CN114940671A - Pleuromutilin derivative with 4-aminobenzenethiol side chain as well as preparation method and application thereof - Google Patents
Pleuromutilin derivative with 4-aminobenzenethiol side chain as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicinal chemistry, and discloses a pleuromutilin derivative with a 4-aminobenzenethiol side chain, and a preparation method and application thereof. The pleuromutilin derivatives with 4-aminophenethiol side chainA compound having a structure represented by formula 2 or a pharmaceutically acceptable salt thereof, or a solvate, enantiomer, diastereomer, tautomer, or mixture thereof in any proportion, including a racemic mixture, of a pharmaceutically acceptable salt thereof: the compound not only has good in-vitro antibacterial activity and water solubility, but also has the advantage of lower preparation cost than valnemulin and ritamolin, so that the compound is particularly suitable to be used as a novel antibacterial drug for preventing and treating bacterial infectious diseases of human beings or animals, especially infectious diseases caused by drug-resistant staphylococcus aureus.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 4-aminobenzenethiol side chain, and a preparation method and application thereof.
Background
Among the multi-drug resistant gram-positive bacteria, methicillin-resistant staphylococcus aureus (MRSA), penicillin-resistant streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE) are major concerns. Therefore, the development of new antibacterial agents and new mechanisms of action, and which exhibit minimal cross-resistance with existing drug therapies, is of great importance to the medical community.
Pleuromutilin (formula 1) is an antibiotic produced by culturing two pleurotides Pleurotus mutilus and Pleurotus paseckerianum of Pleurotus of higher fungal Basidiomycetes, belongs to diterpene compounds, and is firstly separated and identified by Kavanagh et al in 1951, and then the structure of pleurotide Pleurotus paseckerianum is determined by Birch et al in 1966, and the Pleuromutilin is a compound consisting of 5-6-8 tricyclic carbon skeletons with eight stereocenters and C (14) ethanol acid chains through X-ray crystal diffraction technology. In 1976, Knauseder et al conducted preliminary studies on the fermentation conditions, chemical structures and biosynthetic pathways of pleuromutilin producing bacteria Clitoillus paseckerianus.
Researches show that the pleuromutilin compound has other antibacterial drugs widely applied clinically, can selectively inhibit the synthesis of bacterial proteins through the interaction with 23S rRNA of a 50S ribosomal subunit, and has obvious inhibition effects on a plurality of gram-positive bacteria, partial gram-negative bacteria and mycoplasma. According to the unique antibacterial mechanism, the compounds interact with ribosome 50s subunit to inhibit the synthesis of bacterial protein, and basically do not influence the synthesis of protein in eukaryotic cells, and do not interact with the nuclear sugar body of mammal. It is different from the parent nucleus structure of common clinical antibacterial drugs, so that the cross drug resistance of the antibacterial drug with other structures is not easy to generate. It is worth noting that the C14 side chain in the structural molecule of the pleuromutilin compound can penetrate into the hydrophobic part of the ribosome subunit to influence the antibacterial activity, therefore, the chemical modification of the C14 side chain is always the key position for the modification of the pleuromutilin derivative.
At present, through the modification of the C14 side chain, the veterinary antibacterial drugs including tylosin (Tiamulin), Valnemulin (Valnemulin), the external human skin drug including restulin (Retapamulin) and the internal human drug including Lefamulin (Lefammulin) which is approved to be marketed by the FDA in the United states in 2019 are available on the market successfully.
Compared with the case that tens of medicaments are developed successfully based on the same mother nucleus, such as penicillin, cephalosporin and sarcin antibacterial medicaments, pleuromutilins only develop four antibacterial medicaments successfully, and the medicament-resistant bacteria aiming at the pleuromutilin antibacterial medicaments are not rare. The present inventors have previously conducted several patent applications relating to research and development of such derivatives, and in these studies, there have been some technical problems such as insufficient activity enhancement effect (CN 110467603 a and CN 110372615 a) or more steps required (CN 113149929 a). Therefore, there is a need to develop more pleuromutilin derivatives in order to obtain antibacterial agents with higher comprehensive quality.
