CN108863923B - Pyridone derivative and preparation method and application thereof - Google Patents

Pyridone derivative and preparation method and application thereof Download PDF

Info

Publication number
CN108863923B
CN108863923B CN201810543376.5A CN201810543376A CN108863923B CN 108863923 B CN108863923 B CN 108863923B CN 201810543376 A CN201810543376 A CN 201810543376A CN 108863923 B CN108863923 B CN 108863923B
Authority
CN
China
Prior art keywords
pyridone derivative
preparation
reaction
compound
pyridone
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
Application number
CN201810543376.5A
Other languages
Chinese (zh)
Other versions
CN108863923A (en
Inventor
吴静
沈奇
李建新
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 CN201810543376.5A priority Critical patent/CN108863923B/en
Publication of CN108863923A publication Critical patent/CN108863923A/en
Application granted granted Critical
Publication of CN108863923B publication Critical patent/CN108863923B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/36—Sulfur atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention discloses a pyridone derivative, a preparation method and application thereof, wherein the pyridone derivative is mainly prepared from R1，R2，R3Structural modifications of these three substituents are made, wherein R1The modification of (A) is mainly carried out by allyl, isopentenyl, geranyl, p-fluorobenzyl and the like; r2The modification of (a) is mainly by hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, etc.; r3The modification (c) is mainly focused on ethers with certain structural features. The pyridone derivative has obvious inhibition effect on pancreatic cancer cells PANC-1 in a poor nutrition state, and has no influence on the cells in a normal nutrition state (no cytotoxicity is suggested). The preparation method of the pyridone derivative firstly synthesizes basic parent nucleus bicyclo [3.3.1]Nonanone is subjected to rearrangement reaction with a series of alcohol amines or diamines under the catalysis of toluenesulfonic acid to prepare para-pancreasThe pyridone derivative has obvious cancer inhibiting effect and high practicability.

