CN101070308B - Isoxazoline derivative and its use - Google Patents
Isoxazoline derivative and its use Download PDFInfo
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Abstract
This invention belongs to the infection correlative medicine field, provides a dihydroisoxazol derivates having a structure of formula (I) and pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or C1-C6 alkyl, R3 is R8(N)-, R3 is hydrogen or single substituted or polysubstituted C1-C6 alkyl, R4 is single substituted or polysubstituted halogen, R5 is C1-C6 alkyl, halogen single substituted or polysubstituted C1-C6 alkyl, wherein the R6, R7 and R8 are defined as described in specification. The invention also provides the application of the compound or the pharmaceutically acceptable salt as medicines, especially as antibacterial medicines.
Description
Technical field
The invention belongs to and infect relevant pharmaceutical field, more particularly, relate to new the having anti-microbial activity De iso-oxazoline derivates and preparation method thereof, contain their pharmaceutical composition and of a class as the purposes of antibacterials.
Background technology
In recent years, the resistant organism development of all kinds of microbiotic and antiseptic-germicide rapidly, for example: methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE), penicillin resistant streptococcus pneumoniae (PRSP), multi-drug resistant tubercule bacillus, especially the appearance of vancomycin-resistant enterococcus (VRE) has caused huge difficulty to clinical treatment.
Oxazolidine ketone antimicrobial drug is the complete synthesis antimicrobial drug of a class new chemical, the representative of such medicine is the linezolid (linezolid) of drugs approved by FDA listing in 2000, demonstrating effect preferably aspect treatment multidrug resistant gram-positive microorganism and the mycobacterium tuberculosis infection, yet, through clinical use in a few years, the report that existing resistant organism produces, therefore, people also can need the new antibacterials of development constantly in the face of the resistance problem of bacterium.
People have begun to seek new antibacterials in the Zai isoxazoline compounds, and main report has: the aminophenyl that WO9941244 discloses as antiseptic-germicide replaces the De iso-oxazoline derivates; US70815838 discloses and has replaced De iso-oxazoline and they purposes as biocide; DE19909785A1 discloses 3-(condensed ring replaces) phenyl-5-carbonyl (or thiono) acyl aminomethyl isoxazoline derivative as antiseptic-germicide; The 5-nitrofuran base that US3769295 discloses as biocide replaces the De isoxazoline derivative; WO9514680 discloses the 3-aryl-2-isoxazoline as anti-inflammatory agent; WO03/008395 discloses and has replaced De isoxazole and they purposes as biocide; WO96/13502 discloses the phenyl oxazolidone biocide; WO93/09103 discloses substituted aryl and heteroaryl-phenyl oxazolidinones as biocide.
Summary of the invention
An object of the present invention is in order to overcome the resistance problem of bacterium, the antibacterials of development new texture provide Xin Xing iso-oxazoline derivates and pharmacy acceptable salt thereof with general formula I structure.
Another object of the present invention provides the compound with general formula I structure or the preparation method of its pharmacy acceptable salt.
A further object of the present invention provides the compound that contains the general formula I structure or its pharmacy acceptable salt as effective constituent, and the medicinal compositions that contains one or more pharmaceutically acceptable carriers, vehicle or thinner, and in the application of antibiosis.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
Compound of Formula I of the present invention has following structural formula:
Wherein:
n＝1，2，3；
R
1For: hydrogen; C
1-C
6Alkyl;
R
2For:
Wherein:
R
6For:
Hydrogen;
C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
By halogen, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Group list or polysubstituted C such as dialkyl amido, aryl, substituted aryl
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
R
7For:
C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
By halogen, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Group list or polysubstituted C such as dialkyl amido, aryl, substituted aryl
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
2. R
8(N)-; Wherein, R
8For:
The C that contains one or more nitrogen heteroatoms
5-C
6Heterocyclic radical;
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halo C
1-C
4Alkyl, halo C
1-C
4Alkoxyl group, C
3-C
6Cycloalkyl, halogen, itrile group, carbonyl, carboxyl, hydroxyl, nitro, amino, amide group, aryl, substituted aryl, C
3-C
6Group list or the polysubstituted C that contain one or more nitrogen heteroatoms such as heterocyclic radical
5-C
6Heterocyclic radical.
