CN102558183B - Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound - Google Patents
Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound Download PDFInfo
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- CN102558183B CN102558183B CN201010579341.0A CN201010579341A CN102558183B CN 102558183 B CN102558183 B CN 102558183B CN 201010579341 A CN201010579341 A CN 201010579341A CN 102558183 B CN102558183 B CN 102558183B
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- pyrrolidine
- carboxylic acid
- oxo
- pyrazolyl
- acid compound
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Abstract
The invention discloses pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound with the structural formula (I). The experiments show that the gram-positive bacteria resisting effect of the pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound is equal or superior to that of moxifloxacin and ciprofloxacin, and particularly the clinical-drug and pan-drug resistant bacillus activity resisting of the pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound is quite strong.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, be specifically related to a kind of pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound and its production and use.
Background technology
The main trend of current Comprecin research is:
The breakthrough of fundamental research: the fundamental research of relevant quinolones will further be deepened.For example, all may there be important breakthrough structure activity relationship, mechanism of action, resistance mechanism, drug interaction, cytotoxicity and the new aspects such as screening model.And along with going deep into of fundamental research, will promote the development process of this class medicine.
Anti-microbial property further perfect: various countries are the high reactivities that had both retained anti-Gram-negative bacteria at its common feature of Novel Quinolone medicine grinding at present, obviously strengthened again resisting gram-positive bacteria active, and anerobe, mycoplasma, chlamydozoan have also been had certain effect.And along with going deep into that people are familiar with quinolones mechanism of action, will there is the compound higher to some specified germ activity.Further going deep into of drug drug interaction research, it will be more and more extensive making this class medicine and other drug drug combination treat some intractable infection.As Sitafloxacin itself does not have anti-mycotic activity, but it and amphotericin B, fluconazole or rice bran azoles etc. have obvious synergy.
Overcome resistance research: in recent years illustrate Comprecin resistance mechanism and mainly contain 3 points: (1) DNA gyrase subunit A or topoisomerase variation; (2) efflux body system strengthens; (3) outer membrane permeability declines.
Reduce phototoxicity, improve security: along with the appearance of the deep and new variety of studying, people have not only illustrated the structure activity relationship of this class medicine, also understand gradually the relation of its structure-untoward reaction, develop on this basis that anti-microbial property is better, the higher medicine of security.As 8 of quinolone female rings, introduce methoxyl groups or difluoro-methoxy (as Moxifloxacin, Gatifloxacin, Jia Nuosha magnitude) makes its phototoxicity be reduced to bottom line, improved security.
Widening of Application Areas: the oriented antiviral trend of extending with anti-tumor aspect of the research and development of quinolones in recent years.
The present invention be intended to design, prepare and find from above several aspects there is brand new and quinolones high-efficiency low-toxicity can property of medicine compound.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound is provided.
Another object of the present invention is to provide the preparation method of above-claimed cpd.
Another object of the present invention is to provide the purposes of above-claimed cpd aspect medicinal.
Object of the present invention can reach by following measures:
The fluoro-7-of compound 1-cyclopropyl base-6-shown in a kind of formula (I) (2-hydroxyethyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-methoxyl group-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid, it has following structure:
The preparation method of above-claimed cpd is: formula (II) compound is reacted to preparation formula (I) compound with formula (III) compound under alkaline condition, and its reaction scheme is as follows:
The temperature of reaction of its Chinese style (II) compound and formula (III) compound is 20～50 ℃, and reaction solvent is acetonitrile, and alkaline condition is triethylamine.
Formula (II) compound reacts preparation by 1-tertbutyloxycarbonyl-3-cyano group-4-pyrrolidone in ethanol at 20～30 ℃ with hydroxyethyl.
First boric acid and diacetyl oxide are heated to 100～120 ℃ of reactions, react and in backward reaction system, add 1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester, then at 100～120 ℃, react preparation formula (III) compound.
Compound of the present invention can be applicable to prepare antibiotic or antitubercular agent, experiment find this compound to the anti-microbial effect of trial gram positive organism basic and Moses, encircle third quite or more excellent, and to tubercule bacillus, particularly the general resistance bacillus of clinical drug-resistant has great activity.
Embodiment
The preparation of amino Pyrrolidine [3, the 4-c] pyrazole hydrochloride of embodiment 1,2-hydroxyethyl-3-(II)
Under nitrogen protection, the mixture of 1-tertbutyloxycarbonyl-3-cyano group-4-pyrrolidone (1.05g, 5.0mmol), 98% hydroxyethyl (0.42g, 5.5mmol) and ethanol (20ml) reacts 12h in stirring at room.React complete solvent evaporated, gained resistates is dissolved in ethyl acetate (20ml), uses saturated common salt water washing, anhydrous magnesium sulfate drying.Filter, the resistates after concentrating is dissolved in methyl alcohol (10ml), passes into dry HCl gas, and TLC follows the tracks of until react completely.The solid that filtration is separated out, vacuum-drying obtains off-white color solid 0.33g (yield 27.4%).
