CN106866634A - The pyrazoles Shiff base derivative that one class has isatin fragment is used for anti-tumor drug and preparation method - Google Patents
The pyrazoles Shiff base derivative that one class has isatin fragment is used for anti-tumor drug and preparation method Download PDFInfo
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract
The present invention relates to medicinal chemistry art, and in particular to the pyrazoles Shiff base derivative that a class has isatin fragment is used for anti-tumor drug and preparation method.Pharmacological evaluation proves that thing of the present invention can significantly inhibit the propagation of tumour cell.Therefore, thing of the present invention can be used for preventing or treating cell proliferative disorder relevant disease, in particular for the purposes in the medicine for preventing or treating tumour.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a class has the pyrazoles Shiff base derivative of isatin fragment, it
Preparation method and for the purposes in the medicine for preventing or treating tumour.
Background technology
Pyrazoles nitrogen heterocycles are always one of the important directions in drug research field, because pyrazole derivatives are with more
Plant potential pharmacological activity, such as antipyretic-antalgic, hypoglycemic, antibacterial, anti-spasm, calmness and anti-arrhythmia.Additionally, pyrazol derivative
Thing also has certain antitumor activity, and pyrazoles is also the core texture of antitumor Axitinib, pazopanib and Yi Lu for Buddhist nun
Fragment.Therefore, in recent years, people have synthesized a large amount of pyrazole derivatives with antitumor activity, by Pharmacological Activity Screening, hair
Existing some novel pyrazole derivatives with further investigation value（Bioorg. Med. Chem. 2007, 15, 6893;
Bioorg. Med. Chem. 2012, 20, 2101; Lett. Drug Des. Discov. 2014, 11, 1010）.
Isatin is also called istain, is the diketone form of indoles, with potential antitumor activity.Isatin structure is also present
In various antineoplastics, such as Sutent（Anticancer Agents Med. Chem. 2009, 9, 397）.This
Outward, the core texture of isatin or active Chinese drug component active ingredient indigo red, is shown by the research to crystalline protein, isatin group
Important bonding action is served to the kinase amino acid residue such as CDK and GSK-3（J. Med. Chem. 2014, 57,
3715; Curr. Pharm. Design 2013, 19, 4755）.In recent years, it is antitumor activity parent nucleus, people with isatin
Substantial amounts of structure is carried out to it and has derived research, such as Dweedar et al. has designed and synthesized the change of the double acylhydrazones of a series of isatin
Compound, it has significant antitumor activity to MCF-7 Human Breast Cancer Cells, and the activity of part of compounds is suitable with adriamycin
（Eur. J. Med. Chem. 2014, 78, 275）；Nasr et al. has designed and synthesized some cumarin-acylhydrazone-isatin and has sewed
Compound, part of compounds is better than adriamycin to the activity of human pancreas cancer Panc-1 cells（Eur. J. Med. Chem. 2014,
76, 539）.These results of study show that isatin pharmacophore is of great interest in antineoplastic research and development field, research
Compound with isatin structure will be helpful to the discovery of antineoplastic.
Using the pharmacophore heterozygosis principle of medicinal chemistry art, by isatin and pyrazoles, both have the medicine of antitumor activity
Effect group is conjugated by schiff bases, has obtained having no the pyrazoles Shiff base derivative with isatin fragment of document report.
The content of the invention
The present invention discloses the class formula of formula one（I）Compound.Pharmacological evaluation shows that thing of the present invention is to people's non-small cell lung
The in-vitro multiplication of cancer A549 cells has stronger inhibitory activity.Flow cytometry result shows that thing of the present invention can be lured
Lead A549 apoptosis of tumor cells.Therefore, thing of the present invention can be used in preventing or treating cell proliferative disorder relevant disease, especially
For the purposes in the medicine for preventing or treating tumour.
