CN101619061A - Cyanopyridyl-replaced oxazolidinone compound - Google Patents
Cyanopyridyl-replaced oxazolidinone compound Download PDFInfo
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- CN101619061A CN101619061A CN200910013060A CN200910013060A CN101619061A CN 101619061 A CN101619061 A CN 101619061A CN 200910013060 A CN200910013060 A CN 200910013060A CN 200910013060 A CN200910013060 A CN 200910013060A CN 101619061 A CN101619061 A CN 101619061A
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Abstract
The invention relates a cyanopyridyl-replaced oxazolidinone compound with a general formula (I); wherein, R1 is hydrogen, fluorine, chlorine or trifluoromethyl and R is shown in the right structural formula. The invention also provides a preparation method of the compound shown in general formula (I) and medicinal salts of the compound and an application thereof for curing microbial infections, in particular to bacterial infection diseases. Preliminary antibacterial activity tests in vitro show that the compound of the invention has better antibacterial activity compared with linezolid and obvious antibacterial activity to drug-resistant bacteria.
Description
Technical field:
The present invention relates to the pharmaceutical chemistry field, particularly a kind of cyanopyridine-based De oxazolidone compound or its pharmacy acceptable salt, and the pharmaceutical composition, preparation method and the application that contain them.
Background technology:
In recent decades, the abuse of antibacterials causes the mortality ratio of infectious diseases sharply to rise.Clinically, the resistance of cell increases year by year, causes some antibacterials curative effects to reduce, even invalid, as methicillin-resistant golden staphylococci, methicillin-resistant epidermis Portugal Portugal coccus and vancomycin-resistant enterococcus etc.; Some non-pathogenic bacterias become conditioned pathogen, as Bacillus proteus, Pseudomonas aeruginosa etc.The formation and development of all these Resistant strain has caused the difficulty in the treatment, and present antibacterials can not satisfy needs clinically, is badly in need of having the antibacterials of novel mechanism of action clinically.
Oxazolidine ketone antibacterials act on the commitment of protein synthesis, cross resistance seldom occurs with other antimicrobial drug.The DuP721 of E.I.Du Pont Company's report in 1987 is a lead compound, the general strong company of the U.S. has successfully developed the one oxazolidine ketone antiseptic-germicide---linezolid (Linezolid), the gram positive bacteria infection that is used for the treatment of penicillin resistant, Macrolide and other antibacterials, this medicine go on the market in U.S.'s approval in April, 2000.
Not seeing in the prior art that the someone prepares contains cyanopyridine-based replacement De oxazolidone compounds, and it is carried out particularly antimicrobial agent activity research of anti-microbial activity.
Summary of the invention
The present invention relates to general formula I De oxazolidone compounds or its pharmacy acceptable salt,
Wherein,
R
1Be hydrogen, fluorine, chlorine and trifluoromethyl;
R
2For
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, they can be by 1-3 identical or different R
6The optional replacement;
Perhaps R
4And R
5Form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms that is connected with them, described heterocyclic radical and heteroaryl except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-4 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can be by 1～3 identical or different R
6The optional replacement;
R
6Be C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
The present invention preferably relates to compound of Formula I or its pharmacy acceptable salt that is defined as follows,
Wherein, R
1Be fluorine;
R
2For
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, they can be by 1-3 identical or different R
6The optional replacement;
Perhaps R
4And R
5Form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms that is connected with them, described heterocyclic radical and heteroaryl except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-4 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can be by 1～3 identical or different R
6The optional replacement;
R
6Be C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
The present invention preferably also relates to compound of Formula I or its pharmacy acceptable salt that is defined as follows,
Wherein,
R
1Be fluorine;
R
2For
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
4Alkyl and C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
6The optional replacement;
Perhaps R
4And R
5Form guanidine radicals and 5-10 unit heterocyclic radical with the nitrogen-atoms that is connected with them, described heterocyclic radical except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-2 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical can be by 1～3 identical or different R
6The optional replacement;
R
6Be C
1-C
4Alkyl.