Disclosure of Invention
In order to overcome the disadvantages and drawbacks of the prior art, it is a primary object of the present invention to provide pleuromutilin derivatives having a 4-aminobenzenethiol side chain, which have good antibacterial activity and are particularly suitable as novel antibacterial agents for the treatment of systemic infections in animals or humans.
Another object of the present invention is to provide a method for preparing the pleuromutilin derivative having a 4-aminobenzenethiol side chain as described above.
It is a further object of the present invention to provide the use of pleuromutilin derivatives having a 4-aminophenethiol side chain as described above.
The purpose of the invention is realized by the following technical scheme:
a pleuromutilin derivative having a 4-aminobenzenethiol side chain, said derivative being a compound having the structure shown in formula 2 or a pharmaceutically acceptable salt thereof, or a solvate, enantiomer, diastereomer, tautomer, or mixture thereof in any proportion, including a racemic mixture, of a pharmaceutically acceptable salt thereof:
wherein R is
R 1 Is one of nitro, fluorine atom, chlorine atom and hydrogen atom;
R 2 is one of nitro, trifluoromethyl, fluorine atom, chlorine atom and hydrogen atom;
R 3 is one of nitro, trifluoromethyl, cyano, fluorine atom, chlorine atom and hydrogen atom;
R 4 is one of nitro, trifluoromethyl, fluorine atom and chlorine atom;
R 5 is one of nitro, trifluoromethyl, fluorine atom and chlorine atom;
preferably, said R is 1 Is a hydrogen atom, R 2 Is trifluoromethyl, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is trifluoromethyl;
or said R is 1 Is nitro, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is nitro, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is nitro;
or the said R 1 Is a fluorine atom, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a fluorine atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is a fluorine atom;
or said R is 1 Is a chlorine atom, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a chlorine atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is a chlorine atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is a cyano group;
or said R is 1 Is a chlorine atom, R 2 Is a hydrogen atom, R 3 Is a fluorine atom;
preferably, said R is 4 、R 5 Are all trifluoromethyl;
or said R is 4 、R 5 Are all nitro;
or said R is 4 、R 5 Are all fluorine atoms;
or said R is 4 、R 5 Are all chlorine atoms;
or said R is 4 Is a fluorine atom, R 5 Is a chlorine atom;
specific groups of the compounds of the above preferred structures are summarized in Table 1:
compound numbers and specific groups of table 1
The pharmaceutically acceptable salt is a salt formed by a compound with a structure shown in a formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid;
the pharmaceutically acceptable salt preferably has the following structural formula:
the preparation method of the pleuromutilin derivative with the 4-aminobenzenethiol side chain comprises the following steps:
(1) the pleuromutilin and paratoluensulfonyl chloride react to obtain an intermediate I with a structure shown in a formula 3;
(2) taking the intermediate I prepared in the step (1) as a raw material, and reacting the intermediate I with 4-aminobenzenethiol to obtain an intermediate II with a structure shown in a formula 4;
(3) performing acylation reaction on the intermediate II prepared in the step (2) and acyl chloride or derivatives thereof and benzoyl chloride or derivatives thereof according to the molar ratio of 1:1.2 to obtain a target compound with a structure shown in a formula 2, namely the pleuromutilin derivative with a 4-aminobenzenethiol side chain;
the intermediates I and II have the structural formulas 3 and 4 respectively:
the molar ratio of the paratoluensulfonyl chloride to the pleuromutilin in the step (1) is preferably 1.1: 1;
the specific operation of the reaction described in step (2) is preferably:
dissolving the intermediate I and 4-aminothiophenol by using ethyl acetate as a solvent, adding a saturated solution of sodium hydroxide, and heating and refluxing for 2-3 h;
the dosage of the solvent is preferably 10 times of the mass of the intermediate I, and the molar ratio of the 4-aminobenzenethiol to the intermediate I is preferably 1.1: 1;
preferably, methanol is used as a solvent in the reaction in the step (3), and the reaction is carried out for 1-2 hours at room temperature;
the synthetic route of the preparation method is shown as the following reaction formula:
the pleuromutilin derivative with the 4-aminobenzenethiol side chain is applied to the preparation of antibacterial products;
