, 3H, OCH
3), 3.78 (s, 3H, OCH
3) .ESI-MS:506.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
5s:C, H, N.
The preparation of embodiment five: 4-(3-(4-anisole acylhydrazone)-5-(4-tolyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid body, productive rate 65%.m.p.267 ~ 268 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.68 (s, 1H, CONH), 8.48 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.67 (d, J=6.5Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (t, J=6.6Hz, 4H, ArH), 7.13 (s, 1H, CH), 7.04 (d, J=6.5Hz, 2H, ArH), 3.82 (s, 3H, OCH
3), 2.33 (s, 3H, CH
3) .ESI-MS:490.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
4s:C, H, N.
The preparation of embodiment six: 4-(3-(4-anisole acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 56.6%.m.p.185 ~ 187 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.70 (s, 1H, CONH), 8.48 (s, 1H, CHN), 7.91 ~ 7.87 (m, 2H, ArH), 7.67 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.42 ~ 7.39 (m, 2H, ArH), 7.28 (t, J=6.4Hz, 2H, ArH), 7.18 (s, 1H, CH), 7.04 (d, J=6.5Hz, 2H, ArH), 3.82 (s, 3H, OCH
3) .ESI-MS:494.1 [M+H]
+.Anal.CalcdforC
24h
20fN
5o
4s:C, H, N.
The preparation of embodiment seven: 4-(3-(4-anisole acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 80.3%.m.p.264 ~ 267 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.75 (s, 1H, CONH), 8.48 (s, 1H, CHN), 7.91 (t, J=6.4Hz, 2H, ArH), 7.67 ~ 7.60 (m, 6H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.29 (d, J=6.4Hz, 2H, ArH), 7.23 (s, 1H, CH), 7.04 (d, J=6.5Hz, 2H, ArH), 3.82 (s, 3H, OCH3) .ESI-MS:555.0 [M+H]
+.Anal.CalcdforC
24h
20brN
5o
4s:C, H, N.
The preparation of embodiment eight: 4-(3-(2,4,5-trimethoxy-benzene acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow crystals, productive rate 58.2%.m.p.254 ~ 256 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.71 (s, 1H, CONH), 8.81 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.3Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.37 (s, 1H, ArH), 7.27 (d, J=6.4Hz, 2H, ArH), 7.09 (s, 1H, CH), 6.98 (d, J=6.4Hz, 2H, ArH), 6.76 (s, 1H, ArH), 3.87 (s, 6H, OCH
3), 3.78 (s, 6H, OCH
3) .ESI-MS:566.1 [M+H]
+.Anal.CalcdforC
27h
27n
5o
7s:C, H, N.
The preparation of embodiment nine: 4-(3-(3,4,5-trimethoxy-benzene acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 70.8%.m.p.274 ~ 276 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.79 (s, 1H, CONH), 8.47 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.60 (d, J=6.3Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.27 (d, J=6.4Hz, 2H, ArH), 7.11 (s, 1H, CH), 6.99 (t, J=4.8Hz, 4H, ArH), 3.85 (s, 6H, OCH
3), 3.78 (s, 3H, OCH
3), 3.72 (s, 3H, OCH
3) .ESI-MS:566.1 [M+H]
+.Anal.CalcdforC
27h
27n
5o
7s:C, H, N.
The preparation of embodiment ten: 4-(3-(2,4,5-trimethoxy-benzene acylhydrazone)-5-(4-tolyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 80.9%.m.p.171 ~ 173 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.72 (s, 1H, CONH), 8.81 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.37 (s, 1H, ArH), 7.23 (t, J=6.6Hz, 4H, ArH), 7.12 (s, 1H, CH), 6.76 (s, 1H, ArH), 3.87 (s, 6H, OCH
3), 3.78 (s, 3H, OCH
3), 2.33 (s, 3H, CH
3) .ESI-MS:550.1 [M+H]
+.Anal.CalcdforC
27h
27n
5o
6s:C, H, N.