Compound formula of the invention（I）It is as follows：
Wherein, R1Represent C2 ~ C8 alkane, C4 ~ C7 fat ring group, aromatic radical or 5 ~ 6 circle heterocycles bases；
R2Represent C1 ~ C9 alkane, C4 ~ C6 fat ring group, C1 ~ C5 alkoxies, aromatic radical or 5 ~ 6 circle heterocycles bases；
R3Represent H, itrile group, halogen, nitro, trifluoromethyl, C1 ~ C6 alkyl, C1 ~ C4 alkoxies, C4 ~ C6 fat ring groups or fragrance
Base；
Described aromatic radical is xenyl, naphthyl, phenyl or substituted-phenyl；Wherein described substituted-phenyl contains 1 ~ 3 substitution base,
The substitution base takes from halogen, trifluoromethyl, itrile group, nitro, C2 ~ C4 alkoxies, C1 ~ C6 alkyl or C4 ~ C6 fat ring group；
5 ~ 6 described circle heterocycles bases contain 1 ~ 3 hetero atom selected from oxygen, sulphur or nitrogen, can be merged by phenyl, and containing one or
Substitution base of the multiple selected from nitro, trifluoromethyl, halogen, itrile group or aromatic radical；
The halogen is fluorine, chlorine, bromine, iodine.
According to the present invention, pharmaceutically acceptable salt includes formula（I）The acid-addition salts that compound is formed with following acid：Hydrogen
Bromic acid, acetic acid, maleic acid, phosphoric acid, nitric acid, citric acid, formic acid, hydrochloric acid, citric acid, fumaric acid, methanesulfonic acid, lactic acid, butanedioic acid,
Nicotinic acid, tartaric acid, carbonic acid or sulfuric acid.
Pharmaceutical composition of the present invention, wherein containing effective dose thing of the present invention or its pharmaceutically acceptable salt,
Formulation can be tincture, tablet, supensoid agent, sustained release agent, capsule, gel, injection, suppository, patch, granule, spraying
Conventional dosage form on the galenic pharmacies such as agent, emulsion, microspheres agent, oral liquid or drops.
This formula（I）The preparation method of shown compound is as follows：
Wherein R1、R2And R3It is defined as above；
Wherein a represents reaction condition：Solvent is methyl alcohol, ethanol, acetonitrile, n-butanol, the tert-butyl alcohol or isopropanol；Catalyst is sulphur
Acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfamic acid or nitric acid；Reaction temperature is 70 ~ 80 DEG C.
Wherein, intermediate（II）Preparation method can refer to document（Bioorganic & medicinal chemistry,
2007, 15, 6893; Chinese Journal of Organic Chemistry, 2007, 27, 1542）The side of report
Method, with second ketone compounds（IV）It is raw material, synthetic method is as follows：
Pharmacological activity is it is demonstrated experimentally that thing of the present invention there is significant suppression to make the propagation of Non-small cell lung carcinoma A549 cells
With, and induce A549 Apoptosis.
The following is the pharmacological activity method of testing and result of part of compounds of the present invention：
First, CCK-8 methods test anti tumor activity in vitro
Cell line：Non-small cell lung carcinoma A549 cells
Positive drug：Cis-platinum（DDP）
Experimental technique：
By the tumour cell digestion in exponential phase, count, be inoculated in 96 orifice plates, be placed in 37 DEG C, 5%CO2Incubator
Middle culture 24 hours.Set according to group and add the culture medium containing testing drug, and set up solvent group, negative control group and sun
Property control group.In 37 DEG C, 5%CO2After being cultivated 72 hours in incubator, 96 orifice plates add 10 μ L CCK-8 solution per hole, then
Hatching 3 hours.The absorbance (OD) in every hole is determined at 450 nm with ELIASA, and calculates inhibiting rate.Experimental result is used
SPSS17.0 is calculated half-inhibition concentration value (IC50)。
Part of compounds anti tumor activity in vitro result is as follows：
External antiproliferative activity of the part of compounds of the present invention of table 1 to A549 cells
Result shows that thing of the present invention has different degrees of inhibitory activity to A549 cells, and wherein compound I-5's and I-6 is anti-
Tumor promotion is most strong, its IC50Value is respectively 30.418 and 29.695 μM, is weaker than positive drug cis-platinum.
