CN104926792A - Metronidazole derivative and preparing method and application thereof - Google Patents
Metronidazole derivative and preparing method and application thereof Download PDFInfo
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- CN104926792A CN104926792A CN201510396700.1A CN201510396700A CN104926792A CN 104926792 A CN104926792 A CN 104926792A CN 201510396700 A CN201510396700 A CN 201510396700A CN 104926792 A CN104926792 A CN 104926792A
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- PHHATVCYEHIDFB-UHFFFAOYSA-N Cc([n]1CCOC(c2ccncc2)=O)ncc1[N+]([O-])=O Chemical compound Cc([n]1CCOC(c2ccncc2)=O)ncc1[N+]([O-])=O PHHATVCYEHIDFB-UHFFFAOYSA-N 0.000 description 1
- MUNCVHKTVZPRMY-UHFFFAOYSA-N Cc([n]1CCOC(c2cnccc2)=O)ncc1[N+]([O-])=O Chemical compound Cc([n]1CCOC(c2cnccc2)=O)ncc1[N+]([O-])=O MUNCVHKTVZPRMY-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- 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
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Abstract
The invention relates to a metronidazole derivative shown in the formula (1) (please see the specific formula in the specification) and salt or solvate which can be accept by the metronidazole derivative on the pharmaceutical science. R can be the same or different and can be independently selected from hydrogen, halogen, a cyano group, nitro, C1-C6 alkyl, C1-C6 alkoxy, halogenation C1-C6 alkyl, halogenation C1-C6 alkoxy, aryl, aryloxy and the like, and n is an integer from 0 to 4. The invention further relates to a preparing method and application of the metronidazole derivative in the formula (I). The compound or the salt of the compound has the strong inhibitory activity on the colorectal cancer cell strain HCT-116, the human lung cancer cell strain A549 and the breast cancer cell strain MCF-7. The compound has broad spectrum on anti-cancer activity and can serve as candidate medicine or a lead compound for treating tumors, cancers and other diseases.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to a class metronidazole derivative, be specifically related to the preparation of the metronidazole derivative shown in formula (I) and the medical composition and its use containing this analog derivative.Such compound anti-cancering activity wide spectrum, can be used as medicine or the lead compound of disease such as treatment tumour, cancer etc.
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 various organ and tissue in any age, causes dead major cancers kind to have: lung cancer, cancer of the stomach, liver cancer, colorectal carcinoma and mammary cancer etc.
In recent years, lung cancer becomes the highest malignant tumour of sickness rate.Add up according to the World Health Organization (WHO): it is 1 that the whole world in 2008 is diagnosed as the number of lung cancer, 600,000 people, account for 13% of the total number of the infected of cancer, death toll Isosorbide-5-Nitrae 00,000 example, account for 18% (Jemal A, et al.C A Cancer J.Clin.2011,61:69-90) of the total death toll of cancer; 2010, the U.S. increased patients with lung cancer 222 newly, 520 people, death toll 157,330, wherein dies from 85% (the Jemal A that nonsmall-cell lung cancer (NSCLC) patient accounts for the total death toll of lung cancer, et al.C A Cancer J.Clin.2010,60:277-300).From China's front 10 malignant tumours formation in town and country in recent years, lung cancer has replaced liver cancer to become the first lethal malignant tumour of China, account for 22.7% (She J, et al.Chest.2013,143 (4): 1117-1126) of whole mortality of malignant tumors.
Mammary cancer is the cancer the most common that whole world women faces at present, about has 1,380,000 mammary cancer new cases and 45.8 ten thousand example death every year.It is reported: the U.S. is newly-increased 232,340 routine patient with breast cancers every year.2011, the U.S. had close to 40, and 000 women dies from mammary cancer; India has 100 every year, and 000 newly-increased patient with breast cancer is made a definite diagnosis, and has 1 meeting to suffer from breast cancer (Yadav D K, et al.Curr.Med.Chem.2014,21 (9): 1160-1170) in every 28 women; In China, mammary cancer also becomes the modal cancer of women, and end 2008, China adds up to 169, and the new breast cancer patient of 452 example, 449,08 example is dead, accounts for 12.2% and 9.6% of the world respectively.China's mammary cancer detects the half that number is Europe (amounting to 332,000 example for 2008, total population 400,019,800) whole year, substantially suitable with U.S.'s (amounting to 182,000 example for 2008, total population 300,010,400).If this trend remains unchanged, by 2021, China mammary gland patient will up to 2,500,000, sickness rate will increase to above 100 example/100,000 women (Fan L from less than 60 example/100,000 women (age was 55 years old to 69 years old), et al.Lancet Oncol.2014,15:e279-289).With regard to the whole world, women suffers from breast cancer quantity in continuous increase, and the existence of mammary cancer to women causes grave danger.
