CN1850823A - Quinolone compound containing oximino, and its preparing method and use - Google Patents

Quinolone compound containing oximino, and its preparing method and use Download PDF

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CN1850823A
CN1850823A CNA2006100267287A CN200610026728A CN1850823A CN 1850823 A CN1850823 A CN 1850823A CN A2006100267287 A CNA2006100267287 A CN A2006100267287A CN 200610026728 A CN200610026728 A CN 200610026728A CN 1850823 A CN1850823 A CN 1850823A
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compound
reaction
oximido
solvate
alkyl
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杨玉社
党昭
李战
嵇汝运
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Shanghai Institute of Materia Medica of CAS
Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Abstract

This invention discloses quinolone category compound contains hydroximino and its medical used acceptable iorganic or organic salt, and their solvate and preparation method. This kind of compound is tested by several kinds of strains to prove their activity to the strains; it can be used to medicin that used to cure diseasebrought by gel an shi negative and positive bacterium.

Description

One class contains carbostyril compound of oximido and its production and use
Technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field, be specifically related to the synthetic of carbostyril compound and the purposes in preparation treatment infectious disease medicament thereof.
Background technology
1962, people such as Lesher synthesized Nalidixic Acid, the brand-new antibacterials of a class occurred (J Med Pharm Chem1962,5:1063-1065).Nineteen eighty-two first be used for the quinolone medicine Ciprofloxacin listing [Drugs1996,51 (6): 1019-1074] beyond the urinary system, represent this class new antimicrobial agent to enter into a new stage.So far after, the female ring of basic quinolone becomes the starting point of new fluoroquinolone composition optimizes, and through 40 years of development, quinolones is existing to be surpassed 20 kinds and be widely used in clinically, is one of main antibacterials of present clinical application.
Fluoroquinolone medicine that some are new such as Gatifloxacin (Gatifloxacin), gemifloxacin (Gemifloxacin), Q-35 (Balofloxacin) and Moxifloxacin (Moxifloxacin) etc. show broad-spectrum antibacterial activity, good pharmacokinetic parameter and clinical effectiveness, they are bringing into play more and more important effect in the serial respiratory tract infection of treatment [J RespirDis 1999,20 (11): S23-9; J Antimicrob Chemother 1999,44 (5): 679-688].
These new fluoroquinolones great majority structurally comprise that all the nitrogen-atoms cyclopropyl that has kept 1 replaces, and the characteristics of 8 methoxyl groups have been carried out a large amount of structural modification [Drugs 2002,62 (1): 13-59] to 5,7 simultaneously.
The replacement of molecule C-5 position influences external activity, particularly to gram-positive microorganism, mainly is because the influence of steric effect.This position can keep not replacing or be replaced by some less relatively groups, and as amino or methyl, when being replaced by macoradical, anti-microbial activity significantly reduces.The replacement of C-7 position strengthens anti-microbial activity.Basic group is necessary to activity, and best substituting group is proved to be to contain five yuan or hexa-atomic nitrogen heterocyclic ring encircling outer nitrogen-atoms.The C-8 bit substituent mainly influences activity in vivo, anti-anaerobic activity and side effect.This position can keep not replacing or less relatively substituting group, as halogen atom or methoxyl group.
In the trial in the past, the C-7 position is the emphasis of research.This contains the activity that the substituent fluoroquinolone of pyrrole ring shows better resisting gram-positive bacteria, and the activity of the better anti-Gram-negative bacteria of piperazine substituted demonstration.The alkyl that increases on two kinds of rings replaces the activity that can strengthen resisting gram-positive bacteria, and prolong half-life strengthens the water-soluble of molecule, reduces the danger of crystalluria.First oximido in the gemifloxacin (Gemifloxacin) on the pyrrole ring of C-7 position is expanded its antimicrobial spectrum, makes it all have high reactivity to fluoroquinolone sensitivity and drug-fast streptococcus pneumoniae.
Comparatively speaking, piperidines substituent research in C-7 position is less.Disclose the substituent quinolone compounds of a series of C-7 position piperidines in the patents such as U.S. Pat 2003/0216568 and US2003/0096812, but be alkyl-amino or amino methyl-hydroxy piperidine deutero-substituting group.The 7-position that people such as Abbott once were reported in quinolone nuclear introduce 4-oxime (or methyloxime) piperidyl (J.Med.Chem, 1992,35,1392-1398).Europe early stage patent (EP0541086) also discloses the piperidines substituting group that the C-7 position contains oximido.But above-claimed cpd all is not included in the piperidyl that the 7-position has oximido and amino methyl or alkyl-substituted amino simultaneously.
Therefore,, by introducing the piperidyl of various replacements to quinoline nuclei 7-position, and measure the pharmacologically active of the compound that forms, develop the new oxime with broad spectrum antibiotic activity and good pharmacokinetic property-amino piperidine compound based on above-mentioned prior art.
Summary of the invention
One of purpose of the present invention provides the novel carbostyril compound with anti-microbial activity.
Another object of the present invention provides the preparation method of this compounds.
A further object of the present invention provides the application of this compounds on the preparation anti-infectives.
The invention provides quinolone compounds and medicinal acceptable inorganic or organic salt thereof with following general formula (I) structure, and their solvate:
Figure A20061002672800091
Among the formula I
R 5Be H, NH 2
X 8Be CH, CF, C-OCH 3, C-CH 3Or N;
R 7A group for following formula:
Figure A20061002672800092
In the formula
R 1Be H or CH 3
R 2Be hydrogen, straight or branched C 1-C 4Alkyl, cyclopropyl, cyclopropyl methyl, C 3-C 6Alkynyl, 2-halogenated ethyl, methoxymethyl, methoxycarbonyl methyl, aryl or allyl group;
R 3Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
R 4Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
M is 0 or 1.
The present invention also provides the preparation method and the application of this compounds on preparation treatment infectious disease medicament of I compound.
In the piperidyl of formula I compound part, the 3-position or the 4-position carbon atom that have replaced amino methyl or alkylamino on it are unsymmetrical carbons, thus formula I compound can S or the form of R or S and R mixture exist.
Partly there is (replacing arbitrarily) oximido in the piperidyl of formula I compound, according to its geometry can exist genial anti--isomer.Therefore, the present invention also comprises all these geometrical isomers and chiral isomer and their mixture.
The present invention also provides the preparation method of the carbostyril compound with above-mentioned formula I structure.
According to the present invention, shown in following reaction scheme 1, formula I compound can prepare by formula III compound and formula IIa compound or formula IIb compound.
