CN103910663A - Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof - Google Patents
Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN103910663A CN103910663A CN201410129805.6A CN201410129805A CN103910663A CN 103910663 A CN103910663 A CN 103910663A CN 201410129805 A CN201410129805 A CN 201410129805A CN 103910663 A CN103910663 A CN 103910663A
- Authority
- CN
- China
- Prior art keywords
- methyl
- ethanoyl
- oxygen
- compounds
- anilino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Abstract
The invention discloses pleuromutilin derivatives with the structure as shown in a formula (I) in the specification and the antibacterial activity, salts, solvates, optical isomers and polymorphism compounds thereof acceptable in pharmacy and/or veterinary medicines as well as a preparation method and an application of the pleuromutilin derivatives and the salts, solvates, optical isomers and polymorphism compounds thereof in antibacterial compositions. The preparation method has the beneficial effects that two different lead compounds are connected together by covalent bonds so as to generate a synergistic effect, an additive effect or new pharmacological activity in vivo; sulfonamides are spliced into side chains of pleuromutilin so as to generate new pleuromutilin derivatives, the antibacterial activity of the obtained new compounds can be enhanced, the obtained new compounds have obvious antibacterial activity for gram-positive bacterium, gram-negative bacterium and mycoplasma and an obvious inhibiting effect on drug-resistance bacteria such as MRSA, and the antibacterial spectrums of the obtained new compounds are effectively expanded.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of anti-microbial activity pleuromutilin derivative and its preparation method and application.
Background technology
In recent years, methicillin-resistant staphylococcus aureus (MRSA), penicillin resistance pneumococcus (PRSP), the case that the resistant organisms such as multi-resistant Pseudomonas aeruginosa (MDRPA) and vancomycin-resistant enterococcus (VRE) cause is increasing, and the trend of the existing big area outburst in some areas, public health security is formed to grave danger.Bacterial drug resistance just exists from microbiotic generation, it is the result of bacteria live natural selection, but because people depend on unduly antibiotic, make the appearance of Resistant strain more and more faster, and there is transmitting between different genera the trend of drug resistant gene, being the generation of crossing drug resistant, is resistant organism has also just appearred in a lot of new compounds major cause in conceptual phase.Therefore, find a kind of efficient and mechanism of action and be different from the antibiotic newtype drug of the most of main flows particularly important that just seems.
Pleuromutilin (Pleuromutilin) is the meta-bolites of basidiomycetes pleurotus Agaricaceae north phoenix bacterium (Pleurotus mutilus and Pleurotus passeckerianus), belongs to three ring diterpenoids compounds.Itself anti-microbial activity is general, needs, by chemistry, biological means, carry out structural modification, to improve anti-microbial activity and to improve pharmacology medicine dynamic characteristic.There are some researches show, the Antibacterial mechanism of pleuromulins medicine is to be combined with bacterial ribosome 50S subunit position uniquely, and arrestin matter is synthetic, therefore, and less and other main microbiotic generation crossing drug resistants.Woods as wonderful in Thailand (Tiamulin, Tiamulin) is animal specific microbiotic, in cultivation use exceed 30 years, it remains a line main flow microbiotic now, and about the report of resistant organism also less.Auspicious his wonderful woods (Retapamulin) is the first man pleuromulins microbiotic of recently succeeding in developing, and a listing has caused investigator's very big interest, and in succession reports out the novel pleuromutilin derivative in a large number with outstanding anti-microbial activity.As the people such as Peng have synthesized the amino formate pleuromutilin derivative of series containing heterocycle, gram-positive microorganism is had to fabulous anti-microbial activity.
Along with being on the rise of bacterial drug resistance problem, the discovery of novel antibacterial drug molecule is more and more urgent, but the screening of novel drugs molecule and discovery need to expend a large amount of time, manpower and financial resources, and often new drug is not also gone public and just produced Resistant strain.If the antibacterials of similar and different effect are linked together, be expected to develop the antibacterials of multiple action, significant for the generation, reduction R&D costs and the time that delay bacterial drug resistance.
Summary of the invention
For overcoming the defect of prior art, of the present inventionly be to provide a kind of anti-microbial activity pleuromutilin derivative or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, improve the anti-microbial activity of pleuromutilin, obtain a kind of antibacterial active compounds of efficient, long-acting, wide spectrum.
Another object of the present invention is to provide a kind of anti-microbial activity pleuromutilin derivative or its pharmaceutically and/or the preparation method of veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds.
In the present invention, " pharmaceutically and/or veterinarily acceptable salt " comprises the salt forming with basic metal, as the salt of the mineral alkalis such as sodium, potassium, magnesium, calcium, with hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, cross chloric acid, etc. the salt of mineral acid, with the organic acid salt such as fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, tosic acid, tartrate, acetic acid, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid, Phenylsulfonic acid or naphthene sulfonic acid.
In the present invention, term " pharmaceutically and/or veterinarily acceptable solvate " refers to hydrate or dissolves in the solvate of C1-C4 alcohol or other organic solvents.
The technical solution adopted in the present invention is as follows for achieving the above object:
A kind of pleuromutilin derivative of the anti-microbial activity with formula I structure or its are pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds;
Wherein: R
1be selected from the one in heteroaryl, amidino groups, guanidine radicals, the acyl group of C1-C18 and the substitutive derivative of above-mentioned group of aryl, C3-C18 of alkyl, the C6-C30 of hydrogen atom, amino, hydroxyl, C1-C8; X is the one in the alkoxyl group of alkyl, amino, C3-C8 of sulphur atom, Sauerstoffatom, C1-C8.
In such scheme, the substituting group of described substitutive derivative is the one in aryl, C3-C18 heteroaryl, the alkylthio of C1-C8 or the arylthio alkyl of C6-C18 of alkoxyl group, C6-C18 of cycloalkyl, the C1-C18 of alkyl, the C3-C8 of acyl group, the C1-C18 of amino, Heterocyclylalkyl, nitro, halogen, hydroxyl, carboxyl, guanidine radicals, C3-C8.
