CN103910664A - Pleuromutilin-sulfanilamide derivative with antibacterial activity as well as preparation method and application thereof - Google Patents
Pleuromutilin-sulfanilamide derivative with antibacterial activity as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a pleuromutilin-sulfanilamide derivative having a structure shown in formula (I) and the antibacterial activity and/or pharmaceutically and/or veterinarily salt, a solvent compound, an optical isomer or a polycrystalline compound thereof as well as a preparation method and application of the derivative (the structure formula is shown in the specification). According to the invention, two compounds differing in antibacterial action mechanisms are connected through a covalent bond, so as to synthesize a new medicine molecule; sulfanilamide medicines are spliced onto a pleuromutilin side chain to generate a new sulfanilamide-pleuromutilin derivative; the new compound disclosed by the invention has a significant inhibiting activity on gram positive bacteria and partial negative bacteria, mycoplasmas and the like, and has a remarkable inhibiting effect on such drug-resistance bacteria as MRSA (Methicillin-resistant Staphylococcus aureus) as well.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, specifically, a kind of anti-microbial activity pleuromutilin-sulphone amide derivative and its preparation method and application.
Background technology
In recent years, antibiotic widespread use, especially at the abuse of livestock breeding industry, causes bacterial drug resistance problem to be on the rise.In world wide, there is methicillin-resistant staphylococcus aureus (methicillin-resistant Staphylococcus aureus, MRSA), penicillin resistance pneumococcus (penicillin-resistant Streptococcus pneunoniae, PRSP), multi-resistant Pseudomonas aeruginosa (multi drug resistant Pseudomonas aeruginosa, and vancomycin-resistant enterococcus (vancomycin-resistant Enterococci MDRPA), VRE), these resistant organisms form grave danger to human health, therefore, find extremely urgent to the effective newtype drug of resistant organism.
In the past in decades, people are on the structural modification of pleuromutilin (Pleuromutilin), make extensive work, find the wonderful woods (Tiamulin such as Thailand, Tiamulin), the serial highly active semisynthetic antibiotics such as valnemulin (Valnemulin), auspicious his wonderful woods (Retapamulin), his wonderful woods (Retapamulin) of its China and Sweden is the pleuromulins microbiotic that first man is used, and is mainly used in the purulence born of the same parents disease that topical therapeutic streptococcus aureus or streptococcus pyogenes infect.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 microbiotic generation crossing drug resistants.
Recently, investigators transfer to sight on the pleuromutilin derivative with unique antibacterial mechanisms gradually, in succession report for work out and have in a large number the new compound of 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., on thioetherification C-14 side chain pleuromutilin basis, there are larger polarity and water miscible purine skeleton in Hirokawa group by introducing, filters out 2 and has in good body and antibacterial activity in vitro and water-soluble and all good new compounds of metabolic stability.In addition, the people of existing many pleuromulins enters clinical study with Perorally administrable antimicrobial medicine, comprises GSK(GlaxoSmithKline PLC) product type of company is SB-565154, SB-742510, the product type of Nabriva company is BC-3205, BC-7013 etc.
Sulfa drugs has long applicating history, their has a broad antifungal spectrum, determined curative effect, easy to use and low price, be only second to antibiotic one large class medicine therefore be still at present, particularly the novel sulfanilamide (SN) of efficient, long-acting, wide spectrum and Trimethoprim synthetic after, make the clinical application of sulfa drugs have new wide future.In pharmaceutical chemistry, amalgamation is to optimize one of important method of lead compound, and object is that two identical or different lead compounds or medicine are linked together through covalent linkage, produces in vivo synergy, adduction, or it is alive to produce new pharmacology.Therefore, sulfonamides compound is spliced on pleuromutilin side chain, can obtains the sulfanilamide (SN)-pleuromutilin derivative with multiple antibacterial effect.
Summary of the invention
For overcoming the defect of prior art, of the present invention be to provide a kind of antibacterial active compounds 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.
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 anti-microbial activity pleuromutilin-sulphone amide derivative 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 the substitutive derivative of heteroaryl, amidino groups, guanidine radicals and above-mentioned group of aryl, the C3-C18 of alkyl, the C6-C30 of hydrogen atom, amino, hydroxyl, C1-C18; X is the one in the alkoxyl group of alkyl, amino, C3-C8 of sulphur atom, Sauerstoffatom, C1-C8.
The substituting group of described substitutive derivative is the one in alkyl, cycloalkyl, amino, Heterocyclylalkyl, nitro, halogen, hydroxyl, carboxyl, alkoxyl group, guanidine radicals, acyl group, aryl, heteroaryl, alkylthio or arylthio alkyl.
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.
Described anti-microbial activity pleuromutilin-sulphone amide derivative or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, have following formula II or (III) structure:
As preferred scheme of the present invention, the X in said structure formula I, (II), (III) is sulphur atom.
As preferred scheme of the present invention, the R1 in said structure formula I, (II), (III) is the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative group.
As preferred scheme of the present invention, R in said structure formula I, (II), (III)
1for hydrogen, 2-thiazolyl, 2-pyridyl, 6-methoxyl group-2-pyrimidyl, 5-methyl-3-isoxazolyl, 4, the one in 6-dimethyl-2-pyrimidyl.
Anti-microbial activity pleuromutilin-sulphone amide derivative of the present invention or its are pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, one in following compounds: 4-[4-(amino-alkylsulfonyl)-(anilino) carbonyl]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods, { 4-{4-[N-(4, 6-dimethyl-2-pyrimidine amido)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods, 4-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful, 4-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-[4-(amino-alkylsulfonyl)-(anilino) carbonyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods.
Another object of the present invention is to provide a kind of preparation method of anti-microbial activity pleuromutilin-sulphone amide derivative.The present invention at synthetic antimicrobial active compound or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds mainly adopts two kinds of methods, is below the method applied in the present invention.
Method one: the antibacterial active compounds that preparation is described or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, with formula (1):
Described compound pass through successively with tolysulfonyl chlorosulfonylation, with formula (2):
Compound substitution reaction, with (3):
Amidate action, the structure of acquisition formula I; Wherein R
1with X be defined group in above-mentioned any one scheme.