R
3: be hydrogen, the single replacement or polysubstituted C
1-C
6Alkyl.
R
4: replace or polysubstituted halogen for single.
R
5: be C
1-C
6Alkyl is replaced or polysubstituted C by the halogen list
1-C
6Alkyl.
Preferred following compound of Formula I or its pharmacy acceptable salt, wherein,
R
1For:
Hydrogen;
Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl;
R
6For:
Hydrogen;
Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
By fluorine, chlorine, bromine, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Group lists such as dialkyl amido, aryl, substituted aryl or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
By C
1-C
6Alkyl, C
1-C
6Group lists such as alkoxyl group, fluorine, chlorine, itrile group, amino, hydroxyl, nitro or polysubstituted phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
R
7For:
Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
By fluorine, chlorine, bromine, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Group lists such as dialkyl amido, aryl, substituted aryl or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
By C
1-C
6Alkyl, C
1-C
6Group lists such as alkoxyl group, fluorine, chlorine, bromine, itrile group, amino, hydroxyl, nitro or polysubstituted phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
R
8For:
Piperidines, morpholine, piperazine, pyridine, triazole, pyrazoles;
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halo C
1-C
4Alkyl, halo C
1-C
4Alkoxyl group, C
3-C
6Cycloalkyl, fluorine, chlorine, bromine, itrile group, carbonyl, carboxyl, hydroxyl, nitro, amino, amide group, aryl, substituted aryl, C
3-C
6Group lists such as heterocyclic radical or polysubstituted piperidines, morpholine, piperazine, pyridine, triazole, pyrazoles.
R
3: be hydrogen, list or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl.
R
4: replace or polysubstituted fluorine, chlorine for single.
R
5: be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, perhaps by fluorine, the replacement of chlorine list or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl.
More preferably following compound of Formula I or its pharmacy acceptable salt, wherein,
I-1:(±)-N-[[3-[3-fluoro-4-[4-(1-piperidines ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] the acetyl amine salt.
I-2:(±)-N-[[3-[3-fluoro-4-[4-(4-methylpiperazine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-3:(±)-N-[[3-[3-fluoro-4-[4-[4-(2-p-methoxy-phenyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-4:(±)-N-[[3-[3-fluoro-4-[4-[4-(4-p-methoxy-phenyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-5:(±)-N-[[3-[3-fluoro-4-[4-(4-carboxamide piperidyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-6:(±)-N-[[3-[3-fluoro-4-[4-(4-benzhydryl piperazidine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-7:(±)-N-[[3-[3-fluoro-4-[4-(4-cinnamyl piperazine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-8:(±)-N-[[3-[3-fluoro-4-[4-(3,5-lupetidine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-9:(±)-N-[[3-[3-fluoro-4-[4-[4-(4-fluorophenyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-10:(±)-N-[[3-[3-fluoro-4-[4-(4-cyclohexyl piperazinyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-11:(±)-N-[[3-[3-fluoro-4-[4-(4-phenmethyl piperazinyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-12:(±)-N-[[3-[3-fluoro-4-[4-[4-(2-furancarbonyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-13:(±)-N-[[3-[3-fluoro-4-[4-[4-(2-pyridyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-14:(±)-N-[[3-[3-fluoro-4-[4-[4-(4-nitrophenyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-15:(±)-N-[[3-[3-fluoro-4-[4-[(1,2, the 4-triazolyl)-the 1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-16:(±)-N-[[3-[3-fluoro-4-[4-[[N-benzyl-1-methyl-2-(4-p-methoxy-phenyl)] the ethylamino ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-17:(±)-N-[[3-[3-fluoro-4-[4-[N, N-two (2-hydroxyethyl) glycyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-18:(±)-N-[[3-[3-fluoro-4-[4-[N, N-two (2-chloroethyl) glycyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-19:(±)-N-[[3-[3-fluoro-4-[4-(3-hydroxy piperidine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-20:(±)-N-[[3-[3-fluoro-4-[4-(3-carboxyl piperidyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-21:(±)-N-[[3-[3-fluoro-4-[4-[4-(2-tetrahydrofuran (THF) formyl radical) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-22:(±)-N-[[3-[3-fluoro-4-[4-[4-(4-hydroxy phenyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-23:(±)-N-[[3-[3-fluoro-4-[4-[4-(2-hydroxyethyl) piperazinyl-1-ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-24:(±)-N-[[3-[3-fluoro-4-[4-[2-(4-carboxamide piperidyl)-1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-25:(±)-N-[[3-[3-fluoro-4-[4-[2-[4-(4-nitrophenyl) piperazinyl]-the 1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-26:(±)-N-[[3-[3-fluoro-4-[4-[2-[4-(2-pyridyl) piperazinyl]-the 1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-27:(±)-N-[[3-[3-fluoro-4-[4-[2-(3-carboxyl piperidyl)-1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
I-28:(±)-N-[[3-[3-fluoro-4-[4-(4-methylpiperazine base-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] acetamide hydrochloride.
