CN102234302B - Novel ketolide derivatives, and preparation method and medicinal compositions thereof - Google Patents
Novel ketolide derivatives, and preparation method and medicinal compositions thereof Download PDFInfo
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Abstract
The invention provides compounds with a general formula (I) or (II), and acceptable salts or esters prepared from the compounds and inorganic acid or organic acid. In the general formula (I) or (II), Ar refers to aromatic heterocyclic hydrocarbyl or substituted aromatic heterocyclic hydrocarbyl; and X refers to hydrogen or fluorine. The compounds have a novel structure; 9-oxime hydroxyl of ketolide is connected with an aromatic heterocyclic hydrocarbon through a propargyl side chain; and the compounds are easy and convenient to synthesize and are suitable for industrial production. Moreover, the compounds have outstanding antibacterial activity on clinically common sensitive bacteria and drugfast bacteria, such as staphylococcus aureus, streptococcus pneumonia, streptococcus pyogenes, staphylococcus epidermidis and the like, can be independently used or serve as one of active ingredients to be mixed with other medicines to treat bacterial infection and the like in various formulations or medication ways. Correspondingly, the invention also provides a preparation method for the compounds, use of the compounds as anti-infective agents and corresponding medicinal compositions.
Description
Technical field
The present invention relates to the invention belongs to chemosynthesis and pharmacy field, relate to a kind of novel ketone lactone (9-O-aromatic base proyl ketolide derivatives) and preparation method thereof, this compounds is as purposes and the corresponding medicinal compositions of anti-infectives.
Background technology
Widespread use clinically of ten quaternary macrolide antibiotic-erythromycin more than 50 year, is especially applicable to penicillin anaphylaxis person.S-generation erythromycin, as clarithromycin, Azythromycin, Roxithromycin etc. have overcome the acid nonfast problem of erythromycin.At present, the more and more demonstrations of the separated respiratory tract disease bacteria strain obtaining have resistance clinically, as streptococcus pneumoniae (S.pneumoniae), and streptococcus aureus (S.aureus) and streptococcus pyogenes (S.pyogenes) etc.Investigate (Hoban for one in 1997～1999 years at the end of last century, D.J. etc., Clin.Infect.Dis.2001,32, S81-S93.) show: in the 1601 strain streptococcus pneumoniaes that obtain in 34 hospital clinical separation of the U.S., 29.5% bacterial strain penicillin resistant, 19.3% resistance to erythromycin, 13.2% resistance to tsiklomitsin.Therefore, research and development novel structure and to have the task of new antibiotic of antimicrobial agent activity extremely urgent.
Compare with erythromycin, clarithromycin and Azythromycin etc., third generation erythromycin derivatives-one lactone has the activity (Agouridas, C. etc., J.Med.Chem.1998,41:4080-4100) of anti-polymorphic type resistant organism.Its structure activity relationship shows: the inducible resistance of 3-cladinose in original macrolide has been avoided in the introducing of 3-carbonyl, proves 3-cladinose non-essential group simultaneously.But only depend on the introducing of 3-carbonyl cannot improve antimicrobial agent activity, the upper new aromatic side chain of introducing of large ring has produced new combination target spot to resistant organism, thereby it is active to have obtained antimicrobial agent.Therefore, 3-carbonyl and aromatic side chain have formed the important structure feature of ketolide antibiotics.
The power that the binding site of aromatic side chain on ketone lactone and side chain lengths thereof directly have influence on its antimicrobial agent activity.As the aromatic side chain of Ketek (Telithromycin) is connected on 11,12-carbamate, length is 4 atoms (Denis A. etc., Bioorg.Med.Chem.Lett.1999,9:3075-3080.); It is upper that the aromatic side chain of cethromycin (Cethromycin) is connected to 6-OH, and length is 3 atoms (Or Y.S. etc., J.Med.Chem.2000,43:1045-1049).
In the derivative of erythromycin, 9-carbonyl changes into after oxime hydroxyl, and the 9-oxime ether being connected to form with various alkyl or aromatic alkyl is important direction of modification (Gasc J.C. etc., J.Antibiot.1991, a 44:313-330; Kawashima Y. etc., Chem.Pharm.Bull.1994,42:1088-1095; Kato H. etc., WO00/61593; Pandey, D. etc., Bioorg.Med.Chem.2004,12,3807-3813.).Recently, the introducing of oxime ether is also applied in and finds (Agouridas, C. etc., J.Med.Chem.1998,41:4080-4100 on the ketone lactone with antimicrobial agent activity; ChenS.X. etc., J.Antibiot.2001,54:506-509; Ma Z. etc., US2002/0019355; Searle X.B., WO03/090761; Akritopoulou-Zanze I. etc., Bioorg.Med.Chem.Lett.2004,14:3809-3813; Nomura T. etc., Bioorg.Med.Chem.2005,13:6615-6628; Nomura T. etc., Bioorg.Med.Chem.2006,14:3697-3711; Nam, G. etc., Bioorg.Med.Chem.Lett.2010,20:2671-2674), still, the activity of the antimicrobial agent of current published 9-oxime ether ketone lactone is also not ideal.
In a word, need the urgent technical problem solving of those skilled in the art to be exactly: how a kind of novel 9-oxime ether ketolide derivatives can be provided, can adapt to preferably suitability for industrialized production, and there is good anti-sensitive organism and antimicrobial agent activity for respiratory tract germs such as streptococcus pneumoniaes.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of novel ketone lactone (9-O-aromatic base proyl ketolide derivatives) and synthetic method thereof, and this compounds is as purposes and the corresponding medicinal compositions of anti-infectives.。This compound and preparation method thereof can adapt to suitability for industrialized production preferably, and this compound has good anti-sensitive organism for respiratory tract germ etc. and antimicrobial agent is active.
In order to address the above problem, the invention discloses a kind of the have compound of following general formula I or II and acceptable salt or the ester forming with mineral acid or organic acid thereof:
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
Preferably, described Ar is nitrogenous, sulphur or Sauerstoffatom heterocycle; Or nitrogenous, sulphur or the Sauerstoffatom heterocycle of Ar for replacing.