In aforesaid method one; the condition of sulfonylation, substitution reaction, amidate action can be that this area can be to realize any condition of the object of the invention; as further instruction, preferred, preparation method of the present invention can be the method comprising the following steps:
A) sulfonylation: the compound of formula (1) and Tosyl chloride are dissolved in the mixing solutions of ethyl acetate and water, under ice bath, add alkali lye in batches, add rear room temperature reaction 30 minutes, be warming up to 30-60 DEG C, vigorous stirring 0.5-6 hour, dilute with water, filters, be washed to neutrality, be dried to obtain product (4);
B) substitution reaction: 4-Thiosalicylic acid or the 3-Thiosalicylic acid of formula (4) product and formula (2) expression are added in the mixing solutions of ethyl acetate and water, under ice bath, add alkali lye, adjust PH extremely at 8-12, return stirring value reacts completely, again successively after concentrating under reduced pressure, hydrochloric acid water dilution, organic solvent extraction, be washed to neutrality, dry, decompression steams solvent corresponding acquisition formula (5) or formula (6) product:
C) amidate action: by step B) compound of products therefrom formula (5) or formula (6) is dissolved in methylene dichloride, adds excessive alkali, under ice bath, drips activator, and low temperature stirs 0.5-2 hour, adds formula (3) compound:
Stirring at room temperature 1-16 hour, filters, and washing is dry, and decompression steams solvent, crosses after silicagel column to such an extent that structural formula is the product of (II) or (III).
Its concrete synthetic route is as follows:
In aforesaid method, sulfonylation Tosyl chloride used is replaceable is its acid anhydrides; Alkali used is mineral alkali: Na
2cO
3, K
2cO
3, NaOH, KOH or organic bases: the one in pyridine, triethylamine; One or more in the ether solvents such as the low boiling point solvents such as the replaceable one-tenth toluene of solvent for use ethyl acetate, butyl formate or ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane are with arbitrarily than mixing; Reaction process condition is: feed temperature is-10-10 DEG C, taking lower than 5 DEG C as good; Temperature of reaction is 30-80 DEG C; Wherein, as preferred, temperature of reaction is 60 DEG C.
In aforesaid method, substitution reaction alkali used is mineral alkali: NaOH, KOH, or organic bases: the one in pyridine, triethylamine; The replaceable formic acid butyl ester of solvent for use ethyl acetate, methylene dichloride, trichloromethane, 1, the lower boiling halohydrocarbon such as 2-ethylene dichloride, or one or more in the ether solvents such as ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether are with arbitrarily than mixing; Reaction process condition is: adding alkali equivalent is 0.5-5, taking 1.5 as good; Be advisable add-subtract time with 0.5-2 hour, and feed temperature is-10-15 DEG C, taking lower than 0 DEG C as good; Temperature of reaction is 35-90 DEG C.Wherein as preferred, 55 DEG C of temperature of reaction are good.
In aforesaid method, one or more in amidate action activator available chlorine benzyl formate used, Vinyl chloroformate, chloroformic acid isopropyl ester, isobutyl chlorocarbonate, EDC, DCC, HOBT etc. mix and use; Alkali used is mineral alkali: Na
2cO
3, K
2cO
3, one in NaOH, KOH, or organic bases: the one in pyridine, N-methylmorpholine, morpholine, triethylamine; Solvent for use methyl tertiary butyl ether is replaceable is ethyl acetate or butyl formate, methylene dichloride, trichloromethane, 1, one in the ether solvent solvents such as the lower boiling halohydrocarbon such as 2-ethylene dichloride or ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether; Reaction process condition: feed temperature is-30-0 DEG C, taking lower than-10 DEG C as good; Temperature of reaction is-25-40 DEG C, taking room temperature as good; Preferred mol ratio is formula (5) or formula (6) compound: activator=1:(1～5).
Method two: the antibacterial active compounds that preparation is described or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, comprise the following steps:
A) with formula (7):
After reduction reaction with formula (3):
Amidate action obtains formula (8):
B) formula (1):
After tolylsulfonyl chlorosulfonylation, obtain the compound of structure formula I with formula (8) generation substitution reaction; Wherein R
1with X be defined group in above-mentioned any one scheme.
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 further instruction, preferred, preparation method of the present invention can be the method comprising the following steps:
1) reduction reaction:
What formula (7) was represented dissolves in toluene chlorosulfonyl phenylformic acid or m-chloro sulfonyl benzoic acid, adds appropriate triethylamine, at 10 DEG C, and N
2protection adds reductive agent in batches, adds post-heating and is warming up to 40-100 DEG C, stir 1-5 hour, reaction is finished, and adds appropriate mixture of ice and water, stir 15 minutes, separatory, abandons water, alkali lye extraction 3 times for organic phase, merge water, adjust pH value to 1-3 with dilute hydrochloric acid, then use dichloromethane extraction, dry revolving steams solvent, and alcohol recrystallization obtains 4-Thiosalicylic acid formula (9) or 3-Thiosalicylic acid formula (10);
2) amidate action:
The compound of formula (9) or formula (10) is dissolved in methylene dichloride, pyridine is appropriate, ice bath is cooled to 0 DEG C, slowly drip the dichloromethane solution of activator, add the rear room temperature that is naturally warming up to, continue to stir 6-12 hour, reaction is finished, decompression steams solvent, adding methylene dichloride continues to be concentrated into the white cigarette of thing and emits, resistates dissolves with methylene dichloride, then add the compound of formula (3), tetrahydrofuran (THF) is appropriate, the alkali of catalytic amount, add rear stirring at room temperature 12-18 hour, reaction is finished, revolve and steam solvent, in residuum, add appropriate water, dilute hydrochloric acid adjusts pH value to 3-5, there are a large amount of Precipitations, filter, saturated common salt is washed to neutrality, dry, cross silicagel column and obtain formula (11) or formula (12) product:
3) substitution reaction: by step 2) formula (11) or formula (12) product be dissolved in methyl tertiary butyl ether, add formula (4) product, under low temperature (0 DEG C), slowly drip alkali lye, in 1-2 hour, add, be heated to backflow, stir 1-12 hour, reaction completes, and decompression steams solvent, pours in appropriate frozen water, filter, washing, dry, cross silicagel column and obtain product formula II or formula III.Its concrete synthetic route is as follows:
In aforesaid method, reduction reaction triethylamine used is replaceable is mineral alkali K
2cO
3, NaOH, KOH, or organic bases pyridine, piperidines, dicyclohexyl amine, or mineral acid H
2sO
4, one in HCl; The replaceable one-tenth methyl alcohol of solvent for use toluene, ethanol, water isopolarity solvent, or ethyl acetate, methylene dichloride, trichloromethane, 1, one or more mixing in the ether solvents such as lower boiling halohydrocarbon, ether, Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether such as 2-ethylene dichloride; Reductive agent used is triphenylphosphine, LiAlH4, zinc powder, NaBH
4in one.Reaction process condition is: 10 DEG C to 100 DEG C; Preferred mol ratio is chlorosulfonyl phenylformic acid: reductive agent=1:(1～3).
