CN102234302A - 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 the purposes and the corresponding medicinal composition of anti-infectives.
Background technology
Ten quaternary macrolide antibiotic-erythromycin widespread use clinically more than 50 year especially is fit to penicillin anaphylaxis person.S-generation erythromycin has overcome the acid nonfast problem of erythromycin as clarithromycin, Azythromycin, Roxithromycin etc.At present, separate the more and more demonstrations of the respiratory tract disease bacteria strain that obtains clinically and have resistance, as streptococcus pneumoniae (S.pneumoniae), 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: 34 tame hospital clinicals separate in the 1601 strain streptococcus pneumoniaes that obtain in the U.S., 29.5% bacterial strain penicillin resistant, 19.3% anti-erythromycin, 13.2% anti-tsiklomitsin.Therefore, research and development novel structure and to have the task of the active new antibiotic of antimicrobial agent extremely urgent.
Compare with erythromycin, clarithromycin and Azythromycin etc., third generation erythromycin derivatives-ketone lactone have anti-polymorphic type resistant organism activity (Agouridas, C. etc., J.Med.Chem.1998,41:4080-4100).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 and non-essential group simultaneously.But the introducing that only depends on the 3-carbonyl is that can't to improve antimicrobial agent active, big ring go up the new aromatic side chain of introducing resistant organism has been produced new for target spot, thereby obtained the antimicrobial agent activity.Therefore, 3-carbonyl and aromatic side chain have constituted the important structure characteristics of ketolide antibiotics.
Binding site and the side chain lengths thereof of aromatic side chain on the ketone lactone directly has influence on the active power of its antimicrobial agent.Aromatic side chain as Ketek (Telithromycin) is connected 11, on the 12-carbamate, length be 4 atoms (Denis A. etc., Bioorg.Med.Chem.Lett.1999,9:3075-3080.); The aromatic side chain of quinoline erythromycin (Cethromycin) is connected on the 6-OH, length be 3 atoms (Or Y.S. etc., J.Med.Chem.2000,43:1045-1049).
In the derivative of erythromycin, after the 9-carbonyl changed into the oxime hydroxyl, the 9-oxime ether that forms that links to each other with various alkyl or aromatic alkyl was 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 also is applied in to seek and has (Agouridas, C. etc., J.Med.Chem.1998,41:4080-4100 on the active ketone lactone of antimicrobial agent; 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 disclosed 9-oxime ether ketone lactone is also not ideal at present.
In a word, need the urgent technical problem that solves 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 suitability for industrialized production preferably, and have anti-preferably sensitive organism and antimicrobial agent activity at respiratory tract germs such as streptococcus pneumoniaes.
Summary of the invention
Technical problem to be solved by this invention provides a kind of novel ketone lactone (9-O-aromatic base proyl ketolide derivatives) and synthetic method thereof, and this compounds is as the purposes and the corresponding medicinal composition of anti-infectives.。This compound and preparation method thereof can adapt to suitability for industrialized production preferably, and this compound has anti-preferably sensitive organism and antimicrobial agent activity at respiratory tract germ etc.
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 that forms 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; Perhaps 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; Perhaps, 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 preparation method of compound is according to claim 1 also disclosed, comprising:
(1), the compound that has following general formula III:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Described protection reagent is used to realize the R protecting group;
(2), in single solvent of THF or THF/DMSO mixed solvent, under propargyl reagent and alkaline acting in conjunction, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; With oxidising agent 3-OH is oxidized to the 3-carbonyl then, obtains general formula I V compound;
Perhaps, in single solvent of THF or THF/DMSO mixed solvent, under propargyl reagent and alkaline acting in conjunction, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; Use then and close cyclization reagent with 11,12-OH closes ring, with oxidising agent 3-OH is oxidized to the 3-carbonyl again, obtains 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 the 9-oxime hydroxyl forms aromatic side chain, and slough 2 '-the O-R protecting group, obtain having the compound of following general formula I or II;
Perhaps, in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, the propargyl effect on substituted aroma hydrocarbon and the 9-oxime hydroxyl forms aromatic side chain; Further introduce fluorine atom in the 2-position, and slough 2 '-the 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 propargyl 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 propargyl 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; Described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide or contains the oxide compound reagent of 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 that is used for antibacterial therapy is also disclosed, comprise the compound of 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 a kind of aforesaid compound and be used for the application of the medicine of antibacterium infected by microbes treatment in preparation.