Colorectal carcinoma and the rectum cancer are referred to as large bowel cancer, it is digestive tube common cancer, sickness rate is in rising trend, increase progressively 2% every year on average, the 2nd of tumor mortality is occupied in American-European countries's case fatality rate, U.S.'s large bowel cancer new development case loads in 2003 and mortality ratio all occupy the 3rd (Xu Fuxing. international disease for digest magazine .2006,26 (6): 365-366).The sickness rate of China's large bowel cancer rises at a terrific speed in recent years, and with regard to nationwide, large bowel cancer has risen to the 4th of Incidence, in some Economic developments faster city, as Shanghai be in the 2nd (Li Delu, etc.China tumour .2011,20 (6): 413-418).But most of cancer when finding be mid-term to late period, clinical treatment general effect is poor, especially the continuous appearance of multidrug resistance, makes the treatment of cancer difficult.
The cancer therapy drug major part dependence on import that current China applies clinically, price is high.In addition, most of cancer therapy drug still cannot reach gratifying specificity degree, and patient is when carrying out chemotherapy, and the normal cell in body often also can be killed in the lump, has a strong impact on normal physiological function, and with many side effects.Therefore, the specific anti-cancer medicine that activity is high, side effect is low must be developed to meet clinical demand.
In recent years, our research group is devoted to carry out the design of small molecule anti-cancer compound, (patent application publication number CN103360382A discloses the quinazoline derivant that Han isoxazole heterocycle replaces and has significant inhibit activities to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7 in the research of synthesis and antitumour activity aspect; Thiophene [2, the 3-d] pyrimidine derivatives that patent application publication number CN103664991A discloses the replacement of Han isoxazole heterocycle has significant inhibit activities to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7; The ferrocene deriv that patent application publication number CN103601762A discloses Han isoxazole heterocycle has significant inhibit activities to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7; The quinoline that patent application publication number CN104230912A discloses Han isoxazole heterocycle has significant inhibit activities to lung cell A549, colorectal cancer cells HCT-116 and breast cancer cell MCF-7).Above-mentioned references cited therein is as the Research foundation in early stage.
Summary of the invention
The object of the invention is to, class metronidazole derivative and its production and use is provided.This compounds has very strong inhibit activities to human lung carcinoma cell line A549, colorectal cancer cell lines HCT-116 and breast cancer cell line mcf-7.Can be used for Therapeutic cancer or tumour.
The present invention is achieved through the following technical solutions:
Metronidazole derivative shown in a kind of formula (I), or its pharmacy acceptable salt,
Wherein:
For the category-A compound shown in formula (I),
R may be the same or different, and is independently selected from: hydrogen, halogen, cyano group, nitro, C
1~ C
6alkyl, C
1~ C
6alkoxyl group or halo C
1~ C
6alkyl, halo C
1~ C
6alkoxyl group, aryl, aryloxy etc.; Described aryl, aryloxy are optionally replaced by one or more substituting group, or two adjacent R connect together and form 3-8 ring; Described substituting group is independently selected from: C
1~ C
6alkyl, C
1~ C
6alkoxyl group, nitro, cyano group, halogen, halo C
1~ C
6alkyl, halo C
1~ C
6alkoxyl group;
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 ring be connected carbon, such as cyclopentyl, phenyl ring, pyridine ring.More preferably, described two R form quinoline ring, quinazoline ring etc. be connected pyridine ring.Be more preferably quinazoline ring.
According to the present invention, described alkyl refers to have the direct-connected of 1-6 carbon atom or branched-chain alkyl, and described alkyl is such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, sec-butyl, amyl group, neo-pentyl.
According to the present invention, described alkoxyl group refers to have the direct-connected of 1-6 carbon atom or branched-chain alkyl oxygen base, such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, tert.-butoxy, sec-butoxy.
According to the present invention, described halogen is fluorine, chlorine, bromine, iodine, is preferably fluorine, chlorine.
