CN1544450A - Novel macrolides drug 9-deoxidized-9alfa-N-substituted alkane or amide- erythromycin A derivative, synthesis method and uses - Google Patents
Novel macrolides drug 9-deoxidized-9alfa-N-substituted alkane or amide- erythromycin A derivative, synthesis method and uses Download PDFInfo
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- CN1544450A CN1544450A CNA2003101087127A CN200310108712A CN1544450A CN 1544450 A CN1544450 A CN 1544450A CN A2003101087127 A CNA2003101087127 A CN A2003101087127A CN 200310108712 A CN200310108712 A CN 200310108712A CN 1544450 A CN1544450 A CN 1544450A
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Abstract
The invention relates to a 9-deoxy-9 alapha-N-substituted alkyl or amide-erythromycin A derivative whose molecular formula is disclosed in the specification, wherein R 2 is saturated or unsaturated hydrocarbon radical or substituted hydrocarbon radical containing as much as 30 carbon atoms, or the hydrocarbon radical is blocked up by one or several heteroatoms, or with one or several identical or different functional groups, or a heterocyclic ring is formed with the nitrogen atoms connected therewith, wherein the heterocyclic ring may includes one or several heteroatoms selected from nitrogen, sulfur and oxygen. The corresponding N-substited radical product is prepared from erythromycin an oxime as raw material by using amine salt as buffer system, subjecting pd/c catalyst to hydrogenation reaction in organic solvent at room temperature, obtaining the corresponding erythromy amine and reacting in nonaqueous solvent with inorganic or organic base as catalyst at room temperature. The compound can be applied in preparing antibiotic and antiviral medicament.
Description
Technical field
The present invention relates to be used for antibiotic, antiviral and novel Macrocyclolactone lactone kind medicine anti-SARS virus are the preparation method and use that 9-deoxidation-9 α-N-replaces alkane or amide derivatives.
Background technology
At present, the medicine that does not have special efficacy for the SARS disease.But resist the situation of SARS disease from people for the previous period, still sought some for the comparatively effective medicine of this disease of control.In the recommendation treatment plan by proposition in the recommendation treatment plan of " atypical pneumonia " case of Department of Disease Control of Ministry of Health issue or suspected case and the discharge diagnosis reference standard (try), the medicine that is applicable to early treatment can be selected antibiotic medicines such as Macrolide, fluoroquinolones, beta-lactam, tetracyclines for use, Macrocyclolactone lactone kind medicine has wherein comprised Azythromycin, Roxithromycin, amber acetyl erythromycin and erythromycin etc. then based on erythromycin and derivative thereof.The mechanism of action that studies show that this type of antibiosis class is by combining with the ribosomal 50S subunit of sensitive bacterial, and main inhibiting peptide acyl group-tRNA to the P position, suppresses the displacement enzyme by the A displacement, hinders peptide elongation.Thereby it is synthetic and bring into play antibacterial or germicidal action to have suppressed the bacterial cell internal protein.And up-to-date in recent years clinical study also shows, cyclic lactone class microbiotic is except that having direct anti-microbial effect, also lung and respiratory tract infection disease such as asthma and diffuse panbronchiolitis are shown therapeutic action, a series of erythromycin derivatives are all effective in cure to these respiratory tract diseases, so macrolide antibiotics anti-inflammatory activity has in this respect become one of research focus.Nearest research work shows that this type of microbiotic may be to embody its anti-inflammatory action by physiology, cell and molecular process that inflammation-inhibiting reacts.Thereby the research to the Macrocyclolactone lactone kind medicine immunoregulation effect provides foundation for clinical anti-inflammatory, and because of its immunotherapy evident in efficacy, side effect is little, so erythromycin and derivative thereof are probably developed out through further structure of modification and can be become the medicine that by immunomodulatory treatment SARS disease is had definite curative effect clinically.