In aforesaid method, amidate action activator used can be one or more in oxalyl chloride, sulfur oxychloride, Vinyl chloroformate, chloroformic acid benzyl ester; As preferably taking oxalyl chloride as good; Alkali pyridine used is replaceable is mineral alkali K
2cO
3, NaOH, KOH, or one in organic bases triethylamine, piperidines, N-methylmorpholine, DMAP etc.; The replaceable one-tenth ethyl acetate of solvent for use methylene dichloride, benzene, toluene, trichloromethane, 1, one or more mixing in the ether solvents such as lower boiling halohydrocarbon, ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether such as 2-ethylene dichloride; Reaction process condition is: feed temperature is-10 DEG C-15 DEG C, and temperature of reaction is 15-60 DEG C, taking room temperature as good; Adding alkali equivalent is 0.5～5, taking 2.5 as good; Preferred mol ratio is formula (9) or formula (10): activator=1:(1～2.5), formula (9) or formula (10): compound (3)=1:(0.9～1.5).
In aforesaid method, substitution reaction alkali used can be mineral alkali Na
2cO
3, K
2cO
3, NaOH, KOH, or one in organic bases pyridine, morpholine, triethylamine, DMAP, sodium ethylate; Solvent for use methyl tertiary butyl ether is replaceable is ethyl acetate, butyl formate; Methylene dichloride, trichloromethane, 1, the lower boiling halohydrocarbon such as 2-ethylene dichloride, or one or more mixing in the ether solvent such as ether, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, methyl tertiary butyl ether; Reaction process condition is: feed temperature is 0～30 DEG C, taking lower than 0 DEG C as good; Temperature of reaction is 15 DEG C～90 DEG C; Preferred mol ratio is formula (11) or formula (12): compound (2)=1:(1～1.3).
A kind of anti-microbial activity composition, comprise the anti-microbial activity pleuromutilin-sulphone amide derivative described in such scheme and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and pharmaceutically acceptable carrier or thinner.
In the present invention, the formulation of described anti-microbial activity composition is oral preparation or injection.
In anti-microbial activity composition of the present invention, anti-microbial activity pleuromutilin-sulphone amide derivative 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, it is active that the new compound that the present invention obtains has significant inhibition to gram-positive microorganism and part negative bacterium, mycoplasma etc., the resistant organisms such as MRSA are also had to obvious restraining effect, can effectively widen 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 limiting the scope of the invention.In all embodiment, the fusing point of compound is measured with capillary melting point determination instrument,
1hNMR is by Varian AM-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 the GF254 type of producing.
Embodiment 1: tosic acid ester group-ethanoyl-14-oxygen-wonderful woods synthetic
By the pleuromutilin of 11.5g, the Tosyl chloride of 5.8g 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 15.6g white solid.Yield is 96%, fusing point 116-118 DEG C, MS-ESI (M+1): 532.9.Its proton nmr spectra result is as follows:
1H?NMR(DMSO)δ:7.79(d,2H)，7.34(d,2H)，6.41(dd,1H)，5.67(d,1H)，5.25(d,1H)，5.31(d,1H)，4.48(s,2H)，3.33～3.37(m,1H)，2.41(s,3H)，2.02～2.33(m,4H)，1.73～1.76(m,1H)，1.61～1.68(m,2H)，1.60(s,3H)，1.43～1.47(m,5H)，1.38～1.41(m,2H)，1.27(s,3H)，0.89(d,3H)，0.63(d,3H)。
Embodiment 2:3-sulfydryl-benzoic synthetic
22.3g m-chloro sulfonyl benzoic acid is dissolved in 100ml toluene, add the triethylamine of 3.2ml, ice bath is cooled to 10 DEG C, N
2protect, add the PPh of 73g in batches
3, add post-heating and be warming up to 80 DEG C, to stir 4.5 hours, reaction is finished, and pours the mixture of ice and water of 100ml into, stirs 15 minutes, and separatory, abandons water, the Na of 1mol/L for organic phase
2cO
3solution extraction 3 times, merges water, adjusts pH value to 2 with dilute hydrochloric acid, then uses dichloromethane extraction, anhydrous Mg
2sO
4dry, revolve and steam solvent, ethyl alcohol recrystallization obtains 14.5g white solid.Yield 95%, fusing point 116-118 DEG C, MS-ESI (M+1): 155.3.Its proton nmr spectra result is as follows:
1HNMR(DMSO)δ:12.85(s,1H)，8.09(s,1H)，7.89(d,1H)，7.77(d,1H)，7.56(t,1H)，5.76(s,1H)。
Embodiment 3:(4-carboxyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods synthetic
The 4-Thiosalicylic acid of 36g, joins in the methyl alcohol of 400ml, is cooled to 0 DEG C, adds 46.5g formula (4) compound under stirring, slowly drips 20mlKOH solution (10mol/L), and the complete room temperature that is warming up to continues to stir and spends the night.React complete, decompression steams most of solvent, and doubly, dilute hydrochloric acid adjusts pH value to 3-4 to dilute with water 5-10, Precipitation, filters, and is washed to neutrality, a small amount of ethanol is washed to obtain white solid, ethanol: acetone volume ratio is=and the mixing solutions recrystallization of 8:2, obtain solid 80.5g.Yield 89%, fusing point 219-221 DEG C, MS-ESI (M+1): 514.8.Its proton nmr spectra result is as follows:
1HNMR(DMSO)δ:12.90(s,1H)，7.80(d,2H)，7.40(d,2H)，5.99-6.04(m,1H)，5.50(d,1H),4.92-4.95(m,2H)，4.49(d,1H)，3.91-3.99(dd,2H)，3.37(m,1H),2.36(s,1H)，2.13-2.22(m,1H)，1.95-2.11(m,4H)，1.66-1.56(d,2H)，1.45-1.49(m,1H)，1.35-1.42(m,1H)，1.32(s,3H)，1.29-1.06(m,3H)，0.96(s,3H)，0.78(s,3H)，0.56(d,3H)。
Embodiment 4:2-[4-(to sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine synthetic
15.8g is dissolved in to the CH of 150ml to Thiosalicylic acid
2cl
2in, add 4.6ml pyridine, under ice bath, slowly drip the CH of 9.5ml oxalyl chloride
