CN101659654B - 2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof - Google Patents

2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof Download PDF

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CN101659654B
CN101659654B CN200810147545XA CN200810147545A CN101659654B CN 101659654 B CN101659654 B CN 101659654B CN 200810147545X A CN200810147545X A CN 200810147545XA CN 200810147545 A CN200810147545 A CN 200810147545A CN 101659654 B CN101659654 B CN 101659654B
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compound
formula
acid
selected
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CN101659654A (en
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秦元成
罗美明
祝华军
李明验
梁隆
程志鹏
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四川科伦药物研究有限公司
四川科伦药业股份有限公司
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of products other than chlorine, adipic acid, caprolactam, or chlorodifluoromethane, e.g. bulk or fine chemicals or pharmaceuticals
    • Y02P20/55Synthetic design, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention provides a 2-Methylpiperazine fluoroquinolone compound (formula I) and a preparation method and application thereof, wherein Ra is low-grade alkoxyl, preferably-OCH3,-OCH2CH3, and more preferably-OCH3; and Rb is selected from hydrogen, alkali metals, alkaline earth metals or hydroxide thereof. In addition, the invention also provides a pharmaceutical composition containing the compound. The compound shows good antibiotic activity, is obviously better than galtixacin and lays foundation for the intensive research and development of the antibacterials clinical application of the compound.

Description

2-methylpiperazine fluoroquinolone compound and its preparation method and application

Technical field

The present invention relates to the pharmaceutical chemistry field, specifically, relate to 2-methylpiperazine fluoroquinolone compound and preparation method thereof and its application as antibacterials.

Background technology

Nalidixic Acid is the quinolone acid type antimicrobial drug of developing the sixties in 20th century, and wherein norfloxicin, Ofloxacine USP 23, Ciprofloxacin etc. have strong anti-microbial activity to gram-negative aerobic bacteria.Gatifloxacin (gatifloxacin, AM-1155) be the 6-fluoro-8-BAY 128039 compound of Japanese Anzurin Pharmaceutical Co., Ltd innovation, it is due to Gram-negative bacteria, gram-positive microorganism, anerobe, mycoplasma, chlamydozoan and mycobacterium etc. are all had anti-microbial activity preferably, and almost there is no potential photosensitive side reaction, went on the market in the U.S. in 1999.

European patent EP 464823 (open day on January 8th, 1992) and Chinese patent CN1660838A (open day is on August 31st, 2005), CN 1616456A (open day is on May 18th, 2005) disclose with 2-methylpiperazine and intermediate M1 (R 1=OCH 3, the R=OAc) method of the synthetic Gatifloxacin of reaction; WO2005047260 (open day on May 26th, 2005) and WO2005009970 (on February 3rd, 2005) disclose 2-methylpiperazine and intermediate M1 (R 1=OCH 3, the R=F) method of the synthetic Gatifloxacin of reaction; After WO2004069825 (open day on August 19th, 2004) and CN 1257073A (open day June 21 in 2000) disclose 2-methylpiperazine and intermediate M2 and have reacted, then with NaOCH 3The method of the synthetic Gatifloxacin of effect.

However, still exist in prior art and need the stronger methods for quinolones antibacterial agents of anti-microbial effect.

Summary of the invention

The purpose of this invention is to provide a kind of new 2-methylpiperazine fluoroquinolone compound or the salt of its pharmaceutical acceptable acid.

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 pharmaceutical composition that comprises 2-methylpiperazine fluoroquinolone compound or its pharmaceutical acceptable acid salt.

Another object of the present invention be to provide 2-methylpiperazine fluoroquinolone compound or its pharmaceutical acceptable acid salt, comprise the purposes of the pharmaceutical composition of 2-methylpiperazine fluoroquinolone compound or its pharmaceutical acceptable acid salt.

Specifically, the objective of the invention is to implement by the following technical solutions.

The invention provides a kind of formula I compound, or the salt of its pharmaceutical acceptable acid, or solvate,

Formula I

In formula: Ra is rudimentary alkoxyl group, preferably, for-OCH 3,-OCH 2CH 3, more preferably, for-OCH 3Rb is selected from hydrogen, basic metal, alkaline-earth metal or its oxyhydroxide.

In the present invention, described lower alkoxy refers to C 1-C 4Alkoxyl group.

Described basic metal is selected from lithium, sodium, potassium etc., is preferably potassium or sodium.Described alkaline-earth metal is selected from magnesium, calcium etc.Described pharmaceutically acceptable acid is selected from mineral acid or organic acid, and described mineral acid is selected from haloid acid (hydrochloric acid, Hydrogen bromide, hydroiodic acid HI), phosphoric acid, sulfuric acid etc.; Described organic acid is selected from methylsulfonic acid, phenylformic acid, ethane disulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid, fumaric acid, toxilic acid, succsinic acid or naturally occurring amino acid (such as L-glutamic acid, L-Ala, arginine, Methionin, aspartic acid etc.).Described solvate comprises hydrate, ethylate etc.