Compared with prior art, the present invention has the following advantages:
Compound of the present invention has novel texture, connects an aromatic heterocycle hydrocarbon by the propargyl side chain on the 9-of ketone lactone oxime hydroxyl, and synthetic easy, is fit 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 the ketone lactone and side chain lengths thereof and structure directly have influence on the active power of its antimicrobial agent.The present invention has selected propargyl to connect the aromatic side chain of aromatic heterocyclic alkyl as the ketone lactone through test of many times and theoretical investigation, can obtain anti-preferably sensitive organism and antimicrobial agent activity.
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 be separately or mix with other medicines with various formulations or route of administration as one of activeconstituents and to be used for the treatment that bacterium etc. infects.
In a word, the anti-microbial activity that propargyl has improved the ketone lactone greatly at the 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, the present invention is further detailed explanation below in conjunction with embodiment.
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 or the like.In actual applications, Ar also can be the group after further replacement is derived on the 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 is not limited to top giving an example.
Preparation method to compound with above-mentioned general formula carries out simple declaration below.
Preparation process of the present invention is as follows:
1, from erythromycin oxime, through etherificate, silanization, the midbody compound 1,2 that obtains the clarithromycin synthesis technique of methylating ', 4 " two (trimethyl silicane)-6-O-erythromycin A 9-O-(isopropoxy cyclohexyl) oximes of O-;
2, hydrolysis obtains key compound 2:3-OH-6-O-erythromycin oxime then;
3 and then, under the effect of acetic anhydride, 2 '-OH and 9-oxime hydroxyl diacetyl obtain compound 3:2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-acetyl oxime.More than the technological processs in three steps in open source literature, had mentionedly, be not described in detail in this.Similar technology 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, perhaps directly obtain compound 3 from suppliers; 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 the process that obtains compound 3, compound 1 promptly 2 ', 4 " two (trimethyl silicane)-6-O-erythromycin A 9-O-(isopropoxy cyclohexyl) oximes of O-can replace to 2 ', 4 " two (trimethyl silicane)-6-O-erythromycin 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)-6-O-erythromycin A 9-O-(1-methoxyl group-1-methylethyl) oximes of O-; Compound 1 can also replace with 2 ', 4 " two (trimethyl silicane)-6-O-erythromycin A 9-O-(1-oxyethyl group-1-methylethyl) oximes of O-, perhaps 2 ', 4 " two (trimethyl silicane)-6-O-erythromycin A 9-O-(the di-t-butyl methyl silicon) oximes of O-etc.
Certainly, owing to 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, hydrolysis still can obtain key compound 2 under acidity, and is therefore, less to the influence of subsequent step 2,3.
Simultaneously, also need to prove, in the processing step that obtains compound 3, protect the reagent of reagent (being used to realize the reagent of protecting group) also can be replaced as step 3.For example; acetic anhydride can change benzoyl oxide into; or silylating reagent such as trimethyl silicane chlorine, hexamethyldisilazane etc.; obtain the analogue of compound 3; be that ethanoyl on the compound 3 is replaced by benzoyl, trimethyl silicon based; this analogue can be used for follow-up reaction equally, can not change reaction mechanism.
4, in single solvent of THF (tetrahydrofuran (THF)) or THF/DMSO (dimethyl sulfoxide (DMSO)) mixed solvent, the normal potassium tert.-butoxide acting in conjunction of the propargyl bromide of 1.0-4.0 equivalent (molar weight) and 1.0-4.0 can selectivity ethanoyl on the 9-oxime hydroxyl of displacement compound 3 obtain compound 4:2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-propargyl oxime.
5, further; in dichloromethane solvent; use triphosgene with 11; 12-OH closes ring; 3-OH is become the 3-carbonyl to obtain key compound 5:2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime-11,12-cyclic carbonate ester by Corey-Kim oxidation (in the section-Jin oxidation) reagent oxidation again.