From present present Research to such medicine, because this has just obtained extensively reaching clinical application erythromycin after being found, it is to numerous disease, especially to respiratory tract infection, comprise that the atypical pneumonia due to the bacteriums such as legionella pneumophilia, Mycoplasma pneumoniae, chlamydozoan has macrolide antibiotics safely and effectively.Yet erythromycin exists narrow antimicrobial spectrum, poorly water-soluble, and easy hydrolysis formation erythromycylamine, red mould branch sugar and erythromycin ketal and this variation have non-reversibility under the hydrochloric acid in gastric juice effect, thereby make its loss of activity.In addition, this type of medicine makes germ produce resistance and cross resistance easily, thereby its application is severely limited, world pharmacology worker has extensively carried out the research work of erythromycin structural modification and has obtained great progress, as by it being carried out structural modification and effectively having stoped because of the deactivated degraded of acid effect, structurally introduce simultaneously some nitrogenous heteroatomss as forming oxime, amido, fluorine atom and obtained to have good antibiotic active new Macrocyclolactone lactone kind medicine, though above-mentioned erythromycin derivatives is in pharmacokinetics, aspects such as bioavailability have greatly improved than erythromycin, and antimicrobial spectrum all is similar to erythromycin, that have even also widen to some extent, but they are the same with erythromycin, it is too poor that the effect of macrolide antibiotics resistant organism is renderd a service, this has comprised that the Roxithromycin for the treatment of early stage SARS disease just belongs to this analog derivative, dirithromycin (drithromycin), dirithromycin is a kind of 14 new membered macrolides, the oral administration posthydrolysis is red mould cyclammonium, its antimicrobial spectrum is similar with erythromycin, but the pharmacokinetics performance of this medicine, particularly high tissue penetration discharges from tissue and cell and the long transformation period slowly.The Plasma Concentration of dirithromycin is lower than the erythromycin of the identical dosage of curing the disease, but this has reflected that dirithromycin distributes rapidly widely to various tissues.Be used for respiratory tract infection, as pneumonia, acute bronchitis, the chronic bronchitis acute infection, colony's acquired pneumonia, the uncomplicated infection of skin infections and soft tissue infection etc. all have good therapeutic action and tolerance, untoward reaction is littler than erythromycin, but it is not enough or have a further application limit still to have drug effect with them as treatment SARS disease.Therefore, press for the novel Macrocyclolactone lactone kind medicine of developing strong resistance and the SARS disease being had definite curative effect.
In the past by 9 amine of disclosed preparation erythromycin amine by alkylation or acidylate several methods, as J.Am.Chem.Soc., 1971,93,2897; Be converted into behind the erythromycin oxime at TiCl earlier by Erythromycin A
3, sodium cyanoborohydride or sodium borohydride reduction obtain corresponding amino-complex in the methanol solution; By Synthcommun., 1988,18,777, disclosed at 20%TiCl
3It is disclosed by 20% palladium carbon hydrogenating reduction under the normal temperature bar to obtain corresponding 9 (S) configuration US4048306 that occupies the majority with sodium cyanoborohydride or sodium borohydride reduction in the buffer system that methanol solution should be made up of ammonium acetate methyl alcohol; By the disclosed red mould toxic amine compound of US4048306 by erythromycin amine; Under pressurized conditions, reduce row to corresponding compounds by CN85103264 is disclosed by Raney's nickel; After forming western Buddhist alkali, obtain the corresponding N alkylate through reduction again with aldehyde; By J.Med.Chem., 1990,33 (11), the disclosed formation behind the western Buddhist alkali by erythromycin amine and aldehyde of 3086-3094 obtains corresponding N--alkylate through reduction again;
Summary of the invention
It is that 9 amine of dirithromycin are by alkylation or acidylate and related derivatives thereof that one of problem that will solve of the present invention provides novel Macrocyclic lactone compounds.