In the present invention, in term, " alkyl " comprises straight or branched alkyl, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group etc.; " cycloalkyl " comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group; " Heterocyclylalkyl " refers to that containing one or more is selected from the heteroatomic saturated cyclic such as N, O, S, as Pyrrolidine base, tetrahydrofuran base, piperazinyl, thiazolidine base, morpholine base etc., " amido " comprises methylamino, ethylamino-, Propylamino, dimethylin, diethylin etc.; " heteroaryl " refers to that containing one or more is selected from the heteroatomic aryl such as N, O, S, as pyrryl, pyrazolyl, imidazolyl, triazol radical, furyl, thienyl, oxazolyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl etc.; " virtue heterocycle " refer to carbocyclic aromatic (mainly referring to phenyl ring aromatic hydrocarbons) and on contain one or more and be selected from the heteroatomic saturated or unsaturated heterocycle bases such as N, O, S, as indyl, benzofuryl, benzothiazolyl, quinolyl, isoquinolyl, benzimidazolyl-etc.; " heterocycle virtue heterocyclic radical " mainly refers to the also ring of pyrimidine and imidazoles or pyrazine, as purine, pteridine etc.
The pleuromutilin derivative of described anti-microbial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, is characterized in that, has with following formula (A) or (B) structure:
In such scheme, as preferably, wherein R1 is the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative.
In the present invention, as preferred scheme, the pleuromutilin derivative of described anti-microbial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, are selected from the one in following compounds:
4-[4-(amino-alkylsulfonyl)-(anilino) methyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-[4-(amino-alkylsulfonyl)-(anilino) methyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods.
Prepare the pleuromutilin derivative of anti-microbial activity or its pharmaceutically and/or a method for veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, with formula (a)
Through reduction after with formula (b)
There is substitution reaction, obtain product (c)
Product (c) after halogenation with formula (d)
After amination, obtain product (I).
In the present invention, the condition of above-mentioned reduction, amidation, sulfonylation and replacement can be that this area can be to realize any condition of the object of the invention.As preferably, preparation method of the present invention can be the method specifically comprising the following steps:
1) reduction reaction: reductive agent is added in tetrahydrofuran (THF) and forms suspension, add the alkali of catalytic amount, under ice bath, N
2protect, slowly drip the tetrahydrofuran solution of 4-Thiosalicylic acid or 3-Thiosalicylic acid, add rear continuation and stir 45 minutes, be warming up to 25-80 DEG C, stir 5-20 hour, thin layer chromatography identification terminal.Then add respectively appropriate ethyl acetate and acidic aqueous solution, stir 15 minutes, filter, separatory, water is extracted with ethyl acetate 3 times, merges organic phase, neutrality is washed, is washed to saturated common salt successively, dry, revolve and steam solvent, silica gel column chromatography separates to sulfydryl phenylcarbinol (1) or a sulfydryl phenylcarbinol (2);
2) substitution reaction: by pleuromutilin, Tosyl chloride joins in ethyl acetate successively, to strong basicity, is warming up to 30-100 DEG C, vigorous stirring 4 hours with alkali lye adjusting pH value.Reaction is finished, and decompression steams organic solvent, and 10 times of residuum dilute with waters, wash out white solid, and suction filtration, is washed to neutrality, is dried to obtain white solid product (b);
Sodium ethylate is dissolved in dehydrated alcohol, is cooled to 0-10 DEG C, add successively the product (b) of previous step and to sulfydryl phenylcarbinol (1) or a sulfydryl phenylcarbinol (2), add rear intensification, N
2protection, stirs 24h, reacts completely.Decompression steams solvent, residuum dilute with water, and ethyl acetate extraction, separates organic phase, is washed to neutrality, anhydrous MgSO
4dry, filter, boil off ethyl acetate, purification by silica gel column chromatography, obtains product (4-methylol-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods formula (3) or (3-methylol-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods formula (4);
3) halogenating reaction: the product of substitution reaction (3) or (4) are dissolved in methylene dichloride, add the alkali of catalytic amount, under low temperature, slowly drip SOCl
2dichloromethane solution, in 1-2 hour, add, be warming up to backflow, continue stir 1-12 hour, reaction completes, by reaction solution to entering in frozen water, vigorous stirring, filter separatory, organic solvent extraction, washing, dry, concentrating under reduced pressure, crosses silicagel column and obtains product (4-chloromethyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods formula (5) or (3-chloromethyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods formula (6);
4) amination reaction: halogenating reaction products therefrom (5) or (6) are dissolved in DMF, add compound (d), then add the alkali of catalytic amount, after adding, be warming up to 40-120 DEG C, stirring at room temperature 1-24 hour, reaction is finished, reaction solution is fallen in frozen water, stir 15 minutes, ethyl acetate extraction, organic phase time diluted alkaline, saturated common salt washing, anhydrous Na
2sO
4dry, revolve and steam solvent, acetone recrystallization, obtains product A or B.
Above-mentioned preparation method's synthetic route is as follows:
In above-mentioned preparation method, step 1) reductive agent used can be LiAlH
4, (three tert.-butoxies) lithium aluminum hydride, two (methoxyethoxy) alanate, NaBH
4, one in diborane; Alkali can be mineral alkali K
2cO
3, NaOH, KOH, or one in organic bases triethylamine, pyridine, piperidines, dicyclohexyl amine; The replaceable one-tenth methylene dichloride of solvents tetrahydrofurane, the trichloromethane, 1 that wherein adopted, the lower boiling halohydrocarbon such as 2-ethylene dichloride, a kind of or two or more mixing in the ether solvents such as ether, Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether; Acid used can be HCl, H
2sO
4, one in the mineral acid such as HBr, phosphoric acid.Reaction process condition is: preferred, preferably temperature of reaction is 25 DEG C to 60 DEG C, and preferred mol ratio is Thiosalicylic acid (a): reductive agent=1:1～3:5.
In above-mentioned preparation method, step 2) alkali used is mineral alkali NaOH, KOH, or one in organic bases pyridine, triethylamine; Ethyl acetate used is replaceable is methyl acetate, butyl formate, toluene, methylene dichloride, trichloromethane, 1, the lower boiling halohydrocarbon such as 2-ethylene dichloride, one or more mixing in the ether solvents such as ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether; Sodium ethylate used is replaceable is the one in sodium methylate, sodium isopropylate, DMAP; Ethanol used is replaceable is the lower alcohol solvents such as methyl alcohol, Virahol, one or more mixing in the ether solvents such as ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether.Reaction process condition is: adding alkali equivalent is 1-3, taking 1.5 as good; Be advisable add-subtract time with 0.5-2 hour, and feed temperature is 0-25 DEG C, taking lower than 10 DEG C as good; Temperature of reaction is 30-100 DEG C, taking 50 DEG C as good.