Description

Pyridone derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemistry and medicine, and particularly relates to a pyridone derivative and a preparation method and application thereof.
Background
Pancreatic cancer (pancreatetic cancer), known as "cancer king" in the medical field, is the cancer with the worst prognosis among all malignant tumors, and the death rate of patients in one year after diagnosis is 95% -98%, that is to say, about 95% of Pancreatic cancer patients can live for over five years after diagnosis and less than one year. Post-diagnosis surgical resection of pancreatic cancer is the best treatment for this, but over 80-85% of pancreatic cancer patients are diagnosed with advanced stages for which chemotherapy is an acceptable regimen. Prior to 2011, there have been no significant advances in the treatment of advanced pancreatic cancer, despite many trials attempting to combine gemcitabine with other drugs. In recent years, clinical application of targeted inhibitors such as Kras, EGFR and COX-2 has been developed in a breakthrough manner, and prognosis of pancreatic cancer patients can be significantly improved, but further research is still needed due to high cost, multiple side reactions and the like. At present, gemcitabine remains the "gold standard" for the treatment of advanced pancreatic cancer, a drug that can block tumor cell division and promote cell death; however, many patients die within several months, usually because cancer cells find a way to avoid the action of gemcitabine, so that gemcitabine therapy becomes no longer effective, i.e. drug resistance is one of the main causes of chemotherapy failure, there is a need to develop clinical chemotherapeutic drugs for treating pancreatic cancer with a brand-new structure and action mechanism, alleviate the drug resistance of the existing chemotherapeutic drugs, prolong the life of pancreatic cancer patients, and improve the quality of life thereof.
The growth and proliferation of the tumor depend on angiogenesis to realize functional blood flow supply to a great extent, because tumor cells have higher proliferation speed than vascular endothelial cells and disordered new vascular networks and do not have ideal functions of providing oxygen and nutrition for the cells, the tumor obtains the tolerance capability to a poor nutrition state and has strong viability even under the conditions of low oxygen and nutrition supply, and a pancreatic cancer cell line PANC-1 is a typical representative of the low blood supply malignant tumor and can be used for establishing an anti-pancreatic cancer compound screening model; on the other hand, the hypoxia environment in vivo can induce the angiogenesis of pancreatic cancer tumor and promote the infiltration and metastasis of pancreatic cancer, and the activity of the compound in the state of lack of nutrition on pancreatic cancer cells can play a role in inhibiting the cancer metastasis stage, so that the compound which has good inhibitory activity in the state of lack of nutrition and has no cytotoxicity in the state of rich nutrition is found to have great significance.
Disclosure of Invention
The purpose of the invention is as follows: in view of the problems of the prior art, the present invention provides a pyridone derivative, which is mainly represented by R1，R2，R3The three substituent groups are structurally modified, so that the derivative has important biomedical activities of resisting tumors, regulating immune function, inhibiting platelet aggregation and the like. Another object of the present invention is to provide a process for producing the above pyridone derivatives. The invention also aims to provide application of the pyridone derivative.
The technical scheme is as follows: in order to achieve the purpose of the invention, the invention adopts the technical scheme that:
a pyridone derivative of any one of the following structural formulae:
Figure BDA0001677586060000021
R1selected from the group consisting of: allyl, isopentenyl, geranyl, p-fluorobenzyl, and the like, but are not limited to these groups;
R2selected from the group consisting of: hydroxyethyl, hydroxypropyl, aminoethyl, aminopropyl, and the like, but are not limited to these substituents;
R3selected from the group consisting of:
Figure BDA0001677586060000022
Figure BDA0001677586060000023
n is 1, 2, 3, 4; but are not limited to these groups;
R4、R5、R6and R7Are all selected from the group: phenyl, substituted phenyl, heterocyclic, and the like, but are not limited to these groups;
the method for preparing the pyridinone derivative is to obtain a target compound by rearranging a polysubstituted bicyclo [3.3.1] nonanone parent nucleus. The specific process is as follows:
first of all polysubstituted bicyclo [3.3.1]Synthesizing a nonanone parent nucleus, namely condensing and dehydrating 1, 3-cyclohexanedione (1) serving as a raw material and isobutanol under the catalysis of p-toluenesulfonic acid to obtain an vinylogous ester compound 2; compound 2 at-78 ℃ and N2Under protection, pulling out carbonyl alpha-H by LDA, and then reacting with halogenated hydrocarbon to obtain a compound 3; compound 3 with methyllithium at low temperature, N2Carrying out 1, 2-addition reaction under protection, and acidifying to obtain an alpha, beta-unsaturated ketone compound 4; compound 4 and freshly prepared dimethyl copper lithium at low temperature, N2Reacting under protection to generate 1, 4-addition to obtain a compound 5 with a tri-substituted cyclohexanone structure; reacting the compound 5 with tert-butyldimethylsilyl chloride (TBDMSC1) to obtain silyl enol ether 6; because of the difference of double bond positions on enol silyl ether, a pair of isomers exist, 6a/6b exists in the form of mixture, compound 6 reacts with malonyl chloride, and ring closure is carried out to obtain mother nucleus substituted bicyclo [3.3.1] before rearrangement]Nonanone compound 7; and rearranging the compound 7 to obtain the target pyridone derivative. The specific reaction formula is as follows:
Figure BDA0001677586060000031
a method for preparing the pyridone derivative is based on bicyclo [3.3.1] nonanone mother nucleus rearrangement to obtain a brand-new pyridone mother nucleus. The reaction formula is as follows:
Figure BDA0001677586060000032
the method for preparing the pyridone derivative is characterized in that pyridone is used as a matrix, and the activity of four-hydroxyl is utilized to react with a series of pre-modified halides by a Williams synthesis method to obtain a series of derivatives with four-hydroxyl etherified. The reaction formula is as follows:
Figure BDA0001677586060000033
the method for preparing the pyridone derivative is characterized in that pyridone is used as a matrix, and the activity of four-position hydroxyl is utilized to react with a series of isocyanates to obtain a series of derivatives esterified by four-position hydroxyl amino acid. The reaction formula is as follows:
Figure BDA0001677586060000034
the pyridone derivatives can be used for preparing antitumor drugs.
The tumor is pancreatic cancer.
Has the advantages that: compared with the prior art, the pyridone derivative has obvious inhibition effect on pancreatic cancer cells PANC-1 in a poor nutrition state, and has no influence on the cells in a normal nutrition state (no cytotoxicity is suggested). The preparation method of the pyridone derivative firstly synthesizes basic parent nucleus bicyclo [3.3.1] nonanone, and the pyridone derivative with obvious inhibition effect on pancreatic cancer is successfully prepared by rearrangement reaction of the base nucleus bicyclo [3.3.1] nonanone and a series of alcohol amine or diamine under the catalysis of toluenesulfonic acid, and has good practicability.
Drawings
FIG. 1 is a graph showing the results of 2. mu.M in vitro activity data of pyridone derivatives;
FIG. 2 is a graph of the results of mouse weight data;
FIG. 3 is a graph showing the results of the weight of mouse abdominal bilateral subcutaneous graft tumors.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Example 1
1. Preparation of compound S8, reaction formula:
Figure BDA0001677586060000041
1) preparation of Compound S2
Synthesis of 3-isobutoxy-2-cyclohexenone (S2) from 1, 3-cyclohexanedione (S1): a250 mL reaction flask was charged with 1, 3-cyclohexanedione (50mmol, 1.0eq), p-toluenesulfonic acid monohydrate (3mmol, 0.06eq), isobutanol (200mmol, 4.0eq), and toluene (200mL), and refluxed overnight at 120 ℃ over a water separator. After the reaction is finished, the solvent and the excess isobutanol are evaporated under reduced pressure, and the 3-isobutoxycyclohexenone (S2) is separated and purified by column chromatography to obtain a yellow oily liquid with the yield of 95%.
2) Preparation of the Compound S3a/S3b/S3c/S3d
Under nitrogen protection, a solution of 2mol/LLDA in THF (30mmol, 15mL, 1.2eq) was added to freshly distilled THF (100mL) cooled to-78 deg.C and a solution of S2(25mmol, 1.0eq) in THF (20mL) was added dropwise at-78 deg.C. The reaction was allowed to react for 1 hour and slowly return to 0 ℃ and then cooled to-78 ℃, isopentenyl bromide/geranyl bromide/allyl bromide/p-fluorobenzyl bromide (30mmol, 1.2eq) was added dropwise and slowly returned to room temperature, and the reaction solution turned yellow. Monitoring the reaction by TLC, and adding saturated NH after the reaction is finished4The reaction was quenched with Cl solution. Extracting with diethyl ether, mixing organic phases, and adding anhydrous Na2SO4Drying, separating and purifying by column chromatography to obtain yellow oily liquid S3a/S3b/S3c/S3 d.
3) Preparation of Compound S4a/S4b/S4c/S4d