It is that 9 amine of dirithromycin are by the preparation method of alkylation or acidylate and related derivatives thereof that two of the problem that will solve of the present invention provides novel Macrocyclic lactone compounds.So that safer, convenient, synthetic and suitability for industrialized production efficiently.
Three of the problem that will solve of the present invention provides novel Macrocyclic lactone compounds, and to be 9 amine of dirithromycin by alkylation or acidylate and related derivatives thereof antibiotic, antiviral potential use and develop out and can become the potential drug that by immunomodulatory treatment SARS disease is had definite curative effect clinically.
Novel Macrocyclic lactone compounds of the present invention is that a series of new its molecular formula of derivative that 9 amine of dirithromycin form after by alkylation or acylation reaction can be expressed as:
R is recommended as the saturated or undersaturated group that contains 1～30 carbon atom in the formula:
Wherein R can represent a saturated or undersaturated alkyl that can reach 30 carbon atoms that contains, and this alkyl is blocked by one or several heteroatoms sometimes, also can have to be permitted or several identical or different functional group.This can form a heterocycle with the nitrogen-atoms that is attached thereto knot, and this heterocycle can contain one or several heteroatoms of selecting in the middle of nitrogen, sulphur and the oxygen;
The represented alkyl of R can be blocked by one or several identical or different heteroatoms, and these heteroatomss can be nitrogen, sulphur and oxygen; These alkyl can have one or several identical or different group.These groups can be selected from hydroxyl, halogen atom, nitro, cyano group, chain alkenyl or alkynyl alkyl, contain oxyalkyl, contain oxycetylene base or alkene, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, nitrogenous alkynyl or alkene, contain azanyl, these groups can contain 30 carbon atoms at most, and may be replaced by one or several identical or different halogen atom.
R is represented may to be one or several aryl, and individual or several heteroaryls, these groups may be able to have one or more halogen atoms, nitro, carbonyl, carboxyl, sulfur-containing group, nitrogenous aryl that group replaced or heteroaryl except that nitro.Or containing one or several heteroatomic five members, four members, three members, six Yuans or many Yuans fragrant heterocycles, these fragrant heterocycles comprise that sulfur-bearing, nitrogenous, sulfur-bearing or fragrant heterocycle contain the fragrant heterocycle of several above-mentioned three kinds of different elemental nitrogen, oxygen, sulphur.The above-mentioned one or more substituting groups that provide of band cloth on these fragrant heterocycles.
The represented alkyl of R may be an alkyl, alkenyl or alkynyl, and fragrant substituted alkyl, virtue are for alkynyl or thiazolinyl.In these alkyl alkenyl or alkynyl substituting groups, preferable methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, decyl, dodecyl, triacontyl, vinyl allyl group ethynyl, proyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Aryl can be a phenyl or naphthyl.
Aryl can also be an aromatic heterocyclic that replace or non-replacement, as thienyl, furyl, pyrryl, thiazolyl, oxazolyl, triazol radical, tetrazole base, imidazolyl, thiadiazolyl group, pyrazoles or imidazole base, give a tongue-lashing pyridine base, pyrimidyl, reach piperazine or pyrazinyl, also can be indyl, benzofuryl, benzothiazole or quinolyl.These aryl can be with one or several getting base noted earlier.
When the nitrogen-atoms that is attached thereto as R constituted a heterocyclic radical, the heterocyclic radical of outstanding choosing was pyrryl, pyrrolidyl, pyridyl, pyrazinyl, pyrimidyl, piperidyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, imidazolyl, benzimidazolyl-, triazol radical, tetrazole base, thiazolyl, azelidinyl, nitrogen thia cyclobutyl, nitrogen propyl group.
Above-mentioned " several " are recommended as 1～5 except that other explanation, further be recommended as 1～3.
