CN106977508A - Pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma - Google Patents
Pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma Download PDFInfo
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Abstract
Pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma, and the present invention relates to medicinal chemistry art, and in particular to a class has the pyrazole derivatives of isatin structure（I）, its preparation method and medical usage.Pharmacological evaluation proves that thing of the present invention has the effect for suppressing the external malignant proliferation of tumour cell.Therefore, thing of the present invention can be used for preventing or treat cell proliferative disorder relevant disease, the purposes in medicine in particular for preventing or treating tumour.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a class has the pyrazole derivatives of isatin structure, their system
Purposes in Preparation Method and medicine for preventing or treating tumour.
Background technology
Pyrazoles be it is a kind of with potential source biomolecule activity azacyclo-, recent studies indicate that pyrazole derivatives have it is a variety of
Pharmacological activity, such as antitumor, antibacterial and anti-inflammatory.In addition, pyrazole derivatives can also be used as insecticide and herbicide.At present,
Medicine containing pyrrazole structure has NSAIDs Celecoxib, bactericide pyraclostrobin and antineoplastic Axitinib
Deng.In recent years, Zhao Baoxiang seminars construct the 1- benzyl -3- phenyl pyrazoles compound libraries of various structures type, such as acyl
Hydrazine, schiff bases, glycoconjugate and hydroxamic acid derivatives（Bioorg. Med. Chem. 2007, 15, 6893; Bioorg.
Med. Chem. 2009, 17, 1957; Bioorg. Med. Chem. 2009, 17, 7085）.Experimental result shows, portion
Divide pyrazole derivatives that there is the activity of significant anti-non-small cell lung cancer A549 cells propagation.Meanwhile, Berto a's et al. grinds
Study carefully result to also indicate that, pyrazole derivatives can effectively suppress the propagation of A549 cells（Bioorg. Med. Chem. 2012,
20, 2101）.
In addition, isatin is also known as istain, it is the diketone form of indoles, its structure is widely used in antineoplastic research
Field, is the pharmacophore with antitumor activity（Anti-Cancer Agents Med Chem, 2009, 9, 397）.Example
Such as, isatin fragment is present in the antitumor active ingredient indigo red of Chinese medicine indigo naturalis and small molecule Mutiple Targets receptor tyrosine kinase suppresses
In agent Sutent structure.Isatin group can effectively strengthen the antitumor cell drug resistance of natural product podophyllotoxin（RSC
Adv. 2015, 5, 97816）.Research in recent years is it is also shown that Isatine derivatives have stronger suppression to kinds of tumor cells
Make and use（Eur. J. Med. Chem. 2016, 124, 782; Eur. J. Med. Chem. 2015, 90, 684;
Bioorg. Med. Chem. Lett. 2016, 26, 1558）.
Using the pharmacophore principle of hybridization of medicinal chemistry art, the medicine that both have antitumor activity by pyrazoles and isatin
Effect group is conjugated, and has obtained having no the pyrazole derivatives with isatin structure of document report.
The content of the invention
The present invention discloses the class formula of formula one（I）Compound or its pharmaceutically acceptable salt.Shown through pharmacological evaluation,
The compound of thing of the present invention has stronger inhibitory action to Non-small cell lung carcinoma A549 cells propagation.Therefore, it is of the invention
Formula（I）Compound can be used in preventing or treat cell proliferative disorder relevant disease, in particular for preventing or treating tumour
Purposes in medicine.
