CN104926792B - Metronidazole derivative and its preparation method and application - Google Patents
Metronidazole derivative and its preparation method and application Download PDFInfo
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- CN104926792B CN104926792B CN201510396700.1A CN201510396700A CN104926792B CN 104926792 B CN104926792 B CN 104926792B CN 201510396700 A CN201510396700 A CN 201510396700A CN 104926792 B CN104926792 B CN 104926792B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention relates to metronidazole derivative and its pharmaceutically acceptable salts or solvate shown in formula (I).R may be the same or different, independent to be selected from:Hydrogen, halogen, cyano, nitro, C1~C6Alkyl, C1~C6Alkoxy, halogenated C1~C6Alkyl, halogenated C1~C6Alkoxy, aryl, aryloxy group etc.;Or two adjacent R connect together to form 38 membered rings;The aryl, aryloxy group are optionally substituted by one or more substituents, and the substituent group is independent to be selected from:C1~C6Alkyl, C1~C6Alkoxy, nitro, cyano, halogen, halogenated C1~C6Alkyl, halogenated C1~C6Alkoxy;The integer that n is 04.The invention further relates to the preparation method and its usages of formula (I) metronidazole derivative and its salt.Such compound or its salt has stronger inhibitory activity to colorectal cancer cell lines HCT 116, human lung carcinoma cell line A549 and breast carcinoma cell strain MCF 7.Such compound anti-cancering activity wide spectrum can be used as the drug candidate or lead compound of the diseases such as treatment tumour, cancer.
Description
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of metronidazole derivative, and in particular to metronidazole spreads out shown in formula (I)
The preparation of biology and the medical composition and its use containing the analog derivative.Such compound anti-cancering activity wide spectrum, can be used as and control
Treat the drug or lead compound of the diseases such as tumour, cancer.
Background technology
Cancer has become most important fatal disease in world wide, and developed country cancer death leads also very high.
Cancer can occur in any age in various organs and tissue, and dead major cancers type is caused to have:Lung cancer, gastric cancer, liver
Cancer, colon cancer and breast cancer etc..
In recent years, lung cancer becomes the highest malignant tumour of incidence.It is counted according to the World Health Organization (WHO):2008
The number that the whole world is diagnosed as lung cancer is 1,600,000 people, accounts for the 13% of the total number of the infected of cancer, death toll Isosorbide-5-Nitrae 00,
000, account for the total death toll of cancer 18% (Jemal A, et al.C A Cancer J.Clin.2011,61:69-90);
2010, the U.S. increased 222,520 people of patients with lung cancer, death toll 157,330, wherein dying of non-small cell lung cancer (NSCLC) newly
Patient accounts for 85% (Jemal A, et al.C A Cancer J.Clin.2010,60 of the total death toll of lung cancer:277-300).
From the point of view of 10 malignant tumours are constituted before China in recent years town and country, lung cancer replaced liver cancer to become China is the first lethal pernicious to swell
Tumor accounts for 22.7% (She J, et al.Chest.2013,143 (4) of whole mortality of malignant tumors:1117-1126).
Breast cancer is the most commonly seen cancer that whole world women faces at present, and there are about 1,380,000 breast cancer neopathies every year
Example and 45.8 ten thousand death.It is reported that:The U.S. increases 232,340 patient with breast cancers newly every year.2011, the U.S. had close to 40,
000 women dies of breast cancer;India has 100,000 newly-increased patient with breast cancer to be diagnosed every year, and has 1 in every 28 women
Can suffer from breast cancer (Yadav D K, et al.Curr.Med.Chem.2014,21 (9):1160-1170);In China, breast cancer
Also become the most common cancer of women, end 2008, China adds up to 169,452 new breast cancer patients, 449,08
Death accounts for the 12.2% and 9.6% of the world respectively.China's breast cancer whole year detection number is Europe (2008 total 332,000
Example, the half of total population 400,009,008 million), (2008 182,000 total, and total population 300,000,004 is million) with the U.S.