Recommend:
Synthetic method of the present invention is to be starting raw material with the erythromycin A-9 oxime, adopt amine salt do buffer system with organic solvent such as alcohol as solvent palladium charcoal agent catalyzer in carrying out under the room temperature condition that hydrogenation reaction obtains corresponding erythromycylamine and then in anhydrous solvent such as alcohol, under room temperature condition, promptly getting corresponding N-substituting group product with the halides reaction of active fragments R with inorganic or organic alkali as a catalyst.Described halides can be chloro, bromo or iodo thing.
Amidation is instead used organic alkali as a catalyst according to general standard method down in anhydrous condition, and with anhydrous polar solvent such as tetrahydrofuran (THF), acetone etc. are made solvent and promptly got corresponding product with the standard program processing down and behind the acyl chloride reaction in room temperature condition.
Its reaction formula is expressed as follows:
Wherein R as previously mentioned.
The synthetic method that the present invention recommends can specifically describe as follows:
1. alkyl etherification reaction: this is 1: 3.2～4 with the mole of 9 amine of erythromycin and alkali in organic solvent such as alcohol or acetone solvent, recommending mol ratio is 1: 3.5～3.8, temperature of reaction is 0～80 ℃, the recommendation response temperature is 25～40 ℃, reaction times is 0.5～24h, and the recommendation response time, to be that 0.5～5h is treated obtained corresponding pure compound.Catalyzer is that quaternary amine is preferably hexadecyl trimethyl ammonium bromide.
2. acidylate; 9 amine of erythromycin in polar solvent; organic bases; this is 0.6～1.9: 1～2 for the mole of acyl chlorides: 2.1～3.2, and recommending mol ratio is 0.6～1.2: 0.8～1: 1.8～2.0, temperature of reaction is-15～100 ℃; the recommendation response temperature is 0～25 ℃; reaction times is 2～10h, and the recommendation response time is 4～6h, gets pure product through aftertreatment.
What above-mentioned polar solvent was recommended is: water, C
1～C
3Alcohol, acetone, tetrahydrofuran (THF), fine or its mixed solvent of second, C
1～C
3Alcohol is methyl alcohol, ethanol, propyl alcohol.The mineral alkali indication is an alkaline carbonate, and supercarbonate, indication organic bases are triethylamine, diethylamine, Diisopropylamine, quadrol, DBU, pyridine etc.
The above-mentioned aftertreatment of carrying refers to concentrate, and lotion is taken off in underpressure distillation, neutralization, and crystallization is filtered, dilution, extraction, washing, step in recrystallization or the drying or multistep.
Compound of the present invention has the characteristic of potential as the disease due to the easily infected germ of preparation treatment, these diseases that need particularly point out: SARS courses of infection disease, staphylococcal infections disease, as septicemia, the evil staphylococcal infections of face or skin, change dense dermatitis, the infection of wound or change dense, furuncle, carbuncle, cellular tissue's inflammation, erysipelas and acne, the acute pharyngolaryngitis that the disease of staphylococcal infections such as initial stage infect, postgrippal pharyngitis, bronchopneumonia, lung suppurates, the disease of streptococcal infection such as acute pharyngolaryngitis, and the pneumonia that causes of streptococcus pneumoniae, diphtheria, popularity flu hemophilus in addition, rickettsia, mycoplasma pneumoniae, the infection of chlamydozoan etc.
It is good antibacterial that preliminary activity research shows that this analog derivative has, antiviral activity, and also this compounds all has certain potential restraining effect to SARS virus, and this shows that this class thing might be developed to the active drug of treatment SARS.
The present invention introduces some fluorine-containing pyrimidine rings, nitrogen heterocyclic ring and triazole, contains fluoro aryl etc. and form a series of new macrolides compounds for virus and the activated segment of fungi erythromycin series derivative ground-erythromycin, make the SARS bacteria infection be difficult to identification, overcome resistance and cross resistance that Macrocyclolactone lactone kind medicine in the past exists existing germ, thereby it is effectively killed.Thereby find more effective inhibitory anti-virus medicine particularly can find the medicine that definite curative effect is arranged for the SARS disease at short notice.