I-29:(±)-N-[[3-[3-fluoro-4-[4-(4-cyclohexyl piperazinyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] the ethanamide Citrate trianion.
I-30:(±)-N-[[3-[3-fluoro-4-[4-(3-carboxyl piperidyl-1-ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide sylvite.
Compound of Formula I of the present invention is synthetic by following steps:
Wherein, X, Y are chlorine, bromine at the same time or separately, R
1, R
2, R
3, R
4, R
5Definition with above described.
With reference to the method that WO99/41244 provides, be starting raw material with halogenophenyl formaldehyde (1), make corresponding oxime, oximido halogenide, then add in the suitable alkali as triethylamine, obtain itrile oxides (2).Compound 2 generates compound 4 with allyl group amides (3) cyclization.Compound 4 reacts with compound 5 again, prepares compound 6.
Compound 6 is dissolved in organic molten coal, in solvents such as dehydrated alcohol, methyl alcohol, Virahol, methylene dichloride, trichloromethane, ethyl acetate, and add attached sour agent triethylamine, salt of wormwood etc., with haloalkyl acyl halides compound (7) under-15～80 ℃, behind stirring reaction 1～5h, washing in right amount under the room temperature with the extraction of organic solvents such as trichloromethane, ethyl acetate, dry, underpressure distillation, obtains compound 8 again.Compound 8 generates crude product with amino compound (9) reaction again, separates making compound of Formula I through silica gel column chromatography.
The pharmacy acceptable salt of formula I compound of the present invention means: The compounds of this invention and mineral acid, organic acid salify, particularly preferred salt is: hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, lactic acid salt, mesylate, tosilate, maleate, benzoate, succinate, tartrate, citrate, fumarate, taurate or the like.In addition, salt of the present invention can also be the salt that compound and potassium hydroxide, sodium hydroxide form.The preparation method of the pharmacy acceptable salt of formula I compound of the present invention is that formula I compound is dissolved in dropping inorganic acid in the organic solvent, organic acid salify; Also can form pharmacy acceptable salt with potassium hydroxide, sodium hydroxide.Specifically be that formula I compound is dissolved in dehydrated alcohol, ice-water bath is cold, and the dripping hydrochloric acid ethanolic soln is made hydrochloride or formula I compound is dissolved in dehydrated alcohol, adds to wait the mole citric acid, gets its Citrate trianion.Also formula I compound can be dissolved in anhydrous methanol, drip potassium hydroxide aqueous solution, transfer PH11, make its sylvite or the like.
The preparation of pharmaceutical compositions of The compounds of this invention is as follows: use standard and conventional technology; acceptable solid or liquid vehicle are combined, and make it at random to combine and be prepared into particulate or microballoon with acceptable auxiliary and vehicle on the technology of pharmaceutics.Solid dosage comprises tablet, discrete particles, capsule, slow releasing tablet, sustained release pellet or the like.Solid carrier can be at least a material, and it can serve as thinner, flavouring agent, solubilizing agent, lubricant, suspension agent, tackiness agent, disintegrating agent and coating agent.Inert solid carrier comprises trimagnesium phosphate, Magnesium Stearate, smoothers sugar, lactose, pectin, propylene glycol, Polysorbate 80, dextrin, starch, gelatin, cellulose substances for example methylcellulose gum, Microcrystalline Cellulose, low melt point paraffin, polyoxyethylene glycol, N.F,USP MANNITOL, theobroma oil etc.Liquid dosage form comprises solvent, suspension for example injection, pulvis or the like.