The present invention especially preferably relates to compound of Formula I or its pharmacy acceptable salt that is defined as follows,
Wherein,
R
1Be fluorine;
R
2For
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino and C respectively
1-C
4Alkyl;
Perhaps R
4And R
5Form morpholine-4-base, piperidines-1-base, 4-methylpiperazine-1-base and tetramethyleneimine-1-base with the nitrogen-atoms that is connected with them;
R
3Be preferably dimethylamino, first and second amino, morpholine-4-base, piperidines-1-base, 4-methylpiperazine-1-base and tetramethyleneimine-1-base.
The present invention very particularly preferably relates to compound of Formula I or its pharmacy acceptable salt that is defined as follows,
1) (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide;
2) (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
The present invention more especially preferably relates to compound of Formula I or its pharmacy acceptable salt that is defined as follows,
(S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
Scope of the present invention also comprises the hydrate forms of The compounds of this invention, and it contains the water of different amounts, as monohydrate, semihydrate, semihydrate and dihydrate.
According to some usual methods in field under the present invention, compound of Formula I of the present invention can generate its pharmacy acceptable salt with acid.Acid can comprise mineral acid or organic acid, the salt that forms with following acid is particularly preferred: hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthene sulfonic acid, trifluoroacetic acid and aspartic acid.
In addition, the present invention also comprises the prodrug of The compounds of this invention.According to the present invention, prodrug is the derivative of formula I compound, they self may have more weak active or even do not have activity, but after administration, (for example by metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
Be understandable that any racemize, optically active, polymorphic forms or its mixture of The compounds of this invention contained in the present invention, they possess useful quality as herein described.Compound of Formula I of the present invention contains the C-5 position of chiral centre (oxazolidone ring), therefore there are two kinds of enantiomorphs or the racemic mixture of the two.The present invention relates to possess two kinds of enantiomorphs of useful quality described herein and contain two kinds of mixture of isomers.
Unless otherwise noted, term used herein " alkyl " is meant the alkyl of straight or branched; " cycloalkyl " is meant and replaces or unsubstituted cycloalkyl; " thiazolinyl " is meant the thiazolinyl of straight or branched; " alkynyl " is meant the alkynyl of straight or branched; 5-10 unit heteroaryl comprises and contains one or more N of being selected from, the heteroatoms of O and S, wherein the ring-type system of each heteroaryl can be monocycle or polycyclic, the ring-type system is an aromaticity, contain 5-10 atom altogether, can enumerate for example imidazolyl, pyridyl, pyrimidyl, pyrazolyl, (1,2,3)-and (1,2,4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl isoxazolyl oxazolyl, pyrazolyl, pyrryl, thiazolyl, benzothienyl, benzofuryl, benzimidazolyl-, benzothiazolyl, indyl, quinolyl etc.; 5-10 unit heterocyclic radical comprises the heteroatoms that contains one or more N of being selected from, O and S, wherein the ring-type system of each heteroaryl can be monocycle or polycyclic, but be non-aromaticity, the ring-type system contains 5-10 atom altogether, can choose wantonly and comprise 1 or 2 carbon-carbon double bond or carbon-carbon triple bond, can enumerate for example pyrrolidyl, morpholinyl, piperazinyl, piperidyl, thiazolinyl etc.
The present invention also comprises pharmaceutical composition, and said composition comprises that compound of Formula I and their pharmacy acceptable salts and/or solvate are as activeconstituents and pharmaceutically acceptable carrier; Compound of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effect, for example anaphylaxis.
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
The present invention comprises that also it is used for the treatment of the particularly application in the medicine of infectation of bacteria of Mammals infected by microbes in preparation.This application method is given the compound of Formula I of significant quantity, can compound is oral to Mammals in pharmaceutical composition, parenteral, transdermal or topical.
Owing to have particularly antibacterial activity of anti-microbial infection according to general formula I De oxazolidone compounds of the present invention, therefore, it can be as the medicine of preparation treatment Mammals infectation of bacteria, compound according to the present invention can be used as the method that activeconstituents is used to prepare treatment Mammals infectation of bacteria, comprise suffer from or easily suffer from this sick patient significant quantity according to compound of the present invention.