Preferably, described Ar is imidazolyl, pyridyl, pyrimidyl, benzopyrazines base, benzo pyridazinyl, quinolyl, isoquinolyl, imidazoles phenyl, indyl, thienyl; Or Ar is substituted imidazole base, substituted pyridinyl, substituted pyrimidyl, replacement benzo pyrazinyl, replaces benzo pyridazinyl, substd quinolines base, substituted isoquinoline base, substituted imidazole phenyl, substituted indolyl, substituted thiophene base.
Preferably, described Ar is 3-pyridyl, 5-pyrimidyl, 3-quinolyl, 4-isoquinolyl, 4-quinolyl, 5-isoquinolyl, 5-quinolyl, 6-quinolyl, 4-(1-imidazoles) phenyl, 2-thienyl.
Preferably, described mineral acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid; Described organic acid is selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid or stearic acid.
According to embodiments of the invention, a kind of method of compound as claimed in claim 1 of preparing is also disclosed, comprising:
(1) compound, with following general formula III:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Described protection reagent is used for realizing R protecting group;
(2), in the mono-solvent of THF or THF/DMSO mixed solvent, under the acting in conjunction of propargylation reagent and highly basic, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; Then with oxidising agent, 3-OH is oxidized to 3-carbonyl, obtains general formula I V compound;
Or, in the mono-solvent of THF or THF/DMSO mixed solvent, under the acting in conjunction of propargylation reagent and highly basic, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; Then use and close cyclization reagent by 11,12-OH pass ring, then with oxidising agent, 3-OH is oxidized to 3-carbonyl, obtain general formula V compound;
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly;
(3), in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, propargyl effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain, and sloughs 2 '-O-R protecting group, obtains having the compound of following general formula I or II;
Or in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, the propargyl effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain; Further in 2-position, introduce fluorine atom, and slough 2 '-O-R protecting group, obtain having the compound of following general formula I or II
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
Preferably, the equivalence ratio scope of the compound of described propargylation reagent and step (1) is 1.0-4.0; The equivalence ratio scope of the compound of described highly basic and step (1) is 1.0-4.0.
Preferably, described protection reagent is selected from acetic anhydride, benzoyl oxide, trimethyl silicane chlorine or hexamethyldisilazane; Described propargylation reagent is selected from propargyl bromide or propargyl iodide; Described highly basic is selected from potassium tert.-butoxide, potassium hydroxide, sodium hydride or hexamethl disilamine potassium; Described pass cyclization reagent is selected from triphosgene, phosgene or trichloromethyl chloroformyl ester; The oxide compound reagent that described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide or contains methyl-sulphoxide; Described palladium salt is selected from two (triphenylphosphine) palladiums of dichloro or tetrakis triphenylphosphine palladium; Described mantoquita is selected from cuprous iodide or cuprous bromide.
According to embodiments of the invention, a kind of medicinal compositions for antibacterial therapy is also disclosed, comprise the compound of the following general formula I of having of antimicrobial effective amount or II, or its pharmaceutically acceptable additive salt or ester; And pharmaceutically acceptable carrier;
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
The invention also discloses the application of a kind of aforesaid compound in the medicine for the preparation of the treatment of antibacterium infected by microbes.
Compared with prior art, the present invention has the following advantages:
Compound of the present invention has novel texture, on the 9-of ketone lactone oxime hydroxyl, by propargyl side chain, connects an aromatic heterocycle hydrocarbon, and synthetic easy, is applicable to suitability for industrialized production.
The aromatic side chain of ketone lactone is as the pharmacophore of important antimicrobial agent, and its link position on ketone lactone and side chain lengths thereof and structure directly have influence on the power of its antimicrobial agent activity.The present invention, through test of many times and theoretical investigation, has selected propargyl to connect aromatic heterocyclic alkyl as the aromatic side chain of ketone lactone, can obtain good anti-sensitive organism and antimicrobial agent active.
Through overtesting, compound of the present invention all has outstanding anti-microbial activity to clinical common sensitive organism and resistant organism, as streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, staphylococcus epidermidis etc., can separately or mix the treatment that is used for the infection such as bacterium with various formulations or route of administration with other medicines as one of activeconstituents.
In a word, the anti-microbial activity that propargyl has improved ketone lactone greatly at introducing and the further fragrant derivatize thereof of 9-oxime, and also this aromatic side chain is easily synthetic, is easy to suitability for industrialized production.
Embodiment
For above-mentioned purpose of the present invention, feature and advantage can be become apparent more, below in conjunction with embodiment, the present invention is further detailed explanation.
The invention provides a kind of compound with following general structure I or II, and the acceptable salt or the ester that form with mineral acid or organic acid.
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen atom or fluorine atom.
Wherein, preferably, Ar can be 3-pyridyl, 5-pyrimidyl, 3-quinolyl, 4-quinolyl, 4-isoquinolyl, 5-quinolyl, 5-isoquinolyl, 6-quinolyl, 6-isoquinolyl, 8-quinolyl, 4-(1-imidazoles) phenyl, 5-indyl, 2-thienyl, 3-thienyl etc.In actual applications, Ar also can be for further replacing the group after deriving on above-mentioned group basis.
The compound that the present invention has above-mentioned general formula can also form salt or ester with medicinal acceptable various mineral acids or organic acid.Preferably, mineral acid can be selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid; Organic acid can be selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid, stearic acid.But the present invention be not limited to above for example.
To thering is the preparation method of the compound of above-mentioned general formula, be briefly described below.
