CN113149929A

CN113149929A - Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof

Info

Publication number: CN113149929A
Application number: CN202110434606.6A
Authority: CN
Inventors: 汤有志; 刘杰; 李雅军; 靳珍
Original assignee: South China Agricultural University
Current assignee: South China Agricultural University
Priority date: 2021-04-22
Filing date: 2021-04-22
Publication date: 2021-07-23
Anticipated expiration: 2041-04-22
Also published as: CN113149929B

Abstract

The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain, and preparation and application thereof. The pleuromutilin derivative with 1, 3, 4-oxadiazole side chain is a compound shown in formula 2 or pharmaceutically acceptable salt thereof, and a solvate, enantiomer, diastereoisomer, tautomer or mixture of the compound shown in formula 2 or pharmaceutically acceptable salt thereof in any proportionA compound, including a racemic mixture. The pleuromutilin derivative has good antibacterial activity, is particularly suitable to be used as a novel antibacterial drug for the systemic infection of animals or human bodies, and has good water solubility.

Description

Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof

Technical Field

The invention belongs to the field of medicinal chemistry, and particularly relates to a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain, and preparation and application thereof.

Background

As one of the major pathogens with high morbidity and mortality, Multidrug Resistant Staphylococcus Aureus (MRSA) often causes healthcare-related infections, posing a serious threat to human health worldwide. Therefore, there is an urgent need to develop new antibiotics with new modes of action for the treatment of infections caused by multidrug-resistant staphylococcus aureus (MRSA).

Natural products have long played an important role in the management of human diseases, especially in the field of infectious diseases. Despite some disadvantages, a number of natural products or derivatives thereof have been developed and approved for use as antibacterial agents, such as aztreonam, vancomycin, tigecycline, and penicillin G. The development of new antibacterial agents from natural products or their semisynthetic derivatives remains the most effective way to combat MRSA infections.

Pleuromutilin (formula 1) is a natural tricyclic diterpenoid compound, is produced by culturing Pleurotus mutilus and Pleurotus Passtekeriana, and has structures of eight stereocenters, extremely rigid 5-6-8 tricyclic carbon skeletons, an ethanol acid chain of C (14) and the like.

Studies show that pleuromutilins and derivatives thereof show effective antibacterial activity on gram-positive bacteria and are different from other antibacterial drugs widely used clinically, and pleuromutilins and derivatives thereof can inhibit the synthesis of bacterial proteins by being combined with a V region of a Peptidyl Transferase Center (PTC) of bacterial 50s ribosomal subunit 23s RNA. Due to the unique mechanism of action, pleuromutilins and derivatives thereof have a low incidence of cross-resistance with other antibacterial agents and a low tendency to develop bacterial resistance, while not interacting substantially with mammalian nuclear glycosomes and interfering with protein synthesis in eukaryotic cells. The researchers noted that the side chain of C14 in the pleuromutilin structure molecule can penetrate into the hydrophobic group of the ribosome subunit to improve the antibacterial activity. Therefore, modification of the C14 side chain by chemical means has been an important means to improve the potency of pleuromutilin derivatives.

To date, by modifying its C14 side chain, the successful marketed antibacterial drugs are the veterinary antibacterial drugs Tiamulin (Tiamulin), Valnemulin (Valnemulin), the topical human skin drug Retapamulin (Retapamulin) and the human drug lefumulin (Lefamulin) marketed by FDA approval in 2019 for the treatment of community-acquired bacterial pneumonia (CABP), all four.

Compared with tens of drugs developed successfully based on the same mother nucleus, such as penicillin, cephalosporin and sarcin antibacterial drugs, pleuromutilin is only used for successfully developing four antibacterial drugs, and the drug-resistant bacteria aiming at the pleuromutilin antibacterial drugs are not rare. Therefore, development of more pleuromutilin antibacterial agents is necessary.

Disclosure of Invention

In order to overcome the disadvantages and drawbacks of the prior art, the present invention has as its primary object the provision of a pleuromutilin derivative having a 1, 3, 4-oxadiazole side chain, which has good antibacterial activity and is particularly suitable as a novel antibacterial agent for systemic infections in animals or humans.

Another object of the present invention is to provide a process for the preparation of the pleuromutilin derivatives having a 1, 3, 4-oxadiazole side chain as described above.

It is a further object of the present invention to provide the use of pleuromutilin derivatives having a 1, 3, 4-oxadiazole side chain as described above.