2cl
2solution, is warming up to room temperature after adding, and continues to stir 12 hours, reacts complete (adopting thin-layer chromatography identification terminal), and decompression steams solvent, adds CH
2cl
2continue to be concentrated into without white cigarette and emit, resistates 100mlCH
2cl
2dissolve, then add sulfamethazine 28.5g, THF80ml, triethylamine 6.5ml, add rear stirring at room temperature 12 hours, after having reacted, revolve and steam solvent, in residuum, add the water of 50ml, with dilute hydrochloric acid tune pH value to 3, filter, saturated common salt washing, is washed to neutrality, anhydrous Na
2sO
4dry, with sherwood oil: ethyl acetate=8:2(volume ratio) silica gel column chromatography separate, obtain white solid 27.5g, called after 11a.Yield 65%, fusing point 223-225 DEG C, MS-ESI (M+1): 415.1.Its proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.76(s,1H)，10.57(s,1H)，7.96(t,4H)，7.90(d,2H)，7.70(d,2H)，6.76(s,1H)，2.25(s,6H)。
Synthesizing of embodiment 5:4-(to sulfydryl benzoyl amino)-N-(6-methoxyl group-2-pyrimidyl) benzsulfamide
Method is with embodiment 4, and wherein sulphamethazine substitutes with sulfanilamide (SN)-6-methoxy pyrimidine of equimolar amount, product called after (11b).Yield 90%, fusing point 217-219 DEG C, MS-ESI (M+1): 417.3; Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:12.03(s,1H)，10.61(s,1H)，8.40(s,1H)，7.88-7.95(m,6H)，7.70(d,2H)，6.32(s,1H)，3.81(d,3H)。
Synthesizing of embodiment 6:4-(to sulfydryl benzoyl amino)-N-(2-pyridyl) benzsulfamide
10.2g is dissolved in Thiosalicylic acid in the toluene of 100ml, add 1.8ml triethylamine, under room temperature, slowly drip 11.8g sulfur oxychloride, after adding, be warming up to 60 DEG C and continue to stir 2 hours, react complete (thin-layer chromatography identification terminal), decompression steams solvent, adds toluene and continues to be concentrated into without white cigarette and emit, resistates 100mlCH
2cl
2dissolve, filter, in filtrate, add sulfapyridine 16.5g, THF20ml, DMAP8.6g, add rear stirring at room temperature 12 hours, reaction Bi Xuan steams solvent, adds the water of 30ml in residuum, with dilute hydrochloric acid tune pH value to 3, filter, saturated common salt washing, is washed to neutrality, anhydrous Na
2sO
4dry, with sherwood oil: ethyl acetate=7:3(volume ratio) silica gel column chromatography separates, and obtains white solid 13.2g, called after (11c).Yield 52%, fusing point 205-207 DEG C, MS-ESI (M+1): 386.4.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.85(s,1H)，10.55(s,1H，8.01(s,1H)，7.83-7.94(m,4H)，7.70(d,2H),7.42(d,1H)，7.14(d,1H)，6.86(t,1H)，5.82(s,1H)。
Synthesizing of embodiment 7:4-(to sulfydryl benzoyl amino)-N-(5-methyl-3-isoxazolyl) benzsulfamide
Method is with embodiment 4, and wherein sulfapyridine substitutes with sulfanilamide (SN)-5-methyl isoxzzole of equimolar amount, product called after (11d).Yield 47%, fusing point 214-216 DEG C, MS-ESI (M+1): 390.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.39(s,1H)，10.66(s,1H)，7.98(d,4H)，7.86(d,2H)，7.73(d,2H)，6.16(s,1H)，2.30(s,3H)。
Synthesizing of embodiment 8:4-(to sulfydryl benzoyl amino)-N-(2-thiazolyl) benzsulfamide
Method is with embodiment 4, and wherein sulfapyridine substitutes with the sulfanilamide (SN)-thiazole of equimolar amount, product called after (11e).Yield 51%, fusing point 195-197 DEG C, MS-ESI (M+1): 392.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.39(s,1H)，10.66(s,1H)，7.98(d,4H)，7.86(d,2H)，7.73(d,2H)，6.16(s,1H)，2.30(s,3H)。
Embodiment 9:{4-[4-(amino-alkylsulfonyl)-(anilino) carbonyl]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
By the product of 5g embodiment 3, dissolve in the methyl tertiary butyl ether of 100ml, add N-methylmorpholine 1.5g, the acetone soln 20ml of 1.9g sulfanilamide (SN), be cooled to 0 DEG C, slowly drip the THF solution 10ml of 3.5gEDC, after adding, be slowly warming up to 30 DEG C, stirring is spent the night, react complete, filter, the dilution of 50ml water, separatory, organic phase is washed with the HCl solution of a small amount of 1mol/L successively, and saturated common salt washing is dry, boil off methyl tertiary butyl ether, separate with sherwood oil: ethyl acetate=3:7～1:1 silica gel column chromatography, obtain 5.7g white solid, called after II-1.Yield 88.9%, fusing point 209-211 DEG C, MS-ESI (M+1): 669.4.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.34(s,1H)，10.24(s,1H)，7.99(d,2H)，7.90(d,2H)，7.83(d,2H)，7.51(d,2H)，6.04-6.09(dd,1H)，5.53(d,1H)，4.98-5.03(m,2H)，4.49(d,1H)，3.90-4.01(dd,2H)，2.35(s,1H)，2.12-2.18(m,1H)，1.95-2.06(m,3H)，1.55-1.65(m,2H)，1.40-1.45(m,1H)，1.35-1.41(m,1H)，1.32(s,3H)，1.12-1.25(m,3H)，0.99(s,3H)，0.80(d,3H)，0.59(d,3H)。
Embodiment 10:{4-{4-[N-(4,6-dimethyl-2-pyrimidyl)-sulfoamido]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Employing method 1 is synthetic: the product 5g of embodiment 4, be dissolved in the ethyl acetate of 50ml, add triethylamine 5ml, be cooled to-15 DEG C, slowly drip the ethyl acetate solution 30ml of 1g Vinyl chloroformate, after adding, slowly be warming up to-5-0 DEG C, react 45 minutes, add again the acetone soln 20ml of 5.6g sulphamethazine, be warming up to 55 DEG C, react 4 hours, react complete (thin-layer chromatography identification terminal), filter, organic phase is used successively, the HCl solution of 1mol/L is washed, saturated common salt washing, dry, boil off ethyl acetate, separate with sherwood oil: ethyl acetate=3:7～1:1 silica gel column chromatography, obtain 8.7g white solid, called after II-2.Yield 90.2%, fusing point 244.5-246 DEG C, MS-ESI (M+1): 775.4.