Preparation process of the present invention is as follows:
1, from erythromycin oxime, through etherificate, silanization, methylate obtain the midbody compound 1,2 of clarithromycin synthesis technique ', 4 " two (trimethyl silicane)-CAMA A 9-O-(isopropoxy cyclohexyl) oximes of O-;
2, then hydrolysis obtains key compound 2:3-OH-6-O-erythromycin oxime;
3 and then, under the effect of acetic anhydride, 2 '-OH and 9-oxime hydroxyl diacetyl obtain compound 3:2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-acetyl oxime.The technological process of above three steps has had mentioned in open source literature, is not described in detail in this.Similar technique is referring to Liang Jianhua etc., organic chemistry, 2005,438-441; Zhou Baige etc., fine chemistry industry, 2005,314-316; Japanese plum guest etc., fine chemistry industry, 2007,678-680.
It is to be noted, only provided a preparation process example that obtains compound 3 above, those skilled in the art can adopt other various feasible preparation processes to obtain required compound 3 according to open source literature, or directly from suppliers, obtain compound 3; A core of the present invention is improved the technological process that is to obtain from compound 3 novel ketone lactone required for the present invention (9-aromatic base proyl ketolide derivatives).
For example, in obtaining the process of compound 3, compound 12 ', 4 " two (trimethyl silicane)-CAMA A 9-O-(isopropoxy cyclohexyl) oximes of O-can replace to 2 ', 4 " two (trimethyl silicane)-CAMA A 9-O-(oxyethyl group cyclohexyl) oximes of O-.
In fact in the present invention, compound 1 also can replace with 2 ', 4 " two (trimethyl silicane)-CAMA A 9-O-(1-methoxyl group-1-methylethyl) oximes of O-; Compound 1 can also replace with 2 ', 4 " two (trimethyl silicane)-CAMA A 9-O-(1-oxyethyl group-1-methylethyl) oximes of O-; or 2 ', 4 " two (trimethyl silicane)-CAMA A 9-O-(the di-t-butyl methyl silicon) oximes of O-etc.
Certainly, because above-mentioned conversion can be realized based on prior art by those skilled in the art, therefore, do not repeat them here.And because these conversion of compound 1 can not change reaction mechanism, under acidity, hydrolysis still can obtain key compound 2, therefore, less on the impact of subsequent step 2,3.
, also it should be noted that meanwhile, in obtaining the processing step of compound 3, as step 3, protect the reagent of reagent (for realizing the reagent of protecting group) also can be replaced.For example; acetic anhydride can change benzoyl oxide into; or silylating reagent is as trimethyl silicane chlorine, hexamethyldisilazane etc.; obtain the analogue of compound 3; be that ethanoyl on compound 3 is replaced by benzoyl, trimethyl silicon based; this analogue can, equally for follow-up reaction, can not change reaction mechanism.
4, in the single solvent of THF (tetrahydrofuran (THF)) or THF/DMSO (dimethyl sulfoxide (DMSO)) mixed solvent, the propargyl bromide of 1.0-4.0 equivalent (molar weight) and the potassium tert.-butoxide acting in conjunction of 1.0-4.0 equivalent can selectivity ethanoyl on the 9-oxime hydroxyl of displacement compound 3 obtain compound 4:2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-propargyl oxime.
5, further; in dichloromethane solvent; use triphosgene by 11; 12-OH closes ring; 3-OH is become 3-carbonyl to obtain key compound 5:2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime-11,12-cyclic carbonate ester by Corey-Kim oxidation (in section-Jin oxidation) reagent oxidation again.
6, last, in acetonitrile, THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, at palladium salt as dichloro under two (triphenylphosphine) palladiums and mantoquita (as cuprous iodide) catalysis, substituted aroma hydrocarbon (for example, halogenated aromatic) the propargyl effect and on 9-oxime hydroxyl forms aromatic side chain, and in methyl alcohol, slough 2 '-O-Ac and obtain target compound 6:3-carbonyl-CAMA A 9-O-[3-aryl-2-propynyl] oxime-11,12-cyclic carbonate ester;
Or, in acetonitrile, THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, at palladium salt as dichloro under two (triphenylphosphine) palladiums and mantoquita (as cuprous iodide) catalysis, propargyl effect on substituted aroma hydrocarbon and 9-oxime hydroxyl forms aromatic side chain, further in THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, under sodium hydride and the effect of N-fluorobenzene sulphonyl imido, fluorine atom is introduced in 2-position, and in methyl alcohol, sloughs 2 '-O-Ac and obtain the target compound 6 of fluoridizing 2-position.
Fluoridizing of 2-position at ketone lactone can be improved anti-microbial activity.The technical matters comparative maturity of fluoridizing due to the 2-position of ketone lactone, therefore, does not repeat them here.For example, refer to Denis, A. etc., Drug.Future.2001,26,975; Phan, L.T. etc., Org.Lett.2000,2,2951; SearleX.B., WO03/090761.
It should be noted that, if do not carry out 11,12-OH carbonic acid esterification (as " the using triphosgene that 11,12-OH is closed to ring " in processing step 5) in reaction mechanism, what finally obtain is compound of Formula I; If carry out 11,12-OH carbonic acid esterification, what finally obtain is general formula I I compound.Existing research shows: 11, the esterification of 12-carbonic acid is than parent 11,12-OH not carbonic acid esterification can further improve anti-microbial activity (T.Nomura, Deng, Bioorg.Med.Chem.2005,13:6054-6063),, the in the situation that of identical substituted radical, the compound anti-microbial activity of general formula I of the present invention is slightly less than the compound of general formula I I.
In addition, some of them synthesis step can reverse the right order, as first 11,12-OH carbonic acid esterification, then at selectivity propargylation; Or first 3-OH oxidation and then the esterification of 11,12-OH carbonic acid, etc.The variation of these order of operation does not have influence on the synthetic of target compound.Those skilled in the art can carry out some feasible step order transposings based on preparation principle, can not exceed protection scope of the present invention.