Substantially quite.If this trend remains unchanged, by 2021, China mammary gland patient will be up to 2,500,000, incidence will from less than
60/100,000 women (age is between 55 years old to 69 years old) increase to above 100/100,000 women (Fan L, et
al.Lancet Oncol.2014,15:e279-289).From the point of view of the whole world, the women quantity that suffers from breast cancer is being continuously increased, mammary gland
Cancer causes grave danger to the existence of women.
Colon cancer and the carcinoma of the rectum are referred to as colorectal cancer, are alimentary canal common cancers, and incidence is in rising trend, average every
Year it is incremented by 2%, the 2nd of tumor mortality is occupied in American-European countries's case fatality rate, U.S.'s colorectal cancer new development case loads in 2003 and dead
It dies rate and occupies the 3rd (Xu Fu star world disease for digest magazine .2006,26 (6):365-366).The hair of China's colorectal cancer in recent years
Sick rate rises at a terrific speed, and for nationwide, colorectal cancer has risen to the 4th of Incidence, at some
In the faster city of economic development, as Shanghai be in the 2nd (Li Delu, etc..Chinese tumour .2011,20 (6):413-
418).However most of cancer has been mid-term when finding to late period, clinical treatment general effect is poor, especially multidrug resistance
Emergence so that the treatment of cancer is difficult.
The anticancer drug that China clinically applies at present largely relies on import, at high price.In addition, most of anticarcinogen
Object is still unable to reach satisfactory specificity degree, and when carrying out chemotherapy, internal normal cell will also tend to together patient
It is killed, seriously affects normal physiological function, and with many side effects.Therefore, it is necessary to develop, activity is high, side effect is low
Specific anti-cancer drug meet the needs of clinical.
In recent years, our research groups are dedicated to carrying out design, synthesis and the active anticancer side of small molecule anti-cancer compound
(patent application publication number CN103360382A discloses the quinazoline derivant of Han isoxazole heterocycles substitution to lung cancer for the research in face
Cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7 have significant inhibitory activity;Patent application publication number
CN103664991A discloses thiophene [2,3-d] pyrimidine derivatives of Han isoxazole heterocycles substitution to lung cell A549, large intestine
Cancer cell HCT-116 and breast cancer cell MCF-7 has significant inhibitory activity;Patent application publication number CN103601762A is public
The ferrocene derivatives of Han isoxazole heterocycles have been opened to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell
MCF-7 has significant inhibitory activity;The quinoline that patent application publication number CN104230912A discloses Han isoxazole heterocycles spreads out
Biology has significant inhibitory activity to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7).It is above-mentioned
Research foundation of the references cited therein as early period.
Invention content
The object of the present invention is to provide a kind of metronidazole derivatives and its preparation method and application.Such compound pair
Human lung carcinoma cell line A549, colorectal cancer cell lines HCT-116 and breast cancer cell line mcf-7 have very strong inhibitory activity.It can
For treating cancer or tumour.
The present invention is achieved through the following technical solutions:
Metronidazole derivative or its pharmaceutically acceptable salt shown in a kind of formula (I),
Wherein:
R may be the same or different, independent to be selected from:Hydrogen, halogen, cyano, nitro, C1~C6Alkyl, C1~C6Alkoxy or halogen
For C1~C6Alkyl, halogenated C1~C6Alkoxy, aryl, aryloxy group etc.;The aryl, aryloxy group are optionally one or more
Substituent group replaces or two adjacent R connect together to form 3-8 membered rings;The substituent group is independent to be selected from:C1~C6Alkyl,
C1~C6Alkoxy, nitro, cyano, halogen, halogenated C1~C6Alkyl, halogenated C1~C6Alkoxy;
N is the integer of 0-4.
According to the present invention, n can be 2 or 3.
According to the present invention, described two R form 3-6 membered rings, such as cyclopenta, phenyl ring, pyridine ring with the carbon being connect.More
Preferably, described two R form quinoline ring, quinazoline ring etc. with the pyridine ring being connect.More preferably quinazoline ring.