1H-NMR(400MHz，DMSO-d
6)δ
ppm：3.64-3.67(2H，m，pyrrolidine)，3.97-3.98(2H，m，pyrrolidine)，4.08(2H，br，N
CH 2 CH
2OH)，4.17(2H，m，NCH
2 CH 2 OH)，MS(ESI，m/z)：169(M+H)
+
Embodiment 2,1-cyclopropyl-6,7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4the preparation of-diethyl acid group boron (III)
The mixture of boric acid (1.50g, 24.2mmol) and diacetyl oxide (8mL, 80.0mmol) is heated to 110 ℃, stirring reaction 1.5h.Temperature of reaction is down to 50～60 ℃, adds 1-cyclopropyl-6,7-difluoro-8-methoxyl-1 in reaction system, 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (4.55g, 14.1mmol), then be warming up to 110 ℃, continue to stir, TLC follows the tracks of reaction process, and 6h reaction is finished.Be down to room temperature, in the frozen water (200mL) under the slow impouring of reaction solution is fully stirred, continue to filter after stirring 0.5h, filter cake water fully washs, then uses appropriate ethanol rinsing, dry, obtains white powder solid (5.21g, 90.1%).
1H NMR(500MHz，CDCl
3)δ
ppm：1.20-1.45(4H，m，2×cyclopropylCH
2)，2.03(6H，s，2×COCH
3)，4.40-4.42(1H，m，cyclopropylCH)，4.22(3H，s，OCH
3)，8.10(1H，d，J＝9.0Hz，C
5-H)，9.21(1H，s，C
2-H)
The preparation of embodiment 3, the fluoro-7-of 1-cyclopropyl-6-(2-hydroxyethyl-3-amino-pyrazol [3,4-c] Pyrrolidine base)-8-methoxyl group-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid (I)
Under nitrogen protection; the amino Pyrrolidine [3 of 2-hydroxyethyl-3-; 4-c] pyrazole hydrochloride (0.36g; 1.5mmol), after the mixture stirring at room 10min of acetonitrile (10mL) and triethylamine (1.0mL), add 1-cyclopropyl-6; 7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group boron (0.41g, 1.0mmol), 40 ℃ of reacting by heating after continuation stirring 1h, TLC follows the tracks of reaction process, and 36h reaction is complete.Evaporated under reduced pressure after the separation of decompression silicagel column, gained brown color solid is dissolved in 7% aqueous sodium hydroxide solution (10mL), at 40 ℃, stirs, and TLC follows the tracks of reaction process, and 30min reaction is complete.Be down to room temperature, with 5% hydrochloric acid, adjust pH=5～6, after stirring 0.5h, filter, dry, obtain off-white color solid (0.19g, 42.8%).
1H-NMR(400MHz，DMSO-d6)δppm：1.02-1.12(4H，m，2×cyclopropyl CH2)，3.58(3H，s，OCH3)，3.64-3.68(2H，m，pyrrolidine)，3.88-3.91(2H，m，pyrrolidine)，4.15-4.19(1H，m，cyclopropyl CH)，4.53-4.54(4H，m，NCH2CH2OH)，7.72(1H，d，J＝13.6Hz，C5-H)，8.68(1H，s，C2-H)，MS(ESI，m/z)：444(M+H)
+
Effect experiment
Antibiotic and the tuberculosis of the compounds of this invention is active is to realize by measuring its minimum inhibitory concentration (MIC, mg/L) to reference culture, clinical isolates strain.
Bacterium minimum inhibitory concentration is measured as follows: adopt plate doubling dilution and Denlay multi-point inoculator to carry out drug sensitive experiment, experimental bacteria increases bacterium with nutrient broth and angry heart immersion liquid; After medicine dissolution, with the doubling dilution of MH meat soup, become various desired concns, add respectively in right amount in plate, MH nutrient agar dissolves in rear quantitative injection pastille liquid plate and mixes, the final concentration of medicine is respectively 0.03,0.06,0.125......128 μ g/ml, in plate after culture medium solidifying with multi-point inoculator inoculation experiments bacterium (10
5cfu/ point), put 35 ℃ of constant temperature culture observations after 18 hours, in the plate of asepsis growth, the concentration of contained drug minimum is minimum inhibitory concentration (MIC).
Tubercule bacillus activity test method: instrument and reagent: BacT/Alert system, mycobacterium culturing bottle (MB).Trial drug preparation: Rifampin (RIF) solvent dehydrated alcohol, diluent distilled water, vazadrine (INH), Tibutol (EMB), Moxifloxacin, Ciprofloxacin (CIP) solvent, the equal distilled water of diluent; The ultimate density 0.12-128ug/ml of medicine in each culturing bottle.The preparation of former times of bacteria suspension: after the positive reaction of MB bottle, positive MB bottle concussion is broken up to bacterium (in 36 hours); Former times of bacteria suspension of the preparation of 1% former times of bacteria suspension: 0.1ml adds in 10mlMB bottle.Interpretation standard growth control has two kinds of modes, a kind of is direct growth control, as operation index, bacterial concentration is former times of bacteria suspension, another kind is 1% growth control, bacterial concentration is 1% former times of bacteria suspension, as interpretation Rifampin (RIF), and the index of vazadrine (INH), Tibutol (EMB), Moxifloxacin, Ciprofloxacin (CIP) result.