Wherein, some reagent also can be replaced, for example,
Propargyl bromide as propargylation reagent can change propargyl iodide etc. into;
Potassium tert.-butoxide as highly basic can change potassium hydroxide, sodium hydride, hexamethl disilamine potassium etc. into;
As the triphosgene of closing cyclization reagent, can change phosgene, trichloromethyl chloroformyl ester etc. into;
Corey-Kim oxidising agent (N-chloro succinimide/dimethyl sulphide) as oxidising agent can change the various oxide compound reagent that contains methyl-sulphoxide into as methyl-sulphoxide/oxalyl chloride, methyl-sulphoxide/acetic anhydride etc.;
For changing commercialization reagent Selectifluor into the fluorination reagent N-fluorobenzene sulphonyl imido of fluoridizing of the 2-position of ketone lactone
tM;
Two (triphenylphosphine) palladiums of described palladium salt dichloro can replace to tetrakis triphenylphosphine palladium;
Described mantoquita cuprous iodide can replace to cuprous bromide.
The variation of above-mentioned these reagent does not have influence on the synthetic of target compound general formula I or II.
By the mode of structural formula, preparation process is above provided to a concrete example below, is simply described as follows:
Reaction reagent and condition: (a) HCl, EtOH. (b) Ac
2o, CH
2cl
2. (c) KOtBu, Propargyl Bromide, THF. (d) Bis (trichloromethyl) carbonate, Pyridine, CH
2cl
2. (e) Me
2s, N-chlorosuccinimide, Et
3n, CH
2cl
2. (f) ArBr, (PPh
3)
2pdCl
2, CuI, Et
3n, CH
3cN. (g) MeOH.
Embodiment 1 (generating compound 2)
3-hydroxyl-CAMA oxime
13.2g compound 1 is added to 40ml dissolve with ethanol, and the dense HCl of 5ml 36% is diluted in 50ml water and is then added drop-wise in reaction solution, reacts one hour at 40 ℃, adds ammoniacal liquor to regulate pH value to 9 left and right after reaction finishes, and adularescent Precipitation, filters white precipitate.This is deposited in to recrystallization in ethanol, water and obtains 3-OH clarithromycin oxime (5.42g, yield 71%)
Embodiment 2 (generating compound 3)
2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-acetyl oxime
By being equipped with in the flask of 5.42g (8.96mmol) 3-hydroxyl clarithromycin oxime, add 50ml methylene dichloride, drip 2.6ml (24.88mmol) acetic anhydride, react end in a hour, reaction solution is used respectively saturated sodium bicarbonate solution, water, saturated aqueous common salt washing and filtering, removal of solvent under reduced pressure obtains white blister compound 5.60g (8.13mmol, yield 90.7%).
Embodiment 3 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-propargyl oxime
1.00g (1.5mmol) 2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-acetyl oxime is dissolved in 15ml THF solution; add potassium tert.-butoxide 489mg (4.36mmol) and propargyl bromide 0.52ml (5.8mmol) reaction to add 20ml ethyl acetate and 20ml water after one hour; stratification; upper strata saturated aqueous common salt washing and filtering; evaporated under reduced pressure solvent obtains 1.06g solid (1.55mmol, yield 100%).
Embodiment 4 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-propargyl oxime
0.500g (0.73mmol) 2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-acetyl oxime is dissolved in 15ml THF/DMSO solution; add potassium tert.-butoxide 106mg (0.95mmol) and propargyl bromide 0.13ml (1.46mmol) reaction to add 10ml ethyl acetate and 10ml water after one hour; stratification; upper strata saturated aqueous common salt washing and filtering; evaporated under reduced pressure solvent obtains 0.461g solid (0.67mmol, yield 91.8%).
HRMS(ESI)(M+H)
+m/z 685.42599，calcd for C
35H
61N
2O
11685.42699.
1H NMR(400MHz，CDCl
3)δ：0.83(t，3H，15-CH
3)，0.90(d，J＝7.3Hz，3H，8-CH
3)，0.97(d，J＝7.0Hz，4-CH
3)，1.15-1.24(m，15H，H-4′ax，10-CH
3，12-CH
3，2′-CH
3，5′-CH
3)，1.30(s，3H，6-CH
3)，1.31-1.49(m，3H，H-7，H-14ax)，1.71-1.75(m，1H，H-4′eq)，1.94-1.96(m，1H，H-14eq)，2.06(s，3H，2′-O-Ac)，2.06-2.11(m，1H，H-4)，2.26(s，6H，-N(CH
3)
2)，2.49(t，J＝2.1Hz，1H，CH
2-C≡CH)，2.57-2.73(m，3H，H-10，H-2，H-3′)，2.98(s，3H，6-OCH
3)，3.33(s，1H，12-OH)，3.41(d，J＝10.5Hz，1H，H-3)，3.47-3.51(m，1H，H-5′)，3.58-3.62(m，1H，H-8)，3.71(d，J＝1.7Hz，1H，H-5)，3.81(s，1H，H-11)，4.48(s，1H，11-OH)，4.57(s，2H，CH
2-C≡CH)，4.62(d，J＝7.6Hz，1H，H-1′)，4.76(dd，J＝7.7and 10.2Hz，1H，H-2′)，5.25(dd，J＝1.6 and 11.0Hz，1H，H-13).
13C NMR(100MHz，CDCl
3)δ：7.6，10.2，15.0，15.2，16.1，18.2，19.1，20.9，21.2，21.3，26.2，30.8，32.9，35.8，36.8，40.4，44.0，49.9，60.7，62.9，68.4，70.2，71.2，73.8，74.2，77.2，78.0，79.7，80.3，99.5，169.8，170.8，174.6.
Embodiment 5 (generating the first step of compound 5)
2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-propargyl oxime-11,12-cyclic carbonate ester
1.06g (1.55mmol) 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-propargyl oxime is dissolved in 50ml methylene dichloride; add 1.5ml (18.6mmol) pyridine; at-5 ℃, stir 10 minutes; start to drip 0.9g (3.1mmol) triphosgene that is dissolved in methylene dichloride in 30ml, within 30 minutes, dropwise.-5 ℃ of reactions slowly drip 70ml saturated aqueous common salt and finish reaction after 17 hours.Stratification, lower floor's organic phase saturated sodium bicarbonate, water, saturated aqueous common salt washing and filtering, evaporated under reduced pressure solvent obtains 0.70g solid (0.99mmol, yield 63.5%).