Reaction scheme 1
Figure A20061002672800101
In above route
R 1, R 2, R 3, R 4, R 5, X 8With m as defined above;
X 7Represent halogen atom, be preferably chlorine or fluorine.
According to reaction scheme 1, can be by in the presence of solvent and add suitable alkali, formula III compound and formula IIa compound or formula IIb compound under-10～200 ℃ of temperature, stirring reaction 1～20 hour, in the presence of solvent, add suitable alkali and come preparation formula Ia and Ib compound.Can use the form of free alkali form or salt at this reaction Chinese style IIa or formula IIb compound, as use their hydrochloride, hydrobromate or trifluoroacetate etc.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects.Preferred acetonitrile, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO), pyridine or the hexamethylphosphoramide (HMPA) of using.
This reaction is generally carried out in the presence of suitable alkali.The alkali that is preferable over this reaction comprises mineral alkali such as sodium bicarbonate, salt of wormwood etc.; Organic bases such as triethylamine, diisopropylethylamine, pyridine, N, accelerine, N, N-dimethyl aminopyridine, 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) etc.
Formula I compound of the present invention can also prepare by the method shown in the following reaction scheme 2.In formula IIa or IIb compound, introduce amino protecting group P and obtain formula IIaa or IIbb compound.Formula IIaa or IIbb compound under the condition identical with reaction scheme 1 with the reaction of formula III compound, obtain the compound of formula Iaa or Ibb, remove protecting group P and will obtain Compound I a and Ib.
Reaction scheme 2
Figure A20061002672800111
In above-mentioned reaction scheme
R 1, R 2, R 5, X 8With m as defined above;
P represents amino protecting group.
In reaction scheme 2, can use the free alkali form of IIaa or IIbb compound or the form of salt, as using their hydrochloride, hydrobromate or trifluoroacetate etc.
Routine is used for the amino protecting group of organic chemistry filed, all can be used as amino protecting group P suitable in formula IIaa or the IIbb compound.As formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl is to methoxyl group benzyloxy base carbonyl etc.
After reaction was finished, the amino protecting group in the formula Iaa of formation or the Ibb compound can be according to the relevant nature of protecting group, and by hydrolysis, solvolysis or reduction are removed, and form target formula Ia and Ib.
The formula III compound can make that [J.M.Domagala.J.Med.Chem 34,1142 (1991) by currently known methods among the present invention; J.M.Domagala.J.Med.Chem 31,991 (1988); D.Bouzard.J.Med.Chem 35,518 (1992)].
According to the method for following reaction scheme 3,4,5,6 and 7, can easily prepare several initiators in addition of the present invention, formula IIa or formula IIb and formula IIaa or formula IIbb compound.
Reaction scheme 3
Figure A20061002672800121
In above reaction scheme 3: R 1, R 2As defined above, R 3And R 4Represent H, m is 1; P represents amino protecting group.
According to reaction scheme 3, having the amino cyano group ester 1 of protection can react with sodium ethylate in appropriate solvent such as ethanol, obtains 3-cyano group-4-ketone piperidines 2.2 under alkaline condition with haloalkane R 1The X reaction, alkyl on the 3-position obtains 3.At first with the suitable original reagent of going back 3 ketone group is reduced to hydroxyl, preferred reductive agent is sodium borohydride (NaBH 4).And then reducing its cyano group with the suitable original reagent of going back, preferred reductive agent is Li-Al hydrogen (LAH), obtains amino alcohol 4.Optionally protect 4 amino, routine is used for the amino protecting group of organic chemistry filed, all can be used as the amino protecting group P of formula 4.As formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl is to methoxyl group benzyloxy base carbonyl etc.The amine 5 that is protected can obtain ketone compound 6 with various suitable oxygenant oxidations.Preferred oxidant is sulphur trioxide-pyridine mixtures (Py-SO 3).The azanol reaction that ketone compound 6 and alcoxyl replace, the oxime compound 7 that obtains replacing selects appropriate means with its deprotection according to the kind of protecting group, obtains R 3And R 4Be hydrogen, m is 1 formula IIa compound.
Reaction scheme 4
Figure A20061002672800122
In above reaction scheme 4: R 1, R 2As defined above, R 3And R 4Represent H, m is 1; P represents amino protecting group.According to method shown in the reaction scheme 4, ketone compound 6 obtains oxime compound 8 with azanol reaction under proper condition, compound 8 and suitable R 2The X electrophilic compound reacts in the presence of alkali, introduces desired R 2Group, the 9 oxime derivate of preparation formula 7 is used the same procedure in the reaction scheme 3 then, selects appropriate means with its deprotection according to the kind of protecting group, prepares desired oxime compound IIa.
Reaction scheme 5
In above reaction scheme 5: R 2And R 3As defined above, R 1, R 4Represent H, m is 0; P represents amino protecting group.According to method shown in the reaction scheme 5; the amine that the piperidine ring oxygen compound 9 that has a protecting group replaces with ammoniacal liquor or monoalkyl in appropriate solvent such as ethanol; as methylamine; reactions such as cyclopropylamine; use tertbutyloxycarbonyl (BOC) protection amino then, obtain 3-alkylamino-4-hydroxy piperidine 10 and 3-hydroxyl-4-alkylamino-piperidinyl-1 1.Compound 10 can separate by column chromatography silica gel with 11.Same procedure selective oxidation 10 and 11 with in the reaction scheme 3 obtains ketone compound 12 and 13, and ketone compound 12 and 13 can obtain the oxime compound IIa or the IIb that expect by method identical in reaction scheme 3 or the reaction scheme 4 respectively.
Reaction scheme 6
Figure A20061002672800141
In above reaction scheme 6: R 1, R 2And R 3As defined above, R 4Represent H, m is 0; P represents amino protecting group.According to method shown in the reaction scheme 6, the piperidine ring oxygen compound 9 that has protecting group reacts with pair amine of alkyl replacement in appropriate solvent such as ethanol, obtains 3-alkylamino-4-hydroxy piperidine 16.The oxime compound IIa that obtains expecting through series of steps such as oxidations with the same procedure in reaction scheme 3 or the reaction scheme 4.
Reaction scheme 7
Figure A20061002672800142
R in above reaction scheme 7 1, R 2, R 3, R 4With m as defined above; P represents amino protecting group.According to method shown in the reaction scheme 7, under proper condition with suitable protecting group P drawing-in system IIa or IIb compound, selective protection uncle ammonia can obtain formula IIaa or IIbb compound.Routine is used for the amino protecting group of organic chemistry filed, all can be used as amino protecting group P.As formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl is to methoxyl group benzyloxy base carbonyl etc.
