CN103910663B - A kind of pleuromutilin derivative with antibacterial activity and preparation thereof and application - Google Patents
A kind of pleuromutilin derivative with antibacterial activity and preparation thereof and application Download PDFInfo
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Abstract
The invention discloses the pleuromutilin derivative of a kind of antibacterial activity with formula I structure or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and preparation method thereof and in the application of antibacterial combination species；
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, be specifically related to a kind of antibacterial 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 fastbacteria such as multi-resistant Pseudomonas aeruginosa (MDRPA) and vancomycin-resistant enterococcus (VRE) cause is increasing, and the trend of the existing large area outburst in some areas, public health security is constituted grave danger.Bacterial drug resistance just exists from antibiotic produces, it is the result of bacteria live natural selection, but owing to people depend on unduly antibiotic, the appearance making Resistant strain is more and more faster, and there is transmitting between different genera the trend of drug resistant gene, the i.e. generation of crossing drug resistant, is a lot of noval chemical compound main cause of also just having occurred fastbacteria in conceptual phase.Therefore, find a kind of efficiently and the mechanism of action be different from the antibiotic newtype drug of most of main flow and just seem particular importance.
Pleuromutilin (Pleuromutilin) is the metabolite of basidiomycetes pleurotus Agaricaceae north phoenix bacterium (Pleurotusmutilus and Pleurotuspasseckerianus), belongs to tricyclic ditcrpane compounds.Itself antibacterial activity is general, it is necessary to by chemistry, biological means, carry out structural modification, to improve antibacterial 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, it is suppressed that protein synthesis, therefore, less with other major antibiotics generation crossing drug resistants.If safe wonderful woods (taimulin, Tiamulin) is animal specific antibiotic, having used more than in cultivation 30 years, it is currently still a line main flow antibiotic, and the report about fastbacteria is also less.His wonderful woods (Retapamulin) auspicious is the first man pleuromulins antibiotic recently succeeded in developing, and namely a listing causes the great interest of researcher, and in succession reports out the novel pleuromutilin derivative in a large number with outstanding antibacterial activity.As Peng et al. has synthesized the series carbamates pleuromutilin derivative containing heterocycle, gram positive bacteria is had fabulous antibacterial activity.
Along with being on the rise of bacterial resistance sex chromosome mosaicism, the discovery of novel antibacterial drug molecule is more and more urgent, but the screening of novel drugs molecule and discovery need to expend substantial amounts 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 being linked together, it is expected to develop the antibacterials of multiple action, for delaying the generation of bacterial drug resistance, reduction R&D costs and time significant.
Summary of the invention
For overcoming the defect of prior art, being in that of the present invention provide a kind of antibacterial activity pleuromutilin derivative or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, improve the antibacterial activity of pleuromutilin, it is thus achieved that the antibacterial active compounds of a kind of efficient, long-acting, wide spectrum.
Another object of the present invention is to provide a kind of antibacterial activity pleuromutilin derivative or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds preparation method.
In the present invention, the salt that " pharmaceutically and/or veterinarily acceptable salt " includes and alkali metal is formed, salt such as inorganic bases such as sodium, potassium, magnesium, calcium, with hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, cross chloric acid, etc. the salt of mineral acid, with the organic acid salt such as fumaric acid, maleic acid, phosphoric acid, glycolic, lactic acid, salicylic acid, succinic acid, p-methyl benzenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, benzenesulfonic acid or LOMAR PWA EINECS 246-676-2.
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 antibacterial activity with formula I structure or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds；
Wherein: R1One in hydrogen atom, amino, hydroxyl, the alkyl of C1-C8, the aryl of C6-C30, the heteroaryl of C3-C18, amidino groups, guanidine radicals, the acyl group of C1-C18 and the substitutive derivative of above-mentioned group；X is the one in the alkoxyl of sulphur atom, oxygen atom, the alkyl of C1-C8, amino, C3-C8.
In such scheme, the substituent group of described substitutive derivative is the one in amino, Heterocyclylalkyl, nitro, halogen, hydroxyl, carboxyl, guanidine radicals, the acyl group of C3-C8, the alkyl of C1-C18, the cycloalkyl of C3-C8, the alkoxyl of C1-C18, the aryl of C6-C18, C3-C18 heteroaryl, the alkylthio group of C1-C8 or the arylthio alkyl of C6-C18.