According to the present invention, the alkyl refers to the direct-connected or branched alkyl with 1-6 carbon atom, and the alkyl is, for example, first
Base, ethyl, propyl, isopropyl, butyl, isobutyl group, tertiary butyl, sec-butyl, amyl, neopentyl.
According to the present invention, the alkoxy refers to the direct-connected or branched alkyl oxygroup with 1-6 carbon atom, such as methoxy
Base, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy.
According to the present invention, the halogen is fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine.
According to the present invention, the halogenated C1~C6Alkyl is C1~C6One or more of alkyl hydrogen atom is taken by halogen
Generation, such as trifluoromethyl etc..
According to the present invention, the aryl refers to monocycle or polycyclic aromatic base with 6-20 (preferably 6-14) carbon atoms
Group, representative aryl include:Phenyl, naphthalene, anthryl, pyrenyl etc..
According to the present invention, the aryloxy group is aryloxy.
According to the present invention, metronidazole derivative is preferably selected from following any compounds shown in the formula (I):
Metronidazole derivative shown in formula (I), can select to be formed with pharmaceutically acceptable acid respectively can pharmaceutically connect
The salt received.Wherein term " pharmaceutically acceptable salt " includes but not limited to the salt formed with inorganic acid, such as hydrochloride, phosphoric acid
Salt, diphosphate, hydrobromate, sulfate, sulfinate, nitrate and its similar salt;Also include being formed with organic acid
Salt, as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, lactate,
Sulfonate, tosilate, 2- isethionates, benzoate, salicylate, stearate, trifluoroacetic acid or amino
Acid and alkanoate such as acetate, HOOC- (CH2)m- COOH wherein m are the salt of 0-4, and its similar salt.Similarly, pharmaceutically may be used
The cation of receiving includes but not limited to sodium, potassium, calcium, aluminium, lithium and ammonium.
The present invention also provides a kind of pharmaceutical compositions comprising metronidazole derivative shown in formula (I) of the present invention,
Or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable, inert, nontoxic excipient or carrier or dilute
Release agent.
According to the present invention, described pharmaceutical composition further include it is one or more selected from filler, disintegrant, lubricant, help
Flow agent, effervescent agent, corrigent, preservative and coating material pharmaceutically acceptable auxiliary material.The present invention also provides a kind of medicines
Object preparation, which is characterized in that the preparation includes metronidazole derivative shown in the formula (I) of the present invention.
Pharmaceutical preparation according to the present invention, which is characterized in that the preparation is preferably solid orally ingestible, liquid port system of mourning
Agent or injection.
Pharmaceutical preparation according to the present invention, the preparation are selected from tablet (dispersible tablet, enteric coatel tablets, chewable tablets, oral disintegrating tablet), glue
Capsule, granule, oral solution, injection liquid drugs injection, injection freeze-dried powder, big infusion or primary infusion.
The present invention also provides metronidazole derivative or its pharmaceutically acceptable salts shown in a kind of formula (I) to be used in preparation
Application in antitumor or cancer drug.
According to the present invention, the tumour or cancer are the cancers with EGFR transition expression and/or hyperactivity.More preferably
Ground, the tumour or cancer are selected from:Carcinoma of urinary bladder, non-small cell lung cancer, oophoroma, breast cancer, gastric cancer, cancer of the esophagus, lung cancer, neck
Application in cancer, colon cancer, pharynx cancer and cancer of pancreas etc., even more non-small cell lung cancer (NSCLC).
The present invention also provides the preparation methods of metronidazole derivative shown in a kind of formula (I), which is characterized in that the method
Include the following steps:
R substituted pyridines-formic acid (X=OH) or R substituted pyridines formyl chloride (X=Cl) and metronidazole are raw material, organic molten
It reacts and prepares in agent, acid binding agent:
Wherein, X OH, Cl, R, n are as defined above;
If necessary to protect, any functional group in compound shown in formula (I) can be protected.
According to the present invention, in the above preparation method, the temperature of the reaction is 0 DEG C to counterflow condition, preferably 0 DEG C to room
Warm condition.