The compound formula of the present invention（I）It is as follows：
Wherein, R1Represent the fatty ring group of aromatic radical, 5 ~ 7 circle heterocycles bases, C1 ~ C4 alkane or C4 ~ C6；
R2Represent the fatty ring group of C1 ~ C10 alkane, aromatic radical, C4 ~ C6 or 5 ~ 7 circle heterocycles bases；
N represents 1,2,3,4 or 5；
R3Represent halogen, H, aromatic radical, C1 ~ C6 alkyl, itrile group, trifluoromethyl, C1 ~ C4 alkoxies, nitro or C4 ~ C6 cycloaliphatic rings
Base；
Described aromatic radical is naphthyl, xenyl, phenyl or substituted-phenyl；Wherein described substituted-phenyl contains 1 ~ 4 substituent,
The substituent is derived from the fatty ring group of halogen, itrile group, nitro, C1 ~ C4 alkoxies, C4 ~ C6, H, trifluoromethyl or C1 ~ C6 alkyl；
5 ~ 7 described circle heterocycles bases contain 1 ~ 2 hetero atom for being selected from sulphur, oxygen or nitrogen, can be merged by phenyl, and containing one or
Multiple substituents selected from nitro, halogen, trifluoromethyl, aromatic radical or itrile group；
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：Sulphur
Acid, phosphoric acid, nitric acid, hydrochloric acid, fumaric acid, citric acid, lactic acid, maleic acid, methanesulfonic acid, hydrobromic acid, citric acid, butanedioic acid, winestone
Acid, nicotinic acid, carbonic acid, formic acid or acetic acid.
Pharmaceutical composition of the present invention, wherein containing effective dose thing of the present invention or its pharmaceutically acceptable salt,
Formulation can be tablet, injection, sustained release agent, patch, suppository, spray, capsule, gel, granule, tincture, suspension
Conventional dosage form on the galenic pharmacies such as agent.
This formula（I）The preparation method of shown compound is as follows：
Wherein R1、R2, n and R3It is as defined above；
Wherein a ~ b represents reaction condition：
a：Reagent is sodium hydrogen or potassium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Reaction temperature is 20 ~ 35
℃；
b：Reagent is potassium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Catalyst is KI；Reaction temperature
For 70 ~ 110 DEG C.
Wherein, intermediate（IV）Preparation method can refer to document（Chinese Journal of Organic
Chemistry, 2007, 27, 1542; Bioorganic & medicinal chemistry, 2007, 15, 6893;
Chinese Journal of Synthetic Chemistry, 2014, 22, 730）The method of report, with ethyl ketone class chemical combination
Thing（V）For raw material, synthetic method is as follows：
Pharmacological activity is it is demonstrated experimentally that thing of the present invention can effectively suppress the propagation of Non-small cell lung carcinoma A549 cells.
The following is the pharmacological activity method of testing and result of part of compounds of the present invention：
CCK-8 methods test anti tumor activity in vitro
Positive drug：Cis-platinum（DDP）
Experimental method：
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 and is obtained 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
As a result show, thing of the present invention has different degrees of inhibitory action to A549 cells, and wherein compound I-6 activity is most
By force, its IC50It is worth for 58.484 μM, is weaker than positive drug cis-platinum.
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 AgilentAccurate-Mass-Q-TOF-MS 6520, thin layer chromatography board and silica gel are purchased from Haiyang Chemical Plant, Qingdao, other
Agents useful for same is pure to analyze.
The following examples are used for the preparation for illustrating thing of the present invention, but the invention is not limited in the following example.
Embodiment 1：N1- (2- bromoethyls)-indol-2-one（III-1）Preparation
0.68 mmol isatin (II-1) is added in 25 mL round-bottomed flask, 4 mL DMFs are added
Dissolving, ice-water bath is cooled to 0 DEG C, is added portionwise at 1.36 mmol sodium hydrides, 0 DEG C and is added after the min of stirring reaction 15
6.8 mmol 1,2- Bromofumes, the h of stirring reaction 2 ~ 3 at 25 DEG C.Add 30 mL saturated ammonium chloride solutions and reaction, two is quenched
Chloromethanes is extracted 3 times, is washed 2 times, and saturated nacl aqueous solution is washed 1 time, anhydrous sodium sulfate drying, and filtering has been removed under reduced pressure
Machine solvent, obtains crude product, then obtain red solid N through silica gel column chromatography purifying1- (2- bromoethyls)-indol-2-one（III-1）,
Yield 76%.
m.p. 128~129 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.61 (t, J = 8.0 Hz, 2H),
7.14 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.15 (t, J = 6.8 Hz, 2H),
3.61 (t, J = 6.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 182.64, 158.18, 150.42,
138.41, 125.68, 124.05, 117.59, 110.22, 41.93, 27.10.