In above-mentioned preparation method, step 3) alkali used can be mineral alkali Na
2cO
3, K
2cO
3, NaOH, KOH, or one in organic bases pyridine, morpholine, triethylamine; SOCl used
2replaceable is HCl, HBr, PCl
3, PCl
5, POCl
3in with China; Solvent for use methylene dichloride is replaceable is the lower boiling halohydrocarbon such as trichloromethane, 1,2-ethylene dichloride, one or more mixing in the ether solvents such as ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether.Reaction process condition is: feed temperature is-5～30 DEG C, taking lower than 0 DEG C as good; Temperature of reaction is 25 DEG C～90 DEG C; Preferred mol ratio is compound (3) or compound (4): SOCl
2=1:(1～2.5).
In above-mentioned preparation method, step 3) alkali used can be used mineral alkali Na
2cO
3, K
2cO
3, NaOH, KOH, or organic bases pyridine, N-methylmorpholine, morpholine, triethylamine etc., one of them or both mix use; Solvent for use DMF is replaceable is ether solvent or its mixed forms such as DMSO, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether.Reaction process condition is: feed temperature is 25-40 DEG C, taking room temperature as good; Temperature of reaction is 40-120 DEG C, taking 40 DEG C as good; Preferred mol ratio is compound (5) or (6): sulfonamide compounds (d)=1:(1～2).
Another object of the present invention be to provide a kind of pleuromutilin derivative that comprises above-mentioned anti-microbial activity and or its pharmaceutically and/or the anti-microbial activity composition of veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds,
A kind of anti-microbial activity composition, comprise above-mentioned anti-microbial activity pleuromutilin derivative and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and pharmaceutically acceptable carrier or thinner.
As preferred version of the present invention, the formulation of described anti-microbial activity composition is oral preparation or injection.
As preferred version of the present invention, in described anti-microbial activity composition, the pleuromutilin derivative of anti-microbial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds content be 0.1%-99.5%(wt%), surplus is carrier or thinner.
Of the present invention producing effect is: the present invention links together two different lead compounds through covalent linkage, produces in vivo synergy, adduction, or produce new pharmacologically active; Sulfa drugs of the present invention is spliced on pleuromutilin side chain, produce new sulfanilamide (SN)-pleuromutilin derivative, the new compound obtaining can strengthen anti-microbial activity, especially gram-positive microorganism, Gram-negative bacteria and mycoplasma are had to significant anti-microbial activity, and the resistant organisms such as MRSA are also had to obvious restraining effect, effectively widened its antimicrobial spectrum.
Below in conjunction with concrete embodiment, the present invention is described in further detail.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, but these examples are not any limitation of the invention.In all embodiment, the fusing point of compound is measured with capillary melting point determination instrument, and 1HNMR is by VarianAM-400 type nmr determination, and taking TMS as interior mark, chemical shift represents with (ppm); Mass spectrum is measured with Q-TOF type mass spectrograph, and ultimate analysis is measured by CarloErball06 type automatic elemental analyzer.
Column chromatography used silica gel is that Haiyang Chemical Plant, Qingdao produces (column chromatography H type), and thin layer chromatography board is that city buys GF254 type.
Embodiment 1
Synthesizing of 4-sulfydryl phenylcarbinol [formula (1)]
4gLiAlH
4join in 50ml tetrahydrofuran (THF) and form suspension, N
2protection, dissolves in 4-Thiosalicylic acid 8.5g in the tetrahydrofuran (THF) of 100ml, under ice bath, is slowly added drop-wise in above-mentioned suspension, adds rear continuation and stirs 30 minutes, is then warming up to backflow, stirs 16 hours.Reaction is finished, and adds respectively 40ml ethyl acetate and 50ml15%H
2sO
4solution, filters, and water 50ml ethyl acetate extraction 3 times, merges organic phase, saturated common salt washing, anhydrous Na
2sO
4dry, concentrating under reduced pressure obtains the faint yellow or colourless liquid of 7.5g.With purification by silica gel column chromatography (ethyl acetate: sherwood oil=75:25), obtain white solid 7.1g, yield is 93%, fusing point 51-53 DEG C.MS-ESI(M+1)：141.2。Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.52(d,2H)，7.41(d,2H)，4.67(s,2H)。
Embodiment 2
Synthesizing of (4-methylol-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods [formula (3)]
By the pleuromutilin formula (b) of 11.0g, the Tosyl chloride of 5.5g joins in the ethyl acetate of 50ml successively, and ice bath is washed down, regulate pH value to strong basicity with the potassium hydroxide solution 20ml of 1mol/L, be warming up to 35 DEG C, vigorous stirring 2.5 hours, thin-layer chromatography monitors reaction end.Reaction is finished, and decompression steams organic solvent, and 10 times of residuum dilute with waters, wash out white solid, and suction filtration, is washed to neutrality, and dry, acetone recrystallization obtains 14.8g white solid.Yield is 92%, MS-ESI (M+1): 533.1.