Embodiment 6 (generating the second step of compound 5)
2 '-O-ethanoyl-3-carbonyl-CAMA A9-O-propargyl oxime-11,12-cyclic carbonate ester
In 100ml there-necked flask, add 20ml methylene dichloride, add 0.212gN-chlorosuccinimide (NCS) (1.6mmol) under stirring, maintenance system-15 ℃, slowly drip 0.14mlMe
2(1.9mmol) there is white flocks in S (DMS); continue to stir half an hour; to be dissolved with 0.70g (0.99mmol) 2 '-O-ethanoyl-3-hydroxyl-CAMA A9-O-propargyl oxime-11; the 10ml methylene dichloride of 12-cyclic carbonate ester is added drop-wise in system, and dropwise half an hour, reacts 1.5 hours at-15 ℃; TLC demonstration has been reacted; drip triethylamine 0.3ml termination reaction, it is clear that system becomes, and stirs one hour at-5 ℃.Reaction solution is used respectively saturated sodium bicarbonate, water, and saturated common salt water washing is also spent the night with anhydrous magnesium sulfate drying, filters, and evaporated under reduced pressure solvent obtains 0.50g solid (0.71mmol, yield 71.9%).
The following examples of the present invention provide the technological process example that another kind obtains compound 5.
Embodiment 7 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-propargyl oxime
2.00g (2.9mmol) 2 '-ethanoyl-3-hydroxyl-CAMA A 9-O-acetyl oxime is dissolved in 20ml THF solution; add potassium tert.-butoxide 978mg (8.71mmol) and propargyl bromide 0.78ml (8.7mmol) reaction to add 20ml ethyl acetate and 20ml water after one hour; stratification; upper strata saturated aqueous common salt washing and filtering; evaporated under reduced pressure solvent obtains 1.94g solid (2.83mmol, yield 97.5%).
Embodiment 8 (generating the first step of compound 5)
2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime
In 250ml there-necked flask, add 40ml methylene dichloride; under stirring, add 0.483g NCS (3.6mmol); maintenance system-15 ℃; slowly drip 0.3ml DMS (4.29mmol) and occur white flocks; continue to stir half an hour; the 15ml methylene dichloride that is dissolved with 1.61g (2.26mmol) 2 '-O-ethanoyl-3-hydroxyl-CAMA A 9-O-propargyl oxime is added drop-wise in system; dropwise half an hour; at-15 ℃, react 1.5 hours; TLC demonstration has been reacted; drip triethylamine 0.6ml termination reaction, it is clear that system becomes, and stirs one hour at-5 ℃.Reaction solution is used respectively saturated sodium bicarbonate, water, and saturated common salt water washing, filters, and evaporated under reduced pressure solvent obtains 1.344g solid (1.97mmol, yield 87.2%).
Embodiment 9 (generating the second step of compound 5)
2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime-11,12-cyclic carbonate ester
1.344g (1.97mmol) 2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime is dissolved in 50ml methylene dichloride; add 1.9ml (23.62mmol) pyridine; at-5 ℃, stir 10 minutes; start to drip 1.17g (3.94mmol) triphosgene that is dissolved in methylene dichloride in 30ml, within 30 minutes, dropwise.-5 ℃ of reactions slowly drip 70ml saturated aqueous common salt and finish reaction after 17 hours.Stratification, lower floor's organic phase saturated sodium bicarbonate, water, saturated aqueous common salt washing and filtering, evaporated under reduced pressure solvent obtains 1.342g solid (1.89mmol, yield 95.8%).
Embodiment 7,8,9 above, in generating the process of compound 5, first obtains 3-carbonyl, then obtains 11,12-cyclic carbonate ester.And in embodiment 5,6, first obtain 11,12-cyclic carbonate ester, then obtain 3-carbonyl.
Also it should be noted that; if wish to obtain the compound of general formula I; the compound 5 obtaining can be: 2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime; and need not carry out ring closure reaction (11; 12-OH carbonic acid esterification) generate 2 '-O-ethanoyl-3-carbonyl-CAMA A 9-O-propargyl oxime-11,12-cyclic carbonate ester.
Embodiment 10 (generating the compound 6 of 5-pyrimidyl)
3-carbonyl-CAMA A 9-O-[3-(5-pyrimidine)-2-propynyl] oxime-11,12-cyclic carbonate ester
By 0.700g (0.988mmol) compound 5; 19mg (0.099mmol) cuprous iodide; 35mg (0.049mmol) bi triphenyl phosphine dichloride palladium; 0.471mg (2.964mmol) 5-bromo pyrimi piperidine, 0.21ml (1.482mmol) triethylamine, adds in the pressure bottle that 12ml acetonitrile is housed; system is under nitrogen protection; at 80 ℃ of stirring reactions, within 3 hours, finish, in system, add 15ml ethyl acetate and 15ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products 175mg (0.222mmol, yield 22.5%).This compound dissolution, in 25ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) obtain pure compounds 24mg (0.032mmol, yield 14.4%).
HRMS(ESI)(M+H)
+m/z 745.40115，calcd for C
38H
57N
4O
11 745.40184.
