CN108218843A - A kind of pyridine derivatives and its application in antituberculotic - Google Patents
A kind of pyridine derivatives and its application in antituberculotic Download PDFInfo
- Publication number
- CN108218843A CN108218843A CN201810345593.3A CN201810345593A CN108218843A CN 108218843 A CN108218843 A CN 108218843A CN 201810345593 A CN201810345593 A CN 201810345593A CN 108218843 A CN108218843 A CN 108218843A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- pyridine derivatives
- tuberculosis
- drug
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- C07D405/10—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 carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention provides a kind of pyridine derivatives, the chemical structural formula of the pyridine derivatives is formula（Ⅰ）It is shown,
Description
Technical field
The present invention relates to antituberculotic field, specifically, the present invention relates to a kind of pyridine derivatives and its anti-
Application in tubercular drugs.
Background technology
Mycobacterium tuberculosis（M.tuberculosis）, tubercle bacillus is commonly called as, is to cause pathogen lungy, can invade
Each organ of whole body, but using pulmonary tuberculosis to be most common；Tuberculosis is the chronic infectious disease as caused by mycobacterium tuberculosis infection, and tulase can
The various organs of Whole Body can be invaded, but mainly invade lungs, referred to as pulmonary tuberculosis, tuberculosis is young people incidental one
The chronic and deferred infectious disease of kind, 4~8 weeks incubation periods, wherein 80% is happened at lung, other positions（Neck lymph, meninx, abdomen
Film, intestines, skin, bone）Also can secondary infection, interpersonal respiratory infectious be this disease infect major way, the infection sources
It is the lunger for contacting discharge of bacteria, with environmental pollution and the propagation of AIDS, incidence of tuberculosis is more strong, except minority
Morbidity is rapid outer, clinically mostly often has the respiratory systems table such as the constitutional symptoms such as low-heat, weak and cough, spitting of blood in chronic process
It is existing.
Mycobacterium tuberculosis is the important pathogenic bacteria of the mankind, and huge threat is formed to human health；According to investigations, it is complete at present
Ball has infected tubercle bacillus close to 32% population, and the World Health Organization announced that tuberculosis is the urgent shape of Global Health in 1993
State, China are one of 22, whole world tuberculosis high burden countries, and tuberculosis epidemic situation is more serious, and tuberculosis number occupies the second in the world
Position, studies have shown that TB endemic is difficult to contain mainly related with largely increasing for multiple-drug resistance tuberculosis bacillus strain；At present,
There are many new antituberculotics to have shown that the effect of preferable, however multi-drug resistance tuberculosis (MDR-TB) effect is not enough managed
Think, most people in the world is made still to be faced with the danger of infection and morbidity, therefore it is very urgent to find Newer Antibuberculotics.
Invention content
Pyridine derivatives of the present invention is treat choice drug lungy, suitable for various types of tuberculosis, as lung,
The tuberculosis such as lymph, bone, kidney, intestines show tubercular meningitis, pleurisy and peritonitis etc. good treating tuberculosis effect,
Meanwhile with good effects such as the hepatic injuries reduced caused by antituberculotic；Pyridine derivatives of the present invention, which have, to be inhibited to tie
The growth of core bacillus, the effect of anti-mycobacterium tuberculosis adherency.
To achieve the above object, the application the present invention provides a kind of pyridine derivatives and its in antituberculotic,
The chemical structural formula of the pyridine derivatives is formula（Ⅰ）It is shown,
,
Wherein R1ForOr,
Wherein R2ForOr,
Wherein X is、Or；
Further, formula（Ⅰ）Middle R1Adjacent C atoms and R1C atomic bondings adjacent middle *,
Further, formula（Ⅰ）Middle R2Adjacent C atoms and R2C atomic bondings adjacent middle *,
Further, formula（Ⅰ）C atoms adjacent middle X Br, F, CI atomic bonding adjacent with * in X.
Concrete structure and number such as following table：
Further, formula（Ⅰ）The compound of expression, its salt or its solvated compounds.
