CN103910664B - A kind of antibacterial activity pleuromutilin-sulphone amide derivative and its preparation method and application - Google Patents
A kind of antibacterial activity pleuromutilin-sulphone amide derivative and its preparation method and application Download PDFInfo
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- WCDSVWRUXWCYFN-UHFFFAOYSA-O [NH3+]c(cc1)ccc1S Chemical compound [NH3+]c(cc1)ccc1S WCDSVWRUXWCYFN-UHFFFAOYSA-O 0.000 description 1
Abstract
A kind of antibacterial activity pleuromutilin sulphone amide derivative with formula I structure or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds and its preparation method and application；
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis technical field, specifically, a kind of antibacterial activity pleuromutilin-
Sulphone amide derivative and its preparation method and application.
Background technology
In recent years, the extensive application of antibiotic, especially at the abuse of livestock breeding industry, cause bacterial drug resistance
Problem is on the rise.Methicillin-resistant staphylococcus aureus has been occurred in that in world wide
(methicillin-resistant Staphylococcus aureus, MRSA), penicillin resistance pneumococcus
(penicillin-resistant Streptococcus pneunoniae, PRSP), multi-resistant Pseudomonas aeruginosa
(multi drug resistant Pseudomonas aeruginosa, MDRPA) and vancomycin-resistant enterococcus
(vancomycin-resistant Enterococci, VRE), human health is constituted huge by these fastbacteria
Threaten, therefore, find newtype drug effective to fastbacteria extremely urgent.
In the past few decades, people are on the structural modification of pleuromutilin (Pleuromutilin),
Made extensive work, it was found that the most safe wonderful woods (taimulin, Tiamulin), valnemulin (Valnemulin),
The serial highly active semisynthetic antibiotics such as his wonderful woods (Retapamulin) auspicious, his wonderful woods of its China and Sweden
(Retapamulin) it is the pleuromulins antibiotic of first man, is mainly used in local and treats golden yellow
The pus born of the same parents of color staphylococcus or S. pyogenes infection are sick.The Antibacterial mechanism of pleuromulins medicine is
Be combined with bacterial ribosome 50S subunit position uniquely, suppress protein synthesis, therefore, less and other
Antibiotic generation crossing drug resistant.
Recently, sight is gradually transferred to the pleuromutilin derivative with unique antimicrobial mechanism by researchers
On, in succession report for work out and there is the noval chemical compound of outstanding antibacterial activity in a large number.Contain as Peng et al. has synthesized series
The carbamates pleuromutilin derivative of heterocycle, has fabulous antibacterial activity to gram positive bacteria.
Hirokawa group on the basis of thioetherification C-14 side chain pleuromutilin, by introducing have bigger polarity and
Water miscible purine ring, filters out 2 and has good internal and antibacterial activity in vitro and water solublity and metabolism
Stability all preferably noval chemical compound.In addition, people's Perorally administrable antimicrobial of existing many pleuromulins
Medicine enters clinical research, including GSK(GlaxoSmithKline PLC) product type of company is SB-565154,
The product type of SB-742510, Nabriva company is BC-3205, BC-7013 etc..
Sulfa drugs has long applicating history, they has a broad antifungal spectrum, determined curative effect, easy to use and
And low price, therefore it is still the big class medicine being only second to antibiotic at present, the most efficiently, long-acting, wide
After the novel sulfanilamide of spectrum and Trimethoprim synthesis, the clinical practice of sulfa drugs is made to have had new wide
Future.In pharmaceutical chemistry, split is one of important method optimizing lead compound, it is therefore an objective to by two phases
With or different lead compound or medicine link together through covalent bond, produce synergism in vivo, add
Cooperation use, or it is alive to produce new pharmacology.Therefore, sulfonamides compound is spliced on pleuromutilin side chain,
Sulfanilamide-the pleuromutilin derivative with multiple antibacterial effect can be obtained.
Summary of the invention
For overcoming the defect of prior art, being of the present invention provides a kind of antibacterial active compounds or its medicine
On and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, carry
The antibacterial activity of high pleuromutilin, it is thus achieved that a kind of efficient, long-acting, antibacterial active compounds of wide spectrum.
In the present invention, the salt that " pharmaceutically and/or veterinarily acceptable salt " includes and alkali metal is formed, as
The salt of the inorganic bases such as sodium, potassium, magnesium, calcium, with hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, cross chloric acid, etc. nothing
Machine acid salt, with fumaric acid, maleic acid, phosphoric acid, glycolic, lactic acid, salicylic acid, succinic acid, to first
Benzenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, benzenesulfonic acid,
Or the salt of the organic acid such as LOMAR PWA EINECS 246-676-2.
In the present invention, term " pharmaceutically and/or veterinarily acceptable solvate " refer to hydrate or
Dissolve 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 antibacterial activity pleuromutilin-sulphone amide derivative with formula I structure or its pharmaceutically and/
Or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds；
Wherein: R1Selected from hydrogen atom, amino, hydroxyl, the alkyl of C1-C18, the aryl of C6-C30, C3-C18
Heteroaryl, amidino groups, guanidine radicals and above-mentioned group substitutive derivative in one；X is sulphur atom, oxygen
Atom, the alkyl of C1-C8, amino, C3-C8 alkoxyl in one.