Preferably, 2-methylpiperazine fluorine quinolone compounds provided by the present invention is selected from following compounds:

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid; Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sodium salt; Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sylvite; Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride; Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid vitriol; Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrobromate.

The present invention also provides the preparation method of above-claimed cpd, comprises the steps:

I). formula II compound and the reaction of formula III compound obtain formula IV compound;

Here, Rc is selected from acetoxyl group or F;

Wherein, formula II compound is at H by formula V compound 3BO 3And diacetyl oxide (perhaps BF 3(CH 3CH 2) 2O) react under the condition that exists and obtain,

The formula III compound be by the 2-methylpiperazine with (BOC) 2O (uncle's fourth oxycarboxylic acid acid anhydride, BOC acid anhydrides) reaction obtains,

Here, in formula II, formula IV and formula V compound, Ra is F;

Ii). formula IV compound reacts under alkaline condition, obtains formula VI compound, and wherein said alkaline condition is under triethylamine or alkali metal hydroxide (for example, sodium hydroxide or potassium hydroxide) existence,

Here, in formula IV and formula VI compound, Ra is F; Rc is selected from acetoxyl group or F;

Iii). formula VI compound reacts under acidic conditions sloughs BOC protecting group on N, obtains formula VII compound; Can be selected under described acidic conditions under the condition of hydrochloric acid or trifluoroacetic acid existence;

Here, in formula VI and formula VII compound, Ra is F;

Iv). formula VII compound with reactions such as lower alkoxy an alkali metal salt such as sodium methylate (or potassium), sodium ethylates, obtains formula I compound under aprotic polar solvent such as DMSO or DMF existence,

Here, in formula VII compound, Ra is F; And the substituent R a in formula I compound is defined suc as formula the I compound, and Rb is H.

Above-mentioned preparation method comprises further, at iv) after step resulting formula I compound further with basic metal or alkaline earth metal oxide or oxyhydroxide (as sodium hydroxide or potassium hydroxide) reaction, thereby obtain the formula I compound that Rb is basic metal or alkaline-earth metal or its oxyhydroxide;

Perhaps, at iv) after step or Rb be after the formula I compound of basic metal or alkaline-earth metal or its oxyhydroxide, with resulting formula I compound further with pharmaceutically acceptable acid-respons, thereby obtain the salt of formula I compound pharmaceutical acceptable acid.

The invention provides above-mentioned 2-methylpiperazine fluorine quinolone compounds or the interchangeable preparation method of its pharmaceutical acceptable acid salt, selectively, comprise the steps:

I '). formula II compound and the reaction of formula III compound obtain formula IX compound;

Here, Rc is selected from acetoxyl group or F;

Wherein, formula II compound is at H by formula V compound 3BO 3And diacetyl oxide (perhaps BF 3(CH 3CH 2) 2O) react under the condition that exists and obtain,

The formula III compound be by the 2-methylpiperazine with (BOC) 2O (uncle's fourth oxycarboxylic acid acid anhydride, BOC acid anhydrides) reaction obtains,

Here, the substituent R a in formula V, II and VIII compound is defined suc as formula the I compound;

Ii '). formula VIII compound reacts under alkaline condition, obtains formula X compound, and wherein said alkaline condition thing is under triethylamine or alkali metal hydroxide (for example, sodium hydroxide or potassium hydroxide) existence,

Here, Rc is selected from acetoxyl group or F; Substituent R a in formula VIII, X compound is defined suc as formula the I compound;

Iii '). formula X compound reacts under acidic conditions sloughs BOC protecting group on N, obtains formula I compound; Can be selected under described acidic conditions under the condition of hydrochloric acid or trifluoroacetic acid existence;

Here, the substituent R a in formula I compound is defined suc as formula the I compound, and Rb is H.

Above-mentioned preparation method comprises further, at iii ') after step resulting formula I compound further with basic metal or alkaline earth metal oxide or oxyhydroxide (as sodium hydroxide or potassium hydroxide) reaction, thereby obtain the formula I compound that Rb is basic metal or alkaline-earth metal or its oxyhydroxide;

Perhaps, at iii ') after step or Rb be after the formula I compound of basic metal or alkaline-earth metal or its oxyhydroxide, with resulting formula I compound further with pharmaceutically acceptable acid-respons, thereby obtain the salt of formula I compound pharmaceutical acceptable acid.

On the other hand, the invention provides midbody compound for the preparation of formula I compound.

In formula: Ra=F or-OCH 3Rc=F, acetoxyl group.