It is another object of the present invention to provide a kind of pyridine derivatives formulas（Ⅰ）Synthetic route：
。
The formula（Ⅰ）Synthesis step be：
（1）Modus ponens（Ⅱ）Compound is dissolved in benzene, stirring, 6 ether of dicyclohexyl 18- crown-s and finely ground potassium permanganate is added in, 25
DEG C 1h quickly is stirred to react, filters out solid, extracted isonicotinic acid with 5% sodium hydrate aqueous solution, filter off manganese dioxide, then use ether
For wash water solution to remove crown ether, it is 3.6 that aqueous acidification, which adjusts pH, is heated to boiling, obtains formula（Ⅲ）Compound；
（2）Modus ponens（Ⅲ）Compound and formula（Ⅳ）Compound is dissolved in benzene, stirring, is added in copper nitrate and is heated, meeting after heating
Hydrolysis generation basic salt, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into copper oxide, nitrogen dioxide and oxygen, so
The gas of generation is imported in water afterwards, 10min is stirred to react, is washed with deionized water three times, is freeze-dried after Magneto separate, formula is made
（Ⅴ）Compound；
（3）Modus ponens（Ⅴ）Compound and hydrazine hydrate are dissolved in dichloromethane, and ice bath adds in dicyclohexylcarbodiimide to 0 DEG C,
After 30min, ice bath is removed, is being placed at room temperature for 2-4h, dicyclohexylurea (DCU) is filtered off, is washed with a small amount of solvent, filtrate dilute hydrochloric acid and dilute
Caustic washing is dried and evaporated, excess obtains formula through ethyl alcohol recrystallization to neutrality（Ⅰ）Compound.
The compound that the present invention synthesizes have good chemism so that these compounds have can expand well
Property, also good active group is provided for their pharmacological activity.
The present invention is optimized reaction condition and reaction route from economic benefit, either the dosage of solvent,
The selection of the type and dosage or reaction temperature of reactant has all carried out condition optimizing, and the reaction route and condition of gained are
There is Atom economy and the route of the feature of environmental protection in the route that we select.
It is another object of the present invention to provide a kind of pyridine derivatives formulas（Ⅰ）Application in antituberculotic.
It is another object of the present invention to provide a kind of antitubercular pharmaceutical composition, including formula（Ⅰ）It can pharmaceutically connect
The carrier received.
Further, the antitubercular pharmaceutical composition, the formula（Ⅰ）As sole active agent.
Further, the pharmaceutically acceptable carrier further includes adhesive, bulking agent, moisturizer, retarding solvent, disintegration
It is one or more in agent, absorbsion accelerator, lubricant, wetting agent or adsorbent.
The present invention is not to formula（Ⅰ）Or include formula（Ⅰ）The method of application of pharmaceutical composition be particularly limited, it is representative
Method of application include（But it is not limited to）：Oral, intravenous injection.Include capsule, piece for the solid dosage forms of oral medication
Agent, pill, powder and granule.In these solid dosage forms, formula（Ⅰ）With at least one conventional inert excipients（Or carrier）It is mixed
It closes, is mixed such as sodium citrate or Dicalcium Phosphate or with following compositions：（a）Adhesive, for example, it is hydroxymethyl cellulose, alginates, bright
Glue, polyvinylpyrrolidone, sucrose and Arabic gum；（b）Bulking agent, such as starch, lactose, sucrose, glucose, mannitol
And silicic acid；（c）Moisturizer, such as glycerine；（d）Retarding solvent, such as paraffin；（e）Disintegrant, such as agar, calcium carbonate, potato
Starch or tapioca, alginic acid, certain composition silicates, sodium carbonate；（f）Absorbsion accelerator, such as quaternary ammonium compound；（g）Profit
Lubrication prescription, such as talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate；（h）Wetting agent, such as whale
Ceryl alcohol and glycerin monostearate；（i）Adsorbent, such as kaolin.In capsule, tablet and pill, dosage form also may include delaying
Electuary.
