CN109608457A - A kind of drug and preparation method thereof for treating pneumonia - Google Patents
A kind of drug and preparation method thereof for treating pneumonia Download PDFInfo
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- CN109608457A CN109608457A CN201910054344.3A CN201910054344A CN109608457A CN 109608457 A CN109608457 A CN 109608457A CN 201910054344 A CN201910054344 A CN 201910054344A CN 109608457 A CN109608457 A CN 109608457A
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- pneumonia
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- quinoline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The present invention relates to a kind of tetrazolo quinolines that can be used for treating pneumonia, it has stronger antibacterial activity for all kinds of bacteriums such as streptococcus pneumonia, staphylococcus aureus etc., has the antibacterial activity for being substantially better than known drug especially for Antimicrobial Streptococcus Pneumoniae and resistant Staphylococcus aureus.In addition, preparation method route of the present invention is short, step is few, total yield of products is high, is suitable for industrialization large-scale production.
Description
Technical field
The present invention relates to field of medicaments, specifically, further relating to the medicine the present invention relates to a kind of drug for treating pneumonia
The preparation method of object.
Background technique
Pneumonia refers to terminal air flue, and the pulmonary parenchyma infection of alveolar and interstitial tissue of lung, clinical cardinal symptom is fever, cough
It coughs, expectoration, blood-stained sputum, can be with pectoralgia or expiratory dyspnea etc., and have the abnormal change of chest x-ray.Patient with severe symptoms, which can be involved, to follow
Ring, digestion and nervous system and there are corresponding clinical symptoms.Pneumonia can be by disease microorganisms such as bacterium, virus, mycoplasma, clothing
Substance, fungi etc., chemical factors, immunologic mjury, allergy and drug-induced, one of the most common pneumonia are bacterial pneumonias.
Bacterium, mycoplasma, Chlamydia, fungal infection the treatment of pneumonia need using corresponding antibacterials, use now
In treatment pneumonia drug include: Linezolid, penicillin, vancomycin, erythromycin, roxithromycin, azithromycin, A Moxi
Woods, oxacillin, Sulbactam, Cefepime etc. should generally continue to body temperature is normal, respiratory symptom part improves, whole body disease
3~5 days after shape is unobvious, Eaton agent pneumonia at least uses antibacterials 10~14 days, and staphylococcal pneumonia should extend to 3~4
Week is discontinued.
However, a large amount of antibiotic use so that there are a large amount of drug-fast bacterias, such as Antimicrobial Streptococcus Pneumoniae, methicillin-resistant
Staphylococcus aureus etc., this becomes in Present clinical anti-infective therapy stubborn problem the most.In face of multidrug resistance cingula
The challenge come, it is necessary to develop more antibacterials.
Tetrazolo quinolines have various uses, such as antitumor, antidepression, anticonvulsion, treatment diabetes etc.,
Also there are the certain specific tetrazolo quinolines of document report that there is anti-inflammatory analgesic action.The application is studying such chemical combination
During object, it was found that some tetrazolo quinolines have antibacterial action, especially for Antimicrobial Streptococcus Pneumoniae,
The antibacterial activity of the staphylococcus aureus of methicillin-resistant etc. is hopeful to be developed into novel pneumonia therapeutic agent, as
The supplement of existing pneumonia therapeutic agent.
Summary of the invention
The present invention in view of the problems of the existing technology, provide it is a kind of for treating the drug of pneumonia, for all kinds of
Bacterium such as streptococcus pneumonia, staphylococcus aureus etc. has stronger antibacterial activity, especially for Antimicrobial Streptococcus Pneumoniae
There is the antibacterial activity for being substantially better than known drug with resistant Staphylococcus aureus, can be used in the treatment of pneumonia.
Therefore, formula (I) compound that the present invention provides a kind of for treating pneumonia:
Wherein, R1Indicate halogen, preferably fluorine, chlorine or bromine.
In one embodiment, the R1Indicate 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br or 3-Br.
In a preferred embodiment, the R1Indicate 4-F or 4-Cl.
Formula (I) compound of the present invention includes its pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is formula
(I) salt that compound and inorganic acid or organic acid are formed, described inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.,
The organic acids such as acetic acid, propionic acid, malonic acid, butyric acid, lactic acid, benzene sulfonic acid, methanesulfonic acid, maleic acid, p-methyl benzenesulfonic acid, amber
Acid, tartaric acid, citric acid, fumaric acid etc..