1H NMR(400MHz，CDCl
3)δ：0.89(t，3H，15-CH
3)，1.01(d，J＝6.9Hz，3H，8-CH
3)，1.22-1.30(m，10H，4-CH
3，10-CH
3，5′-CH
3，H-4ax)，1.36(d，J＝6.8Hz，3H，2-CH
3)，1.43(s，3H，6-CH
3)，1.55(s，3H，12-CH
3)，1.55-1.63(m，1H，H-14ax)，1.66-1.72(m，2H，H-7，H-4eq)，1.88-1.92(m，1H，H-14eq)，2.28(s，6H，-N(CH
3)
2)，2.43-2.55(m，2H，H-3′，H-10)，2.71(s，3H，6-OCH
3)，2.98-3.05(m，1H，H-4)，3.19(dd，J＝7.2 and 7.3Hz，1H，H-2′)，3.51-3.56(m，1H，H-5′)，3.64(br，1H，H-8)，3.82(q，J＝6.7Hz，1H，H-2)，4.19(d，J＝8.4Hz，1H，H-5)，4.29(d，J＝7.3Hz，1H，H-1′)，4.79(s，1H，H-11)，4.89(d，J＝7.8Hz，2H，CH
2C≡C-Ar)，5.05(dd，J＝2.6and 10.2Hz，1H，H-13)，[8.75(s，2H)，9.13(s，1H)，pyrimidyl].
Embodiment 11 (generating the compound 6 of 4-isoquinolyl)
3-carbonyl-CAMA A 9-O-[3-(4-isoquinoline 99.9)-2-propynyl] oxime-11,12-cyclic carbonate ester
By 0.700g (0.988mmol) compound 5; 19mg (0.099mmol) cuprous iodide; 35mg (0.049mmol) bi triphenyl phosphine dichloride palladium; 411mg (1.976mmol) 4-bromo-isoquinoline, 0.21ml (1.482mmol) triethylamine, adds in the pressure bottle that 12ml acetonitrile is housed; system is under nitrogen protection; at 80 ℃ of stirring reactions, within 3 hours, finish, in system, add 15ml ethyl acetate and 15ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products 72mg (0.086mmol, yield 8.70%).This compound dissolution, in 25ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) obtain pure compounds 23mg (0.029mmol, yield 33.7%).
HRMS(ESI)(M+H)
+m/z 794.42221，calcd for C
43H
60N
3O
11 794.42224.
1H NMR(400MHz，CDCl
3)δ：0.89(t，3H，15-CH
3)，1.02(d，J＝6.8Hz，3H，8-CH
3)，1.21-1.33(m，12H，4-CH
3，10-CH
3，5′-CH
3，2-CH
3)，1.46(s，3H，6-CH
3)，1.57(s，3H，12-CH
3)，1.64-1.75(m，3H，H-7，H-4eq)，1.89-1.93(m，1H，H-14eq)，2.26(s，6H，-N(CH
3)
2)，2.40-2.47(m，1H，H-3′)，2.63(br，1H，H-10)，2.69(s，3H，6-OCH
3)，3.01-3.05(m，1H，H-4)，3.18(dd，J＝7.3and 10.2Hz，1H，H-2′)，3.46-3.55(m，2H，H-2，H-5′)，3.78(br，1H，H-8)，4.17(d，J＝8.5Hz，1H，H-5)，4.28(d，J＝7.3Hz，1H，H-1′)，4.82(s，1H，H-11)，4.97-5.06(m，3H，CH
2-C≡C-Ar，H-13)，[7.64(t，1H)，7.79(t，1H)，7.97(d，1H)，8.30(d，1H)，8.65(s，1H)，9.17(s，1H)，isoquinolyl].
13C NMR(100MHz，CDCl
3)δ：10.4，13.2，14.3，15.5，15.8，18.9，19.8，21.2，22.5，26.5，28.2，38.4，40.2，46.1，47.8，49.7，51.1，62.0，65.9，69.5，70.4，76.4，77.2，78.5，79.4，80.9，82.7，84.7，93.2，103.9，115.5，125.2，127.7，127.9，131.2，135.8，146.5，152.1，154.4，165.9，169.0，203.9.
Embodiment 12 (generating the compound 6 of 3-quinolyl)
3-carbonyl-CAMA A 9-O-[3-(3-quinoline)-2-propynyl] oxime-11,12-cyclic carbonate ester
By 0.633g (0.892mmol) compound 5; 17mg (0.089mmol) cuprous iodide; 31mg (0.045mmol) bi triphenyl phosphine dichloride palladium; 0.24ml (1.784mmol) 3-bromoquinoline, 0.19ml (1.338mmol) triethylamine, adds in the pressure bottle that 12ml acetonitrile is housed; system is under nitrogen protection; at 80 ℃ of stirring reactions, within 3 hours, finish, in system, add 15ml ethyl acetate and 15ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products 99mg (0.118mmol, yield 13.3%).This compound dissolution, in 25ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) obtain pure compounds 33mg (0.042mmol, yield 35.6%).
HRMS(ESI)(M+H)
+m/z 794.42311，calcd for C
43H
60N
3O
11 794.42224.
1H NMR(400MHz，CDCl
3)δ：0.89(t，3H，15-CH
3)，1.08(d，3H，8-CH
3)，1.22-1.34(m，13H，4-CH
3，10-CH
3，5′-CH
3，2-CH
3，H-4ax)，1.46(s，3H，6-CH
3)，1.57(s，3H，12-CH
3)，1.66-1.74(m，2H，H-7，H-4eq)，1.89-1.93(m，1H，H-14eq)，2.27(s，6H，-N(CH
3)
2)，2.44-2.57(m，2H，H-3′，H-10)，2.73(s，3H，6-OCH
3)，3.00-3.06(m，1H，H-4)，3.20(dd，1H，H-2′)，3.51-3.55(m，2H，H-2，H-5′)，3.79-3.84(m，1H，H-8)，4.19(d，J＝8.4Hz，1H，H-5)，4.29(d，J＝7.3Hz，1H，H-1′)，4.80(s，1H，H-11)，4.93(d，J＝9.5Hz，2H，CH
2C≡C-Ar)，5.05(dd，J＝2.6 and 10.0Hz，1H，H-13)，[7.53(t，1H)，7.72(t，1H)，7.78(d，1H)，8.07(d，1H)，8.24(d，1H)，8.88(d，1H)，quinolyl].