The amount of the active ingredient that contains in pharmaceutical composition and the unit dosage form (The compounds of this invention) can be according to patient's the state of an illness, specific being applied of situation of diagnosis, the amount of used compound or concentration are regulated in the scope of a broad, usually, the weight range of active compound is 0.5%～90% (weight) of composition.Another preferred range is 0.5%-70%.
Further specify the restraining effect of The compounds of this invention below by bacteriostatic experiment to bacterium.
Substratum: microorganism identification substratum PH 7.9 ± 0.1 Beijing three medicine scientific and technological development company products; Bacterial classification: standard gold staphylococcus aureus CMCC26003, standard Sarcina lutea CMCC28001, standard Pseudomonas aeruginosa CMCC10211, standard klebsiella pneumoniae CMCC46117, above bacterial classification is all purchased in Nat'l Pharmaceutical ﹠ Biological Products Control Institute.
(1) mensuration of fungistatic effect (inhibition zone mensuration)
The sample preparation: take by weighing above-mentioned each sample of about 2mg respectively, in the 50ml volumetric flask, after a spot of DMF dissolving, add to scale with distilled water, concentration is 10 μ mol/L, and filtration sterilization is with the centrifuge tube packing of 2ml.
The preparation of culture dish: the microorganism identification substratum I after a certain amount of sterilization (making substratum thickness is 3mm), be chilled to 48-50 ℃, add an amount of bacterium liquid (bacteria concentration is 0.1%) respectively, pour in the culture dish of the level of mixing up, carefully drive bubble away, after the culture medium solidifying, carry out mark in the graze cattle position of Tianjin cup of needs, standby.
The mensuration of sample: at interval 2.5-3cm places the Oxford cup on culture dish, notes correspondingly with mark position, gets each sample 50 μ l application of sample with micro sample adding appliance, is 2-3 and manages again, carries out the application of sample record, is placed on 37 ℃ of CO
2After cultivating 16-18h in the incubator, use the vernier caliper measurement antibacterial circle diameter.
(2) mensuration of minimal inhibitory concentration (MIC)
Adopt doubling dilution.Add bacterium liquid and broth culture contrast in first 1 hole, 12 holes respectively, then in the 2-11 hole, from the lower concentration to the high density, add the above-mentioned sample solution 0.25 μ gmL that uses the substratum doubling dilution successively with micro-adjustable pipette at already sterilised 96 orifice plates
-1--128 μ gmL
-1, every hole 100 μ l add dilution bacterium liquid 100 μ l then in every hole, make that sample concentration is respectively 0.125,0.25,0.5,1,2,4,8,16,32,64 μ gmL in each hole
-1Place the 1min that vibrates on the vibrator, make in the hole behind the abundant mixing of solution, microwell plate is added a cover blended rubber paper sealing and is hatched evaporation in the process with minimizing, hatches 18h in 37 ℃ of incubators, and naked-eye observation does not have the contained lowest concentration of drug in bacterial growth hole and is minimal inhibitory concentration.Experiment repeats 3 times, asks its mean value.
Figure of description
Fig. 1 Wei isoxazoline derivative (I) structural formula.
Embodiment:
The present invention is described further below in conjunction with embodiment, embodiment only is indicative, mean that never it limits the scope of the invention by any way, the compound of invention is through high performance liquid chromatography (HPLC), thin-layer chromatography (TLC), fusing point (m.p.) detects, can also adopt subsequently nucleus magnetic resonance (
1HNMR/
13CNMR) prove conclusively its structure.
