CN102558183A - Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound - Google Patents
Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound Download PDFInfo
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- CN102558183A CN102558183A CN2010105793410A CN201010579341A CN102558183A CN 102558183 A CN102558183 A CN 102558183A CN 2010105793410 A CN2010105793410 A CN 2010105793410A CN 201010579341 A CN201010579341 A CN 201010579341A CN 102558183 A CN102558183 A CN 102558183A
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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 the pharmaceutical chemistry field, be specifically related to a kind of Pyrrolidine and pyrazolyl Oxoquinoline carboxylic acid compound.
Background technology
The main trend of current Comprecin research is:
The breakthrough of fundamental research: the fundamental research of relevant QNS will further be deepened.For example, structure activity relationship, mechanism of action, resistance mechanism, drug interaction, cytotoxicity and new aspects such as screening model all have important breakthrough.And, will promote the development process of this type medicine along with going deep into of fundamental research.
Anti-microbial property further perfect: various countries are the high reactivities that had both kept anti-Gram-negative bacteria at its common feature of Novel Quinolone medicine that grinds at present; It is active obviously to have strengthened resisting gram-positive bacteria again, and anerobes, mycoplasma, chlamydozoan are also had certain effect.And Along with people's is goed deep into QNS mechanism of action understanding, the compound higher to some specified germ activity will occur.Further going deep into of drug drug interaction research, making this type medicine and other drug drug combination treat some intractable infection will be more and more widely.Do not have anti-mycotic activity like Sitafloxacin itself, but it and amphotericin B, fluconazole or rice bran azoles etc. there is the obvious synergistic effect.
Overcome resistance research: illustrate the Comprecin resistance mechanism in recent years and mainly contain 3 points: (1) dna gyrase subunit A or topoisomerase enzyme variant; (2) system that effluxes strengthens; (3) outer membrane permeability descends.
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 type medicine, also understand the relation of its structure-untoward reaction gradually, develop better, the higher medicine of security of anti-microbial property on this basis.Make its phototoxicity be reduced to bottom line like female ring 8 introducings methoxyl group of quinolone or difluoro-methoxy (like Moxifloxacin, Gatifloxacin, Jia Nuosha magnitude), improved security.
Widening of Application Areas: the oriented antiviral trend of extending of the research and development of QNS in recent years with anti-tumor aspect.
But the present invention is intended to design, prepare and seek from above several aspects to have quinolones property of medicine compound brand new and high-efficiency low-toxicity.
Summary of the invention
The objective of the invention is on the basis of existing technology, a kind of Pyrrolidine and pyrazolyl Oxoquinoline carboxylic acid compound are provided.
Another object of the present invention provides the preparation method of above-claimed cpd.
Another purpose of the present invention provides the purposes of above-claimed cpd aspect medicinal.
The object of the invention can reach through following measure:
Compound 1-cyclopropyl base shown in a kind of formula (I)-6-fluoro-7-(2-hydroxyethyl-3-is amino) Pyrrolidine [3,4-c] pyrazoles-5-base-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid, it has following structure:
The preparation method of above-claimed cpd is: with formula (II) compound and formula (III) compound prepared in reaction formula (I) compound under alkaline condition, its reaction scheme is following:
The temperature of reaction of its Chinese style (II) compound and formula (III) compound is 20～50 ℃, and reaction solvent is an acetonitrile, and alkaline condition is a triethylamine.
Formula (II) compound by 1-tertbutyloxycarbonyl-3-cyanic acid-4-pyrrolidone and hydroxyethyl in ethanol in 20～30 ℃ of following prepared in reaction.
Earlier boric acid and diacetyl oxide are heated to 100～120 ℃ of reactions, the reaction back adds 1-cyclopropyl-6 in reaction system, 7-two fluoro-8-methoxyl groups-1, and 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester is again at 100～120 ℃ of following prepared in reaction formulas (III) compound.