In addition, the invention provides a kind of pharmaceutical composition, it comprises the formula I compound for the treatment of effective dose, or the salt of its pharmaceutical acceptable acid, or solvate, and one or more pharmaceutically acceptable carriers;

Formula I

In formula: Ra is rudimentary alkoxyl group, preferably, for-OCH 3,-OCH 2CH 3, more preferably, for-OCH 3Rb is selected from hydrogen, basic metal, alkaline-earth metal or its oxyhydroxide.

Described basic metal is selected from lithium, sodium, potassium etc., is preferably potassium or sodium.Described alkaline-earth metal is selected from magnesium, calcium etc.Described pharmaceutically acceptable acid is selected from mineral acid or organic acid, and described mineral acid is selected from haloid acid (hydrochloric acid, Hydrogen bromide, hydroiodic acid HI), phosphoric acid, sulfuric acid etc.; Described organic acid is selected from methylsulfonic acid, phenylformic acid, ethane disulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid, fumaric acid, toxilic acid, succsinic acid or naturally occurring amino acid (such as L-glutamic acid, L-Ala, arginine, Methionin, aspartic acid etc.).Described solvate comprises hydrate, ethylate etc.

The invention provides aforementioned pharmaceutical compositions and preferably contain the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contain the activeconstituents that weight ratio is 0.5%-99.5%.

Preferably, pharmaceutical composition of the present invention comprises and is selected from arbitrary following compound:

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid (compound 8); Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sodium salt (compound 14); Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sylvite (compound 15); Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride (compound 16); Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid vitriol (compound 17); Or

1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrobromate (compound 18).

On the other hand, the invention provides formula I compound of the present invention, or the salt of its pharmaceutical acceptable acid, or solvate, perhaps comprise formula I compound of the present invention, or the salt of its pharmaceutical acceptable acid, or the pharmaceutical composition of solvate is as the purposes of antiseptic-germicide.

The various formulations of aforementioned pharmaceutical compositions provided by the invention, such as tablet, capsule, injection etc. can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, then is made into required formulation.

In addition, the present invention has also carried out the anti-microbial activity research of 2-methylpiperazine fluoroquinolone compound.The in vitro tests result of study shows, the compounds of this invention all shows good anti-microbial activity, is better than to significance Gatifloxacin, for further investigation from now on and the antibacterials clinical application of the described compound of exploitation are laid a good foundation.

In addition, according to above said synthetic route and method, obtain compound of the present invention but synthesize with can both stablizing repeated rows.

Active compound of the present invention can be used for killing Gram-positive bacillus, gram negative bacillus chlamydozoan, mycoplasma, mycobacterium and other microorganism, and is used for prevention, improves and treats the disease that is caused by these pathogenic agent.

Embodiment

The below adopts embodiment, and the invention will be further described, but should not be construed as limiting the scope of the invention.

Embodiment 1---the preparation of 4-tertbutyloxycarbonyl-2-methylpiperazine (formula III compound):

In the 250mL three-necked bottle, 7.5g (0.075 mol) 2-methylpiperazine is dissolved in 150mLCH 2Cl 2, with frozen water, it is cooled to 0 ℃.Stirring reaction, keep temperature of reaction be under the condition of 0 ℃ with 16.35g (0.075mol) (BOC) 2The CH of O (uncle's fourth oxycarboxylic acid acid anhydride) and 50mL 2Cl 2Solution joins in reaction flask.After adding, keep 0 ℃, continue to stir 1h.Reaction solution wash with water (3 * 100mL), the organic phase anhydrous sodium sulfate drying filters, the pressure reducing and steaming solvent, vacuum-drying obtains 14g formula III compound, productive rate 93%.

MS(ESI):m/z?calcd?for?C 10H 20N 2O 2[M] +:200.1;found[M] +=200.3

1H?NMR(CDCl 3,δ,ppm):δ=4.11-3.75(m,2H),2.94-2.91(m,1H),2.79-2.61(m,3H),2.42-2.26(m,1H),1.67-1.61(m,1H),1.45(s,9H),1.05(d,J=8.4Hz,3H)

Embodiment 2---1-cyclopropyl-6,7, and the preparation of 8-three fluoro-Isosorbide-5-Nitrae-dihydros-4-Oxoquinoline-3-carboxylic acid oxalic acid Boric coordination complex (formula II, Ra are F, and Rc is acetoxyl group):

2.11g (32mmol) boric acid, 11.4mL (105mmol) aceticanhydride and 0.08g zinc chloride are placed in the 100mL three-necked bottle, be warming up to 110 ℃ of reactions 1 hour under stirring, be cooled to 60 ℃, add 7.15g (23mmol) 1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester, (formula V) are warming up to 80 ℃ of reactions 2 hours, are cooled to room temperature, add the 20mL water washing, filtration, water washing 3 times, vacuum-drying obtain 8.5g light yellow solid formula II compound, and (Ra is F, Rc is acetoxyl group), productive rate 89.2%.