6, last, in acetonitrile, THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, under palladium salt such as two (triphenylphosphine) palladiums of dichloro and mantoquita (as cuprous iodide) catalysis, the substituted aroma hydrocarbon (for example, halogenated aromatic) with 9-oxime hydroxyl on the propargyl effect form aromatic side chain, and in methyl alcohol, slough 2 '-O-Ac obtains target compound 6:3-carbonyl-6-O-erythromycin A 9-O-[3-aryl-2-propynyl] and oxime-11, the 12-cyclic carbonate ester;
Perhaps, in acetonitrile, THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, under palladium salt such as two (triphenylphosphine) palladiums of dichloro and mantoquita (as cuprous iodide) catalysis, propargyl effect on substituted aroma hydrocarbon and the 9-oxime hydroxyl forms aromatic side chain, further in THF (tetrahydrofuran (THF)) or DMF (dimethyl formamide) solvent, fluorine atom is introduced in the 2-position under sodium hydride and the effect of N-fluorobenzene sulphonyl imido, and in methyl alcohol, slough 2 '-O-Ac obtains 2-position fluorizated target compound 6.
Fluoridizing of 2-position at the ketone lactone can be improved anti-microbial activity.Because therefore the fluorizated technical matters comparative maturity of the 2-position of ketone lactone, does not repeat them here.For example, see also Denis, A. etc., Drug.Future.2001,26,975; Phan, L.T. etc., Org.Lett.2000,2,2951; SearleX.B., WO03/090761.
Need to prove, if do not carry out 11 in the reaction mechanism, 12-OH carbonic acid esterification (as " use triphosgene with 11,12-OH closes ring " in the processing step 5), 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 studies show that: 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), promptly under the situation 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, the some of them synthesis step can reverse the right order, and as elder generation 11, the esterification of 12-OH carbonic acid is then in the selectivity propargylization; Perhaps first 3-OH oxidation and then 11, the esterification of 12-OH carbonic acid, or the like.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 sequence of steps 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 propargyl reagent can change propargyl iodide etc. into;
Can change potassium hydroxide, sodium hydride, hexamethl disilamine potassium etc. into as the alkaline potassium tert.-butoxide;
Can change phosgene, trichloromethyl chloroformyl ester etc. into as the triphosgene of closing cyclization reagent;
Corey-Kim oxidising agent (N-chloro succinimide/dimethyl sulphide) as oxidising agent can change various oxide compound reagent such as the methyl-sulphoxide/oxalyl chlorides that contain methyl-sulphoxide, methyl-sulphoxide/acetic anhydride etc. into;
Be used for to change commercialization reagent Selectifluor into to the fluorizated fluorination reagent N-fluorobenzene sulphonyl imido 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.
Mode with structural formula provides a concrete example to top preparation process 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-6-O-erythromycin oxime
13.2g compound 1 is added the 40ml dissolve with ethanol, and 5ml 36% dense HCl is diluted to and is added drop-wise to then in the 50ml water in the reaction solution, and 40 ℃ were reacted one hour down, and reaction finishes the back and adds about ammoniacal liquor adjusting pH value to 9, and the adularescent precipitation is separated out, and filters white precipitate.This is deposited in recrystallization obtains 3-OH clarithromycin oxime (5.42g, yield 71%) in ethanol, the water
Embodiment 2 (generating compound 3)
2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-acetyl oxime
To be equipped with and add the 50ml methylene dichloride in the flask of 5.42g (8.96mmol) 3-hydroxyl clarithromycin oxime, drip 2.6ml (24.88mmol) acetic anhydride, react end in a hour, reaction solution is used saturated sodium bicarbonate solution respectively, water, saturated aqueous common salt washing and filtering, removal of solvent under reduced pressure get white blister compound 5.60g (8.13mmol, yield 90.7%).
Embodiment 3 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-propargyl oxime
1.00g (1.5mmol) 2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-acetyl oxime is dissolved in the 15ml THF solution; add potassium tert.-butoxide 489mg (4.36mmol) and propargyl bromide 0.52ml (5.8mmol) reaction and add 20ml ethyl acetate and 20ml water after one hour; standing demix; upper strata saturated aqueous common salt washing and filtering; the evaporated under reduced pressure solvent gets 1.06g solid (1.55mmol, yield 100%).