The preparation of embodiment 11: 4-(3-(3,4,5-trimethoxy-benzene acylhydrazone)-5-(4-tolyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 68.8%.m.p.304 ~ 307 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.80 (s, 1H, CONH), 8.47 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (t, J=6.6Hz, 4H, ArH), 7.14 (s, 1H, CH), 7.00 (s, 2H, ArH), 3.85 (s, 6H, OCH
3), 3.72 (s, 3H, OCH
3), 2.33 (s, 3H, CH
3) .ESI-MS:550.1 [M+H]
+.Anal.CalcdforC
27h
27n
5o
6s:C, H, N.
The preparation of embodiment 12: 4-(3-(2,4,5-trimethoxy-benzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 80.5%.m.p.269 ~ 270 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.74 (s, 1H, CONH), 8.81 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.42 ~ 7.32 (m, 3H, ArH), 7.31 ~ 7.26 (m, 2H, ArH), 7.17 (s, 1H, CH), 6.76 (s, 1H, ArH), 3.87 (s, 6H, OCH
3), 3.78 (s, 3H, OCH
3) .ESI-MS:554.1 [M+H]
+.Anal.CalcdforC
26h
24fN
5o
6s:C, H, N.
The preparation of embodiment 13: 4-(3-(3,4,5-trimethoxy-benzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 60.8%.m.p.259 ~ 262 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.82 (s, 1H, CONH), 8.47 (s, 1H, CHN), 7.90 (d, J=6.5Hz, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.43 ~ 7.39 (m, 2H, ArH), 7.29 (t, J=6.4Hz, 2H, ArH), 7.19 (s, 1H, CH), 7.01 (s, 2H, ArH), 3.86 (s, 6H, OCH
3), 3.72 (s, 3H, OCH
3) .ESI-MS:554.1 [M+H]
+.Anal.CalcdforC
26h
24fN
5o
6s:C, H, N.
The preparation of embodiment 14: 4-(3-(2,4,5-trimethoxy-benzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 84.1%.m.p.180 ~ 182 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.78 (s, 1H, CONH), 8.81 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.65 ~ 7.59 (m, 4H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.36 (s, 1H, ArH), 7.29 (d, J=6.4Hz, 2H, ArH), 7.22 (s, 1H, CH), 6.76 (s, 1H, ArH), 3.86 (s, 6H, OCH
3), 3.78 (s, 3H, OCH
3) .ESI-MS:615.1 [M+H]
+.Anal.CalcdforC
26h
24brN
5o
6s:C, H, N.
The preparation of embodiment 15: 4-(3-(3,4,5-trimethoxy-benzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 75.4%.m.p.286 ~ 288 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.87 (s, 1H, CONH), 8.46 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.65 ~ 7.60 (m, 4H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.30 (d, J=6.4Hz, 2H, ArH), 7.24 (s, 1H, CH), 7.00 (s, 2H, ArH), 3.85 (s, 6H, OCH
3), 3.72 (s, 3H, OCH
3) .ESI-MS:615.1 [M+H]
+.Anal.CalcdforC
26h
24brN
5o
6s:C, H, N.
The preparation of embodiment 16: 4-(3-(3,4,5-trimethoxy-benzene acylhydrazone)-5-phenyl-1H-pyrazoles)
Preparation method is with embodiment one.Obtain white solid, productive rate 58.7%.m.p.243 ~ 246 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.77 (s, 1H, CONH), 8.82 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.43 (t, J=4.5Hz, 3H, ArH), 7.37 ~ 7.34 (m, 3H, ArH), 7.18 (s, 1H, CH), 6.76 (s, 1H, ArH), 3.87 (s, 6H, OCH
3), 3.78 (s, 3H, OCH
3) .ESI-MS:536.1 [M+H]
+.Anal.CalcdforC
26h
25n
5o
6s:C, H, N.
