CN114671865A - Pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chain and preparation method and application thereof - Google Patents

Pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chain and preparation method and application thereof Download PDF

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CN114671865A
CN114671865A CN202210319456.9A CN202210319456A CN114671865A CN 114671865 A CN114671865 A CN 114671865A CN 202210319456 A CN202210319456 A CN 202210319456A CN 114671865 A CN114671865 A CN 114671865A
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thiazole
side chain
quaternary ammonium
pleuromutilin
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梁承远
赵宇晴
李京忆
辛亮
田蕾
张洁
张少军
武康雄
韩俊杰
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Xixian New Area Fenghou Original Medical Technology Co ltd
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Abstract

The invention discloses a pleuromutilin derivative containing a thiazole-pyridine alkyl quaternary ammonium salt side chain as well as a preparation method and application thereof, belonging to the technical field of medical chemistry. The C-14 side chain of the pleuromutilin is modified by using 2-sulfydryl-4- (4-pyridyl) thiazole and further quaternized by using bromoalkane, so that the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain which is not reported is synthesized. Preliminary biological activity tests show that the derivatives containing thiazole-pyridine alkyl quaternary ammonium salt side chain pleuromutilin have better antibacterial activity, particularly resist drug-resistant bacteria, the drug effect of the derivatives is obviously superior to that of three marketed pleuromutilin antibiotics, and the results show that the derivatives have important value in the development of drug-resistant bacteria resistant drugs and have potential to be applied to the treatment of infectious diseases as novel antibiotics.

Description

Pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chain as well as preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a pleuromutilin derivative containing a thiazole-pyridine alkyl quaternary ammonium salt side chain, and a preparation method and application thereof.
Background
Bacterial resistance to antibiotics is increasingly becoming a huge threat affecting global population health, and the spread of antibiotic resistance is faster than the rate at which newly discovered compounds enter the clinic, and has created a public health crisis. The World Health Organization (WHO) states that mutation of microorganisms leads to drug resistance, thereby rendering the drug ineffective, increasing the risk of transmission to others due to the persistence of infection in the body, and about 30% of all people worldwide die from infection with drug-resistant staphylococcus aureus every year. Researchers have developed new antibiotics by chemically modifying already synthesized antibiotics to obtain "semi-synthetic" antibiotics. Among them, Pleuromutilin (Pleuromutilin) has been developed into four antibiotics, which are natural products with unique action mechanism and novel structure. Pleuromutilins and derivatives thereof have raised promise for the treatment of drug resistant strains such as methicillin-resistant Staphylococcus aureus and broadly drug resistant Mycobacterium tuberculosis.
The heterocyclic structure has unique biological activity such as high systemic property, low toxicity and good bacteriostatic property, is often used as a structural component unit of medicines and pesticides, and plays an important role in the synthesis of medicines and pesticides. The pyridine heterocycle is one of the most important nitrogen-containing heterocycles, and is an important component fragment which is frequently developed by operating bacteriostatic drugs in recent years, such as a high-efficiency bactericide, namely flurazole, and gradually forms a large specific drug series.
The quaternary ammonium salt is a compound generated by replacing four hydrogen atoms in ammonium ions with alkyl, can hydrolyze quaternary ammonium cations in water, has strong adsorption effect on negative charges on cell walls on the surfaces of bacteria, can penetrate cell membranes, enables substances in the cells to leak, hinders the semi-permeation effect of the cell membranes, finally denatures proteins, kills the bacteria cells, and has good bactericidal property.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a pleuromutilin derivative containing a thiazole-pyridine alkyl quaternary ammonium salt side chain, and a preparation method and application thereof for treating infectious diseases.
In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:
the invention discloses a pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chains, which is a compound shown in a general formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer, a tautomer or a mixture of the compound shown in the general formula I and the pharmaceutically acceptable salt thereof in any proportion, and comprises a racemic mixture:
Figure BDA0003571017990000011
wherein: r is one of alkyl with 3-16 carbon atoms or one of cycloalkyl with 3-7 carbon atoms.
Preferably, representative compounds are shown below:
Figure BDA0003571017990000021
preferably, the pharmaceutically acceptable salt is a salt of the compound of the general formula i with 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 invention also discloses a preparation method of the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain, which comprises the following steps:
1) the pleuromutilin and paratoluensulfonyl chloride are used as raw materials to react to obtain an intermediate I;
wherein the intermediate I is
Figure BDA0003571017990000022
2) Taking the intermediate I obtained in the step 1) and 2-mercapto-4- (4-pyridyl) thiazole as raw materials, heating to react under the condition of an alkaline catalyst, and purifying to obtain an intermediate II;
wherein the intermediate II is
Figure BDA0003571017990000023
3) Reacting the intermediate II obtained in the step 2) with various substituted alkyl bromides, and purifying to obtain the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain and having the structure shown in the general formula I.
Preferably, in the step 1), the solvent used for the reaction is dichloromethane; the reaction condition is that the reaction lasts for 5 hours at room temperature; the molar ratio of pleuromutilin to p-toluenesulfonyl chloride is 1: 1.2; in the step 2), the solvent used for the reaction is N, N-dimethylformamide; the reaction condition is heating reaction at 60 ℃ for 6 h; the alkaline catalyst is potassium carbonate and potassium iodide; in the step 3), the solvent used for the reaction is acetonitrile, toluene or acetone; the reaction condition is room temperature reaction for 8-12 h.
The invention also discloses application of the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain in preparing a medicinal preparation for treating infectious diseases.
Preferably, the infectious disease is a disease caused by infection of a human or an animal by a pathogenic microorganism.
Further preferably, the pathogenic microorganism is a drug-resistant bacterium.