For the preparation method of formula (I) compound, the preparation method prior art discloses the compound includes following step
It is rapid:
The reaction route step is more, severe reaction conditions, and total recovery is low.In order to overcome the disadvantage of the prior art, this
Invention provides a kind of new preparation method of formula (I) compound, the described method comprises the following steps:
Wherein, step 1 in organic solvent, diphenyl phosphate azide, triphenylphosphine, diethyl azodiformate, ion
It is carried out in the presence of liquid；
Step 2 in organic solvent, carries out in the presence of N-bromosuccinimide；
Step 3 in organic solvent, palladium acetate, cesium carbonate, 2- dicyclohexyl phosphorus -2,4, the presence of 6- tri isopropyl biphenyl
Lower progress.
In one embodiment, ionic liquid described in step 1 is 1- butyl -3- methyl-imidazoles hexafluorophosphoric acid, 1- fourth
The mixed liquor of one or more of base -3- methyl-imidazoles tetrafluoro boric acid, 1,2- dimethyl -4- fluorine pyrazoles tetrafluoroborate.
In one embodiment, 3,4- dihydroquinoline -2 (1H) -one, diphenyl phosphate azide, triphenyl in step 1
Phosphine, diethyl azodiformate molar ratio be 1:2~6:2~6:2~6；(1H) -one of 3,4- dihydroquinoline -2 and ionic liquid
Mass volume ratio be 1~6g/mL.
In one embodiment, 4,5- dihydro tetrazolo [1,5-a] quinoline in step 2, N-bromosuccinimide
Molar ratio is 1:1.05~1.2.
In one embodiment, bromo- 4,5- dihydro tetrazolo [1, the 5-a] quinoline of 7- in step 3, halogenophenyl methanol,
Palladium acetate, cesium carbonate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl molar ratio be 1:1.05~1.2:0.01~0.2:
2~4:0.05~0.15.
In another aspect of this invention, a kind of pharmaceutical composition is provided, it includes formula (I) compound of the present invention or its medicines
Acceptable salt and pharmaceutically acceptable excipient on.
It can be configured to take orally in conjunction with pharmaceutically acceptable excipient by formula (I) compound, non-gastrointestinal application
Or solid, semisolid or the liquid pharmaceutical formulation of local application.It can be solid for can be used for the pharmaceutically acceptable excipient of the purpose
State or liquid.Pulvis, tablet, dispersible pulvis, capsule, cachet, suppository and the solid or semisolid compared with cream form can be prepared
Pharmaceutical preparation, in this case usually using solid-state carrier.Workable solid-state carrier be preferably selected from diluent, flavoring agent,
One of solubilizer, lubricant, suspending agent, adhesive, swelling agent etc. or many kinds of substance, or can be encapsulating substance.In powdery
In preparation, in the carrier containing 5% or 10% to 70% micronised active ingredient.The specific example packet of suitable solid-state carrier
Include magnesium carbonate, magnesium stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, yellow thermophilic glue, methylcellulose, carboxymethyl
Sodium cellulosate, low boiling point wax, cocoa butter etc..Since they are easy to be administered, tablet, pulvis, cachet and Capsules representative are most advantageous
Oral solid formulation.
Liquid preparation includes solution, suspension and lotion.For example, the injectable formulation of parenteral administration can be water or water-
Propylene glycol solution form, adjusts its isotonic degree, and pH etc. makes the physiological condition suitable for living body.Liquid preparation may also be fabricated which in poly- second two
Solution form in alcohol solution.Colorant appropriate, flavoring agent, steady can be added by the way that active constituent to be dissolved in water
Agent and thickener are determined, to prepare oral aqueous solution.It is for example natural or synthetic the active constituent of micronized can be dispersed in stickum
Preparation is suitable for oral aqueous suspensions in glue, methylcellulose, sodium carboxymethylcellulose and other known suspending agent.
It is uniform for ease of administration and dosage, said medicine preparation is configured to dosage unit form and is particularly advantageous.
The dosage unit form of preparation refers to the physical separation unit for being suitable for single dose, and each unit, which contains, generates desired control
The active constituent for the predetermined amount of therapeutic effect calculated.This dosage unit form can be packaged form, such as tablet, capsule or dress
Pulvis in tubule or bottle, or ointment, gel or creme in pipe or bottle.
Although the amount of contained active constituent can change in dosage unit form, generally according to selected active constituent
Effect is adjusted within the scope of 1-100mg.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Generally, start treatment
Amount is lower than the optimal dose of active constituent, dosage is then gradually increased, until reaching optimum therapeuticing effect.It rises for convenience
See, total daily dose can be divided into several parts, be administered in several times.