Employing method 2 is synthetic: product 2-[4-(to sulfydryl the Benzamido)-benzene sulfonamido of embodiment 3]-4,6-dimethyl pyrimidine 15g's, join in the acetic ester of 100ml and the water of 20ml, be cooled to 5-10 DEG C, under stirring, add 20.8g formula (4) compound, tetra-tert ammonium chloride 1.5g, then slowly drips 28mlNaOH solution (10mol/L), dropwise and be warming up to room temperature, continue to stir and spend the night.Reaction is finished, and decompression steams organic solvent, imports in 200ml frozen water and dilutes, and adjusts pH value to 3-4 with dilute hydrochloric acid, and Precipitation, filters, and is washed to neutrality, and a small amount of ethanol is washed to obtain white solid.With sherwood oil: ethyl acetate=3:7(volume ratio) silica gel column chromatography separates, and obtains white solid 25.4g, called after II-2.Yield 86%, fusing point 244.5-246 DEG C, MS-ESI (M+1): 775.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.82(s,1H)，10.50(s,1H)，7.98(d,2H)，7.89-7.94(m,4H)，7.47(d,2H)，6.76(s,1H)，6.01-6.08(dd,1H)，5.53(d,1H)，4.99(d,1H)，4.94(s,1H)，4.53(s,1H)，3.88-4.01(dd,2H)，2.39(s,1H)，2.25(s,6H)，2.14-2.18(m,1H)，1.94-2.07(m,3H)，1.55-1.62(m,2H)，1.35-1.45(m,2H)，1.33(s,3H)，1.20-1.25(t,1H)，1.14-1.20(m,2H)，0.99(s,3H)，0.80(d,3H)，0.60(d,3H)。
Embodiment 11:{4-{4-[N-(2-pyridyl)-sulfoamido]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
By the product of 10g embodiment 4, dissolve in the methyl tertiary butyl ether of 150ml, add N-methylmorpholine 2.5g, the acetone soln 20ml of 4.5g sulfapyridine, be cooled to 0 DEG C, slowly drip the THF solution 50ml of 4.7gEDC, after adding, slowly be warming up to 30 DEG C, stirring is spent the night, react complete, filter, the dilution of 100ml water, separatory, organic phase is washed with the HCl solution of a small amount of 1mol/L successively, saturated common salt washing, dry, boil off methyl tertiary butyl ether, separate with sherwood oil: ethyl acetate=3:7～1:1 silica gel column chromatography, obtain 12.7g white solid, called after II-3.Yield 87%, fusing point 251-252 DEG C, MS-ESI (M+1): 745.8.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.83(s,1H)，10.47(s,1H)，8.02(s,1H)，7.89-7.93(dd,4H),7.87-(d,2H)，7.71(t,1H)，7.46(d,2H)，7.16(d,1H)，6.87(t,1H)，6.03-6.08(dd,1H)，5.52(d,1H)，4.96-4.98(m,2H)，4.5(s,1H)，3.94-4.03(dd,2H)，2.36(s,1H)，2.15-2.20(m,1H)，1.98-2.04(m,3H)，1.57-1.65(m,2H)，1.44-1.48(m,1H)，1.36-1.41(m,1H)，1.33(s,3H)，1.16-1.28(m,3H)，1.00(s,3H)，0.80(d,3H)，0.59(d,3H)。
Embodiment 12:{4-{4-[N-(6-methoxyl group-2-pyrimidyl)-sulfoamido]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with the method 1 in embodiment 10, adopts the product of the product alternate embodiment 4 of the embodiment 5 of equimolar amount, the white solid obtaining name II-4.Yield is respectively 87%, 96.5%, fusing point 260-262 DEG C, MS-ESI (M+1): 777.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.89(s,1H),10.54(s,1H),8.40(s,1H),7.95(d,2H),7.89-7.91(m,4H),7.45(d,2H),6.34(s,1H),6.02-6.07(dd,1H),5.51(d,1H),4.95-4.98(t,2H),4.52(d,1H),3.93-4.0(dd,2H),3.83(s,3H),2.35(s,1H),2.14-2.19(m,1H),1.98-2.08(m,3H),1.56-1.64(m,2H),1.42-1.47(m,1H),1.35-1.39(m,1H),1.32(s,3H),1.15-1.25(m,3H),0.98(s,3H),0.78(d,3H),0.58(d,3H)。
Embodiment 13:{4-{4-[N-(5-methyl-3-isoxazolyl)-sulfoamido]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
The product 10g of embodiment 4 is dissolved in the THF of 120ml, adds pyridine 40ml, is cooled to 10 DEG C, slowly drips the THF solution 30ml of 3.0g Vinyl chloroformate, after adding, is slowly warming up to room temperature DEG C, stirs 2 hours, filters, for subsequent use.The sulfamethoxazole of 5.6g is added in 50ml pyridine, be cooled to 10 DEG C, then the reaction solution of previous step is dripped wherein, be warming up to 30 DEG C and stir 5 hours, react complete, filter, revolve and steam solvent, in residuum, add 50ml water and 100ml ethyl acetate, separatory, organic phase saturated common salt is washed to neutrality, anhydrous Na
2sO
4dry, boil off ethyl acetate, silica gel column chromatography separates, and obtains 13g white solid called after II-5.Yield 92%, fusing point 243.5-245 DEG C, MS-ESI (M+1): 750.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.34(s,1H),10.54(s,1H),7.97(d,2H),7.90(d,2H),7.85(d,2H),7.47(d,2H),6.14(s,1H),6.04-6.09(dd,1H),5.53(d,1H),4.96-5.00(m,2H),4.49(d,1H),3.94-4.01(dd,2H),2.37(s,1H),2.30(s,3H),2.15-2.20(m,1H),1.98-2.09(m,3H),1.57-1.66(m,2H),1.44-1.48(m,1H),1.37-1.41(m,1H),1.34(s,3H),1.16-1.28(m,3H),1.00(s,3H),0.80(d,3H),0.59(d,3H)。
Embodiment 14:{4-{4-[N-(2-thiazole amino)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods
Method is with method 2 in embodiment 10, adopt 4-(to sulfydryl benzoyl amino)-N-(2-thiazolyl) benzsulfamide of equimolar amount to substitute 2-[4-(to sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine, the white solid obtaining name II-6.Its yield 90.4%, fusing point 236.5-239 DEG C, MS-ESI (M+1): 752.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.54(s,1H)，10.64(s,1H)，7.98(d,2H)，7.92(d,2H)，7.85(d,2H)，7.50(d,2H)，6.62(d,1H)6.27(d,1H)，6.03-6.08(dd,1H)，5.54(d,1H)，4.97-5.01(m,2H)，4.48(d,1H)，3.92-4.00(dd,2H)，2.36(s,1H)，2.14-2.19(m,1H)，1.97-2.07(m,3H)，1.56-1.65(m,2H)，1.43-1.47(m,1H)，1.36-1.40(m,1H)，1.33(s,3H)，1.15-1.27(m,3H)，0.98(s,3H)，0.81(d,3H)，0.58(d,3H)。
Embodiment 15:(3-carboxyl-benzene sulfydryl)-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 3, adopts the 3-Thiosalicylic acid of equimolar amount to substitute 4-Thiosalicylic acid.Yield 95%, fusing point 199-201 DEG C, MS-ESI (M+1): 515.1.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:12.64(s,1H)，7.28(s,2H)，7.22-7.26(dd,1H)，7.21(d,1H)，7.15(d,1H)，6.02-6.07(m,1H)，5.50(d,1H)，4.95-4.97(m,2H)，4.46(d,2H)，3.75-3.84(dd,2H)，2.37(s,1H)，2.15-2.20(m,1H)，1.97-2.09(m,4H)，1.57-1.66(m,2H)，1.44-1.48(m,1H)，1.35-1.42(m,1H)，1.32(s,3H)，1.13-1.28(m,3H)，0.99(s,3H)，0.81(s,3H)，0.57(d,3H)。
Embodiment 16:2-[4-(a sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine synthetic
Method is with embodiment 4, and between employing equimolar amount, Thiosalicylic acid substitutes Thiosalicylic acid, yield 58%, fusing point 209-211 DEG C, MS-ESI (M+1): 415.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.84(s,1H)，10.66(s,1H)，8.11(s,1H)，7.98(d,2H)，7.91(d,2H)，7.88(d,1H)，7.78(d,1H)，7.58(t,1H)，6.76(s,1H)，2.26(s,6H)。
Synthesizing of embodiment 17:4-(a sulfydryl benzoyl amino)-N-(2-pyridyl) benzsulfamide
Method is with embodiment 6, and between employing equimolar amount, Thiosalicylic acid substitutes Thiosalicylic acid.Yield 62%, fusing point 185-187 DEG C, MS-ESI (M+1): 386.0.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.54(s,1H)，10.66(s,1H)，8.15(s,1H)，7.75(d,2H)，7.48(d,2H)，7.26(t,3H)，7.14(d,2H)，7.07(d,1H)，6.56(d,1H)，5.80(s,1H)。
Synthesizing of embodiment 18:4-(a sulfydryl benzoyl amino)-N-(6-methoxyl group-2-pyrimidyl) benzsulfamide
Method is with embodiment 5, and between employing equimolar amount, Thiosalicylic acid substitutes Thiosalicylic acid.Yield 41%, fusing point 202-204 DEG C, MS-ESI (M+1): 417.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.73(s,1H)，10.54(s,1H)，8.31(s,1H)，7.88-7.95(m,5H)，7.72(d,1H),7.58(s,1H)，7.44(t,1H)，6.31(s,1H)，3.78(d,3H)。
Synthesizing of embodiment 19:4-(a sulfydryl benzoyl amino)-N-(5-methyl-3-isoxazolyl) benzsulfamide
Method is with embodiment 7, and between employing equimolar amount, Thiosalicylic acid substitutes Thiosalicylic acid.Yield 31.5%, fusing point 179-181 DEG C, MS-ESI (M+1): 389.9.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.37(s,1H)，10.64(s,1H),7.97(d,2H)，7.87(d,3H)，7.67(d,1H)，7.53(d,1H)，7.41(t,1H)，6.14(s,1H)，5.78(s,1H),2.29(s,3H)。
Synthesizing of embodiment 20:4-(a sulfydryl benzoyl amino)-N-(2-thiazolyl) benzsulfamide
Method is with embodiment 8, and between employing equimolar amount, Thiosalicylic acid substitutes Thiosalicylic acid.Yield 55.7%, fusing point 170-172 DEG C, MS-ESI (M+1): 392.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.25(s,1H)，10.54(s,1H)，7.98(d,2H)，7.86(d,3H)，7.66(d,1H)，7.51(d,1H)，7.43(t,1H)，6.89(s,1H)，6.27(s,1H)。
Embodiment 21:{3-[4-(amino-alkylsulfonyl)-(anilino) carbonyl]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods is synthetic
Method, with embodiment 9, adopts the product of the product alternate embodiment 3 of equimolar embodiment 15, obtains white solid called after III-1, yield 85%, fusing point 188-190 DEG C, MS-ESI (M+1): 669.3.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.32(s,1H),10.56(s,1H),7.90(d,2H),7.75(d,1H),7.59(d,1H),7.46(t,1H),7.36(s,2H),7.25-7.29(dd,1H),6.75(s,1H),6.01-6.05(dd,1H),5.51(d,1H),4.92-4.94(dd,1H),4.90(s,1H),4.49(s,1H),3.75-3.88(dd,2H),2.35(s,1H),2.27(s,6H),2.15-2.20(m,1H),1.96-2.09(m,3H),1.54-1.64(m,2H),1.32-1.49(m,2H),1.31(s,3H),1.20-1.25(t,1H),1.12-1.19(m,2H),0.98(s,3H),0.76(d,3H),0.56(d,3H)。
Embodiment 22:{3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 10, adopts the product of the product alternate embodiment 4 of the embodiment 16 of equimolar amount, obtains white solid called after III-2.Yield is respectively 75.9%, 85%, fusing point 218-220 DEG C, MS-ESI (M+1): 775.2.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.56(s,1H),10.55(s,1H),7.93-7.99(m,5H),7.75(d,1H),7.59(d,1H),7.47(t,1H),6.76(s,1H),5.97-6.04(dd,1H),5.51(d,1H),4.89-4.92(dd,2H),4.5(s,1H),3.96-3.89(dd,2H),2.34(s,1H),2.26(s,6H),2.14-2.19(m,1H),1.94-2.08(m,3H),1.56-1.63(m,2H),1.31-1.46(m,2H),1.29(s,3H),1.23-1.25(t,1H),1.12-1.20(m,2H),0.94(s,3H),0.78(d,3H),0.57(d,3H)。
Embodiment 23:{3-{4-[N-(2-pyridine amido)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 11, adopts the product alternate embodiment 6 of the embodiment 17 of equimolar amount, obtains white solid called after III-3.Yield 77%, fusing point 212-214 DEG C, MS-ESI (M+1): 746.3, ultimate analysis: C40H47N3O7S2, calculated value (%) C64.45, H6.35, O15.02, measured value (%) C64.26, H6.71, O14.98.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.72(s,1H),10.50(s,1H),8.03(s,1H),7.99-7.93(m,5H),7.77(d,1H),7.69(d,1H),7.58(d,1H),7.46(t,1H),7.15(d,1H),6.88(t,1H),6.01-6.06(dd,1H),5.50(d,1H),4.94-4.97(m,2H),4.51(s,1H),3.94-4.02(dd,2H),2.37(s,1H),2.14-2.18(m,1H),1.97-2.03(m,3H),1.55-1.64(m,2H),1.43-1.46(m,1H),1.37-1.41(m,1H),1.34(s,3H),1.15-1.24(m,3H),0.98.00(s,3H),0.76(d,3H),0.57(d,3H)。