Further preferably, the drug-resistant bacteria is multidrug-resistant pseudomonas aeruginosa, multidrug-resistant klebsiella pneumoniae, methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococcus faecalis or carbapenem-resistant acinetobacter baumannii.
Preferably, the pharmaceutical preparation for treating infectious diseases is used alone or mixed with pharmaceutically acceptable excipient and diluent to be prepared into tablets, capsules, granules, syrups, premixes or micro-pills for oral administration, or prepared into liniments or injections for non-oral administration.
The invention also discloses a pharmaceutical composition which contains the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain as an active ingredient.
Compared with the prior art, the invention has the following beneficial effects:
the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain is structurally modified by taking pleuromutilin as a parent nucleus, and is subjected to wide biological activity screening to synthesize the pleuromutilin quaternary ammonium salt antibiotic with novel structure and anti-pathogenic microorganism activity. In vitro antibacterial activity experiments prove that the pleuromutilin derivative containing the thiazole-pyridylalkyl quaternary ammonium salt side chain synthesized by the invention has excellent anti-pathogenic microorganism activity, particularly on drug-resistant bacteria, the inhibition capacity of most of the synthesized compounds on the drug-resistant bacteria is stronger than that of three marketed drugs (Rettamolin, tiamulin and valnemulin), the MIC value of the compound 4 on staphylococcus epidermidis (ATCC 12228) can reach 1 mu g/mL, the MIC values on staphylococcus aureus (ATCC25923 and ATCC 29213) can reach 8 mu g/mL and 1 mu g/mL, the MIC values on acinetobacter baumannii (ATCC 19606) and escherichia coli (ATCC 25922 and CMCC 44103) can reach 4, 2 and 4 mu g/mL respectively, and the bacteriostatic ability is far better than that of the marketed drugs. In addition, the compounds 1, 2 and 4 also preferably show good antibacterial action on clinically separated drug-resistant strains (MDR-PA 18-126, MDR-KP 18-893, MRSA 18-171, VRE 18-80 and CR-AB 18-882), wherein the three compounds have the best activity on methicillin-resistant Staphylococcus aureus MRSAM18-171, the minimum inhibitory concentration is less than 10 mu g/mL, and the antibacterial activity is greatly superior to that of a control drug retamo lin, which shows that the pleuromutilin derivative synthesized by the invention can be applied to the treatment of infectious diseases of human beings or animals, particularly the infectious diseases caused by drug-resistant bacteria, and has good medicine development value.
According to the preparation method of the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain, the C-14-site side chain of the pleuromutilin is modified by using 2-sulfydryl-4- (4-pyridyl) thiazole, and the bromination alkane is further used for quaternization to prepare the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound 4 in deuterated DMSO in accordance with the present invention;
FIG. 2 is a nuclear magnetic carbon spectrum of Compound 4 of the present invention in deuterated DMSO;
FIG. 3 is a nuclear magnetic hydrogen spectrum of compound 6 in deuterated DMSO in accordance with the present invention;
FIG. 4 is a nuclear magnetic carbon spectrum of Compound 6 of the present invention in deuterated DMSO;
FIG. 5 is the result of in vitro antimicrobial activity assay of Compound 4 against Staphylococcus epidermidis (ATCC 12228);
FIG. 6 shows the results of in vitro determination of antibacterial activity of Compound 4 against Salmonella (ATCC 14028);
FIG. 7 shows the in vitro antibacterial activity of Compound 4 against Staphylococcus aureus (ATCC 29213).
Detailed Description
In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be noted that the terms "first," "second," and the like in the description and claims of the present invention and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in sequences other than those illustrated or described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention is described in further detail below with reference to the accompanying drawings:
the invention provides a pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chain, which is a general formula I or pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereoisomer, tautomer or mixture of the compound of the general formula I and the pharmaceutically acceptable salt thereof in any proportion, and comprises a racemic mixture:
Figure BDA0003571017990000041
wherein: r is one of alkyl with 3-16 carbon atoms or one of cycloalkyl with 3-7 carbon atoms; the pharmaceutically acceptable salt is a salt formed by the compound shown in the general formula I 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, and the pharmaceutically acceptable salt of the representative derivative is shown as follows:
Figure BDA0003571017990000051
the invention also provides a preparation method of the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain, which comprises the following steps:
(1) the pleuromutilin and paratoluensulfonyl chloride are used as raw materials to react to obtain an intermediate I, and the reaction formula is as follows:
Figure BDA0003571017990000052
wherein the solvent used in the reaction is dichloromethane; the reaction condition is that the reaction lasts for 5 hours at room temperature; the molar ratio of pleuromutilin to p-toluenesulfonyl chloride is 1: 1.2;
(2) taking the intermediate I obtained in the step (1) and 2-mercapto-4- (4-pyridyl) thiazole as raw materials, heating to react under the condition of a basic catalyst, and purifying to obtain an intermediate II, wherein the reaction formula is as follows:
Figure BDA0003571017990000053
wherein the solvent used in the reaction is N, N-dimethylformamide; the reaction condition is heating reaction at 60 ℃ for 6 h; the alkaline catalyst is potassium carbonate and potassium iodide;
(3) reacting the intermediate II obtained in the step (2) with various substituted alkyl bromides, and purifying to obtain the pleuromutilin derivative containing the thiazole-pyridylalkyl quaternary ammonium salt side chain and having the structure shown in the general formula I, wherein the reaction formula is as follows:
Figure BDA0003571017990000054
wherein, the reaction solvent can be selected from acetonitrile, toluene or acetone, and the preferable solvent is acetonitrile; the reaction is carried out at room temperature for 8 to 12 hours, preferably 11 hours.
