CN109053731B - P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof - Google Patents
P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN109053731B CN109053731B CN201811172919.3A CN201811172919A CN109053731B CN 109053731 B CN109053731 B CN 109053731B CN 201811172919 A CN201811172919 A CN 201811172919A CN 109053731 B CN109053731 B CN 109053731B
- Authority
- CN
- China
- Prior art keywords
- indolizine
- derivative
- pyrazoline
- chloro
- pyridazinone
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/20—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof, wherein a1, 3-dipolar cycloaddition method is used for introducing a pyrazole ring into an (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -one structure, so that the p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative is synthesized. The p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a foundation for further application in the medical field.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof.
Background
(E) -7-p-chlorobenzylidene-6, 7-indolizin-8 (5H) -one having the following chemical formula:
wherein Ar is 4-ClC6H4-。
The 1, 3-dipolar cycloaddition reaction is the most important method for synthesizing five-membered heterocyclic compounds with good regioselectivity and body selectivity, and is also a more active reaction in heterocyclic pharmaceutical chemistry research. In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Therefore, the heterocyclic compound has high synthetic value in terms of pharmacology and synthesis angle.
Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. The indolizine skeleton is a common structural unit in bioactive alkaloids, and has remarkable anti-mitotic property or the effect of treating cardiovascular diseases and hypertension. Therefore, it is of great significance to research the influence of different heterocycles on pharmacological activity caused by aggregation in the same molecule.
Disclosure of Invention
The invention aims to provide a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, and a preparation method and application thereof, and the p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative is prepared.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative has the following chemical structural formula:
wherein Ar is 4-ClC6H4-。
The invention also provides a preparation method of the p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, which comprises the following steps:
and 3, adding (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -ketone and the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after the dropwise adding is finished, tracking by TLC (thin layer chromatography), removing the solvent by rotary evaporation after the reaction is completed, dissolving the residue left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain the spiro [ indolizine-pyrazoline ] derivative with the p-chloro substituted pyridazinone structure.
Further, the mass ratio of the α -chloropyridazinone structure chromone aldehyde hydrazone derivative to the (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -ketone is 1.6: 1-2: 1.
Further, the volume ratio of triethylamine to dichloromethane is: 1: 10-1: 20.
further, the spreading agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)＝1:5。
The invention also provides application of the p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative in antitumor drugs.
The invention provides a p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and a preparation method and application thereof, wherein a1, 3-dipolar cycloaddition method is used for introducing a pyrazole ring into an (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -one structure, so that the p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative is synthesized. The p-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative prepared by the invention has a strong tumor cell inhibition effect, and provides a foundation for further application in the medical field.
Drawings
FIG. 1 is a flow chart of a preparation method of compound 1 and compound 2 containing a pyridazinone structure according to the present invention;
FIG. 2 is a schematic diagram of the chemical structure of the compound 4 of the present invention.
Detailed Description
The technical solutions of the present invention are further described in detail below with reference to the drawings and examples, which should not be construed as limiting the present invention.
In recent years, pyridazinone compounds become hot spots of research in the pharmaceutical field due to the unique physiological activity of pyridazinone compounds, and have strong effects of inhibiting cancer cell diffusion, resisting bacteria and viruses, reducing blood fat, reducing blood sugar, promoting metabolism and the like. Pyrazole derivatives have attracted considerable attention as a class of useful intermediates and as a variety of pharmaceutical activities that they themselves exhibit. The indolizine skeleton is a common structural unit in bioactive alkaloids, and has remarkable anti-mitotic property or the effect of treating cardiovascular diseases and hypertension.
In order to better research the influence of different heterocycles on pharmacological activity caused by aggregation in the same molecule, the technical scheme synthesizes the spiro [ indolizine-pyrazoline ] derivative with a p-chloro substituted pyridazinone structure through 1, 3-dipolar cycloaddition reaction.
The invention provides an embodiment of a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, which has the following chemical structural formula:
wherein: Ar-4-ClC6H4-, Br is bromine.