According to the present invention, described halo C
1~ C
6alkyl is C
1~ C
6one or more hydrogen atoms in alkyl are optionally substituted by halogen, such as trifluoromethyl etc.
According to the present invention, described aryl refers to monocycle or the polycyclic aromatic group with 6-20 (preferred 6-14) carbon atom, and representational aryl comprises: phenyl, naphthyl, anthryl, pyrenyl etc.
According to the present invention, described aryloxy is aryloxy.
According to the present invention, the metronidazole derivative shown in described formula (I) is preferably selected from any one compound following:
Metronidazole derivative shown in formula (I), can select to form pharmacy acceptable salt with pharmaceutically acceptable acid respectively.Wherein term " pharmacy acceptable salt " includes but not limited to and the salt that mineral acid is formed, and example hydrochloric acid salt, phosphoric acid salt, diphosphate, hydrobromate, vitriol,-sulfinate, nitrate and class thereof are saloid; Also the salt formed with organic acid is comprised, as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, Citrate trianion, lactic acid salt, sulfonate, tosilate, 2-isethionate, benzoate, salicylate, stearate, trifluoroacetic acid or amino acid and alkanoate as acetate, HOOC-(CH
2)
m-COOH wherein m is the salt of 0-4, and class is saloid.Similarly, pharmaceutically acceptable positively charged ion includes but not limited to sodium, potassium, calcium, aluminium, lithium and ammonium.
The present invention also provides a kind of pharmaceutical composition, it comprises the metronidazole derivative shown in formula of the present invention (I), or its pharmacy acceptable salt, and pharmaceutically acceptable, inertia, the nontoxic vehicle of at least one or carrier or thinner.
According to the present invention, described pharmaceutical composition also comprises the acceptable subsidiary material of one or more pharmacy being selected from weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas and coating material.The present invention also provides a kind of pharmaceutical preparation, it is characterized in that, described preparation comprises the metronidazole derivative shown in formula of the present invention (I).
According to pharmaceutical preparation of the present invention, it is characterized in that, described preparation is preferably solid orally ingestible, liquid oral medicine or injection.
According to pharmaceutical preparation of the present invention, described preparation is selected from tablet (dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet), capsule, granule, oral solution, injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
The present invention also provides the metronidazole derivative shown in a kind of formula (I) or its pharmacy acceptable salt for the preparation of the application in antitumor or cancer drug.
According to the present invention, described tumour or cancer are the cancers with EGFR transition expression and/or hyperactivity.More preferably, described tumour or cancer are selected from: bladder cancer, nonsmall-cell lung cancer, ovarian cancer, mammary cancer, cancer of the stomach, esophagus cancer, lung cancer, head and neck cancer, colorectal carcinoma, pharynx cancer, and carcinoma of the pancreas etc., the application especially in nonsmall-cell lung cancer (NSCLC).
The present invention also provides the preparation method of the metronidazole derivative shown in a kind of formula (I), it is characterized in that, described method comprises the steps:
Category-A compound shown in formula (I) is prepared by following process:
R substituted pyridines-formic acid (X=OH) or R substituted pyridines formyl chloride (X=Cl) and metronidazole are raw material, reaction preparation in organic solvent, acid binding agent:
Wherein, X is OH, Cl, and R, n define as above-mentioned;
Category-B compound shown in formula (I) is prepared by following process:
2-quinolinecarboxylic acid (X=OH) or 2-quinoline formyl chlorine (X=Cl) and metronidazole are raw material, reaction preparation in organic solvent, acid binding agent:
Wherein, X is OH, Cl, and R, n define as above-mentioned;
If need protection, any functional group in the category-A compound shown in formula (I) can be protected.
According to the present invention, in the preparation method of above-mentioned A, category-B compound, the temperature of described reaction be 0 DEG C to reflux conditions, preferably 0 DEG C to room temperature condition.
According to the present invention, in the preparation method of above-mentioned A, category-B compound, described organic solvent is benzene,toluene,xylene, methylene dichloride, chloroform, acetonitrile, dioxane, tetrahydrofuran (THF) or DMF, is more preferably tetrahydrofuran (THF).Described organic solvent is dry.
According to the present invention, described acid binding agent (basic catalyst) is organic bases or mineral alkali, and described organic bases is preferably triethylamine, tripropyl amine, DMAP, potassium tert.-butoxide etc.; Described mineral alkali is preferably salt of wormwood, sodium hydride, sodium carbonate etc.Preferred acid binding agent is DMAP.