The preparation of embodiment 17: 4-(3-(4-methylbenzene acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 60.4%.m.p.272 ~ 274 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.75 (s, 1H, CONH), 8.51 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.61 (t, J=5.7Hz, 4H, ArH), 7.51 (s, 2H, SO
2nH
2), 7.28 (t, J=5.7Hz, 4H, ArH), 7.11 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.78 (s, 3H, OCH
3), 2.36 (s, 3H, CH3) .ESI-MS:490.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
4s:C, H, N.
The preparation of embodiment 18: 4-(3-(4-methylbenzene acylhydrazone)-5-(4-tolyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 66.8%.m.p.300 ~ 301 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.75 (s, 1H, CONH), 8.51 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.63 ~ 7.58 (m, 4H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.29 (d, J=6.0Hz, 2H, ArH), 7.23 (t, J=6.6Hz, 4H, ArH), 7.14 (s, 1H, CH), 2.36 (s, 3H, CH
3), 2.33 (s, 3H, CH
3) .ESI-MS:474.1 [M+H]
+.Anal.CalcdforC
25h
23n
5o
3s:C, H, N.
The preparation of embodiment 19: 4-(3-(4-methylbenzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 66.6%.m.p.253 ~ 256 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.77 (s, 1H, CONH), 8.51 (s, 1H, CHN), 7.91 ~ 7.89 (m, 2H, ArH), 7.61 (t, J=6.0Hz, 4H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.42 ~ 7.39 (m, 2H, ArH), 7.31 ~ 7.26 (m, 4H, ArH), 7.19 (s, 1H, CH), 2.36 (s, 3H, CH
3) .ESI-MS:478.1 [M+H]
+.Anal.CalcdforC
24h
20fN
5o
3s:C, H, N.
The preparation of embodiment 20: 4-(3-(4-methylbenzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 82.6%.m.p.310 ~ 312 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.82 (s, 1H, CONH), 8.51 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.65 ~ 7.60 (m, 6H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.31 ~ 7.28 (m, 4H, ArH), 7.24 (s, 1H, CH), 2.36 (s, 3H, CH
3) .ESI-MS:539.0 [M+H]
+.Anal.CalcdforC
24h
20brN
5o
3s:C, H, N.
The preparation of embodiment 21: 4-(3-(4-hydroxybenzene acylhydrazone)-5-(4-p-methoxy-phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 54.3%.m.p.298 ~ 301 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.59 (s, 1H, CONH), 9.92 (s, 1H, OH), 8.43 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.60 ~ 7.54 (m, 4H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.26 (d, J=6.5Hz, 2H, ArH), 7.09 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 6.85 (d, J=6.3Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:492.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
5s:C, H, N.
The preparation of embodiment 22: 4-(3-(2-hydroxybenzene acylhydrazone)-5-(4-p-methoxy-phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 54.4%.m.p.298 ~ 301 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.14 (s, 1H, CONH), 11.28 (s, 1H, OH), 8.74 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.61 (d, J=6.4Hz, 4H, ArH), 7.50 (d, J=3.4Hz, 3H, ArHandSO
2nH
2), 7.33 ~ 7.26 (m, 3H, ArH), 7.13 (s, 1H, CH), 6.99 ~ 6.91 (m, 4H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:492.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
5s:C, H, N.
The preparation of embodiment 23: 4-(3-(3-hydroxybenzene acylhydrazone)-5-(4-p-methoxy-phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 60.9%.m.p.292 ~ 294 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.75 (s, 1H, CONH), 9.62 (s, 1H, OH), 8.45 (s, 1H, CHN), 7.90 (t, J=6.4Hz, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.26 (t, J=6.5Hz, 3H, ArH), 7.20 (s, 1H, CH), 7.09 (t, J=4.1Hz, 2H, ArH), 6.98 (d, J=6.5Hz, 2H, ArH), 6.84 (d, J=6.5Hz, 1H, ArH), 3.78 (s, 3H, OCH3) .ESI-MS:492.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
5s:C, H, N.