The substituent group of described substitutive derivative be alkyl, cycloalkyl, amino, Heterocyclylalkyl, nitro, halogen,
In hydroxyl, carboxyl, alkoxyl, guanidine radicals, acyl group, aryl, heteroaryl, alkylthio group or arylthio alkyl
One.
The present invention, in term, " alkyl " includes straight or branched alkyl, as methyl, ethyl, n-pro-pyl,
Isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group, hexyl, heptyl, octyl group etc.；" cycloalkyl "
Including 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, tetrahydrochysene
Furyl, piperazinyl, tetrahydro-thiazoles base, morpholine base etc., " amido " include methylamino, ethylamino-,
Propylamino, dimethylamino, diethylin etc.；" heteroaryl " refer to containing one or more selected from N, O,
The heteroatomic aryl such as S, as pyrrole radicals, pyrazolyl, imidazole radicals, triazol radical, furyl, thienyl,
Oxazolyl, pyridine radicals, thiazolyl, pyrimidine radicals, pyrazinyl etc.；" virtue heterocycle " refers to that carbocyclic aromatic is (main
Phenyl ring aromatic hydrocarbons to be referred to) and upper heteroatomic saturated or unsaturated selected from N, O, S etc. containing one or more
Heterocyclic radical, such as indyl, benzofuranyl, benzothiazolyl, quinolyl, isoquinolyl, benzimidazole
Base etc.；" heterocycle virtue heterocyclic radical " is primarily referred to as the also ring of pyrimidine and imidazoles or pyrazine, such as purine, pteridine
Deng.
Described antibacterial activity pleuromutilin-sulphone amide derivative or its pharmaceutically and/or veterinarily can connect
The salt that is subject to, solvated compounds, optical isomer, multi-crystalline compounds, have following formula II or (III)
Structure:
As one preferred scheme of the present invention, the X in said structure formula I, (II), (III)
For sulphur atom.
As one preferred scheme of the present invention, the R1 in said structure formula I, (II), (III)
For the one in pyridine ring, thiazole ring, pyrimidine ring, oxazole ring or their substitutive derivative group.
As one preferred scheme of the present invention, R in said structure formula I, (II), (III)1For hydrogen,
2-thiazolyl, 2-pyridine radicals, 6-methoxyl group-2-pyrimidine radicals, 5-methyl-3-isoxazolyl, 4,6-dimethyl-2-are phonetic
One in piperidinyl.
Antibacterial activity pleuromutilin-sulphone amide derivative of the present invention or its pharmaceutically and/or veterinary
Upper acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds, in following compounds
A kind of: { 4-[4-(amino-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods, { 4-{4-[N-
(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
4-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful,
4-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-
Oxygen-wonderful woods,
4-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-
Oxygen-wonderful woods,
4-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-[4-(amino-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-
Oxygen-wonderful woods,
3-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
3-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-
Oxygen-wonderful woods,
3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-
Oxygen-wonderful woods.
Another object of the present invention is to provide the preparation side of a kind of antibacterial activity pleuromutilin-sulphone amide derivative
Method.The present invention synthetic antimicrobial reactive compound or its pharmaceutically and/or veterinarily acceptable salt, molten
Immunomodulator compounds, optical isomer, multi-crystalline compounds mainly use two kinds of methods, the following is the present invention and are adopted
Method.
Method one: antibacterial active compounds described in preparation or its pharmaceutically and/or veterinarily acceptable
Salt, solvated compounds, optical isomer, multi-crystalline compounds, with formula (1):
Described compound sequentially passes through and tolysulfonyl chlorosulfonylation and formula (2):
Compound substitution reaction and (3):
Amidation process, it is thus achieved that the structure of formula I；Wherein R1It is defined in any one scheme above-mentioned with X
Group.
In said method one, sulfonylation, substitution reaction, the condition of amidation process can be that this area can
With to realize any condition of the object of the invention, as further instruction, it is preferred that the present invention's
Preparation method can be the method comprised the following steps:
A) sulfonylation: the compound of formula (1) and paratoluensulfonyl chloride are dissolved in ethyl acetate and water
In mixed solution, under ice bath, it is dividedly in some parts alkali liquor, adds rear room temperature reaction 30 minutes, be warming up to 30-60 DEG C,
It is stirred vigorously 0.5-6 hour, dilute with water, filters, be washed to neutrality, be dried to obtain product (4)；
B) substitution reaction: the 4-mercaptobenzoic acid that formula (4) product and formula (2) are represented or 3-sulfydryl benzene first
Acid adds in the mixed solution of ethyl acetate and water, adds alkali liquor under ice bath, adjusts PH at 8-12, and backflow is stirred
Mix value reaction completely, then after sequentially passing through concentrating under reduced pressure, hydrochloric acid water dilution, organic solvent extraction, be washed to
Neutrality, is dried, and reduces pressure and steams solvent correspondence acquisition formula (5) or formula (6) product:
C) amidation process: by step B) compound of products therefrom formula (5) or formula (6) is dissolved in dichloro
In methane, adding the alkali of excess, drip activator under ice bath, low temperature stirs 0.5-2 hour, adds formula (3)
Compound:
Being stirred at room temperature 1-16 hour, filtration, washing, be dried, decompression steams solvent, obtains structural formula after crossing silicagel column
For (II) or the product of (III).