In following preparation example, will more specifically explain above-mentioned synthetic method.
The present invention also provides and contains the defined new compound as following formula I, or its pharmacy acceptable salt is as activeconstituents, and the antimicrobial compound of pharmaceutically acceptable carrier.
The structural formula of compound that the present invention relates to sees Table 1.
Wherein Q is
The structural formula of table 1 compound 02-48
Figure A20061002672800171
Biological activity determination
Antibacterial activity in vitro is measured:
1. test method: adopt the agar doubling dilution to measure this series compound and positive control medicine gemifloxacin, Gatifloxacin, LZ and vancomycin are to the minimum inhibitory concentration (MIC) of examination bacterial strain.In the agar plate surface that contains different pharmaceutical concentration, every some inoculation bacterium amount is about 10 to employing multiple spot inoculation instrument (Denley A400) with microbionation 6CFU/ml is hatched 18-24 hour observations for 37 ℃, is the minimum inhibitory concentration (MIC value) of medicine to this bacterium with contained drug minimum concentration in the plate substratum of asepsis growth.
2. test strain: the experiment bacterial strain uses therefor is 2003.10～2005.2 years from Sichuan, the inpatient of ground hospitals such as Chongqing, Beijing clinical separation pathogenic bacterium of collecting, used bacterial classification is being collected isolating unit (clinical laboratory of Huaxi Medical Univ, Medical University Of Chongqing's contagious department and Beijing Hospital's Bacteriology Room) all after the automatic bacteria detector is identified, again through using after the evaluation again.Test-compound all adds the DMSO of 2ml earlier, can help its fully good dissolving, adds aseptic double-distilled water again to desired concn; . the positive control medicine directly use distilled water can excellent dissolution to desired concn, adding the 20ml heating and melting in the culture dish of each adding soup is liquid MH substratum, and making the medicine final concentration in the culture dish is 8,4,2,1 ... 0.002,0.001,0.0005ug/m
3. positive controls is a gemifloxacin, LZ and vancomycin.
4. this series compound is to the MIC of test strain 50, MIC 90, and MIC RangeThe results are shown in Table 2.Wherein majority of compounds has better antibacterial activity, has several compounds that excellent anti-microbial activity is arranged, and the activity of resisting gram-positive bacteria is better than vancomycin and LZ.
The invention provides quinolone compounds and medicinal acceptable inorganic or organic salt thereof, and their solvate, and the pharmaceutical composition that contains them can be used for preparing anti-infectives with following general formula (I) structure.
Table 2 compound 21-40 is to the MIC of test strain 50Add up etc. the result
Medicine Bacterium (strain number) MIC relevant item (ug/ml)
MIC 50 MIC 90 MIC range
21 22 23 MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ESBL ( 4 ) ( 4 ) ( 3 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) ＜0.001 ＞16 ＜0.001 ＜0.001 ＞16 1 ＞16 ＞16 0.25 ＜0.001 ＞16 ＜0.001 ＜0.001 ＞16 ＞16 2 ＞16 2 ＜0.001 ＞16 ＜0.001 ＜0.001 ＞16 ＞16 2 ＞16 2 0.004 ＞16 0.008 0.008 ＞16 2 ＞16 ＞16 ＞16 ＜0.001 ＞16 8 0.004 ＞16 ＞16 8 ＞16 ＞16 0.008 ＞16 0.5 0.008 ＞16 ＞16 4 ＞16 ＞16 ＜0.001-0.004 0.5-＞16 ＜0.001-0.008 ＜0.001-0.008 ＞16 1-2 ＞16 2-＞16 0.06-＞16 ＜0.001 8-＞16 ＜0.001-8 ＜0.001-0.004 ＞16 ＞16 2-8 8-＞16 1-＞16 ＜0.001-0.008 4-＞16 ＜0.001-0.5 ＜0.001-0.008 ＞16 ＞16 1-4 4-＞16 0.125-＞16
24 25 26 27 MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) ＜0.001 ＞16 ＜0.001 ＜0.001 ＞16 ＞16 16 ＞16 1 0.06 8 0.25 0.06 ＞16 ＞16 4 ＞16 1 0.03 ＞16 0.03 0.015 ＞16 ＞16 8 ＞16 8 ＜0.001 ＞16 ＜0.001 ＜0.001 ＞16 ＞16 4 ＞16 0.25 ＜0.001 ＞16 0.5 ＜0.001 ＞16 ＞16 ＞16 ＞16 ＞16 2 16 1 0.125 ＞16 ＞16 8 ＞16 8 0.03 ＞16 4 0.06 ＞16 ＞16 ＞16 ＞16 ＞16 0.002 ＞16 0.5 0.03 ＞16 ＞16 8 ＞16 ＞16 ＜0.001 2-＞16 ＜0.001-0.5 ＜0.001 ＞16 ＞16 16-＞16 16-＞16 1-＞16 0.03-2 2-16 0.03-1 0.03-0.125 ＞16 ＞16 2-8 4-＞16 0.06-8 0.03 16-＞16 0.015-4 0.008-0.06 ＞16 ＞16 8-＞16 ＞16 2-＞16 ＜0.001-0.002 2-＞16 ＜0.001-0.5 ＜0.001-0.03 ＞16 ＞16 4-8 8-＞16 0.25-＞16
28 29 30 31 32 MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) 0.125 ＞16 0.25 0.125 ＞16 ＞16 ＞16 ＞16 4 0.015 16 0.004 0.004 ＞16 ＞16 ＞16 ＞16 0.5 0.002 ＞16 0.06 0.002 ＞16 ＞16 ＞16 ＞16 8 0.06 8 0.06 0.06 ＞16 ＞16 ＞16 ＞16 2 0.5 0.125 ＞16 1 0.25 ＞16 ＞16 ＞16 ＞16 ＞16 0.015 ＞16 2 0.06 ＞16 ＞16 ＞16 ＞16 ＞16 0.002 ＞16 8 0.06 ＞16 ＞16 ＞16 ＞16 ＞16 0.06 8 1 0.5 ＞16 ＞16 ＞16 ＞16 ＞16 0.5 0.06-0.125 16-＞16 0.25-1 0.03-0.25 ＞16 ＞16 ＞16 ＞16 2-＞16 0.015 2-＞16 ＜0.001-2 0.004-0.06 ＞16 ＞16 ＞16 ＞16 0.5-＞16 0.002 2-＞16 0.06-8 0.002-0.06 ＞16 ＞16 ＞16 ＞16 8-＞16 0.06 1-8 0.06-1 0.06-0.5 ＞16 ＞16 8-＞16 ＞16 0.5-＞16 0.5
33 34 35 36 MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ＞16 0.25 0.25 ＞16 ＞16 ＞16 ＞16 ＞16 2 ＞16 2 16 ＞16 ＞16 ＞16 ＞16 ＞16 4 ＞16 0.25 1 ＞16 ＞16 ＞16 ＞16 ＞16 0.03 ＞16 0.03 0.03 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 16 0.5 ＞16 ＞16 ＞16 ＞16 ＞16 2 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 4 ＞16 ＞16 4 ＞16 ＞16 ＞16 ＞16 ＞16 0.03 ＞16 8 0.03 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 0.25-16 0.25-0.5 ＞16 ＞16 ＞16 ＞16 ＞16 2 ＞16 2-＞16 16-＞16 ＞16 ＞16 ＞16 ＞16 ＞16 2-4 ＞16 0.25-＞16 0.5-4 ＞16 ＞16 ＞16 ＞16 ＞16 0.03 8-＞16 0.03-8 0.03 ＞16 ＞16 16-＞16 ＞16 ＞16 ＞16 ＞16