Result judgement:
1.GC bottle presents and positive within latter two days, include medicine bottle and be also positive, and represents that this medicine is invalid.
2.GC bottle presents the positive two days later, containing medicine bottle, is just positive (not generally being), represents this susceptibility sense.
Table 1 has been listed some representation compounds in the application's formula I compound antibacterial activity in vitro to various gram-positive microorganisms and negative bacterium, and compares with two Comprecin Moxifloxacins, Ciprofloxacins.
Table 1, MIC (ug/ml)
| Compound | Embodiment 3 | Moxifloxacin | Ciprofloxacin |
| Klebsiella Pneumoniae | 0.5 | 0.5 | 1.0 |
| Klebsiella Pneumoniae | 1.0 | 1.0 | 2.0 |
| Klebsiella Pneumoniae (ESBL+AMPC) | 4.0 | 8.0 | 64.0 |
| Klebsiella Pneumoniae (ESBL+AMPC) | 4.0 | 8.0 | 128 |
| Klebsiella Pneumoniae (ESBL+AMPC) | 4.0 | 8.0 | 64.0 |
| Escherichia coli | 0.5 | 0.5 | 0.5 |
| Escherichia coli | 0.5 | 0.5 | 0.5 |
| Escherichia coli (ESBL+AMPC) | 8.0 | 8.0 | 128.0 |
| Escherichia coli (ESBL+AMPC) | 8.0 | 8.0 | 128.0 |
| Escherichia coli (ESBL+AMPC) | 8.0 | 8.0 | 128.0 |
| Streptococcus aureus (MSSA) | 0.25 | 0.25 | 1.0 |
| Streptococcus aureus (MSSA) | 0.5 | 0.5 | 0.5 |
| Streptococcus aureus (MRSA) | 2.0 | 2.0 | 64.0 |
| Streptococcus aureus (MRSA) | 1.0 | 2.0 | 128.0 |
| Streptococcus aureus (MRSA) | 2.0 | 2.0 | 64.0 |
| ATCC29213 | 0.25 | 0.12 | 0.5 |
| ATCC35218 | 0.25 | 0.5 | 0.5 |
Table 2 embodiment 3 compounds and 4 kinds of antibacterials are to the MIC of mycobacterium tuberculosis (ug/ml)
| Antibacterials | H37Rv ATCC27294 | Tubercule bacillus (clinical strain MDR926) |
| Vazadrine | 0.12 | 64.0 |
| Rifampin | 2.0 | ＞256.0 |
| Tibutol | 1.0 | 128.0 |
| Moxifloxacin | 0.25 | 1.0 |
| Embodiment 3 | 0.12-0.25 | 0.5-1.0 |
H37Rv ATCC27294 standard Quality Control bacterial strain
The clinical general Resistant strain of tubercule bacillus (clinical strain MDR926)
The acute toxicity comparison of table 3 embodiment 3 compounds and Moxifloxacin
Claims (3)
1. the compound shown in formula (I),
2. the application of compound claimed in claim 1 aspect preparation antibacterials.
3. compound claimed in claim 1 is in the application of preparing aspect antitubercular agent.
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| CN102558183B true CN102558183B (en) | 2014-02-05 |
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| CN103145615B (en) * | 2013-03-20 | 2015-07-29 | 浙江医药股份有限公司 | A kind of post-treating method of Nai Nuosha star inner complex |
| CN108239098B (en) * | 2016-12-26 | 2021-01-12 | 中国医学科学院药物研究所 | Benzoxazine oxazolidinone compound containing tetrahydropyridine and preparation method and application thereof |
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Non-Patent Citations (6)
| Title |
|---|
| Xin Guo et al..Synthesis and in vitro antibacterial activities of aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H) -yl)quinolone derivatives.《chinese chemical letters》.2010,第21卷(第10期),1141-1144. |
| Xin Guo et al..Synthesis and in vitro antibacterial activities of aminopyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)quinolone derivatives.《chinese chemical letters》.2010,第21卷(第10期),1141-1144. * |
| 加替沙星合成工艺改进研究;李倩 等;《精细化工中间体》;20091028;第39卷(第5期);37-69 * |
| 加替沙星的合成研究;周文 等;《中南药学》;20101020;第8卷(第10期);751-753 * |
| 周文 等.加替沙星的合成研究.《中南药学》.2010,第8卷(第10期),751-753. |
| 李倩 等.加替沙星合成工艺改进研究.《精细化工中间体》.2009,第39卷(第5期),37-69. |
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Effective date of registration: 20200123 Address after: 230000 No. 61 Science Avenue, Hefei High-tech Zone, Anhui Province Patentee after: Hefei Huawei Pharmaceutical Co., Ltd. Address before: Dongshan Street run Qi Road Jiangning District of Nanjing City, Jiangsu Province, No. 99 210012 Patentee before: NANJING MESE PHARMACEUTICAL Co.,Ltd. |
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