Reference example 1 (preparation of compound 6)
With 3, the 4-difluorobenzaldehyde is a starting raw material, under strong alkaline condition, generate 3 with the oxammonium hydrochloride reaction, 4-two fluorobenzene oximes generate 3, the muriate of 4-two fluorobenzene oximes with the reaction of N-chlorosuccinimide again, generate (±)-N-5-(ethanamide methyl)-3-(3 with the cyclization of allyl group ethanamide then, 4-difluorophenyl) isoxazoline, the back generates (±)-N-[[3-[3-fluoro-4-(1-piperazinyl) phenyl with the Piperazine anhydrous reaction]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide (compound 6).m.p.160.2-161.3℃，HPLC99.7％，
1H-NMR(DMSO-d
6，400MHz)δ：8.11-8.08(1H，t，NH)，7.377-7.337(2H，m，ArH)，7.057-7.013(1H，t，ArH)，4.722-4.650(1H，m，CH)，3.458-3.349(1H，m)，3.239-3.210(2H，t)，3.089-3.029(1H，m)，2.982-2.959(4H，t)，2.833-2.822(4H，d)，2.494-2.458(1H，t)，1.085(3H，s)。
(±)-N-[[3-[3-fluoro-4-(4-(2-chloracetyl)-1-piperazinyl) phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide (compound 8-1)
In three mouthfuls of round-bottomed flasks of 100ml, add 3.2g (±)-N-[[3-[3-fluoro-4-(1-piperazinyl) phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide, 40ml trichloromethane, 2.5ml triethylamine, ice bath is cooled to-5 ℃, gradation slowly drips the 1.2g chloroacetyl chloride under stirring, and maintains the temperature at below 10 ℃ in the dropping process.After dropwising, rise to room temperature, react about 3h, finish through the TLC monitoring reaction.Add the 60ml washing, tell organic layer, anhydrous sodium sulfate drying, underpressure distillation gets oldlace solid (8-1) 3.4g, yield 85.8%, Rf=0.75 (developping agent: dehydrated alcohol), HPLC99.3%.
1H-NMR(DMSO-d
6，400MHz)δ：8.110-8.081(1H，t，NH)，7.424-7.355(2H，m，ArH)，7.104-7.061(1H，t，ArH)，4.735-4.663(1H，m，CH)，4.419(1H，s，CH)，3.619(4H，s)，3.428-3.359(1H，m)，3.304-3.216(2H，m)，3.112-3.038(5H，m)，1.806(3H，s)。
Embodiment 2
(±)-N-[[3-[3-fluoro-4-(4-(2-bromine butyryl radicals)-1-piperazinyl) phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide (compound 8-2)
Operation steps gets oldlace solid 4.1g, yield 87.4% with embodiment 1.HPLC99.1％。
1H-NMR(DMSO-d
6，400MHz)δ：8.113-8.084(1H，t，NH)，7.423-7.351(2H，m，ArH)，7.100-7.066(1H，t，ArH)，4.934-4.899(1H，t，CH)，4.735-4.664(1H，m，CH)，3.733-3.644(4H，m)，3.427-3.358(1H，m)，3.309-3.218(2H，m)，3.154-3.040(5H，m)，2.051-1.858(2H，m)，1.807(3H，s)，0.950-0.914(3H，t)。
Embodiment 3
(±)-N-[[3-[3-fluoro-4-[4-(1-piperidines ethanoyl)-1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide (I-1)
The 0.32g piperidines is dissolved in the 70ml chloroform, adds about 2ml triethylamine, stir, gradation adds 1.6g compound 8-1 under the room temperature, adds in about 30 minutes.Then the about 3h of back flow reaction finishes through the TLC monitoring reaction.Add the 50ml washing, tell chloroform layer, anhydrous sodium sulfate drying, underpressure distillation gets crude product.Through silica gel column chromatography separate (eluent: 6% ethanol/methylene), drying, Off-white solid (I-1) 0.3g, m.p.144.6-146.1 ℃, Rf=0.63 (developping agent: methylene dichloride/anhydrous methanol (v: v)=11: 1), HPLC98.5%.
Embodiment 4-25
With reference to the operation of embodiment 3, distinguish the piperidines in the aminocompound alternate embodiment 3 that has been to select for use different structure, obtain following formula I compound with compound 8-1 reaction.
The physicochemical constant of prepared compound of Formula I is as follows:
I-2: Off-white solid, yield 78.8%.M.p.128.1-129.2 ℃, Rf=0.28 (developping agent: methylene dichloride/anhydrous methanol (v: v)=11: 1), HPLC98.2%.
I-3: light yellow solid, yield 77.2%.M.p.138.1-140.0 ℃, Rf=0.60 (developping agent: methylene dichloride/anhydrous methanol (v: v)=11: 1), HPLC99.3%.
I-4: light gray solid, yield 72.6%.M.p.142.2-143.9 ℃, Rf=0.59 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.1%.
I-5: white solid, yield 70.1%.M.p.182.2-184.1 ℃, Rf=0.36 (developping agent: methylene dichloride/anhydrous methanol (v: v)=11: 1), HPLC98.2%.