Particularly the accurate amount of the required The compounds of this invention of infectation of bacteria will be different because of the curee for the treatment microorganism, depend on curee's kind, age and general condition, the severity of disease for the treatment of, used specific compound and administering mode, for example the approach of administration and frequency or the like.Those of ordinary skills only utilize the normal experiment method can determine suitable significant quantity.
The dosage of compound can be from about 0.1～100mg/kg body weight every day, preferred 1～50mg/kg body weight/day.Be understandable that dosage can be because of patient's demand, the seriousness of the infectation of bacteria of being treated and employed specific compound and different.And, being understandable that the initial dosage of institute's administration can increase and exceeds the upper limit, purpose is to reach the desired blood level rapidly, and perhaps initial dosage can be less than optimum value, and every day, dosage can increase during treating gradually, and this depends on concrete situation.If necessary, every day, dosage also can be divided into multiple dose administration, for example every day 2-4 time.
Mammals is represented the human or animal.
Activeconstituents, the amount of compound just according to the present invention in pharmaceutical composition and unit dosage thereof can have nothing in common with each other, and depends on the effectiveness and the desired concn of application-specific, specific compound.Generally speaking, the content of activeconstituents will be between 0.5%～90%, by the gross weight of composition.
In conjoint therapy, The compounds of this invention and other compound can be by simultaneously or administration at interval, and at the same time during administration, The compounds of this invention and other compounds can be bonded in the single pharmaceutical composition or in the composition that separates.
Below synthetic route A, B and the C preparation of having described compound of Formula I of the present invention, all raw materials all are the method preparation known by the method for describing in these synoptic diagram, by the organic chemistry filed those of ordinary skill or commercially available.All final compound of the present invention all is to prepare by the method for describing in these synoptic diagram or by method similar with it, and these methods are that the organic chemistry filed those of ordinary skill is known.Whole variable factors of using in these synoptic diagram are as hereinafter definition or as the definition in the claim.
According to compound of Formula I of the present invention, in route A and route B, R
1Be hydrogen, fluorine, chlorine and trifluoromethyl; R
3Be NR
4R
5R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, they can be by 1-3 identical or different R
7The optional replacement; Perhaps R
4And R
5Form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms that is connected with them, described heterocyclic radical and heteroaryl except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-4 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can be by 1～3 identical or different R
6The optional replacement; R
6Be C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
Route A Compound I-i and I-ii's is synthetic
Route B Compound I-iii and I-iv's is synthetic
In route A, with R
1The aniline (1) that replaces is starting raw material, through with methyl-chloroformate generation acylation reaction after, obtain R
1The phenylcarbamic acid methyl esters (2) that replaces makes the 4-ethanoyl-3-fluorophenyl Urethylane (3) of replacement then with Acetyl Chloride 98Min. generation Friedel-Crafts reaction.In the presence of trimethyl carbinol lithium, compound 3 and S-N-[2-(acetoxyl group)-3-chloropropyl] ethanamide (4) reacts, make compound N-[[(5S)-3-(4-ethanoyl-3-R
1-phenyl)-and 2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide (5).In the presence of hexamethyldisilazane, compound 5 makes compound 6 with the propane dinitrile reaction, compound 6 and N, and dinethylformamide dimethylacetal (DMF-DMA) reacts, and obtains compound 7.Compound 7 and ammoniacal liquor generation ring-closure reaction make compound of Formula I I-i and (work as R
3For-NH
2The time).Compound I-i (works as R through Compound I-ii that diazotization, bromo, substitution reaction make general formula I
3Such as in the claim definition, but-NH
2Except).
In route B, compound 5 reacts with DMF-DMA, makes compound 9.Compound 9 and propane dinitrile generation ring-closure reaction make compound of Formula I I-iii and (work as R
3For-NH
2The time).Compound I-iii makes Compound I-iv through diazotization, bromo, substitution reaction and (works as R
3Such as in the claim definition, but-NH
2Except).
In route A, the preparation of compound 4 is a starting raw material with (S)-epoxy chloropropane shown in route C, through with reaction of phenyl aldehyde, ammoniacal liquor and acid hydrolysis after make (S)-1-amino-3-chloro-2-propylate hydrochlorate, make with diacetyl oxide generation acylation reaction again.