Embodiment 13 (generating the compound 6 of 6-quinolyl)
3-carbonyl-CAMA A 9-O-[3-(6-quinoline)-2-propynyl] oxime-11,12-cyclic carbonate ester
By 0.946g (1.335mmol) compound 5; 25mg (0.134mmol) cuprous iodide; 47mg (0.067mmol) bi triphenyl phosphine dichloride palladium; 0.36ml (2.67mmol) 6-bromoquinoline, 0.30ml (1.338mmol) triethylamine, adds in the pressure bottle that 15ml acetonitrile is housed; system is under nitrogen protection; at 80 ℃ of stirring reactions, within 3 hours, finish, in system, add 15ml ethyl acetate and 15ml water, stratification.Through column chromatography, (200-300 order silicagel column, moving phase is chloroform: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be compared with pure products 155mg (0.185mmol, yield 13.9%).This compound dissolution, in 25ml methyl alcohol, is refluxed at 65 ℃ and within 3 hours, takes off ethanoyl and obtain compound crude product.Crude product is crossed silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) obtain pure compounds 29mg (0.035mmol, yield 18.8%).
HRMS(ESI)(M+H)
+m/z 794.42082，calcd for C
43H
60N
3O
11 794.42224.
1H NMR(400MHz，CDCl
3)δ：0.89(t，3H，15-CH
3)，1.02(d，J＝6.8Hz，3H，8-CH
3)，1.22-1.32(m，4-CH
3，10-CH
3，5′-CH
3，2-CH
3)，1.46(s，3H，6-CH
3)，1.57(s，3H，12-CH
3)，1.67-1.73(m，2H，H-7，H-4eq)，1.88-1.94(m，1H， H-14eq)，2.29(s，6H，-N(CH
3)
2)，2.45-2.58(m，2H，H-3′，H-10)，2.73(s，3H，6-OCH
3)，2.99-3.07(m，1H，H-4)，3.21(dd，1H，H-2′)，3.49-3.55(m，1H，H-5′)，3.77(br，1H，H-8)，4.18(d，J＝8.5Hz，1H，H-5)，4.29(d，J＝7.3Hz，1H，H-1′)，4.81(s，1H，H-11)，4.91(d，J＝7.2Hz，2H，CH
2C≡C-Ar)，5.04(dd，J＝2.5Hz and 10.0Hz，1H，H-13)，[7.41(q，1H)，7.69(dd，1H)，7.93(s，1H)，8.02(d，1H)，8.11(d，1H)，8.90(dd，1H)，quinolyl].
Embodiment 14
Similarly, [or other substituted aroma hydrocarbon reagent is as 3-bromopyridine to adopt 4-bromoquinoline, the iodo-4-oil of mirbane of 1-, 1-(4-imidazoles)-bromobenzene, 2-bromoquinoline, 5-bromoquinoline, 7-bromoquinoline, 8-bromoquinoline, 5-bromo-isoquinoline, 6-bromo-isoquinoline, 7-bromo-isoquinoline, 8-bromo-isoquinoline, 2-bromothiophene, 3 bromo thiophene etc., or the derivative of above aromatic hydrocarbon] under palladium salt and mantoquita catalysis, there is Sonogashira with compound 5 and react, through deacetylation, can obtain other target compound in this patent coverage again.
Embodiment 15
Medicinal compositions
The present invention can also be provided for the medicinal compositions of antibacterial therapy, and said composition can comprise the compound with aforementioned formula of antimicrobial effective amount, or its pharmaceutically acceptable additive salt or ester, and pharmaceutically acceptable carrier.
Antibacterial therapy effect to the medicinal compositions of above-mentioned 9-oxime ether ketolide derivatives is measured.
According to Clinical and Laboratory Standards Institute (CLSI, 2010) standard of recommending, the antibacterial activity in vitro (MIC) of part target compound to responsive streptococcus pneumoniae ATCC49619, erm+mef type Antimicrobial Streptococcus Pneumoniae PU-11, mef type Antimicrobial Streptococcus Pneumoniae PU-09, erm type Antimicrobial Streptococcus Pneumoniae PU-27 that adopted broth dilution method determination.Measurement result is in Table 1.
The anti-microbial activity MIC value (μ g/mL) of table 19-O-arylprop alkynyl oxime ether ketolide derivatives
Clarithromycin Azythromycin embodiment 10 embodiment 11 embodiment 12 embodiment 13
ATCC49619 0.032 0.064 ≤0.016 ≤0.016 ≤0.016 ≤0.016
PU-11 128 256 128 16 32 16
PU-09 4 8 0.125 0.032 0.064 0.125
PU-27 16 32 0.5 0.032 0.064 0.064
Further, according to Clinical and Laboratory Standards Institute (CLSI, 2010) standard of recommending, target compound and the antibacterial activity in vitro (MIC) of reference substance (9-O-fragrance propenyl ketolide derivatives) to responsive streptococcus pneumoniae ATCC49619, erm+mef type Antimicrobial Streptococcus Pneumoniae PU-11, mef type Antimicrobial Streptococcus Pneumoniae PU-09, erm type Antimicrobial Streptococcus Pneumoniae PU-27 of embodiment 13 that adopted broth dilution method determination.Measurement result is in Table 2.
Anti-microbial activity comparison (the MIC value: μ g/mL) of table 2 9-O-arylprop alkynyl oxime ether ketolide derivatives and 9-O-arylprop thiazolinyl oxime ether ketolide derivatives
Embodiment 13 reference substances
ATCC49619 ≤0.016 ≤0.016
PU-11 16 32
PU-09 0.125 0.25
PU-27 0.064 1
Wherein, reference substance is: 3-carbonyl-CAMA A 9-O-[3-(6-quinoline)-2-propenyl] oxime-11,12-cyclic carbonate ester.
From table 1 and table 2, target compound is compared with Azythromycin with current clinical main medication clarithromycin, has all shown outstanding anti-sensitive organism and antimicrobial agent active.Target compound 3-carbonyl-CAMA A 9-O-[3-(6-quinoline)-2-propynyl of embodiment 13] oxime-11,12-cyclic carbonate ester is compared with analogue (reference substance) 9-O-(3-(6-quinoline)-2-propenyl) ketone lactone, and anti-microbial activity further improves.