Embodiment 2：N1- (2- bromoethyls) -4- chloro-indole -2- ketone（III-2）Preparation
4- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent be the same as Example 1 obtain Huang
Color solid N1- (2- bromoethyls) -4- chloro-indole -2- ketone（III-2）, yield 62%.
m.p. 167~169 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.52 (t, J = 8.0 Hz, 1H),
7.09 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 4.15 (s, 2H), 3.61 (s,
2H); 13C NMR (CDCl3, 100 MHz) δ: 179.51, 157.29, 151.52, 138.51, 134.21,
125.60, 114.70, 108.54, 42.13, 27.08.
Embodiment 3：N1- (2- bromoethyls) -4- bromo indole -2- ketone（III-3）Preparation
4- bromo-isatins are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent be the same as Example 1 obtain Huang
Color solid N1- (2- bromoethyls) -4- bromo indole -2- ketone（III-3）, yield 70%.
m.p. 177~179 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.43 (t, J = 8.0 Hz, 1H),
7.29 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 4.16 (t, J = 6.0 Hz, 2H),
3.61 (t, J = 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 157.23, 151.97, 138.31,
128.78, 122.07, 108.99, 42.03, 27.00.
Embodiment 4：N1- (2- bromoethyls) -5- chloro-indole -2- ketone（III-4）Preparation
5- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent be the same as Example 1 obtain red
Color solid N1- (2- bromoethyls) -5- chloro-indole -2- ketone（III-4）, yield 65%.
m.p. 111~113 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.59 (d, J = 8.8 Hz, 2H),
6.99 (d, J = 8.0 Hz, 1H), 4.15 (t, J = 6.4 Hz, 2H), 3.61 (t, J = 6.4 Hz, 2H);13C NMR (CDCl3, 100 MHz) δ: 181.66, 157.66, 148.79, 137.75, 129.89, 125.53,
118.39, 111.65, 42.17, 27.20.
Embodiment 5：N1- (2- bromoethyls) -6- chloro-indole -2- ketone（III-5）Preparation
6- chlorisatides are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent be the same as Example 1 obtain Huang
Color solid N1- (2- bromoethyls) -6- chloro-indole -2- ketone（III-5）, yield 75%.
m.p. 106~108 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.58 (t, J = 7.6 Hz, 1H),
7.14 (d, J = 7.6 Hz, 1H), 7.02 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.62 (t, J
= 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 181.12, 158.15, 151.46, 144.91,
126.70, 124.31, 115.89, 111.13, 42.19 27.07
Embodiment 6：N1- (2- bromoethyls) -6- bromo indole -2- ketone（III-6）Preparation
6- bromo-isatins are replaced into isatin, the method as described in embodiment 1, remaining required raw material, reagent be the same as Example 1 obtain Huang
Color solid N1- (2- bromoethyls) -6- bromo indole -2- ketone（III-6）, yield 58%.
m.p. 165~166 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.49 (d, J = 8.0 HZ, 1H),
7.31 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 4.13 (t, J = 6.4 Hz, 2H), 3.61 (t, J
= 6.4 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 181.39, 158.02, 151.23, 133.70,
127.31, 126.60, 116.26, 113.96, 42.16, 27.07.
Embodiment 7：2- (1-N '-indoles -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrroles
Azoles -5- bases) -1,3,4- oxadiazoles（I-1）Preparation
By 0.30 mmol N1- (2- bromoethyls)-(substitution) indol-2-one (III-1), 0.27 mmol 5- [3- (4- methoxies
Base phenyl) -1- benzyl pyrazoles -5- bases] -2- sulfydryl -1,3,4- oxadiazoles (IV-1), 0.41 mmol potassium carbonate and catalysis
The KI of amount is added in 10 mL round-bottomed flask, adds the h of stirring reaction 1 ~ 2 at 4 mL DMF, 80 DEG C.By reaction solution
It is poured into 80 mL water, suction filtration, solid is washed 3 times, vacuum drying, then yellow solid 2- (1- is obtained through silica gel column chromatography purifying
N '-indoles -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- Evil
Diazole（I-1）, yield 79%.