1. Specific examples of Synthesis of Compounds 1-12
The structural formula and the number of the representative compound are shown as follows:
Figure BDA0003571017990000061
examples of the synthesis of the above compounds are given below, the structures of which are characterized by NMR.
Example 1
(1) Preparation of intermediate I
Figure BDA0003571017990000062
Pleuromutilin (757mg, 2mmol) and p-toluenesulfonyl chloride (456mg, 2.4mmol) were dissolved in dichloromethane (30mL), TEA (0.8mL, 6mmol) and DMAP (24.4mg, 0.2mmol) were added and stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure, and the concentrated product was washed with saturated aqueous sodium bicarbonate (50mL) to give intermediate I (1012.1mg, 1.9mmol) in 95.0% yield. The prepared intermediate I is used as a raw material of an intermediate II.
(2) Preparation of intermediate II
Figure BDA0003571017990000063
Intermediate I (1012.1mg, 1.9mmol) and 2-mercapto-4- (4-pyridyl) thiazole (388mg, 2mmol) were dissolved in N, N-dimethylformamide (40mL), placed in a reactor, added with potassium carbonate (524.4mg, 3.8mmol) and potassium iodide (31.54mg, 0.19mmol), and heated at 60 ℃ for 6 h. After the reaction is finished, saturated ammonium chloride aqueous solution is used for dilution, ethyl acetate is used for extraction, an ethyl acetate phase is concentrated, and column chromatography separation is carried out to obtain an intermediate II (943mg, 1.7mmol), and an eluent is dichloromethane: methanol 20: 1, yield 89.4%.
(3) Synthesis of Compound 1
Compound 1: preparation of 1-butyl-4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propiopheno [8] cycloalken-5-yl) oxy) -2-oxoethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000071
Dissolving the intermediate II (166mg, 0.3mmol) and bromobutane (164.4mg, 1.2mmol) in toluene (10mL), reacting at room temperature for 8h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder is used as a stationary phase, and dichloromethane: methanol (V: V) ═ 20: 1 as a mobile phase), and drying to obtain the compound 1(94.08mg, 0.136mmol) with the yield of 45.3%.
1H NMR(600MHz,DMSO)δ9.33(d,J＝6.4Hz,2H),9.23(s,1H),8.79(d,J＝6.5Hz,2H),6.14(dd,J＝16.6,11.3Hz,1H),5.60(d,J＝8.7Hz,1H),5.13–4.98(m,2H),4.67(t,J＝7.8Hz,2H),4.51(d,J＝5.7Hz,1H),4.34(s,2H),2.33(s,1H),2.20(dd,J＝19.4,12.8Hz,1H),2.10–2.08(m,1H),2.03–1.94(m,4H),1.73–1.61(m,2H),1.54–1.41(m,1H),1.37–1.13(m,9H),1.09(d,J＝15.6Hz,1H),1.03–0.96(m,1H),0.91–0.86(m,6H),0.81(d,J＝7.3Hz,3H),0.72(d,J＝7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.52,166.93,166.77,162.76,148.46,147.92,145.90,126.08,124.32,115.64,73.01,70.89,63.16,57.63,45.36,44.36,43.92,41.97,36.85,36.73,36.38,34.46,32.60,30.52,28.90,27.01,24.86,21.10,16.59,14.92,13.80,11.98
Example 2
Compound 2: preparation of 1-pentyl 4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propylcyclopenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000072
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromopentane (181.2mg, 1.2mmol) in acetonitrile (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh silica gel powder as a stationary phase and dichloromethane: methanol (V: V): 30: 1 as a mobile phase), and drying to obtain the compound 2(105.75.1mg, 0.15mmol) with the yield of 50.0%.
1H NMR(600MHz,DMSO)δ9.31(d,J＝6.4Hz,2H),9.10(s,1H),8.40(d,J＝6.1Hz,2H),6.10(dd,J＝17.9,11.4Hz,1H),5.60(d,J＝8.5Hz,1H),4.89–4.78(m,2H),4.63(t,J＝7.4Hz,3H),4.31(s,2H),2.50(s,1H),2.39(dd,J＝19.3,11.6Hz,1H),2.21–2.19(m,1H),2.09–1.85(m,4H),1.71–1.65(m,2H),1.58–1.47(m,1H),1.44–1.21(m,10H),1.17–1.09(m,2H),1.05–1.00(m,1H),0.94–0.87(m,6H),0.84(d,J＝6.9Hz,3H),0.78(d,J＝7.2Hz,3H).
13C NMR(151MHz,DMSO)δ217.53,166.91,166.74,162.76,148.46,147.92,145.95,126.38,124.36,115.64,73.01,70.89,63.18,57.63,45.32,44.36,43.92,41.96,36.85,36.73,36.18,34.44,32.60,30.53,28.98,27.01,24.89,22.40,21.11,16.59,14.92,13.80,11.98
Example 3
Compound 3: preparation of 1-hexyl-4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxy-7-vinyldecahydro-4, 9 a-propylcyclopenta [8] cycloalken-5-yl) oxy) -2-oxyethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000081
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromohexane (198mg, 1.2mmol) in acetone (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, performing column chromatography on the residue, separating and purifying (200-mesh 300-mesh silica gel powder as a stationary phase, dichloromethane: methanol (V: V) ═ 10: 1 as a mobile phase), and drying to obtain the compound 3(95.6mg, 0.133mmol) with the yield of 44.3%.