Its concrete synthetic route is as follows:
In said method, the paratoluensulfonyl chloride used by sulfonylation can be replaced its anhydride；Alkali used is
Inorganic base: Na2CO3、K2CO3, NaOH, KOH or organic base: the one in pyridine, triethylamine；
The low boiling point solvents such as solvent for use ethyl acetate replaceable one-tenth toluene, butyl formate or ether, oxolane, 1,
One or more in the ether solvents such as 4-dioxane are with any ratio mixing；Reaction process condition is: throw
Material temperature degree is-10-10 DEG C, to be preferred less than 5 DEG C；Reaction temperature is 30-80 DEG C；Wherein as preferred,
Reaction temperature is 60 DEG C.
In said method, the alkali used by substitution reaction is inorganic base: NaOH, KOH, or organic base: pyridine,
One in triethylamine；Solvent for use ethyl acetate replaceable formic acid butyl ester, dichloromethane, chloroform,
The low boiling halogenated hydrocarbons such as 1,2-dichloroethanes, or ether, oxolane, Isosorbide-5-Nitrae-dioxane, methyl-tert
One or more in the ether solvents such as butyl ether are with any ratio mixing；Reaction process condition is: add alkali
Equivalent is 0.5-5, is preferred with 1.5；Add-subtract time was advisable with 0.5-2 hour, and feed temperature is-10-15 DEG C,
To be preferred less than 0 DEG C；Reaction temperature is 35-90 DEG C.Wherein as preferably, reaction temperature 55 DEG C is preferred.
In said method, the activator available chlorine benzyl formate used by amidation process, ethyl chloroformate, chlorine
One or more mixing in formic acid isopropyl ester, isobutyl chlorocarbonate, EDC, DCC, HOBT etc.
Use；Alkali used is inorganic base: Na2CO3、K2CO3, one in NaOH, KOH, or organic base:
One in pyridine, N-methylmorpholine, morpholine, triethylamine；Solvent for use methyl tertiary butyl ether(MTBE) can replace
Be changed to ethyl acetate or butyl formate, dichloromethane, chloroform, 1, the low boiling halo such as 2-dichloroethanes
One in hydrocarbon or ether, oxolane, Isosorbide-5-Nitrae-ether solvent solvent such as dioxane, methyl tertiary butyl ether(MTBE)；
Reaction process condition: feed temperature is-30-0 DEG C, to be preferred less than-10 DEG C；Reaction temperature is-25-40 DEG C,
It is preferred with room temperature；Preferably mol ratio is formula (5) or formula (6) compound: activator=1:(1～5).
Method two: antibacterial active compounds described in preparation or its pharmaceutically and/or veterinarily acceptable
Salt, solvated compounds, optical isomer, multi-crystalline compounds, comprise the following steps:
A) with formula (7):
With formula (3) after reduction reaction:
Amidation process obtains formula (8):
B) formula (1):
Substitution reaction is occurred to obtain the compound of structure formula I with formula (8) after tosyl chlorosulfonylation；
Wherein R1It is the group defined in any one scheme above-mentioned with X.
In the present invention, above-mentioned reduction, amidatioon, sulfonylation and substituted condition can be that this area is permissible
To realize any condition of the object of the invention, as further instruction, it is preferred that the system of the present invention
Preparation Method can be the method comprised the following steps:
1) reduction reaction:
Formula (7) represented dissolves in toluene to chlorosulfonyl benzoic acid or m-chloro sulfonyl benzoic acid, adds
Appropriate triethylamine, at 10 DEG C, N2Protection, is dividedly in some parts reducing agent, adds post-heating and be warming up to 40-100
DEG C, to stir 1-5 hour, reaction is finished, and adds appropriate mixture of ice and water, stirs 15 minutes, separatory, abandon water
Phase, organic facies alkali dose 3 times, merge aqueous phase, adjust pH value to 1-3 with dilute hydrochloric acid, then use dichloro
Methane extracts, and dry rotation steams solvent, and alcohol recrystallization obtains 4-mercaptobenzoic acid formula (9) or 3-mercaptobenzoic acid
Formula (10)；
2) amidation process:
Dissolving in dichloromethane by the compound of formula (9) or formula (10), pyridine is appropriate, and ice bath is cooled to 0
DEG C, slowly drip the dichloromethane solution of activator, after adding, warm naturally to room temperature, continue stirring 6-12
Hour, reaction is finished, and decompression steams solvent, adds dichloromethane and continues to be concentrated into the releasing of thing white cigarette, residue
Dissolving with dichloromethane, be subsequently adding the compound of formula (3), oxolane is appropriate, and the alkali of catalytic amount adds
Being stirred at room temperature after complete 12-18 hour, reaction is finished, and rotation steams solvent, adds appropriate water in residue, dilute
Hydrochloric acid adjusts pH value to 3-5, has a large amount of Precipitation, filters, and saturated common salt is washed to neutrality, is dried, mistake
Silicagel column obtains 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(MTBE),
Addition formula (4) product, under low temperature (0 DEG C), slowly drips alkali liquor, adds in 1-2 hour, heat temperature raising
To backflow, stirring 1-12 hour, reaction completes, and decompression steams solvent, pours in appropriate frozen water, filters,
Washing, is dried, and crosses silicagel column and obtains product formula II or formula III.Its concrete synthetic route is as follows:
In said method, the triethylamine used by reduction reaction can be replaced inorganic base K2CO3, NaOH, KOH,
Or organic base pyridine, piperidines, hexanamine, or mineral acid H2SO4, one in HCl；Solvent for use first
Benzene replaceable one-tenth methanol, ethanol, water polar solvent, or ethyl acetate, dichloromethane, chloroform, 1,
Low boiling halogenated hydrocarbons, ether, the Isosorbide-5-Nitrae-ether solvents such as dioxane, methyl tertiary butyl ether(MTBE) such as 2-dichloroethanes
In one or more mixing；Reducing agent used is triphenylphosphine, LiAlH4, zinc powder, NaBH4In
One.Reaction process condition is: 10 DEG C to 100 DEG C；Preferably mol ratio is chlorosulfonyl benzoic acid: also
Former dose=1:(1～3).