The invention provides a preparation method of a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative, which comprises the following steps:
The invention synthesizes the chromone aldehyde hydrazone derivative containing a pyridazinone structure by a method of generating Schiff base by dehydration reaction of 6-bromo chromone with a formaldehyde group substituted at the 3-position and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate. The chromone aldehyde hydrazone derivative having a pyridazinone structure is also referred to as compound 1 hereinafter.
Example 1: adding 2mmol of 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate into a flask containing 15mL of ethanol, refluxing and stirring in a boiling water bath until the mixture is dissolved, slowly dropwise adding 20mL of anhydrous ethanol solution in which 2mmol of 6-bromochromone substituted by 3-formaldehyde groups is dissolved, continuing refluxing and stirring in the boiling water bath for 1 hour, dropwise adding 10 drops of hydrochloric acid, and allowing a light yellow precipitate to appear. And (3) refluxing and stirring in a continuous boiling water bath for 5 hours, stopping the water bath, adding 20mL of distilled water, stirring, deepening the color of the light yellow precipitate, and performing suction filtration to obtain a yellowish red needle-shaped product. Washing with anhydrous ether for multiple times, recrystallizing with ethanol, and vacuum drying to obtain compound 1: chromone aldehyde hydrazone derivatives containing a pyridazinone structure.
And 2, synthesizing α -chloropyridazinone structure chromone aldehyde hydrazone derivatives.
Example 2 Compound 1(10.0mmol) was added to 12.5mL of DMF, and the mixture was completely dissolved under stirring at room temperature, the reaction was controlled to 35 ℃ or lower, 15.0mmol NCS was added in 5 to 10 portions, followed by TLC, and after completion of the reaction, the mixture was poured into water, extracted with diethyl ether for 3 times, the extracted solution was dried over anhydrous magnesium sulfate, and after removing the diethyl ether by rotary evaporation, the mixture was recrystallized from chloroform/petroleum ether to obtain a chromone aldehyde hydrazone derivative having a structure of α -chloropyridazinone, and a chromone aldehyde hydrazone derivative having a structure of α -chloropyridazinone was hereinafter also referred to as Compound 2.
It should be noted that many methods have been studied in the art for synthesizing compounds 1 and 2, and this example only exemplifies specific examples used in a laboratory, and those skilled in the art can also prepare compounds 1 and 2 by other methods.
And 3, adding (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -ketone and the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after the dropwise adding is finished, tracking by TLC (thin layer chromatography), removing the solvent by rotary evaporation after the reaction is completed, dissolving the residue left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain the spiro [ indolizine-pyrazoline ] derivative with the p-chloro substituted pyridazinone structure.
Example 3 adding 1mmol of the compound 3((E) -7-p-chlorobenzylidene-6, 7-indolizino-8 (5H) -one) and 1.6mmol of the compound 2(α -chromone aldehyde hydrazone derivative of the chloropyridazinone structure) to 20mL of dichloromethane, dropping a mixed solution of 0.5mL of triethylamine and 5mL of dichloromethane to the solution with a constant pressure dropping funnel, continuing stirring at room temperature for 24 hours after dropping, tracking by TLC, removing the solvent by rotary evaporation after the reaction is completed, dissolving 3mL of ethyl acetate for standby, and finally dissolving with V(Ethyl acetate):V(Petroleum ether)Silica gel column chromatography 1:5 gave compound 4.
It should be noted that the above dichloromethane is a reaction solvent for dissolving the compounds 2 and 3, and the present invention is not limited to a specific amount of dichloromethane.
In the step, the mass ratio of the chromone aldehyde hydrazone derivative with the α -chloropyridazinone structure to the (E) -7-p-chlorobenzylidene-6, 7-indolizino-8 (5H) -ketone is 1.6: 1-2: 1, and the volume ratio of triethylamine to dichloromethane in the mixed solution of triethylamine and dichloromethane is 1: 10-1: 20.