The compounds of this invention can be administered alone or with other pharmaceutically acceptable other medicines administering drug combinations.
Obviously, the above according to the present invention according to the ordinary technical knowledge and means of this field, is not departing from this hair
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Compared with prior art, the present invention it has the advantages that：
1st, pyridine derivatives of the present invention is treat choice drug lungy, suitable for various types of tuberculosis, such as lung, leaching
Bar, the tuberculosis such as bone, kidney, intestines, good treating tuberculosis effect is shown to tubercular meningitis, pleurisy and peritonitis etc.；Together
When, with good effects such as the hepatic injuries reduced caused by antituberculotic.
2nd, pyridine derivatives of the present invention have the function of to inhibit growth of bacillus tubercle, anti-mycobacterium tuberculosis adherency, for controlling
Mycobacterium tuberculosis infection is treated, can increase the tuberculosis therapy window of antituberculotic, improves the ability for effectively killing tubercle bacillus, and then
Increase drug effect, shorten treatment cycle, reduce the generation of Mycobacterium tuberculosis drug-resistant, may also suppress the biosynthesis of mycolic acid, improve
The effect of antituberculosis drugs treat tuberculosis drug effect.
Specific embodiment
Present invention is further elaborated in following combination specific embodiment.
Embodiment 1
Following formula（Ⅰ）The synthesis of compound.
Structural formula：
。
Synthetic route is：
。
Synthesis step is：
（1）Modus ponens（Ⅱ）Compound 69g (0.7mol) holds in 300ml benzene, stirring, adds in 6 ether of dicyclohexyl 18- crown-s（DC-
18-C-6）25g（0.07mol）With finely ground potassium permanganate 300g (1.9mol), 1h quickly is stirred to react at 25 DEG C, is filtered out solid
Body extracts isonicotinic acid with 5% sodium hydrate aqueous solution, filters off manganese dioxide, then with ether wash water solution to remove crown ether, water
It is 3.6 that liquid acidification, which adjusts pH, is heated to boiling, obtains clear crystal formula（Ⅲ）Compound 78g, yield 93%；
（2）Modus ponens（Ⅲ）Compound 78g（0.68mol）And formula（Ⅳ）Compound 60g（0.68mol）It is dissolved in benzene, stirs, add in
Copper nitrate is heated, and generation basic salt can be hydrolyzed after heating, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into oxygen
Change copper, nitrogen dioxide and oxygen, then the gas of generation imported in water, 10min is stirred to react, is washed with deionized water three times,
It is freeze-dried after Magneto separate, formula is made（Ⅴ）Compound 81g, yield 90%；
（3）Modus ponens（Ⅴ）Compound 81g（0.66mol）It is dissolved in 200ml dichloromethane with hydrazine hydrate 33g (0.66mol), ice bath
To 0 DEG C, dicyclohexylcarbodiimide 135g is added in（0.66mol）, after 30min, ice bath is removed, is being placed at room temperature for 2-4h, filtered off
Dicyclohexylurea (DCU) is washed with a small amount of solvent, and filtrate washes neutrality with dilute hydrochloric acid and dilute sodium hydroxide, is dried and evaporated, and excess is through ethyl alcohol
Recrystallization, obtains white crystalline body formula（Ⅰ）Compound 72.3g, yield 80%.
Wherein, formula（Ⅰ）For 1- ［ 1- oxacyclohexyl -2- bromines ］ base -2- acetyl group -4- hydrazides yl pyridines, formula（Ⅱ）For 2-
Acetyl group -1H- pyridines, formula（Ⅲ）For 2- acetyl group -1H-4- pyridine carboxylic acids, formula（Ⅳ）For -2 bromo- 4- benzene of 1- oxacyclohexyls
Phenol, formula（Ⅴ）For 1- ［ 1- oxacyclohexyl -2- bromines ］ base -2- acetyl group-Isonicotinic acid.
Embodiment 2
Following formula（Ⅰ）The synthesis of compound.