the antibacterial product is preferably a medicament for treating infectious diseases;
the antibacterial product is further preferably an antibacterial drug for treating infectious diseases caused by gram-positive bacteria;
the infectious diseases are caused by infection of human or animals by drug-resistant staphylococcus aureus or multidrug-resistant bacteria;
the medicament contains pleuromutilin derivatives with 4-aminobenzenethiol side chains and one or more pharmaceutically acceptable carriers, excipients or diluents;
the preparation of the medicine comprises various clinical medicine dosage forms, such as tablets, injection, liposome nanoparticles, controlled release agents and the like;
an antibiotic medicament comprising a therapeutically effective amount of a pleuromutilin derivative having a 4-aminophenethiol side chain, the balance being pharmaceutically acceptable adjuvants or other compatible agents;
the pharmaceutical excipients refer to conventional pharmaceutical excipients, such as solvents, disintegrants, flavoring agents, preservatives, coloring agents, binders and the like;
the other compatible medicines are prepared by taking an effective dose of pleuromutilin derivative with a 4-aminobenzenethiol side chain as a medicinal raw material and then adding other natural medicines or chemical medicines;
compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the pleuromutilin compounds provided by the invention are novel compounds which have not been reported.
(2) The invention synthesizes a large number of pleuromutilin derivatives with brand new structures and 4-aminobenzenethiol side chains through extensive and intensive research, and performs extensive antibacterial activity screening, and discovers that the compounds not only have good in-vitro antibacterial activity, but also have the advantage of lower preparation cost than Valnemulin (Valnemulin) and Retapamulin (Retapamulin) for the first time, so the invention is particularly suitable for being used as a novel antibacterial agent for preventing and treating bacterial infectious diseases of human beings and animals, especially infectious diseases caused by drug-resistant staphylococcus aureus.
(3) The pleuromutilin derivative with the 4-aminobenzenethiol side chain prepared by the invention has good water solubility.
Drawings
FIG. 1 is a nuclear magnetic map of Compound 1.
FIG. 2 is a nuclear magnetic spectrum of Compound 3.
FIG. 3 is a nuclear magnetic map of Compound 7.
FIG. 4 is the nuclear magnetic spectrum of Compound 11.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
(1) Preparation of an intermediate I: 10.0g (26.5mmol) of pleuromutilin are dissolved in 20ml of acetonitrile and placed in an ice bath; dissolving 5.6g (29.2mmol) of p-methylbenzenesulfonyl chloride in 10ml of acetonitrile, slowly adding the pleuromutilin acetonitrile solution, stirring the mixed solution in an ice bath for 3 hours, evaporating the solvent under reduced pressure, sequentially adding 50ml of water and 50ml of dichloromethane, transferring the mixture into a separating funnel, shaking, and standing for layering; taking an organic phase, and sequentially washing the organic phase by using 100ml of 4mol/L sulfuric acid, 100ml of saturated sodium bicarbonate solution and 100ml of deionized water; and (3) evaporating the organic solution under reduced pressure after washing, adding 20ml of isopropanol into the residual solid, heating to dissolve, cooling to separate out a large amount of white powder, performing suction filtration, washing filter residue with isopropanol, and drying to obtain an intermediate I with a structure shown in the formula 3, wherein the yield is 81%.
(2) Preparation of intermediate II: dissolving 2g (3.75mmol) of intermediate I in 15ml of ethyl acetate, dissolving 0.47g (4.13mmol) of 4-aminobenzenethiol in the solution, adding 5ml of sodium hydroxide solution, and heating and refluxing at 70 ℃ for 3 h; the reaction solution was poured into a separatory funnel, extracted with 40ml of dichloromethane, washed twice with an aqueous sodium chloride solution (15% w/v) and dried over anhydrous sodium sulfate to obtain an organic phase; and (3) rotationally evaporating the obtained organic phase to obtain a mixture, redissolving the mixture, and purifying the crude product by using a column chromatography and a column (silica gel powder of 200-300 meshes is used as a stationary phase, and dichloromethane and methanol are 80: 1(V: V) are used as mobile phases) to obtain an intermediate II with a structure shown in a formula 4, wherein the yield is 72%.