1.5g sodium methylate is dissolved in 250ml methyl alcohol, is cooled to 15 DEG C, add successively the product 4-sulfydryl phenylcarbinol formula (1) of 4.8g embodiment 1, the product of 17.6g step 1), adds rear room temperature, the N of being naturally warmed up to
2protection, stirs 24h under room temperature, reacts completely.Decompression steams solvent, residuum 50ml water dissolution, and ethyl acetate extraction, separates organic phase, is washed to neutrality, anhydrous MgSO
4dry, filter, boil off ethyl acetate, purification by silica gel column chromatography (ethyl acetate: sherwood oil=80:20); Obtain white solid [formula (3)] 20.1g, yield is 85%, fusing point 145-148.5 DEG C, MS-ESI (M+1): 501.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.76(d,2H)，7.38(d,2H)，5.99-6.04(m,1H)，5.50(d,1H)，4.92-4.95(m,2H)，4.45(d,2H)，3.81-3.90(dd,2H)，3.37(m,1H)，2.36(s,1H)，2.12-2.23(m,1H)，1.92-1.98(m,4H)，1.65-1.72(d,2H)，1.46-1.51(m,1H)，1.37-1.44(m,1H)，1.34(s,3H)，1.29-1.06(m,3H)，0.99(s,3H)，0.79(s,3H)，0.57(d,3H)。
Embodiment 3
Synthesizing of (4-chloromethyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods [formula (5)]
Product formula (3) 5g of embodiment 2, is dissolved in the methylene dichloride of 100ml, then adds triethylamine 1.5g, and DMF0.75ml, is cooled to 0 DEG C, under vigorous stirring, drips 2.1gSOCl
2dichloromethane solution 10ml, after adding, be naturally warming up to room temperature, continue stir 1.5h.Reaction completes, reaction solution poured in 80ml frozen water, and ethyl acetate extraction, separatory, organic phase is washed to neutrality, anhydrous Na
2sO
4dry, concentrating under reduced pressure, silica gel column chromatography separates, and obtains 5.8g formula (5) solid.Yield 70.5%, fusing point: 121.1-123.8MS-ESI (M+1): 519.5.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.70(d,2H)，7.42(d,2H)，6.00-6.04(m,1H)，5.51(d,1H)，4.90-4.94(m,2H)，4.56(s,2H)，3.84-3.93(dd,2H)，3.35(m,1H)，2.30(s,1H)，2.09-2.22(m,1H)，1.94-2.02(m,4H)，1.60-1.67(d,2H)，1.40-1.51(m,2H)，1.36(s,3H)，1.29(m,3H)，1.01(s,3H)，0.77(d,3H),0.55(d,3H)。
Embodiment 4
{ 4-[4-(amino-alkylsulfonyl)-anilino]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Product formula (5) 10.2g of embodiment 3, be dissolved in the DMF of 120ml, then add the sulfanilamide (SN) sodium of 8.5g, after adding, be warming up to 55-60 DEG C, stirring is spent the night, reaction is finished, and reaction solution is poured in the frozen water of 300ml, stirs 15 minutes, ethyl acetate extraction, separatory, ethyl acetate is mutually successively by diluted alkaline, saturated common salt washing, anhydrous Na
2sO
4dry, revolve and steam solvent, acetone recrystallization, obtains 8.4g solid, called after A1.Yield 65.3%, fusing point 191-193.5 DEG C.MS-ESI(M+1)：655.3。Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.67(d,2H)，7.59(d,2H)，7.21(d,2H)，7.15(d,2H)，6.84(s,1H)，5.99-6.07(m,1H)，5.50(d,1H)，5.28(s,2H)，4.95-4.99(dd,2H)，4.56(d,1H)，3.78-3.81(dd,2H)，3.37(t,1H)，2.37(s,1H)，2.05-2.14(m,1H)，1.95-2.01(m,4H)，1.57-1.66(d,2H)，1.36-1.52(m,2H)，1.31(s,3H)，1.14-1.20(m,3H)，0.97(s,3H)，0.75(d,3H)，0.52(d,3H)。
Embodiment 5
{ 4-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Product formula (5) 15.0g of embodiment 3 is dissolved in the DMF of 150ml, then adds the sulphamethazine of 6.3g, the K of 2.5g
2cO
3, after adding, being warming up to 80 DEG C, stirring is spent the night, and reaction is finished, and reaction solution is poured in the frozen water of 500ml, stirs 25 minutes, filters, and is washed to neutrality, and acetone recrystallization, obtains 11.4g solid, called after A2.Yield 51.5%, fusing point 195-197 DEG C, MS-ESI (M+1): 761.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.65(d,2H)，7.54-7.61(d,4H)，7.18(d,2H)，6.79(s,1H)，6.10(s,1H)，6.01-6.04(dd,1H)，5.53(d,1H)，5.32(s,2H)，4.90-4.95(dd,2H)，4.57(d,1H)，3.79-3.82(dd,2H)，3.35(m,1H)，2.37(s,1H)，2.25(s,6H)，2.04-2.12(m,1H)，1.95-2.01(m,4H)，1.58(d,2H)，1.33-1.52(m,2H)，1.32(s,3H)，1.10-1.17(m,3H)，1.00(s,3H)，0.79(d,3H)，0.55(d,3H)。
Embodiment 6
{ 4-{4-[N-(2-pyridine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A3 obtaining with the sulfapyridine of equimolar amount.Yield 62%, fusing point 205-207.3 DEG C, MS-ESI (M+1): 732.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:8.20(d,1H)，7.81(m,1H)，7.61-7.67(m,4H)，7.58(d,2H)，7.29(m,2H)，6.79(d,2H)，6.18(s,1H)，5.97-6.05(dd,1H)，5.57(d,1H)，4.91-4.96(m,4H)，4.55(d,1H)，3.71-3.75(dd,2H)，2.37(s,1H)，2.11-2.19(m,1H)，1.99-2.09(m,4H)，1.55-1.64(m,2H)，1.41(m,1H)，1.25-1.38(m,4H)，1.08-1.25(m,3H)，0.99(s,3H)，0.76(d,3H)，0.50(d,3H)。
Embodiment 7