According to the present invention, in the above preparation method, the organic solvent is benzene,toluene,xylene, dichloromethane, chlorine
Imitative, acetonitrile, dioxane, tetrahydrofuran or DMF, more preferably tetrahydrofuran.The organic solvent is dry.
According to the present invention, the acid binding agent (basic catalyst) is organic base or inorganic base, and the organic base is preferably three
Ethamine, tripropyl amine (TPA), DMAP, potassium tert-butoxide etc.;The inorganic base is preferably potassium carbonate, sodium hydride, sodium carbonate etc..Preferably tie up acid
Agent is DMAP.
Formula (I) compound of the present invention, including but not limited to:Their optical isomer, racemic modification and its mixed
Close object.
Term " effective quantity " refers at least one compound and/or at least one pharmaceutically acceptable salt pair
In can effective " treatment " individual a kind of disease or uncomfortable dosage.When if it is cancer, effective quantity can reduce cancer or tumour
The number of cell;Reduce the size of tumour;Inhibit or prevent intrusion of the tumour cell to peripheral organs, for example, tumour spread into
In soft tissue or bone;Inhibit or prevent the transfer of tumour;Inhibit or prevent the growth of tumour;Mitigate to a certain extent it is a kind of or
The a variety of and relevant symptom of cancer;Reduce morbidity and mortality;It improves the quality of living;The either combination of said effect.Have
Effect amount can reduce the dosage of disease symptoms by inhibiting activity of EGFR.For treatment of cancer, the effect of experiment in vivo can
To pass through assessment such as survival period, disease developing time (Time to Disease Progression, TTP), reactivity
(Response Rates, RR), sustained response phase and/or quality of life measure.
Those skilled in the art are it has been realized that effective quantity can be with the approach of administration, the dosage of excipient, Yi Jiyu
Sharing for other drugs and change.
Term " effective quantity " also may refer at least one compound and/or its at least one is pharmaceutically acceptable
Overexpression and/or hyperactivity effective dosage of the salt to inhibition EGFR.
The compound of the present invention has antitumor, active anticancer, especially to human lung carcinoma cell line A549, colorectal cancer cells
Strain HCT116 and breast cancer cell line mcf-7 have very strong inhibitory activity, and the compounds of this invention is to A549, HCT115 and MCF-
The IC of 7 cancer cell line50Value has all reached nanomole grade.Such as compound YJP-6 inhibits the IC of lung cancer cell types50For
535.13 μM, inhibit the IC of colorectal cancer cell lines HCT11650It is 922.26 μM, inhibits the IC of breast cancer cell line mcf-750For
774.38μM。
Therefore the compound of the present invention has the anticancer of wide spectrum, antitumor activity, can be used as the candidate for the treatment of tumour, cancer
Drug or lead compound.
Specific implementation mode
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments cannot function as
Limiting the scope of the invention, any spirit improved all without prejudice to the present invention made on the basis of the present invention.
Instrument and reagent:
AVANCE III Nuclear Magnetic Resonance (400MHz, DMSO-d6, TMS is internal standard), instrument is used in conjunction in ion trap liquid matter
(DECAX-30000LCQ Deca XP), XT5 numbers display micro melting point apparatus (tech electric light instrument plant of Beijing manufactures,
Temperature is not calibrated), wavelengthtunable declines orifice plate microplate reader (Molecular Devies SPECTRAMAX190).Chemical reagent
It is the pure or chemically pure reagent of commercially available analysis, RPMI1640 is purchased from Gibco companies, tetrazolium bromide [3- (4,5-
Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide, MTT] Sigma companies are purchased from, it is other
Reagent is that commercially available analysis is pure, is not handled by using preceding no specified otherwise, and tetrahydrofuran is divided using preceding with dry
Sub- sieve processing.
The synthesis of metronidazole derivative shown in 1 formula of embodiment (I)
Only using the reaction of niacin and metronidazole as illustrating, the preparation process of remaining metronidazole derivative is and niacin
It is similar with the reaction process of metronidazole, it no longer illustrates one by one in embodiment.