1H NMR(600MHz,DMSO)δ9.16(d,J＝6.4Hz,2H),9.11(s,1H),8.77(d,J＝6.4Hz,2H),6.11(dd,J＝16.9,11.4Hz,1H),5.63(d,J＝8.6Hz,1H),5.10–4.96(m,2H),4.55(t,J＝7.5Hz,2H),4.46(d,J＝5.9Hz,1H),4.31(s,2H),2.30(s,1H),2.24(dd,J＝19.3,12.7Hz,1H),2.11–2.06(m,1H),2.01–1.90(m,4H),1.71–1.63(m,2H),1.50–1.42(m,1H),1.39–1.18(m,13H),1.10(d,J＝15.9Hz,1H),1.02–0.94(m,1H),0.90–0.84(m,6H),0.80(d,J＝7.2Hz,3H),0.67(d,J＝7.3Hz,3H).
13C NMR(151MHz,DMSO)δ217.58,166.93,166.74,162.76,148.44,147.92,145.96,126.38,124.39,115.64,73.03,70.89,63.17,57.67,45.31,44.36,43.92,41.93,36.85,36.77,36.18,34.45,32.60,31.53,30.52,28.98,27.04,24.89,22.41,21.14,16.59,14.93,13.80,11.97
Example 4
And (3) a product 4: preparation of 1-decyl-4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxy-7-vinyldecahydro-4, 9 a-propylcyclopenta [8] cycloalken-5-yl) oxy) -2-oxyethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000082
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromodecane (265.4mg, 1.2mmol) in acetonitrile (10mL), reacting at room temperature for 10h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh silica gel powder as a stationary phase, dichloromethane: methanol (V: V): 20: 1 as a mobile phase), and drying to obtain the compound 4(98.54mg, 0.127mmol) with the yield of 42.3%. The nuclear magnetic hydrogen spectrum of the compound 4 in deuterated DMSO is shown in figure 1, and the nuclear magnetic carbon spectrum in deuterated DMSO is shown in figure 2.
1H NMR(600MHz,DMSO)δ9.23(d,J＝6.3Hz,2H),9.08(s,1H),8.62(d,J＝6.2Hz,2H),6.07(dd,J＝17.8,11.2Hz,1H),5.58(d,J＝8.4Hz,1H),4.99–4.90(m,2H),4.65(t,J＝7.3Hz,3H),4.33(s,2H),2.42(s,1H),2.22(dd,J＝19.2,11.0Hz,1H),2.16–2.08(m,1H),2.06–1.95(m,4H),1.72–1.62(m,2H),1.56–1.47(m,1H),1.45–1.23(m,20H),1.18–1.10(m,2H),1.07–1.01(m,1H),0.93–0.88(m,6H),0.83(d,J＝6.9Hz,3H),0.64(d,J＝7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.52,166.95,166.57,148.64,147.33,145.67,141.22,126.79,123.90,115.58,72.87,70.87,60.47,57.61,45.38,44.39,43.90,41.98,36.87,36.73,36.31,34.44,31.75,31.09,30.52,29.34,29.28,29.12,28.93,28.87,27.04,25.82,24.89,22.57,16.58,14.90,14.43,11.95.
Example 5
Compound 5: preparation of 1-dodecyl-4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxy-7-vinyldecahydro-4, 9 a-propilopenta [8] cycloalken-5-yl) oxy) -2-oxyethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000091
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromododecane (299.08mg, 1.2mmol) in acetonitrile (10mL), reacting at room temperature for 10h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder is used as a stationary phase, and dichloromethane: methanol (V: V): 25: 1 as a mobile phase), and drying to obtain the compound 5(101.30mg, 0.126mmol) with the yield of 42.0%.
1H NMR(600MHz,DMSO)δ9.30(d,J＝6.3Hz,2H),9.12(s,1H),8.73(d,J＝6.5Hz,2H),6.09(dd,J＝17.9,11.1Hz,1H),5.60(d,J＝8.5Hz,1H),5.02–4.87(m,2H),4.54(t,J＝7.4Hz,2H),4.61(d,J＝5.8Hz,1H),4.42(s,2H),2.38(s,1H),2.25(dd,J＝19.1,12.9Hz,1H),2.16–2.09(m,1H),2.02–1.91(m,4H),1.72–1.65(m,2H),1.54–1.43(m,1H),1.41–1.20(m,25H),1.12(d,J＝15.8Hz,1H),1.03–0.93(m,1H),0.91–0.87(m,6H),0.81(d,J＝7.1Hz,3H),0.65(d,J＝7.2Hz,3H).
13C NMR(151MHz,DMSO)δ217.59,166.93,166.86,162.76,148.53,147.92,145.66,126.38,124.38,115.66,73.03,70.86,63.17,57.63,45.31,44.32,43.92,41.91,36.85,36.78,36.18,34.47,32.60,31.59,30.52,29.93,29.63,29.31,28.98,27.04,24.89,22.73,22.41,21.80,20.31,16.59,15.63,14.93,13.80,11.97
Example 6
Compound 6: preparation of 1-hexadecyl-4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxy-7-vinyldecahydro-4, 9 a-propilopenta [8] cycloalken-5-yl) oxy) -2-oxyethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000101
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromohexadecane (366.41mg, 1.2mmol) in toluene (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh silica gel powder 300-mesh is used as a stationary phase, and dichloromethane: methanol (V: V) ═ 20: 1 as a mobile phase), and drying to obtain the compound 6(99.77mg, 0.116mmol) with the yield of 38.7%, wherein the nuclear magnetic hydrogen spectrum of the compound 6 in deuterated DMSO is shown in figure 3, and the nuclear magnetic carbon spectrum in deuterated DMSO is shown in figure 4.