Embodiment
Following examples help to understand the present invention, but do not limit content of the present invention.
Embodiment 1
The preparation of Erythromycin A amine
With 12.5g erythromycin A-9 oxime .10g, 2.5g Raney's nickel, the mixture of ammonium acetate and 180mL anhydrous methanol place the high-pressure hydrogenation still in 5kg/cm
2Under the condition bar keep after this reaction pressure 48h with TLC detect exhaust to reaction raw materials till stopped reaction, the elimination catalyzer, after being evaporated to behind the 60mL mixing solutions that its impouring 250mL water and 200mL chloroform are formed water layer PH is transferred to 5.4, water with chloroform further extraction percentage extraction is discarded together with separating obtained organic phase of last time.Extract the merging organic phase repeatedly with chloroform after water PH transfers to 9.6 and concentrate, with getting required product behind the Virahol recrystallization with anhydrous sodium sulfate drying.6.3g
Embodiment 2
The preparation of Erythromycin A amine N-substitution compound
In reaction flask, add 10.273g Erythromycin A amine, reach a small amount of hexadecyl trimethyl ammonium bromide behind the 150mL methyl alcohol, open to stir and slowly will be dissolved with the methanol solution that waits with normal halides (chloro, bromo or iodo thing) and be added drop-wise in the reaction flask, at this moment reaction system form uniform suspension.After finishing reaction is immersed in the oil bath back flow reaction TLC detect treat reaction finish relief its be cooled under the room temperature, filter the back decompression and remove acetone, residue gets product through recrystallization
Compound 1:
1H?NMR(300MHz)δ
ppm：8.57(1H，s，CH)，4.51-4.66(1H，m，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
19F?NMR(300MHz)δ
ppm-134.6，-155.51
Compound 2
1H?NMR(300MHz)δ
ppm：9.00-8.99(1H，m，CH)，7.74-8.29(1H，s，CH)，5.64-5.17(2H，m，CH
2)，3.84(3H，sOMe)，2.27(6H，s，NMe)1.42(3H，s，Me)，1.24(s，Me).
Compound 3
1H?NMR(300MHz)δ
ppm：8.03(1H，s，CH)，7.57(1H，s，CH)，6.60(1H，s，CH)5.5?1(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 4
1H?NMR(300MHz)δ
ppm：8.04-8.06(1H，s，CH)，7.15(1H，s，CH)，6.61(1H，s，CH)，5.49(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 5
1H?NMR(300MHz)δ
ppm：7.68-7.64(1H，m，CH)，7.57(1H，s，CH)，7.12-7.05(1H，m，CH)，6.43(1H，m，CH)，5.51(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 6
1H?NMR(300MHz)δ
ppm：8.63(1H，s，CH).，3.84(3H，s，OMe)，2..27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 7
1H?NMR(300MHz)δ
ppm：7.58-7.44(1H，m，CH)，6.87-6.99(1H，m，CH)，6.74-6.87(1H，m，CH)，4.96(2H，s，CH
2)，3.84(3H，s，OMe)，2..27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 9
1H?NMR(300MHz)δ
ppm：4.11(2H，s，CH
2)，6.74-6.87(1H，m，CH)，4.96(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 15
1H?NMR(300MHz)δ
ppm：6.78(1H，s，CH)，4.95(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 17
1H?NMR(300MHz)δ
ppm：4，54-4.67(2H，m，CH)，4.35(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 22
1H?NMR(300MHz)δ
ppm：6.75(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)1.24(s，Me).
Compound 26
1H?NMR(300MHz)δ
ppm：6.45(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)1.24(s，Me).
Compound 27
1H?NMR(300MHz)δ
ppm：3.99-3.439(2H，m，CH
2)，3.69-33.77(2H，m，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)1.24(s，Me).