Example 4 adding 1mmol of the compound 3((E) -7-p-chlorobenzylidene-6, 7-indolizino-8 (5H) -one) and 2mmol of the compound 2(α -chromone aldehyde hydrazone derivative of the chloropyridazinone structure) to 20mL of dichloromethane, dropping a mixed solution of 0.5mL of triethylamine and 10mL of dichloromethane to the solution with a constant pressure dropping funnel, continuing stirring at room temperature for 24 hours after dropping, tracking by TLC, removing the solvent by rotary evaporation after the reaction is completed, dissolving 3mL of ethyl acetate for standby, and finally dissolving with V(Ethyl acetate):V(Petroleum ether)Silica gel column chromatography 1:5 gave compound 4.
In examples 3, 4, ethyl acetate was used to dissolve the residue remaining from the rotary evaporation, to facilitate removal, and to facilitate addition to the top of the column. It will be readily understood that the residue may be dissolved with a solvent other than ethyl acetate, for example, ethanol, acetone may also be used.
Preferably, the expanding agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)1: 5. Of course, other proportions of extender may be used, e.g. V(Ethyl acetate):V(Petroleum ether)＝1:6。
The experimental data are as follows: a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative (compound 4) is a pale yellow powder, yield 47.5%, melting point: 223-:
1H NMR(DMSO-d6)δ:10.17(s,1H,NHN),7.36-7.20(m,9H,Ar-H),6.87(t,J＝8.0,1H),6.58(s,1H),6.50(s,1H,C＝C-H),6.32(d,J＝4.0,1H),4.53(t,J＝12.5,1H),4.47(s,1H,C＝C-H),4.06(d,J＝12.5,1H),2.42(t,J＝14.0,1H),1.69(d,J＝14.5,1H)
IR(KBr)v/cm-13435(N-C＝O),3098(ArH),1772(C＝O,pyridazinone),1663(C＝O),1634,1580,1464(C＝N,C＝C),1256(C-O-C),1610(chromone-ring)
m/e:643(100.0％)
Anal.calcd.for C30H19BrClN5O5：C,55.90；H,2.99；N,10.84。
wherein pyridazinone is pyridazinone and chromone-ring is chromone mother ring.
In this example, MTT method is used to determine the in vitro inhibitory effect of compound 4 on different tumor strains, and the results of the determination of the anti-tumor activity of the chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative are as follows:
dissolving compound 4 in DMSO, diluting, inoculating tumor cells KB (oral cancer cells), SGC7901 (gastric cancer cells), HL-60 (leukemia cells), Bel-7402 (human liver cancer cells), HO8901 (ovarian cancer cells), and ECA109 (intestinal cancer cells) into a 96-well plate at 4000/200 μ L/well, adding compound 2 μ L per well to the final concentration of 12.0 μ M, 6.0 μ M, 3.0 μ M, 1.5 μ M, and mixing at 37 deg.C and 5% CO2The cells were incubated in an incubator for 72 hours, with DMSO (1%) as a blank control. After 72 hours, MTT was added to a final concentration of 0.25mg/mL and the mixture was left at 37 ℃ with 5% CO2After 4 hours in the cell incubator, the solvent was blotted, 100. mu.l DMSO was added to each well, absorbance (OD value) was measured at 570nm with an enzyme-linked immunosorbent assay, and the data obtained was used to calculate IC50The value is obtained. Selecting compounds with high inhibitory activity, and determining the influence of different action times of the compounds at different concentrations on the human tumor cell cycle and apoptosis.
The test compounds of different concentrations were coarse-screened in 96-well plates and IC was calculated from the resulting inhibition50Values, results are given in the table below.
TABLE 1
In Table 1, spiro [ indolizine-pyrazoline ] having a p-chloro-substituted pyridazinone structure is shown]IC of derivative (Compound 4) against six tumor cell lines50The values indicate that the compound has strong tumor cell inhibiting effect on KB (oral cancer cells), SGC7901 (gastric cancer cells), HL-60 (leukemia cells) and Bel-7402 (human liver cancer cells), and further indicate that the compound has strong tumor cell inhibiting effect on KB (oral cancer cells), SGC7901 (gastric cancer cells), HL-60 (leukemia cells) and Bel-7402 (human liver cancer cells)The application in the medical field provides a foundation.