In said method, activator used by amidation process can be oxalyl chloride, thionyl chloride, ethyl chloroformate,
One or more in benzyl chloroformate；As being preferably preferred with oxalyl chloride；Alkali pyridine used can replace
It is changed to inorganic base K2CO3, NaOH, KOH, or organic bases triethylamine, piperidines, N-methylmorpholine,
One in DMAP etc.；Solvent for use dichloromethane replaceable one-tenth ethyl acetate, benzene, toluene, three chloromethanes
Alkane, 1, low boiling halogenated hydrocarbons, ether, oxolane, Isosorbide-5-Nitrae-dioxane, the methyl-tert such as 2-dichloroethanes
One or more mixing in the ether solvents such as butyl ether；Reaction process condition is: feed temperature is-10
DEG C-15 DEG C, reaction temperature is 15-60 DEG C, is preferred with room temperature；Adding alkali equivalent is 0.5～5, is preferred with 2.5；
Preferably 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 said method, alkali used by substitution reaction can be inorganic base Na2CO3、K2CO3、NaOH、KOH,
Or the one in organic base pyridine, morpholine, triethylamine, DMAP, Sodium ethylate；Solvent for use methyl-tert fourth
Base ether can be replaced ethyl acetate, butyl formate；Dichloromethane, chloroform, 1,2-dichloroethanes etc. is low
Boiling point halogenated hydrocarbons, or ether, oxolane, Isosorbide-5-Nitrae-ether solvent such as dioxane, methyl tertiary butyl ether(MTBE)
In one or more mixing；Reaction process condition is: feed temperature is 0～30 DEG C, with less than 0 DEG C
It is preferred；Reaction temperature is 15 DEG C～90 DEG C；Preferably mol ratio is formula (11) or formula (12): compound
(2)=1:(1～1.3).
A kind of antibacterial activity compositions, spreads out including the antibacterial activity pleuromutilin-sulfanilamide described in such scheme
Biological and or its pharmaceutically and/or veterinarily acceptable salt, solvated compounds, optical isomer, many
Crystal-form compound and pharmaceutically acceptable carrier or diluent.
In the present invention, the dosage form of described antibacterial activity compositions is oral agents or injection.
In the antibacterial activity compositions of the present invention, antibacterial activity pleuromutilin-sulphone amide derivative or its medicine
On and/or veterinarily acceptable salt, solvated compounds, optical isomer, multi-crystalline compounds content
For 0.1%-99.5%(wt%), surplus is carrier or diluent.
The effective of the present invention is: the present invention is the lead compound that two different to be connected to through covalent bond
Together, produce synergism, adduction in vivo, or produce new pharmacologically active；The sulfanilamide of the present invention
Class medicine is spliced on pleuromutilin side chain, produces new sulfanilamide-pleuromutilin derivative, institute of the present invention
The noval chemical compound obtained has significant inhibitory activity to gram positive bacteria and part negative bacterium, mycoplasma etc.,
The fastbacteria such as MRSA also there are is obvious inhibitory action, can effectively widen 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 that the present invention is protected model
The restriction enclosed.In all embodiments, the fusing point of compound capillary melting point determination instrument measures,1HNMR by
Varian AM-400 type nmr determination, with TMS as internal standard, 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 made a living
The GF254 type produced.
Embodiment 1: the synthesis of p-methyl benzenesulfonic acid ester group-acetyl group-14-oxygen-wonderful woods
By the pleuromutilin of 11.5g, the paratoluensulfonyl chloride of 5.8g is added sequentially to the ethyl acetate of 50ml
In, ice bath is washed down, with the potassium hydroxide solution 20ml regulation pH value of 1mol/L to strong basicity, is warming up to
35 DEG C, being 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, is dried, acetone recrystallization
Obtain 15.6g white solid.Yield is 96%, fusing point 116-118 DEG C, MS-ESI (M+1): 532.9.Its core
Magnetic resonance hydrogen spectrum 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).
The synthesis of embodiment 2:3-thio-benzoic acid
22.3g m-chloro sulfonyl benzoic acid is dissolved in 100ml toluene, adds the triethylamine of 3.2ml, ice bath
It is cooled to 10 DEG C, N2Protection, is dividedly in some parts the PPh of 73g3, add post-heating and be warming up to 80 DEG C, stirring
4.5 hours, reaction was finished, and pours the mixture of ice and water of 100ml into, stirs 15 minutes, separatory, abandon aqueous phase,
The Na of organic facies 1mol/L2CO3Solution extracts 3 times, merges aqueous phase, with dilute hydrochloric acid tune pH value to 2,
Then extract with dichloromethane, anhydrous Mg2SO4Being dried, rotation steams solvent, and 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
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) synthesis of-acetyl group-14-oxygen-wonderful woods
The 4-mercaptobenzoic acid of 36g, joins in the methanol of 400ml, is cooled to 0 DEG C, and stirring is lower to add
46.5g formula (4) compound, slowly dropping 20mlKOH solution (10mol/L), complete is warming up to room temperature,
Continue to be stirred overnight.Reacting complete, decompression steams major part solvent, dilute with water 5-10 times, and dilute hydrochloric acid is adjusted
PH value, to 3-4, Precipitation, filters, is washed to neutrality, and white solid washed to obtain by a small amount of ethanol, ethanol:
Acetone volume ratio is=the mixed solution 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).
