Application of spiramycin acylated derivative and medicine or bactericidal composition

Abstract

The invention relates to an application of a spiramycin acylated derivative. The spiramycin acylated derivative disclosed by the invention can be used as an anti-gram-positive bacterium drug or bactericide, or the spiramycin acylated derivative can be used as an active ingredient of the anti-gram-positive bacterium drug or bactericide; or the spiramycin acylated derivative can be used as an active ingredient for preparing gram-positive bacterium resisting drugs or bactericides, and has an application prospect in preparation of antibacterial drugs.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to the use of spiramycin acylated derivatives in the preparation of drugs for treating diseases caused by Gram-positive bacteria. Background Technology

[0002] Spiramycin is a 16-membered macrolide antibiotic. Its active ingredients are a mixture of compounds produced by *Streptomyces* species, primarily spiramycin-I, -II, and -III. Spiramycin exhibits potent in vivo antibacterial activity and post-antibacterial effects, showing good antibacterial activity against Gram-positive and some Gram-negative bacteria, such as *Staphylococcus aureus*, *Streptococcus pneumoniae*, hemolytic streptococci, *Neisseria*, and *Corynebacterium diphtheriae*. It also has inhibitory effects on difficult-to-treat mycoplasma, chlamydia, *Toxoplasma gondii*, and *Cryptosporidium*. Another 16-membered macrolide antibiotic, calamycin, produced by recombinant *Streptomyces spirulina* carrying the 4”-O-isovaleryltransferase gene, can be considered a biosynthetic derivative of spiramycin. Its main components are 4”-O-isovalerylspiramycin-I, -II, and -III. Studies have found that calamycin not only has excellent antibacterial activity but can also be used to treat coronaviruses and various other viruses, and has shown in vivo and in vitro anticancer effects in various cancer models. Clearly, appropriate derivatization of spiramycin could potentially generate a variety of compounds with novel biological activities, thereby promoting drug development. However, it is difficult to achieve rapid and diversified derivatization of spiramycin using biosynthetic methods.

[0003]

[0004] According to literature reports, spiramycin-I has four hydroxyl groups that can be modified, but selective acylation often requires cumbersome synthetic steps involving various protection and deprotection processes (J. Antibiot., 1984, 760-772). Therefore, few acylated derivatives of spiramycin-I are obtained through chemical synthesis. Our recent research has found that by using a bulky acylation reagent under appropriate conditions, the 4”-OH group can be preferentially and selectively acylated, followed by the 3”-OH group, thus yielding 4”-O-acylated spiramycin derivatives, 3”-O-acylated spiramycin derivatives, or 3,4”-O-diacytized spiramycin derivatives (Patent Application 202310057657.0).

[0005] By conducting antibacterial tests on these spiramycin derivatives, we found that most of the derivatives showed superior antibacterial activity against a variety of Gram-positive bacteria compared to spiramycin or azithromycin. These spiramycin derivatives can be used in novel antibacterial drugs. Summary of the Invention

[0006] The purpose of this invention is to provide a safe and effective drug against Gram-positive bacteria and its application.

[0007] One of the advantages of this invention is that the general formula compound I generally has good anti-Gram-positive bacteria activity, and this antibacterial activity has a broad spectrum.

[0008] In some respects, the present invention proposes a spiramycin acylated derivative with resistance to Gram-positive bacteria, the derivative having the general structural formula I as follows:

[0009]

[0010] Among them, R 1 R 2 ArR, independently a CO-, R b CO- or R c R d NR e One or more of CO-; here, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic aryl group, wherein the substituents on the substituted phenyl group or the substituted heterocyclic aryl group are independently F, Cl, -CF3, -OCH3, C, respectively. 1-5 One or more of the alkyl groups; here, R a It refers to any one or more of the following chemical bonding bonds: -, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH=CH-; in R 1 In the middle, R b It refers to C 5-15 Alkyl or C 3-15 One or more of the cycloalkyl groups; in R 2 In the middle, R b It refers to C 1-15 Alkyl or C 3-15 One or more of the cycloalkyl groups; R c R d NR e CO-Chinese R c and R d H and C are independent of each other. 1-5 Alkyl or C 3-6 Cycloalkyl, C 2-5 alkenyl, C 2-5 One or more of the following: alkynyl group, substituted or unsubstituted phenyl group, and substituted or unsubstituted benzoyl group; wherein the substituents on the substituted phenyl group or the substituted benzoyl group independently refer to C1. 1-5 One or more of alkyl, F, -OCH3, and -CF3; R e It refers to one or more of the following chemical bonding bonds: -, -CH2-, and -CH2CH2-.