2nd, Apoptosis by Flow Cytometry
Cell line：Non-small cell lung carcinoma A549 cells
Experimental technique：
A549 cells are inoculated into 6 orifice plates, 37 DEG C, 5%CO are placed in2Incubator in hatch 24 h.Set further according to group,
Pastille culture medium is added, and sets up negative control group.After medicine acts on 48 h, 500 μ L Binding Buffer are added, then
5 μ L Annexin V-APC and 5 μ L 7-AAD are separately added into, 15 min are placed.Finally, it is thin with flow cytomery
Born of the same parents' apoptosis situation.
Flow cytometry result is as follows：
The Apoptosis result of table 2
Test result indicate that, the antitumor activity of thing of the present invention is related to inducing apoptosis of tumour cell.
Specific embodiment
Instrument and reagent
Fusing point is SGWX-4 micro-meldometers, and NMR is the types of Agilent-NMR-vnmrs 400, and mass spectrograph is
The types of Agilent Accurate Mass Q TOF MS 6520, other agents useful for same are pure for analysis.
The following examples are used to illustrate the preparation of thing of the present invention, but the invention is not limited in the following example.
Embodiment 1：N'- (3- imino groups-indol-2-one) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-1）Preparation
By 0.31 mmol 1- benzyls -3- (4- methoxyphenyls) pyrazoles -5- formylhydrazines（II-1）With 0.31 mmol isatin
（III-1）It is added in the round-bottomed flask of 25 mL, adds 5 mL ethanol and the 1 drop concentrated sulfuric acid, N2Protect lower 78 DEG C of reactions 4
~5 h.Cooling, suction filtration, filter cake is washed 3 times with ice ethanol, is vacuum dried, and obtains yellow solid N'- (3- imino groups-indoles -2-
Ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines（I-1）, yield 89%.
m.p. 297~299 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.77 (s, 1H), 11.38
(s, 1H), 7.78 (d, J = 7.2 Hz, 2H), 7.58 (d, J = 6.8 Hz, 1H), 7.39~7.21 (m,
7H), 7.10 (t, J = 6.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 2H), 6.96 (d, J = 7.6 Hz,
1H), 5.78 (s, 2H), 3.78 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ: 163.34, 159.83,
150.07, 143.08, 137.83, 132.53, 128.98, 127.74, 127.15, 124.84, 123.28,
121.55, 120.02, 114.71, 111.76, 55.61, 54.67; HR-MS calcd for C26H22N5O3 [M +
H]+ 452.1717, found 452.1720.
Embodiment 2：N'- (3- imino group -4- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-2）Preparation
4- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent obtain Huang with embodiment 1
Color solid N'- (3- imino group -4- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines
（I-2）, yield 93%.
m.p. 281~283 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.96 (s, 1H), 11.59
(s, 1H), 7.75 (d, J = 6.8 Hz, 2H), 7.38~7.24 (m, 6H), 7.14 (d, J = 8.0 Hz,
1H), 7.01 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 7.2 Hz, 1H), 5.79 (s, 2H), 3.77
(s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ: 162.82, 159.80, 144.35, 137.93, 128.96,
127.94, 127.66, 126.98, 124.92, 124.27, 117.01, 114.74, 110.46, 55.62, 54.85;
HR-MS calcd for C26H21ClN5O3 [M + H]+ 486.1327, found 486.1331.