1H NMR(600MHz,DMSO)δ9.22(d,J＝6.3Hz,2H),9.06(s,1H),8.61(d,J＝6.3Hz,2H),6.07(dd,J＝17.8,11.1Hz,1H),5.58(d,J＝8.4Hz,1H),5.00–4.90(m,2H),4.64(t,J＝7.3Hz,2H),4.59(d,J＝5.9Hz,1H),4.33(s,2H),2.42(s,1H),2.22(dd,J＝19.2,10.9Hz,1H),2.15–2.07(m,1H),2.06–1.90(m,4H),1.71–1.62(m,2H),1.55–1.47(m,1H),1.44–1.24(m,33H),1.15(d,J＝15.7Hz,1H),1.07–0.99(m,1H),0.94–0.88(m,6H),0.83(d,J＝6.9Hz,3H),0.63(d,J＝7.1Hz,3H).
13C NMR(151MHz,DMSO)δ217.49,166.94,166.59,148.63,147.33,145.65,141.21,126.75,123.89,115.58,72.88,70.87,60.47,57.61,45.38,44.39,43.91,41.98,36.86,36.73,36.31,34.44,31.77,31.08,30.53,29.53,29.48,29.39,29.28,29.19,28.92,28.88,27.04,25.82,24.89,22.57,16.58,14.90,14.43,11.94.
Example 7
Compound 7: preparation of 4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propilopenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thiazol-4-yl) -1- (2-methylbutyl) pyridylbromide salt
Figure BDA0003571017990000102
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and 1-bromo-2-methylbutane (181.2mg, 1.2mmol) in toluene (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder is used as a stationary phase, dichloromethane: methanol (V: V) ═ 15: 1 is used as a mobile phase), and drying to obtain the compound 7(86.11mg, 0.122mmol) with the yield of 40.7%.
1H NMR(600MHz,DMSO)δ9.32(d,J＝6.5Hz,2H),9.19(s,1H),8.80(d,J＝6.6Hz,2H),6.10(dd,J＝16.9,11.0Hz,1H),5.63(d,J＝8.9Hz,1H),5.20–4.96(m,2H),4.69(t,J＝7.9Hz,2H),4.49(d,J＝5.8Hz,1H),4.30(s,2H),2.31(s,1H),2.23(dd,J＝19.3,12.7Hz,1H),2.14–2.07(m,1H),2.04–1.93(m,4H),1.74–1.63(m,2H),1.56–1.42(m,1H),1.39–1.16(m,7H),1.10(d,J＝15.5Hz,1H),1.04–0.98(m,4H),0.96–0.84(m,6H),0.81(d,J＝7.4Hz,3H),0.78(d,J＝7.5Hz,4H).
13C NMR(151MHz,DMSO)δ217.53,166.97,166.77,162.76,148.45,147.92,145.93,126.08,124.34,115.65,73.01,70.84,63.16,57.63,45.33,44.36,43.94,41.96,36.85,36.77,36.38,34.48,32.60,30.58,28.90,27.09,24.86,21.10,19.35,16.56,14.92,13.80,11.98
Example 8
Compound 8: preparation of 4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propilopenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thiazol-4-yl) -1-isopentylpyridinylbromide salt
Figure BDA0003571017990000111
The procedure for the preparation of intermediate I and intermediate II is as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and 1-bromo-3-methylbutane (181.26mg, 1.2mmol) in acetone (10mL), reacting at room temperature for 10h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder is used as a stationary phase, dichloromethane: methanol (V: V) ═ 20: 1 is used as a mobile phase), and drying to obtain the compound 8(87.52mg, 0.124mmol) with the yield of 41.3%.
1H NMR(600MHz,DMSO)δ9.34(d,J＝6.5Hz,2H),9.21(s,1H),8.86(d,J＝6.5Hz,2H),6.14(dd,J＝16.6,11.0Hz,1H),5.61(d,J＝9.1Hz,1H),5.22–4.93(m,2H),4.71(t,J＝7.6Hz,2H),4.46(d,J＝5.9Hz,1H),4.32(s,2H),2.33(s,1H),2.29(dd,J＝11.3,12.8Hz,1H),2.16–2.06(m,1H),2.01–1.92(m,4H),1.78–1.63(m,2H),1.53–1.41(m,1H),1.36–1.21(m,7H),1.16(d,J＝15.9Hz,1H),1.08–0.97(m,4H),0.95–0.86(m,6H),0.83(d,J＝7.5Hz,3H),0.79(d,J＝7.6Hz,4H).
13C NMR(151MHz,DMSO)δ217.56,166.93,166.78,162.76,149.47,147.92,145.96,125.07,124.31,115.65,73.01,70.81,63.16,57.64,46.36,44.38,43.92,41.97,36.84,36.73,36.38,34.46,32.60,30.58,28.99,27.01,24.86,21.10,16.62,14.93,13.87,11.96
Example 9
Compound 9: preparation of 1- (3, 4-dimethylpentyl) -4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxy-7-vinyldecahydro-4, 9 a-propiopentao [8] cycloalken-5-yl) oxy) -2-oxyethyl) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000121
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and 1-bromo-3, 4-methylpentane (214.9mg, 1.2mmol) in acetonitrile (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder is used as a stationary phase, dichloromethane: methanol (V: V) ═ 10: 1 is used as a mobile phase), and drying to obtain the compound 9(107.1mg, 0.146mmol) with the yield of 48.7%.
1H NMR(600MHz,DMSO)δ9.29(d,J＝6.5Hz,2H),9.16(s,1H),8.44(d,J＝6.2Hz,2H),6.15(dd,J＝17.6,11.5Hz,1H),5.68(d,J＝8.6Hz,1H),4.90–4.81(m,2H),4.66(t,J＝7.6Hz,3H),4.34(s,2H),2.58(s,1H),2.40(dd,J＝19.6,11.7Hz,1H),2.26–2.20(m,1H),2.10–1.86(m,4H),1.73–1.68(m,2H),1.59–1.48(m,1H),1.43–1.20(m,6H),1.18–1.06(m,2H),1.03–0.98(m,7H),0.93–0.86(m,6H),0.83(d,J＝6.8Hz,5H),0.74(d,J＝7.3Hz,3H).