Compound 29
1H?NMR(300MHz)δ
ppm：835(1H，d，J＝2.4Hz，CH)，7.61(1H，dd，J＝8.1，2.4Hz，CH)，7.34(1H，d，J＝8.1Hz，CH)，5.5.04(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me
Compound 31
1H?NMR(300MHz)δ
ppm：8.39-8.67(1H，s，CH)，8.23-8.45(1H，s，CH)，8.05-7.79(1H，s，CH)，7.99-7.86(1H，s，CH)，7.48-7.56(1H，s，CH)，6.58-6.45(1H，s，CH)，4.86(2H，s，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Embodiment 2
The preparation of Erythromycin A acid amides
Method one, 12.2g Erythromycin A amine and 26.95g anhydrous sodium bicarbonate are dissolved in the 260mL exsiccant tetrahydrofuran (THF), the tetrahydrofuran solution that is cooled in good stirring and with reaction flask after-5 ℃ slowly the equivalent acyl chlorides is added drop-wise in the reaction flask, be allowed to condition under the room temperature continue stirring reaction 12h question response fully after, the removal of solvent under reduced pressure behind the after-filtration that reacts completely, residue gets product through recrystallization.
Method two, 5g Erythromycin A amine and 16.95g anhydrous sodium bicarbonate are dissolved in the 100mL exsiccant acetone, under good stirring, after again reaction flask being cooled to-5 ℃ slowly the acetone soln of equivalent acyl chlorides be added drop-wise in the reaction flask, be allowed to condition under the room temperature continue stirring reaction 12h question response fully after, acetone is removed in the decompression that reacts completely behind the after-filtration, and residue gets product through recrystallization.
Compound 8:
1H?NMR(300MHz)δ
ppm：8.69(1H，s，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 10
1H?NMR(300MHz)δ
ppm：8.34-8.11(2H，m，CH
2)，7.74-7.46(2H，m，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 11
1H?NMR(300MHz)δ
ppm：8.01-7.89(1H，m，CH)，7.57-7.45(1H，m，CH)，7.07-6.99(1H，m，CH)3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 12
1H?NMR(300MHz)δ
ppm：8.03-7.78(2H，m，CH
2)，6.67-7.65(2H，m，CH
2)，6.61(1H，s，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 13
1H?NMR(300MHz)δ
ppm：7.98(1H，d，J＝2.0Hz，CH)，7.67(1H，dd，J＝8.1，2.4Hz，CH)，7.56(1H，d，J＝8.1Hz，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me
Compound 14
1H?NMR(300MHz)δ
ppm：7.04(1H，s，CH).，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 16
Compound 18
1H?NMR(300MHz)δ
ppm：7.78(1H，s，CH)，7.27(1H，s，CH)，7.06(1H，s，CH)，4.25-4.87(2H，m，CH
2)，4.22-4.56(2H，m，CH
2)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me
Compound 19
1H?NMR(300MHz)δ
ppm：5.78-6.09(1H，m，CH)，5.24-5.45(1H，m，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 20
1H?NMR(300MHz)δ
ppm：7.51(1H，s，CH)，3.98(3H，s，OCH
3)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 21
1H?NMR(300MHz)δ
ppm：8.21-7.99(1H，m，CH)，7.87-7.65(1H，m，CH)，7.07-6.79(1H，m，CH)3.98(3H，s，OMe)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Compound 23
1H?NMR(300MHz)δ
ppm：2.94(3H，s，NCH
3)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)1.24(s，Me).
Compound 24
1H?NMR(300MHz)δ
ppm：7.87-7.99(1H，m，C＝CH)，7.45(1H，s，CH)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)1.24(s，Me).
Compound 25
1H?NMR(300MHz)δ
ppm：8.01-7.79(2H，m，CH
2)，7.87-7.89(2H，m，CH
2)，7.07-6.79(1H，m，CH)，3.98(3H，s，OMe)，3.84(3H，s，OMe)，2.27(6H，s，NMe)，1.42(3H，s，Me)，1.24(s，Me).
