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 PDF

Info

Publication number
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
Authority
CN
China
Prior art keywords
arh
reaction
clocoumarol
acylhydrazone
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201510407971.2A
Other languages
Chinese (zh)
Inventor
朱海亮
卢小院
王忠长
严晓强
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing University
Original Assignee
Nanjing University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanjing University filed Critical Nanjing University
Priority to CN201510407971.2A priority Critical patent/CN104945388A/en
Publication of CN104945388A publication Critical patent/CN104945388A/en
Pending legal-status Critical Current

Links

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

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

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
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)

  1. 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 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.
  2. 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.
CN201510407971.2A 2015-07-09 2015-07-09 Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs Pending CN104945388A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510407971.2A CN104945388A (en) 2015-07-09 2015-07-09 Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510407971.2A CN104945388A (en) 2015-07-09 2015-07-09 Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs

Publications (1)

Publication Number Publication Date
CN104945388A true CN104945388A (en) 2015-09-30

Family

ID=54160511

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510407971.2A Pending CN104945388A (en) 2015-07-09 2015-07-09 Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs

Country Status (1)

Country Link
CN (1) CN104945388A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777690A (en) * 2016-04-08 2016-07-20 南京大学 Design and synthesis for coumarin piperazine antineoplastic compound
CN108690002A (en) * 2017-04-12 2018-10-23 南京大学 The preparation method of pyrazole derivatives of the one kind containing cumarin and the application in anticancer drug
WO2019017857A3 (en) * 2017-04-28 2019-03-07 Ataturk Universitesi Bilimsel Arastirma Projeleri Birimi Synthesis of potential anticancer effective compounds containing pyrazole – benzensulfonamide moieties, enlightenment of their structures and their cytotoxic activities

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015316A1 (en) * 1993-11-30 1995-06-08 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
CN101121711A (en) * 2007-09-19 2008-02-13 山东大学 Pyrazolcarbazone derivatives and application thereof
WO2009109991A2 (en) * 2008-01-23 2009-09-11 Sun Pharma Advanced Research Company Ltd., Novel hydrazide containing tyrosine kinase inhibitors
CN103086972A (en) * 2013-01-16 2013-05-08 南京大学 Preparation of pyrazole-acylhydrazone compounds and application of pyrazole-acylhydrazone compounds in anticancer treatment
CN103450178A (en) * 2012-05-29 2013-12-18 南京大学 Coumarin grafted thiazole hydrazone derivatives and preparation method thereof
CN103664785A (en) * 2013-11-04 2014-03-26 南京大学 Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug
CN104546843A (en) * 2015-01-28 2015-04-29 山东大学齐鲁医院 Application of pyrazole hydrazone derivative in preparation of anti-breast cancer drug

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015316A1 (en) * 1993-11-30 1995-06-08 G. D. Searle & Co. Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
CN101121711A (en) * 2007-09-19 2008-02-13 山东大学 Pyrazolcarbazone derivatives and application thereof
WO2009109991A2 (en) * 2008-01-23 2009-09-11 Sun Pharma Advanced Research Company Ltd., Novel hydrazide containing tyrosine kinase inhibitors
CN103450178A (en) * 2012-05-29 2013-12-18 南京大学 Coumarin grafted thiazole hydrazone derivatives and preparation method thereof
CN103086972A (en) * 2013-01-16 2013-05-08 南京大学 Preparation of pyrazole-acylhydrazone compounds and application of pyrazole-acylhydrazone compounds in anticancer treatment
CN103664785A (en) * 2013-11-04 2014-03-26 南京大学 Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug
CN104546843A (en) * 2015-01-28 2015-04-29 山东大学齐鲁医院 Application of pyrazole hydrazone derivative in preparation of anti-breast cancer drug