Formula of the present invention (I) compound, includes but not limited to: their optical isomer, racemic modification and composition thereof.
Term " significant quantity " refer to described at least one compound and/or at least one pharmacy acceptable salt for can the consumption of a kind of disease that effectively " treatment " is individual or discomfort.If during cancer, significant quantity can reduce the number of cancer or tumour cell; Reduce the size of tumour; Suppress or stop tumour cell to the intrusion of peripheral organs, such as, tumour spreads in soft tissue or bone; Suppress or stop the transfer of tumour; Suppress or stop the growth of tumour; Alleviate the symptom that one or more are relevant to cancer to a certain extent; Reduce M & M; Improve the quality of living; Or the combination of above-mentioned effect.Significant quantity can be the consumption by suppressing activity of EGFR to reduce disease symptoms.For cancer therapy, the effect of experiment in vivo can by assessment as survival time, disease developing time (Time to Disease Progression, TTP), reactivity (Response Rates, RR), sustained reaction phase and/or quality of life are measured.
Those skilled in the art recognize, significant quantity can change along with the dosage of the approach of administration, vehicle and with share of other drug.
Term " significant quantity " also can refer to described at least one compound and/or its at least one pharmacy acceptable salt to the overexpression and/or the effective dosage of hyperactivity that suppress EGFR.
Compound of the present invention has antitumor, antitumour activity, especially have very strong inhibit activities to human lung carcinoma cell line A549, colorectal cancer cell lines HCT116 and breast cancer cell line mcf-7, the compounds of this invention is to the IC of A549, HCT115 and MCF-7 JEG-3
50value all reaches nmole level.Such as compound YJP-6 suppresses the IC of lung cancer cell types
50be 535.13 μMs, suppress the IC of colorectal cancer cell lines HCT116
50be 922.26 μMs, suppress the IC of breast cancer cell line mcf-7
50it is 774.38 μMs.
Therefore compound of the present invention has anticancer, the anti-tumor activity of wide spectrum, can be used as treatment tumour, the drug candidate of cancer or lead compound.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment can not as limiting the scope of the invention, and any improvement made on basis of the present invention is all without prejudice to spirit of the present invention.
Instrument and reagent:
AVANCE III nuclear magnetic resonance analyser (400MHz, DMSO-d
6tMS is interior mark), ion trap liquid matter is used in conjunction instrument (DECAX-30000LCQ Deca XP), (tech electric light instrument plant of Beijing manufactures XT5 numerical monitor micro melting point apparatus, temperature is not calibrated), wavelengthtunable declines orifice plate microplate reader (Molecular DeviesSPECTRAMAX190).Chemical reagent is commercially available analytical pure or chemically pure reagent, RPMI1640 is purchased from Gibco company, tetrazolium bromide [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, MTT] available from Sigma, other reagent is commercially available analytical pure, do not have specified otherwise to process before use, tetrahydrofuran (THF) uses dry molecular sieves process before use.
The synthesis of the category-A metronidazole derivative shown in embodiment 1 formula (I)
Only exemplarily illustrate with the reaction of nicotinic acid and metronidazole, the preparation process of all the other category-A metronidazole derivatives is all similar with the reaction process of nicotinic acid and metronidazole, illustrates no longer one by one in an embodiment.
The synthesis of metronidazole derivative YJP-1:
0.123g (1mmol) nicotinic acid and 0.206g (1mmol) DCC are added 50mL round-bottomed flask, add the THF of 10mL drying, after ice bath stirring reaction 30min, the 10mL THF solution being dissolved with 0.171g (1mmol) metronidazole and 0.122g (1mmol) DMAP is slowly added dropwise to reaction system, after ice bath stirring reaction 30min, naturally rises to room temperature reaction.After TLC detection reaction completes, reaction solution vacuum concentration, the direct post of residue is separated V
(sherwood oil): V
(ethyl acetate)=5:1 ~ 2:1) namely obtain 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 the category-B metronidazole derivative YJP-12 shown in embodiment 2 formula (I)
0.173g (1mmol) 2-quinolinecarboxylic acid and 0.206g (1mmol) DCC are added 50mL round-bottomed flask, add the THF of 10mL drying, after ice bath stirring reaction 30min, the 10mL THF solution being dissolved with 0.171g (1mmol) metronidazole and 0.122g (1mmol) DMAP is slowly added dropwise to reaction system, after ice bath stirring reaction 30min, naturally rises to room temperature reaction.After TLC detection reaction completes, reaction solution vacuum concentration, the direct post of residue is separated V
(sherwood oil): V
(ethyl acetate)=5:1 ~ 2:1), obtain target compound YJP-12.