{ 4-{4-[N-(6-methoxyl group-2-pyrimidine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A4 obtaining with sulfanilamide (SN)-6-methoxy pyrimidine of equimolar amount.Yield 43.8%, fusing point 196-198.5 DEG C, MS-ESI (M+1): 763.4.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:8.42(s,1H)，7.65(d,2H)，7.51-7.59(m,4H)，7.15(d,2H)，6.75(s,1H)，6.68(d,2H)，6.31(d,2H)，6.01-6.09(dd,1H)，5.47(d,1H)，5.16(s,2H)，4.93(t,2H)，4.57(d,1H)，3.72-3.81(m,5H)，3.37(s,1H)，2.35(s,1H)，1.95-2.16(m,5H)，1.66(m,2H)，1.23-1.45(m,7H)，1.12-1.21(m,2H)，0.99(s,3H)，0.81(d,3H)，0.57(d,3H)。
Embodiment 8
{ 4-{4-[N-(5-methyl-3-isoxzzole amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 4, with the alternative sulfanilamide (SN) sodium of sulfamethoxazole of equimolar amount, obtains white solid called after A5.Yield 59%, fusing point 189.5-191.8 DEG C, MS-ESI (M+1): 736.1.Nuclear magnetic resonance result is as follows:
1HNMR(DMSO)δ:7.54-7.61(m,4H)，7.27(d,2H)，6.69(d,2H)，6.48(s,1H)，6.25(s,2H)，6.01-6.06(dd,1H)，5.53(d,1H)，4.95-4.99(t,2H)，4.77(s,2H)，4.50(d,1H)，3.75-3.79(dd,2H)，3.34(s,1H)，2.35(s,1H)，2.32(s,3H)，1.97-2.20(m,5H)，1.53-1.61(m,2H)，1.04-1.43(m,8H)，1.01(s,4H)，0.77(d,3H)，0.56(d,3H)。
Embodiment 9
{ 4-{4-[N-(2-thiazole amino)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A6 obtaining with the Sulphathiazole of equimolar amount.Yield 70.7%, fusing point 199.5-202 DEG C, MS-ESI (M+1): 738.0.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.78(d,2H)，7.45-7.52(m,4H)，7.19(d,1H)，6.98(d,2H)，6.85(d,1H)，6.55(d,2H)，6.02-6.11(dd,1H)，5.89(s,2H)，5.42(d,1H)，5.05(s,2H)，4.92(m,2H)，4.55(d,1H)，3.81-3.89(dd,2H)，3.38(s,1H)，2.39(s,1H)，2.01-2.25(m,5H)，1.66(m,2H)，1.30-1.42(m,4H)，1.27(m,4H)，1.08-1.23(m,3H)，0.98(s,3H)，0.77(d,3H)，0.52(d,3H)。
Embodiment 10
Synthesizing of (3-methylol-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods [formula (4)]
Method is with embodiment 2, wherein, and with the Tosyl chloride in toluene sulfonyl chloride alternate embodiment 2 between equimolar amount, product yield 88.4%, fusing point 152.6-155 DEG C, MS-ESI (M+1): 501.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.66(d,1H)，7.57(m1H)，7.38(m,2H)，5.98-6.05(m,1H)，5.51(d,1H)，4.91-4.95(m,2H)，4.47(d,2H)，3.80-3.89(dd,2H)，3.35(m,1H)，2.37(s,1H)，2.10-2.24(m,1H)，1.93-2.01(m,5H)，1.64-1.75(d,2H)，1.47(m,1H)，1.37-1.45(m,1H)，1.32(s,3H)，1.28-1.07(m,4H)，0.98(s,3H)，0.78(s,3H)，0.51(d,3H)。
Embodiment 11
Synthesizing of (3-chloromethyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods [formula (6)]
Product formula (4) 5g of embodiment 10, is dissolved in the methylene dichloride of 100ml, then adds triethylamine 1.15g, and DMF0.75ml, is cooled to 0 DEG C, under vigorous stirring, drips 2.1gPCl
3dichloromethane solution 10ml, after adding, be naturally warming up to room temperature, continue stir 1.5h.Reaction completes, reaction solution poured in 80ml frozen water, and ethyl acetate extraction, separatory, organic phase is washed to neutrality, anhydrous Na
2sO
4dry, concentrating under reduced pressure, silica gel column chromatography separates, and obtains 3.9g solid type (6).Yield 75.1%, fusing point MS-ESI (M+1): 519.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.61(d,1H)，7.54(m1H)，7.35(m,2H)，5.97-6.03(m,1H)，5.54(d,1H)，4.90-4.96(m,2H)，4.54(s,2H)，3.85-3.91(dd,2H)，3.37(m,1H)，2.35(s,1H)，2.12-2.25(m,1H)，1.94-2.05(m,5H)，1.64-1.78(d,2H)，1.48(m,1H)，1.36-1.44(m,1H)，1.30(s,3H),1.07-1.27(m,4H)，0.95(s,3H)，0.77(s,3H)，0.53(d,3H)。
Embodiment 12
{ 3-[4-(amino-alkylsulfonyl)-(anilino) methyl]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 4, adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B1 obtaining.Product yield 65.6%, fusing point 188-190 DEG C, MS-ESI (M+1): 655.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.59(m,1H)，7.51(d,2H)，7.40(d,1H)，7.35(m,1H)，7.14(d,2H)，6.95(s,1H)，5.97-6.05(m,1H)，5.53(d,1H)，5.29(s,2H)，4.90-4.97(dd,2H)，4.59(d,1H)，3.79-3.88(dd,2H)，3.36(t,1H)，2.35(s,1H)，2.01-2.12(m,1H)，1.94-2.05(m,4H)，1.55(d,2H)，1.36-1.52(m,2H)，1.32(s,3H)，1.12-1.25(m,4H)，0.99(s,3H)，0.78(d,3H)，0.57(d,3H)。
Embodiment 13
{ 3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 5, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B2 obtaining.Product yield is 70.9%, fusing point 178-181 DEG C, MS-ESI (M+1): 761.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.61(d,2H)，7.36(s,1H)，7.23(m,2H)，7.14(m,1H)，6.80(s,1H)，6.53(d,2H)，6.11(s,1H)，5.98-6.03(m,1H)，5.50(d,1H)，5.29(s,2H)，4.93-4.97(dd,2H)，4.55(d,1H)，3.77-3.80(dd,2H)，3.38(m,1H)，2.36(s,1H)，2.26(s,6H)，2.06-2.13(m,1H)，1.97-2.03(m,4H)，1.56-1.64(d,2H)，1.35-1.51(m,2H)，1.29(s,3H)，1.13-1.18(m,3H)，0.99(s,3H)，0.80(d,3H)，0.53(d,3H)。
Embodiment 14