In the present invention, in term, " alkyl " includes straight or branched alkyl, such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, heptyl, octyl group etc.；" cycloalkyl " includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group；" Heterocyclylalkyl " refers to containing one or more selected from the heteroatomic saturated cyclic such as N, O, S, such as nafoxidine base, tetrahydrofuran base, piperazinyl, tetrahydro-thiazoles base, morpholine base etc., " amido " includes methylamino, ethylamino-, Propylamino, dimethylamino, diethylin etc.；" heteroaryl " refers to containing one or more selected from the heteroatomic aryl such as N, O, S, such as pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, furyl, thienyl, oxazolyl, pyridine radicals, thiazolyl, pyrimidine radicals, pyrazinyl etc.；" virtue heterocycle " refer to carbocyclic aromatic (referring mainly to phenyl ring aromatic hydrocarbons) and upper containing one or more selected from N, O, S etc. heteroatomic saturated or unsaturated heterocycle base, such as indyl, benzofuranyl, benzothiazolyl, quinolyl, isoquinolyl, benzimidazolyl etc.；" heterocycle virtue heterocyclic radical " is primarily referred to as the also ring of pyrimidine and imidazoles or pyrazine, such as purine, pteridine etc..
The pleuromutilin derivative of described antibacterial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, it is characterised in that there is below 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 antibacterial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, the one in following compounds:
{ 4-[4-(amino-sulfonyl)-(anilino-) methyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-[4-(amino-sulfonyl)-(anilino-) methyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods.
A kind of pleuromutilin derivative preparing antibacterial activity or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds method, by formula (a)
After carrying out reduction with formula (b)
There is substitution reaction, obtain product (c)
Product (c) after halogenation with formula (d)
Product (I) is obtained after amination.
In the present invention, the condition of above-mentioned reduction, amidatioon, sulfonylation and replacement can be that this area can to realize any condition of the object of the invention.As preferably, the preparation method of the present invention can be the method specifically including following steps:
1) reduction reaction: reducing agent is added formation suspension in oxolane, adds the alkali of catalytic amount, under ice bath, N2Protection, the slowly tetrahydrofuran solution of dropping 4-mercaptobenzoic acid or 3-mercaptobenzoic acid, continue stirring 45 minutes, be warming up to 25-80 DEG C, stir 5-20 hour after adding, thin layer chromatography identification terminal.It is then respectively adding appropriate ethyl acetate and acidic aqueous solution, stir 15 minutes, filter, separatory, aqueous phase is extracted with ethyl acetate 3 times, merges organic facies, saturated common salt is washed, is washed to neutrality successively, dry, rotation steams solvent, and silica gel column chromatography separates sulfydryl benzyl alcohol (1) or a sulfydryl benzyl alcohol (2)；
2) substitution reaction: by pleuromutilin, paratoluensulfonyl chloride is added sequentially in ethyl acetate, regulates pH value to strong basicity with alkali liquor, is warming up to 30-100 DEG C, is stirred vigorously 4 hours.Reaction is finished, and decompression steams organic solvent, residue dilute with water 10 times, washes out white solid, sucking filtration, is washed to neutrality, dries to obtain white solid product (b)；
Sodium ethylate is dissolved in dehydrated alcohol, is cooled to 0-10 DEG C, be sequentially added into the product (b) of previous step and to sulfydryl benzyl alcohol (1) or a sulfydryl benzyl alcohol (2), heat up after adding, N2Protection, stirs 24h, reacts completely.Decompression steams solvent, residue dilute with water, extraction into ethyl acetate, separates organic facies, is washed to neutrality, anhydrous MgSO4Dry, filter, boil off ethyl acetate, purification by silica gel column chromatography, obtain product (4-methylol-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods formula (3) or (3-methylol-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods formula (4)；
3) halogenation: be dissolved in dichloromethane by the product (3) of substitution reaction or (4), adds the alkali of catalytic amount, under low temperature, slowly drips SOCl2Dichloromethane solution, add in 1-2 hour, be warming up to backflow; continuing stirring 1-12 hour, reaction completes, by reactant liquor to entering in frozen water; it is stirred vigorously; filter, separatory, organic solvent extraction; washing; dry, concentrating under reduced pressure, cross silicagel column and obtain product (4-chloromethyl-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods formula (5) or (3-chloromethyl-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods formula (6)；
4) aminating reaction: halogenation products therefrom (5) or (6) are dissolved in DMF, add compound (d), it is subsequently adding the alkali of catalytic amount, is warming up to 40-120 DEG C after adding, is stirred at room temperature 1-24 hour, reaction is finished, reactant liquor is fallen in frozen water, stir 15 minutes, extraction into ethyl acetate, the secondary diluted alkaline of organic facies, saturated common salt are washed, anhydrous Na2SO4Dry, rotation steams solvent, acetone recrystallization, obtains product A or B.