To a solution of S3a/S3b/S3c/S3d (17.5mmol, 1.0eq) in freshly distilled THF (70mL) cooled to-10 deg.C under nitrogen protection was added dropwise a 1.6mol/L solution of methyllithium in diethyl ether (26.4mmol, 16.5mL, 1.5 eq). The reaction was slowly returned to room temperature and the progress of the reaction was checked by TLC. After the material point disappears, the solution is cooled to 0 ℃, 1mol/L dilute hydrochloric acid (50mL) is slowly dropped into the solution, and the solution is stirred for 0.5h at room temperature. The aqueous phase is extracted with diethyl ether and the organic phases are combined, anhydrous Na2SO4Drying, separating and purifying by column chromatography to obtain light yellow oily liquid S4a/S4b/S4c/S4 d.
4) Preparation of Compound S5a/S5b/S5c/S5d
To a suspension of freshly distilled anhydrous ether (150mL) of CuI (30mmol, 2.0eq) cooled to-10 deg.C under nitrogen protection was added dropwise a solution of 1.6mol/L methyllithium in ether (60mmol, 37.5mL, 4.0 eq). The color of the reaction liquid gradually turns yellow from gray and finally turns into light brown transparent liquid. After the addition was complete, the mixture was stirred at-10 ℃ for 1h, then a solution of S4a/S4b/S4c/S4d (15mmol) in dry ether (100mL) was added slowly dropwise and the progress of the reaction was monitored by TLC. After the reaction is completed, saturated NH is added4The reaction was quenched with Cl solution and ammonia was added to make the reaction dark blue and transparent. Extracting with diethyl ether, mixing organic phases, and extracting with anhydrous Na2SO4Drying, separating and purifying by column chromatography to obtain colorless to yellowish oily liquid S5a/S5b/S5c/S5 d.
5) Preparation of Compound S6a/S6b/S6c/S6d
A100 mL reaction bottle is filled with S5a/S5b/S5c/S5d (12.5mmol, 1.0e), freshly distilled triethylamine (16mmol, 1.25eq) and dry acetonitrile (30mL), then tert-butyldimethylchlorosilane (16mmol, 1.25eq) and NaI (16mmol, 1.25eq) are added, stirring and refluxing are carried out at 90 ℃ for 2h, the reaction is monitored by TLC, after the reaction is finished, triethylamine and a solvent are distilled out under reduced pressure, petroleum ether (50mL) is added, stirring and filtering are carried out, the filter cake is washed by petroleum ether, the filtrate is concentrated, and column chromatography separation and purification are carried out, so that a colorless oily liquid mixture S6a/S6b/S6c/S6d consisting of a pair of enol silyl ether isomers is obtained.
6) Preparation of the Compound S7a/S7b/S7c/S7d
The silyl enol ether S6a/S6b/S6c/S6d (12mmol, 1.0eq) was dissolved in dry DCM (5mL), cooled to-10 deg.C, a solution of malonyl chloride (24mmol, 2.0eq) in DCM (4mL) was slowly added dropwise, the reaction was stirred at-10 deg.C for 12h, then a solution of potassium hydroxide (96mmol, 8.0eq) and TEBA (0.6mmol, 0.05eq) in water (6mL) was slowly added dropwise, the reaction was maintained at-10 deg.C for 1h, and then the reaction was slowly returned to room temperature and stirred overnight. Adding 100mL of water and DCM respectively, adjusting pH to 12, extracting with DCM for 3 times, combining organic phases, and anhydrous Na2SO4Drying, evaporating to dryness under reduced pressure, and purifying by column chromatography to recover S5a/S5b/S5c/S5 d; adjusting pH of water phase to 1, extracting with DCM for 3 times, mixing organic phases, drying, and evaporating under reduced pressure to obtainOrange foamy solid S7a/S7b/S7c/S7d (white to pale yellow solid after purification) was allowed to proceed to the next reaction without purification.
7) Preparation of the Compound S8a/S8b/S8c/S8d
Adding S7a/S7b/S7c/S7d (3mmol, 1.0eq), p-toluenesulfonic acid monohydrate (0.9mmol, 0.3eq), n-propanolamine (6mmol, 2.0eq) and toluene (150mL) into a reaction bottle, installing an oil-water separator (Dean-Starkappaatatus) for reaction at 120 ℃ for 4 hours, evaporating the toluene under reduced pressure after the reaction is finished, and separating and purifying the residue by column chromatography to obtain a white/light yellow foam solid S8a/S8b/S8c/S8 d.
2. Preparation of the Compound S8e/S8f/S8g/S8h/S8i, of the formula:
Figure BDA0001677586060000061
s7a (3mmol, 1.0eq), p-toluenesulfonic acid monohydrate (0.9mmol, 0.3eq), alcohol amine (6mmol, 2.0eq) and toluene (150mL) are added into a reaction flask, an oil-water separator (Dean-Starkapparatus) is arranged to react for 4 hours at 120 ℃, after the reaction is finished, the toluene is evaporated under reduced pressure, and the residue is subjected to column chromatography separation and purification to obtain a white/light yellow foamy solid S8e/S8f/S8g/S8h/S8 i.
3. Preparing a compound 1-60 according to the following reaction formula:
Figure BDA0001677586060000062