The purpose of the invention is realized by the following technical scheme:

a pleuromutilin derivative having a 1, 3, 4-oxadiazole side chain, which is a compound of formula 2 or a pharmaceutically acceptable salt thereof, and a solvate, enantiomer, diastereomer, tautomer, or mixture thereof, in any proportion, including a racemic mixture, of said compound of formula 2 or a pharmaceutically acceptable salt thereof:

wherein R is R₁Or

R₁Is one of hydrogen atom, furyl, thienyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and pyrazinyl;

R₂is one of methyl, trifluoromethyl, amino, hydroxyl, hydrogen atom, fluorine atom, chlorine atom and bromine atom;

R₃is one of methyl, nitryl, amino, hydrogen atom, fluorine atom, chlorine atom and bromine atom;

R₄is one of methyl, trifluoromethyl, amino, dimethylamino, hydroxyl, methoxyl, hydrogen atom, fluorine atom, chlorine atom and bromine atom;

and R is₂、R₃、R₄Cannot be simultaneously hydrogen atoms;

preferably, said R is₂Is methyl, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is methyl, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is methyl;

or R₂Is trifluoromethyl, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is trifluoromethyl;

or R₂Is a hydrogen atom, R₃Is amino, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is amino;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is dimethylamino;

or R₂Is a hydrogen atom, R₃Is nitro, R₄Is a hydrogen atom;

or R₂Is hydroxy, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a hydroxyl group;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is methoxy;

or R₂Is a fluorine atom, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a fluorine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a fluorine atom;

or R₂Is a chlorine atom, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a chlorine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a chlorine atom;

or R₂Is a hydrogen atom, R₃Is a bromine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a bromine 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 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;

the pharmaceutically acceptable salt preferably has the following structural formula:

the preparation method of the pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain comprises the following steps:

(1) the pleuromutilin and p-methylbenzenesulfonyl chloride are reacted to obtain an intermediate I with a structure shown in a formula 3;

(2) reacting carboxylic acid serving as a raw material with absolute ethyl alcohol to obtain an intermediate II with a structure shown in a formula 4;

(3) reacting the intermediate II prepared in the step (2) with hydrazine hydrate to obtain an intermediate III with a structure shown in a formula 5;

(4) reacting the intermediate III prepared in the step (3) with carbon disulfide to obtain an intermediate IV shown as a formula 6 (corresponding to compounds 1 c-28 c in the embodiment of the invention);

(5) taking the intermediate I prepared in the step (1) as a raw material, further activating by sodium iodide, and then reacting with the intermediate IV prepared in the step (4) to obtain the pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain and the structure shown in the formula 2;

the intermediates I, II, III and IV respectively have structural formulas of 3-6:

the molar ratio of the paratoluensulfonyl chloride to the pleuromutilin in the step (1) is preferably 1.1: 1;

the molar ratio of the carboxylic acid to the absolute ethyl alcohol in the step (2) is preferably 1: 1.1;

preferably, absolute ethyl alcohol is adopted as a solvent in the reaction in the step (3), the molar ratio of the intermediate II to hydrazine hydrate is preferably 1:1, and the reaction condition is preferably 25-40 ℃ for 2-3 h;

the specific operation of the reaction described in step (4) is preferably:

dissolving potassium hydroxide by using 95% (v/v) ethanol as a solvent, adding the intermediate III in an ice bath, dropwise adding carbon disulfide, and heating and refluxing at 78-80 ℃ for 3-4 hours;

the dosage of the 95% (v/v) ethanol is preferably 5-20 times of the mass of the intermediate III, the molar ratio of the potassium hydroxide to the intermediate III is preferably 1.2:1, and the molar ratio of the carbon disulfide to the intermediate III is preferably 1.1: 1;

the specific operation of the activation in the step (5) is preferably:

dissolving the intermediate I by using acetonitrile as a solvent, adding sodium iodide and alkali, and heating and refluxing for 1-3 h at 78 ℃;

the using amount of the acetonitrile is preferably 30-40 times of the mass of the intermediate I, the molar ratio of the alkali to the intermediate I is preferably 2:1, and the molar number of the sodium iodide is preferably 10% of that of the alkali;

the alkali is preferably sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate or cesium carbonate;

the reaction condition in the step (5) is preferably heating reflux at 78-80 ℃ for 1-3 h;

the synthetic route is shown as the following formula:

the pleuromutilin derivative with the 1, 3, 4-oxadiazole 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 the infectious diseases caused by the infection of human or animals by drug-resistant staphylococcus aureus or multi-drug-resistant bacteria;

the medicament may contain 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 an effective amount of a pleuromutilin derivative having a 1, 3, 4-oxadiazole side chain, the balance being a pharmaceutically acceptable adjuvant or other compatible agent;

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 1, 3, 4-oxadiazole side chain as a medicine raw material and then adding other natural medicines or chemicals;

compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the pleuromutilin derivatives provided by the invention are novel compounds which have not been reported.