Synthesizing of route C compound 4
Compound of the present invention has been carried out antibacterial activity in vitro research, and the result is as follows:
1) for becoming a series of concentration with M-H meat soup two-fold dilution after the test agent degerming, maximum concentration is 128mg/L.Add 100 μ LM-H broth cultures in the 12nd hole as blank every row of 96 micropores dilution plate, the 11st hole adds 50 μ LM-H meat soups, according to adding 50 μ L sample test liquids successively from 1 hole, the 10th hole to the from low paramount order.
Picking is tried bacterium in right amount and reference culture is seeded in Mueller-Hinton (M-H) nutrient broth medium that is fit to its growth, cultivate 16-18h in 37 ℃, bacterium liquid after the growth uses physiological saline corrected concentrations to 0.5 Maxwell than turbid standard, use the dilution in 1: 100 of M-H meat soup again, this liquid is as supplying examination bacterium liquid.Inoculate 50 μ L test organisms liquid then in the 1st～11 hole, the jolting mixing is placed in the square tray anth cap that is lined with wet gauze, cultivates 18-20h for 37 ℃.
Observations under the light source of black background is being arranged, having to have the diffusivity muddiness in the hole of bacteria growing or the bottom, hole is clasp sample precipitation, this phenomenon of the nothing hole of asepsis growth in.Contained lowest concentration of drug is minimum inhibitory concentration (MIC) in the hole of asepsis growth.Test-results sees Table 1-3.
Table 1 embodiment 1 and 2 compounds are to the anti-microbial activity MIC value (ug/mL) of golden Portugal bacterium
| ??ATCC-25923 | ??SA2 | ??SA3 | ??SA4 | ??SA5 | ??MRSA2 * | ??MRSA7 | ??MRSA8 | |
| Linezolid | ??4 | ??4 | ??4 | ??4 | ??2 | ??2 | ??4 | ??4 |
| Embodiment 1 compound | ??2 | ??2 | ??2 | ??2 | ??2 | ??2 | ??1 | ??2 |
| Embodiment 2 compounds | ??1 | ??2 | ??1 | ??1 | ??2 | ??2 | ??＜0.25 | ??＜0.25 |
Annotate: SA is a streptococcus aureus;
*MRSA is a methicillin resistant staphylococcus aureus
Table 2 embodiment 1 and 2 compounds are to the anti-microbial activity MIC value (ug/mL) of streptococcus pneumoniae
| ??ATCC-25923 | ??SPN2 | ??SPN11 | ??SPN22 | ??PRSP3 | ??PRSP4 | |
| Linezolid | ??4 | ??＜0.5 | ??1 | ??4 | ??＜0.5 | ??＜0.5 |
| Embodiment 1 compound | ??1 | ??＜0.5 | ??＜0.5 | ??1 | ??＜0.5 | ??＜0.5 |
| Embodiment 2 compounds | ??1 | ??2 | ??＜0.5 | ??1 | ??1 | ??＜0.5 |
Annotate: SPN is a streptococcus pneumoniae, and PRSP is penicillin-fast streptococcus pneumoniae
Table 3 embodiment 1 and 2 compounds are to enterococcal anti-microbial activity MIC value (ug/mL)
| ??ATCC-25923 | ??ATCC-25922 | ??Efa6 | ??Efa7 | ??Efm1 | ??Efm3 | |||
| Linezolid | ??2 | ??32 | ??1 | ??1 | ??1 | ??1 | ??4 | ??1 |
| Embodiment 1 compound | ??1 | ??0.5 | ??0.5 | ??0.5 | ??0.5 | ??0.5 | ??0.5 | ??＜0.25 |
| Embodiment 2 compounds | ??1 | ??2 | ??0.5 | ??1 | ??0.5 | ??1 | ??1 | ??＜0.25 |
Annotate: Efa is an enterococcus faecalis; Efm is a faecium
Preliminary antibacterial activity in vitro test result shows, the compound among the present invention has the how more good anti-microbial activity of oxazolone of Billy, and remarkable to the resistant organism anti-microbial activity.