Structural formula：
。
Synthetic route is：
。
Synthesis step is：
（1）Modus ponens（Ⅱ）Compound 68g (0.7mol) holds in 300ml benzene, stirring, adds in 6 ether of dicyclohexyl 18- crown-s（DC-
18-C-6）25g（0.07mol）With finely ground potassium permanganate 300g (1.9mol), 1h quickly is stirred to react at 25 DEG C, is filtered out solid
Body extracts isonicotinic acid with 5% sodium hydrate aqueous solution, filters off manganese dioxide, then with ether wash water solution to remove crown ether, water
It is 3.6 that liquid acidification, which adjusts pH, is heated to boiling, obtains clear crystal formula（Ⅲ）Compound 77g, yield 92%；
（2）Modus ponens（Ⅲ）Compound 77g（0.68mol）And formula（Ⅳ）Compound 61g（0.68mol）It is dissolved in benzene, stirs, add in
Copper nitrate is heated, and generation basic salt can be hydrolyzed after heating, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into oxygen
Change copper, nitrogen dioxide and oxygen, then the gas of generation imported in water, 10min is stirred to react, is washed with deionized water three times,
It is freeze-dried after Magneto separate, formula is made（Ⅴ）Compound 80g, yield 89%；
（3）Modus ponens（Ⅴ）Compound 80g（0.66mol）It is dissolved in 200ml dichloromethane with hydrazine hydrate 32g (0.66mol), ice bath
To 0 DEG C, dicyclohexylcarbodiimide 135g is added in（0.66mol）, after 30min, ice bath is removed, is being placed at room temperature for 2-4h, filtered off
Dicyclohexylurea (DCU) is washed with a small amount of solvent, and filtrate washes neutrality with dilute hydrochloric acid and dilute sodium hydroxide, is dried and evaporated, and excess is through ethyl alcohol
Recrystallization, obtains white crystalline body formula（Ⅰ）Compound 73.2g, yield 81%.
Wherein, formula（Ⅰ）For 1- ［ 1- oxacyclohexyl -2- bromines ］ base -2- propiono -4- hydrazides yl pyridines, formula（Ⅱ）For 2-
Propiono -1H- pyridines, formula（Ⅲ）For 2- propiono -1H-4- pyridine carboxylic acids, formula（Ⅳ）For -2 bromo- 4- benzene of 1- oxacyclohexyls
Phenol, formula（Ⅴ）For 1- ［ 1- oxacyclohexyl -2- bromines ］ base -2- propionos-Isonicotinic acid.
Embodiment 3
Following formula（Ⅰ）The synthesis of compound.
Structural formula：
。
Synthetic route is：
。
Synthesis step is：
（1）Modus ponens（Ⅱ）Compound 67g (0.7mol) holds in 300ml benzene, stirring, adds in 6 ether of dicyclohexyl 18- crown-s（DC-
18-C-6）25g（0.07mol）With finely ground potassium permanganate 300g (1.9mol), 1h quickly is stirred to react at 25 DEG C, is filtered out solid
Body extracts isonicotinic acid with 5% sodium hydrate aqueous solution, filters off manganese dioxide, then with ether wash water solution to remove crown ether, water
It is 3.6 that liquid acidification, which adjusts pH, is heated to boiling, obtains clear crystal formula（Ⅲ）Compound 76g, yield 90%；
（2）Modus ponens（Ⅲ）Compound 76g（0.68mol）And formula（Ⅳ）Compound 62g（0.68mol）It is dissolved in benzene, stirs, add in
Copper nitrate is heated, and generation basic salt can be hydrolyzed after heating, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into oxygen
Change copper, nitrogen dioxide and oxygen, then the gas of generation imported in water, 10min is stirred to react, is washed with deionized water three times,
It is freeze-dried after Magneto separate, formula is made（Ⅴ）Compound 79g, yield 91%；
（3）Modus ponens（Ⅴ）Compound 79g（0.66mol）It is dissolved in 200ml dichloromethane with hydrazine hydrate 31g (0.66mol), ice bath
To 0 DEG C, dicyclohexylcarbodiimide 135g is added in（0.66mol）, after 30min, ice bath is removed, is being placed at room temperature for 2-4h, filtered off
Dicyclohexylurea (DCU) is washed with a small amount of solvent, and filtrate washes neutrality with dilute hydrochloric acid and dilute sodium hydroxide, is dried and evaporated, and excess is through ethyl alcohol
Recrystallization, obtains white crystalline body formula（Ⅰ）Compound 74.1g, yield 82%.