The synthesis of embodiment 4:2-[4-(to sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine
Mercaptobenzoic acid is dissolved in by 15.8g the CH of 150ml2Cl2In, add 4.6ml pyridine, under ice bath,
Slowly drip the CH of 9.5ml oxalyl chloride2Cl2Solution, is warming up to room temperature after adding, continue stirring 12 hours,
Reacting complete (using indentification by TLC reaction end), decompression steams solvent, adds CH2Cl2Continue dense
It is reduced to release without white cigarette, residue 100mlCH2Cl2Dissolve, be subsequently adding sulfamethazine 28.5g,
THF80ml, triethylamine 6.5ml, be stirred at room temperature after adding 12 hours, and after having reacted, rotation steams solvent,
Adding the water of 50ml in residue, adjust pH value to 3 with dilute hydrochloric acid, filter, saturated common salt is washed, washing
To neutral, anhydrous Na2SO4Be dried, with petroleum ether: ethyl acetate=8:2(volume ratio) silica gel column layer
Analysis separates, and obtains white solid 27.5g, named 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).
The synthesis of embodiment 5:4-(to sulfydryl benzoyl amino)-N-(6-methoxyl group-2-pyrimidine radicals) benzsulfamide
Method is with embodiment 4, and wherein sulfanilamide-6-the methoxy pyrimidine of sulfadimidine equimolar amounts substitutes,
Product named (11b).Yield 90%, fusing point 217-219 DEG C, MS-ESI (M+1): 417.3；Nuclear-magnetism is altogether
The hydrogen that shakes spectrum 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).
The synthesis of embodiment 6:4-(to sulfydryl benzoyl amino)-N-(2-pyridine radicals) benzsulfamide
Mercaptobenzoic acid is dissolved in by 10.2g in the toluene of 100ml, add 1.8ml triethylamine, under room temperature,
Slowly dropping 11.8g thionyl chloride, after adding, is warming up to 60 DEG C and continues stirring 2 hours, react complete (thin
Layer chromatography identification terminal), decompression steams solvent, adds toluene and continues to be concentrated into and release without white cigarette, residual
Excess 100mlCH2Cl2Dissolve, filter, filtrate adds sulfapyridine 16.5g, THF20ml, DMAP
8.6g, is stirred at room temperature after adding 12 hours, and reaction Bi Xuan steams solvent, adds the water of 30ml in residue,
Adjusting pH value to 3 with dilute hydrochloric acid, filter, saturated common salt is washed, and is washed to neutrality, anhydrous Na2SO4It is dried,
With petroleum ether: ethyl acetate=7:3(volume ratio) silica gel column chromatography separation, obtain white solid 13.2g, life
Entitled (11c).Yield 52%, fusing point 205-207 DEG C, MS-ESI (M+1): 386.4.Proton nmr spectra is tied
Fruit 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).
The synthesis of embodiment 7:4-(to sulfydryl benzoyl amino)-N-(5-methyl-3-isoxazolyl) benzsulfamide
Method is with embodiment 4, and wherein sulfanilamide-5-the methylisoxazole of sulfapyridine equimolar amounts substitutes, and produces
Thing named (11d).Yield 47%, fusing point 214-216 DEG C, MS-ESI (M+1): 390.1.Nuclear magnetic resonance, NMR
Hydrogen spectrum 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).
The synthesis of embodiment 8:4-(to sulfydryl benzoyl amino)-N-(2-thiazolyl) benzsulfamide
Method is with embodiment 4, and wherein the sulfanilamide of sulfapyridine equimolar amounts-thiazole substitutes, and product is named
(11e).Yield 51%, fusing point 195-197 DEG C, MS-ESI (M+1): 392.3.Proton nmr spectra result
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-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods
Synthesis
By the product of 5g embodiment 3, dissolve in the methyl tertiary butyl ether(MTBE) of 100ml, add N-methylmorpholine
The acetone soln 20ml of 1.5g, 1.9g sulfanilamide, is cooled to 0 DEG C, slowly drips the THF solution of 3.5gEDC
10ml, after adding, is to slowly warm up to 30 DEG C, is stirred overnight, react complete, filters, and 50ml water dilutes,
Separatory, organic facies washes with the HCl solution of a small amount of 1mol/L successively, and saturated common salt is washed, and is dried, boils off first
Base tertbutyl ether, with petroleum ether: ethyl acetate=3:7～1:1 silica gel column chromatography separates, obtains 5.7g white
Solid, named II-1.Yield 88.9%, fusing point 209-211 DEG C, MS-ESI (M+1): 669.4.Nuclear-magnetism is altogether
The hydrogen that shakes spectrum 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-pyrimidine radicals)-sulfoamido]-(anilino-) carbonyl }-
Benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Employing method 1 synthesizes: the product 5g of embodiment 4, is dissolved in the ethyl acetate of 50ml, adds three
Ethamine 5ml, is cooled to-15 DEG C, slowly drips the ethyl acetate solution 30ml of 1g ethyl chloroformate, adds
After, it is to slowly warm up to-5-0 DEG C, reacts 45 minutes, add the acetone soln 20ml of 5.6g sulfadimidine,
It is warming up to 55 DEG C, reacts 4 hours, react complete (indentification by TLC reaction end), filter, organic
Mutually use the most successively, the HCl solution of 1mol/L washes, and saturated common salt is washed, and is dried, boils off ethyl acetate, with stone
Oil ether: ethyl acetate=3:7～1:1 silica gel column chromatography separates, obtains 8.7g white solid, and named II-2.