The synthetic route of above-mentioned preparation method is as follows:
In above-mentioned preparation method, reducing agent used by step 1) can be LiAlH4, (three tert-butoxies) lithium aluminium hydride reduction, double; two (methoxyethoxy) alanate, NaBH4, one in diborane；Alkali can be inorganic base K2CO3, NaOH, KOH, or the one in organic bases triethylamine, pyridine, piperidines, hexanamine；The low boiling halogenated hydrocarbons such as the replaceable one-tenth dichloromethane of solvents tetrahydrofurane that wherein adopts, chloroform, 1,2-dichloroethanes, one in ether, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE) or two or more mixing；Acid used can be HCl, H2SO4, HBr, one in the mineral acid such as phosphoric acid.Reaction process condition is: preferred, it is advantageous to reaction temperature be 25 DEG C to 60 DEG C, it is preferred that mol ratio is mercaptobenzoic acid (a): reducing agent=1:1～3:5.
In above-mentioned preparation method, step 2) used by alkali be inorganic base NaOH, KOH, or the one in organic base pyridine, triethylamine；Ethyl acetate used can be replaced methyl acetate, butyl formate, toluene, dichloromethane, chloroform, 1, the low boiling halogenated hydrocarbons such as 2-dichloroethanes, one or more mixing in ether, oxolane, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE)；Sodium ethylate used can be replaced the one in Feldalat NM, sodium isopropylate, DMAP；Ethanol used can be replaced the lower alcohol solvent such as methanol, isopropanol, one or more mixing in ether, oxolane, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE).Reaction process condition is: adding alkali equivalent is 1-3, is preferred with 1.5；Add-subtract time was advisable with 0.5-2 hour, and feed temperature is 0-25 DEG C, to be preferred lower than 10 DEG C；Reaction temperature is 30-100 DEG C, is preferred with 50 DEG C.
In above-mentioned preparation method, alkali used by step 3) can be inorganic base Na2CO3、K2CO3, NaOH, KOH, or the one in organic base pyridine, morpholine, triethylamine；SOCl used2Can be replaced HCl, HBr, PCl3、PCl5、POCl3In with China；Solvent for use dichloromethane can be replaced the low boiling halogenated hydrocarbons such as chloroform, 1,2-dichloroethanes, one or more mixing in ether, oxolane, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE).Reaction process condition is: feed temperature is-5～30 DEG C, to be preferred lower than 0 DEG C；Reaction temperature is 25 DEG C～90 DEG C；Preferred mol ratio is compound (3) or compound (4): SOCl2=1:(1～2.5).
In above-mentioned preparation method, alkali used by step 3) can use inorganic base Na2CO3、K2CO3, NaOH, KOH, or organic base pyridine, N-methylmorpholine, morpholine, triethylamine etc., either or both of which mixing uses；Solvent for use DMF can be replaced DMSO, oxolane, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE) or its mixed form.Reaction process condition is: feed temperature is 25-40 DEG C, is preferred with room temperature；Reaction temperature is 40-120 DEG C, is preferred with 40 DEG C；Preferred mol ratio is compound (5) or (6): sulfonamide compounds (d)=1:(1～2).
A further object of the present invention be in that provide a kind of pleuromutilin derivative comprising above-mentioned antibacterial activity and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds antibacterial activity compositions,
A kind of antibacterial activity compositions, including above-mentioned antibacterial activity pleuromutilin derivative and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and pharmaceutically acceptable carrier or diluent.
As the preferred version of the present invention, the dosage form of described antibacterial activity compositions is oral agents or injection.
Preferred version as the present invention, in described antibacterial activity compositions, the pleuromutilin derivative of antibacterial 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 diluent.
The effective of the present invention is in that: the lead compound that two different is linked together by the present invention through covalent bond, produces synergism, adduction in vivo, or produces new pharmacologically active；The sulfa drugs of the present invention is spliced on pleuromutilin side chain, produce new sulfanilamide-pleuromutilin derivative, the noval chemical compound obtained can strengthen antibacterial activity, especially gram positive bacteria, gram negative bacteria and mycoplasma had significant antibacterial activity, and the fastbacteria such as MRSA also there are is obvious inhibiting effect, has effectively widened its antimicrobial spectrum.