Wherein, formula（Ⅰ）For 1- ［ 1-（2- methyl）Oxacyclohexyl -2- bromines ］ base -2- acetyl group -4- hydrazides yl pyridines, formula
（Ⅱ）For 2- acetyl group -1H- pyridines, formula（Ⅲ）For 2- acetyl group -1H-4- pyridine carboxylic acids, formula（Ⅳ）For 1-（2- methyl）Oxa-
The bromo- 4- phenol of cyclohexyl -2, formula（Ⅴ）For 1- ［ 1-（2- methyl）Oxacyclohexyl -2- bromines ］ base -2- acetyl group -4- pyridine first
Acid.
Embodiment 4
Following formula（Ⅰ）The synthesis of compound.
Structural formula：
。
Synthetic route is：
。
Synthesis step is：
（1）Modus ponens（Ⅱ）Compound 67g (0.7mol) holds in 300ml benzene, stirring, adds in 6 ether of dicyclohexyl 18- crown-s（DC-
18-C-6）25g（0.07mol）With finely ground potassium permanganate 300g (1.9mol), 1h quickly is stirred to react at 25 DEG C, is filtered out solid
Body extracts isonicotinic acid with 5% sodium hydrate aqueous solution, filters off manganese dioxide, then with ether wash water solution to remove crown ether, water
It is 3.6 that liquid acidification, which adjusts pH, is heated to boiling, obtains clear crystal formula（Ⅲ）Compound 75g, yield 90%；
（2）Modus ponens（Ⅲ）Compound 75g（0.68mol）And formula（Ⅳ）Compound 59g（0.68mol）It is dissolved in benzene, stirs, add in
Copper nitrate is heated, and generation basic salt can be hydrolyzed after heating, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into oxygen
Change copper, nitrogen dioxide and oxygen, then the gas of generation imported in water, 10min is stirred to react, is washed with deionized water three times,
It is freeze-dried after Magneto separate, formula is made（Ⅴ）Compound 83g, yield 89%；
（3）Modus ponens（Ⅴ）Compound 83g（0.66mol）It is dissolved in 200ml dichloromethane with hydrazine hydrate 31g (0.66mol), ice bath
To 0 DEG C, dicyclohexylcarbodiimide 135g is added in（0.66mol）, after 30min, ice bath is removed, is being placed at room temperature for 2-4h, filtered off
Dicyclohexylurea (DCU) is washed with a small amount of solvent, and filtrate washes neutrality with dilute hydrochloric acid and dilute sodium hydroxide, is dried and evaporated, and excess is through ethyl alcohol
Recrystallization, obtains white crystalline body formula（Ⅰ）Compound 75.9g, yield 85%.
Wherein, formula（Ⅰ）For 1- ［ 1-（2- methyl）Oxacyclohexyl -2- bromines ］ base -2- propiono -4- hydrazides yl pyridines, formula
（Ⅱ）For 2- propiono -1H- pyridines, formula（Ⅲ）For 2- propiono -1H-4- pyridine carboxylic acids, formula（Ⅳ）For 1-（2- methyl）Oxa-
The bromo- 4- phenol of cyclohexyl -2, formula（Ⅴ）For 1- ［ 1-（2- methyl）Oxacyclohexyl -2- bromines ］ base -2- propiono -4- pyridine first
Acid.
Experimental example 1
This experimental example is measured the Tuberculosis in vitro nuclear activity of pyridine derivatives obtained by embodiment 1-4.