Yield 90.2%, fusing point 244.5-246 DEG C, MS-ESI (M+1): 775.4.
The 2-in-1 one-tenth of employing method: product 2-[4-(to sulfydryl Benzamido)-the benzene sulfonamido]-4,6-of embodiment 3
Dimethyl pyrimidine 15g's, join in the acetas of 100ml and the water of 20ml, be cooled to 5-10 DEG C, stir
Mix lower addition 20.8g formula (4) compound, tetra-tert ammonium chloride 1.5g, the most slowly drip 28mlNaOH
Solution (10mol/L), drips and complete is warming up to room temperature, continue to be stirred overnight.Reaction is finished, and decompression has steamed
Machine solvent, imports in 200ml frozen water and dilutes, and adjusts pH value to 3-4, Precipitation with dilute hydrochloric acid, filters,
Being washed to neutrality, white solid washed to obtain by a small amount of ethanol.With petroleum ether: ethyl acetate=3:7(volume ratio) silicon
Plastic column chromatography separates, and obtains white solid 25.4g, and named 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-pyridine radicals)-sulfoamido]-(anilino-) carbonyl }-benzene sulfydryl }-second
The synthesis of acyl group-14-oxygen-wonderful woods
By the product of 10g embodiment 4, dissolve in the methyl tertiary butyl ether(MTBE) of 150ml, add N-methylmorphine
The acetone soln 20ml of quinoline 2.5g, 4.5g sulfapyridine, is cooled to 0 DEG C, slowly drips the THF of 4.7gEDC
Solution 50ml, after adding, is to slowly warm up to 30 DEG C, is stirred overnight, react complete, filters, 100ml water
Diluting, separatory, organic facies is washed with the HCl solution of a small amount of 1mol/L successively, and saturated common salt is washed, and is dried,
Boil off methyl tertiary butyl ether(MTBE), with petroleum ether: ethyl acetate=3:7～1:1 silica gel column chromatography separates, and obtains 12.7g
White solid, named II-3.Yield 87%, fusing point 251-252 DEG C, MS-ESI (M+1): 745.8.Core
Magnetic resonance hydrogen spectrum 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-pyrimidine radicals)-sulfoamido]-(anilino-) carbonyl }-benzene
Sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with the method 1 in embodiment 10, uses the product alternate embodiment of the embodiment 5 of equimolar amounts
The product of 4, the white solid obtained name II-4.Yield is respectively 87%, and 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),0.7
8(d,3H),0.58(d,3H)。
Embodiment 13:{4-{4-[N-(5-methyl-3-isoxazolyl)-sulfoamido]-(anilino-) carbonyl }-benzene
Sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
The product 10g of embodiment 4 is dissolved in the THF of 120ml, adds pyridine 40ml, is cooled to 10 DEG C,
Slowly drip the THF solution 30ml of 3.0g ethyl chloroformate, after adding, be to slowly warm up to room temperature DEG C, stir
Mix 2 hours, filter, standby.The sulfamethoxazole of 5.6g is added in 50ml pyridine, is cooled to 10 DEG C,
Then the reactant liquor of previous step is dripped wherein, is warming up to 30 DEG C and stirs 5 hours, react complete, filter,
Rotation steams solvent, adds 50ml water and 100ml ethyl acetate, separatory, organic facies saturated common salt in residue
It is washed to neutrality, anhydrous Na2SO4Being dried, boil off ethyl acetate, silica gel column chromatography separates, and obtains 13g white
Solid named II-5.Yield 92%, fusing point 243.5-245 DEG C, MS-ESI (M+1): 750.2.Nuclear-magnetism is altogether
The hydrogen that shakes spectrum 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),3.9
4-4.01(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-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-second
Acyl group-14-oxygen-wonderful woods
Method, with method 2 in embodiment 10, uses 4-(to sulfydryl benzoyl amino)-N-(the 2-thiazole of equimolar amounts
Base) benzsulfamide replacement 2-[4-(to sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine, obtain
White solid 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) synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 3, uses the 3-mercaptobenzoic acid of equimolar amounts to substitute 4-mercaptobenzoic 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).
The synthesis of embodiment 16:2-[4-(a sulfydryl Benzamido)-benzene sulfonamido]-4,6-dimethyl pyrimidine
Method, with embodiment 4, uses mercaptobenzoic acid between equimolar amounts to substitute mercaptobenzoic 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).
The synthesis of embodiment 17:4-(a sulfydryl benzoyl amino)-N-(2-pyridine radicals) benzsulfamide
Method, with embodiment 6, uses mercaptobenzoic acid between equimolar amounts to substitute mercaptobenzoic 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).
The synthesis of embodiment 18:4-(a sulfydryl benzoyl amino)-N-(6-methoxyl group-2-pyrimidine radicals) benzsulfamide
Method, with embodiment 5, uses mercaptobenzoic acid between equimolar amounts to substitute mercaptobenzoic 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).