EXAMPLE 222 Synthesis of- ((4-m-trifluoromethylbenzoyl) phenyl) Thiodexymulin (Compound 1)
0.9g (1.85mmol) of intermediate II, 0.46g (2.21mmol) of m-trifluoromethylbenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate were dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) rotatably evaporating the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the granularity of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the granularity of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4-m-trifluoromethyl benzoyl) phenyl) thiodeoxymianserin, and the yield is 76.2%. Wherein, FIG. 1 is the nuclear magnetic map of the compound 1.
EXAMPLE 322 Synthesis of- ((4-O-Nitrobenzoyl) phenyl) Thiodexymulin (Compound 3)
0.9g (1.85mmol) of intermediate II, 0.41g (2.21mmol) of o-nitrobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) rotatably evaporating the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4-o-nitrobenzoyl) phenyl) thio-deoxymianserin, and the yield is 41.5%. Wherein, FIG. 2 is the nuclear magnetic map of the compound 3.
EXAMPLE 422 Synthesis of- ((4-m-fluorobenzoyl) phenyl) thioxodexymuline (Compound 7)
0.9g (1.85mmol) of intermediate II, 0.35g (2.21mmol) of m-fluorobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) evaporating the obtained organic phase to dryness in a rotating manner to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the particle size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the particle size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4-m-fluorobenzoyl) phenyl) sulfo-deoxymianserin with the yield of 71.7%. Wherein, FIG. 3 is the nuclear magnetic map of Compound 7.
EXAMPLE 522 Synthesis of- ((4-p-chlorobenzoyl) phenyl) thiodeoxymuelin (Compound 11)
0.9g (1.85mmol) of intermediate II, 0.39g (2.21mmol) of p-chlorobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) rotatably evaporating the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4-p-chlorobenzoyl) phenyl) thiodeoxymianserin with the yield of 73.9%. Wherein, FIG. 4 is the nuclear magnetic spectrum of the compound 11.
EXAMPLE 622- ((4-P-Cyanobenzoyl) phenyl) Thiodexymulin (Compound 12) Synthesis
0.9g (1.85mmol) of intermediate II, 0.37g (2.21mmol) of p-cyanobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) performing rotary evaporation on the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of 100-200-mesh silica gel, fully mixing the mixture, and after the solvent is volatilized, purifying the crude product-silica gel powder mixture by using column chromatography (the silica gel powder with 200-300 meshes is used as a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is used as a mobile phase) to obtain a pure product of the product 22- ((4-p-cyanobenzoyl) phenyl) sulfo-deoxymialin with the yield of 36.0%.
Example 722 Synthesis of- ((4- (3, 5-dinitro) benzoyl) phenyl) thiodeoxymirinolin (Compound 14)
0.9g (1.85mmol) of intermediate II, 0.51g (2.21mmol) of 3, 5-dinitrobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and 50ml of dichloromethane, transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) evaporating the obtained organic phase to dryness in a rotating manner to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the particle size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the particle size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4- (3, 5-dinitro) benzoyl) phenyl) thio-deoxymianserin with the yield of 51.6%.
EXAMPLE 822- ((4- (3, 5-dichloro) benzoyl) phenyl) thioxodexymulin (Compound 18) Synthesis
0.9g (1.85mmol) of intermediate II, 0.51g (2.21mmol) of 3, 5-dichlorobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) evaporating the obtained organic phase to dryness in a rotating manner to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the particle size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the particle size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4- (3, 5-dichloro) benzoyl) phenyl) thio-deoxymianserin with the yield of 63.9%.