m.p. 96~98 ℃; 1H NMR (CDCl3, 400 MHz) δ: 7.79 (d, J = 8.4 Hz, 2H),
7.61~7.59 (m, 2H), 7.36~7.23 (m, 6H), 7.12 (t, J = 7.6 Hz, 1H), 7.07 (s, 1H),
6.97 (d, J = 8.8Hz, 2H), 5.92 (s, 2H), 4.25 (t, J = 7.2 Hz, 2H), 3.85 (s,
3H), 3.54 (t, J = 7.2 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ: 182.74, 163.44,
159.82, 158.64, 158.30, 151.50, 150.35, 138.81, 136.55, 128.57, 127.81,
127.64, 127.38, 126.99, 125.61, 124.86, 124.09, 114.15, 110.56, 105.61,
55.34, 55.09, 39.13, 29.00; HR-MS calcd for C29H23N5NaO4S [M + Na]+ 560.1363,
found 560.1368.
Embodiment 8：2- (1-N ' -4- chloro-indole -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxybenzenes
Base) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-2）Preparation
By N1- (2- bromoethyls) -4- chloro-indole -2- ketone replaces N1- (2- bromoethyls)-(substitution) indol-2-one, by embodiment 7
Described method, remaining required raw material, reagent be the same as Example 7 obtain orange/yellow solid 2- (1-N ' -4- chloro-indoles -2,3- bis-
Ketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-2）, yield
68%。
m.p. 200~202 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.81 (d, J = 8.4 Hz,
2H), 7.61 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J = 7.2 Hz, 2H), 7.25
(t, J = 8.8 Hz, 4H), 7.09 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 5.81
(s, 2H), 4.13 (s, 2H), 3.77 (s, 3H), 3.55 (s, 2H); 13C NMR (DMSO-d6, 100 MHz)
δ: 180.26, 164.12, 159.83, 158.23, 157.95, 151.13, 139.10, 137.37, 131.54,
129.02, 128.08, 127.66, 127.13, 124.82, 124.66, 114.93, 114.64, 110.04,
105.98, 55.62, 54.71, 29.89; HR-MS calcd for C29H22ClN5NaO4S [M + Na]+
594.0973, found 594.0972.
Embodiment 9：2- (1-N ' -4- bromo indole -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxybenzenes
Base) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-3）Preparation
By N1- (2- bromoethyls) -4- bromo indole -2- ketone replaces N1- (2- bromoethyls)-(substitution) indol-2-one, by embodiment 7
Described method, remaining required raw material, reagent be the same as Example 7, obtain yellow solid 2- (1-N ' -4- bromo indoles -2,3- diketone) -
Ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-3）, yield 80%.
m.p. 193~195 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.81 (d, J = 8.8 Hz,
2H), 7.52 (t, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.32~7.23 (m, 7H), 7.00 (d, J =
8.8 Hz, 2H), 5.81 (s, 2H), 4.13 (s, 2H), 3.77 (s, 3H), 3.55 (s, 2H); 13C NMR
(DMSO-d6, 100 MHz) δ: 180.81, 164.11, 159.83, 158.22, 157.91, 152.49, 151.12,
139.01, 137.37, 129.03, 128.07, 127.78, 127.65, 127.13, 124.82, 119.90,
116.55, 114.64, 110.45, 105.98, 55.62, 54.72, 29.86; HR-MS calcd for
C29H23BrN5O4S [M + H]+ 616.0649, found 616.0647.
Embodiment 10：2- (1-N ' -5- chloro-indole -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxybenzenes
Base) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-4）Preparation
By N1- (2- bromoethyls) -5- chloro-indole -2- ketone replaces N1- (2- bromoethyls)-(substitution) indol-2-one, by embodiment 7
Described method, remaining required raw material, reagent be the same as Example 7 obtain orange/yellow solid 2- (1-N ' -5- chloro-indoles -2,3- bis-
Ketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-4）, yield
66%。
m.p. 219~220 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.82 (d, J = 8.4 Hz,
2H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.34~7.23 (m, 6H),
6.99 (d, J = 8.4 Hz, 2H), 5.81 (s, 2H), 4.13 (s, 2H), 3.77 (s, 3H), 3.56 (s,
2H); 13C NMR (DMSO-d6, 100 MHz) δ: 182.31, 164.08, 159.83, 158.22, 151.13,
149.25, 137.43, 137.37, 129.03, 128.07, 127.66, 127.13, 124.84, 124.37,
119.25, 114.64, 113.06, 105.99, 55.62, 54.70, 29.88; HR-MS calcd for
C29H22ClN5NaO4S [M + Na]+ 594.0973, found 594.0976.