[0011] In some embodiments, spiramycin acylated derivative I is characterized by ArR a In CO-, Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic aryl group, and R represents... a This refers to any one or more of the chemical linkages -, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH=CH-. Here, the substituent on the substituted phenyl or substituted heterocyclic aryl group refers to one or more substituents at any position on the phenyl or heterocyclic aryl group, including methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, tert-butyl, -OCH3, -OCH2CH3, F, Cl, and -CF3. Further, ArR... a In CO-, Ar is a substituted or unsubstituted phenyl group, and R... a This refers to one or more of the chemical bonds -, -CH2-, -CH2CH2-, and -CH=CH-. Here, the substituent on the substituted phenyl group refers to one or more of the following substituents that are methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, tert-butyl, -OCH3, F, Cl, and -CF3 substituted at any position on the phenyl group; preferably, ArR... a CO- is one or more of benzoyl, 4-butylbenzoyl, 4-tert-butylbenzoyl, 4-tert-butylphenylacetyl, 4-CF3-benzoyl, and 4-CF3-phenylacryloyl.

[0012] In some embodiments, spiramycin acylated derivative I is characterized by R b R in CO- b In R 1 In the middle, it refers to the C of a straight chain or a branch chain. 5-15 One or more of alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, and cyclohexyl; further, R b It refers to one or more of the following: pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; preferably, R b It refers to one or more of the following: pentyl, hexyl, heptyl, and cyclohexyl.

[0013] In some embodiments, spiramycin acylated derivative I is characterized by R b R in CO- b In R 2 In the middle, it refers to the C of a straight chain or a branch chain. 1-15 One or more of alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, and cyclohexyl; further, R bIt refers to one or more of the following: methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, and cyclohexyl; preferably, R b It refers to one or more of methyl, ethyl, and propyl.

[0014] In some embodiments, spiramycin acylated derivative I is characterized by R c R d NR e CO-Chinese R c and R d Each of the following groups can be independently selected from one or more of H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, propargyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzoyl: substituted phenyl or substituted benzoyl groups can be methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, F, -OCH3, -CF3, R. e This refers to one or more of the following: chemical linkage bonds, -CH2-, and -CH2CH2-; furthermore, R c R d NR e CO-Chinese R c and R d Each and every one is independently one or more of the following: H, methyl, ethyl, propyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, propyne, substituted or unsubstituted phenyl, substituted or unsubstituted benzoyl. The substituents on the substituted phenyl or substituted benzoyl groups refer to methyl, butyl, tert-butyl, -CF3, R. e It refers to one or more of the chemical bonding types - and -CH2-; preferably, R c R d NR e CO- is One or more of the following acids: HCl, HBr, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid, camphorsulfonic acid, citric acid, benzoic acid, and gluconic acid.

[0015] In some embodiments, the antibacterial agent has one or more of the following as active ingredients: spiramycin acylated derivative I, or spiramycin acylated derivative I combined with a pharmaceutically acceptable acid salt. These acids are selected from one or more of HCl, HBr, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid, camphorsulfonic acid, citric acid, benzoic acid, and gluconic acid. The compounds include one or more of their corresponding diastereomer mixtures, diastereomer monomers, enantiomer mixtures, and enantiomer monomers, as well as one or more of their pharmaceutically acceptable salts, solvates, hydrates, or various crystal forms.

[0016] In some embodiments, preferred compounds of spiramycin acylated derivative I are shown in the table below:

[0017]

[0018] In compound I of general formula, appropriate groups Ar, R a R b R c R d and R e If applicable, they are selected independently. The embodiments described in this invention can be combined, and such combinations remain within the scope of this invention. For example, if applicable, any one of the variables Ar, R in general formula compound I... a R b R c R d and R e The definition can be the same as any other variable Ar, R described in this article. a R b R c R d and R e The definitions can be combined. Such combinations are still within the scope of protection of this invention.

[0019] The present invention also relates to pharmaceutical compositions comprising one or more of the above-described spiramycin acylated derivatives. In other words, compounds according to the present invention can be used as pharmaceutically active substances in pharmaceutical compositions or bactericidal compositions composed of one or more of any pharmaceutically acceptable excipients and / or one or more of other active compounds. Such compositions are used as antibacterial agents.