The above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and those skilled in the art can make various corresponding changes and modifications according to the present invention without departing from the spirit and the essence of the present invention, but these corresponding changes and modifications should fall within the protection scope of the appended claims.
Claims (6)
1. The p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative is characterized in that the chemical structural formula of the p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative is as follows:
wherein Ar is 4-ClC6H4-。
2. A preparation method of a p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative is characterized by comprising the following steps:
step 1, synthesizing a chromone aldehyde hydrazone derivative containing a pyridazinone structure by adopting 6-bromochromone with a formaldehyde group substitution at the 3-position and 6-oxo-1, 6-dihydropyridazine-3-hydrazine carbonate, wherein the chromone aldehyde hydrazone derivative containing the pyridazinone structure has the following chemical structural formula:
step 2, synthesizing α -chloropyridazinone structure chromone aldehyde hydrazone derivative, wherein the α -chloropyridazinone structure chromone aldehyde hydrazone derivative has the following chemical structural formula:
step 3, adding (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -ketone and a chromone aldehyde hydrazone derivative with a α -chloropyridazinone structure into dichloromethane, dropwise adding a mixed solution of triethylamine and dichloromethane into the solution by using a constant-pressure dropping funnel, continuously stirring at normal temperature for 20-30 hours after dropwise adding, tracking by TLC, performing rotary evaporation to remove the solvent after complete reaction, dissolving residues left after the rotary evaporation, and performing chromatographic separation by using a silica gel column to obtain a p-chloro substituted spiro [ indolizine-pyrazoline ] derivative with a pyridazinone structure, wherein the p-chloro substituted spiro [ indolizine-pyrazoline ] derivative with the pyridazinone structure has the following chemical structural formula:
wherein Ar is 4-ClC6H4-。
3. The method for preparing p-chloro substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivatives according to claim 2, wherein the ratio of the amount of the α -chloropyridazone-structure chromonaldehyde hydrazone derivative to the amount of the (E) -7-p-chlorobenzylidene-6, 7-indolizine-8 (5H) -one is 1.6: 1 to 2: 1.
4. The method for preparing p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivatives according to claim 2, wherein the mixed solution of triethylamine and dichloromethane has a volume ratio of triethylamine to dichloromethane of: 1: 10-1: 20.
5. the para-chloro substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] according to claim 2]The preparation method of the derivative is characterized in that the expanding agent adopted in the silica gel column chromatography separation is V(Ethyl acetate):V(Petroleum ether)＝1:5。
6. The use of the p-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative according to claim 1 in the preparation of an antitumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811172919.3A CN109053731B (en) | 2018-10-09 | 2018-10-09 | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811172919.3A CN109053731B (en) | 2018-10-09 | 2018-10-09 | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109053731A CN109053731A (en) | 2018-12-21 |
| CN109053731B true CN109053731B (en) | 2020-07-07 |
Family
ID=64763652
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811172919.3A Active CN109053731B (en) | 2018-10-09 | 2018-10-09 | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109053731B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112608322A (en) * | 2020-12-24 | 2021-04-06 | 绍兴文理学院 | Methoxy-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112608321A (en) * | 2020-12-24 | 2021-04-06 | 绍兴文理学院 | Fluorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112625044A (en) * | 2020-12-24 | 2021-04-09 | 绍兴文理学院 | Methylthio-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112694478A (en) * | 2020-12-24 | 2021-04-23 | 绍兴文理学院 | Nitro-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112625045A (en) * | 2020-12-24 | 2021-04-09 | 绍兴文理学院 | 3,4, 5-trimethoxy substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112608319A (en) * | 2020-12-24 | 2021-04-06 | 绍兴文理学院 | Methyl-substituted pyridazinone-structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112608323A (en) * | 2020-12-24 | 2021-04-06 | 绍兴文理学院 | Chlorine-substituted pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