In another aspect of this invention, formula (I) compound or its pharmaceutically acceptable salt are provided in medicine preparation
Application, the drug is for treating pneumonia.Wherein, the pneumonia preferred bacterium pneumonia, more preferably by streptococcus pneumonia or
Bacterial pneumonia caused by staphylococcus aureus, is most preferably caused by Antimicrobial Streptococcus Pneumoniae or resistant Staphylococcus aureus
Bacterial pneumonia.
Beneficial effect
The beneficial effects of the present invention are embodied in:
1. having found tetrazolo quinolines in the excellent effect of antibiosis.Pharmacological activity test demonstrates this hair
Bright compound has stronger antibacterial activity for all kinds of bacteriums such as streptococcus pneumonia, staphylococcus aureus etc., especially pair
There is the antibacterial activity for being substantially better than known drug in Antimicrobial Streptococcus Pneumoniae and resistant Staphylococcus aureus.Therefore, this hair
The bright one kind that provides is suitable for various bacterial pneumonias are treated, particularly suitable for treating by Antimicrobial Streptococcus Pneumoniae and drug resistance
The newtype drug of bacterial pneumonia caused by staphylococcus aureus.
2. preparation method route of the present invention is short, step is few, total yield of products is high, is suitable for industrializing extensive life
It produces.In particular, in step 1, the use of ionic liquid substantially increases the yield of reaction.
Specific embodiment
The present invention is described below in more detail to facilitate the understanding of the present invention.
It should be understood that the term or word used in the specification and in the claims is not construed as having
The meaning limited in dictionary, and be interpreted as having on the basis of following principle and its meaning one in the context of the present invention
The meaning of cause: the concept of term can suitably limit best illustration of the invention by inventor.
Preparation example 1:7- (4- fluorine benzyloxy) -4,5- dihydro tetrazolium [1,5-a] quinoline (compound 1)
Step 1: by 3,4- dihydroquinoline -2 (1H) -one (5.0mmol) and triphenylphosphine (20.0mmol), azoformic acid
Diethylester (20.0mmol) is added in tetrahydrofuran (30mL), adds 1- butyl -3- methyl-imidazoles hexafluorophosphoric acid (2mL),
Then diphenyl phosphate azide (20.0mmol) is added, the mixture is stirred at 40 DEG C 15 hours, TLC monitoring reaction carries out.
Upon reaction completion, reaction solution is cooled to room temperature and water (50mL) is used to dilute, then extracted and closed with ethyl acetate (80mL × 3)
And extract liquor, extract liquor are washed with saturated sodium bicarbonate aqueous solution, organic layer is dried and concentrated with anhydrous sodium sulfate.Residue is used
Silicagel column purification by flash chromatography, uses petroleum ether: methylene chloride (v:v=10:1) obtains 4,5- dihydro four as eluting solvent
Azoles simultaneously [1,5-a] quinoline 0.73g, yield 85.0%.MS m/z:173 [M+H]+
Step 2: 4,5- dihydro tetrazolo [1,5-a] quinoline (3.0mmol) being added in acetonitrile (30mL), at 0 DEG C
NBS (3.5mmol) is added portionwise.The mixture is stirred 2 hours at 0 DEG C, water (30ml) then is added, and acquired solution is used
Ethyl acetate (50mL × 3) extraction, organic layer are dried and concentrated with anhydrous sodium sulfate, and residue recrystallize with dichloromethane obtains
To bromo- 4,5- dihydro tetrazolo [1,5-a] the quinoline 0.69g of 7-, yield 92.1%.MS m/z:251 [M+H]+
Step 3: by bromo- 4,5- dihydro tetrazolo [1,5-a] quinoline (2.0mmol) of 7-, (4- fluoro-phenyl)-methanol
(2.2mmol), palladium acetate (0.2mmol), cesium carbonate (4.0mmol) and 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl
(0.4mmol) is added in toluene (30mL), is stirred 5 minutes under nitrogen protection.Then 85 DEG C are heated under air-proof condition
And it reacts 5 hours.Then filtering is concentrated under reduced pressure, residue silicagel column purification by flash chromatography uses hexamethylene: ethyl acetate
(v:v=8:1) it is used as eluting solvent, ethyl alcohol recrystallization is used again after collecting main flow point evaporated under reduced pressure, obtains target product
0.48g。
Fusing point: 137-138 DEG C；
MS m/z:297 [M+H]+
Elemental analysis: C16H13FN4O theoretical value C, 64.86；H,4.42；F,6.41；N,18.91；O,5.40；Actual value: C,
64.77；H,4.57；F,6.64；N,18.86；O,5.16.