37 38 39 40 ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ( 4 ) ( 3 ) ESBL ( 4 ) ( 4 ) ESBL ( 3 ) ( 4 ) MSSA ( 5 ) MRSA ( 4 ) ( 4 ) ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 0.015 ＞16 0.015 0.015 ＞16 ＞16 16 ＞16 0.5 0.004 ＞16 0.002 0.004 ＞16 ＞16 2 ＞16 0.5 0.5 ＞16 0.125 0.25 ＞16 ＞16 ＞16 ＞16 2 0.015 ＞16 0.015 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 ＞16 0.015 ＞16 0.125 0.03 ＞16 ＞16 ＞16 ＞16 ＞16 0.004 ＞16 0.015 0.004 ＞16 ＞16 16 ＞16 ＞16 2 ＞16 2 1 ＞16 ＞16 ＞16 ＞16 ＞16 0.015 ＞16 4 ＞16 ＞16 ＞16 ＞16 16-＞16 ＞16 ＞16 0.002-0.015 1-＞16 0.015-0.125 0.015-0.03 ＞16 ＞16 16-＞16 ＞16 0.5-＞16 0.004 1-＞16 0.002-0.015 0.004 ＞16 ＞16 1-16 16-＞16 0.125-＞16 0.125-2 2-＞16 0.125-2 0.25-1 ＞16 ＞16 ＞16 ＞16 2-＞16 0.008-0.015 4-＞16 0.015-4
Gemifloxacin LZ vancomycin Enterococcus (4 strain) EHEC common product enzyme strain (3) EHEC ESBL strain (4) Cray uncle pulmonitis strain common product enzyme strain (4) the Cray uncle golden MRSA of Portugal of the golden MSSA of Portugal of the golden MRSA of Portugal of the golden MSSA of Portugal of pulmonitis strain ESBL strain (3) pseudomonas aeruginosa (4) the golden MSSA of Portugal (5 strain) the golden MRSA of Portugal (4 strain) streptococcus pneumonia (4 strain) enterococcus (4 strain) EHEC common product enzyme strains (3) EHEC ESBL strains (4) (5 strain) (4 strain) streptococcus pneumonias (4 strain) enterococcus (4 strain) (5 strain) (4 strain) streptococcus pneumonias (4 strain) enterococcus (4 strain) 0.06 ＞16 ＞16 16 ＞16 8 0.002 4 0.004 0.004 ＞16 ＞16 0.5 1 0.5 0.5 0.004 0.5 0.004 0.004 1 ＞16 ＞16 ＞16 ＞16 ＞16 0.004 16 0.25 0.004 ＞16 ＞16 0.5 1 0.5 0.5 0.004 0.5 0.125 0.004 0.06-1 ＞16 ＞16 16-＞16 ＞16 2-＞16 0.002-0.004 0.004-16 0.004-0.25 0.004 ＞16 ＞16 0.5 1 0.5 0.125-0.5 0.004 0.5 0.004-0.125 0.004
Embodiment
In following preparation example and embodiment, will more specifically explain the present invention.But should be understood that following preparation example and embodiment to be intended to the present invention is described and scope of the present invention is not constituted any restriction.Among all embodiment, 1H-NMR Varian Mercury400 nuclear magnetic resonance analyser record, chemical shift is represented with δ (ppm); Separate with the unaccounted 200-300 order that is of silica gel.
Preparation example 1
Synthesizing of 1-(2-cyano group-ethylamino) methyl propionate
1-alanine methyl esters (103.1g 1mol) (Tetrahedron.Lett.42.21.2001.3525-3528) is dissolved in the 300ml methyl alcohol, add third rare nitrile (63.7g, 1.2mol).Stirred reaction mixture is 5 hours under the reflux, removes and desolvates.Underpressure distillation residuum (110-130 ℃/10.0 holder) obtains 64.2g (yield 42.0%) title compound. 1H NMR(CDCl 3，ppm)：δ3.59(3H，s)，2.82(4H，q)，2.42(4H，t)。MS(EI，m/e)：156(M +)
Preparation example 2
Synthesizing of 3-cyano group-1-(N-tertbutyloxycarbonyl)-piperidin-4-one-
Following formula and following various in, Boc represents tertbutyloxycarbonyl.(29.0g 0.186mol) is dissolved in the 200ml chloroform, and to wherein adding two tertbutyloxycarbonyls, two carbonic ethers (45.0g, 1.1mol equivalent), at room temperature stirred reaction mixture is 17 hours with the compound that makes in the preparation example 1.Concentrated reaction solution, residuum dilutes with the 250ml absolute ethanol.Under reflux the solution that forms is added in the alcohol sodium solution, the latter is added to sodium Metal 99.5 (Na) (10.7g, 2.5mol equivalent) to make in the 220ml absolute ethanol.Finish, be reflected at and proceed 1 hour under the reflux again.The concentrating under reduced pressure reaction soln, residue diluted with water is used washed with dichloromethane again.Tell organic layer, water layer is regulated pH value to 4 with 1N hydrochloric acid, uses ethyl acetate extraction.The extraction liquid anhydrous magnesium sulfate drying filters.Concentrated filtrate obtains 33.3g (yield 80.1%) title compound. 1H NMR(CDCl 3，ppm)：δ4.4-2.5(7H，m)，1.45(9H，s)。MS(EI，m/e)：224(M +)
Preparation example 3
Synthesizing of 3-methyl-3-cyano group-1-(N-tertbutyloxycarbonyl)-piperidin-4-one-
Figure A20061002672800242
With the compound that makes in the preparation example 2 (2.24g, 10mmol) and the tetrahydrofuran solution (12ml, 1mol/L, 1.2mol equivalent) of tetra-n-butyl Neutral ammonium fluoride (TBAF) be dissolved in the 100ml tetrahydrofuran (THF).To wherein adding methyl iodide (CH 3I) (2.82g, 2mol equivalent).At room temperature stirred reaction mixture spends the night.Concentrated reaction solution, residuum are dissolved in the 200ml ethyl acetate, washing, and the saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: sherwood oil=1: 10), get 1.49g (yield 63.0%) title compound. 1H NMR(CDCl 3，ppm)：δ4.2(2H，m)，3.4-2.5(4H，m)，1.45(9H，s)，1.4(3H，s)。MS(EI，m/e)：238(M +)
Preparation example 4
The preparation of 3-(N-tertbutyloxycarbonyl) aminomethyl-1,2-(N-tertbutyloxycarbonyl) piperidines-4-alcohol
Figure A20061002672800251