1st, experiment reagent
Rifampin (RIFAMPICIN, Rifampin), lavo-ofloxacin (levofloxacin, LOFX) are purchased from Chinese drug biology
Product examines and determine institute；Aseptically, 4 kinds of compounds obtained by embodiment 1-4 are made into a concentration of 4mg/ml respectively with DMSO
Solution, fully dissolving after with 0.22 μm of membrane filtration, putting -20 DEG C of preservations, (in use, avoiding the influence of DMSO, DMSO is being trained
Concentration in nutrient solution<0.5%), as testing compound solution；7H9 liquid mediums are purchased from Difco companies of the U.S..
2nd, bacterial strain
Mycobacterium tuberculosis reference culture H37Va (ATCC25177) and H37Rv (ATCC27294), 2 plants of drug resistance knots being clinically separated
(certain disease prevention and control center provides, and wherein H7 is more to ethambutol, streptomysin, Ofloxacin by core mycobacterium H7, H10
Weight antibody-resistant bacterium, H10 are to rifampin-resistance bacterial strain).
3rd, experimental method
（1）The preparation of bacterial suspension：The tubercle bacillus for cultivating 2~3 weeks cell ages oese is taken out in access sterile vial, is mixed
It is even into emulsus, normal saline dilution, by, than turbid, bacterium solution to be configured to the bacterium of 1mg/ml with NO.1 Maxwells standard opacity tube
Liquid, then with normal saline dilution to 1 × 105CFU is spare.
（2）On 48 well culture plates, the testing compound solution for adding in 200 μ L suitable concentrations (is trained with sterile 7H9 liquid
Nutrient solution dilutes testing compound solution to 100 μ g/ml), then testing compound solution is diluted again, and sets as needed
Whether there is medicine control wells.The bacterium solution diluted is added in all detection holes and without in medicine control wells, by these plates as perseverance
In warm incubator, per plate at 37 DEG C, 5%CO2Under the conditions of cultivate 21 days.40 × micro- sem observation, visually have no bacterial growth
Lowest concentration of drug is the minimum inhibitory concentration (MIC) of the medicine.Meanwhile using rifampin, lavo-ofloxacin as positive control, with
DMSO and the culture bacterium solution of any compound is not added as negative control.Experimental result see the table below shown.
The Tuberculosis in vitro nuclear activity (MIC) of each test sample is as follows in table：
As can be seen from the above table, the pyridine derivatives obtained by embodiment 1-4 are to Mycobacterium tuberculosis type strain H37Ra、
H37Rv has good inhibitory activity in vitro, while also shows that preferable inhibition is lived to drug-resistant Mycobacterium tuberculosis H7, H10
Property.
Experimental example 2
This experimental example is measured the vitro cytotoxicity of pyridine derivatives obtained by embodiment 1-4.
1st, experiment reagent
Rifampin (RIFAMPICIN, Rifampin), lavo-ofloxacin (ofloxacin, LOFX) are purchased from Chinese drug biology system
Institute is determined in product examine；Aseptically, 4 kinds of compounds obtained by embodiment 1-4 are made into the solution of a concentration of 4mg/ml with DMSO,
- 20 DEG C of preservations are fully put with 0.22 μm of membrane filtration after dissolving.RPMI-1640 culture solutions, trypsase (TRGPSIN).
2nd, cell strain
VERO cells are purchased from Chinese Academy of Sciences's Shanghai cell bank.
3rd, experimental method (mtt assay)
By cell with 106Cells/ml is laid in 48 porocyte culture plates, 37 DEG C, 5%CO2Cultivated in constant temperature incubator, for 24 hours after,
Add in various concentration drug culture solution, drug initial concentration be 10mmol/L, and be diluted to successively final concentration of 10 μm of ol/L,
5 μm of ol/L, 2.5 μm of ol/L, 1.25 μm of ol/L, 0.625 μm of ol/L, each concentration are repeated 3 times；Meanwhile with rifampin, left oxygen fluorine
Sha Xing is property control；Add in 20 μ L MTT after the parallel addition of DMSO groups and the DMSO of drug same volume, 48h per hole, 37 DEG C after
Continuous to be incubated 4h, buckle method takes out culture solution, and the DMSO of 200 μ L is added in per hole, and oscillation 10min is until blue crystal is completely molten
Solution detects OD with full-automatic microplate reader immediately570Value.Cell proliferation inhibition rate sees below formula by formula calculating：
；
Then linear regression is made to the inhibiting rate under each concentration with each drug concentration logarithm, from gained docs-effect equation meter
Calculate half-inhibition concentration (IC of each test compound to experimental cell50).Experimental result see the table below shown.