Example 922- ((4-cinnamoyl) phenyl) thiodeoxymirianine (compound 19) Synthesis 0.9g (1.85mmol) of intermediate II, 0.37g (2.21mmol) of cinnamoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate were dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) rotatably evaporating the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the size of 200-300 meshes is a stationary phase, and dichloromethane and methanol are 200: 1(V: V) are mobile phases to obtain a pure product of the product 22- ((4-cinnamamide) phenyl) sulfo-deoxymianserin with the yield of 22.8%.
EXAMPLE 1022 Synthesis of- ((4-Thiophenecarboxamido) phenyl) Thiodexymulin (Compound 20)
0.9g (1.85mmol) of intermediate II, 0.32g (2.21mmol) of thenoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) rotatably evaporating the obtained organic phase to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of 100-200-mesh silica gel, fully mixing, and after the solvent is volatilized, purifying the crude product-silica gel powder mixture by using column chromatography (the silica gel powder with 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase) to obtain a pure product of the product 22- ((4-thiophene formamido) phenyl) sulfo-deoxymianserin, wherein the yield is 66.4%.
EXAMPLE 1122- ((4-Furancarboxamido) phenyl) Thiodeoxymatrine (Compound 22) Synthesis
0.9g (1.85mmol) of intermediate II, 0.29g (2.21mmol) of furoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate are dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) evaporating the obtained organic phase to dryness in a rotating manner to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the particle size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the particle size of 200-300 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4-furoylamino) phenyl) sulfo-deoxymianserin with the yield of 67.3%.
Example 1222 Synthesis of- ((4- (2,3,4,5, 6-pentafluoro) benzoyl) phenyl) thiodeoxymuelin (Compound 25)
0.9g (1.85mmol) of intermediate II, 0.51g (2.21mmol) of 2,3,4,5, 6-pentafluorobenzoyl chloride and 1.20g (8.68mmol) of anhydrous potassium carbonate were dissolved in 25ml of methane; stirring the reaction system at normal temperature for 3h, sequentially adding 50ml of water and dichloromethane, then transferring to a separating funnel, shaking, standing for layering, washing an organic phase twice with a sodium chloride aqueous solution (15% w/v), drying with anhydrous sodium sulfate, and taking the organic phase; and (3) evaporating the obtained organic phase to dryness in a rotating manner to obtain a mixture, redissolving the mixture by using dichloromethane, adding 2g of silica gel with the particle size of 100-200 meshes, fully mixing the mixture, and purifying the crude product-silica gel powder mixture by using column chromatography after the solvent is volatilized, wherein the silica gel powder with the particle size of 200-300 meshes is a stationary phase, and the dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of the product 22- ((4- (2,3,4,5, 6-pentafluoro) benzoyl) phenyl) thio-deoxymirin, wherein the yield is 38.1%.
Effects of the embodiment
(1) In vitro bacteriostasis experiment
The experiment was performed by broth dilution. The experimental control drugs are selected from tiamulin, valnemulin, ritamolin, vancomycin, compound 1 and compound 8 in the patent application with the publication number CN 110372615A. Tiamulin is pleuromutilin antibiotic and is one of ten veterinary antibiotics in the world, valnemulin is a veterinary antibiotic which is widely applied at present in the pleuromutilin antibiotics, ritamicin is listed on the market as a first human pleuromutilin antibiotic medicament through US FDA approval in 2007, and vancomycin is a glycopeptide antibiotic and is a high-efficiency antibacterial medicament of methicillin-resistant staphylococcus aureus.
The strains used in the experiment were methicillin-resistant staphylococcus aureus ATCC43300 and staphylococcus aureus ATCC 29213.
Preparing a target compound stock solution: accurately weighing 6.4mg of target compound respectively, placing in a 5mL volumetric flask, dissolving with 0.25mL of LDMSO, adding 0.25mL of Tween 80 and 4.5mL of ultrapure water, mixing thoroughly with a vortex instrument to obtain stock solution, sterilizing with 0.22 μm filter membrane, packaging with small tube, and storing at-20 deg.C. The control drugs tiamulin, valnemulin, ritamoulin and vancomycin were prepared in the same manner as described above.