Below in conjunction with specific embodiment, the present invention is described in further detail.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further elaborated, but these examples are not any limitation of the invention.In all embodiments, the fusing point of compound capillary melting point determination instrument measures, and 1HNMR is by VarianAM-400 type nmr determination, and with TMS for interior mark, chemical shift represents with (ppm)；Mass spectrum Q-TOF type mass spectrograph measures, and elementary 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
The synthesis of 4-sulfydryl benzyl alcohol [formula (1)]
4gLiAlH4Join formation suspension, N in 50ml oxolane2Protection, dissolves in 4-mercaptobenzoic acid 8.5g in the oxolane of 100ml, under ice bath, is slowly added drop-wise in above-mentioned suspension, continues stirring 30 minutes, then heat to backflow, stir 16 hours after adding.Reaction is finished, and is separately added into 40ml ethyl acetate and 50ml15%H2SO4Solution, filters, aqueous phase 50ml extraction into ethyl acetate 3 times, merges organic facies, and saturated common salt is washed, anhydrous Na2SO4Dry, concentrating under reduced pressure obtains that 7.5g is faint yellow or colourless liquid.With purification by silica gel column chromatography (ethyl acetate: petroleum ether=75:25), obtaining 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
The synthesis of (4-methylol-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods [formula (3)]
By pleuromutilin formula (b) of 11.0g, the paratoluensulfonyl chloride of 5.5g is added sequentially in the ethyl acetate of 50ml, and ice bath is washed down, with the potassium hydroxide solution 20ml of 1mol/L adjustment pH value to strong basicity, being warming up to 35 DEG C, be stirred vigorously 2.5 hours, thin layer chromatography monitors reaction end.Reaction is finished, and decompression steams organic solvent, residue dilute with water 10 times, washes out white solid, sucking 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 Feldalat NM is dissolved in 250ml methanol, is cooled to 15 DEG C, be sequentially added into product 4-sulfydryl benzyl alcohol formula (1) of 4.8g embodiment 1, the product of 17.6g step 1), after adding, be naturally warmed up to room temperature, N2Protection, stirs 24h, reacts completely under room temperature.Decompression steams solvent, residue 50ml water dissolution, and extraction into ethyl acetate separates organic facies, is washed to neutrality, anhydrous MgSO4Dry, filter, boil off ethyl acetate, purification by silica gel column chromatography (ethyl acetate: petroleum ether=80:20)；Obtaining 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
The synthesis of (4-chloromethyl-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods [formula (5)]
Product formula (3) 5g of embodiment 2, is dissolved in the dichloromethane of 100ml, is subsequently adding triethylamine 1.5g, DMF0.75ml, be cooled to 0 DEG C, is stirred vigorously lower dropping 2.1gSOCl2Dichloromethane solution 10ml, after adding, warm naturally to room temperature, continue stirring 1.5h.Reaction completes, and is poured into by reactant liquor in 80ml frozen water, extraction into ethyl acetate, and separatory, organic facies is washed to neutrality, anhydrous Na2SO4Dry, 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
The synthesis of { 4-[4-(amino-sulfonyl)-anilino-]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods
Product formula (5) 10.2g of embodiment 3, it is dissolved in the DMF of 120ml, is subsequently adding the sulfanilamide sodium of 8.5g, after adding, is warming up to 55-60 DEG C, stirring is overnight, reaction is finished, and is poured into by reactant liquor in the frozen water of 300ml, stirs 15 minutes, extraction into ethyl acetate, separatory, ethyl acetate is mutually successively by diluted alkaline, saturated common salt washing, anhydrous Na2SO4Dry, rotation steams 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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Product formula (5) 15.0g of embodiment 3 is dissolved in the DMF of 150ml, is subsequently adding the K of the sulfadimidine of 6.3g, 2.5g2CO3, it being warming up to 80 DEG C after adding, overnight, reaction is finished, and is poured into by reactant liquor in the frozen water of 500ml, stirs 25 minutes in stirring, filters, is washed to neutrality, 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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A3 obtained with the sulfapyridine of equimolar amounts.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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A4 obtained with the sulfanilamide-6-methoxy pyrimidine of equimolar amounts.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-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 4, substitutes sulfanilamide sodium with the sulfamethoxazole of equimolar amounts, 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-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 5, wherein substitutes sulfamethazine, the white solid called after A6 obtained with the sulfathiazole of equimolar amounts.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