Test compound is in vitro to the measure (IC of VERO cytotoxicities in table50, 10-6Mol/L it is) as follows：
As can be seen from the above table, pyridine derivatives obtained by embodiment 1-4 show good anti-tubercular in vitro, and
And without apparent cytotoxicity, available for developing antituberculotic efficiently, less toxic.
Conclusion
The present invention be used as a kind of novel pyridine derivatives anti-tubercular drug, medicines structure and effect uniqueness, simplicity safe to use,
Pyridine derivatives adverse reaction of the present invention is few, therefore clinical practice is more extensive.
Based on the embodiments of the present invention, those of ordinary skill in the art are obtained without making creative work
The every other embodiment obtained, shall fall within the protection scope of the present invention.
Claims (7)
1. a kind of pyridine derivatives, it is characterised in that：The chemical structural formula of the pyridine derivatives is formula（Ⅰ）It is shown,
,
Wherein R1ForOr,
Wherein R2ForOr,
Wherein X is、Or。
2. a kind of pyridine derivatives according to claim 1, it is characterised in that：The formula（Ⅰ）Synthetic route be：
。
3. a kind of pyridine derivatives according to claim 1, it is characterised in that：The formula（Ⅰ）Synthesis step be：
（1）Modus ponens（Ⅱ）Compound is dissolved in benzene, stirring, 6 ether of dicyclohexyl 18- crown-s and finely ground potassium permanganate is added in, 25
DEG C 1h quickly is stirred to react, filters out solid, extracted isonicotinic acid with 5% sodium hydrate aqueous solution, filter off manganese dioxide, then use ether
For wash water solution to remove crown ether, it is 3.6 that aqueous acidification, which adjusts pH, is heated to boiling, obtains formula（Ⅲ）Compound；
（2）Modus ponens（Ⅲ）Compound and formula（Ⅳ）Compound is dissolved in benzene, stirring, is added in copper nitrate and is heated, meeting after heating
Hydrolysis generation basic salt, containing 2.5 crystallizations water, is further heated to 170 DEG C and is decomposed into copper oxide, nitrogen dioxide and oxygen, so
The gas of generation is imported in water afterwards, 10min is stirred to react, is washed with deionized water three times, is freeze-dried after Magneto separate, formula is made
（Ⅴ）Compound；
（3）Modus ponens（Ⅴ）Compound and hydrazine hydrate are dissolved in dichloromethane, and ice bath adds in dicyclohexylcarbodiimide to 0 DEG C,
After 30min, ice bath is removed, is being placed at room temperature for 2-4h, dicyclohexylurea (DCU) is filtered off, is washed with a small amount of solvent, filtrate dilute hydrochloric acid and dilute
Caustic washing is dried and evaporated, excess obtains formula through ethyl alcohol recrystallization to neutrality（Ⅰ）Compound.
4. a kind of pyridine derivatives according to claim 1, it is characterised in that：The formula（Ⅰ）In antituberculotic
Application.
5. a kind of antitubercular pharmaceutical composition, it is characterised in that：Including formula described in claim 1（Ⅰ）With it is pharmaceutically acceptable
Carrier.
6. a kind of antitubercular pharmaceutical composition according to claim 5, it is characterised in that：The formula（Ⅰ）As unique living
Property ingredient.