(2.24g 10mmol) is dissolved in 100ml ethanol with the compound that makes in the preparation example 2.Cool off this solution with ice bath, in 20 minutes to wherein add sodium borohydride (0.77g, 2mol equivalent) in batches.Restir reaction mixture 30 minutes is to finish reaction, concentrating under reduced pressure.Residuum is dissolved in the 100ml ethyl acetate, washing, and anhydrous magnesium sulfate drying filters.Concentrated filtrate, obtaining wherein, ketone group is reduced to pure compound.(2.26g 10mmol) is dissolved in the 100ml exsiccant tetrahydrofuran (THF), with ice-salt bath this solution is cooled to-5 ℃ with the alkylol cpd that generates.In 20 minutes to wherein add Li-Al hydrogen (0.60g, 15mmol).The restir reaction mixture is 30 minutes under uniform temp.Reaction finishes the back to wherein adding 0.6ml water, 0.6ml15% sodium hydroxide and 1.8ml water successively.At room temperature stirred this mixture 1 hour.After adding the 1.4g anhydrous magnesium sulfate, this mixture of restir 30 minutes filters.Concentrated filtrate, (2: 1V/V) dilution, to wherein add two tertbutyloxycarbonyls, two carbonic ethers (2.4g, 1.1mol equivalent) in batches, at room temperature stirred reaction mixture is 1 hour with 50ml diox-water with product.Concentration of reaction solution after reaction finishes, residuum dilutes with the 100ml ethyl acetate, the saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 5), get 2.47g (yield 75.2%) title compound. 1H NMR(DMSO-d 6，ppm)：δ4.6(1H，m)，3.8(1H，m)，3.6-2.8(6H，m)，1.6(3H，m)，1.4(18H，s)。MS(EI，m/e)：330(M +)
Preparation example 5
3-methyl-3-(N-tertbutyloxycarbonyl) aminomethyl-1,2-(N-tertbutyloxycarbonyl) piperidines-4-alcohol
Figure A20061002672800252
According to the same steps as of preparation example 4, the compound that is prepared by preparation example 3 makes (yield 70%).
1H NMR(DMSO-d 6，ppm)：δ4.6(1H，m)，3.8(1H，m)，3.6-2.8(5H，m)，2.(1H，m)，1.8-1.6(2H，m)，1.4(18H，s)，0.9(3H，s)。MS(EI，m/e)：344(M +)
Preparation example 6
3-(N-methyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-pure and mild 4-(N-methyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol
(N-tertbutyloxycarbonyl)-4-nitrogen-7-oxabicyclo [4.1.0] heptane (Tetrahedron.Lett.45.37.2004.6841-6846) (19.9g, 0.1mol) be dissolved in 200ml ethanol, add 100ml 30% aqueous methylamine solution (excessive greatly), 50-60 ℃ was stirred 15 hours.Concentration of reaction solution after reaction finishes, residuum is dissolved in the 200ml chloroform, adds two tertbutyloxycarbonyls, two carbonic ethers (24g, 1.1mol equivalent), and at room temperature stirred reaction mixture is 17 hours.The reaction solution washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 5), get 9.9g (yield 30.4%) compound 3-(N-methyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-alcohol. 1H NMR(CDCl 3，ppm)：δ4.4-3.5(4H，m)，2.8(3H，s)，2.6(2H，m)，1.7(2H，m)，1.4(18H，s)。MS(EI，m/e)：330(M +)
Can obtain simultaneously compound 4-(N-methyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol 11.6g (yield 35.1%). 1H NMR(CDCl 3，ppm)：δ4.4-3.5(4H，m)，2.8(3H，s)，2.6(2H，m)，1.7(2H，m)，1.4(18H，s)。MS(EI，m/e)：330(M +)
Preparation example 7
3-(N-cyclopropyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-pure and mild 4-(N-cyclopropyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol
Figure A20061002672800261
According to the same steps as of preparation example 6, attack reagent is cyclopropylamine, can make 3-(N-cyclopropyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-alcohol (yield 25.0%). 1H NMR(CDCl 3，ppm)：δ4.4-3.6(4H，m)，2.5(2H，m)，2.4(1H，m)，2.0(1H，m)，1.8(1H，m)，1.4(18H，s)，0.9(4H，m)。MS(EI，m/e)：356(M +)
Simultaneously can obtain compound 4-(N-cyclopropyl-N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol (yield 30.1%). 1H NMR(CDCl 3，ppm)：δ4.4-3.6(4H，m)，2.5(2H，m)，2.4(1H，m)，2.0(1H，m)，1.8(1H，m)，1.4(18H，s)，0.9(4H，m)。MS(EI，m/e)：356(M +)
Preparation example 8
3-(N, N-dimethyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-alcohol
Figure A20061002672800262
(10.0g 0.05mol) is dissolved in 100ml ethanol to (N-tertbutyloxycarbonyl)-4-nitrogen-7-oxabicyclo [4.1.0] heptane, adds 100ml 33% dimethylamine agueous solution (excessive greatly), stirs 15 hours under the reflux.Concentration of reaction solution after reaction finishes, residuum is dissolved in the 100ml ethyl acetate, washing, the saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 1), get 3.7g (yield 30.0%) title compound. 1H NMR(CDCl 3，ppm)：δ4.2(2H，m)，3.5(1H，m)，3.0(1H，m)，2.6(2H，m)，2.4(6H，s)，2.2(2H，m)1.4(9H，s)。MS(EI，m/e)：244(M +)
Preparation example 9
3-(N-tertbutyloxycarbonyl) the pure and mild 4-of amino-1-(N-tertbutyloxycarbonyl) piperidines-4-(N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol
Figure A20061002672800271
According to the same steps as of preparation example 6, attack reagent is ammoniacal liquor, can make 3-(N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-4-alcohol (yield 25.0%). 1H NMR(CDCl 3，ppm)：δ4.7(1H，m)，4.0-3.4(4H，m)，3.0(1H，m)，2.9(1H，m)，1.9(1H，m)，1.5(1H，m)，1.45(9H，s)。MS(EI，m/e)：316(M +)
Simultaneously can obtain compound 4-(N-tertbutyloxycarbonyl) amino-1-(N-tertbutyloxycarbonyl) piperidines-3-alcohol (yield 30.1%). 1H NMR(CDCl 3，ppm)：δ4.6(1H，m)，4.2(2H，m)，3.4(2H，m)，2.7(1H，m)，2.6(1H，m)，1.9(1H，m)，1.42(9H，s)，1.4(1H，m)。MS(EI，m/e)：316(M +)