(2) According to the invention, through extensive and intensive research, a large number of pleuromutilin derivatives with brand-new structures and 1, 3, 4-oxadiazole side chains are synthesized, and extensive antibacterial activity screening is carried out, so that the compounds are firstly found to have good in-vitro antibacterial activity and have the advantage of low preparation cost compared with Valnemulin (Valnemulin) and Retapamulin (Retapamulin), and therefore, the pleuromutilin derivatives are particularly suitable for being used as novel antibacterial drugs for preventing and treating bacterial infectious diseases of human beings or animals, especially infectious diseases caused by drug-resistant staphylococcus aureus.

(3) The pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain prepared by the invention has good water solubility.

Drawings

FIG. 1 is a nuclear magnetic map of Compound 2.

FIG. 2 is a nuclear magnetic map of Compound 3.

FIG. 3 is a nuclear magnetic map of Compound 15.

FIG. 4 is a nuclear magnetic map of Compound 19.

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.

In the examples, R-COOCH₂CH₃Wherein R is R₁Or

Wherein, the specific group R₁、R₂、R₃、R₄See table 1, all are commercially available, as are other reagents.

Example 1

(1) Preparation of an intermediate I: 10.0g (26.5mmol) of pleuromutilin are dissolved in 20ml of pyridine and placed in an ice bath; dissolving 5.6g (29.2mmol) of p-methylbenzenesulfonyl chloride in 10ml of pyridine, then slowly adding the pleuromutilin pyridine solution, stirring the mixed solution in an ice bath for 3 hours, sequentially adding 50ml of ice water and 50ml of trichloromethane, transferring the mixed solution to 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; evaporating the organic solution under reduced pressure after washing, adding 20ml of isopropanol into the residual solid, heating for dissolving, cooling, precipitating a large amount of white powder, performing suction filtration, washing the filter residue with isopropanol, and drying to obtain an intermediate I with a structure shown in formula 3, wherein the yield is 81%;

(2) intermediate II1a preparation: 155.5mmol of carboxylic acid (R-COOCH) was taken₂CH₃Wherein R is H) is dissolved in 10ml of absolute ethyl alcohol, the mixed solution is stirred for 3min in an ice bath, 0.15ml of concentrated sulfuric acid is slowly added, and the heating reflux is carried out for 4H at the temperature of 115 ℃; pouring the reaction solution into a separating funnel, adding 30ml of dichloromethane for extraction, washing twice with deionized water, drying with anhydrous sodium sulfate after washing, and taking an organic phase; the obtained organic phase is subjected to rotary evaporation to dryness to obtain an intermediate II1a with a structure shown in a formula 4, and the yield is 76.72%;

(3) intermediate III1b preparation: under the mechanical stirring, slowly adding 2.0g (40mmol) of hydrazine hydrate into 10ml of absolute ethyl alcohol, then slowly adding 40mmol of intermediate II, reacting at room temperature of 25 ℃ for 2h, then carrying out ice bath, separating out a large amount of solid, and carrying out suction filtration; the product was dried in a vacuum desiccator over CaCl₂Drying, finally using P₂ O₅Drying to obtain an intermediate III1b with a structure shown in a formula 5, wherein the yield is 70.88%;

(4) preparation of Compound 1c (intermediate IV-1): 0.67g (12mmol) of potassium hydroxide is dissolved in 15ml of 95% (v/v) ethanol, and 60.06mg (10mmol) of intermediate III is added under ice bath conditions; slowly dripping 0.84g (11mmol) of carbon disulfide into the reaction system, and heating and refluxing at 80 ℃ after dripping is finished; heating and refluxing for 3h, dropwise adding concentrated hydrochloric acid into the reaction system under the ice bath condition, adjusting the pH value of the reaction system to 1, precipitating a large amount of crystals, and performing suction filtration; the crystals were dried in a vacuum desiccator over CaCl₂Drying, finally using P₂ O₅Drying to obtain the compound 1c (intermediate IV-1) with the structure shown in the formula 6, wherein the yield is 81.17%.