The preparation of embodiment 24: 4-(3-(4-hydroxybenzene acylhydrazone)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 70.5%.m.p.332 ~ 336 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.60 (s, 1H, CONH), 9.92 (s, 1H, OH), 8.43 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.59 ~ 7.54 (m, 4H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (t, J=6.6Hz, 4H, ArH), 7.12 (s, 1H, CH), 6.85 (d, J=6.5Hz, 2H, ArH), 2.33 (s, 3H, CH
3) .ESI-MS:476.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
4s:C, H, N.
The preparation of embodiment 25: 4-(3-(2-hydroxybenzene acylhydrazone)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 75.5%.m.p.304 ~ 307 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.16 (s, 1H, CONH), 11.27 (s, 1H, OH), 8.74 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.60 (d, J=6.5Hz, 2H, ArH), 7.52 (s, 1H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.34 ~ 7.29 (m, 1H, ArH), 7.23 (t, J=6.6Hz, 4H, ArH), 7.16 (s, 1H, CH), 6.94 (t, J=6.5Hz, 2H, ArH), 2.33 (s, 3H, CH
3) .ESI-MS:476.1 [M+H]
+.Anal.CalcdforC
24h
21n
5o
4s:C, H, N.
The preparation of embodiment 26: 4-(3-(2-hydroxybenzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 66.8%.m.p.256 ~ 257 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.17 (s, 1H, CONH), 11.26 (s, 1H, OH), 8.75 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.51 (d, J=4.5Hz, 3H, ArHandSO
2nH
2), 7.43 ~ 7.39 (m, 2H, ArH), 7.32 ~ 7.27 (m, 3H, ArH), 7.21 (s, 1H, CH), 6.94 (t, J=6.5Hz, 2H, ArH) .ESI-MS:480.1 [M+H]
+.Anal.CalcdforC
23h
18fN
5o
4s:C, H, N.
The preparation of embodiment 27: 4-(3-(4-hydroxybenzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 52.3%.m.p.304 ~ 306 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.67 (s, 1H, CONH), 9.96 (s, 1H, OH), 8.43 (s, 1H, CHN), 7.90 (t, J=6.4Hz, 2H, ArH), 7.65 ~ 7.59 (m, 4H, ArH), 7.56 ~ 7.50 (m, 4H, ArHandSO
2nH
2), 7.29 (d, J=6.5Hz, 2H, ArH), 7.22 (s, 1H, CH), 6.85 (d, J=6.4Hz, 2H, ArH) .ESI-MS:541.0 [M+H]
+.Anal.CalcdforC
23h
18brN
5o
4s:C, H, N.
The preparation of embodiment 28: 4-(3-(2-hydroxybenzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 76.3%.m.p.289 ~ 291 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.21 (s, 1H, CONH), 11.26 (s, 1H, OH), 8.74 (s, 1H, CHN), 7.92 (d, J=6.4Hz, 2H, ArH), 7.66 ~ 7.61 (m, 4H, ArH), 7.52 (t, J=5.0Hz, 3H, ArHandSO
2nH
2), 7.34 ~ 7.29 (m, 3H, ArH), 7.26 (s, 1H, CH), 6.93 (t, J=6.4Hz, 2H, ArH) .ESI-MS:541.0 [M+H]
+.Anal.CalcdforC
23h
18brN
5o
4s:C, H, N.
The preparation of embodiment 29: 4-(3-(the fluorine-based benzoyl hydrazone of 4-)-5-(4-p-methoxy-phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 60.3%.m.p.269 ~ 272 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.82 (s, 1H, CONH), 8.55 (s, 1H, CHN), 7.90 (d, J=6.4Hz, 2H, ArH), 7.80 ~ 7.76 (m, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.29 (m, 4H, ArH), 7.11 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:494.1 [M+H]
+.Anal.CalcdforC
24h
20fN
5o
4s:C, H, N.