Preparing a bacterial liquid: taking out the strain which is well preserved at the temperature of minus 20 ℃, inoculating the strain on a new MH plate, culturing for 24h at the temperature of 37 ℃, selecting a single colony, inoculating the single colony in an MH culture medium, and culturing for 24h again; single colonies were picked, transferred to sterile saline and adjusted to a turbidity of 0.5 McF. The concentration of the bacterial liquid at this time was 10 5 CFU/mL。
Preparation of MIC plate: respectively diluting the target compound stock solutions (1280 mu g/mL) by 4 times to obtain target compound solutions with the concentration of 160 mu g/mL; taking a sterile 96-well plate, adding 180 mu L of MH broth culture medium into the 1 st well, respectively adding 100 mu L of MH broth culture medium into the 2 nd to 12 th wells, adding 20 mu L of antibacterial drug with the concentration of 160 mu g/mL into the 1 st well, uniformly mixing, adding 100 mu L into the 2 nd well, uniformly mixing, sucking 100 mu L to the 3 rd well, and the like, sucking 100 mu L from the 12 th well and discarding. The drug concentration in each well is as follows: 16. 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.0075g/mL, three groups of each concentration of drug were made in parallel.
Inoculating a bacterial liquid: 100. mu.L of the bacterial suspension was added to each of the 1 to 12 wells so that the final bacterial suspension concentration in each well was about 5X 10 5 CFU/mL, and the drug concentrations from the 1 st to the 12 th holes are respectively 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03, 0.015, 0.0075 and 0.00325 mug/mL. And placing the inoculated 96-well plate in an incubator at 37 ℃ for culture, and observing the growth condition of the bacterial liquid for 24 hours. Control drugs were plated in the same way. The lowest drug concentration that completely inhibited bacterial growth in the wells was the MIC, and the bacteria in the positive control wells (i.e., no drug) needed to grow significantly. When a single hop occurs in the microbuly dilution method, the highest concentration of drug that inhibits the bacteria is recorded, and the test is repeated if multiple hops occur.
Table 3 shows the MIC results, which indicates that compared with the control drug, the target compound has good bacteriostatic activity on the selected strains, can significantly inhibit the growth of the drug-resistant staphylococcus aureus, and is particularly suitable for being used as a novel antibacterial drug for preventing and treating infectious diseases caused by human or animals or drug-resistant staphylococcus aureus or multidrug-resistant bacteria.
TABLE 3 in vitro bacteriostatic data
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A pleuromutilin derivative having a 4-aminophenethiol side chain, wherein: the derivative is a compound with a structure shown in formula 2 or a pharmaceutically acceptable salt thereof, or a solvate, enantiomer, diastereoisomer, tautomer or mixture thereof in any proportion of the pharmaceutically acceptable salt, including a racemic mixture:
wherein R is
R 1 Is one of nitro, fluorine atom, chlorine atom and hydrogen atom;
R 2 is one of nitro, trifluoromethyl, fluorine atom, chlorine atom and hydrogen atom;
R 3 is one of nitro, trifluoromethyl, cyano, fluorine atom, chlorine atom and hydrogen atom;
R 4 is one of nitro, trifluoromethyl, fluorine atom and chlorine atom;
R 5 is one of nitro, trifluoromethyl, fluorine atom and chlorine atom.
2. Pleuromutilin derivatives with a 4-aminophenethiol side chain as claimed in claim 1, characterized in that:
the R is 1 Is a hydrogen atom, R 2 Is trifluoromethyl, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is trifluoromethyl;
or said R is 1 Is nitro, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is nitro, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is nitro;
or the said R 1 Is a fluorine atom, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a fluorine atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is a fluorine atom;
or the said R 1 Is a chlorine atom, R 2 Is a hydrogen atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a chlorine atom, R 3 Is a hydrogen atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is a chlorine atom;
or said R is 1 Is a hydrogen atom, R 2 Is a hydrogen atom, R 3 Is cyano;
or said R is 1 Is a chlorine atom, R 2 Is a hydrogen atom, R 3 Is a fluorine atom.