MS(ESI):m/zcalcd?for?C 17H 13BF 3NO 7[M] +:411.1;found[M] +=411.1

1H?NMR(CDCl 3,δ,ppm):δ=9.31(s,1H),8.20(dd,J=10.8Hz,8.4Hz,1H),4.25-4.74(m,1H),1.92(s,6H),1.12-1.58(m,4H)

Embodiment 3---1-cyclopropyl-6, and the preparation of 8-two fluoro-7-(2-methyl-4-tertbutyloxycarbonyl-1-piperazinyl)-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid oxalic acid Boric coordination complex (formula IV, Ra are F, and Rc is acetoxyl group):

In the 250mL three-necked bottle, (Ra is F with 8.3g (20.1mmol) formula II compound, Rc is acetoxyl group), the formula III compound of 8.1g (40.3mmol) and the triethylamine of 8mL be dissolved in the 100mL acetonitrile, then temperature of reaction risen to 60 ℃, reacted 24 hours.React complete, reaction solution is poured in 400mL water, produce the tawny solid, filter, vacuum-drying obtains 4.2g formula IV compound (Ra is F, and Rc is acetoxyl group), productive rate 35.2%.

MS(ESI):m/z?calcd?for?C 27H 32BF 2N 3O 9[M] +:591.2;found[M] +=591.3

1H?NMR(CDCl 3,δ,ppm):δ=8.91(s,1H),8.01(d,J=10.8Hz,1H),4.10-4.06(m,1H),3.66-3.62(m,1H),3.27-3.24(m,3H),3.11-3.03(m,3H),1.92(s,6H),1.45(s,9H),1.32-1.25(m,2H),1.21-1.09(m,2H),1.05(d,J=6.4Hz,3H)

Embodiment 4---1-cyclopropyl-6, and 8-two fluoro-Isosorbide-5-Nitrae-dihydro-7-(2-methyl-4-tertbutyloxycarbonyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid's (formula VI, Ra are F) preparation:

In the 250mL three-necked bottle, 4.0g (6.7mmol) formula IV compound (Ra is F, and Rc is acetoxyl group) is dissolved in the ethanol of 150mL80%, add the 5mL triethylamine, be heated to reflux, reaction 8h, pressure reducing and steaming solvent, solid 200mL CH 2Cl 2Dissolving, wash with water (3 * 60mL), the organic phase anhydrous sodium sulfate drying filters, the pressure reducing and steaming solvent, and vacuum-drying obtains 2.39g formula VI compound (Ra is F), productive rate 76.4%.

MS(ESI):m/z?calcd?for?C 23H 27F 2N 3O 5[Mr] +:463.2;found[M] +=463.4

1H?NMR(CDCl 3,δ,ppm):δ=13.82(s,1H),8.90(s,1H),7.98(d,J=10.8Hz,1H),4.08-4.05(m,1H),3.56-3.52(m,1H),3.23-3.19(m,3H),3.11-3.05(m,3H),1.46(s,9H),1.31-1.25(m,2H),1.22-1.10(m,2H),1.04(d,J=6.4Hz,3H)

Embodiment 5---1-cyclopropyl-6, and 8-two fluoro-Isosorbide-5-Nitrae-dihydro-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid's (formula VII, compound 7) preparation:

In the 250mL three-necked bottle, with 2.2g (4.7mmol) formula VI compound dissolution in 80mLCH 2Cl 2, with frozen water, it is cooled to 0 ℃.Stir that lower to keep temperature of reaction be 0 ℃, the trifluoroacetic acid of 5mL is added drop-wise in reaction flask slowly, after dropwising, rise to room temperature reaction 6h, the pressure reducing and steaming solvent adds saturated NaHCO 3The aqueous solution, and the use ethyl acetate extraction (3 * 60mL), then use CH2Cl 2Extracted several times, CH 2Cl 2The solution anhydrous sodium sulfate drying filters the pressure reducing and steaming solvent.Solid dehydrated alcohol recrystallization obtains the compound 7 of 1.07g, productive rate 62.2%.