According to the methods of the steps (1) - (4) (the molar weight of each reactant, the reaction conditions, the purification and the like are the same), intermediates II2 a-II 28a (yield 75.55-88.64%), intermediates III2 b-III 28b (yield 62.84-74.25%) and compounds 2 c-28 c (yield 75.35-86.54%) are obtained, and the yield of each intermediate is shown in Table 2.

Example 222 preparation of O- (1, 3, 4-oxadiazolyl) thiaacetyl sulindac (Compound 1)

Dissolving 2.13g (4mmol) of the intermediate I prepared in example 1 in 81ml of acetonitrile, adding 0.12g (0.8mmol) of anhydrous sodium iodide and 1.11g (8mmol) of anhydrous potassium carbonate, heating and refluxing at 78 ℃ for reaction for 2h, then adding 0.45g (4.4mmol) of 1, 3, 4-1, 3, 4-oxadiazole-2-thiol (intermediate IV-1) prepared in example 1 in the system, continuing to react at 78 ℃ for 3h, pouring the reaction liquid into a separating funnel, sequentially adding 50ml of distilled water and chloroform, shaking, standing for layering, washing an organic phase twice with an aqueous solution of sodium chloride (15% w/v), drying with anhydrous sodium sulfate, and taking an organic phase; and (3) rotationally evaporating the obtained organic phase to dryness 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, 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 100-200 meshes is a stationary phase, and dichloromethane: methanol is 200: 1(V: V) is a mobile phase to obtain a pure product of 22-O- (1, 3, 4-1, 3, 4-oxadiazolyl) thioacetyl mianserin, and the yield is 73.74%.

EXAMPLE 3 preparation of Compounds 2 to 28

Following the same procedures as in example 2 (the molar amounts of the reactants, the reaction conditions, the purification, etc. were the same as in example 2), the corresponding products represented by formula 2, numbered 2 to 28, were obtained by replacing only compound 1c (intermediate IV-1) with compounds 2c to 28c (intermediate IV-2 to intermediate IV-28). Wherein, FIGS. 1 to 4 are nuclear magnetic map spectra of the compounds 2, 3, 15 and 19.

The yields of the above compounds are summarized in Table 2.

TABLE 2 Compound numbers and yields

Effects of the embodiment

(1) In vitro bacteriostasis experiment

The experiment was performed by broth dilution. Tiamulin is selected as an experimental control medicament. Tiamulin is a pleuromutilin antibiotic, and is one of ten veterinary antibiotics in the world.

The strains used in the experiments were methicillin-resistant Staphylococcus aureus ATCC43300 and Staphylococcus aureus ATCC29213, clinical Staphylococcus aureus (Staphylococcus aureus) AD3 and clinical Staphylococcus aureus (S.aureus)144 (clinical strains AD3 and 144 were isolated and identified in the Pharmacology laboratory of the college of veterinary medicine of the southern agricultural university, as disclosed in the literature Zhe Z A, Kang L A, Gyz A, et al Design, Synthesis and biological activities of novel and synergistic tissue derivatives, and their derivatives are available in the literature Zhe Z A, Kang L A, Gyz A, et al.

Preparing a target compound stock solution: accurately weighing 6.4mg of target compound respectively, placing in a 10mL volumetric flask, dissolving with 0.25mL of LDMSO, adding 9.5mL of distilled water and 0.25mL of Tween 80 to a constant volume, shaking up sufficiently to obtain stock solution (6.4mg/mL), sterilizing with a 0.22 μm filter membrane, packaging with small tube, and storing at-20 deg.C. The control drug tiamulin was also formulated 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; selecting single colony, transferring into sterile physiological saline, and adjusting turbidity to 0.6McF, wherein the bacterial liquid concentration is 10⁶CFU/mL。

Preparation of MIC plate: respectively diluting the stock solutions (6.4mg/mL) of the target compounds by 10 times to obtain target compound solutions with the concentration of 640 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 10 th wells, adding 20 mu L of antibacterial drug with the concentration of 640 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: 64. 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 μ g/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 concentration of the bacterial suspension per well was about 5X 10⁵CFU/mL, and the drug concentrations of the 1 st to 12 th holes are 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, 0.03 and 0.015 mu g/mL respectively. 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. The control drug tiamulin is determined by the same method, the minimum drug concentration for completely inhibiting the growth of bacteria in a small hole is MIC, and the bacteria in a positive control hole (containing no drug) need to obviously grow. 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 indicate that the target compound has good bacteriostatic activity against the selected strains and good activity against drug-resistant staphylococcus aureus, and is particularly suitable for use as a novel antibacterial agent for preventing or treating infectious diseases caused by humans or animals or drug-resistant staphylococcus or multi-drug-resistant bacteria.