Embodiment 4 (generating compound 4)
2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-propargyl oxime
0.500g (0.73mmol) 2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-acetyl oxime is dissolved in the 15ml THF/DMSO solution; add potassium tert.-butoxide 106mg (0.95mmol) and propargyl bromide 0.13ml (1.46mmol) reaction and add 10ml ethyl acetate and 10ml water after one hour; standing demix; upper strata saturated aqueous common salt washing and filtering; the evaporated under reduced pressure solvent gets 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-6-O-erythromycin A9-O-propargyl oxime-11, the 12-cyclic carbonate ester
1.06g (1.55mmol) 2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A9-O-propargyl oxime is dissolved in the 50ml methylene dichloride; add 1.5ml (18.6mmol) pyridine;-5 ℃ were stirred 10 minutes down; begin to drip 0.9g (3.1mmol) triphosgene that is dissolved in methylene dichloride among the 30ml, dropwised in 30 minutes.-5 ℃ of reactions slowly drip the 70ml saturated aqueous common salt and finish reaction after 17 hours.Standing demix, lower floor's organic phase saturated sodium bicarbonate, water, saturated aqueous common salt washing and filtering, evaporated under reduced pressure solvent get 0.70g solid (0.99mmol, yield 63.5%).
Embodiment 6 (generating second step of compound 5)
2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A9-O-propargyl oxime-11, the 12-cyclic carbonate ester
Add the 20ml methylene dichloride in the 100ml there-necked flask, stir down and add 0.212gN-chlorosuccinimide (NCS) (1.6mmol), maintenance system-15 ℃ slowly drips 0.14mlMe
2S (DMS) (1.9mmol) white flocks occurs; continue to stir half an hour; to be dissolved with 0.70g (0.99mmol) 2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A9-O-propargyl oxime-11; the 10ml methylene dichloride of 12-cyclic carbonate ester is added drop-wise in the system, and dropwise half an hour, reacts 1.5 hours down at-15 ℃; TLC demonstration reaction is finished; drip triethylamine 0.3ml termination reaction, it is clear that system becomes, and-5 ℃ were stirred one hour down.Reaction solution is used saturated sodium bicarbonate respectively, water, and the saturated common salt water washing is also spent the night with anhydrous magnesium sulfate drying, filters, and the evaporated under reduced pressure solvent gets 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-6-O-erythromycin A 9-O-propargyl oxime
2.00g (2.9mmol) 2 '-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-acetyl oxime is dissolved in the 20ml THF solution; add potassium tert.-butoxide 978mg (8.71mmol) and propargyl bromide 0.78ml (8.7mmol) reaction and add 20ml ethyl acetate and 20ml water after one hour; standing demix; upper strata saturated aqueous common salt washing and filtering; the evaporated under reduced pressure solvent gets 1.94g solid (2.83mmol, yield 97.5%).
Embodiment 8 (generating the first step of compound 5)
2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime
In the 250ml there-necked flask, add the 40ml methylene dichloride; stir and add 0.483g NCS (3.6mmol) down; maintenance system-15 ℃; slowly drip 0.3ml DMS (4.29mmol) and white flocks occurs; continue to stir half an hour; the 15ml methylene dichloride that will be dissolved with 1.61g (2.26mmol) 2 '-O-ethanoyl-3-hydroxyl-6-O-erythromycin A 9-O-propargyl oxime is added drop-wise in the system; dropwise half an hour; reacted 1.5 hours down at-15 ℃; TLC demonstration reaction is finished; drip triethylamine 0.6ml termination reaction, it is clear that system becomes, and-5 ℃ were stirred one hour down.Reaction solution is used saturated sodium bicarbonate respectively, water, and the saturated common salt water washing is filtered, and the evaporated under reduced pressure solvent gets 1.344g solid (1.97mmol, yield 87.2%).