Preparation example 10
The preparation of 3-(N-tertbutyloxycarbonyl) aminomethyl-1,2-(N-tertbutyloxycarbonyl) piperidin-4-one-
(14.5g 0.044mol) is dissolved in the 64ml dimethyl sulfoxide (DMSO), and adds triethylamine (18.5ml, 3mol equivalent) with the compound that makes in the preparation example 4.Ice bath cools off this compound to 5 ℃, adds pyridine-sulphur trioxide (Py-SO in batches 3) oxygenant (12.7g, 1.8mol equivalent).Finish and remove ice bath, stirring at room 5 hours.The reaction solution dilute with water is used ethyl acetate extraction.The extraction liquid anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 4), get 10.9g (yield 75.0%) title compound. 1H NMR(CDCl 3，ppm)：δ4.6(1H，m)，4.1(1H，m)，3.3-2.4(7H，m)，1.4(18H，s)。MS(EI，m/e)：328(M +)
Preparation example 11-18
Below the listed compound of table 5 can be by preparation example 5,6,7,8 gained compounds are according to the identical steps preparation of preparation example 10.
Table 5 preparation example 11-18
Figure A20061002672800291
Preparation example 19
The preparation of 1-(N-tertbutyloxycarbonyl)-3-(N-tertbutyloxycarbonyl) amino methyl-piperidin-4-one-oxime
Figure A20061002672800292
(315mg 0.96mmol) is dissolved in the mixture of 6ml95% ethanol and 3ml tetrahydrofuran (THF), to wherein adding oxammonium hydrochloride (NH with prepared compound in the preparation example 10 2OH-HCl) (232mg, 3.5mol equivalent) adds the sodium bicarbonate (281mg, 3.5mol equivalent) that is dissolved in the 3ml distilled water again.40 ℃ of stirred reaction mixtures 40 minutes.Postcooling reaction solution, concentrating under reduced pressure are finished in reaction.Residuum dissolves with ethyl acetate 50ml.The saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 2), get 230mg (yield 70.2%) title compound. 1H NMR(CDCl 3，ppm)：δ4.9(1H，m)，4.2(1H，m)，3.3-2.4(8H，m)，1.4(18H，s)。MS(EI，m/e)：343(M +)
Preparation example 20-27
Below the listed compound of table 6 can be by preparation example 11-18 gained compound according to the identical steps preparation of preparation example 19.
Table 6 preparation example 20-27
Figure A20061002672800293
Figure A20061002672800301
Preparation example 28
The preparation of 1-(N-tertbutyloxycarbonyl)-3-(N-tertbutyloxycarbonyl) amino methyl-piperidin-4-one-methyloxime
Figure A20061002672800312
With prepared compound (273mg in the preparation example 10,0.83mmol) be dissolved in the mixture of 5ml95% ethanol and 2.5ml tetrahydrofuran (THF), to the hydrochloride (256mg that wherein adds methoxyl group amine, 3.7mol equivalent), add the sodium bicarbonate (256mg, 3.7mol equivalent) that is dissolved in the 2.5ml distilled water again.40 ℃ of stirred reaction mixtures 40 minutes.Postcooling reaction solution, concentrating under reduced pressure are finished in reaction.Residuum dissolves with ethyl acetate 50ml.The saturated common salt washing, anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 4), get 260mg (yield 85.0%) title compound. 1H NMR(CDCl 3，ppm)：δ4.9(1H，m)，4.2(1H，m)，3.8(3H，s)，3.3-2.4(8H，m)，1.4(18H，s)。MS(EI，m/e)：357(M +)
Preparation example 29-36
Below the listed compound of table 7 can be by preparation example 11-18 gained compound according to the identical steps preparation of preparation example 28.
Table 7 preparation example 29-36
Figure A20061002672800313
Figure A20061002672800321
1.45(18H，s)
Preparation example 37
The preparation of 1-(N-tertbutyloxycarbonyl)-3-(N-tertbutyloxycarbonyl) amino methyl-piperidin-4-one-benzyl oxime
Figure A20061002672800331
With prepared compound (343mg in the preparation example 19,1mmol) be dissolved in the 15ml methylene dichloride, to wherein adding tetra-n-butyl ammonium bromide (97mg, 0.25mol equivalent), add 5ml 15% aqueous sodium hydroxide solution and cylite (428mg, 2mol equivalent) again.Stirring at room reaction mixture 3 hours.After finishing, reaction tells organic layer, the saturated common salt washing, and anhydrous magnesium sulfate drying filters.Concentrated filtrate, thick product column chromatography (ethyl acetate: normal hexane=1: 5), get 327mg (yield 82.2%) title compound. 1H NMR(CDCl 3，ppm)：δ7.38(5H，m)，5.13(2H，s)，4.95(1H，bs)，3.7-2.4(9H，m)，1.45(9H，s)，1.42(9H，s)。MS(EI，m/e)：433(M +)
Preparation example 38-72
Below the listed compound of table 8 can be by preparation example 20-27 gained compound and various haloalkanes according to the identical step reaction preparation of preparation example 37.
Table 8 preparation example 38-72
Figure A20061002672800332
Figure A20061002672800351
Figure A20061002672800361
Figure A20061002672800371
Figure A20061002672800381
Figure A20061002672800391
Embodiment 1:
7-(3-methylamino--4-methoxyimino-piperidines-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid
(460mg 1.3mmol) is dissolved in the 5ml tetrahydrofuran (THF), adds methanesulfonic (370mg, 3mol equivalent), stirring at room 5 hours with the compound that makes in the preparation example 30.The concentrating under reduced pressure reaction mixture is dissolved in the minimum acetonitrile, solidifies with ether, can get 3-methylamino--4-methoxyimino-piperidines dimethanesulfonate of 380mg (productive rate 85.1%).