Compound of the present invention can be applicable to prepare antibiotic or antitubercular agent; Experiment finds that this compound to the anti-microbial effect of try gram positive organism basically and the 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 embodiment 1, amino Pyrrolidine [3, the 4-c] pyrazole hydrochloride of 2-hydroxyethyl-3-(II)
Under the nitrogen protection, 1-tertbutyloxycarbonyl-3-cyanic acid-4-pyrrolidone (1.05g, 5.0mmol), 98% hydroxyethyl (0.42g, 5.5mmol) and the mixture of ethanol (20ml) react 12h in stirring at room.React the solvent evaporated that finishes, the gained resistates is dissolved in ETHYLE ACETATE (20ml), uses the saturated common salt water washing, anhydrous magnesium sulfate drying.Filter, the resistates after concentrating is dissolved in methyl alcohol (10ml), feeds exsiccant HCl gas, and TLC follows the tracks of until reacting completely.The solid that filtration is separated out, vacuum-drying get 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-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4The preparation of-diethyl acid group boron (III)
Boric acid (1.50g, 24.2mmol) and diacetyl oxide (8mL, mixture heating up to 110 80.0mmol) ℃, stirring reaction 1.5h.Temperature of reaction is reduced to 50～60 ℃, in reaction system, adds 1-cyclopropyl-6,7-two fluoro-8-methoxyl groups-1; (4.55g 14.1mmol), is warming up to 110 ℃ to 4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester again; Continue to stir, TLC follows the tracks of reaction process, and the 6h reaction is finished.Reduce to room temperature, in the frozen water (200mL) under the slow impouring of reaction solution is fully stirred, continue to stir the 0.5h after-filtration, filter cake water thorough washing is used an amount of ethanol rinsing again, and drying gets 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)
Embodiment 3,1-cyclopropyl-6-fluoro-7-(2-hydroxyethyl-3-amino-pyrazol [3,4-c] Pyrrolidine base)-8-methoxyl group-1, the preparation of 4-dihydro-4-Oxoquinoline-3-carboxylic acid (I)
Under the nitrogen protection; Amino Pyrrolidine [3, the 4-c] pyrazole hydrochloride of 2-hydroxyethyl-3-(0.36g, 1.5mmol), adding 1-cyclopropyl-6 behind the mixture stirring at room 10min of acetonitrile (10mL) and triethylamine (1.0mL); 7-two fluoro-8-methoxyl groups-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid root-O
3, O
4-diethyl acid group boron (0.41g, 1.0mmol), 40 ℃ of reacting by heating behind the continuation stirring 1h, TLC follows the tracks of reaction process, and the 36h reaction finishes.The decompression silicagel column separates the back evaporated under reduced pressure, and the pale brown look solid of gained is dissolved in 7% aqueous sodium hydroxide solution (10mL), stirs down in 40 ℃, and TLC follows the tracks of reaction process, and the 30min reaction finishes.Reduce to room temperature, transfer pH=5～6 with 5% hydrochloric acid, stir the 0.5h after-filtration, drying gets 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 to be that (MIC mg/L) realizes to the minimum inhibitory concentration of reference culture, clinical isolates strain through measuring it.
The bacterium minimum inhibitory concentration is measured as follows: adopt plate doubling dilution and Denlay multiple spot inoculator to carry out drug sensitive experiment, experimental bacteria increases bacterium with nutrient broth and angry heart immersion liquid; Become various desired concns with the doubling dilution of MH meat soup behind the medicine dissolution; Add respectively in right amount in plate; The MH nutrient agar dissolves quantitative injection the in back and contains mixing in the soup plate; The final concentration of medicine is respectively 0.03,0.06,0.125......128 μ g/ml, in the plate after the culture medium solidifying with multiple spot inoculator inoculation experiments bacterium (10
5The cfu/ point), put 35 ℃ of constant temperature culture observations after 18 hours, the minimum concentration of contained drug is minimum inhibitory concentration (MIC) in the plate of asepsis growth.