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MUSILIYU A.MUSA, 等: "《A review of coumarin derivatives in pharmacotherapy of breast cancer》", 《CURRENT MEDICINAL CHEMISTRY 》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105777690A (en) * 2016-04-08 2016-07-20 南京大学 Design and synthesis for coumarin piperazine antineoplastic compound
CN108690002A (en) * 2017-04-12 2018-10-23 南京大学 The preparation method of pyrazole derivatives of the one kind containing cumarin and the application in anticancer drug
WO2019017857A3 (en) * 2017-04-28 2019-03-07 Ataturk Universitesi Bilimsel Arastirma Projeleri Birimi Synthesis of potential anticancer effective compounds containing pyrazole – benzensulfonamide moieties, enlightenment of their structures and their cytotoxic activities

Similar Documents

Publication Publication Date Title
CN104558093A (en) C21 steroid saponin aglycone derivative as well as preparation method and application thereof in preparing anti-tumor drugs
CN103664785A (en) Synthesis of novel dihydro-pyrazole sulfonamide derivative and application of novel dihydro-pyrazole sulfonamide derivative in anti-cancer drug
CN103664689A (en) Chalcone oxime derivatives having inhibiting effect on cancer cell tubulin polymerization, and preparation method thereof
CN104230905A (en) Synthesis of dihydropyrazol sulfonamide derivatives containing benzodioxane skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs
CN104530021A (en) Compounds and preparation method thereof, application of compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds
CN104945388A (en) Preparing method for 4-(3-(3-(4-clocoumarol)-acylhydrazone)-5-phenyl-pyrazol) benzene sulfonamide derivate and application to anti-cancer drugs
CN102731493A (en) Anti-tumor compound containing benzothiazole heterocyclic structure and application thereof
CN104230904A (en) Synthesis of dihydropyrazol sulfonamide derivatives containing naphthalene ring skeletons and application of dihydropyrazol sulfonamide derivatives in anti-cancer drugs
CN106496123B (en) A kind of pyrazoline analog derivative and its preparation method and application
CN103664786A (en) Synthesis method of dihydro-pyrazole sulfonamide derivatives of salicylaldehydes and application of dihydro-pyrazole sulfonamide derivatives to preparation of anticancer drugs
CN104829534A (en) Preparation method of dihydro-pyrazole morpholine derivatives containing naphthalene nucleus frameworks and application of dihydro-pyrazole morpholine derivatives to preparation of antitumor drugs
CN108033913A (en) A kind of pyrazoline quinoline derivant and its preparation method and application
CN105037268A (en) Synthesis for sulfaphenazole acylhydrazone derivatives and application of sulfaphenazole acylhydrazone derivatives in anti-cancer drugs
CN105037265A (en) Preparation method of quinolinone derivative containing chalcone framework, and application of the quinolinone derivative in anti-cancer medicines
CN107827828B (en) Quinoxaline derivative containing phenylhydrazide skeleton, preparation method thereof and application thereof in preparation of antitumor drugs
CN104961683A (en) Preparation method of dihydropyrazol piperazine derivatives containing naphthalene ring skeleton and application in anti-cancer drugs
CN101619063B (en) 3,7,8-polysubstituted pyridine-[4,3-d] pyrimidine derivant with antitumor activity and preparation
CN104804064A (en) Pyrazoline hydroxamic acid C21 steroid saponin aglycone derivative containing naphthalene skeleton, as well as preparation method and application of derivative
CN104861026A (en) Furan skeleton included 2H-pyrazole hydroxamic acid C21 steroid saponin aglycone derivative and preparation method and application thereof
CN104804066A (en) Novel anti-cancer compound, preparation method for anti-cancer compound and application of anti-cancer compound to preparation of anti-cancer drugs
CN104804065A (en) Pyrazoline sulfanilamide C21 steroid saponin aglycone derivative containing naphthalene skeleton, as well as preparation method and application of derivative
CN103588769B (en) The synthesis of pyrazoline-thiazolinone analog derivative that one class is novel and the application in cancer therapy drug
CN103992289B (en) Substituted tetrahydrothiazole dithiocarbamic acid bismuth title complex and uses thereof
CN104211642B (en) The synthesis and the application in cancer therapy drug of pyrazoline sulphone amide derivative of one class containing tetrahydronaphthalene or chroman skeleton
CN104610420A (en) Anti-tumor compound as well as preparation method and application thereof in preparation of anti-tumor drug

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20150930