The synthesis of embodiment 19:4-(a sulfydryl benzoyl amino)-N-(5-methyl-3-isoxazolyl) benzsulfamide
Method, with embodiment 7, uses mercaptobenzoic acid between equimolar amounts to substitute mercaptobenzoic 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).
The synthesis of embodiment 20:4-(a sulfydryl benzoyl amino)-N-(2-thiazolyl) benzsulfamide
Method, with embodiment 8, uses mercaptobenzoic acid between equimolar amounts to substitute mercaptobenzoic 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-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods
Synthesis
Method, with embodiment 9, uses the product of the product alternate embodiment 3 of equimolar embodiment 15,
To white solid named 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),2.15-2.2
0(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,1
H),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)-sulfonyl]-(anilino-) carbonyl }-
Benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 10, uses the product of the product alternate embodiment 4 of the embodiment 16 of equimolar amounts,
Obtain the solid named III-2 of white.Yield is respectively 75.9%, and 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)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl
The synthesis of base-14-oxygen-wonderful woods
Method, with embodiment 11, uses the product alternate embodiment 6 of the embodiment 17 of equimolar amounts, obtains white
The solid named III-3 of color.Yield 77%, fusing point 212-214 DEG C, MS-ESI (M+1): 746.3, element
Analyze: C40H47N3O7S2, value of calculation (%) 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)-sulfonyl]-(anilino-) carbonyl }-
Benzene sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 10, uses the product alternate embodiment 6 of the embodiment 17 of equimolar amounts, obtains white
The solid named III-4 of color, yield is respectively 80%, and 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-isoxazole amido)-sulfonyl]-(anilino-) carbonyl }-benzene
Sulfydryl } synthesis of-acetyl group-14-oxygen-wonderful woods
Method, with embodiment 13, uses the product alternate embodiment 7 of the embodiment 19 of equimolar amounts, obtains white
The solid named III-5 of color.Yield 71.8%, fusing point 212-125 DEG C, MS-ESI (M+1): 750.5.Nuclear-magnetism
Resonance hydrogen spectrum 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-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl
The synthesis of base-14-oxygen-wonderful woods
Method, with embodiment 14, uses the product alternate embodiment 8 of the embodiment 14 of equimolar amounts, obtains white
The solid named III-6 of color.Yield 79.5%, fusing point 198.8-202 DEG C, MS-ESI (M+1): 752.1,
Elementary analysis: C38H45N3O7S3, value of calculation (%) 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 partial target compound of the present invention is as follows:
1. test method: use document (Chen Xiushu, Tu Tao etc., micro-broth dilution method MIC
Evaluation, Chinese journal of medical examination, 1994,2:95-98) the trace meat soup doubling dilution reported is to being subject to
The minimum inhibitory concentration (MIC) of examination bacterial strain is measured.The inoculum concentration of antibacterial is 105CFU/ml, often
Plant medicine and every kind of bacterium is all carried out 3 repetitions.Tested material with after dimethyl sulfoxide hydrotropy, with sterile purified water or
Lower alcohol wiring solution-forming uses.
2. test strain: totally 18 strain laboratory standard bacterial strains (include that 9 strains are gram positive bacteria (G+), 4
Strain gram negative bacteria (G-), 5 strain mycoplasmas).Staphylococcus aureus CMCC26003(Staphylococcus
Aureus), staphylococcus aureus ATCC29213(Staphylococcus aureus), Staphylococcus aureus
Bacterium CICC26112(Staphylococcus aureus), methicillin-resistant staphylococcus aureus (Methicillin
Resistant Staphylococcus aureus, MRSA), streptococcus pneumoniae ATCC49619(Streptococcus
Pneumoniae), Streptococcus suis CVCC3307(Streptococcus suis), beta hemolytic streptococcus
CICC10373(beta Hemolytic streptococcus), enterococcus faecalis CICC10396(Enterococcus
Faecalis), staphylococcus epidermidis 26069(Staphylococcus epidermidis), adenitis equorum streptococcus
CVCC556(Strepococcus equinus)；Escherichia coli ATCC25922(Escherichia coli), very
Different Bacillus proteus CMCC49003(Proteus mirabilis), bacillus pyocyaneus ATCC15442 (Pseudomonas
Aeruginosa), Salmonella enteritidis CICC21482(Salmonella enteritidis)；Chicken virus mycoplasma S6
(Mycoplasma gallisepticum), chicken virus mycoplasma CVCC351(Mycoplasma
Gallisepticum), synovial fluid 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 shown in Table 1.