MS(ESI):m/z?calcd?for?C 18H 19F 2N 3O 3[M] +:363.1;found[M+1] +=364.3

1H?NMR(CDCl 3,δ,ppm):δ=8.80(s,1H),7.98(d,J=10.8Hz,1H),4.03-4.01(m,1H),3.56-3.53(m,2H),3.30-3.28(m,1H),3.11-3.05(m,3H),2.95-2.90(m,1H),1.31-1.25(m,2H),1.14(d,J=6.4Hz,3H),1.05-0.98(m,2H)

Embodiment 6---1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid's (compound 8) preparation:

In the 100mL three-necked bottle, the compound 7 of 0.98g (2.7mmol), the sodium methylate of 0.2g (2.9mmol) are dissolved in the 30mL dimethyl sulfoxide (DMSO), be heated to 120 ℃; The slightly cold sodium methylate of adding again 0.2g (2.9mmol) continues reaction 2 hours.The pressure reducing and steaming dimethyl sulfoxide (DMSO) adds the 2.0N hydrochloric acid soln of 40mL to make it dissolving, regulates pH to 8.0 with saturated sodium bicarbonate solution, the adularescent solid is separated out, and filters, and solid is used respectively the dehydrated alcohol recrystallization, get the compound 8 of 0.28g white crystal, productive rate 27%.Fusing point 163-164 ℃.

HRMS(ESI):m/z?calcd?for?C 19H 23FN 3O 4[M+1] +:376.1673;found[M+1] +:376.1661

1H?NMR(400?MHz,CDCl 3,δ,ppm):??δ=8.85(s,1H),7.90(d, 3J F-H=12Hz,1H),4.11-4.05(m,1H),3.99(s,3H),3.66-3.62(m,1H),3.37-3.34(m,1H),3.22-3.16(m,2H),3.11-3.03(m,2H),2.71(dd,J=11.6Hz,8Hz,1H),1.32-1.25(m,1H),1.21-1.09(m,2H),1.05(d,J=6.4Hz,3H),0.95-0.90(m,1H). 13C?NMR(100MHz,CDCl 3):δ=177.1,166.8,158.8(d, 1J C-F=252Hz),150.1,149.0,138.3(d, 3J C-F=12Hz),133.4,124.3,124.2,107.8(d, 3J C-F=24Hz),62.5,53.8,53.2,51.5,46.6,40.7,16.6,9.9,9.0

Embodiment 7---1-cyclopropyl-6, and the preparation of 7-difluoro-8-methoxyl-Isosorbide-5-Nitrae-dihydro-4-Oxoquinoline-3-carboxylic acid bifluoride Boric coordination complex (formula II, Ra are methoxyl group, and Rc is F):

In the 250mL three-necked bottle, with 7.56g (23.4mmol) 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester (formula V, Ra is methoxyl group) be dissolved in 180mLTHF, add the 36mL boron trifluoride diethyl etherate, be heated to reflux, reaction 48h, the pressure reducing and steaming solvent adds ether, separates out white solid, filter, solid is used respectively ether, chloroform, water washing, gets white crystal, and vacuum-drying obtains 4.5g formula II compound, and (Ra is methoxyl group, Rc is F), productive rate 56%.Fusing point 220-222 ℃.

MS(ESI):m/z?calcd?for?C 14H 10BF 4NO 4[M] +:343.1;found[M] +=343.2

1H?NMR(CD 3CN,δ,ppm):δ=9.17(s,1H),8.18(dd,1H,J=9.8Hz,8.1Hz),4.47(m,1H),4.18(s,3H),1.23-1.35(m,4H)。

Embodiment 8---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl-4-tertbutyloxycarbonyl-1-piperazinyl)-4-Oxoquinoline-3-carboxylic acid bifluoride Boric coordination complex (formula VIII, Ra are methoxyl group, and Rc is F):

In the 250mL three-necked bottle, (Ra is methoxyl group with 4.32g (12.6mmol) formula II compound, Rc is F) be dissolved in the 90mL acetonitrile, being cooled to 0~5 ℃, is under the condition of 0~5 ℃, the acetonitrile solution of 5.4g (27mmol) formula III compound and 90mL to be added drop-wise to reaction flask slowly keeping temperature of reaction.After dropwising, keep 0~5 ℃, continue to stir 30min, then temperature of reaction is risen to 40 ℃, reacted 3 days.React complete, reaction solution is poured in 300mL water, produce yellow solid, filter, vacuum-drying obtains 1.5g formula VIII compound (Ra is methoxyl group, and Rc is F), productive rate 23%.Fusing point 198-200 ℃.