1H NMR (400MHz, CDCl3) δ 7.95 (d, 1H, J=7.5Hz), 7.40-7.51 (m, 4H), 6.90-6.97 (m,
2H), 5.08 (s, 2H), 3.00-3.24 (m, 4H).
The above results and reported in the literature consistent, show that product is 7- (4- fluorine benzyloxy) -4,5- dihydro tetrazolium [1,5-a]
Quinoline, yield 81.6%.
Preparation example 2:7- (4- benzyl chloride oxygroup) -4,5- dihydro tetrazolium [1,5-a] quinoline (compound 2)
Step 1 and step 2 are the same as preparation example 1.
Step 3: by bromo- 4,5- dihydro tetrazolo [1,5-a] quinoline (2.0mmol) of 7-, (the chloro- phenyl of 4-)-methanol
(2.2mmol), palladium acetate (0.2mmol), cesium carbonate (4.0mmol) and 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl
(0.4mmol) is added in toluene (30mL), is stirred 5 minutes under nitrogen protection.Then 85 DEG C are heated under air-proof condition
And it reacts 5 hours.Then filtering is concentrated under reduced pressure, residue silicagel column purification by flash chromatography uses hexamethylene: ethyl acetate
(v:v=7:1) it is used as eluting solvent, ethyl alcohol recrystallization is used again after collecting main flow point evaporated under reduced pressure, obtains target product
0.52g。
Fusing point: 188-190 DEG C；
MS m/z:313 [M+H]+
Elemental analysis: C16H13ClN4O theoretical value C, 61.45；H,4.19；Cl,11.33；N,17.91；O,5.12；It is practical
Value: C, 61.32；H,4.40；Cl,11.18；N,17.77；O,5.33.
1H NMR (400MHz, CDCl3) δ 7.90 (d, 1H, J=7.5Hz), 7.43-7.54 (m, 4H), 6.93-6.99 (m,
2H), 5.08 (s, 2H), 3.00-3.24 (m, 4H).
The above results and reported in the literature consistent, show that product is 7- (4- benzyl chloride oxygroup) -4,5- dihydro tetrazolium [1,5-a]
Quinoline, yield 83.5%.
The experiment of pharmacodynamics test-target compound antibacterial activity in vitro
Test method: using Double broth dilution method (Antimicrobial Agents and Chemotherapy, 40,
The compounds of this invention and positive control medicine Linezolid and azithromycin 1996.720-726) are measured to the minimum of tried bacterial strain
Mlc (MIC).Using multiple spot inoculation instrument by microbionation in the agar plate surface of the concentration containing different pharmaceutical, every inoculation
Bacterium amount is about 106CFU/mL, 35 ± 1 DEG C are incubated for observation in 18 hours as a result, with contained drug in the plating medium of asepsis growth
Minimum concentration is minimum inhibitory concentration (MIC value) of the drug to the bacterium.
The DMSO that 2mL is first added in test-compound sufficiently dissolves, and adds sterile distilled water and is diluted；Add each
Entering that 20mL heating and melting is added in the culture dish of medical fluid is liquid MH culture medium, keeps the drug in culture dish final concentration of
128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.0625、0.031μg/mL。
Test strain used includes: sensitive streptococcus pneumonia (S.pneumoniae ATCC49619), ermB type drug resistance lung
Scorching streptococcus (S.pneumoniae B1), mefA type Antimicrobial Streptococcus Pneumoniae (S.pneumoniae A22072), ermB+mefA
It is type Antimicrobial Streptococcus Pneumoniae (S.pneumoniae AB11), sensitive staphylococcus aureus (S.aureus ATCC25923), resistance to
Methicillin staphylococcus aureus (S.aureus ATCC29213).
In acquired results table 1 listed below, the unit of numerical value is μ g/mL in table.
Table 1:
| Strain | Compound 1 | Compound 2 | Linezolid | Azithromycin |
| S.pneumoniae ATCC49619 | 0.0625 | 0.031 | 0.031 | 0.031 |
| S.pneumoniae B1 | 16 | 4 | 128 | 128 |
| S.pneumoniae A22072 | 4 | 2 | 16 | 4 |
| S.pneumoniae AB11 | 1 | 8 | 128 | >128 |
| S.aureus ATCC25923 | 0.25 | 0.125 | 0.5 | 0.25 |
| S.aureus ATCC29213 | 1 | 0.5 | 8 | 2 |
Test result shows: the compounds of this invention has all kinds of bacteriums such as streptococcus pneumonia, staphylococcus aureus etc.