The synthesis of metronidazole derivative YJP-1:
50mL round-bottomed flasks are added in 0.123g (1mmol) niacin and 0.206g (1mmol) DCC, 10mL dryings are added
THF will be dissolved with the 10mL of 0.171g (1mmol) metronidazoles and 0.122g (1mmol) DMAP after ice bath stirring reacts 30min
THF solution is slowly added dropwise into reaction system, and ice bath stirring is warmed to room temperature reaction naturally after reacting 30min.TLC detection reactions are completed
Afterwards, reaction solution is concentrated in vacuo, the direct post separation V of residue(petroleum ether):V(ethyl acetate)=5:1~2:1) up to target compound YJP-1.
The preparation of compound YJP-2-YJP-11 is synthesized according to the building-up process of compound YJP-1.
The synthesis of metronidazole derivative YJP-12 shown in 2 formula of embodiment (I)
50mL round-bottomed flasks are added in 0.173g (1mmol) 2- quinolinecarboxylic acids and 0.206g (1mmol) DCC, 10mL is added
Dry THF will be dissolved with 0.171g (1mmol) metronidazoles and 0.122g (1mmol) DMAP after ice bath stirring reacts 30min
10mL THF solutions are slowly added dropwise into reaction system, and ice bath stirring is warmed to room temperature reaction naturally after reacting 30min.TLC detections are anti-
After the completion of answering, reaction solution is concentrated in vacuo, the direct post separation V of residue(petroleum ether):V(ethyl acetate)=5:1~2:1) to get target compound
YJP-12。
The structure of the compound prepared in embodiment 1-2 passes through1The analysis methods such as H NMR, ESI-MS are characterized.
Their Physical Constants and spectroscopic data illustrate in the form of a list:
The structure of compound, number transitivity constant are as shown in the table:
Table 1- compound structures are numbered and mass spectrum
Number | MS (m/e, 100%) | Number | MS (m/e, 100%) |
YJP-1 | 277([M+1]+,50) | YJP-2 | 277([M+1]+,80) |
YJP-3 | 345([M+1]+,20) | YJP-4 | 359([M+1]+,50) |
YJP-5 | 325([M+1]+,10) | YJP-6 | 369([M+1]+,100) |
YJP-7 | 345([M]+,100) | YJP-8 | 341([M+1]+,100) |
YJP-9 | 311([M+1]+,85) | YJP-10 | 295([M+1]+,50) |
YJP-11 | 355([M]+,100) | YJP-12 | 327([M+1]+,100) |
The NMR data of table 2- compounds
3 active anticancer of embodiment is tested
Anti- colorectal cancer cell lines HCT-116, human lung carcinoma cell line A549 and breast carcinoma cell strain have been carried out using mtt assay
The screening active ingredients of MCF-7.Specific screening process is as follows:
(1) lung cancer cell types are laid in 96 orifice plates, 100 μ L medium cultures is added, wait for that cell is grown to 90%, it will
In 1 μ L drug adding holes, 8 kinds of different concentration of each drug detection (the respectively initial concentration of drug, 50 μM, 5 μM,
500nM, 50nM, 5nM, 500pM, 50pM), each drug concentration is parallel to do 3 multiple holes, after culture for 24 hours, in each Kong Zhongjia
Enter 20 μ L of prepared 5mg/mL MTT solution, culture medium is sucked out after 4 hours, 150 μ L DMSO is added per hole, in 595nm waves
Its optical density (OD) value is measured under length.Wherein negative control is DMSO.Inhibiting rate is calculated according to formula.
Its IC50Value is calculated by GraphPad Prism5 softwares.
(2) screening process of colorectal cancer cell lines HCT-116 and breast cancer cell line mcf-7 is the same as lung cancer cell types
Screening process.
The compounds of this invention inhibits human lung cancer cell A549, colorectal cancer cells pearl HCT-116 and breast cancer cell line mcf-7
Activity Results see the table below 3, table 4 and table 5.