Embodiment 9 (generating second step of compound 5)
2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime-11, the 12-cyclic carbonate ester
1.344g (1.97mmol) 2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime is dissolved in the 50ml methylene dichloride; add 1.9ml (23.62mmol) pyridine;-5 ℃ were stirred 10 minutes down; begin to drip 1.17g (3.94mmol) triphosgene that is dissolved in methylene dichloride among the 30ml, dropwised in 30 minutes.-5 ℃ of reactions slowly drip the 70ml saturated aqueous common salt and finish reaction after 17 hours.Standing demix, lower floor's organic phase saturated sodium bicarbonate, water, saturated aqueous common salt washing and filtering, evaporated under reduced pressure solvent get 1.342g solid (1.89mmol, yield 95.8%).
Top embodiment 7,8,9 obtains the 3-carbonyl earlier in the process that generates compound 5, obtain 11 again, the 12-cyclic carbonate ester.And in embodiment 5,6, obtaining 11 earlier, the 12-cyclic carbonate ester obtains the 3-carbonyl again.
Also need to prove; if wish to obtain the compound of general formula I; the compound 5 that then obtains can for: 2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime; and need not carry out ring closure reaction (11; 12-OH carbonic acid esterification) generation 2 '-O-ethanoyl-3-carbonyl-6-O-erythromycin A 9-O-propargyl oxime-11, the 12-cyclic carbonate ester.
Embodiment 10 (generating the compound 6 of 5-pyrimidyl)
3-carbonyl-6-O-erythromycin A 9-O-[3-(5-pyrimidine)-2-propynyl] oxime-11, the 12-cyclic carbonate ester
With 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 and is equipped with in the pressure bottle of 12ml acetonitrile; system is under nitrogen protection; finished in 3 hours at 80 ℃ of stirring reactions, in system, add 15ml ethyl acetate and 15ml water, standing demix.(200-300 order silicagel column, moving phase are methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be than pure products 175mg (0.222mmol, yield 22.5%) through column chromatography.In 25ml methyl alcohol, 65 ℃ of following backflows were taken off ethanoyl in 3 hours and are got the compound crude product with this compound dissolution.Crude product is crossed the silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) get the pure product 24mg of compound (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-6-O-erythromycin A 9-O-[3-(4-isoquinoline 99.9)-2-propynyl] oxime-11, the 12-cyclic carbonate ester
With 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 and is equipped with in the pressure bottle of 12ml acetonitrile; system is under nitrogen protection; finished in 3 hours at 80 ℃ of stirring reactions, in system, add 15ml ethyl acetate and 15ml water, standing demix.(200-300 order silicagel column, moving phase are methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be than pure products 72mg (0.086mmol, yield 8.70%) through column chromatography.In 25ml methyl alcohol, 65 ℃ of following backflows were taken off ethanoyl in 3 hours and are got the compound crude product with this compound dissolution.Crude product is crossed the silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) get the pure product 23mg of compound (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-6-O-erythromycin A 9-O-[3-(3-quinoline)-2-propynyl] oxime-11, the 12-cyclic carbonate ester
With 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 and is equipped with in the pressure bottle of 12ml acetonitrile; system is under nitrogen protection; finished in 3 hours at 80 ℃ of stirring reactions, in system, add 15ml ethyl acetate and 15ml water, standing demix.(200-300 order silicagel column, moving phase are methylene dichloride: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be than pure products 99mg (0.118mmol, yield 13.3%) through column chromatography.In 25ml methyl alcohol, 65 ℃ of following backflows were taken off ethanoyl in 3 hours and are got the compound crude product with this compound dissolution.Crude product is crossed the silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) get the pure product 33mg of compound (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-6-O-erythromycin A 9-O-[3-(6-quinoline)-2-propynyl] oxime-11, the 12-cyclic carbonate ester