The synthesis of (3-methylol-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods [formula (4)]
Method is with embodiment 2, wherein, with the paratoluensulfonyl chloride in toluene sulfochloride alternate embodiment 2 between equimolar amounts, and 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
The synthesis of (3-chloromethyl-benzene sulfydryl)-acetyl group-14-oxygen-wonderful woods [formula (6)]
Product formula (4) 5g of embodiment 10, is dissolved in the dichloromethane of 100ml, is subsequently adding triethylamine 1.15g, DMF0.75ml, be cooled to 0 DEG C, is stirred vigorously lower dropping 2.1gPCl3Dichloromethane solution 10ml, after adding, warm naturally to room temperature, continue stirring 1.5h.Reaction completes, and is poured into by reactant liquor in 80ml frozen water, extraction into ethyl acetate, and separatory, organic facies is washed to neutrality, anhydrous Na2SO4Dry, 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
The synthesis of { 3-[4-(amino-sulfonyl)-(anilino-) methyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 4, adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B1 obtained.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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 5, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B2 obtained.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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 7, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B3 obtained.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)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 6, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B4 obtained.Yield is 50.1%, fusing point 189.5-192 DEG C, MS-ESI (M+1): 763.2.Elementary analysis: C40H49N3O6S2, value of calculation (%) 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-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 8, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B5 obtained.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-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 9, wherein adopts product formula (6) substituted (5) of the embodiment 11 of equimolar amounts, the white solid called after B6 obtained.Product yield is 75.4%, fusing point 185.8-186.9 DEG C, MS-ESI (M+1): 738.1, and elementary analysis: C38H47N3O6S3, value of calculation (%) 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 partial target compound of the present invention
1. test method: adopt meat soup doubling dilution that the minimum inhibitory concentration (MIC) of strain subject is measured.The inoculum concentration of antibacterial is 105CFU/ml, and every kind of bacterium is all carried out 3 times and repeats by every kind of medicine.Tested material is with, after dimethyl sulfoxide hydrotropy, using with sterile purified water or lower alcohol wiring solution-forming.
2. test strain: (include 8 strains is gram positive bacteria (G to totally 15 strain laboratory standard bacterial strains+), 2 strain gram negative bacterias (G-), 5 strain mycoplasmas).Staphylococcus aureus ATCC29213(Staphylococcusaureus), staphylococcus aureus CICC26112(Staphylococcusaureus), methicillin-resistant staphylococcus aureus (MethicillinResistantStaphylococcusaureus, MRSA), streptococcus pneumoniae ATCC49619(Streptococcuspneumoniae), Streptococcus suis CVCC3307(Streptococcussuis), beta hemolytic streptococcus CICC10373(betaHemolyticstreptococcus) staphylococcus epidermidis 26069(Staphylococcusepidermidis), adenitis equorum streptococcus CVCC556(Strepococcusequinus)；Escherichia coli ATCC25922(Escherichiacoli), proteus mirabilis CMCC49003(Proteusmirabilis)；Chicken virus mycoplasma S6(Mycoplasmagallisepticum), chicken virus mycoplasma CVCC351(Mycoplasmagallisepticum), synovial fluid mycoplasma CVCC358(Mycoplasmasynoviae), mycoplasma hyopneumoniae CVCC354(Mycoplasmahyopneumoniae), mycoplasma pneumoniae ATCC15531(Mycoplasmapneumonia)
3. positive control medicine is sulfapyridine (Sulfapyridine) and valnemulin (valnemulin).
The MIC value of each compound is listed in table 1
Table 1 partial target Compound ira vitro antibacterial activity data (MIC, μ g/ml)
Note: wherein, Sau1 staphylococcus aureus ATCC29213；Sau3 staphylococcus aureus CICC26112；MRSA methicillin-resistant staphylococcus aureus；Spn streptococcus pneumoniae；Ssu Streptococcus suis；BHS beta hemolytic streptococcus；Sep staphylococcus epidermidis；Seq adenitis equorum streptococcus；Eco escherichia coli；Pm proteus mirabilis；Mg chicken virus mycoplasma；Ms synovial fluid mycoplasma；Mhy mycoplasma hyopneumoniae；Mpn mycoplasma pneumoniae.