With 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, (92mg 0.33mmol) is suspended in the 10ml acetonitrile with 3-methylamino--4-methoxyimino-piperidines dimethanesulfonate (380mg, 3.3mol equivalent) to 8-naphthyridine-3-carboxylic acid.Under the ice bath cooling, slowly to wherein adding 1,8-diazabicyclo [5,4,0] 11 carbon-7-alkene (DBU) (500mg, 10mol equivalent).Finish and slowly rise to room temperature, mixture stirring at room 3 hours.Add 10ml water, leach solid, filter cake washes with water, and acetonitrile is washed, and obtains 110mg (productive rate 83.0%) title compound.Total recovery (71.0%). 1H NMR(DMSO-d 6，ppm)：δ8.62(1H，s)，8.05(1H，d)，4.38(2H，m)，3.79(3H，s)，3.73(2H，m)，3.20(1H，m)，2.85(2H，m)，2.18(3H，s)，1.05-1.25(4H，m)。MS(ESI，m/e)：404(M ++H)
Embodiment 2-40
Below the listed compound of table 9 can be by preparation example 19,20,28,29,31-34 and 37-72 gained compound are according to the identical step preparation of embodiment 1.
Wherein Q is
Figure A20061002672800402
Table 9 embodiment 2-40
Figure A20061002672800411
Figure A20061002672800421
Figure A20061002672800431
Figure A20061002672800461
Embodiment 41
7-(3-amino-4-methoxyimino-piperidines-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1, the mesylate of 8-naphthyridine-3-carboxylic acid
Figure A20061002672800482
(400mg 1.2mmol) is dissolved in the 5ml tetrahydrofuran (THF), adds methanesulfonic (350mg, 3mol equivalent), stirring at room 5 hours with the compound that makes in the preparation example 35.The concentrating under reduced pressure reaction mixture is dissolved in the minimum acetonitrile, solidifies with ether, can get 3-amino-4-methoxyimino-piperidines dimethanesulfonate 340mg (productive rate 87.0%).
(340mg 1.02mmol) is dissolved in 2.85ml acetonitrile and the 0.15ml water with 3-amino-4-methoxyimino-piperidines dimethanesulfonate.Ice bath is cooled to 0-5 ℃, adds phenyl aldehyde (132mg, 1.2mol equivalent) and triethylamine (314mg, the 3mol equivalent), stir adding 7-chloro-1-cyclopropyl-6-fluoro-1 after 0.5 hour, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (113mg, 0.4mmol).Slowly rise to room temperature, restir 3 hours.Leach solid, filter cake washes with water, and acetonitrile is washed, and obtains 7-(3-benzylidene amino-4-methoxyimino-piperidines-1-the yl)-1-cyclopropyl-6-fluoro-1 of 160mg (productive rate 84.0%), 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid.
7-(3-benzylidene amino-4-methoxyimino-piperidines-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (160mg, 0.33mmol) be dissolved in 0.3ml water and the 1ml Virahol, oil bath is heated to 40-45 ℃, slowly drip methylsulfonic acid (32mg, 1mol equivalent).40-45 ℃ was stirred 0.5 hour, and slowly was chilled to room temperature, restir 17 hours.Leach solid, filter cake is washed with Virahol, obtains the title compound of 130mg (productive rate 81.0%).Total recovery (59.2%). 1H NMR(DMSO-d 6，ppm)：δ8.65(1H，s)，8.19(1H，d)，4.68(1H，m)，4.35(1H，m)，4.28(1H，m)，3.89(3H，s)，3.75(1H，m)，3.56(2H，m)，3.10(1H，m)，2.45(1H，m)，2.18(3H，s)，1.25-1.05(4H，m)。MS(ESI，m/e)：390(M ++H)
Embodiment 42-47
Below the listed compound of table 10 can be by preparation example 36 and 68-72 gained compound according to the identical steps preparation of embodiment 41.
Wherein Q is
Figure A20061002672800491
Table 10 embodiment 42-47
Figure A20061002672800492
Figure A20061002672800501

Claims (10)

1. the following quinolone compounds that contains oximido and pharmacologically acceptable salts or their solvate of a class general formula,
Figure A2006100267280002C1
Among its Chinese style I
R 5Be H, NH 2
X 8Be CH, CF, C-OCH 3, C-CH 3Or N;
R 7For:
In the formula
R 1Be H or CH 3
R 2Be hydrogen, straight or branched C 1-C 4Alkyl, cyclopropyl, cyclopropyl methyl, C 3-C 6Alkynyl, 2-halogenated ethyl, methoxymethyl, methoxycarbonyl methyl, aryl or allyl group;
R 3Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
R 4Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
M is 0 or 1.
2. quinolone compounds and pharmacologically acceptable salts or their solvate that contains oximido according to claim 1 is characterized in that working as R 7For
R in the formula 5Be H, NH 2
X 8Be CH, CF, COCH 3,-CH 3Or H:
R 1Be H or CH 3
R 2Be hydrogen, straight or branched C 1- C4Alkyl, cyclopropyl, cyclopropyl methyl, C 3-C 6Alkynyl, 2-halogenated ethyl, methoxymethyl, methoxycarbonyl methyl, aryl or allyl group;
R 3Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
R 4Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
M is 0 or 1.
3. quinolone compounds and pharmacologically acceptable salts or their solvate that contains oximido according to claim 1 is characterized in that working as R 7For
R in the formula 5Be H, NH 2
X 8Be CH, CF, COCH 3,-CH 3Or N:
R 1Be H or CH 3
R 2Be hydrogen, straight or branched C 1-C 4Alkyl, cyclopropyl, cyclopropyl methyl, C 3-C 6Alkynyl, 2-halogenated ethyl, methoxymethyl, methoxycarbonyl methyl, aryl or allyl group;
R 3Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
R 4Be H, straight or branched C 1-C 4Alkyl, cycloalkyl;
M is 0 or 1.
4. quinolone compounds and acceptable salt of medical science or their solvate that contains oximido according to claim 1 is characterized in that formula I compound comprises their S or R or S and the existence of R form of mixtures.
5. quinolone compounds and pharmacologically acceptable salts or their solvate that contains oximido according to claim 1 comprises its suitable, trans-isomer(ide) and their mixture when it is characterized in that having oximido in the formula I compound.