Embodiment 24:{3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 10, adopts the product alternate embodiment 6 of the embodiment 17 of equimolar amount, obtains white solid called after III-4, and yield is respectively 80%, 92%, fusing point 220-222.5 DEG C, MS-ESI (M+1): 777.0.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.85(s,1H)，10.60(s,1H)，8.42(s,1H)，7.89-7.97(m,5H)，7.75(d,1H)，7.60(s,1H)，7.47(t,1H)，6.34(s,1H)，5.96-6.03(dd,1H)，5.50(d,1H)，4.88-4.92(t,2H)，4.50(d,1H)，3.92-4.01(dd,2H)，3.93(s,3H)，2.35(s,1H)，2.143-2.18(m,1H)，1.97-2.07(m,3H)，1.55-1.65(m,2H)，1.41-1.48(m,1H)，1.34-1.38(m,1H)，1.29(s,3H)，1.15-1.23(m,3H)，0.95(s,3H)，0.79(d,3H)，0.55(d,3H)。
Embodiment 25:{3-{4-[N-(5-methyl-3-isoxzzole amido)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 13, adopts the product alternate embodiment 7 of the embodiment 19 of equimolar amount, obtains white solid called after III-5.Yield 71.8%, fusing point 212-125 DEG C, MS-ESI (M+1): 750.5.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.40(s,1H)，10.62(s,1H)，7.98(d,2H)，7.90(s,1H)，7.86(d,2H)，7.75(d,1H)，7.60(d,1H)，7.48(t,1H)，6.15(s,1H)，5.97-6.05(dd,1H)，5.49(d,1H)，4.88-4.93(dd,2H)，4.50(d,1H)，4.49(s,1H)，3.93-3.96(dd,2H)，2.36(s,1H)，2.30(s,3H)，2.12-2.19(m,1H)，1.95-2.08(m,3H)，1.53-1.63(m,2H)，1.31-1.45(m,2H)，1.29(s,3H)，1.20-1.24(t,1H)，1.11-1.18(m,2H)，0.94(s,3H)，0.77(d,3H)，0.56(d,3H)。
Embodiment 26{3-{4-[N-(2-thiazole amino)-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods synthetic
Method, with embodiment 14, adopts the product alternate embodiment 8 of the embodiment 14 of equimolar amount, obtains white solid called after III-6.Yield 79.5%, fusing point 198.8-202 DEG C, MS-ESI (M+1): 752.1, ultimate analysis: C38H45N3O7S3, calculated value (%) C60.75, H6.03, O14.90, measured value (%) C60.16, H6.33, O14.96.Proton nmr spectra result is as follows:
1HNMR(DMSO)δ:11.72(s,1H)，10.60(s,1H)，7.99(d,2H)，7.93(d,1H)，7.85(d,2H)，7.76(d,1H)，7.61(d,1H)，7.50(d,1H)，6.60(d,1H)，6.33(d,1H)，5.98-6.05(dd,1H)，5.52(d,1H)，4.91-4.98(m,2H)，4.48(d,1H)，3.92-3.98(dd,2H)，2.37(s,1H)，2.17-2.21(m,1H)，1.96-2.05(m,3H)，1.44-1.64(m,3H)，1.36-1.40(m,1H)，1.32(s,3H)，1.15-1.25(m,3H)，0.97(s,3H)，0.79(d,3H)，0.55(d,3H)。
The antibacterial activity in vitro research of part target compound of the present invention is as follows:
1. test method: adopt document (Chen Xiushu, slaughter Chung great waves etc., the evaluation of micro-broth dilution method MIC, Chinese journal of medical examination, 1994,2:95-98) minimum inhibitory concentration (MIC) of micro-meat soup doubling dilution to strain subject of report 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 18 strain laboratory standard bacterial strains (comprise that 9 strains are gram-positive microorganism (G
+), 4 strain Gram-negative bacteria (G
-), 5 strain mycoplasmas).Streptococcus aureus CMCC26003(Staphylococcus aureus), 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), enterococcus faecalis CICC10396(Enterococcus faecalis), staphylococcus epidermidis 26069(Staphylococcus epidermidis), strangles suis CVCC556(Strepococcus equinus), intestinal bacteria ATCC25922(Escherichia coli), Proteus mirabilis CMCC49003(Proteus mirabilis), Pseudomonas aeruginosa ATCC15442 (Pseudomonas aeruginosa), Salmonella enteritidis CICC21482(Salmonella enteritidis), 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: Sau1 golden staphylococci CMCC26003; Sau2 streptococcus aureus ATCC29213; Sau3 streptococcus aureus CICC26112; MRSA methicillin-resistant staphylococcus aureus; Spn streptococcus pneumoniae; Ssu swine streptococcus; BHS beta hemolytic streptococcus; Efa enterococcus faecalis; Sep staphylococcus epidermidis; Seq strangles suis; Eco intestinal bacteria; Pm Proteus mirabilis; Pa Pseudomonas aeruginosa; Sae Salmonella enteritidis; 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: streptococcus aureus, MRSA, streptococcus pneumoniae, hyopneumoniae suis, staphylococcus epidermidis, faecalis, the streptococcic anti-microbial activity of strangles that II-3, III-3 pair are surveyed are all better than control drug sulfapyridine and valnemulin, especially the anti-microbial activity of methicillin-resistant staphylococcus aureus (MRSA) are significantly better than to control drug valnemulin; What the anti-microbial activity of streptococcus aureus was better than to control drug valnemulin has II-6, III-6, and what the anti-microbial activity of streptococcus pneumoniae was better than to control drug valnemulin has II-3, III-2, III-3, III-6; What the anti-microbial activity of epidermis streptococcus aureus was better than to control drug valnemulin has II-3, III-6, and what hyopneumoniae suis anti-microbial activity was better than to control drug valnemulin has III-3.