Embodiment 3：N'- (3- imino group -4- bromo indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-3）Preparation
4- bromo-isatins are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent obtain Huang with embodiment 1
Color solid N'- (3- imino group -4- bromo indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines
（I-3）, yield 95%.
m.p. 272~274 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.96 (s, 1H), 11.57
(s, 1H), 7.76 (d, J = 7.6 Hz, 2H), 7.32~7.24 (m, 8H), 7.00 (d, J = 8.4 Hz,
2H), 6.95 (s, 1H), 5.78 (s, 2H), 3.77 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ:
162.87, 159.80, 144.54, 137.94, 133.24, 128.96, 127.94, 127.65, 127.47,
127.02, 124.92, 118.68, 114.73, 110.88, 55.62, 54.81; HR-MS calcd for
C26H21BrN5O3 [M + H]+ 530.0822, found 530.0824.
Embodiment 4：N'- (3- imino group -5- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-4）Preparation
5- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent obtain Huang with embodiment 1
Color solid N'- (3- imino group -5- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines
（I-4）, yield 92%.
m.p. 310~312 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.70 (s, 1H), 11.49
(s, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7.56 (s, 1H), 7.45 (d, J = 7.6 Hz, 1H),
7.32 (d, J = 6.0 Hz, 2H), 7.25 (d, J = 7.6 Hz, 4H), 6.99 (t, J = 9.2 Hz, 3H),
5.78 (s, 2H), 3.78 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ: 163.16, 159.85,
150.10, 141.76, 137.79, 131.90, 128.98, 128.01, 127.74, 127.37, 127.17,
124.79, 121.77, 121.07, 114.71, 113.31, 55.63, 54.73; HR-MS calcd for
C26H21ClN5O3 [M + H]+ 486.1327, found 486.1328
Embodiment 5：N'- (3- imino group -6- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-5）Preparation
6- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent obtain Huang with embodiment 1
Color solid N'- (3- imino group -6- chloro-indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines
（I-5）, yield 88%.
m.p. 278~279 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.65 (s, 1H), 11.53
(s, 1H), 7.78 (s, 2H), 7.58 (s, 1H), 7.31~7.00 (m, 10H), 5.78 (s, 2H), 3.78
(s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ: 163.34, 159.85, 150.10, 144.25, 137.80,
136.54, 128.98, 128.01, 127.73, 127.17, 124.80, 123.18, 122.96, 114.72,
111.82, 55.63, 54.71; HR-MS calcd for C26H20ClN5NaO3 [M + Na]+ 508.1147, found
508.1146.
Embodiment 6：N'- (3- imino group -6- bromo indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5-
Formylhydrazine（I-6）Preparation
6- bromo-isatins are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent obtain Huang with embodiment 1
Color solid N'- (3- imino group -6- bromo indole -2- ketone) -1- benzyls -3- (4- methoxyphenyls) -1H- pyrazoles -5- formylhydrazines
（I-6）, yield 97%.
m.p. 274~275 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 13.65 (s, 1H), 11.51
(s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.2 Hz, 1H), 7.30~7.22 (m,
7H), 7.12 (s, 1H), 7.01 (d, J = 7.6 Hz, 2H), 5.78 (s, 2H), 3.78 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) δ: 163.21, 159.85, 150.10, 144.29, 137.79, 128.98,
128.01, 127.72, 127.17, 126.05, 125.16, 123.13, 119.34, 114.72, 114.56,
55.63, 54.69; HR-MS calcd for C26H21BrN5O3 [M + H]+ 530.0822, found 530.0821。
Claims (5)
1. the pyrazoles Shiff base derivative that a class has isatin fragment is used for anti-tumor drug and preparation method, it is characterised in that：
Such as formula（I）Compound：
Wherein, R1Represent C2 ~ C8 alkane, C4 ~ C7 fat ring group, aromatic radical or 5 ~ 6 circle heterocycles bases；
R2Represent C1 ~ C9 alkane, C4 ~ C6 fat ring group, C1 ~ C5 alkoxies, aromatic radical or 5 ~ 6 circle heterocycles bases；
R3Represent H, itrile group, halogen, nitro, trifluoromethyl, C1 ~ C6 alkyl, C1 ~ C4 alkoxies, C4 ~ C6 fat ring groups or fragrance
Base；
Described aromatic radical is xenyl, naphthyl, phenyl or substituted-phenyl；Wherein described substituted-phenyl contains 1 ~ 3 substitution base,
The substitution base takes from halogen, trifluoromethyl, itrile group, nitro, C2 ~ C4 alkoxies, C1 ~ C6 alkyl or C4 ~ C6 fat ring group；
5 ~ 6 described circle heterocycles bases contain 1 ~ 3 hetero atom selected from oxygen, sulphur or nitrogen, can be merged by phenyl, and containing one or
Substitution base of the multiple selected from nitro, trifluoromethyl, halogen, itrile group or aromatic radical；
The halogen is fluorine, chlorine, bromine, iodine.