13C NMR(151MHz,DMSO)δ217.53,166.91,166.74,162.76,148.46,147.92,145.95,126.38,124.36,115.64,73.01,70.89,63.18,57.63,45.32,44.36,43.92,41.96,36.85,36.73,36.18,34.44,32.60,30.53,28.98,27.01,24.89,22.40,21.11,20.86,17.93,16.59,14.92,13.80,11.98
Example 10
Compound 10: preparation of 1- (cyclopropylmethyl) -4- (2- ((2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propiopentapenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thio) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000122
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromomethylcyclopropane (162mg, 1.2mmol) in acetonitrile (10mL), reacting at room temperature for 11h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh 300-mesh silica gel powder as stationary phase, dichloromethane: methanol (V: V) ═ 20: 1 as mobile phase), and drying to obtain the compound 10(100.02mg, 0.145mmol) with 48.3% yield.
1H NMR(600MHz,DMSO)δ9.31(d,J＝6.5Hz,2H),9.27(s,1H),8.80(d,J＝6.6Hz,2H),6.13(dd,J＝16.7,11.4Hz,1H),5.63(d,J＝8.8Hz,1H),5.14–4.97(m,2H),4.65(t,J＝7.9Hz,2H),4.50(d,J＝5.8Hz,1H),4.31(s,2H),2.32(s,1H),2.23(dd,J＝19.5,12.9Hz,1H),2.13–2.04(m,1H),2.01–1.93(m,4H),1.72–1.60(m,2H),1.56–1.39(m,1H),1.36–1.11(m,9H),1.06(d,J＝15.9Hz,1H),1.01–0.95(m,1H),0.93–0.88(m,3H),0.84(d,J＝7.2Hz,3H),0.74(d,J＝7.1Hz,4H).
13C NMR(151MHz,DMSO)δ217.52,166.86,166.77,162.73,148.44,147.92,145.93,126.28,124.32,115.64,73.01,70.54,63.16,57.35,45.36,44.73,43.92,41.57,36.85,36.77,36.39,34.46,32.63,30.54,28.91,27.11,24.84,21.17,14.94,4.76,3.71
Example 11
Compound 11: preparation of 1- (cyclobutylmethyl) -4- (2- ((2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propilopenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thio) thiazol-4-yl) pyridylbromide salt
Figure BDA0003571017990000131
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromomethylcyclobutane (178.8mg, 1.2mmol) in acetone (10mL), reacting at room temperature for 9h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh silica gel powder 300-mesh is used as a stationary phase, and dichloromethane: methanol (V: V) ═ 10: 1 is used as a mobile phase), and drying to obtain the compound 11(98.4mg, 0.14mmol) with the yield of 46.7%.
1H NMR(600MHz,DMSO)δ9.30(d,J＝6.6Hz,2H),9.24(s,1H),8.81(d,J＝6.7Hz,2H),6.14(dd,J＝16.6,11.4Hz,1H),5.61(d,J＝8.8Hz,1H),5.21–4.98(m,2H),4.67(t,J＝7.6Hz,2H),4.53(d,J＝5.9Hz,1H),4.30(s,2H),2.31(s,1H),2.24(dd,J＝19.6,12.6Hz,1H),2.11–2.03(m,1H),2.00–1.96(m,4H),1.86–1.71(m,2H),1.62–1.49(m,1H),1.40–1.21(m,11H),1.16(d,J＝15.6Hz,1H),1.10–1.06(m,1H),1.04–0.98(m,3H),0.90(d,J＝7.3Hz,3H),0.83(d,J＝7.1Hz,4H).
13C NMR(151MHz,DMSO)δ217.54,166.91,166.76,162.76,148.59,147.92,145.93,126.35,124.36,115.66,73.01,70.83,63.18,57.21,45.38,44.36,43.76,41.53,36.38,36.61,36.44,34.76,32.53,30.46,28.97,27.01,26.56 21.11,17.68,14.92,13.60,11.97
Example 12
Compound 12: preparation of 1- (cycloheptylmethyl) -4- (2- ((3aR, 4R, 5R, 7S, 8S, 9R, 9aS, 12R) -8-hydroxy-4, 7,9, 12-tetramethyl-3-oxo-7-vinyldecahydro-4, 9 a-propylcyclopenta [8] cycloalken-5-yl) oxy) -2-oxoethyl) thio) thiazol-4-yl) pyridylbromide
Figure BDA0003571017990000132
The procedure for the preparation of intermediate I and intermediate II was as in example 1. Dissolving the intermediate II (166mg, 0.3mmol) and bromomethylcycloheptane (229.3mg, 1.2mmol) in acetone (10mL), reacting at room temperature for 9h, concentrating the solvent under reduced pressure, separating and purifying the residue by column chromatography (200-mesh silica gel powder 300-mesh as stationary phase, dichloromethane: methanol (V: V) ═ 20: 1 as mobile phase), and drying to obtain the compound 12(74.5mg, 0.1mmol) with a yield of 33.3%.
1H NMR(600MHz,DMSO)δ9.28(d,J＝6.5Hz,2H),9.21(s,1H),8.83(d,J＝6.8Hz,2H),6.06(dd,J＝16.7,11.3Hz,1H),5.63(d,J＝8.9Hz,1H),5.24–4.93(m,2H),4.69(t,J＝7.8Hz,2H),4.51(d,J＝5.6Hz,1H),4.34(s,2H),2.30(s,1H),2.24(dd,J＝19.4,12.1Hz,1H),2.16–2.08(m,1H),2.04–1.98(m,4H),1.87–1.78(m,2H),1.68–1.51(m,1H),1.48–1.26(m,17H),1.16(d,J＝15.7Hz,1H),1.13–1.05(m,1H),1.03–0.97(m,3H),0.91(d,J＝7.6Hz,3H),0.86(d,J＝7.3Hz,4H).