MS(ESI):m/z?calcd?for?C 24H 29BF 3N 3O 6[M] +:523.2;found[M] +=523.3

1H?NMR(CD 3CN,δ,ppm)δ=8.97(s,1H),7.88(d,J=10.8Hz,1H),4.27(m,1H),4.18(s,3H),4.08-4.05(m,1H),3.56-3.52(m,1H),3.23-3.19(m,3H),3.11-3.05(m,2H),1.45(s,9H),1.30-1.25(m,2H),1.21-1.10(m,2H),1.05(d,J=6.4Hz,3H)

Embodiment 9---1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl-4-tertbutyloxycarbonyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid's (formula X compound, Ra are methoxyl group) preparation:

In the 250mL three-necked bottle, 3g (5.7mmol) formula VIII compound (Ra is methoxyl group, and Rc is F) is dissolved in the ethanol of 120mL80%, add the 4.2mL triethylamine, be heated to reflux, reaction 8h, pressure reducing and steaming solvent, solid 180mL CH 2Cl 2Dissolving, wash with water (3 * 60mL), the organic phase anhydrous sodium sulfate drying filters, the pressure reducing and steaming solvent, and vacuum-drying obtains 0.82g formula X compound (Ra is methoxyl group), productive rate 31%.Fusing point 182-184 ℃.

MS(ESI):m/z?calcd?for?C 24H 30FN 3O 6[M] +:475.2;found[M] +=475.1

1H?NMR(CD 3CN,δ,ppm):δ=12.8(s,1H),8.87(s,1H),7.86(d,J=10.8Hz,1H),4.23(m,1H),4.16(s,3H),4.08-4.05(m,1H),3.56-3.52(m,1H),3.36-3.32(m,1H),3.23-3.19(m,2H),3.11-3.05(m,2H),1.45(s,9H),1.29-1.25(m,2H),1.21-1.09(m,2H),1.05(d,J=6.4Hz,3H)

Embodiment 10---1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid's preparation:

In the 100mL three-necked bottle, 2g (4.2mmol) formula X compound (Ra is methoxyl group) is dissolved in 45mL CH 2Cl 2, with frozen water, it is cooled to 0 ℃.Stirring reaction is under the condition of 0 ℃, the 4.5mL trifluoroacetic acid to be added drop-wise to reaction flask slowly keeping temperature of reaction, after dropwising, rises to room temperature reaction 6h, and the pressure reducing and steaming solvent is used saturated NaHCO 3At first aqueous solution dissolving uses ethyl acetate extraction (3 * 60mL), then use CH 2Cl 2Extracted several times, CH 2Cl 2The solution anhydrous sodium sulfate drying filters the pressure reducing and steaming solvent.Solid dehydrated alcohol recrystallization obtains 0.7g1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid, and productive rate is 44%.

Embodiment 11---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sodium salt (compound 14):

The 1-cyclopropyl of 500mg-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid is dissolved in the CH of 50ml 2Cl 2In, slowly add 55mg sodium hydroxide to be dissolved in the solution of 2ml water, stirring at room 30 minutes; Filter, with a small amount of anhydrous diethyl ether washing, vacuum-drying 8 hours.Obtain the whitening compound 14 of 358mg, yield is 63.8%.

1H?NMR(D 2O,δ,ppm):δ=8.78(s,1H),7.92(d,J=12Hz,1H),4.05-4.01(m,1H),3.96(s,3H),3.68-3.54(m,1H),3.32-3.29(m,1H),3.22-3.18(m,2H),3.13-3.06(m,2H),2.75-2.66(m,1H),1.34-1.28(m,1H),1.21-1.08(m,2H),1.04(d,J=6.4Hz,3H),0.93-0.90(m,1H)

Embodiment 12---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sylvite (compound 15):

The compound 8 of 500mg is dissolved in the CH of 50ml 2Cl 2In, slowly add 55mg potassium hydroxide to be dissolved in the solution of 2ml water, stirring at room 30 minutes; Filter, with a small amount of acetone, anhydrous diethyl ether washing, vacuum-drying 8 hours.Obtain the whitening compound 15 of 395mg, yield is 71.7%.

1H?NMR(D 2O,δ,ppm):δ=8.76(s,1H),7.92(d,J=12Hz,1H),4.06-4.01(m,1H),3.96(s,3H),3.69-3.56(m,1H),3.31-3.29(m,1H),3.20-3.16(m,2H),3.12-3.06(m,2H),2.75-2.67(m,1H),1.33-1.28(m,1H),1.20-1.08(m,2H),1.03(d,J=6.4Hz,3H),0.92-0.89(m,1H)

Embodiment 13---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride (compound 16):

The 1-cyclopropyl of 500mg-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid is dissolved in the acetone of 60ml, slowly adds the 0.67ml hydrochloric acid soln of 2M, stirring at room 30 minutes; Filter, use a small amount of washing with acetone, vacuum-drying 8 hours.Obtain the whitening compound 16 of 410mg, yield is 74.7%.