2. the class as described in claim 1 has the pyrazoles Shiff base derivative of isatin fragment for the system of anti-tumor drug
Standby method, it is characterised in that：Such as formula（I）The preparation method of middle compound, including：
Wherein R1、R2And R3Definition with claim 1；
Wherein a represents reaction condition：Solvent is methyl alcohol, ethanol, acetonitrile, n-butanol, the tert-butyl alcohol or isopropanol；Catalyst is sulphur
Acid, hydrochloric acid, acetic acid, formic acid, phosphoric acid, sulfamic acid or nitric acid；Reaction temperature is 70 ~ 80 DEG C.
3. the pyrazoles Shiff base derivative that the class as described in claim 1 or 2 has isatin fragment is used for anti-tumor drug
And prepare method, it is characterised in that：Such as formula（I）Any one of formula（I）Compound or its pharmaceutically acceptable salt, wherein
Pharmaceutically acceptable salt is formula（I）The acid-addition salts that compound is formed with following acid：Hydrobromic acid, acetic acid, maleic acid, phosphorus
Acid, nitric acid, citric acid, formic acid, hydrochloric acid, citric acid, fumaric acid, methanesulfonic acid, lactic acid, butanedioic acid, nicotinic acid, tartaric acid, carbonic acid or
Sulfuric acid.
4. the class as described in any one of claim 1 ~ 3 has the pyrazoles Shiff base derivative of isatin fragment for antineoplastic
Medicine and preparation method, it is characterised in that：Such as formula（I）Compound：
Formula containing effective dose（I）The pharmaceutical composition of compound or its pharmaceutically acceptable salt, its formulation includes tincture
Agent, tablet, supensoid agent, sustained release agent, capsule, gel, injection, suppository, patch, granule, spray, emulsion, microballoon
Agent, oral liquid or drops.
5. the formula as any one of claim 1 ~ 4（I）Compound or its pharmaceutically acceptable salt, its feature exist
In：Application in the medicine for preparing prevention or treatment tumour.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094009A2 (en) * | 2009-02-13 | 2010-08-19 | Children's Hospital Medical Center | Methods and compositions for the treatment of ras associated disorders |
-
2017
- 2017-04-28 CN CN201710293502.1A patent/CN106866634A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010094009A2 (en) * | 2009-02-13 | 2010-08-19 | Children's Hospital Medical Center | Methods and compositions for the treatment of ras associated disorders |
Non-Patent Citations (5)
| Title |
|---|
| LIANG-WEN ZHENG等: "Synthesis of novel substituted pyrazole-5-carbohydrazide hydrazone derivatives and discovery of a potent apoptosis inducer in A549 lung cancer cells", 《BIOORGANIC & MEDICINAL CHEMISTRY 》 * |
| WAGDY M. ELDEHNA等: "Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| YONG XIA等: "Synthesis and structure–activity relationships of novel 1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide derivatives as potential agents against A549 lung cancer cells", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| 张磊 等: "吡唑类化合物的活性研究进展", 《国外医药抗生素分册》 * |
| 王京 等: "靛红衍生物的抗肿瘤活性研究进展", 《广东化工》 * |
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Application publication date: 20170620 |