Claims (10)
1. 9-deoxidation-9 α-N-replaces alkane or amides-erythromycin A derivant, and its molecular formula can be expressed as:
R is the saturated or undersaturated group that contains 1～30 carbon atom in the formula:
Described group is that the aromatic heterocyclic or the R of alkyl, substituted hydrocarbon radical, aryl, substituted aryl, replacement or non-replacement can form a heterocycle with the nitrogen-atoms that is attached thereto knot;
Perhaps above-mentioned alkyl is blocked by 1～5 heteroatoms, and these heteroatomss can be nitrogen, sulphur and oxygen;
Perhaps above-mentioned alkyl has 1～5 identical or different functional group, described functional group is selected from hydroxyl, halogen atom, nitro, cyano group, chain alkenyl or alkynyl alkyl, contains oxyalkyl, contains oxycetylene base or alkene, sulfur-bearing alkyl, sulfur-bearing alkynyl or sulfur-bearing thiazolinyl, nitrogenous alkynyl or alkene, contains azanyl, these groups contain 1～30 carbon atom, and may be replaced by 1～3 identical or different halogen atom;
The heteroaryl of the aryl of perhaps above-mentioned replacement or non-replacement, replacement or non-replacement has 1～3 following radicals: halogen atom, nitro, carbonyl, carboxyl, sulfur-containing group, nitrogenous aryl that group replaced or heteroaryl except that nitro;
Wherein said alkyl is alkyl, cycloalkyl, alkenyl or alkynyl, and fragrant substituted alkyl, virtue are for alkynyl or thiazolinyl; Described heterocycle is to contain 1～5 heteroatomic three Yuans to eight Yuans fragrant heterocycle, and these fragrant heterocycles are fragrant heterocycles that sulfur-bearing, nitrogenous, sulfur-bearing or fragrant heterocycle contain 2～5 above-mentioned three kinds of different elemental nitrogen, oxygen, sulphur.
2. erythromycin A derivant as claimed in claim 1 is characterized in that described alkyl, alkenyl or alkynyl substituting group are methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, decyl, dodecyl, triacontyl, vinyl allyl group ethynyl, proyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Described aryl can be a phenyl or naphthyl;
Aromatic heterocyclic described replacement or non-replacement is thienyl, furyl, pyrryl, thiazolyl, oxazolyl, triazol radical, tetrazole base, imidazolyl, thiadiazolyl group, pyrazoles or imidazole base, gives a tongue-lashing pyridine base, pyrimidyl, reaches piperazine or pyrazinyl, also can be indyl, benzofuryl, benzothiazole or quinolyl, these aryl can be with one or several substituting group noted earlier;
When the nitrogen-atoms that is attached thereto as R constituted a heterocyclic radical, heterocyclic radical was pyrryl, pyrrolidyl, pyridyl, pyrazinyl, pyrimidyl, piperidyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indyl, imidazolyl, benzimidazolyl-, triazol radical, tetrazole base, thiazolyl, azelidinyl, nitrogen thia cyclobutyl, nitrogen propyl group.
3. erythromycin A derivant as claimed in claim 1 is characterized in that described R is R ', CH
2R ', C (O) R ', CH (CH
3) R ', C (O) CH
2R ', C (O) CH (COOC
2H
5) R ', C (O) C (NOCH
3) R ' or
Described R ' is that aromatic heterocyclic, phenyl, the substituted-phenyl, five of three cycloalkyl to seven-membered ring, aromatic heterocyclic, replacement arrives the Azacyclyl of seven-membered ring or five Azacyclyls to seven-membered ring of replacement, described aromatic heterocyclic is five aromatic heterocyclics to seven-membered ring that contain 1～5 N, O or S atom, and described substituting group is selected from halogen, C (O) H, (O), HS, CF
3, OH, C
1～C
4Alkyl, halogen, NH
2, contain 1～5 N, O or S atom five to the seven-membered ring aromatic heterocyclic.