Embodiment:
Following examples are intended to set forth rather than limit the scope of the invention.The proton nmr spectra of compound is measured with Bruker ARX-300, and mass spectrum is measured with Agilent 1100 LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1 (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
The preparation of step 1 (S)-1-amino-3-chloro-2-propylate hydrochlorate
Phenyl aldehyde 59.0g (0.56mol) is dissolved among the ethanol 150ml, and dropping ammonia 58.0ml (0.55mol) in reaction solution stirs, and drips (S)-epoxy chloropropane 58ml (0.88mol) in reaction solution, and the control rate of addition keeps temperature of reaction to be lower than 40 ℃.Drip and finish, 35-40 ℃ of reaction 6h reduces to reaction solution room temperature then and continues reaction 12h.Decompression steams most of solvent, adds toluene 100ml.Stir, solution is risen to 35-40 ℃, splash into aqueous hydrochloric acid (68ml hydrochloric acid, 77ml water), drip and finish, 35-40 ℃ is stirred 3h.Leave standstill, divide water-yielding stratum, organic layer washing, combining water layer.Add ethanol 40mL, remove ethanol under reduced pressure, add ethanol and steaming repeatedly except that ethanol.Residual solution is separated out white solid in-18 ℃ of freeze overnight, and suction filtration is washed with cold small amount of ethanol, and vacuum-drying gets (S)-1-amino-3-chloro-2-propylate hydrochlorate 43g, yield 52.7%
Step 2 S-N-[2-(acetoxyl group)-3-chloropropyl] preparation of ethanamide (4)
(S)-1-amino-3-chloro-2-propylate hydrochlorate 40g (0.27mol), diacetyl oxide 60ml (0.62mol) are added among the methylene dichloride 100mL, and controlled temperature drips pyridine 28ml (0.34mol) at 35-40 ℃.Drip and finish, under this temperature, react 5h, then room temperature reaction 14h.Reaction is finished, and adds entry 50mL in reaction solution, and the ice-water bath cooling splashes into 47% wet chemical 800mL, and control reaction temperature is lower than 10 ℃.Drip and finish, dichloromethane extraction merges organic layer, washing, anhydrous sodium sulfate drying.Evaporate to dryness gets solid, suction filtration, the octane-iso washing gets solid N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 43.7g, yield is 88.3%.
The preparation of step 3 (3-fluorophenyl) Urethylane
3-fluoroaniline 20.0g (0.18mol) is added among the methylene dichloride 120ml, add pyridine 14.2g (0.18mol), stir, drip the dichloromethane solution 30mL of methyl-chloroformate 18.7g (0.2mol) in reaction solution, the control rate of addition makes temperature of reaction be lower than 40 ℃.Drip and finish room temperature reaction 5h.Reaction is finished, washed reaction liquid, and the organic layer anhydrous sodium sulfate drying, evaporate to dryness gets white solid 30.1g, yield 98.8%.
The preparation of step 4 (4-ethanoyl-3-fluorophenyl) Urethylane (V)
(3-fluorophenyl) Urethylane (VI) 16.9g (0.1mol) is added in the three-necked bottle, add aluminum chloride 40.0g (0.3mol), stir and be warming up to 35-40 ℃, dripping acetyl chloride 15.7g (0.2mol) in reaction flask.Drip and finish, be warmed up to 50-60 ℃ of reaction 3h.Reaction solution is poured in an amount of trash ice, stirred, suction filtration, filter cake 80% recrystallizing methanol gets (4-ethanoyl-3-fluorophenyl) Urethylane (V) 14.9g, yield 70.8%.