{ 3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 7, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B3 obtaining.Yield 67.3%, fusing point 185.7-187 DEG C, MS-ESI (M+1): 732.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:8.46(s,1H)，7.67(m,1H)，7.49(d,2H)，7.22-7.28(m,3H)，7.10(d,1H)，6.73(s,1H)，6.59(d,2H)，6.28(s,2H)，6.00-6.07(dd,1H)，5.49(d,1H)，5.19(s,2H)，4.96(t,2H)，4.55(d,1H)，3.78-84(m,5H)，3.36(s,1H)，2.34(s,1H)，1.94-2.18(m,5H)，1.65(m,2H)，1.25-1.46(m,7H)，1.13-1.20(m,2H)，0.97(s,3H)，0.80(d,3H)，0.52(d,3H)。
Embodiment 15
{ 3-{4-[N-(2-pyridine amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 6, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B4 obtaining.Yield is 50.1%, fusing point 189.5-192 DEG C, MS-ESI (M+1): 763.2.Ultimate analysis: C
40h
49n
3o
6s
2, calculated value (%) C63.06, H6.47, N5.51, measured value (%) C64.26, H6.71, N5.48.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:8.26(d,1H),7.75(m,1H),7.48(d,1H),7.13-7.26(m,6H)7.07(d,1H),6.56(d,2H),6.14(s,2H),5.99-6.06(dd,1H),5.55(d,1H),4.90-4.94(m,4H),4.54(d,1H),3.74-3.77(dd,2H),2.35(s,1H),2.12-2.18(m,1H),1.98-2.06(m,4H),1.56-1.65(m,2H),1.41-1.46(m,1H),1.27-1.39(m,4H),1.07-1.23(m,3H),0.98(s,3H),0.78(d,3H),0.51(d,3H)。
Embodiment 16
{ 3-{4-[N-(5-methyl-3-isoxzzole amido)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 8, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B5 obtaining.Product yield 61.8%, fusing point 185.2-187.5 DEG C, MS-ESI (M+1): 736.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.46(d,2H)，7.23-7.27(t,3H)，7.12(d,1H)，6.61(d,2H)，6.42(s,1H)，6.27(s,2H)，6.00-6.08(dd,1H)，5.50(d,1H)，4.93-4.97(t,2H)，4.78(s,2H)，4.54(d,1H)，3.79-3.82(dd,2H)，3.37(s,1H)，2.36(s,1H)，2.30(s,3H)，1.96-2.21(m,5H)，1.58-1.63(m,2H)，1.09-1.44(m,9H)，0.98(s,3H)，0.79(d,3H)，0.55(d,3H)。
Embodiment 17
{ 3-{4-[N-(2-thiazole amino)-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 9, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amount, the white solid called after B6 obtaining.Product yield is 75.4%, fusing point 185.8-186.9 DEG C, and MS-ESI (M+1): 738.1, ultimate analysis: C
38h
47n
3o
6s
3, calculated value (%) C61.91, H6.42, N5.71, measured value (%) C61.57, H6.51, N5.66.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:7.71(d,1H)，7.43(d,1H)，7.40(d,2H)，7.34(s,1H)，7.26(d,1H)，7.21(t,1H)，6.98(d,1H)，6.85(d,1H)，6.53(d,2H)，6.00-6.06(dd,1H)，5.87(s,2H)，5.48(d,1H)，5.03(s,2H)，4.96(s,1H)，4.93(d,1H)，4.54(d,1H),，3.80-3.85(dd,2H)，3.35(s,1H)，2.38(s,1H)，2.00-2.23(m,5H)，1.61(m,2H)，1.32-1.41(m,4H)，1.30(s,3H)，1.08-1.23(m,2H)，0.99(s,3H)，0.80(d,3H)，0.55(d,3H)。
The antibacterial activity in vitro research of part target compound of the present invention
1. test method: adopt the minimum inhibitory concentration (MIC) of meat soup doubling dilution to strain subject to measure.The inoculum size of bacterium is 105CFU/ml, and every kind of medicine all carries out 3 times to every kind of bacterium to be repeated.Tested material is with after methyl-sulphoxide hydrotropy, with sterile purified water or the use of lower alcohol wiring solution-forming.
2. test strain: totally 15 strain laboratory standard bacterial strains (comprise that 8 strains are gram-positive microorganism (G
+), 2 strain Gram-negative bacterias (G-), 5 strain mycoplasmas).Streptococcus aureus ATCC29213(Staphylococcus aureus), streptococcus aureus CICC26112(Staphylococcus aureus), methicillin-resistant staphylococcus aureus (Methicillin Resistant Staphylococcus aureus, MRSA), streptococcus pneumoniae ATCC49619(Streptococcus pneumoniae), swine streptococcus CVCC3307(Streptococcus suis), beta hemolytic streptococcus CICC10373(beta Hemolytic streptococcus) staphylococcus epidermidis 26069(Staphylococcus epidermidis), strangles suis CVCC556(Strepococcus equinus), intestinal bacteria ATCC25922(Escherichia coli), Proteus mirabilis CMCC49003(Proteus mirabilis), chicken virus mycoplasma S6(Mycoplasma gallisepticum), chicken virus mycoplasma CVCC351(Mycoplasma gallisepticum), synovia mycoplasma CVCC358(Mycoplasma synoviae), mycoplasma hyopneumoniae CVCC354(Mycoplasma hyopneumoniae), mycoplasma pneumoniae ATCC15531(Mycoplasma pneumonia)
3. positive control medicine is sulfapyridine (Sulfapyridine) and valnemulin (valnemulin).
The MIC value of each compound is listed in table 1
Table 1 part target compound antibacterial activity in vitro data (MIC, μ g/ml)
Note: wherein, Sau1 streptococcus aureus ATCC29213; Sau3 streptococcus aureus CICC26112; MRSA methicillin-resistant staphylococcus aureus; Spn streptococcus pneumoniae; Ssu swine streptococcus; BHS beta hemolytic streptococcus; Sep staphylococcus epidermidis; Seq strangles suis; Eco intestinal bacteria; Pm Proteus mirabilis; Mg chicken virus mycoplasma; Ms synovia mycoplasma; Mhy mycoplasma hyopneumoniae; Mpn mycoplasma pneumoniae.
As shown in Table 1, compound of the present invention has obvious anti-microbial activity.