There is stronger antibacterial activity, has known to being substantially better than especially for Antimicrobial Streptococcus Pneumoniae and resistant Staphylococcus aureus
The antibacterial activity of drug such as Linezolid, azithromycin.Therefore, the compounds of this invention is suitable for the various bacillary lungs for the treatment of
Inflammation, particularly suitable for treating the bacterial pneumonia as caused by Antimicrobial Streptococcus Pneumoniae or resistant Staphylococcus aureus.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
Member, under the premise of not departing from the method for the present invention, can also make several improvement and supplement, these are improved and supplement also should be regarded as
Protection scope of the present invention.
Claims (9)
1. a kind of formula (I) compound or its pharmaceutically acceptable salt for treating pneumonia:
Wherein, R1Indicate halogen, preferably fluorine, chlorine or bromine.
2. compound according to claim 1, which is characterized in that the R1Indicate 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-
Cl, 2-Br or 3-Br.
3. compound according to claim 1, which is characterized in that the R1Indicate 4-F or 4-Cl.
4. a kind of preparation method of formula according to claim 1 (I) compound, the described method comprises the following steps:
Wherein, step 1 in organic solvent, diphenyl phosphate azide, triphenylphosphine, diethyl azodiformate, ionic liquid
In the presence of carry out；
Step 2 in organic solvent, carries out in the presence of N-bromosuccinimide；
Step 3 in organic solvent, palladium acetate, cesium carbonate, 2- dicyclohexyl phosphorus -2,4, in the presence of 6- tri isopropyl biphenyl into
Row.
5. the preparation method according to claim 4, which is characterized in that ionic liquid described in step 1 is 1- butyl -3- first
Base-imidazoles hexafluorophosphoric acid, 1- butyl -3- methyl-imidazoles tetrafluoro boric acid, in 1,2- dimethyl -4- fluorine pyrazoles tetrafluoroborate
One or more of mixed liquors.
6. preparation method according to claim 4 or 5, which is characterized in that 3,4- dihydroquinoline -2 (1H) -one in step 1,
Diphenyl phosphate azide, triphenylphosphine, diethyl azodiformate molar ratio be 1:2~6:2~6:2~6,3,4- dihydro quinoline
The mass volume ratio of (1H) -one of quinoline -2 and ionic liquid is 1~6g/mL；4,5- dihydro tetrazolo [1,5-a] quinoline in step 2,
The molar ratio of N-bromosuccinimide is 1:1.05~1.2；Bromo- 4,5- dihydro tetrazolo [1,5-a] quinoline of 7- in step 3,
Halogenophenyl methanol, palladium acetate, cesium carbonate, 2- dicyclohexyl phosphorus -2,4,6- tri isopropyl biphenyl molar ratio be 1:1.05~
1.2:0.01~0.2:2~4:0.05~0.15.
7. a kind of pharmaceutical composition, it includes formula according to claim 1 (I) compound or its is pharmaceutically acceptable
Salt and pharmaceutically acceptable excipient.
8. the application of formula (I) compound according to claim 1 or its pharmaceutically acceptable salt in medicine preparation, institute
Drug is stated for treating pneumonia.
9. application according to claim 8, which is characterized in that the pneumonia is bacterial pneumonia, preferably by pneumonia streptococcus
Bacterial pneumonia caused by bacterium or staphylococcus aureus, more preferably by Antimicrobial Streptococcus Pneumoniae or resistant Staphylococcus aureus
Caused bacterial pneumonia.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014045305A1 (en) * | 2012-09-21 | 2014-03-27 | Advinus Therapeutics Limited | Substituted fused tricyclic compounds, compositions and medicinal applications thereof |
| WO2015103756A1 (en) * | 2014-01-09 | 2015-07-16 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
-
2019
- 2019-01-21 CN CN201910054344.3A patent/CN109608457B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014045305A1 (en) * | 2012-09-21 | 2014-03-27 | Advinus Therapeutics Limited | Substituted fused tricyclic compounds, compositions and medicinal applications thereof |
| WO2015103756A1 (en) * | 2014-01-09 | 2015-07-16 | Merck Sharp & Dohme Corp. | Inhibitors of the renal outer medullary potassium channel |
Non-Patent Citations (3)
| Title |
|---|
| GRETCHEN M. SCHROEDER ET AL.: "Improved conditions for converting sterically hindered amides to 1,5-disubstituted tetrazoles", 《TETRAHEDRON LETTERS》 * |
| XIAN-YU SUN ET AL.: "Synthesis and study of the antidepressant activity of novel 4,5-dihydro-7-alkoxy(phenoxy)-tetrazolo[1,5-a]quinoline derivatives", 《MED CHEM RES》 * |
| 代玲玲等: "四唑类化合物的合成及应用研究新进展", 《有机化学》 * |
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