13C NMR(151MHz,DMSO)δ217.56,166.93,166.75,162.76,148.47,147.92,145.98,126.38,124.35,115.67,73.05,70.89,63.18,57.67,45.33,44.36,43.73,41.43,36.18,36.78,36.53,34.75,32.68,31.12,30.93,29.63,27.07,22.89,22.13,17.76,15.91,13.80,11.97
2. In vitro antimicrobial Activity assay
The Minimum Inhibitory Concentration (MIC) of the side chain pleuromutilin derivative containing thiazole-picolyl heteroaromatic quaternary ammonium salt is tested by adopting a trace broth dilution method and taking moxifloxacin as a positive control (purchased from Shanghai Michelin Biochemical technology Co., Ltd.), and meanwhile, the Minimum Inhibitory Concentration (MIC) of the side chain pleuromutilin derivative is compared with the marketed pleuromutilin antibiotics Retinomolin (purchased from Nanjing Conman chemical industry Co., Ltd.), tiamulin (purchased from Shanghai leaf Biotechnology Co., Ltd.) and valnemulin (purchased from Shanghai Ji to Biochemical technology Co., Ltd.) so as to screen the pleuromutilin derivative with better activity.
Standard strains include gram-positive bacteria: staphylococcus epidermidis ATCC 12228, staphylococcus aureus ATCC 29213, ATCC25923 and methicillin-resistant staphylococcus aureus ATCC 33591; gram-negative bacteria: salmonella ATCC14028, acinetobacter baumannii ATCC 19606, escherichia coli ATCC 25922, CMCC 44103, all of which were purchased from american type culture collection.
The clinical drug-resistant bacteria comprise multiple drug-resistant pseudomonas aeruginosa (MDR-PA)18-126, multiple drug-resistant klebsiella pneumoniae (MDR-KP)18-893, methicillin-resistant staphylococcus aureus (MRSA)18-171, vancomycin-resistant enterococcus faecalis (VRE)18-80 and carbapenem-resistant acinetobacter baumannii (CR-AB)18-882, and all clinical drug-resistant strains are from the subsidiary Huashan hospital of the university of Compound Dane.
The specific operation steps are as follows:
(1) MHB culture medium preparation: weighing 20.0g MHB culture medium (purchased from Kyowa Microscience and technology Co., Ltd.), adding into 1L distilled water, heating and boiling to dissolve completely, subpackaging in conical flask, and autoclaving at 121 deg.C for 15min for use.
(2) The experimental strain is cultured to logarithmic growth phase: inoculating the recovered experimental strain into 100mL MHB culture medium under aseptic condition, and culturing in a constant temperature and humidity incubator at 37 ℃ for 20-22h for later use.
(3) Preparing a sample solution: weighing a sample to be tested (the compound 1-12 synthesized by the invention, the Rettamolin, the tiamulin and the valnemulin) and dissolving the sample in a DMSO solution to prepare a sample solution with the concentration of 10.24mg/mL, and dissolving a positive control (the moxifloxacin) in the DMSO solution to prepare a sample solution with the concentration of 5.12 mg/mL.
(4) Preparing a bacterial suspension: under aseptic conditions, the experimental strains cultured to the logarithmic growth phase were adjusted to 0.5 M.multidot.turbidity standard using MHB medium and then treated as follows: diluting at a ratio of 200 for later use.
(5) Determining MIC by a micro double dilution method: taking a sterile 96-well plate, adding 10 mu L of moxifloxacin sample liquid into the 2 nd well, 4 th-Add 10. mu.L DMSO solution to 11 wells, add 10. mu.L sample diluted in gradient setup to 3,4 wells, and double dilute the drug to 10 th well, 11 th well is solvent control. Then 190. mu.L of diluted bacterial suspension was added to each well to give a final bacterial suspension concentration of 5X 10 per well5CFU/mL, and placing in a constant temperature and humidity box at 37 ℃ for culturing for 20-22 h.
(6) MIC endpoint interpretation: the concentration of the total inhibition of bacterial growth observed in the 96-well plate by naked eye against a black background was the minimum inhibitory concentration of the sample against the bacteria. (partial in vitro antibacterial results for Compound 4 are shown in FIGS. 5-7)
TABLE 1 minimum inhibitory concentration (μ g/mL) of test drugs
Figure BDA0003571017990000151
As can be seen from table 1, in addition to compound 6, the other 11 compounds all have good inhibitory effects on staphylococcus epidermidis (ATCC 12228) and staphylococcus aureus (ATCC25923 and ATCC 29213), and the inhibitory effects of compounds 1 to 5 on staphylococcus epidermidis (ATCC 12228) are far better than those of the marketed pleuromutilin antibiotics, wherein the inhibitory effect of compound 4 is the best, the MIC value can reach 1 μ g/mL, and is far lower than that of tiamulin (MIC is 16 μ g/mL) with the best bacteriostatic effect in the marketed drugs; compounds 1-12 all have significant inhibitory effects against Staphylococcus aureus (ATCC25923 and ATCC 29213), with the MIC of Compound 4, which is the most inhibitory, reaching 8. mu.g/mL and 1. mu.g/mL; in addition to compound 6, the synthesized compounds all produced good inhibition of methicillin-resistant Staphylococcus aureus (ATCC 33591), with MIC values of 4 to 32. mu.g/mL.