The structure of the compound prepared in embodiment 1-2 is all passed through
1h NMR, the analytical procedures such as ESI-MS characterize.Their Physical Constants and spectroscopic data are described in the form of a list:
Structure, the numbering transitivity constant of compound are as shown in the table:
Table 1-compound structure numbering and mass spectrum
| Numbering | MS(m/e,100％) | Numbering | 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-compound
Embodiment 3 antitumour activity is tested
Mtt assay is adopted to carry out the screening active ingredients of anti-colorectal cancer cell lines HCT-116, human lung carcinoma cell line A549 and breast cancer cell line mcf-7.Concrete screening process is as follows:
(1) lung cancer cell types is laid in 96 orifice plates, add 100 μ L culture medium culturing, treat that cell grows to 90%, add in hand-hole by 1 μ L medicine, often kind of medicine detects 8 kinds of different concentration and (is respectively the starting point concentration of medicine, 50 μMs, 5 μMs, 500nM, 50nM, 5nM, 500pM, 50pM), often kind of drug concentration is parallel does 3 multiple holes, after cultivating 24h, the 5mg/mL MTT solution 20 μ L prepared is added in each hole, by substratum sucking-off after 4 hours, every hole adds 150 μ L DMSO, measures its optical density(OD) (OD) value under 595nm wavelength.Wherein negative control is DMSO.According to formulae discovery inhibiting rate.
Its IC
50value is drawn by GraphPad Prism5 computed in software.
(2) screening process of colorectal cancer cell lines HCT-116 and breast cancer cell line mcf-7 is with the screening process of lung cancer cell types.
The compounds of this invention suppresses human lung cancer cell A549, the Activity Results of colorectal cancer cells pearl HCT-116 and breast cancer cell line mcf-7 sees the following form 3, table 4 and table 5.
In table 3-formula (I), section Example compound suppresses the active testing result of human lung cancer cell A549
In table 4-formula (I), section Example compound suppresses the active testing result of colorectal cancer cells pearl HCT-116
In table 5-formula (I), section Example compound suppresses the active testing result of breast cancer cell line mcf-7
Claims (9)
1. the metronidazole derivative shown in formula (I) and a pharmacy acceptable salt thereof,
Wherein:
For the category-A compound shown in formula (I),
R may be the same or different, and is independently selected from: hydrogen, halogen, cyano group, nitro, C
1~ C
6alkyl, C
1~ C
6alkoxyl group, halo C
1~ C
6alkyl, halo C
1~ C
6alkoxyl group, aryl, aryloxy etc.; Or two adjacent R connect together and form 3-8 ring; Described aryl, aryloxy are optionally replaced by one or more substituting group, and described substituting group is independently selected from: C
1~ C
6alkyl, C
1~ C
6alkoxyl group, nitro, cyano group, halogen, halo C
1~ C
6alkyl, halo C
1~ C
6alkoxyl group; N is the integer of 0-4.
2. metronidazole derivative according to claim 1 and pharmacy acceptable salt thereof, wherein, n is 2 or 3.
Preferably, described two R form 3-6 ring be connected carbon, such as cyclopentyl, phenyl ring, pyridine ring.More preferably, described two R form quinoline ring, quinazoline ring etc. be connected pyridine ring.Be more preferably quinazoline ring.
3. metronidazole derivative according to claim 1 and 2 and pharmacy acceptable salt thereof, the compound described in its Chinese style (I) is selected from:
4. the metronidazole derivative according to any one of claim 1-3 and pharmacy acceptable salt thereof, wherein,
Pharmacy acceptable salt comprises the salt formed with mineral acid, and example hydrochloric acid salt, phosphoric acid salt, diphosphate, hydrobromate, vitriol,-sulfinate, nitrate and class thereof are saloid; Also the salt formed with organic acid is comprised, as lactic acid, oxalic acid, malate, maleate, fumarate, tartrate, succinate, Citrate trianion, sulfonate, tosilate, 2-isethionate, benzoate, salicylate, stearate, trifluoroacetate or amino acid salts and alkanoate as acetate, HOOC-(CH
2)
m-COOH and class saloid, wherein m is the salt of 0-4.