I-6: white solid, yield 77.3%.M.p.146.1-148.0 ℃, Rf=0.55 (developping agent: methylene dichloride/anhydrous methanol (v: v)=11: 1), HPLC99.0%.
I-7: white solid, yield 71.1%.M.p.169.2-171.0 ℃, Rf=0.78 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.6%.
I-8: Off-white solid, yield 74.6%.M.p.178.2-180.1 ℃, Rf=0.57 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.9%.
I-9: light yellow solid, yield 69.0%.M.p.190.1-192.0 ℃, Rf=0.59 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.3%.
I-10: white solid, yield 61.5%.M.p.152.4-154.3 ℃, Rf=0.50 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.3%.
I-11: white solid, yield 73.0%.M.p.189.4-191.3 ℃, Rf=0.331 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.5%.
I-12: light beige solid, yield 75.3%.M.p.160.4-161.9 ℃, Rf=0.68 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.5%.
I-13: khaki color solid, yield 65.6%.M.p.180.1-181.6 ℃, Rf=0.75 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.9%.
I-14: yellow solid, yield 75.3%.M.p.168.1-170.0 ℃, Rf=0.62 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.8%.
I-15: white solid, yield 80.1%.M.p.181.5-182.7 ℃, Rf=0.72 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.9%.
I-16: yellow solid, yield 73.3%.M.p.149.2-151.2 ℃, Rf=0.63 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.5%.
I-17: beige solid, yield 76.9%.M.p.192.1-194.0 ℃, Rf=0.31 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.9%.
I-18: Off-white solid, yield 73.9%.M.p.194.9-197.0 ℃, Rf=0.69 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.6%.
I-19: white solid, yield 76.9%.M.p.155.4-157.2 ℃, Rf=0.38 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.9%.
I-20: yellow solid, yield 55.1%.M.p.108.6-110.5 ℃, Rf=0.20 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.7%.
I-21: yellow solid, yield 62.7%.M.p.139.9-141.6 ℃, Rf=0.63 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.5%.
I-22: shallow khaki color solid, yield 58.9%.M.p.99.7-101.5 ℃, Rf=0.29 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.9%.
I-23: light beige solid, yield 69.7%.M.p.102.6-104.3 ℃, Rf=0.28 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.1%.
Embodiment 26-29
With reference to the operation of embodiment 3, distinguish the piperidines in the aminocompound alternate embodiment 3 that has been to select for use different structure, obtain following formula I compound with compound 8-2 reaction.
I-24: yellow solid, yield 33.4%.M.p.139.8-141.6 ℃, Rf=0.24 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.6%.
I-25: light yellow solid, yield 30.8%.M.p.95.5-97.2 ℃, Rf=0.63 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.5%.
I-26: light yellow solid, yield 30.1%.M.p.128.6-129.9 ℃, Rf=0.69 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC99.1%.
I-27: light yellow solid, yield 28.1%.M.p.150.2-152.0 ℃, Rf=0.40 (developping agent: methylene dichloride/anhydrous methanol (v: v)=10: 1), HPLC98.9%.
Embodiment 30
Compound I-2 one-tenth hydrochloride: get above-mentioned I-2 product 1.0g, be dissolved in the 20ml dehydrated alcohol, ice-water bath is cooled to about 5 ℃, drips 23.3% (8.3molmL
-1) ethanol solution hydrochloride, transfer to PH=2-3, continue to stir 30min then.Filter, white solid, drying, its hydrochloride (I-28), m.p.＞220 ℃.
Embodiment 31
Compound I-10 one-tenth Citrate trianion: get above-mentioned I-10 product 1.0g, be dissolved in the 30ml dehydrated alcohol, be heated to backflow, add and wait mole citric acid, insulation reaction 45min.Reduce to room temperature, left standstill 12 hours.Separate out white solid, filter, drying promptly gets its Citrate trianion (I-29), m.p.＞220 ℃.
Embodiment 32
Compound I-20 one-tenth sylvite: get above-mentioned I-20 product 1g, be dissolved in about 80ml anhydrous methanol, ice bath is cooled to 10 ℃, stirs the potassium hydroxide aqueous solution of dropping 25% down, transfers to PH11.Solvent is to the greatest extent steamed in decompression, add 30ml dehydrated alcohol/water (6/4, V/V) mixing solutions is heated to backflow, insulation reaction 10min, filtered while hot, filtrate chamber is gentle and quiet puts, and separates out white solid, filters, drying promptly gets its sylvite (I-30), m.p.＞220 ℃.