Tubercule bacillus activity test method: instrument and reagent: BacT/Alert system, mycobacterium culturing bottle (MB).Trial drug preparation: Rifampin (RIF) solvent absolute ethyl alcohol, diluent zero(ppm) water, vazadrine (INH), Tibutol (EMB), Moxifloxacin, CIPROFLOXACIN USP 24 (CIP) solvent, the equal zero(ppm) 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, break up bacterium (in 36 hours) to positive MB bottle concussion; Former times of bacteria suspension of the preparation of 1% former times of bacteria suspension: 0.1ml adds in the 10mlMB bottle.The interpretation standard growth control has dual mode; A kind of is that direct growth is controlled, and as operation index, bacterial concentration is a 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 vazadrine (INH), Tibutol (EMB), Moxifloxacin, CIPROFLOXACIN USP 24 (CIP) result's index.
The result judges:
1.GC bottle appears and included medicine bottle in positive back two days and also be positive, and representes that this medicine is invalid.
2.GC bottle presents the positive two days later, contains medicine bottle and just is positive (generally not being), representes this susceptibility sense.
Table 1 has been listed some representation compounds in the application's the formula I compound to the antibacterial activity in vitro of various gram-positive microorganisms and negative bacterium, and compares with two Comprecin Moxifloxacins, CIPROFLOXACIN USP 24s.
Table 1, MIC (ug/ml)
| Compound | Embodiment 3 | Moxifloxacin | CIPROFLOXACIN USP 24 |
| 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 (ug/ml) of mycobacterium tuberculosis
| Antibacterials | H37Rv?ATCC27294 | Tubercule bacillus (clinical strain MDR926) |
| The 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 of table 3 embodiment 3 compounds and Moxifloxacin relatively
Claims (7)
1. the compound shown in the formula (I),
2. the preparation method of the said compound of claim 1, with formula (II) compound and formula (III) compound prepared in reaction formula (I) compound under alkaline condition, its reaction scheme is following:
3. preparation method according to claim 2 is characterized in that the temperature of reaction of formula (II) compound and formula (III) compound is 20～50 ℃, and reaction solvent is an acetonitrile, and alkaline condition is a triethylamine.
4. preparation method according to claim 2, it is characterized in that formula (II) compound by 1-tertbutyloxycarbonyl-3-cyanic acid-4-pyrrolidone and hydroxyethyl in ethanol in 20～30 ℃ of following prepared in reaction.
5. preparation method according to claim 2; It is characterized in that earlier boric acid and diacetyl oxide being heated to 100～120 ℃ of reactions; The reaction back adds 1-cyclopropyl-6 in reaction system; 7-two fluoro-8-methoxyl groups-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester is again at 100～120 ℃ of following prepared in reaction formulas (III) compound.
6. the application of the described compound of claim 1 aspect the preparation antibacterials.
7. the application of the described compound of claim 1 aspect the preparation antitubercular agent.
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|---|---|---|---|
| CN201010579341.0A CN102558183B (en) | 2010-12-08 | 2010-12-08 | Pyrrolidine pyrazolyl oxo-quinoline carboxylic acid compound |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145615A (en) * | 2013-03-20 | 2013-06-12 | 浙江医药股份有限公司新昌制药厂 | Posttreatment method of nemonoxacin chelate |
| CN108239098A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Ben Bing Evil Qin oxazolidinone compounds containing tetrahydropyridine and its preparation method and application |
-
2010
- 2010-12-08 CN CN201010579341.0A patent/CN102558183B/en active Active
Non-Patent Citations (3)
| 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》 * |
| 周文 等: "加替沙星的合成研究", 《中南药学》 * |
| 李倩 等: "加替沙星合成工艺改进研究", 《精细化工中间体》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103145615A (en) * | 2013-03-20 | 2013-06-12 | 浙江医药股份有限公司新昌制药厂 | Posttreatment method of nemonoxacin chelate |
| 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 |
| CN108239098A (en) * | 2016-12-26 | 2018-07-03 | 中国医学科学院药物研究所 | Ben Bing Evil Qin oxazolidinone compounds containing tetrahydropyridine and its preparation method and application |
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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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