The preparation of embodiment 30: 4-(3-(the fluorine-based benzoyl hydrazone of 4-)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 62.3%.m.p.302 ~ 304 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.84 (s, 1H, CONH), 8.55 (s, 1H, CHN), 7.91 ~ 7.89 (m, 2H, ArH), 7.80 ~ 7.76 (m, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.31 (t, J=6.6Hz, 2H, ArH), 7.23 (t, J=6.6Hz, 4H, ArH), 7.15 (s, 1H, CH), 2.33 (s, 3H, CH
3) .ESI-MS:478.1 [M+H]
+.Anal.CalcdforC
24h
20fN
5o
3s:C, H, N.
The preparation of embodiment 31: 4-(3-(the fluorine-based benzoyl hydrazone of 4-)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 53.3%.m.p.310 ~ 312 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.90 (s, 1H, CONH), 8.55 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.80 ~ 7.76 (m, 2H, ArH), 7.65 ~ 7.60 (m, 4H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.34 ~ 7.29 (m, 4H, ArH), 7.24 (s, 1H, CH) .ESI-MS:543.0 [M+H]
+.Anal.CalcdforC
23h
17brFN
5o
3s:C, H, N.
The preparation of embodiment 32: 4-(3-(4-oil of mirbane acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 58.6%.m.p.294 ~ 298 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.14 (s, 1H, CONH), 8.66 (s, 1H, CHN), 8.32 (d, J=6.5Hz, 2H, ArH), 7.98 (d, J=6.5Hz, 2H, ArH), 7.91 (d, J=6.4Hz, 2H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.27 (d, J=6.5Hz, 2H, ArH), 7.15 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:521.1 [M+H]
+.Anal.CalcdforC
24h
20n
6o
6s:C, H, N.
The preparation of embodiment 33: 4-(3-(2-oil of mirbane acylhydrazone)-5-(4-methoxyphenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 68.6%.m.p.262 ~ 264 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.24 (s, 1H, CONH), 8.96 (s, 1H, CHN), 8.15 (d, J=6.0Hz, 1H, ArH), 8.08 (d, J=6.3Hz, 1H, ArH), 7.90 (d, J=6.4Hz, 2H, ArH), 7.84 (t, J=6.0Hz, 1H, ArH), 7.70 (t, J=6.0Hz, 1H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.27 (d, J=6.5Hz, 2H, ArH), 7.14 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:521.1 [M+H]
+.Anal.CalcdforC
24h
20n
6o
6s:C, H, N.
The preparation of embodiment 34: 4-(3-(4-oil of mirbane acylhydrazone)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 85.4%.m.p.297 ~ 300 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.15 (s, 1H, CONH), 8.66 (s, 1H, CHN), 8.32 (d, J=6.6Hz, 2H, ArH), 7.98 (d, J=6.6Hz, 2H, ArH), 7.91 ~ 7.89 (m, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (s, 4H, ArH), 7.18 (s, 1H, CH), 2.33 (s, 3H, CH
3) .ESI-MS:505.1 [M+H]
+.Anal.CalcdforC
24h
20n
6o
5s:C, H, N.
The preparation of embodiment 35: 4-(3-(4-oil of mirbane sulphur hydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 66.4%.m.p.297 ~ 299 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.17 (s, 1H, CONH), 8.66 (s, 1H, CHN), 8.32 (d, J=6.6Hz, 2H, ArH), 7.99 (d, J=6.6Hz, 2H, ArH), 7.91 (t, J=6.6Hz, 2H, ArH), 7.61 (d, J=6.4Hz, 2H, ArH), 7.51 (s, 2H, SO
2nH
2), 7.43 ~ 7.39 (m, 2H, ArH), 7.31 ~ 7.24 (m, 3H, ArH) .ESI-MS:509.1 [M+H]
+.Anal.CalcdforC
23h
17fN
6o
5s:C, H, N.