4. erythromycin A derivant as claimed in claim 1 is characterized in that R is one of following group:
5. the synthetic method of erythromycin A derivant as claimed in claim 1, it is characterized in that with the erythromycin A-9 oxime being starting raw material, adopt amine salt do buffer system in organic solvent palladium charcoal agent catalyzer in carrying out under the room temperature condition that hydrogenation reaction obtains corresponding erythromycylamine and then in anhydrous solvent, under room temperature condition, react promptly to get corresponding N-substituting group product with inorganic or organic alkali as a catalyst.
R as previously mentioned in the formula.
6. the synthetic method of erythromycin A derivant as claimed in claim 5, it is characterized in that the alkyl etherification reaction be in alcohol or acetone solvent with 9 amine of erythromycin and alkali the mole this be 1: 3.2～4, temperature of reaction is 0～80 ℃, reaction times is 0.5～24h, treatedly obtains corresponding pure compound.Catalyzer is a quaternary amine.
7. the synthetic method of erythromycin A derivant as claimed in claim 5; it is characterized in that acylation reaction is 9 amine of erythromycin in polar solvent; organic bases; this is 0.6～1.9: 1～2 for the mole of acyl chlorides: 2.1～3.2; temperature of reaction is-15～100 ℃; reaction times is 2～10h, gets pure product through aftertreatment.
8. the synthetic method of erythromycin A derivant as claimed in claim 5 is characterized in that described alkali is mineral alkali or organic bases, and described mineral alkali is an alkaline carbonate, supercarbonate, described organic bases is a triethylamine, diethylamine, Diisopropylamine, quadrol, DBU, pyridine; Described quaternary amine is preferably hexadecyl trimethyl ammonium bromide.
9. the purposes of erythromycin A derivant as claimed in claim 1 is characterized in that being used to prepare antibiotic, antiviral.
10. the purposes of erythromycin A derivant as claimed in claim 1 is characterized in that being used to prepare the medicine for the treatment of following disease: SARS courses of infection disease; Staphylococcal infections disease, is changed the infection of dense dermatitis, wound or is changed the acute pharyngolaryngitis that dense, furuncle, carbuncle, cellular tissue's inflammation, erysipelas and acne, initial stage infect, postgrippal pharyngitis, bronchopneumonia, lung's suppuration, the disease of streptococcal infection, pneumonia, the diphtheria that streptococcus pneumoniae causes the evil staphylococcal infections of face or skin; Hemophilus influenzae genus, rickettsia, mycoplasma pneumoniae, chlamydial infection.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101087127A CN1544450A (en) | 2003-11-19 | 2003-11-19 | Novel macrolides drug 9-deoxidized-9alfa-N-substituted alkane or amide- erythromycin A derivative, synthesis method and uses |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2003101087127A CN1544450A (en) | 2003-11-19 | 2003-11-19 | Novel macrolides drug 9-deoxidized-9alfa-N-substituted alkane or amide- erythromycin A derivative, synthesis method and uses |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188187A (en) * | 2016-07-31 | 2016-12-07 | 合肥远志医药科技开发有限公司 | A kind of dirithromycin industrialized preparing process |
| CN111423482A (en) * | 2020-04-26 | 2020-07-17 | 梯尔希（南京）药物研发有限公司 | Method for synthesizing isotope-labeled erythromycylamine |
-
2003
- 2003-11-19 CN CNA2003101087127A patent/CN1544450A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106188187A (en) * | 2016-07-31 | 2016-12-07 | 合肥远志医药科技开发有限公司 | A kind of dirithromycin industrialized preparing process |
| CN111423482A (en) * | 2020-04-26 | 2020-07-17 | 梯尔希（南京）药物研发有限公司 | Method for synthesizing isotope-labeled erythromycylamine |
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