In order to explain enforcement of the present invention more fully, provide following example of formulations.These embodiment explain rather than limit the scope of the invention.Preparation can adopt any one compound among the present invention as activeconstituents.
Embodiment 33
Every tablet preparation that contains the 100mg activeconstituents:
The mg/ sheet
I-7 100mg
Lactose 80mg
Microcrystalline Cellulose 20mg
Starch 50mg
Hypromellose 10mg
Add 5mg in the carboxymethylstach sodium and add 5mg
Magnesium Stearate qs
Technology: with activeconstituents, lactose, starch, Microcrystalline Cellulose are crossed 100 mesh sieves respectively, take by weighing and abundant mixing by recipe quantity, the 2% hydroxyl methylcellulose aqueous solution joined in the said mixture granulate, cross 20 mesh sieve system softwoods, make wet granular in 45-55 ℃ dry about 2-3 hour, with remain carboxymethylstach sodium, Magnesium Stearate joins compressing tablet in the above-mentioned dried particles.
Embodiment 34
Capsular being prepared as follows:
Prescription consumption/capsule
I-7 100mg
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium starch glycolate 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate qs
Talcum powder qs
Amount to 200mg
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and the auxiliary material thorough mixing of recipe quantity; add hypromellose solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, Magnesium Stearate and talcum powder and particle are mixed whole; measure intermediate content, with No. 2 capsule cans.
Embodiment 35
The preparation of injection liquid
I-7 50mg
SODIUM PHOSPHATE, MONOBASIC 10mg
Citric acid 20mg
Sodium-chlor 90mg
Water for injection 50ml
Technology: get water for injection 50ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 4.0-7.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.1% 20 minutes.Filter with 045 μ m filter membrane earlier, again with the smart filter of 022 μ m.Cut open 2 milliliters of cans by every peace, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
Embodiment 36
Compound of Formula I is to the antibacterial activity in vitro result of bacterium
| Sample | Streptococcus aureus | Sarcina lutea | Klebsiella pneumoniae | Pseudomonas aeruginosa |
| I-1： | + | + | - | - |
| I-2： | + | + | - | - |
| I-3： | + | + | - | - |
| I-4： | + | + | - | - |
| I-5： | + | + | - | - |
| I-6： | + | + | - | - |
| I-7： | + | + | - | - |
| I-8： | + | + | - | - |
| I-9： | + | + | - | - |
| I-10 | + | + | - | - |
| I-11 | + | + | - | - |
| I-12 | + | + | - | - |
| I-16 | + | + | - | - |
| I-17 | + | + | - | - |
| I-18 | + | + | - | - |
| I-19 | + | + | - | - |
| I-20 | + | + | - | - |
| I-21 | + | + | - | - |
| I-22 | + | + | - | - |
| I-23 | + | + | - | - |
| I-24 | + | + | - | - |
| I-25 | + | + | - | - |
| I-26 | + | + | - | - |
| I-27 | + | + | - | - |
+：MIC≤32μg·mL
-1；-：MIC＞32μg·mL
-1
The result shows: above-mentioned compound with general formula I structure has bacteriostatic action to standard gold staphylococcus aureus, standard Sarcina lutea etc.; Standard klebsiella pneumoniae and standard Pseudomonas aeruginosa there is not bacteriostatic action.Point out the compound of this class formation to have anti-G
+The effect of bacterium.