The preparation of embodiment 36: 4-(3-(4-oil of mirbane acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain yellow solid, productive rate 74.4%.m.p.306 ~ 308 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 12.21 (s, 1H, CONH), 8.66 (s, 1H, CHN), 8.32 (d, J=6.6Hz, 2H, ArH), 7.98 (d, J=6.6Hz, 2H, ArH), 7.92 (d, J=6.6Hz, 2H, ArH), 7.63 (t, J=6.4Hz, 4H, ArH), 7.53 (s, 2H, SO
2nH
2), 7.31 ~ 7.26 (m, 3H, ArHandCH) .ESI-MS:570.1 [M+H]
+.Anal.CalcdforC
23h
17brN
6o
5s:C, H, N.
The preparation of embodiment 37: 4-(3-(4-bromobenzene acylhydrazone)-5-(4-p-methoxy-phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 68.4%.m.p.284 ~ 286 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.89 (s, 1H, CONH), 8.52 (s, 1H, CHN), 7.91 ~ 7.85 (m, 3H, ArH), 7.67 (s, 4H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.27 (d, J=6.5Hz, 2H, ArH), 7.12 (s, 1H, CH), 6.98 (d, J=6.5Hz, 2H, ArH), 3.78 (s, 3H, OCH
3) .ESI-MS:550.0 [M+H]
+.Anal.CalcdforC
24h
20brN
5o
4s:C, H, N.
The preparation of embodiment 38: 4-(3-(4-bromobenzene acylhydrazone)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 58.4%.m.p.290 ~ 292 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.90 (s, 1H, CONH), 8.53 (s, 1H, CHN), 7.91 ~ 7.85 (m, 2H, ArH), 7.67 (s, 4H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (s, 4H, ArH), 7.15 (s, 1H, CH), 2.33 (s, 3H, CH
3) .ESI-MS:539.0 [M+H]
+.Anal.CalcdforC
24h
20brN
5o
3s:C, H, N.
The preparation of embodiment 39: 4-(3-(4-bromobenzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 66.4%.m.p.173 ~ 175 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.92 (s, 1H, CONH), 8.53 (s, 1H, CHN), 7.91 ~ 7.89 (m, 2H, ArH), 7.67 (s, 4H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.42 ~ 7.38 (m, 2H, ArH), 7.31 ~ 7.26 (m, 2H, ArH), 7.20 (s, 1H, CH) .ESI-MS:543.0 [M+H]
+.Anal.CalcdforC
23h
17brFN
5o
3s:C, H, N.
The preparation of embodiment 40: 4-(3-(4-bromobenzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 77.4%.m.p.278 ~ 281 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.97 (s, 1H, CONH), 8.52 (s, 1H, CHN), 8.32 (d, J=6.6Hz, 2H, ArH), 7.91 (d, J=6.4Hz, 2H, ArH), 7.85 (s, 1H, ArH), 7.67 ~ 7.60 (m, 8H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.30 (d, J=6.4Hz, 2H, ArH), 7.25 (s, 1H, CH) .ESI-MS:600.9 [M+H]
+.Anal.CalcdforC
23h
17br
2n
5o
3s:C, H, N.
The preparation of embodiment 41: 4-(3-(4-bromobenzene acylhydrazone)-5-phenyl-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 70.4%.m.p.200 ~ 203 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.96 (s, 1H, CONH), 8.53 (s, 1H, CHN), 7.89 (d, J=6.4Hz, 2H, ArH), 7.68 (s, 4H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.52 (s, 2H, SO
2nH
2), 7.43 (t, J=2.7Hz, 4H, ArH), 7.36 ~ 7.33 (m, 2H, ArH), 7.21 (s, 1H, CH) .ESI-MS:525.0 [M+H]
+.Anal.CalcdforC
23h
18brN
5o
3s:C, H, N.