We and analogue 9-O-aromatic base allyl ketone lactone carry out anti-microbial activity comparison, find that the compound in the present invention has higher anti-microbial activity, and the target compound of embodiment 13 in table 2 to compare mainly with reference substance be the difference of " allyl group " and " propargyl ", the side-chain structure that propargyl of the present invention is described, antibacterial effect is better.
Compound for general formula I of the present invention and II, existing research shows: 11, the esterification of 12-carbonic acid is than parent 11,12-OH not carbonic acid esterification can further improve anti-microbial activity (T.Nomura, etc., Bioorg.Med.Chem.2005,13:6054-6063), therefore can derive, the in the situation that of identical substituted radical, the compound anti-microbial activity of general formula I of the present invention is less than the compound of general formula I I.
It should be noted that, in the medicine that the present invention can treat for infected by microbes such as multiple antibacteriums, comprise chlamydozoan or mycoplasma infection etc.
Above to a kind of novel ketone lactone provided by the present invention (9-aromatic base proyl ketolide derivatives) and synthesis preparation method thereof, and this compounds is as purposes and the corresponding medicinal compositions of anti-infectives, be described in detail, applied specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment is just for helping to understand method of the present invention and core concept thereof; , for one of ordinary skill in the art, according to thought of the present invention, all will change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention meanwhile.
Claims (8)
1. one kind has the compound of following general formula II and the acceptable salt forming with mineral acid or organic acid thereof:
Wherein, Ar is pyrimidyl, quinolyl or isoquinolyl; X is hydrogen or fluorine.
2. compound as claimed in claim 1 or acceptable salt, is characterized in that,
Described Ar is 5-pyrimidyl, 3-quinolyl, 4-isoquinolyl, 4-quinolyl, 5-isoquinolyl, 5-quinolyl, 6-quinolyl.
3. compound as claimed in claim 1 or acceptable salt, is characterized in that,
Described mineral acid is selected from hydrochloric acid, sulfuric acid, Hydrogen bromide or phosphoric acid;
Described organic acid is selected from acetic acid, propanedioic acid, methylsulfonic acid, succsinic acid, tosic acid, citric acid, toxilic acid, fumaric acid or stearic acid.
4. prepare a method for compound as claimed in claim 1, it is characterized in that, comprising:
(1) compound, with following general formula III:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Protection reagent is used for realizing R protecting group; Described protection reagent is selected from acetic anhydride, benzoyl oxide, trimethyl silicane chlorine or hexamethyldisilazane;
（2）、
In the mono-solvent of THF or THF/DMSO mixed solvent, under the acting in conjunction of propargylation reagent and highly basic, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; Then use and close cyclization reagent by 11,12-OH pass ring, then with oxidising agent, 3-OH is oxidized to 3-carbonyl, obtain general formula V compound;
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly;
(3), in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, propargyl effect on substituted aroma hydrocarbon reagent and 9-oxime hydroxyl forms aromatic side chain, and sloughs 2'-O-R protecting group, obtains having the compound of following general formula II;
Or in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, the propargyl effect on substituted aroma hydrocarbon reagent and 9-oxime hydroxyl forms aromatic side chain; Further in 2-position, introduce fluorine atom, and slough 2'-O-R protecting group, obtain having the compound of following general formula II
Wherein, Ar is pyrimidyl, quinolyl or isoquinolyl; X is hydrogen or fluorine;
Described substituted aroma hydrocarbon reagent comprises: 4-bromoquinoline, 2-bromoquinoline, 3-bromoquinoline, 5-bromoquinoline, 6-bromoquinoline, 7-bromoquinoline, 8-bromoquinoline, 4-bromo-isoquinoline, 5-bromo-isoquinoline, 6-bromo-isoquinoline, 7-bromo-isoquinoline, 8-bromo-isoquinoline, 5-bromo pyrimi piperidine.
5. preparation method as claimed in claim 4, is characterized in that,
The equivalence ratio scope of the compound of described propargylation reagent and step (1) is 1.0-4.0;
The equivalence ratio scope of the compound of described highly basic and step (1) is 1.0-4.0.
6. preparation method as claimed in claim 4, is characterized in that,
Described propargylation reagent is selected from propargyl bromide or propargyl iodide;
Described highly basic is selected from potassium tert.-butoxide, potassium hydroxide, sodium hydride or hmds potassium;
Described pass cyclization reagent is selected from triphosgene, phosgene or trichloromethyl chloroformyl ester;
The oxide compound reagent that described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide or contains methyl-sulphoxide;
Described palladium salt is selected from two (triphenylphosphine) palladiums of dichloro or tetrakis triphenylphosphine palladium;
Described mantoquita is selected from cuprous iodide or cuprous bromide.
7. for a medicinal compositions for antibacterial therapy, it is characterized in that, comprise the compound of the following general formula II of having of antimicrobial effective amount, or its pharmaceutically acceptable additive salt; And pharmaceutically acceptable carrier;
Wherein, Ar is pyrimidyl, quinolyl or isoquinolyl; X is hydrogen or fluorine.
8. the application of compound as claimed in claim 1 in the medicine for the preparation of the treatment of antibacterium infected by microbes.
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| WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
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| WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
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| Constantin Agouridas, et al..Synthesis and Antibacterial Activity of Ketolides (6-O-Methyl-3-oxoerythromycin Derivatives): A New Class of Antibacterials Highly Potent Against Macrolide-Resistant and-Susceptible Respiratory Pathogens.《J. Med. Chem.》.1998,第41卷(第21期),4080-4100. * |
| Ghilsoo Nama,et al..Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides.《Bioorganic & Medicinal Chemistry Letters》.2010,第20卷2671-2674. |
| Ghilsoo Nama,et al..Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides.《Bioorganic & * |
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