Embodiment 11：2- (1-N ' -6- chloro-indole -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxybenzenes
Base) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-5）Preparation
By N1- (2- bromoethyls) -6- chloro-indole -2- ketone replaces N1- (2- bromoethyls)-(substitution) indol-2-one, by embodiment 7
Described method, remaining required raw material, reagent be the same as Example 7, obtain yellow solid 2- (1-N ' -6- chloro-indoles -2,3- diketone) -
Ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-5）, yield 72%.
m.p. 202~203 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.82 (d, J = 7.6 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H), 7.43 (s, 1H), 7.33 (d, J = 7.2 Hz, 2H), 7.26
(t, J = 6.8 Hz, 3H), 7.12 (d, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 2H), 5.81
(s, 2H), 4.13 (s, 2H), 3.78 (s, 3H), 3.57 (s, 2H); 13C NMR (DMSO-d6, 100 MHz)
δ: 182.04, 164.11, 159.83, 158.73, 158.24, 151.85, 151.11, 142.97, 137.36,
129.01, 128.06, 127.70, 127.13, 126.30, 124.84, 123.58, 116.76, 114.64,
105.99, 55.62, 55.36, 54.70, 29.85; HR-MS calcd for C29H22ClN5NaO4S [M + Na]+
594.0973, found 594.0972
Embodiment 12：2- (1-N ' -6- bromo indole -2,3- diketone)-ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxybenzenes
Base) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-6）Preparation
By N1- (2- bromoethyls) -6- bromo indole -2- ketone replaces N1- (2- bromoethyls)-(substitution) indol-2-one, by embodiment 7
Described method, remaining required raw material, reagent be the same as Example 7, obtain yellow solid 2- (1-N ' -6- bromo indoles -2,3- diketone) -
Ethyl -2- sulfenyls) -5- (1- benzene first -3- (4- methoxyphenyls) pyrazoles -5- bases) -1,3,4- oxadiazoles（I-6）, yield 72%.
m.p. 223~224 ℃; 1H NMR (DMSO-d6, 400 MHz) δ: 7.82 (d, J = 7.6 Hz,
2H), 7.65 (s, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.34~7.24 (m, 6H), 7.00 (d, J =
7.2 Hz, 2H), 5.81 (s, 2H), 4.12 (s, 2H), 3.78 (s, 3H), 3.56 (s, 2H); 13C NMR
(DMSO-d6, 100 MHz) δ: 182.30, 164.13, 159.83, 158.65, 158.23, 151.64, 151.12,
137.36, 132.31, 129.02, 128.08, 127.69, 127.15, 126.57, 126.25, 124.83,
117.06, 114.64, 105.99, 55.62, 54.71, 29.87; HR-MS calcd for C29H23BrN5O4S [M +
H]+ 638.0468, found 638.0468。
Claims (5)
1. the pyrazole derivatives with isatin structure are used for the medicine of anti-curing oncoma, it is characterised in that：
Formula（I）Compound：
Wherein, R1Represent the fatty ring group of aromatic radical, 5 ~ 7 circle heterocycles bases, C1 ~ C4 alkane or C4 ~ C6；
R2Represent the fatty ring group of C1 ~ C10 alkane, aromatic radical, C4 ~ C6 or 5 ~ 7 circle heterocycles bases；
N represents 1,2,3,4 or 5；
R3Represent halogen, H, aromatic radical, C1 ~ C6 alkyl, itrile group, trifluoromethyl, C1 ~ C4 alkoxies, nitro or C4 ~ C6 cycloaliphatic rings
Base；
Described aromatic radical is naphthyl, xenyl, phenyl or substituted-phenyl；Wherein described substituted-phenyl contains 1 ~ 4 substituent,
The substituent is derived from the fatty ring group of halogen, itrile group, nitro, C1 ~ C4 alkoxies, C4 ~ C6, H, trifluoromethyl or C1 ~ C6 alkyl；
5 ~ 7 described circle heterocycles bases contain 1 ~ 2 hetero atom for being selected from sulphur, oxygen or nitrogen, can be merged by phenyl, and containing one or
Multiple substituents selected from nitro, halogen, trifluoromethyl, aromatic radical or itrile group；
The halogen is fluorine, chlorine, bromine, iodine.