To surveyed G
+bacterium: A6, B6 are better than control drug sulfapyridine and valnemulin to surveyed streptococcus aureus, MRSA, streptococcus pneumoniae, hyopneumoniae suis, staphylococcus epidermidis, faecalis, the streptococcic anti-microbial activity of strangles, especially the anti-microbial activity of methicillin-resistant staphylococcus aureus (MRSA) are significantly better than to control drug valnemulin; The anti-microbial activity of streptococcus aureus is better than to the A6 that has of control drug valnemulin, B1, B6, is better than the A1 that has of control drug valnemulin, A6, B2, B3, B6 to the anti-microbial activity of streptococcus pneumoniae; The anti-microbial activity of epidermis streptococcus aureus is better than to the B6 that has of control drug valnemulin, hyopneumoniae suis anti-microbial activity is better than to the B4 that has of control drug valnemulin.
G-bacterium to surveyed: compd A 6, B4, B6 is shown medium anti-microbial activity to survey 2 strain G-bacterium.
Mycoplasma to surveyed: A3, A6, B1, B6 are to the anti-microbial activity of surveyed mycoplasma all quite or be better than control drug valnemulin.
Application Example 1
A kind of anti-microbial activity pre-mixture
By weight by 1 part of the compound of embodiment 12 (A6), 1 part of polyvinylpyrrolidone, 5 parts of starch, are prepared as pre-mixture according to the method for this area routine
Application Example 2
A kind of anti-microbial activity injection
By 1 part of the compound of embodiment 16 (B6), 10 parts of waters for injection, are prepared as injection according to the method for this area routine by weight.
Above-mentioned embodiment is only the preferred embodiment of the present invention; can not limit the scope of protection of the invention with this, the variation of any unsubstantiality that those skilled in the art does on basis of the present invention and replacement all belong to the present invention's scope required for protection.
Claims (10)
1. the pleuromutilin derivative of an anti-microbial activity with formula I structure or its are pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds;
Wherein: R
1be selected from the one in heteroaryl, amidino groups, guanidine radicals, the acyl group of C1-C8 and the substitutive derivative of above-mentioned group of aryl, C3-C18 of alkyl, the C6-C18 of hydrogen atom, amino, hydroxyl, C1-C8; X is the one in the alkoxyl group of alkyl, C3-C8 of sulphur atom, Sauerstoffatom, amino, C1-C8.
2. the pleuromutilin derivative of anti-microbial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, is characterized in that: the substituting group of described substitutive derivative is the one in aryl, C3-C18 heteroaryl, the alkylthio of C1-C8 or the arylthio alkyl of C6-C18 of alkoxyl group, C6-C18 of cycloalkyl, the C1-C8 of alkyl, the C3-C8 of acyl group, the C1-C8 of amino, Heterocyclylalkyl, nitro, halogen, hydroxyl, carboxyl, guanidine radicals, C3-C8.
3. the pleuromutilin derivative of anti-microbial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, is characterized in that: R
1be selected from the one in methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, base, ethylamino-, Propylamino, dimethylin, diethylin, pyrryl, pyrazolyl, imidazolyl, triazol radical, furyl, thienyl, oxazolyl, pyridyl, thiazolyl, pyrimidyl, pyrazinyl.
4. the pleuromutilin derivative of anti-microbial activity according to claim 1 or its are pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, it is characterized in that having with following formula (A) or (B) structure:
5. the pleuromutilin derivative of anti-microbial activity according to claim 4 or its are pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, it is characterized in that, R1 is the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative.
6. the pleuromutilin derivative of anti-microbial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, are selected from the one in following compounds:
4-[4-(amino-alkylsulfonyl)-(anilino) methyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-[4-(amino-alkylsulfonyl)-(anilino) methyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) methyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods.
7. prepare the pleuromutilin derivative of anti-microbial activity as claimed in claim 1 or its pharmaceutically and/or a method for veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, it is characterized in that, with formula (a)
Through reduction after with formula (b)
There is substitution reaction, obtain product (c)
Product (c) after halogenation with formula (d)
After amination, obtain product (I).
8. an anti-microbial activity composition, comprise the anti-microbial activity as described in claim 1-6 any one pleuromutilin derivative and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and pharmaceutically acceptable carrier or thinner.
9. anti-microbial activity composition according to claim 8, is characterized in that: its formulation is oral preparation or injection.
10. anti-microbial activity composition according to claim 8, it is characterized in that: wherein the pleuromutilin derivative of anti-microbial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds content be 0.1%-99.5%(wt%), surplus is carrier or thinner.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410129805.6A CN103910663B (en) | 2014-03-31 | 2014-03-31 | A kind of pleuromutilin derivative with antibacterial activity and preparation thereof and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410129805.6A CN103910663B (en) | 2014-03-31 | 2014-03-31 | A kind of pleuromutilin derivative with antibacterial activity and preparation thereof and application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103910663A true CN103910663A (en) | 2014-07-09 |
| CN103910663B CN103910663B (en) | 2016-06-29 |
Family
ID=51036714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410129805.6A Active CN103910663B (en) | 2014-03-31 | 2014-03-31 | A kind of pleuromutilin derivative with antibacterial activity and preparation thereof and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103910663B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311509A (en) * | 2014-09-15 | 2015-01-28 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative, and preparation method and application thereof |
| CN104803926A (en) * | 2015-03-25 | 2015-07-29 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative |
| CN105399684A (en) * | 2015-11-03 | 2016-03-16 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin compound, preparation method of pleuromutilin compound, polymorphism and preparation method of polymorphism |
| CN105622524A (en) * | 2016-03-22 | 2016-06-01 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative and application thereof |