G-bacterium to surveyed: the compound ii-6 pair 4 strain G-bacterium of surveying all show medium anti-microbial activity, compound ii-3, except slightly poor to colibacillary anti-microbial activity, surveyed 3 strain G-bacterium to other and are all shown medium anti-microbial activity.
Mycoplasma to surveyed: the anti-microbial activity of II-3, II-6, III-3, the III-6 pair mycoplasma of surveying all quite or be better than control drug valnemulin.
Application Example 1
Antibacterial active compounds of the present invention is made to pre-mixture
By weight by compound ii-6:1 part of embodiment 14, polyvinylpyrrolidone: 1 part, 5 parts of starch, are prepared as pre-mixture according to the method for this area routine.
Application Example 2
Antibacterial active compounds of the present invention is made to injection:
By weight by compound III-3:1 part of embodiment 23, water for injection: 10 parts, be prepared as injection according to the method for this area routine.
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 (12)
1. an anti-microbial activity pleuromutilin-sulphone amide derivative 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-C18; X is the one in the alkoxyl group of alkyl, amino, C3-C8 of sulphur atom, Sauerstoffatom, C1-C8.
2. anti-microbial activity pleuromutilin-sulphone amide derivative 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-C18 of alkyl, the C3-C8 of acyl group, the C1-C18 of amino, Heterocyclylalkyl, nitro, halogen, hydroxyl, carboxyl, guanidine radicals, C3-C8.
3. anti-microbial activity pleuromutilin-sulphone amide derivative 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. anti-microbial activity pleuromutilin-sulphone amide derivative according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, have following formula II or (III) structure:
5. anti-microbial activity pleuromutilin-sulphone amide derivative according to claim 3 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, is characterized in that: R1 is the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative group.
6. anti-microbial activity pleuromutilin-sulphone amide derivative according to claim 3 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, is characterized in that: R
1for hydrogen, 2-thiazolyl, 2-pyridyl, 6-methoxyl group-2-pyrimidyl, 5-methyl-3-isoxazolyl, 4, the one in 6-dimethyl-2-pyrimidyl.
Anti-microbial activity pleuromutilin-sulphone amide derivative according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, the one in following compounds:
4-[4-(amino-alkylsulfonyl)-(anilino) carbonyl]-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful,
4-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
4-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-[4-(amino-alkylsulfonyl)-(anilino) carbonyl] and-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-thiazole amino) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxzzole amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido) and-alkylsulfonyl]-(anilino) carbonyl }-benzene sulfydryl }-ethanoyl-14-oxygen-wonderful woods.
8. prepare anti-microbial activity pleuromutilin-sulphone amide derivative described in claim 1-7 any one or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, a multi-crystalline compounds, it is characterized in that, with formula (1):
Described compound pass through successively with tolysulfonyl chlorosulfonylation, with formula (2):
Compound substitution reaction, with (3):
Amidate action, the structure of acquisition formula I; Wherein R
1with X be any one defined group of claim 1-6.
9. prepare anti-microbial activity pleuromutilin-sulphone amide derivative described in claim 1-7 any one or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds for one kind, it is characterized in that, comprise the following steps:
A) with formula (7):
Through reduction after with formula (3):
Amidate action obtains formula (8):
B) formula (1):
After tolylsulfonyl chlorosulfonylation, obtain the compound of structure formula I with formula (8) generation substitution reaction; Wherein R
1with X be any one defined group of claim 1-6.
10. an anti-microbial activity composition, comprise anti-microbial activity pleuromutilin-sulphone amide derivative as described in claim 1-7 any one and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and pharmaceutically acceptable carrier or thinner.
11. anti-microbial activity compositions according to claim 10, is characterized in that: its formulation is oral preparation or injection.
12. anti-microbial activity compositions according to claim 10, it is characterized in that: wherein anti-microbial activity pleuromutilin-sulphone amide derivative 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.
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