Step 5 S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
Method 1: (V 0.1mol) adds among the dry DMF 100mL, and stirring and dissolving adds anhydrous methanol 8.14mL (0.2mol) with compound (4-ethanoyl-3-fluorophenyl) Urethylane (V) 21.1g.Under 20 ℃, drip the dry DMF 100mL solution of trimethyl carbinol lithium 23.7g (0.3mol) in reaction solution, the control rate of addition is kept temperature of reaction and is lower than 24 ℃.Drip and finish, reaction solution is chilled to 0-5 ℃, add N-[(2S)-2-(acetoxyl group)-3-chloropropyl] ethanamide 34.6g (0.2mol).Reaction solution slowly is warming up to 20-25 ℃ of reaction 21h.Reaction is finished, and drips saturated ammonium chloride solution 100mL in reaction solution, stirs; add 200mL water and 200mL methylene dichloride again, separatory, water layer dichloromethane extraction; merge organic layer, saturated nacl aqueous solution is washed, drying; the evaporated under reduced pressure solvent gets oily matter, recrystallizing methanol; get S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-yl] methyl] ethanamide 10.2g, yield 34.7%, [M+H
+]: 295.5.
Method 2: trimethyl carbinol lithium 18.3g (0.23mol) is added in the 100mL tetrahydrofuran (THF); be cooled to 0～5 ℃; in solution, drip absolute anhydrous methanol 6.3mL (0.15mol); drip Bi Jixu and stir 1h, add N-[(2S then)-2-(acetoxyl group)-3-chloropropyl] the acetonitrile 100mL solution of ethanamide 3.0g (0.15mol) and (4-ethanoyl-3-fluorophenyl) Urethylane 16.3g (0.08mol).Reaction solution is warming up to 18 ℃ of stirring reaction 18h then in 0～5 ℃ of stirring 0.5h.Reaction is finished, and drips glacial acetic acid 9.0mL (0.15mol) in reaction solution, and the control rate of addition makes reacting liquid temperature be lower than 25 ℃, drips to finish to stir 0.5h.The evaporated under reduced pressure reaction solvent adds 50ml water in resistates, be stirred to fully and disperse suction filtration; washing, ethanol filter wash cake gets yellow solid S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1; 3-oxazolidine-5-yl] methyl] ethanamide 15.1g, yield 66.5%, [M+H
+]: 295.5.
Step 6:S-N-[[3-[4-(1,1-dicyano-1-propylene-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
In the 50ml glacial acetic acid, drip hexamethyldisilazane 4.3ml (20.4mmol), drip and finish, be warming up to 65-70 ℃ and stir 30min.In this reaction solution, drip S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl] the 25ml glacial acetic acid solution of ethanamide and propane dinitrile 2.3g (34mmol), drip and finish, the 65-70 ℃ of 48h of committee.Reaction is finished, and adds 100mL water, dichloromethane extraction in reaction solution, merge organic layer, washing, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, solvent evaporated must be revolved solvent evaporated, gets S-N-[[3-[4-(1,1-dicyano-1-propylene-2-yl)-the 3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 5.9g, yield 51.2%, [M+H
+]: 343.1.
Step 7S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-butadiene-2-yl]-the 3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] preparation of ethanamide
With S-N-[[3-[4-(1,1-dicyano-1-propylene-2-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 2.0g (5.8mmol) adds among the DMF-DMA 20mL, stirs, and adds trifluoroacetic acid 0.2mL.Reaction is warming up to 85 ℃ of reaction 6h.Reaction is finished, and is cooled to room temperature, adds entry 50mL in reaction solution, dichloromethane extraction merges organic layer, washing, saturated nacl aqueous solution is washed, anhydrous magnesium sulfate drying, solvent evaporated, get S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-butadiene-2-yl]-the 3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 1.46g, yield 63.6%, [M+H
+]: 398.2
Step 8 (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
With S-N-[[3-[4-[1,1-dicyano-4-(dimethylamino)-1,3-butadiene-2-yl]-the 3-fluorophenyl]-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 1.0g (2.5mmol) adds among the methyl alcohol 40mL, adds ammoniacal liquor 12mL (150mmol) then.Reaction solution back flow reaction 2h.Reaction is finished, and is cooled to room temperature, suction filtration, and an amount of methyl alcohol is washed, and gets crude product.With recrystallizing methanol, get (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.58g, yield 63.6%, [M+H
+]: 370.2
1H-NMR：(DMSO)：1.84(s，3H)，3.43(t，2H)，4.18(t，2H)，4.77(m，1H)，6.67(s，1H)，7.01(d，1H)，7.51(m，1H)，7.66(d，1H)，8.26(t，1H).