Section Example compound inhibits the active testing result of human lung cancer cell A549 in table 3- formulas (I)
Section Example compound inhibits the active testing result of colorectal cancer cells pearl HCT-116 in table 4- formulas (I)
Section Example compound inhibits the active testing result of breast cancer cell line mcf-7 in table 5- formulas (I)
Claims (14)
1. metronidazole derivative and its pharmaceutically acceptable salt shown in a kind of formula (I),
Wherein:
R may be the same or different, independent to be selected from:Hydrogen, halogen, cyano, nitro, C1~C6Alkyl, C1~C6Alkoxy, halogenated C1~
C6Alkyl, halogenated C1~C6Alkoxy, C6~C14Aryl, C6~C14Aryloxy group;The C6~C14Aryl, C6~C14Aryloxy group is appointed
Choosing is substituted by one or more substituents, and the substituent group is independent to be selected from:C1~C6Alkyl, C1~C6Alkoxy, nitro, cyanogen
Base, halogen, halogenated C1~C6Alkyl, halogenated C1~C6Alkoxy;N is the integer of 0-4;
Wherein, do not include following compound in formula (I) compound represented:
2. metronidazole derivative according to claim 1 and its pharmaceutically acceptable salt, wherein n is 2 or 3.
3. metronidazole derivative according to claim 1 and its pharmaceutically acceptable salt, the wherein chemical combination described in formula (I)
Object is selected from:
4. according to claim 1-3 any one of them metronidazole derivatives and its pharmaceutically acceptable salt, wherein
Pharmaceutically acceptable salt be hydrochloride, phosphate, diphosphate, hydrobromate, sulfate, sulfinate, nitrate,
Lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, citrate, sulfonate, to toluene
Sulfonate, 2- isethionates, benzoate, salicylate, stearate, trifluoroacetate, amino-acid salt, alkanoic acid
Salt, HOOC- (CH2)mThe salt of-COOH, wherein m are 0-4.
5. a kind of pharmaceutical composition comprising metronidazole derivative described in any one of claim 1-4 or its pharmaceutically may be used
The salt of receiving and at least one pharmaceutically acceptable, inert, nontoxic excipient or carrier or diluent.
6. pharmaceutical composition as claimed in claim 5, wherein described pharmaceutical composition also includes one or more selected from filling
Agent, disintegrant, lubricant, glidant, effervescent agent, corrigent, preservative and coating material pharmaceutically acceptable auxiliary material.
7. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition is dosage form.
8. pharmaceutical composition according to claim 7, wherein the dosage form is solid orally ingestible, liquid oral
Preparation or injection.
9. pharmaceutical composition according to claim 7, wherein the preparation is selected from tablet, capsule, granule, oral molten
Liquor, big infusion.
10. pharmaceutical composition according to claim 7, wherein the preparation is selected from dispersible tablet, enteric coatel tablets, chewable tablets, mouth
Disintegrating tablet, injection liquid drugs injection or injection freeze-dried powder.
11. claim 1-4 any one of them metronidazole compound or its pharmaceutically acceptable salt are being prepared for anti-swollen
Application in tumor medicine.
12. application according to claim 11, wherein the tumour is and EGFR transition expression and/or hyperactivity
Cancer.
13. application according to claim 11, wherein the tumour is selected from:Carcinoma of urinary bladder, non-small cell lung cancer, oophoroma,
Breast cancer, gastric cancer, cancer of the esophagus, lung cancer, head and neck cancer, colon cancer, pharynx cancer and cancer of pancreas.
14. the preparation method of metronidazole compound shown in the formula (I) of any one of claim 1-4 a kind of, it is characterised in that:Institute
The method stated includes the following steps:
R substituted pyridines-formic acid or R substituted pyridines formyl chloride and metronidazole are raw material, and system is reacted in organic solvent, acid binding agent
It is standby:
Wherein, X OH, Cl, any one of R, n such as claim 1-4 are defined;
If necessary to protect, any functional group in compound shown in formula (I) can be protected.
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