1H?NMR(D 2O,δ,ppm):δ=8.83(s,1H),7.91(d,J=12Hz,1H),4.09-4.04(m,1H),3.98(s,3H),3.69-3.56(m,1H),3.33-3.29(m,1H),3.24-3.19(m,2H),3.15-3.07(m,2H),2.73-2.65(m,1H),1.33-1.28(m,1H),1.20-1.08(m,2H),1.05(d,J=6.4Hz,3H),0.94-0.90(m,1H)

Embodiment 14---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid vitriol (compound 17):

The 1-cyclopropyl of 500mg-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid is dissolved in the acetone of 60ml, slowly adds the 0.67ml sulphuric acid soln of 2M, stirring at room 30 minutes; Filter, use a small amount of washing with acetone, vacuum-drying 8 hours.Obtain the whitening compound 17 of 427mg, yield is 67.7%.

1H?NMR(D 2O,δ,ppm):δ=8.80(s,1H),7.95(d,J=12Hz,1H),4.06-4.01(m,1H),3.97(s,3H),3.68-3.54(m,1H),3.33-3.29(m,1H),3.25-3.20(m,2H),3.16-3.08(m,2H),2.76-2.66(m,1H),1.35-1.28(m,1H),1.23-1.08(m,2H),1.06(d,J=6.4Hz,3H),0.92-0.89(m,1H)

Embodiment 15---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrobromate (compound 18):

The 1-cyclopropyl of 500mg-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid is dissolved in the acetone of 60ml, slowly adds the 0.67ml hydrobromic acid solution of 2M, stirring at room 30 minutes; Filter, use a small amount of washing with acetone, vacuum-drying 8 hours.Obtain the whitening compound 18 of 418mg, yield is 68.8%.

1H?NMR(D 2O,δ,ppm):δ=8.79(s,1H),7.91(d,J=12Hz,1H),4.04-4.00(m,1H),3.98(s,3H),3.69-3.56(m,1H),3.36-3.30(m,1H),3.24-3.19(m,2H),3.16-3.08(m,2H),2.76-2.68(m,1H),1.36-1.31(m,1H),1.22-1.08(m,2H),1.06(d,J=6.4Hz,3H),0.94-0.90(m,1H)

Embodiment 16---the mensuration of anti-microbial activity

The mensuration of anti-microbial activity adopts the agar dilution of world health organisation recommendations to measure minimum inhibitory concentration (MIC), eight tested bacterium are seeded on the flat board that contains quantitative concentrations compound and control drug simultaneously, measure the lowest drug concentration that suppresses tested bacterium.Band medicine substratum pastille maximum concentration 12.5 μ g/ml, minimum concentration is 0.025 μ g/ml, for ease of comparing with DMF, ethanol as solubility promoter, dilute with stroke-physiological saline solution, final solubility promoter concentration DMF≤5.0%, ethanol≤2.5% does not affect each test organisms growth through blank.The antibacterial activity in vitro of part of compounds and Gatifloxacin (MIC, μ g/ml) sees Table 1:

The anti-microbial activity of table 1 part of compounds and Gatifloxacin (MIC, μ g/ml)

Embodiment 17---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid (compound 8) sheet:

Recipe quantity is:

Get above-mentioned formula routinely the preparation method make tablet.

Embodiment 18---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid (compound 8) capsule:

Recipe quantity is:

Get above-mentioned formula, according to a conventional method preparation.

Embodiment 19---the preparation of 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid (compound 8) sodium chloride injection:

Recipe quantity is:

(1). compound 8 1.0g

(2). medicinal lactic acid is appropriate

(3). sodium-chlor 8.5g

(4). water for injection 1000ml

Concrete preparation method is as follows:

Take the 1-cyclopropyl of recipe quantity-6-fluoro-1,4-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid, it is joined in the water for injection of 900ml, add appropriate medicinal lactic acid, stirring and dissolving, activated carbon decolorizing filters, add water for injection to capacity, after essence filter, can sterilization and.

Claims (15)