Embodiment 2 (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Step 1:(S, E)-N-[[3-[3-fluoro-4-[(3-dimethylamino-2-propylene) acyl group] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With S-N-[[3-(4-ethanoyl-3-fluorophenyl)-2-oxo-1,3-oxazolidine-5-yl] methyl] ethanamide 5.0g (17mmol) and DMF-DMA13.6ml (102mmol) add in the 50ml acetonitrile, is warming up to backflow stirring reaction 7h.Reaction is finished, and reaction solution is cooled to room temperature, suction filtration, and acetonitrile is washed, and gets yellow solid 5.1g, yield 86%, [M+H
+]: 350.1
Step 2:(S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With (S; E)-and N-[[3-[3-fluoro-4-[(3-dimethylamino-2-propylene) acyl group] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 5g (14.3mmol), the third two eyeball 1.1g (17.2mmol) and ammonium acetate 5.5g (71.6mmol) add in the 20ml ethanol, is warming up to backflow stirring reaction 6h.Reaction is finished, and is cooled to room temperature, suction filtration, and ethanol is washed, the acetonitrile/water recrystallization gets (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.8g, yield: 51.4%, [M+H
+]: 370.1.
1H-NMR：(DMSO)：1.83(s，3H)，3.78(t，1H)，4.17(t，1H)，4.77(m，1H)，6.99(s，1H)，7.07(d，1H)，7.97(m，2H)，8.25(t，1H)
Embodiment 3 (S)-N-[[3-[3-fluoro-4-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Step 1:(S)-N-[[3-[3-fluoro-4-(2-bromo-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
Embodiment 1 compound 1.0g (2.7mmol) is added among the pyridine 10mL, stir, be cooled to-10 ℃, be added dropwise in reaction solution in the 6mL aqueous solution that contains Sodium Nitrite 0.94g (13.5mmol) and vitriol oil 6.8mL, it is-10 ℃ that the control rate of addition makes reacting liquid temperature.Drip and finish, reaction solution is warming up to 0 ℃ of reaction 1h.Reaction is finished, and adds the 3.5mL aqueous solution of KBr1.94g (16.2mmol) in reaction solution, room temperature reaction 16h.Reaction is finished, suction filtration, the washing filter cake gets (S)-N-[[3-[3-fluoro-4-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.41g, yield: 35.3%, [M+H
+]: 433.1.
Step 2:(S) N-[[3-[3-fluoro-4-[2-(piperidino)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] preparation of ethanamide
Under the room temperature, with (S)-N-[[3-[3-fluoro-4-(2-bromo-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 0.5g (1.1mmol) is dissolved in the 10ml acetone, add Anhydrous potassium carbonate 0.24g (1.65mmol), piperidines 0.099g (1.2mmol), finish, be warming up to back flow reaction 3h.Reaction is finished, and suction filtration with the filtrate decompression evaporate to dryness, gets crude product, does recrystallization with an amount of ethanol, gets product 0.23g, yield 48.9%, [M+H
+]: 438.2.
Embodiment 4 (S)-N-[[3-[3-fluoro-4-[2-(1-pyrrolidyl)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
(S)-N-[[3-[3-fluoro-4-(the 2-bromo-3-cyano group-4-pyridyl) phenyl that obtains with step 1 among the embodiment 3]-2-oxo-5-oxazolidinyl] methyl] ethanamide is raw material, method according to embodiment 3 steps 2, carry out substitution reaction with tetramethyleneimine, can make (S)-N-[[3-[3-fluoro-4-[2-(1-pyrrolidyl)-3-cyano group-4-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, yield 61.3%, [M+H
+]: 424.2.
Embodiment 5 (S)-N-[[3-[3-fluoro-4-(2-dimethylamino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
With embodiment 2 compounds is starting raw material, according to the method for step 1 among the embodiment 3, at first makes (S)-N-[[3-[3-fluoro-4-(2-bromo-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide; With it is raw material, according to the method for embodiment 3 steps 2, carry out substitution reaction with diformazan ammonia, can make (S)-N-[[3-[3-fluoro-4-(2-dimethylamino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide, yield 52.6%, [M+H
+]: 398.2.