With 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 and is equipped with in the pressure bottle of 15ml acetonitrile; system is under nitrogen protection; finished in 3 hours at 80 ℃ of stirring reactions, in system, add 15ml ethyl acetate and 15ml water, standing demix.(200-300 order silicagel column, moving phase are chloroform: ethanol: ammoniacal liquor=15: 0.4: 0.1) must be than pure products 155mg (0.185mmol, yield 13.9%) through column chromatography.In 25ml methyl alcohol, 65 ℃ of following backflows were taken off ethanoyl in 3 hours and are got the compound crude product with this compound dissolution.Crude product is crossed the silicagel column purifying, and (moving phase is sherwood oil: acetone: triethylamine=5: 5: 0.2) get the pure product 29mg of compound (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, adopt 4-bromoquinoline [perhaps other substituted aroma hydrocarbon reagent such as 3-bromopyridine, 1-iodo-4-oil of mirbane, 1-(4-imidazoles)-bromobenzene, the 2-bromoquinoline, 5-bromoquinoline, 7-bromoquinoline, the 8-bromoquinoline, the 5-bromo-isoquinoline, 6-bromo-isoquinoline, 7-bromo-isoquinoline, the 8-bromo-isoquinoline, the 2-bromothiophene, 3 bromo thiophene or the like, the perhaps derivative of above aromatic hydrocarbon] the Sonogashira reaction takes place under palladium salt and mantoquita catalysis with compound 5, 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, perhaps 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 Tui Jianing, the antibacterial activity in vitro (MIC) of part target compound that adopted broth dilution method determination to responsive streptococcus pneumoniae ATCC49619, erm+mef type resistance streptococcus pneumoniae PU-11, mef type resistance streptococcus pneumoniae PU-09, erm type resistance streptococcus pneumoniae PU-27.Measurement result sees 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 Tui Jianing, the adopted broth dilution method determination target compound of embodiment 13 and reference substance (9-O-fragrance propenyl ketolide derivatives) is to the antibacterial activity in vitro (MIC) of responsive streptococcus pneumoniae ATCC49619, erm+mef type resistance streptococcus pneumoniae PU-11, mef type resistance streptococcus pneumoniae PU-09, erm type resistance streptococcus pneumoniae PU-27.Measurement result sees Table 2.
The anti-microbial activity of table 2 9-O-arylprop alkynyl oxime ether ketolide derivatives and 9-O-arylprop thiazolinyl oxime ether ketolide derivatives is (MIC value: μ g/mL) relatively
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-6-O-erythromycin A 9-O-[3-(6-quinoline)-2-propenyl] oxime-11, the 12-cyclic carbonate ester.
By table 1 and table 2 as can be known, target compound is compared with Azythromycin with clinical main medication clarithromycin at present, has all shown outstanding anti-sensitive organism and antimicrobial agent activity.The target compound 3-carbonyl of embodiment 13-6-O-erythromycin A 9-O-[3-(6-quinoline)-2-propynyl] oxime-11, the 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 relatively, find that the compound among the present invention has higher anti-microbial activity, and the target compound of the embodiment 13 in the table 2 to compare mainly with reference substance be the difference of " allyl group " and " propargyl ", the side-chain structure of propargyl of the present invention is described, antibacterial effect is better.
Compound for general formula I of the present invention and II, existing studies show that: 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 is etc., Bioorg.Med.Chem.2005,13:6054-6063), therefore can derive, under the situation 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.
Need to prove that the present invention can be used for the medicine of infected by microbes treatments such as multiple antibacterium, comprises chlamydozoan or mycoplasma infection or the like.
More than 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 the purposes and the corresponding medicinal composition of anti-infectives, be described in detail, used specific case herein principle of the present invention and embodiment are set forth, the explanation of above embodiment just is used for helping to understand method of the present invention and core concept thereof; Simultaneously, for one of ordinary skill in the art, according to thought of the present invention, the part that all can change in specific embodiments and applications, in sum, this description should not be construed as limitation of the present invention.
Claims (10)
1. one kind has the compound of following general formula I or II and acceptable salt or the ester that forms with mineral acid or organic acid thereof:
Wherein, Ar represents aromatic heterocyclic alkyl or replaces aromatic heterocyclic alkyl; X is hydrogen or fluorine.
2. compound as claimed in claim 1 or acceptable salt or ester is characterized in that,
Described Ar is nitrogenous, sulphur or Sauerstoffatom heterocycle; Perhaps nitrogenous, sulphur or the Sauerstoffatom heterocycle of Ar for replacing.
3. compound as claimed in claim 2 or acceptable salt or ester is characterized in that,
Described Ar is imidazolyl, pyridyl, pyrimidyl, benzopyrazines base, benzo pyridazinyl, quinolyl, isoquinolyl, imidazoles phenyl, indyl, thienyl;
Perhaps, 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.