Table 1: partial target Compound ira vitro antibacterial activity data (MIC, μ g/ml)
Note: Sau1 golden staphylococci CMCC26003；Sau2 staphylococcus aureus ATCC29213；Sau3 golden yellow Fructus Vitis viniferae
Coccus CICC26112；MRSA methicillin-resistant staphylococcus aureus；Spn streptococcus pneumoniae；Ssu Streptococcus suis；bHS
Beta hemolytic streptococcus；Efa enterococcus faecalis；Sep staphylococcus epidermidis；Seq adenitis equorum streptococcus；Eco escherichia coli；
Pm proteus mirabilis；Pa bacillus pyocyaneus；Sae Salmonella enteritidis；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: II-3, III-3 staphylococcus aureus to being surveyed, MRSA, pneumonia streptococcus
Bacterium, hyopneumoniae streptococcus, staphylococcus epidermidis, enterococcus, the streptococcic antibacterial activity of adenitis equorum are better than
Control drug sulfapyridine and valnemulin, especially to methicillin-resistant staphylococcus aureus (MRSA)
Antibacterial activity is significantly better than control drug valnemulin；The antibacterial activity of staphylococcus aureus is better than comparison
Medicine valnemulin have II-6, III-6, the antibacterial activity of streptococcus pneumoniae is better than control drug valnemulin
Have II-3, III-2, III-3, III-6；The antibacterial activity of epidermis staphylococcus aureus is better than control drug
Valnemulin have II-3, III-6, hyopneumoniae streptococcus antibacterial activity is better than control drug valnemulin has
Ⅲ-3。
G-bacterium to being surveyed: compound ii-6 is all shown medium antibacterial activity to surveying 4 strain G-bacterium, changes
Other, in addition to slightly worse to colibacillary antibacterial activity, surveyed 3 strain G-bacterium and are all shown medium by compound II-3
Antibacterial activity.
Mycoplasma to being surveyed: II-3, II-6, III-3, III-6 is the most suitable to the antibacterial activity of surveyed mycoplasma
Or it is better than control drug valnemulin.
Application Example 1
The antibacterial active compounds of the present invention is made pre-mixing agent
By weight by compound ii-6:1 part of embodiment 14, polyvinylpyrrolidone: 1 part, starch 5
Part, the method conventional according to this area is prepared as pre-mixing agent.
Application Example 2
The antibacterial active compounds of the present invention is made injection:
By weight by compound III-3:1 part of embodiment 23, water for injection: 10 parts, according to this area
Conventional method is prepared as injection.
Above-mentioned embodiment is only the preferred embodiment of the present invention, it is impossible to limit present invention protection with this
Scope, the change of any unsubstantiality that those skilled in the art is done on the basis of the present invention and replacement
Belong to scope of the present invention.
Claims (11)
1. antibacterial activity pleuromutilin-sulphone amide derivative with formula I structure or its pharmaceutically and/or veterinarily acceptable salt；
Wherein: R1One in the substitutive derivative of hydrogen atom, amino, hydroxyl, the alkyl of C1-C18, the aryl of C6-C30, the heteroaryl of C3-C18, amidino groups, guanidine radicals, the acyl group of C1-C18 and above-mentioned group；X is the one in the alkoxyl of sulphur atom, oxygen atom, the alkyl of C1-C8, amino, C3-C8.
Antibacterial activity pleuromutilin-sulphone amide derivative the most 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.
Antibacterial activity pleuromutilin-sulphone amide derivative the most according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, there is following formula II or (III) structure:
4. according to the antibacterial activity pleuromutilin-sulphone amide derivative described in claim 2 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 group.
Antibacterial activity pleuromutilin-sulphone amide derivative the most according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, it is characterised in that: R1For the one in hydrogen, 2-thiazolyl, 2-pyridine radicals, 6-methoxyl group-2-pyrimidine radicals, 5-methyl-3-isoxazolyl, 4,6-dimethyl-2-pyrimidine radicals.
Antibacterial activity pleuromutilin-sulphone amide derivative the most according to claim 1 or its pharmaceutically and/or veterinarily acceptable salt, the one in following compounds:
{ 4-[4-(amino-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful,
{ 4-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 4-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-[4-(amino-sulfonyl)-(anilino-) carbonyl]-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(4,6-dimethyl-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(2-thiazoleamino)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(2-pyridine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(5-methyl-3-isoxazole amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods,
{ 3-{4-[N-(6-methoxyl group-2-pyrimidine amido)-sulfonyl]-(anilino-) carbonyl }-benzene sulfydryl }-acetyl group-14-oxygen-wonderful woods.
7. the antibacterial activity pleuromutilin-sulphone amide derivative as described in any one of claim 1-6 or its pharmaceutically and/or the preparation method of veterinarily acceptable salt, it is characterised in that with formula (1):
Described compound sequentially passes through and tolysulfonyl chlorosulfonylation and formula (2):
Compound substitution reaction and (3):
Amidation process, it is thus achieved that the structure of formula I；Wherein R1Group defined in claim 1-5 any one, X is sulphur atom.
8. the antibacterial activity pleuromutilin-sulphone amide derivative as described in any one of claim 1-6 or its pharmaceutically and/or the preparation method of veterinarily acceptable salt, it is characterised in that comprise the following steps:
A) with formula (7):
After carrying out reduction with formula (3):
Amidation process obtains formula (8):
B) formula (1):
Substitution reaction is occurred to obtain the compound of structure formula I with formula (8) after tosyl chlorosulfonylation；Wherein R1Group defined in claim 1-5 any one, X is sulphur atom.
9. an antibacterial activity compositions, including the antibacterial activity pleuromutilin-sulphone amide derivative as described in any one of claim 1-6 and or its pharmaceutically and/or veterinarily acceptable salt and pharmaceutically acceptable carrier or diluent.
Antibacterial activity compositions the most according to claim 9, it is characterised in that: its dosage form is oral agents or injection.
11. antibacterial activity compositionss according to claim 9, it is characterized in that: wherein antibacterial activity pleuromutilin-sulphone amide derivative or its pharmaceutically and/or veterinarily acceptable salt mass percentage content is 0.1%-99.5%, surplus is carrier or diluent.
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