As shown in Table 1, the compound of the present invention has obvious antibacterial activity.
To the G surveyed+Bacterium: staphylococcus aureus to surveying of A6, B6, MRSA, streptococcus pneumoniae, hyopneumoniae streptococcus, staphylococcus epidermidis, enterococcus, the streptococcic antibacterial activity of adenitis equorum are better than control drug sulfapyridine and valnemulin, especially the antibacterial activity of methicillin-resistant staphylococcus aureus (MRSA) are significantly better than control drug valnemulin；What the antibacterial activity of staphylococcus aureus was better than control drug valnemulin has A6, B1, B6, and what the antibacterial activity of streptococcus pneumoniae was better than control drug valnemulin has A1, A6, B2, B3, B6；What the antibacterial activity of epidermis staphylococcus aureus was better than control drug valnemulin has B6, and what hyopneumoniae streptococcus antibacterial activity was better than control drug valnemulin has B4.
G-bacterium to surveying: compound A6, B4, B6 are shown medium antibacterial activity to surveying 2 strain G-bacterium.
Mycoplasma to surveying: the antibacterial activity of surveyed mycoplasma all quite or is better than control drug valnemulin by A3, A6, B1, B6.
Application Example 1
A kind of antibacterial activity pre-mixing agent
By weight by the compound (A6) 1 part of embodiment 12, polyvinylpyrrolidone 1 part, starch 5 parts, is pre-mixing agent according to the method preparation that this area is conventional
Application Example 2
A kind of antibacterial activity injection
By weight by the compound (B6) 1 part of embodiment 16, water for injection 10 parts, is injection according to the method preparation that this area is conventional.
Above-mentioned embodiment is only the preferred embodiment of the present invention, it is impossible to limit the scope of protection of the invention with this, and the change of any unsubstantiality that those skilled in the art does on the basis of the present invention and replacement belong to present invention scope required for protection.
Claims (9)
1. the pleuromutilin derivative of an antibacterial activity with formula I structure or its pharmaceutically and/or veterinarily acceptable salt；
Wherein: R1One in hydrogen atom, amino, hydroxyl, the alkyl of C1-C8, the aryl of C6-C18, the heteroaryl of C3-C18, amidino groups, guanidine radicals, the acyl group of C1-C8 and the substitutive derivative of above-mentioned group；X is the one in the alkoxyl of sulphur atom, oxygen atom, amino, the alkyl of C1-C8, C3-C8.
2. the pleuromutilin derivative of antibacterial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, it is characterised in that: R1One in methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, heptyl, octyl group, ethylamino-, Propylamino, dimethylamino, diethylin, pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, furyl, thienyl, oxazolyl, pyridine radicals, thiazolyl, pyrimidine radicals, pyrazinyl.
3. the pleuromutilin derivative of antibacterial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, it is characterised in that there is below formula (A) or (B) structure:
4. the pleuromutilin derivative of antibacterial activity according to claim 3 or its pharmaceutically and/or veterinarily acceptable salt, it is characterised in that R1 is the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative.
5. the pleuromutilin derivative of antibacterial activity according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, the one in following compounds:
{ 4-[4-(amino-sulfonyl)-(anilino-) methyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-[4-(amino-sulfonyl)-(anilino-) methyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) methyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods.
6. the pleuromutilin derivative of an antibacterial activity as claimed in claim 1 or its pharmaceutically and/or the preparation method of veterinarily acceptable salt, it is characterised in that with formula (a)
After carrying out reduction with formula (b)
There is substitution reaction, obtain product (c)
Product (c) after halogenation with formula (d)
Product (I) is obtained after amination.
7. an antibacterial activity compositions, including the antibacterial activity as described in any one of claim 1-5 pleuromutilin derivative and or its pharmaceutically and/or veterinarily acceptable salt and pharmaceutically acceptable carrier or diluent.
8. antibacterial activity compositions according to claim 7, it is characterised in that: its dosage form is oral agents or injection.
9. antibacterial activity compositions according to claim 7, it is characterized in that: wherein the pleuromutilin derivative of antibacterial activity or its pharmaceutically and/or veterinarily acceptable salt mass percentage content be 0.1%-99.5%, surplus is carrier or diluent.
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| 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 |
| CN114436870B (en) * | 2021-12-21 | 2023-05-30 | 华南农业大学 | Pleuromutilin derivative with amino side chain, and preparation method and application thereof |
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