1. formula I compound, or the salt of its pharmaceutical acceptable acid,
In formula: Ra is C 1-C 4Alkoxyl group; Rb is selected from hydrogen or basic metal;
And regulation, described compound does not comprise 1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid.
2. compound according to claim 1, wherein, Ra is-OCH 3, or-OCH 2CH 3
3. compound according to claim 2, wherein, Ra is-OCH 3
4. the described compound of arbitrary claim according to claim 1 to 3, wherein, described basic metal is selected from lithium, sodium or potassium.
5. compound according to claim 4, wherein, described basic metal is selected from sodium or potassium.
6. the described compound of arbitrary claim according to claim 1 to 3, wherein, described pharmaceutically acceptable acid is selected from mineral acid or organic acid, and described mineral acid is selected from haloid acid, phosphoric acid or sulfuric acid; Described organic acid is selected from methylsulfonic acid, phenylformic acid, ethane disulfonic acid, formic acid, acetic acid, propionic acid, butyric acid, lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid, fumaric acid, toxilic acid or succsinic acid.
7. compound according to claim 6, wherein, described pharmaceutically acceptable acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, methylsulfonic acid, lactic acid.
8. the described compound of arbitrary claim according to claim 1 to 3 is selected from following arbitrary compound:
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sodium salt; Or
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid sylvite; Or
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrochloride; Or
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid vitriol; Or
1-cyclopropyl-6-fluoro-Isosorbide-5-Nitrae-dihydro-8-methoxyl group-7-(2-methyl isophthalic acid-piperazinyl)-4-oxo-3-quinoline carboxylic acid hydrobromate.
9. the preparation method of the described compound of arbitrary claim in claim 1 to 8, comprise the steps:
I). formula II compound and the reaction of formula III compound obtain formula IV compound;
Here, Rc is selected from acetoxyl group or F;
Wherein, formula II compound is at H by formula V compound 3BO 3With diacetyl oxide or BF 3(CH 3CH 2) 2React under the condition that O exists and obtain,
The formula III compound be by the 2-methylpiperazine with (BOC) 2The O reaction obtains,
Here, in formula II, formula IV and formula V compound, Ra is F;
Ii). formula IV compound reacts under alkaline condition, obtains formula VI compound, and wherein said alkaline condition is under triethylamine or alkali metal hydroxide existence,
Here, in formula IV and formula VI compound, Ra is F; Rc is selected from acetoxyl group or F;
Iii). formula VI compound reacts under acidic conditions sloughs BOC protecting group on N, obtains formula VII compound;
Here, in formula VI and formula VII compound, Ra is F;
Iv). formula VII compound is under aprotic polar solvent exists, with C 1-C 4The alkoxy base reacting metal salt obtains formula I compound,
Here, in formula VII compound, Ra is F; In substituent R a in formula I compound such as claim 1 to 8, arbitrary claim is defined, and Rb is H;
At iv) after step resulting formula I compound further with alkalimetal oxide or oxyhydroxide reaction, be alkali-metal formula I compound thereby obtain Rb;
Perhaps, at iv) after step or Rb be after alkali-metal formula I compound, with resulting formula I compound further with pharmaceutically acceptable acid-respons, thereby obtain the salt of formula I compound pharmaceutical acceptable acid.
10. the preparation method of the described compound of arbitrary claim in claim 1 to 8, comprise the steps:
I '). formula II compound and the reaction of formula III compound obtain formula VIII compound;
Here, in formula II and formula VIII compound, Rc is selected from acetoxyl group or F;
Wherein, formula II compound is at H by formula V compound 3BO 3With diacetyl oxide or BF 3(CH 3CH 2) 2React under the condition that O exists and obtain,
The formula III compound be by the 2-methylpiperazine with (BOC) 2The O reaction obtains,
Here, the substituent R a in formula V, II and VIII compound is as compound definition as described in arbitrary claim in claim 1 to 8;
Ii '). formula VIII compound reacts under alkaline condition, obtains formula X compound, and wherein said alkaline condition is under triethylamine or alkali metal hydroxide existence,
Here, Rc is selected from acetoxyl group or F; In substituent R a in formula VIII, X compound such as claim 1 to 8, arbitrary claim is defined;
Iii '). formula X compound reacts under acidic conditions sloughs BOC protecting group on N, obtains formula I compound; Can be selected under described acidic conditions under the condition of hydrochloric acid or trifluoroacetic acid existence;
Here, in the substituent R a in formula I compound such as claim 1 to 8, arbitrary claim is defined, and Rb is H;
At iii ') after step resulting formula I compound further with alkalimetal oxide or oxyhydroxide reaction, be alkali-metal formula I compound thereby obtain Rb;
Perhaps, at iii ') after step or Rb be after alkali-metal formula I compound, with resulting formula I compound further with pharmaceutically acceptable acid-respons, thereby obtain the salt of formula I compound pharmaceutical acceptable acid.
11. a pharmaceutical composition, it comprises the described compound of arbitrary claim in the claim 1 to 8 for the treatment of effective dose, and one or more pharmaceutically acceptable carriers.
12. pharmaceutical composition according to claim 11, the weight percent of wherein said compound are 0.1%-99.5%.
13. pharmaceutical composition according to claim 12, the weight percent of wherein said compound are 0.5%-99.5%.
14. in claim 1 to 8, the described compound of arbitrary claim is preparing as the application in the medicine of antiseptic-germicide.
15. in claim 11 to 13, the described pharmaceutical composition of arbitrary claim is preparing as the application in the medicine of antiseptic-germicide.
CN200810147545XA 2008-08-28 2008-08-28 2-Methylpiperazine fluoroquinolone compound and preparation method and application thereof CN101659654B (en)

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