6. the preparation method who contains quinolone compounds and the pharmacologically acceptable salts or their solvate of oximido as claimed in claim 1 is characterized in that being made by following steps:
The III compound in organic solvent alkali in the presence of, temperature of reaction is-10-200 ℃ down must target compound Ia or Ib with IIa or the reaction of IIb compound 1-20 hour;
The IIaa of III compound and amino protecting group P protection or IIbb react Iaa or Ibb compound, again by hydrolysis, solvolysis or reduction desamidizate must protect basic P, must target compound Ia or Ib;
Figure A2006100267280005C1
Have the amino cyano group ester 1 of protection at C 1-C 4The reaction of alcoholic solvent and sodium alkoxide, 3-cyano group-4-ketone piperidines 2, compound 2 under alkaline condition with haloalkane R 1X reaction, compound 3, earlier the ketone group of compound 3 is reduced into hydroxyl and restores cyano group and get amino alcohol 4; the amino compound 5 that gets of selective protection compound 4 gets ketone compound 6 through oxidation again, and compound 6 reacts with the oxyamine that alcoxyl replaces; obtain oxime compound 7, the deprotection base gets R again 5And R 1For hydrogen m be 1 the IIa compound;
Ketone compound 6 obtains oxime compound 8, compound 8 and R with azanol reaction 2X electrophilic compound prepared in reaction in the presence of alkali get compound 79 oxime derivates again the deprotection base get oxime compound IIa;
Figure A2006100267280006C1
The piperidine ring oxygen compound 9 that has protecting group is amino with the protecting group protection then with the amine reaction of ammoniacal liquor or monoalkyl replacement in solvent, get compound 11, compound 10 or 11 separates by column chromatography silica gel, again with the method selective oxidation 10 of above-mentioned reaction scheme III or 11 ketone compound 12 or 13, obtained oxime compound IIa or IIb respectively by reaction scheme III or IV again;
Figure A2006100267280006C2
The amine reaction that the piperidine ring oxygen compound compound 9 that has a protecting group replaces with two alkyl in solvent, compound 16,16 obtains 17,17 through oxidation and obtains oxime compound IIa with the hydroxylamine derivative condensation;
IIa or IIb selective protection uncle ammonia get IIaa and IIbb.
7. the preparation method who contains quinolone compounds and the pharmacologically acceptable salts or their solvate of oximido according to claim 6, it is characterized in that step I reaction solvent is selected from acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), pyridine or hexamethylphosphoramide, alkali is selected from the mineral alkali of sodium bicarbonate or salt of wormwood, organic bases is selected from triethylamine, diisopropylethylamine, pyridine, N, accelerine, N, the N-dimethyl aminopyridine, 1,8-diazabicyclo [5,4,0]+-carbon-7-alkene, temperature of reaction is controlled at-10-200 ℃ under, reaction times 1-20 hour.
8. the preparation method who contains quinolone compounds and the pharmacologically acceptable salts or their solvate of oximido according to claim 6, when it is characterized in that the reaction of Compound I Ia or IIb and III compound, hydrochloride, hydrobromate or trifluoroacetate in the form of use free alkali form or salt.
9. the preparation method who contains quinolone compounds and the pharmacologically acceptable salts or their solvate of oximido according to claim 6 is characterized in that amino protecting group P is selected from formyl radical, ethanoyl, trifluoroacetyl group, benzoyl, right-tosyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or right-methoxyl group benzyloxy base carbonyl.
10. the purposes that contains quinolone compounds and the pharmacologically acceptable salts or their solvate of oximido as claimed in claim 1, the medicine that prevent in preparation, treatment is caused disease by the infection of gram yin, yang bacterium.
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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2008008398A2 (en) 2006-07-14 2008-01-17 Shionogi & Co., Ltd. Oxime compounds and the use thereof
WO2009030106A1 (en) * 2007-09-03 2009-03-12 Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences 7-(4-oximino-3-amino-1-piperidyl)quinolinecarboxylic acid derivatives and their preparation methods
CN101450938B (en) * 2007-12-04 2012-11-14 中国医学科学院医药生物技术研究所 7-(4-oximido-3-amido-3-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof
US8518934B2 (en) 2008-06-11 2013-08-27 Shonogi & Co., Ltd. Oxycarbamoyl compounds and the use thereof
US8563732B2 (en) 2007-05-31 2013-10-22 Shionogi & Co., Ltd. Oxyimino compounds and the use thereof
CN103739591A (en) * 2014-01-02 2014-04-23 浙江司太立制药股份有限公司 7-(3-acylamino-4-oxyiminomethyl-1-piperidyl) fluoroquinolone carboxylic acid and preparation method thereof
CN105377812A (en) * 2013-06-21 2016-03-02 庵原化学工业株式会社 Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof
CN109608460A (en) * 2018-12-17 2019-04-12 上海合全药业股份有限公司 A kind of synthetic method of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008008398A2 (en) 2006-07-14 2008-01-17 Shionogi & Co., Ltd. Oxime compounds and the use thereof
US8563732B2 (en) 2007-05-31 2013-10-22 Shionogi & Co., Ltd. Oxyimino compounds and the use thereof
WO2009030106A1 (en) * 2007-09-03 2009-03-12 Institute Of Medicinal Biotechnology Chinese Academy Of Medical Sciences 7-(4-oximino-3-amino-1-piperidyl)quinolinecarboxylic acid derivatives and their preparation methods
CN101450938B (en) * 2007-12-04 2012-11-14 中国医学科学院医药生物技术研究所 7-(4-oximido-3-amido-3-alkyl-1-piperidine)quinoline carboxylic acid derivates and preparation method thereof
US8518934B2 (en) 2008-06-11 2013-08-27 Shonogi & Co., Ltd. Oxycarbamoyl compounds and the use thereof
CN105377812A (en) * 2013-06-21 2016-03-02 庵原化学工业株式会社 Manufacturing method for 2-amino-2-hydroxyimino-n-alkoxy acetoimidoyl cyanide, and manufacturing intermediate thereof
CN105377812B (en) * 2013-06-21 2018-09-18 组合化学工业株式会社 The preparation method of 2- amino -2- oximido-N- alkoxy acetimidoyl cyanides and its prepare intermediate
CN103739591A (en) * 2014-01-02 2014-04-23 浙江司太立制药股份有限公司 7-(3-acylamino-4-oxyiminomethyl-1-piperidyl) fluoroquinolone carboxylic acid and preparation method thereof
CN109608460A (en) * 2018-12-17 2019-04-12 上海合全药业股份有限公司 A kind of synthetic method of 1,10- dioxy subunit -2,7- diaza spiro [4.5] decane -7- t-butyl formate

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