5. a pharmaceutical composition, it comprises metronidazole derivative according to any one of claim 1-4 or its pharmacy acceptable salt, and pharmaceutically acceptable, inertia, the nontoxic vehicle of at least one or carrier or thinner.
Preferably, described pharmaceutical composition also comprises the acceptable subsidiary material of one or more pharmacy being selected from weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas and coating material.
6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is dosage form, is preferably solid orally ingestible, liquid oral medicine or injection.
Preferably, described preparation is selected from tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
7. the metronidazole compound described in an any one of claim 1-4 or its pharmacy acceptable salt are for the preparation of the application in antitumor or cancer drug.
8. application according to claim 7, wherein said tumour or cancer are the cancers with EGFR transition expression and/or hyperactivity.More preferably, described tumour or cancer are selected from: bladder cancer, nonsmall-cell lung cancer, ovarian cancer, mammary cancer, cancer of the stomach, esophagus cancer, lung cancer, head and neck cancer, colorectal carcinoma, pharynx cancer, and carcinoma of the pancreas etc., the application especially in nonsmall-cell lung cancer.
9. a preparation method for the metronidazole compound shown in formula (I) of any one of claim 1-4, is characterized in that: described method comprises the steps:
Category-A compound shown in formula (I) is prepared by following process:
R substituted pyridines-formic acid (X=OH) or R substituted pyridines formyl chloride (X=Cl) and metronidazole are raw material, reaction preparation in organic solvent, acid binding agent:
Wherein, X is OH, Cl, R, n as any one of claim 1-4 define;
Category-B compound shown in formula (I) is prepared by following process:
2-quinolinecarboxylic acid (X=OH) or 2-quinoline formyl chlorine (X=Cl) and metronidazole are raw material, reaction preparation in organic solvent, acid binding agent:
Wherein, X is OH, Cl, R, n as any one of claim 1-4 define;
If need protection, any functional group in the category-A compound shown in formula (I) can be protected.
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| CN106699738A (en) * | 2015-11-18 | 2017-05-24 | 南京大学 | Design, synthesis and biological activity evaluation of antibacterial compound containing metronidazole pyrazol skeleton |
| CN107474043A (en) * | 2017-09-13 | 2017-12-15 | 厦门稀土材料研究所 | Nicotinic acid derivates and preparation method thereof and purposes |
| CN109942566A (en) * | 2019-03-19 | 2019-06-28 | 厦门稀土材料研究所 | Isonicotinic acid derivatives and its preparation method and application |
| CN110066274A (en) * | 2019-03-19 | 2019-07-30 | 厦门稀土材料研究所 | Pyridine -2- formic acid derivates and preparation method thereof and purposes |
| JP2022551393A (en) * | 2019-09-06 | 2022-12-09 | 武漢人福創新薬物研発中心有限公司 | Pyrimidine compound and preparation method thereof |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699738A (en) * | 2015-11-18 | 2017-05-24 | 南京大学 | Design, synthesis and biological activity evaluation of antibacterial compound containing metronidazole pyrazol skeleton |
| CN107474043A (en) * | 2017-09-13 | 2017-12-15 | 厦门稀土材料研究所 | Nicotinic acid derivates and preparation method thereof and purposes |
| CN111646986A (en) * | 2017-09-13 | 2020-09-11 | 厦门稀土材料研究所 | Nicotinic acid derivative and preparation method and application thereof |
| CN111646986B (en) * | 2017-09-13 | 2022-03-25 | 厦门稀土材料研究所 | Nicotinic acid derivative and preparation method and application thereof |
| CN109942566A (en) * | 2019-03-19 | 2019-06-28 | 厦门稀土材料研究所 | Isonicotinic acid derivatives and its preparation method and application |
| CN110066274A (en) * | 2019-03-19 | 2019-07-30 | 厦门稀土材料研究所 | Pyridine -2- formic acid derivates and preparation method thereof and purposes |
| JP2022551393A (en) * | 2019-09-06 | 2022-12-09 | 武漢人福創新薬物研発中心有限公司 | Pyrimidine compound and preparation method thereof |
| JP7389238B2 (en) | 2019-09-06 | 2023-11-29 | 武漢人福創新薬物研発中心有限公司 | Pyrimidine compounds and their preparation methods |
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