3. Pleuromutilin derivatives with a 4-aminophenethiol side chain as claimed in claim 1, characterized in that:
said R is 4 、R 5 Are all trifluoromethyl;
or the said R 4 、R 5 Are all nitro;
or the said R 4 、R 5 Are all fluorine atoms;
or the said R 4 、R 5 Are all chlorine atoms;
or said R is 4 Is a fluorine atom, R 5 Is a chlorine atom.
4. A pleuromutilin derivative having a 4-aminophenethiol side chain as claimed in any one of claims 1 to 3 wherein:
the pharmaceutically acceptable salt is a salt formed by the compound shown in the formula 2 and hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, glutamic acid or aspartic acid.
5. Pleuromutilin derivatives with a 4-aminophenethiol side chain as claimed in claim 4, characterized in that:
the pharmaceutically acceptable salt preferably has the following structural formula:
6. the method for producing a pleuromutilin derivative having a 4-aminophenethiol side chain according to any one of claims 1 to 5, characterized by comprising the steps of:
(1) the pleuromutilin and paratoluensulfonyl chloride react to obtain an intermediate I with a structure shown in a formula 3;
(2) taking the intermediate I prepared in the step (1) as a raw material, and reacting the intermediate I with 4-aminobenzenethiol to obtain an intermediate II with a structure shown in a formula 4;
(3) performing acylation reaction on the intermediate II prepared in the step (2) and acyl chloride or derivatives thereof and benzoyl chloride or derivatives thereof according to the molar ratio of 1:1.2 to obtain a target compound with a structure shown in a formula 2, namely the pleuromutilin derivative with a 4-aminobenzenethiol side chain;
the intermediate I and the intermediate II have structural formulas shown as formula 3 and formula 4 respectively:
7. the method of claim 6, wherein: the molar ratio of the p-toluenesulfonyl chloride to the pleuromutilin in the step (1) is 1.1: 1;
the reaction in the step (2) specifically comprises the following steps: dissolving the intermediate I and 4-aminobenzenethiol by using ethyl acetate as a solvent, adding a sodium hydroxide saturated solution, and heating and refluxing for 2-3 h; the dosage of the solvent is 10 times of the mass of the intermediate I, and the molar ratio of the 4-aminobenzenethiol to the intermediate I is 1.1: 1;
and (3) reacting for 1-2 hours at room temperature by using methanol as a solvent.
8. Use of a pleuromutilin derivative having a 4-aminophenethiol side chain as claimed in any one of claims 1 to 5 in the manufacture of an antibacterial product.
9. Use according to claim 8, characterized in that: the antibacterial product comprises a pleuromutilin derivative having a 4-aminophenethiol side chain and one or more pharmaceutically acceptable carriers, excipients or diluents.
10. An antibiotic drug comprising a therapeutically effective amount of a pleuromutilin derivative having a 4-aminophenethiol side chain as claimed in any one of claims 1 to 5, with the balance being pharmaceutically acceptable adjuvants or other compatible drugs.
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| CN115850137A (en) * | 2022-11-12 | 2023-03-28 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative compound and preparation method and application thereof |
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| CN1364158A (en) * | 1999-07-30 | 2002-08-14 | 生物化学有限公司 | Mutilin derivatives and their use as antibacterials |
| CN106565564A (en) * | 2016-09-30 | 2017-04-19 | 华南农业大学 | Pleuromutilin derivative with 2-amino phenyl mercaptan side chain and preparing method and application of pleuromutilin derivative |
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| CN1364158A (en) * | 1999-07-30 | 2002-08-14 | 生物化学有限公司 | Mutilin derivatives and their use as antibacterials |
| CN106565564A (en) * | 2016-09-30 | 2017-04-19 | 华南农业大学 | Pleuromutilin derivative with 2-amino phenyl mercaptan side chain and preparing method and application of pleuromutilin derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115850137A (en) * | 2022-11-12 | 2023-03-28 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative compound and preparation method and application thereof |
| CN115850137B (en) * | 2022-11-12 | 2024-04-12 | 中国农业科学院兰州畜牧与兽药研究所 | Pleuromutilin derivative compound and preparation method and application thereof |
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