The preparation of embodiment 42: 4-(3-(4-chlorobenzene acylhydrazone)-5-(4-aminomethyl phenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 80.4%.m.p.293 ~ 294 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.90 (s, 1H, CONH), 8.54 (s, 1H, CHN), 7.91 ~ 7.89 (m, 2H, ArH), 7.74 (d, J=6.4Hz, 2H, ArH), 7.59 (d, J=6.4Hz, 2H, ArH), 7.54 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.23 (s, 4H, ArH), 7.15 (s, 1H, CH), 2.33 (s, 3H, CH
3) .ESI-MS:495.0 [M+H]
+.Anal.CalcdforC
24h
20clN
5o
3s:C, H, N.
The preparation of embodiment 43: 4-(3-(4-chlorobenzene acylhydrazone)-5-(4-fluorophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 52.4%.m.p.185 ~ 187 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.92 (s, 1H, CONH), 8.55 (s, 1H, CHN), 7.90 (d, J=6.5Hz, 2H, ArH), 7.75 (d, J=6.4Hz, 2H, ArH), 7.60 (d, J=6.4Hz, 2H, ArH), 7.54 (d, J=6.4Hz, 2H, ArH), 7.50 (s, 2H, SO
2nH
2), 7.42 ~ 7.39 (m, 2H, ArH), 7.31 ~ 7.26 (m, 2H, ArH), 7.20 (s, 1H, CH) .ESI-MS:499.0 [M+H]
+.Anal.CalcdforC
23h
17clFN
5o
3s:C, H, N.
The preparation of embodiment 44: 4-(3-(4-chlorobenzene acylhydrazone)-5-(4-bromophenyl)-1H-pyrazoles) benzsulfamide
Preparation method is with embodiment one.Obtain white solid, productive rate 86.4%.m.p.314 ~ 316 DEG C;
1hNMR (DMSO-d
6, 300MHz) and δ: 11.96 (s, 1H, CONH), 8.54 (s, 1H, CHN), 7.91 (d, J=6.4Hz, 2H, ArH), 7.74 (d, J=6.4Hz, 2H, ArH), 7.65 ~ 7.60 (m, 4H, ArH), 7.53 (t, J=6.4Hz, 4H, SO
2nH
2andArH), 7.30 (d, J=6.4Hz, 2H, ArH), 7.25 (s, 1H, CH) .ESI-MS:558.9 [M+H]
+.Anal.CalcdforC
23h
17brClN
5o
3s:C, H, N.
Embodiment 45: sulfaphenazole acylhydrazone anti tumor activity in vitro 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 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, HEPES2.38g.
(2) preparation of D-Hanks damping fluid (often liter): NaCl8.00g, KCl0.40g, 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 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 MTT40 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.
Sulfaphenazole acylhydrazone listed by table 1 the present invention is to the suppression IC of tumour cell
50value (μM)
a3 parallel tests, experimental result is averaged, and error is between 5%-10%
Embodiment 46: sulfaphenazole acylhydrazone anti tumor activity in vitro is about Cytotoxic research
The present invention tests new synthetic compound 21-64 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 LDMSO 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.
Listed by table 2 the present invention, a class sulfaphenazole acylhydrazone 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:1. the synthesis of a class sulfaphenazole acyl hydrazone derivative, is characterized in that it has following general formula:A synthesis for above-mentioned sulfaphenazole acylhydrazone, it is made up of the following step:Sodium methylate (80mmol) is dissolved in 40mL anhydrous methanol by step 1. at 0 DEG C, then each substituent methyl phenyl ketone 1-5 (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 6-10.Step 2. under stirring at room temperature, 6-10 (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 11-15.Step 3. successively by 11-15 (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 16-20.Step 4. under stirring at room temperature, successively the phenyl aldehyde (0.6mmol) of 16-20 (0.5mmol), different substituents, 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 21-64.
- 2. the synthesis of a class sulfaphenazole acyl hydrazone derivative according to claim and the application in cancer therapy drug.
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