| CN112645957A (en) * | 2020-12-24 | 2021-04-13 | 绍兴文理学院 | Pyridazinone structure-containing spiropyrazole-pyrrolizine derivative and preparation method and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107674083B (en) * | 2017-11-07 | 2019-07-16 | 绍兴文理学院 | A kind of preparation method and applications of the L-Leu ring substituent norcantharidin derivative of the structure containing pyridazinone |
-
2018
- 2018-10-09 CN CN201811172919.3A patent/CN109053731B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN109053731A (en) | 2018-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109053731B (en) | P-chloro-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN112110969B (en) | Triazole glucoside derivative of 3-nitro-1-ethyl formate-7-azaindole, and preparation method and application thereof | |
| CN109232570B (en) | Pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN110128444B (en) | P-nitrophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN109180676B (en) | 3,4, 5-trimethoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method thereof | |
| CN109232572B (en) | P-methyl-substituted pyridazinone-structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109180675B (en) | P-methoxy substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109053732B (en) | Para-fluorine substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN109232571B (en) | P-methylmercapto-substituted pyridazinone structure-containing spiro [ indolizine-pyrazoline ] derivative and preparation method and application thereof | |
| CN110642864B (en) | Spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110183467B (en) | P-methoxyphenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof | |
| CN110759920A (en) | P-methoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110734442B (en) | 3,4, 5-trimethoxyphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure, and preparation method and application thereof | |
| CN108623604B (en) | D-phenylalanine substituted maleimide derivative and preparation method and application thereof | |
| CN110746431B (en) | P-methylmercapto phenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN110790769B (en) | P-methylphenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN108623603B (en) | L-leucine substituted maleimide derivative and preparation method and application thereof | |
| CN110724148B (en) | P-chlorophenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN108707153B (en) | D-valine substituted maleimide derivative and preparation method and application thereof | |
| CN108727383B (en) | L-phenylalanine substituted maleimide derivative and preparation method and application thereof | |
| CN110655522B (en) | O-chlorophenyl substituted spiro [ indazole-pyrazoline ] derivative containing pyrazole structure and preparation method and application thereof | |
| CN108690028B (en) | L-valine substituted maleimide derivative and preparation method and application thereof | |
| CN110128446B (en) | 3,4, 5-trimethoxy phenyl substituted spiro [ indazole-isoxazole ] derivative containing chromone structure, and preparation method and application thereof | |
| CN108676008B (en) | D-leucine substituted maleimide derivative and preparation method and application thereof | |
| CN110256462B (en) | Para-fluorophenyl substituted chromone structure-containing spiro [ indazole-isoxazole ] derivative, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211021 Address after: 250000 1422, building n, Hengda City, No. 58, Gongye North Road, Licheng District, Jinan City, Shandong Province Patentee after: Jinan Weiyang Technology Co.,Ltd. Address before: No. 2799, Qunxian Middle Road, Shaoxing City, Zhejiang Province Patentee before: SHAOXING UNIVERSITY YUANPEI College |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20220311 Address after: 110027 No.1-3, No.10 Road, Shenyang Economic and Technological Development Zone, Shenyang City, Liaoning Province Patentee after: SHENYANG SUNSHINE PHARMACEUTICAL Co.,Ltd. Address before: 224500 No. 142-2, private entrepreneurship Park, Tongyu Town, Binhai County, Yancheng City, Jiangsu Province Patentee before: Binhai meidaxin technical consulting service studio Effective date of registration: 20220311 Address after: 224500 No. 142-2, private entrepreneurship Park, Tongyu Town, Binhai County, Yancheng City, Jiangsu Province Patentee after: Binhai meidaxin technical consulting service studio Address before: 250000 1422, building n, Hengda City, No. 58, Gongye North Road, Licheng District, Jinan City, Shandong Province Patentee before: Jinan Weiyang Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |