Pleuromutilin derivative with furan side chain as well as preparation method and application of pleuromutilin derivative

Abstract

The invention belongs to the technical field of antibacterial drugs, and provides a pleuromutilin derivative with a furan side chain and a preparation method and application of the pleuromutilin derivative. In particular to pleuromutilin derivatives with furan side chains as shown in a general formula (I), pharmaceutical compositions containing the derivatives and application of the pleuromutilin derivatives to preparation of drugs for preventing and treating human and / or animal bacterial infectious diseases. The compound can be applied to medicines, especially medicines for preventing and treating infection of gram-positive bacteria such as staphylococcus aureus, drug-resistant staphylococcus aureus, staphylococcus intermedius and the like. Structural general formula (I) of pleuromutilin derivative containing furan side chain is # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of antibacterial drugs, and in particular relates to a pleuromutilin derivative with a furan side chain and a preparation method and application thereof. Background Art

[0002] Gram-positive bacteria can produce exotoxins that cause disease in humans, mainly including Staphylococcus aureus, Staphylococcus intermedius, Streptococcus, etc. Staphylococcus aureus is a representative of Gram-positive bacteria and a typical zoonotic pathogen that is widely present in nature. With the long-term and large-scale use of antibiotics in humans and animals, the problem of drug resistance of Staphylococcus aureus is becoming increasingly serious, especially the problem of drug resistance transmission from animals to humans needs to be paid great attention. Pleuromutilin is a natural tricyclic diterpenoid compound derived from fungi. It has a 5-6-8 tricyclic carbon skeleton with eight stereo centers and is extremely rigid. It is different from the common clinical antibacterial nucleus. It is not easy to produce cross-resistance with other structural antibacterial drugs and is an excellent nucleus for antibacterial drugs.

[0003] Currently, 4 pleuromutilin antibiotics have been approved and several are in the clinical research stage, such as tylosin and valnemulin for poultry, as well as retapamulin for local human infections and lefamulin for systemic human treatment. In order to solve the problem of local Staphylococcus aureus or Staphylococcus intermedius infection on animal skin and more effectively prevent and treat Gram-positive bacterial infections in humans and / or animals, it is urgent to develop new pleuromutilin antibiotics for veterinary use. Summary of the invention

[0004] The present invention aims to solve the technical problems existing in the prior art and provides a pleuromutilin derivative with a furan side chain and a preparation method and application thereof.

[0005] The technical solution of the present invention is as follows:

[0006] In a first aspect, the present invention provides a pleuromutilin derivative having a furan side chain, wherein the general structural formula of the derivative is shown in formula (I):

[0007]

[0008] Where R is selected from Preferably, the pleuromutilin derivative having a furan side chain is selected from structures 1-7 in the following table:

[0009]

[0011] The pleuromutilin derivatives with furan side chains represented by the general formula (I) of the present invention can also exist in the form of their salts, which are converted into the derivatives represented by the general formula (I) in vivo. For example, within the scope of the present invention, the derivatives of the present invention can be converted into the form of pharmaceutically acceptable salts according to processes known in the art, and they are used in the form of salts.

[0012] All tautomeric forms of the derivatives of the general formula (I) of the present invention are included within the scope of the present invention. The compounds of the present invention may exist in specific geometric or stereoisomer forms. The present structure contains 8 chiral centers and all of these isomers and their mixtures are included within the scope of the present invention.

[0013] The pharmaceutically acceptable salts include, but are not limited to, salts formed by the derivatives represented by general formula (I) and the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, salicylic acid or phenylacetic acid.

[0014] In a second aspect, the present invention also provides a synthetic route for a pleuromutilin derivative having a furan side chain represented by the general formula (I):

[0015]

[0016] The derivatives represented by the general formula (I) of the present invention can be obtained by the above or similar preparation methods, and the corresponding starting materials can be selected according to the different substituents and the different positions of the substituents. Step 1 of the synthetic route is to react the starting materials in a certain molar ratio, obtain the product by substitution reaction, and obtain the pure product without purification or column chromatography; step 2 is to obtain the target compound by condensation reaction, and obtain the pure product by column chromatography purification.

[0017] Those skilled in the art should realize that the above schemes are helpful for understanding the present invention, but are not limited to the present invention. Unless otherwise specified, the variables are defined as mentioned in the general formula (I).

[0018] The third aspect of the present invention provides a pharmaceutical composition, which comprises a pleuromutilin derivative having a furan side chain represented by the general formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0019] The pharmaceutical composition of the present invention can be administered in various known ways, such as orally, parenterally, or by spraying. The pharmaceutical composition of the present invention can be administered alone or in combination with other drugs. The oral composition can be in any oral acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, adhesives, colorants, fillers, emulsifiers, etc.

[0020] The sterile injection composition can be formulated according to the techniques known in the art using suitable dispersants or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

[0021] The fourth aspect of the present invention provides a pleuromutilin derivative having a furan side chain represented by the general formula (I) and its crystal form, hydrate, solvate, prodrug, racemate and metabolite.

[0022] The fifth aspect of the present invention provides use of a pleuromutilin derivative having a furan side chain represented by general formula (I) or the pharmaceutical composition in the preparation of a drug for preventing and treating infectious diseases.

[0023] Preferably, the infectious disease is the use of the drug to prevent and treat Gram-positive bacteria such as Staphylococcus aureus and drug-resistant Staphylococcus aureus, Staphylococcus intermedius, etc. that parasitize inside and outside the target animals such as ruminants, livestock, poultry, dogs, cats, etc.

[0024] Beneficial effects:

[0025] The truncated pleuromutilin derivatives with furan side chains reported in the present invention are a new type of compound with strong activities against Staphylococcus aureus, anti-resistant Staphylococcus aureus, anti-intermediate Staphylococcus, etc., and are expected to be developed into new antibacterial drugs for the prevention and treatment of bacterial infectious diseases in humans and / or animals, and have broad prospects for clinical use. DETAILED DESCRIPTION

[0026] The preparation methods of the derivatives of general formula (I) of the present invention are described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.

[0027] The starting materials, reaction reagents, etc. used in the specific embodiments of the present invention are all conventional reagents in the art and are commercially available. The present invention can be prepared in the form of salts using salt-forming methods commonly used in the art.

[0028] The experimental methods in the examples of the present invention where specific conditions are not specified are generally carried out under conventional conditions or under conditions recommended by raw material or product manufacturers.

[0029] The structures of all compounds in the examples were determined by waters QDa mass spectrometry and H NMR spectra ( 1 H-NMR) characterization.

[0030] Example 1

[0031] Preparation of compound 1

[0032]

[0033] Step 1:

[0034] Dissolve 2.8g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and obtain the intermediate 3 solution, which is directly used in the next step without spin drying. [M+H] + :143.1.

[0035] Step 2:

[0036] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 1. [M+H] + :503.2, 1 H-NMR(DMSO-d6,300MHz)δ:7.45(d,1H),6.78(d,1H),6.17(t,1H),5.55(d,1 H),5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.43(t,1H),2.42(s,1H),2.37( s,3H),2.21(dd,1H),2.05(m,3H),1.68(t,2H),1.48(t,1H),1.37(m,4H),1. 32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0037] Example 2

[0038] Preparation of compound 2

[0039]

[0040] Step 1:

[0041] Dissolve 4.1g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate to obtain the intermediate 3 solution, which is directly used in the next step without spin drying. [M+H] + :205.1.

[0042] Step 2:

[0043] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 2. [M+H] + :565.2, 1 H-NMR(DMSO-d6,300MHz)δ:8.06(d,2H),7.61(t,1H),7.56(m,2H),7.45(d,1H),6. 78(d,1H),6.17(d,1H),5.55(d,1H),5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.43( t,1H),2.42(s,1H),2.21(dd,1H),2.05(m,3H),1.68(t,2H),1.48(t,1H),1.37(m, 4H),1.32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0044] Example 3

[0045] Preparation of compound 3

[0046]

[0047] Step 1:

[0048] Dissolve 3.5g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate to obtain the intermediate 3 solution, which is directly used in the next step without spin drying. [M+H]+ :172.2.

[0049] Step 2:

[0050] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 3. [M+H] + :532.2, 1 H-NMR(DMSO-d6,300MHz)δ:7.45(d,1H),7.29(d,1H),6.17(t,1H),5.55(d,1 H),5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.43(t,1H),3.03(s,6H),2.42( s,1H),2.21(dd,1H),2.05(m,3H),1.68(t,2H),1.48(t,1H),1.37(m,4H),1. 32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0051] Example 4

[0052] Preparation of compound 4

[0053]

[0054] Step 1:

[0055] Dissolve 4.3g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, and dry over anhydrous sodium sulfate to obtain intermediate 3, which is directly used in the next step without spin drying. [M+H] + :213.2.

[0056] Step 2:

[0057] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 4. [M+H] + :573.2,1 H-NMR(DMSO-d6,300MHz)δ:7.41(d,1H),6.72(d,1H),6.17(t,1H),5.55(d,1H),5.11(t,1 H),5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.67(t,2H),3.43(t,1H),2.42(s,1H),2.21( dd,1H),2.05(m,3H),1.98(t,1H),1.76(m,3H),1.68(t,2H),1.55(m,2H),1.48(t,1H),1. 37(m,4H),1.32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0058] Example 5

[0059] Preparation of compound 5

[0060]

[0061] Step 1:

[0062] Dissolve 4.2g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, dry with anhydrous sodium sulfate, and obtain the intermediate 3 solution, which is directly used in the next step without spin drying. [M+H] + :212.2.

[0063] Step 2:

[0064] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 5. [M+H] + :572.2, 1H-NMR(DMSO-d6,300MHz)δ:7.45(d,1H),7.28(d,1H),6.17(t,1H),5.55(d,1H),5. 08(dd,2H),4.55(d,1H),3.87(s,2H),3.43(t,1H),3.36(t,4H),2.42(s,1H),2.21( dd,1H),2.05(m,3H),1.68(t,2H),1.61(m,1H),1.56(m,4H),1.48(t,1H),1.37(m, 4H),1.32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0065] Example 6

[0066] Preparation of compound 6

[0067]

[0068] Step 1:

[0069] Dissolve 4.0g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and obtain intermediate 3 solution, which is directly used in the next step without spin drying. [M+H] + :198.2.

[0070] Step 2:

[0071] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, and compound 6 was obtained. [M+H] + :558.2, 1H-NMR(DMSO-d6,300MHz)δ:7.45(d,1H),7.29(d,1H),6.17(t,1H),5.55(d,1H) ,5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.43(t,1H),3.09(t,4H),2.42(s,1H) ,2.21(dd,1H),2.05(m,3H),1.93(t,4H),1.68(t,2H),1.48(t,1H),1.37(m,4H) ,1.32(d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0072] Example 7

[0073] Preparation of compound 7

[0074]

[0075] Step 1:

[0076] Dissolve 3.1g of starting material 2 in 20mL of water, add 2.6g of starting material 1 dropwise at room temperature, continue stirring and reacting for 1h after the addition, cool in an ice bath, adjust pH to 1 with 1M dilute hydrochloric acid, extract with ethyl acetate 10mL×3, combine the organic phases, wash once with saturated brine, dry over anhydrous sodium sulfate, and use directly in the next step without spin drying. [M+H] + :153.9.

[0077] Step 2:

[0078] Dissolve 2.8 g of p-toluenesulfonyl chloride and 3.8 g of pleuromutilin in 20 mL of methyl tert-butyl ether, add 10 mL of 10 M sodium hydroxide in an ice bath, heat to 60 ° C for 1 h, cool to room temperature, add the intermediate 3 solution, continue to heat and reflux for 1 h, cool to room temperature, filter, and wash the filter cake with water. After drying the filter cake, column chromatography was performed to obtain the pure product, namely compound 7. [M+H] + :514.2, 1H-NMR(DMSO-d6,300MHz)δ:7.65(d,1H),7.34(d,1H),6.17(t,1H),5.55(d,1H),5.08(dd,2H),4.55(d,1H),3.87(s,2H),3.43(t,1H),2.42(s,1H) ,2.21(dd,1H),2.05(m,3H),1.68(t,2H),1.48(t,1H),1.37(m,4H),1.32 (d,1H),1.24(m,2H),1.06(s,3H),0.98(d,1H),0.83(d,3H),0.65(d,3H).

[0079] Example 8 In vitro antibacterial activity study

[0080] The minimum inhibitory concentration of the pleuromutilin derivatives obtained in Examples 1-7 was determined by broth dilution method against standard Staphylococcus aureus (ATCC 29213), clinical drug-resistant Staphylococcus aureus (ATCC43300), and Staphylococcus intermedius (ATCC29663), with tylosin as the positive control drug. The concentration of the bacterial solution in each test well was about 1×10 6 CFU·mL, the drug concentrations were 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06, and 0.03, respectively. The inoculated 96-well plate was placed in a 37°C incubator for culture, and the bacterial growth was observed for 24 hours. The results are shown in Table 1:

[0081] Table 1 Minimum inhibitory concentration in vitro of pleuromutilin derivatives (μg / mL)

[0082]

[0083] Conclusion: The antibacterial activity of the pleuromutilin derivatives prepared in the present invention against standard Staphylococcus aureus (ATCC29213), clinical drug-resistant Staphylococcus aureus (ATCC43300) and Staphylococcus intermedius (ATCC 29663) in vitro is superior to that of the control drug tylosin, and has broad clinical application prospects and great development value.

Claims

1. A pleuromutilin derivative having a furan side chain represented by general formula (I):

2. The pleuromutilin derivative having a furan side chain according to claim 1, characterized in that R is selected from 3. The pleuromutilin derivative having a furan side chain according to claim 1 or 2, characterized in that: The derivative is any one of the following structures:

4. A pharmaceutical composition, characterized in that The invention comprises the pleuromutilin derivative having a furan side chain as claimed in any one of claims 1 to 3, and one or more pharmaceutically acceptable carriers and / or excipients.

5. Use of the pleuromutilin derivative having a furan side chain according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for preventing and treating infectious diseases.

6. The use according to claim 5, characterized in that: The infectious disease is a disease caused by Gram-positive bacteria.

7. The use according to claim 6, characterized in that: The Gram-positive bacteria are Staphylococcus aureus, drug-resistant Staphylococcus aureus, and Staphylococcus intermedius.

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