According to the method for embodiment 5, can make embodiment 6-7 compound.
Embodiment 6 (S)-N-[[3-[3-fluoro-4-[2-(4-morpholinyl)-3-cyano group-6-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
[M+H
+]：440.2。
Embodiment 7 (S)-N-[[3-[3-fluoro-4-[2-(4-methyl isophthalic acid-piperazinyl)-3-cyano group-6-pyridyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide
[M+H
+]：453.2
Embodiment 8 (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide bitartrate salt
With (S)-N-[[3-[3-fluoro-4-prepared among the embodiment 1 (2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide 1.0g (2.7mmol) adds in the 25ml methyl alcohol, add 0.49g (3.3mmol) tartrate, backflow 15min, cooling, separate out solid, suction filtration, solid is washed with small amount of methanol, get white plates crystallization (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide bitartrate salt 1.02g, yield 72.3%.
Claims (10)
1, general formula I De oxazolidone compounds or its pharmacy acceptable salt,
Wherein,
R
1Be hydrogen, fluorine, chlorine and trifluoromethyl;
R
2For
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
10Alkyl, C
3-C
7Cycloalkyl, C
2-C
10Thiazolinyl and C
2-C
10Alkynyl, they can be by 1-3 identical or different R
6The optional replacement;
Perhaps R
4And R
5Form guanidine radicals, 5-10 unit's heterocyclic radical or 5-10 unit heteroaryl with the nitrogen-atoms that is connected with them, described heterocyclic radical and heteroaryl except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-4 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical and heteroaryl can be by 1～3 identical or different R
6The optional replacement;
R
6Be C
1-C
4Alkyl, C
1-C
4Alkoxyl group, halo, hydroxyl, cyano group, carboxyl, ester group and nitro.
2, the compound of Formula I of claim 1 or its pharmacy acceptable salt, wherein,
R
1Be fluorine.
3, the compound of Formula I of claim 1 or its pharmacy acceptable salt, wherein,
R
1Be fluorine;
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino, C respectively
1-C
4Alkyl and C
3-C
6Cycloalkyl, they can be by 1-3 identical or different R
6The optional replacement;
Perhaps R
4And R
5Form guanidine radicals and 5-10 unit heterocyclic radical with the nitrogen-atoms that is connected with them, described heterocyclic radical except with R
4And R
5Outside the nitrogen-atoms that connects, can contain 1-2 heteroatoms that is selected from N, O and S, except R
4And R
5Outside the nitrogen-atoms that is connected, described heterocyclic radical is optional to comprise 1 or 2 carbon-carbon double bond or three key, and described heterocyclic radical can be by 1～3 identical or different R
6The optional replacement;
R
6Be C
1-C
4Alkyl.
4, the compound of Formula I of claim 1 or its pharmacy acceptable salt, wherein,
R
1Be fluorine;
R
3Be NR
4R
5
R
4And R
5Identical or different, be independently selected from hydrogen, amino and C respectively
1-C
4Alkyl;
Perhaps R
4And R
5Form morpholine-4-base, piperidines-1-base, 4-methylpiperazine-1-base and tetramethyleneimine-1-base with the nitrogen-atoms that is connected with them.
5, each compound of Formula I or its pharmacy acceptable salt of claim 1-4, wherein,
R
3Be dimethylamino, first and second amino, morpholine-4-base, piperidines-1-base, 4-methylpiperazine-1-base and tetramethyleneimine-1-base.
6, the compound of Formula I of claim 4 or its pharmacy acceptable salt, this compound is preferably:
1) (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-4-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide;
2) (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
7, the compound of Formula I of claim 6 or its pharmacy acceptable salt, this compound is preferably especially: (S)-N-[[3-[3-fluoro-4-(2-amino-3-cyano group-6-pyridyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] ethanamide.
8, a kind of pharmaceutical composition, described composition contain each compound of claim 1-7.
9, the compound of any one described general formula I is used for the treatment of application in the medicine of infected by microbes in preparation among the claim 1-7.
10, the application in the claim 9, wherein said infected by microbes is an infectation of bacteria.
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