| CN105949146A (en) * | 2016-05-06 | 2016-09-21 | 武汉工程大学 | Pleuromutilin-tizoxanide hybrid drug and preparation method thereof |
| CN114436870A (en) * | 2021-12-21 | 2022-05-06 | 华南农业大学 | Pleuromutilin derivative with amino side chain as well as preparation method and application thereof |
| CN114853782A (en) * | 2022-06-27 | 2022-08-05 | 潍坊医学院 | Pleuromutilin derivative with pyrimidine side chain and preparation method and application thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003042354A2 (en) * | 2001-09-04 | 2003-05-22 | Aventis Pharmaceuticals Inc. | Abrogen polypeptides, nucleic acids encoding them and methods for using them to inhibit angiogenesis |
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
| CN103265487A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Pleuromutilin expansion ring derivative, and preparation method and application thereof |
| CN103265442A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Novel pleuromutilin derivatives, as well as preparation method and anti-tumour application thereof |
| CN103319437A (en) * | 2013-06-20 | 2013-09-25 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof |
-
2014
- 2014-03-31 CN CN201410129805.6A patent/CN103910663B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003042354A2 (en) * | 2001-09-04 | 2003-05-22 | Aventis Pharmaceuticals Inc. | Abrogen polypeptides, nucleic acids encoding them and methods for using them to inhibit angiogenesis |
| EP2014645A1 (en) * | 2007-07-13 | 2009-01-14 | Nabriva Therapeutics AG | Pleuromutilin derivatives and their use as antimicrobials |
| CN102229580A (en) * | 2011-05-12 | 2011-11-02 | 南通大学 | Novel pleuromutilin derivate, preparation method and medical use thereof |
| CN103265487A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Pleuromutilin expansion ring derivative, and preparation method and application thereof |
| CN103265442A (en) * | 2013-06-05 | 2013-08-28 | 北京理工大学 | Novel pleuromutilin derivatives, as well as preparation method and anti-tumour application thereof |
| CN103319437A (en) * | 2013-06-20 | 2013-09-25 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311509A (en) * | 2014-09-15 | 2015-01-28 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative, and preparation method and application thereof |
| CN104803926A (en) * | 2015-03-25 | 2015-07-29 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative |
| CN104803926B (en) * | 2015-03-25 | 2017-05-03 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative |
| CN105399684A (en) * | 2015-11-03 | 2016-03-16 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin compound, preparation method of pleuromutilin compound, polymorphism and preparation method of polymorphism |
| CN105622524A (en) * | 2016-03-22 | 2016-06-01 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative and application thereof |
| CN105622524B (en) * | 2016-03-22 | 2018-03-16 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin analog derivative and its application |
| CN105949146A (en) * | 2016-05-06 | 2016-09-21 | 武汉工程大学 | Pleuromutilin-tizoxanide hybrid drug and preparation method thereof |
| CN114436870A (en) * | 2021-12-21 | 2022-05-06 | 华南农业大学 | Pleuromutilin derivative with amino side chain as well as preparation method and application thereof |
| WO2023115691A1 (en) * | 2021-12-21 | 2023-06-29 | 华南农业大学 | Pleuromutilin derivative with amino side chain, and preparation method therefor and use thereof |
| CN114853782A (en) * | 2022-06-27 | 2022-08-05 | 潍坊医学院 | Pleuromutilin derivative with pyrimidine side chain and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103910663B (en) | 2016-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103910663A (en) | Pleuromutilin derivatives with antibacterial activity as well as preparation method and application thereof | |
| ES2927182T3 (en) | Apoptosis-inducing agents | |
| CA2675884C (en) | Quinoxaline compounds and use thereof | |
| PT91620B (en) | PROCESS FOR THE PREPARATION OF ANTIFUNG COMPOUNDS BASED ON PHENYL GROUP AMOALS AND FUNGICID COMPOSITIONS CONTAINING THEM | |
| CN102229580B (en) | Novel pleuromutilin derivate, preparation method and medical use thereof | |
| BRPI0615968B1 (en) | USE OF A COMPOUND, COMPOUND AND PHARMACEUTICAL COMPOSITION | |
| PT1432705E (en) | Dual action antibiotics | |
| JPH068278B2 (en) | Pluromutilin derivative, production method and use thereof | |
| BR112020019399A2 (en) | MACROCYCLIC COMPOUNDS AS TRK KINASE INHIBITORS | |
| CN104177305A (en) | Novel method for synthesizing thiotriazinone (TTZ) by using mixed solvent | |
| AU2017339104A1 (en) | 2-amino-N-(arylsulfinyl)-acetamide compounds as inhibitors of bacterial aminoacyl-tRNA synthetase | |
| JPH06500085A (en) | Benzimidazole, its manufacture and use | |
| CN103910664B (en) | A kind of antibacterial activity pleuromutilin-sulphone amide derivative and its preparation method and application | |
| Ravichandiran et al. | Synthesis, molecular docking and antibacterial evaluation of 2-(4-(4-aminophenylsulfonyl) phenylamino)-3-(thiophen-2-ylthio) naphthalene-1, 4-dione derivatives | |
| AU2006300882B2 (en) | Crystalline sodium salt of cephalosporin antibiotic | |
| CN115197169B (en) | Preparation method and application of pleuromutilin derivative with 2-aminobenzene mercapto alcohol as connecting group | |
| ES2290192T3 (en) | PLEUROMUTILINE DERIVATIVES WITH ANTIMICROBIAL ACTIVITY. | |
| DK2601193T3 (en) | Compounds with antibacterial activity against clostridium | |
| CN109678900B (en) | Sulfanilamide derivative and preparation method and application thereof | |
| CN102603553A (en) | Compound with collaborative antifungal effect and application thereof in pharmaceuticals | |
| US10421715B2 (en) | Pleuromutilin derivative having 2-amino phenyl mercaptan side chain as well as preparation method and application thereof | |
| HU205936B (en) | Process for producing cephalosporing derivatives and pharmaceutical compositions containing them | |
| JPH05508170A (en) | Novel difluoroquinolones, their synthesis methods, and pharmaceuticals containing them | |
| Ajani et al. | Synthesis and Antibacterial Activity of N, N-Diethylamide Bearing Benzenesulfonamide Derivatives | |
| RU2782469C2 (en) | Apoptosis-inducing agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| GR01 | Patent grant | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160607 Address after: 510000 No. five, 483 mountain road, Guangzhou, Guangdong, Tianhe District Applicant after: South China Agricultural University Applicant after: GUANGDONG WENS DAHUANONG BIOTECHNOLOGY CO., LTD. Address before: 510000 No. five, 483 mountain road, Guangzhou, Guangdong, Tianhe District Applicant before: South China Agricultural University Applicant before: Guangdong Dahuanong Animal Health Products Co., Ltd. |