7. a kind of antitubercular pharmaceutical composition according to claim 5, it is characterised in that：The pharmaceutically acceptable load
Body is further included in adhesive, bulking agent, moisturizer, retarding solvent, disintegrant, absorbsion accelerator, lubricant, wetting agent or adsorbent
It is one or more.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810345593.3A CN108218843A (en) | 2018-04-18 | 2018-04-18 | A kind of pyridine derivatives and its application in antituberculotic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810345593.3A CN108218843A (en) | 2018-04-18 | 2018-04-18 | A kind of pyridine derivatives and its application in antituberculotic |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108218843A true CN108218843A (en) | 2018-06-29 |
Family
ID=62658051
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810345593.3A Withdrawn CN108218843A (en) | 2018-04-18 | 2018-04-18 | A kind of pyridine derivatives and its application in antituberculotic |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108218843A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103889223A (en) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | Antibacterial compounds and methods for use |
| CN104402902A (en) * | 2014-12-15 | 2015-03-11 | 河南大学 | Chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative as well as preparation method and application thereof |
-
2018
- 2018-04-18 CN CN201810345593.3A patent/CN108218843A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103889223A (en) * | 2011-08-29 | 2014-06-25 | Ptc医疗公司 | Antibacterial compounds and methods for use |
| CN104402902A (en) * | 2014-12-15 | 2015-03-11 | 河南大学 | Chirality 7-(piperazine-substituted pyrazol aldehyde condensation isoniazide) fluoroquinolone carboxylic acid derivative as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113181339B (en) | Medicinal application of aldehyde compound | |
| CN108349968A (en) | Antibacterial therapy agent and prophylactic | |
| CN104136436B (en) | Compound of anti-fibrosis and application thereof | |
| CN103269587A (en) | New forms of rifaximin and uses thereof | |
| US3849561A (en) | Anti-peptic ulcer substance from corydalis tubers | |
| CN106916177A (en) | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes | |
| WO2021151387A1 (en) | Pharmaceutical use of ketoamide-based compound | |
| CN109021058A (en) | With active ocotillol type sapogenin derivative of tumor drug resistance reversal and its preparation method and application | |
| CN106588911A (en) | Novel thiazole compound XQH-3-6 resisting streptococcus mutans and application of compound | |
| CN108358917A (en) | Imidazo [1,2-a] pyridine -3- amides compounds containing alkaline condensed ring segment and preparation method thereof | |
| CN105622596B (en) | Benzothiazine -4- ketone compounds and preparation method thereof containing alcoxyl imido grpup azacyclo- segment | |
| CN109503510A (en) | A kind of thiazole compound and preparation method thereof of preventing decayed tooth antibacterial | |
| CN105820130B (en) | Triazole n Propanoic acid class URAT1 inhibitor, preparation method and its purposes in hyperuricemia and gout treatment | |
| CN106632133B (en) | Thiazole derivative and the preparation method and application thereof | |
| CN108218843A (en) | A kind of pyridine derivatives and its application in antituberculotic | |
| Flippin et al. | Sulfapyridine and sulfathiazole therapy in pneumococcic pneumonia | |
| CN104177373A (en) | Anti-tuberculosis compound IMB-CC223 | |
| CN110590779B (en) | 3, 10 di-p-chlorophenyl 6, 12 diazatetracubane compound, and synthetic method, application and pharmaceutical composition thereof | |
| CN102786536A (en) | Sulbactam amoxicillin amide complex for treatment of acute bacterial infection of pig and synthesis method | |
| JPS62164626A (en) | Hypotensive and diuretic | |
| CN106146612B (en) | A kind of glyoxalase I irreversible inhibitor and its preparation method and application | |
| CN108218894A (en) | A kind of cefoxitin sodium crystal-form compound | |
| CN108047253A (en) | A kind of Ceftriaxone Sodium crystal-form compound | |
| JPS6122090A (en) | Amino-substituted phenothiazine type rifamycin and its use of drug | |
| CN118290502A (en) | Erigeron breviscapus-huperzine A co-amorphous substance with synergistic antioxidation effect and preparation method 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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20180629 |