2. the pyrazole derivatives with isatin structure described in claim 1 are used for the preparation method of the medicine of anti-curing oncoma, its feature
It is：
Formula of（I）The preparation method of compound, including：
Wherein R1、R2, n and R3Definition with claim 1；
Wherein a ~ b represents reaction condition：
a：Reagent is sodium hydrogen or potassium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Reaction temperature is 20 ~ 35
℃；
b：Reagent is potassium carbonate；Solvent is N,N-dimethylformamide or dimethyl sulfoxide (DMSO)；Catalyst is KI；Reaction temperature
For 70 ~ 110 DEG C.
3. the pyrazole derivatives with isatin structure described in claim 1 or 2 are used for the medicine and its preparation method of anti-curing oncoma, its
It is characterised by：Any one of 1 ~ 2 formula（I）Compound or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt
For formula（I）The acid-addition salts that compound is formed with following acid：Sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid, fumaric acid, citric acid, lactic acid,
Maleic acid, methanesulfonic acid, hydrobromic acid, citric acid, butanedioic acid, tartaric acid, nicotinic acid, carbonic acid, formic acid or acetic acid.
4. the pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma, it is characterised in that：Containing effective
The formula of any one of the claim 1 ~ 3 of dosage（I）The pharmaceutical composition of compound or its pharmaceutically acceptable salt, its formulation
Including tablet, injection, sustained release agent, patch, suppository, spray, capsule, gel, granule, tincture, supensoid agent.
5. the pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma, it is characterised in that：The right
It is required that any one of 1 ~ 4 formula（I）Compound or its pharmaceutically acceptable salt are preparing the medicine of prevention or treatment tumour
In application.
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| CN201710310779.0A CN106977508A (en) | 2017-05-05 | 2017-05-05 | Pyrazole derivatives with isatin structure are used for the medicine and its preparation method of anti-curing oncoma |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024530A (en) * | 2021-03-15 | 2021-06-25 | 合肥工业大学 | Isatin-1, 2, 4-oxadiazole compound and preparation method and application thereof |
| CN116621767A (en) * | 2023-02-23 | 2023-08-22 | 中山大学 | Isatin derivative and preparation method and application thereof |
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|---|---|---|---|---|
| CN1278794A (en) * | 1997-09-05 | 2001-01-03 | 葛兰素集团有限公司 | Substituted di-hydroxyl-indol derivatives as protein tyrosine kinase and as protein serine/threenine kinase inhibitors |
| CN103965182A (en) * | 2014-05-22 | 2014-08-06 | 遵义医学院 | Medicament of 1,3,4-oxadiazole containing pyrazole compound prepared for treating tumor |
| CN104311470A (en) * | 2014-09-10 | 2015-01-28 | 首都师范大学 | N-substituted indoline-2-keto-3-hydrazine disulfide formate and preparation method and use thereof |
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2017
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| CN1278794A (en) * | 1997-09-05 | 2001-01-03 | 葛兰素集团有限公司 | Substituted di-hydroxyl-indol derivatives as protein tyrosine kinase and as protein serine/threenine kinase inhibitors |
| CN103965182A (en) * | 2014-05-22 | 2014-08-06 | 遵义医学院 | Medicament of 1,3,4-oxadiazole containing pyrazole compound prepared for treating tumor |
| CN104311470A (en) * | 2014-09-10 | 2015-01-28 | 首都师范大学 | N-substituted indoline-2-keto-3-hydrazine disulfide formate and preparation method and use thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024530A (en) * | 2021-03-15 | 2021-06-25 | 合肥工业大学 | Isatin-1, 2, 4-oxadiazole compound and preparation method and application thereof |
| CN113024530B (en) * | 2021-03-15 | 2023-07-18 | 合肥工业大学 | Isatin-1, 2, 4-oxadiazole compound and preparation method and application thereof |
| CN116621767A (en) * | 2023-02-23 | 2023-08-22 | 中山大学 | Isatin derivative and preparation method and application thereof |
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