In addition, compounds 1-5 and compounds 7-10 were superior in inhibitory effect against Salmonella (ATCC 14028) to the three pleuromutilin antibiotics on the market, and the MIC values of all the compounds were between 1-32. mu.g/mL. In the case of Acinetobacter baumannii (ATCC 19606) and E.coli (ATCC 25922 and CMCC 44103), the other synthetic compounds produced different degrees of inhibition in addition to compounds 6, 11 and 12. Compound 4 has the best inhibitory effect on Acinetobacter baumannii (ATCC 19606) and Escherichia coli (ATCC 25922 and CMCC 44103), and MIC values can reach 4, 2 and 4 mu g/mL respectively.
TABLE 2 minimum inhibitory concentration (μ g/mL) of test drugs against clinically resistant bacteria
Figure BDA0003571017990000161
As can be seen from Table 2, the preferred compounds 1, 2 and 4 also exhibit good antibacterial effects against clinically isolated drug-resistant strains, of which three compounds have the best activity against methicillin-resistant Staphylococcus aureus MRSAM18-171, and the minimum inhibitory concentration is less than 10. mu.g/mL. Overall, the antibacterial activity of the three preferred compounds for the clinical isolation of drug-resistant strains was significantly better than that of the control drug retamopilin.
In conclusion, the pleuromutilin derivative containing the thiazole-pyridine alkyl aromatic heterocycle quaternary ammonium salt side chain has an inhibition effect on gram-positive bacteria and gram-negative bacteria, and most compounds have stronger inhibition capability on drug-resistant bacteria than three marketed drugs, so that the pleuromutilin derivative has significance for further clinical research.
The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.

Claims (10)

1. A pleuromutilin derivative containing thiazole-pyridine alkyl quaternary ammonium salt side chain is characterized in that the pleuromutilin derivative is a compound shown in a general formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, an enantiomer, a diastereoisomer, a tautomer or a mixture thereof in any proportion of the compound shown in the general formula I and the pharmaceutically acceptable salt thereof, and comprises a racemic mixture:
Figure FDA0003571017980000011
wherein: r is one of alkyl with 3-16 carbon atoms or one of cycloalkyl with 3-7 carbon atoms.
2. The pleuromutilin derivative with thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in claim 1, wherein the representative compounds are as follows:
Figure FDA0003571017980000012
3. the pleuromutilin derivative containing the thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in claim 1, wherein the pharmaceutically acceptable salt is a salt of the compound of formula i with 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. A process for the preparation of a pleuromutilin derivative containing a thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in any one of claims 1 to 3 comprising the steps of:
1) the pleuromutilin and paratoluensulfonyl chloride are used as raw materials to react to obtain an intermediate I;
wherein the intermediate I is
Figure FDA0003571017980000021
2) Taking the intermediate I obtained in the step 1) and 2-mercapto-4- (4-pyridyl) thiazole as raw materials, heating to react under the condition of a basic catalyst, and purifying to obtain an intermediate II;
wherein the intermediate II is
Figure FDA0003571017980000022
3) Reacting the intermediate II obtained in the step 2) with various substituted alkyl bromides, and purifying to obtain the pleuromutilin derivative containing the thiazole-pyridine alkyl quaternary ammonium salt side chain and having the structure shown in the general formula I.
5. The method for preparing the pleuromutilin derivative with the thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in claim 4, wherein in the step 1), the solvent used in the reaction is dichloromethane; the reaction condition is that the reaction lasts for 5 hours at room temperature; the molar ratio of pleuromutilin to p-toluenesulfonyl chloride is 1: 1.2; in the step 2), the solvent used for the reaction is N, N-dimethylformamide; the reaction condition is heating reaction for 6h at 60 ℃; the alkaline catalyst is potassium carbonate and potassium iodide; in the step 3), the solvent used for the reaction is acetonitrile, toluene or acetone; the reaction condition is room temperature reaction for 8-12 h.
6. Use of a pleuromutilin derivative comprising a thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in any one of claims 1 to 3 in the manufacture of a pharmaceutical formulation for the treatment of infectious diseases.
7. Use according to claim 6, wherein the infectious disease is a disease caused by infection of a human or an animal by a pathogenic microorganism.
8. Use according to claim 7, characterized in that said pathogenic microorganisms are resistant bacteria.
9. The use of claim 6, wherein the pharmaceutical preparation for treating infectious diseases is prepared into tablets, capsules, granules, syrups, premixes or pellets for oral administration, or is prepared into liniments or injections for non-oral administration, which are used alone or mixed with pharmaceutically acceptable excipients and diluents.
10. A pharmaceutical composition comprising as an active ingredient a pleuromutilin derivative containing a thiazole-pyridylalkyl quaternary ammonium salt side chain as claimed in any one of claims 1 to 3.
CN202210319456.9A 2022-03-29 2022-03-29 Pleuromutilin derivative containing thiazole-pyridinylalkyl quaternary ammonium salt side chain, and preparation method and application thereof Active CN114671865B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110818648A (en) * 2019-12-05 2020-02-21 华南农业大学 Pleuromutilin derivative with triazole side chain as well as preparation method and application thereof
CN111253322A (en) * 2020-03-12 2020-06-09 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivatives containing N-alkylated pyrimidine side chain and application thereof
CN113149929A (en) * 2021-04-22 2021-07-23 华南农业大学 Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110818648A (en) * 2019-12-05 2020-02-21 华南农业大学 Pleuromutilin derivative with triazole side chain as well as preparation method and application thereof
CN111253322A (en) * 2020-03-12 2020-06-09 中国农业科学院兰州畜牧与兽药研究所 Pleuromutilin derivatives containing N-alkylated pyrimidine side chain and application thereof
CN113149929A (en) * 2021-04-22 2021-07-23 华南农业大学 Pleuromutilin derivative with 1, 3, 4-oxadiazole side chain and preparation and application thereof

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