Claims (6)
1. the compound and the pharmacy acceptable salt thereof that have the general formula I structure:
Wherein:
n＝1；
R
1For: hydrogen; C
1-C
6Alkyl;
Work as R
1During for hydrogen, R
2For:
R
6, R
7For:
C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
By halogen, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Dialkyl amido, aryl list or polysubstituted C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
Work as R
1Be C
1-C
6During alkyl, R
2For:
R
6, R
7For:
C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
By halogen, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Dialkyl amido, aryl list or polysubstituted C
1-C
6Alkyl, C
3-C
6Cycloalkyl, aryl contains the C of sulphur, oxygen, nitrogen heteroatom
3-C
6Heterocyclic radical;
2. R
8(N)-, wherein, R
8For::
The C that contains one or more nitrogen heteroatoms
5-C
6Heterocyclic radical;
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halo C
1-C
4Alkyl, halo C
1-C
4Alkoxyl group, C
3-C
6Cycloalkyl, halogen, itrile group, carboxyl, hydroxyl, nitro, amino, amide group, aryl, C
3-C
6Heterocyclic radical list or the polysubstituted C that contains one or more nitrogen heteroatoms
5-C
6Heterocyclic radical;
R
3: be hydrogen;
R
4: be halogen;
R
5: be C
1-C
6Alkyl is replaced or polysubstituted C by the halogen list
1-C
6Alkyl.
2. the compound and the pharmacy acceptable salt thereof that have following formula:
Wherein:
n＝1；
R
1For: hydrogen; Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl;
Work as R
1During for hydrogen, R
2For:
Wherein:
R
6, R
7For:
Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
By fluorine, chlorine, bromine, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Dialkyl amido, aryl list or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, fluorine, chlorine, itrile group, amino, hydroxyl, nitro list or polysubstituted phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
Work as R
1During for methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, R
2For:
R
6, R
7For:
Methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
By fluorine, chlorine, bromine, hydroxyl, C
1-C
6Alkoxyl group, C
1-C
6Dialkyl amido, aryl list or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, fluorine, chlorine, itrile group, amino, hydroxyl, nitro list or polysubstituted phenyl, naphthyl, anthryl, imidazoles, pyridine, oxazole, isoxazole, furans, thiazole, pyrazoles, thiophene, pyrroles, pyridazine, pyrimidine, pyrazine, piperidines, morpholine, piperazine, tetrahydrofuran (THF);
2. R
8(N)-, wherein, R
8For::
Piperidines, morpholine, piperazine, pyridine, triazole, pyrazoles;
By C
1-C
6Alkyl, C
1-C
6Alkoxyl group, halo C
1-C
4Alkyl, halo C
1-C
4Alkoxyl group, C
3-C
6Cycloalkyl, fluorine, chlorine, bromine, itrile group, carboxyl, hydroxyl, nitro, amino, amide group, aryl, C
3-C
6Heterocyclic radical list or polysubstituted piperidines, morpholine, piperazine, pyridine, triazole, pyrazoles;
R
3: be hydrogen;
R
4: be fluorine, chlorine;
R
5: be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl, perhaps by fluorine, the replacement of chlorine list or polysubstituted methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, isopentyl.
3. following compound and pharmacy acceptable salt thereof:
I-16:(±)-N-[[3-[3-fluoro-4-[4-[[N-benzyl-1-methyl-2-(4-p-methoxy-phenyl)] the ethylamino ethanoyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-17:(±)-N-[[3-[3-fluoro-4-[4-[N, N-two (2-hydroxyethyl) glycyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-18:(±)-N-[[3-[3-fluoro-4-[4-[N, N-two (2-chloroethyl) glycyl]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-24:(±)-N-[[3-[3-fluoro-4-[4-[2-(4-carboxamide piperidyl)-1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-25:(±)-N-[[3-[3-fluoro-4-[4-[2-[4-(4-nitrophenyl) piperazinyl]-the 1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-26:(±)-N-[[3-[3-fluoro-4-[4-[2-[4-(2-pyridyl) piperazinyl]-the 1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide;
I-27:(±)-N-[[3-[3-fluoro-4-[4-[2-(3-carboxyl piperidyl)-1-butyryl radicals]-the 1-piperazinyl] phenyl]-4,5-dihydro-5-isoxazolyl] methyl] ethanamide.
4. claim 1 or 2 or 3 described compound and pharmacy acceptable salts thereof, its pharmacy acceptable salt be meant with mineral acid and organic acid salify or with alkali-metal oxyhydroxide salify.
5. pharmaceutical composition for the treatment of the sensitive bacterial infected patient,
It contains claim 1 or 2 or 3 defined compounds or its pharmacy acceptable salt as effective constituent, and contains one or more pharmaceutically acceptable carriers.
6. claim 1 or 2 or 3 described compounds and pharmacy acceptable salt thereof are in the purposes of preparation aspect the antibacterials.
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