4. compound as claimed in claim 2 or acceptable salt or ester is characterized in that,
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.
5. compound as claimed in claim 1 or acceptable salt or ester 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.
6. one kind prepares the method for compound according to claim 1, it is characterized in that, comprising:
(1), the compound that has following general formula III:
Wherein, described R base is ethanoyl, benzoyl or trimethyl silicon based accordingly; Described protection reagent is used to realize the R protecting group;
(2), in single solvent of THF or THF/DMSO mixed solvent, under propargyl reagent and alkaline acting in conjunction, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; With oxidising agent 3-OH is oxidized to the 3-carbonyl then, obtains general formula I V compound;
Perhaps, in single solvent of THF or THF/DMSO mixed solvent, under propargyl reagent and alkaline acting in conjunction, ethanoyl, benzoyl or trimethyl silicon based on the 9-oxime hydroxyl of selectivity displacement step (1) compound; Use then and close cyclization reagent with 11,12-OH closes ring, with oxidising agent 3-OH is oxidized to the 3-carbonyl again, obtains 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 the 9-oxime hydroxyl forms aromatic side chain, and slough 2 '-the O-R protecting group, obtain having the compound of following general formula I or II;
Perhaps, in acetonitrile, THF or DMF solvent, under the catalysis of palladium salt and mantoquita, the propargyl effect on substituted aroma hydrocarbon and the 9-oxime hydroxyl forms aromatic side chain; Further introduce fluorine atom in the 2-position, and slough 2 '-the 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.
7. preparation method as claimed in claim 6 is characterized in that,
The equivalence ratio scope of the compound of described propargyl 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.
8. preparation method as claimed in claim 6 is characterized in that,
Described protection reagent is selected from acetic anhydride, benzoyl oxide, trimethyl silicane chlorine or hexamethyldisilazane;
Described propargyl 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;
Described oxidising agent is selected from N-chloro succinimide/dimethyl sulphide or contains the oxide compound reagent of 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.
9. a medicinal compositions that is used for antibacterial therapy is characterized in that, comprises the compound of 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.
10. compound as claimed in claim 1 is used for the application of the medicine of antibacterium infected by microbes treatment in preparation.
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| CN106916194A (en) * | 2017-01-13 | 2017-07-04 | 北京理工大学 | A kind of new ketolide derivatives containing amino, preparation method and application |
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|---|---|---|---|---|
| US20020019355A1 (en) * | 2000-02-24 | 2002-02-14 | Zhenkun Ma | Anti-infective agents useful against multidrug-resistant strains of bacteria |
| WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
-
2010
- 2010-05-07 CN CN201010171484.8A patent/CN102234302B/en not_active Expired - Fee Related
-
2011
- 2011-05-06 WO PCT/CN2011/073762 patent/WO2011137758A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020019355A1 (en) * | 2000-02-24 | 2002-02-14 | Zhenkun Ma | Anti-infective agents useful against multidrug-resistant strains of bacteria |
| WO2002032919A2 (en) * | 2000-10-16 | 2002-04-25 | Abbott Laboratories | 6-o-substituted erythromycin derivatives having improved gastrointestinal tolerance |
Non-Patent Citations (2)
| Title |
|---|
| 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.》, vol. 41, no. 21, 19 September 1998 (1998-09-19), pages 4080 - 4100 * |
| GHILSOO NAMA,ET AL.: "Synthesis and antibacterial activity of new 9-O-arylpropenyloxime ketolides", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 1 March 2010 (2010-03-01), pages 2671 - 2674 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104961785A (en) * | 2015-06-19 | 2015-10-07 | 北京理工大学 | Novel acylide derivative and preparing method thereof |
| CN104961785B (en) * | 2015-06-19 | 2019-01-11 | 北京理工大学 | A kind of novel acyl lactone derivative and preparation method thereof |
| CN106916194A (en) * | 2017-01-13 | 2017-07-04 | 北京理工大学 | A kind of new ketolide derivatives containing amino, preparation method and application |
| CN106916194B (en) * | 2017-01-13 | 2020-05-08 | 北京理工大学 | Novel ketolide derivative containing amino, preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102234302B (en) | 2014-05-07 |
| WO2011137758A1 (en) | 2011-11-10 |
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