synthesis of amino acid ester derivatives: adding S8(3mmol, 1.0eq), isocyanate (1.2eq) and DCM (150mL) into a reaction bottle, reacting for 4 hours at room temperature, after the reaction is finished, spin-drying the residue, and performing column chromatography separation and purification to obtain 1-8, 47-60 white solids.
Synthesis of ether derivatives: adding S8(3mmol, 1.0eq), corresponding halohydrocarbon (6mmol, 1.2eq), potassium carbonate (2eq) and DMF (15mL) into a reaction bottle, reacting at room temperature for 4h, after the reaction is finished, spin-drying the residue, and performing column chromatography separation and purification to obtain a white solid 9-46, wherein the specific structure is shown in Table 2.
TABLE 1 Compound Nuclear magnetic data
Figure BDA0001677586060000063
Figure BDA0001677586060000071
Figure BDA0001677586060000081
Figure BDA0001677586060000091
Figure BDA0001677586060000101
Figure BDA0001677586060000111
Figure BDA0001677586060000121
Figure BDA0001677586060000131
Figure BDA0001677586060000141
Figure BDA0001677586060000151
Figure BDA0001677586060000161
Figure BDA0001677586060000171
Figure BDA0001677586060000181
Figure BDA0001677586060000191
Figure BDA0001677586060000201
Figure BDA0001677586060000211
Figure BDA0001677586060000221
Figure BDA0001677586060000231
Figure BDA0001677586060000241
Figure BDA0001677586060000251
Figure BDA0001677586060000261
Figure BDA0001677586060000271
Figure BDA0001677586060000281
TABLE 2 Structure of the Compounds
Figure BDA0001677586060000282
Figure BDA0001677586060000291
Figure BDA0001677586060000301
Figure BDA0001677586060000311
Figure BDA0001677586060000321
Example 2 specific Activity of pyridone derivatives
1. Inhibition of pancreatic cancer cells in vitro PANC-1 experiment (Table 3)
The culture conditions are as follows: high-glucose DMEM/10% FBS medium, 5% CO2In vitro simulation conditions at 37 ℃; when the cell confluence is 80%, washing with PBS, digesting with pancreatin, and stopping the culture medium containing serum; the cells were collected, centrifuged, the supernatant removed, resuspended in culture medium and counted at 1X 105mL-1The density of (2) is inoculated on a 96-well cell culture plate, and each well is 100 mu L of cell liquid and cultured for 24 h; replacing the nutrient-poor culture medium, simultaneously adding a control (DMSO, 0.1%) and compounds with different concentrations respectively, and culturing for 24 h; MTT method for analyzing nutritional deficiency (D) and normal nutrition of PANC-1 cellsSurvival rate of the cells cultured (R).
In vitro results suggest that pyridone derivatives are not toxic under normal nutritional conditions (table 3), but show higher inhibitory activity against pancreatic cancer cells PANC-1 under fastidious (no glucose and amino acids) (table 3, fig. 1).
TABLE 3 in vitro pancreatic cancer cell inhibition Activity data for Compounds
Figure BDA0001677586060000331
Figure BDA0001677586060000341
2. Test for in vivo anti-pancreatic cancer Activity of pyridone derivatives (FIGS. 2 and 3)
Establishment of bilateral abdominal subcutaneous transplantation tumor model of C57/BL6 mouse
Preparation of reagents and surgical instruments: mice (animal qualification No.: SCXK (threo) 2015-0001) were randomly divided into 4 groups according to body weight, namely a negative Control group (Control, saline injection), two intraperitoneal injection groups (1 and 5mg/kg/d) with different concentrations, a positive drug Control group (Arctigenin, 5mg/kg/d), and then Pan-02 cells (mouse pancreatic cancer cells) were digested and resuspended in PBS buffer to 1X 10 cells6mL-1The cell suspension of (a); scraping the two sides of the abdomen of the mouse, sucking the cell suspension by using an injector for subcutaneous injection, and injecting 100 mu L of suspension each time; observing and weighing every day, growing out tumor after three days, injecting compound solution into abdominal cavity, and measuring tumor volume every day; during the period, the mouse implanted with tumor is subjected to MRI experiment after qi and blood numbness, and the change of the size of the tumor of the mouse is observed; after the experiment, blood was taken from the eyeball and the liver and bilateral tumors were weighed.
In the experiment results in subcutaneous tumor transplants on two sides of the abdomen of the C57/BL6 mouse, the weight of the mouse in the administration group is not obviously different from that of the mouse in the negative control group (figure 2), which indicates that the compound has no obvious toxicity; the weight of the bilateral tumor is obviously different from that of a negative control group (figure 3), the weight of the solid tumor is obviously reduced, and the compound has dose dependence, which indicates that the compound has obvious inhibition effect on the pancreatic cancer of the mouse.