TABLE 3 in vitro bacteriostatic data

(2) Determination of solubility of Compounds

Compounds 2, 3, 15 and 19 were sulfated as compared to the sulfate salt of ritalalin. High performance liquid chromatography is adopted to measure the solubility of the compounds in water. The test results are shown in Table 4.

TABLE 4 solubility of sulfate salts of compounds 2, 3, 15, 19 and of ritamalin

Compound (I)	Solubility (mg/mL, pH 7.0 in water)
		2	1.42
3	1.57
		15	1.85
19	2.32
		Rutacamulin (Retapamulin)	0.11

As can be seen from Table 4, the tested compounds all have good water solubility, are superior to the solubility of the salt of rituximab, and improve the solubility of the pleuromutilin derivatives, wherein the water solubility of the sulfate salt of the compound 19 reaches 2.32 mg/mL.

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

1. A pleuromutilin derivative having a 1, 3, 4-oxadiazole side chain, characterized by being a compound of formula 2 or a pharmaceutically acceptable salt thereof, and a solvate, enantiomer, diastereomer, tautomer, or mixture thereof, in any proportion, including a racemic mixture, of said compound of formula 2 or a pharmaceutically acceptable salt thereof:

wherein R is R₁Or

and R is₂、R₃、R₄Cannot be simultaneously hydrogen atoms.

2. Pleuromutilin derivatives with a 1, 3, 4-oxadiazole side chain according to claim 1, characterized in that:

the R is₂Is methyl, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is methyl, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is methyl;

or R₂Is trifluoromethyl, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is trifluoromethyl;

or R₂Is a hydrogen atom, R₃Is amino, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is amino;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is dimethylamino;

or R₂Is a hydrogen atom, R₃Is nitro, R₄Is a hydrogen atom;

or R₂Is hydroxy, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a hydroxyl group;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is methoxy;

or R₂Is a fluorine atom, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a fluorine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a fluorine atom;

or R₂Is a chlorine atom, R₃Is a hydrogen atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a chlorine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a chlorine atom;

or R₂Is a hydrogen atom, R₃Is a bromine atom, R₄Is a hydrogen atom;

or R₂Is a hydrogen atom, R₃Is a hydrogen atom, R₄Is a bromine atom.

3. Pleuromutilin derivatives with a 1, 3, 4-oxadiazole side chain according to claim 1, characterized in that:

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.

4. Pleuromutilin derivatives with a 1, 3, 4-oxadiazole side chain according to claim 3, characterized in that:

the pharmaceutically acceptable salt has the following structural formula:

5. a process for the preparation of a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain as claimed in any of claims 1 to 4, comprising the steps of:

(4) reacting the intermediate III prepared in the step (3) with carbon disulfide to obtain an intermediate IV shown as a formula 6;

(5) and (3) taking the intermediate I prepared in the step (1) as a raw material, further activating by sodium iodide, and then reacting with the intermediate IV prepared in the step (4) to obtain the pleuromutilin derivative with the 1, 3, 4-oxadiazole side chain and the structure shown in the formula 2.

6. The process for the preparation of pleuromutilin derivatives with a 1, 3, 4-oxadiazole side chain according to claim 5, wherein:

7. use of a pleuromutilin derivative having a 1, 3, 4-oxadiazole side chain as claimed in any one of claims 1 to 4 in the preparation of an antibacterial product.

8. Use of a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain according to claim 7 in the preparation of an antibacterial product, wherein:

the antibacterial product is a medicament for treating infectious diseases.

9. Use of a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain according to claim 8 in the preparation of an antibacterial product, wherein:

the infectious diseases are the infectious diseases caused by the infection of human beings or animals by drug-resistant staphylococcus aureus or multi-drug-resistant bacteria.

10. Use of a pleuromutilin derivative with a 1, 3, 4-oxadiazole side chain according to claim 8 in the preparation of an antibacterial product, wherein:

the medicament contains one or more pharmaceutically acceptable carriers, excipients or diluents.