Claims (2)

1. A pyridone derivative having the structural formula:
Figure 23846DEST_PATH_IMAGE001
or
Figure 285194DEST_PATH_IMAGE002
。
2. The use of the pyridone derivative of claim 1 for the preparation of a medicament against pancreatic cancer.
CN201810543376.5A 2018-05-29 2018-05-29 Pyridone derivative and preparation method and application thereof Active CN108863923B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810543376.5A CN108863923B (en) 2018-05-29 2018-05-29 Pyridone derivative and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810543376.5A CN108863923B (en) 2018-05-29 2018-05-29 Pyridone derivative and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN108863923A CN108863923A (en) 2018-11-23
CN108863923B true CN108863923B (en) 2022-02-18

Family

ID=64336051

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810543376.5A Active CN108863923B (en) 2018-05-29 2018-05-29 Pyridone derivative and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN108863923B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107536833A (en) * 2017-10-24 2018-01-05 山东大学 A kind of application of pyridinone alkaloid of 4 hydroxyl 2 in antitumor product is prepared

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107536833A (en) * 2017-10-24 2018-01-05 山东大学 A kind of application of pyridinone alkaloid of 4 hydroxyl 2 in antitumor product is prepared

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Synthesis of heterocyclic carbamates with potential activity in plant protection;Wolfgang STADLBAUER et al.;《17th International Electronic conference on synthetic organic Chemistry（ECSOC-17）》;20131031 *
参见D1第28-29页第2.1节. *
多取代2-吡啶酮衍生物的合成及其抗胰腺癌活性研究;王悦;《中国优秀硕士学位论文全文数据库医药卫生科技辑》;20170215;第33-34页Scheme2-5和Scheme2-6; 第32页Scheme2-3; 第31页第2.2.2节; 第31页Scheme2-2; 第30页Scheme2-1; 参见D1第28-29页第2.1节 *
王悦.多取代2-吡啶酮衍生物的合成及其抗胰腺癌活性研究.《中国优秀硕士学位论文全文数据库医药卫生科技辑》.2017,第33-34页Scheme2-5和Scheme2-6 *
第30页Scheme2-1 *
第31页Scheme2-2 *
第31页第2.2.2节 *
第32页Scheme2-3 *

Also Published As

Publication number Publication date
CN108863923A (en) 2018-11-23

Similar Documents

Publication Publication Date Title
CA3053805C (en) Combination treating prostate cancer, pharmaceutical composition and treatment method
CN109293657A (en) A kind of α-carboline ketone compounds and its preparation method and application
CN108947949B (en) Anxiolytic deuterated compounds and medical application thereof
CN113480559B (en) Artemether derivative and preparation method and application thereof
CN108863923B (en) Pyridone derivative and preparation method and application thereof
CN114671751B (en) O-hydroxyphenylketone compound and preparation method and application thereof
CN112409431B (en) Cytarabine structural analogue, and preparation method and application thereof
CN111269253B (en) Chalcone Sanjunolide derivative and application thereof in preparation of castration-resistant prostate cancer drugs
CN110437313B (en) Rakicidins esterified derivative and preparation method and application thereof
CN104856987B (en) Application of 14 aryl-ether andrographolide derivatives in antibacterial field
CN113493443A (en) Erlotinib derivative with killing performance on wild lung cancer tumor cells and preparation method thereof
KR102368555B1 (en) COMPOSITIONS, APPLICATIONS THEREOF AND METHODS OF TREATMENT
CN108358858B (en) Deuterium labeled 1-substituted phenyl-4-substituted aniline methyl-1, 2, 3-triazole derivative and preparation method and application thereof
CN106966970B (en) Compound with anticancer effect and anti-helicobacter pylori activity, preparation method and application thereof
CN106928224B (en) Indoles Sophoridine derivative and preparation method thereof
CN107540528B (en) A kind of fat-soluble emodin derivates and its preparation method and application
CN103044326A (en) 5-bromo oxoisoaporphine, and synthesis method and application thereof
CN110183471B (en) Piperazine derivative, preparation method and application
CN111072606B (en) Octahydrobenzofuran derivative, preparation method and application thereof
JP6238956B2 (en) NOVEL COMPOUND, PROCESS FOR PRODUCING THE SAME AND USE THEREOF
CN108484629A (en) A kind of Artesunate derivative and its synthetic method and application
CN115010782B (en) Ursolic acid N-glycoside derivative and preparation method and application thereof
CN110693864B (en) Application of tricarbonyl compound in preparation of anti-human cervical cancer drugs
CN103130803B (en) Oxidized iso-aporphine alkaloid derivative, synthetic method and application
CN110194743B (en) Phenyl (3-methoxy-4- (4-methyl-1H-imidazole-1-yl) phenyl) ketone compound

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