[0020] They can be used to prepare pharmaceutical formulations containing at least one of the compounds.

[0021] The compounds according to the invention, or salts formed with pharmaceutically acceptable acids, can be formulated into suitable galen dosage forms, such as oral, injectable, or spray-administered compositions, according to acceptable pharmaceutical procedures. Pharmaceutical compositions according to the invention comprise an effective amount of the compound of the invention, and a suitable pharmaceutically acceptable carrier or diluent, which are well known in the art. The carrier can be any inert raw material, organic or inorganic, suitable for enteral, transdermal, or parenteral administration, such as water, gelatin, gum arabic, lactose, microcrystalline starch, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silica, etc. The composition may also contain other pharmaceutically active agents and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc.

[0022] The compositions according to the invention can be formulated into solid or liquid dosage forms for oral administration, such as tablets, capsules, powders, and syrups; into sterile solutions, suspensions, or emulsions for parenteral administration; and into dry powder formulations, sterile solutions, suspensions, or emulsions for spray administration.

[0023] These spiramycin acylated derivatives exhibit excellent activity against Gram-positive bacteria, such as Staphylococcus, Streptococcus, Streptococcus pneumoniae, Bacillus anthracis, Corynebacterium diphtheriae, and Clostridium tetani, one or more of these bacteria. They can be used as active pharmaceutical ingredients to treat diseases caused by various Gram-positive bacteria, such as respiratory infections, purulent tonsillitis, bronchitis, pneumonia, gastrointestinal diseases, reproductive system diseases, and infections of the skin and surgical sites, one or more of these. The specific dosage of the compound will vary depending on its potency, route of administration, patient age and weight, and the severity of the treated condition.

[0024] "Compounds of the present invention" includes any compound represented by general formula I, and its pharmaceutically acceptable salt. Compounds of the present invention may also exist as hydrates or solvates. Compounds of the present invention may contain asymmetrically substituted R or S configurations of carbon or nitrogen atoms. Compounds of the present invention are not limited to specific stereoisomers; for example, in some embodiments, compounds of the present invention may be a single R or S configuration for each chiral center, or a mixture of R and S in any proportion.

[0025] The term "alkyl" itself, or as part of other groups, refers to straight-chain or branched aliphatic hydrocarbons, such as methyl, propyl, 2-methylpropyl, pentyl, etc.

[0026] The term "cycloalkyl" refers to an alkyl group with an alicyclic group in its structure, such as cyclopropyl, cyclopropylmethylene, cyclopentyl, 2-ethylcyclopentyl, cyclopentylethylene, cyclohexyl, etc.

[0027] The term "substituted or unsubstituted" means that the target group may be optionally substituted by one or more substituents.

[0028] Unless specifically mentioned as conflicting, in this invention, combinations of substituents and / or variables refer to chemically permissible combinations that produce stable compounds. A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain unchanged over a period of time, sufficient to allow it to be used for some of the purposes described in this invention (e.g., medication of a subject).

[0029] In the structural formula of this invention, the wavy line indicates that it is connected to the skeleton at this location.

[0030] Appendix Explanation

[0031] Table 1: Minimum inhibitory concentrations of spiramycin acylated derivatives against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis. Detailed Implementation

[0032] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0034] Furthermore, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0035] Experimental Section

[0036] General methods

[0037] The instruments and reagents used in the experiment mainly included: a microplate reader (Biotek Cytation 5); 96-well plates purchased from Shanghai Yisheng Biotechnology Co., Ltd.; MH medium purchased from Beijing Junlikang Technology Development Co., Ltd.; NB medium purchased from Shanghai Zeye Biotechnology Co., Ltd.; dimethyl sulfoxide purchased from Thermo Fisher Scientific; Staphylococcus aureus (ATCC25923), methicillin-resistant Staphylococcus aureus (ATCC515992), Bacillus subtilis (ATCC12228), Staphylococcus epidermidis (ATCC6633), NB solid medium and CA-B solid medium were all purchased from Beina Chuanglian Biotechnology Co., Ltd.

[0038] Bacterial resuscitation: Frozen standard strains of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermidis were dissolved in water at room temperature. The standard strains of Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Staphylococcus epidermidis were inoculated into NB solid medium, while the standard strain of Bacillus subtilis was inoculated into CA-B solid medium. The cultures were incubated at 37°C for 12 hours. The next day, 2-3 well-grown single colonies were picked and cultured in MH medium with shaking for later use.

[0039] Preparation of bacterial suspension: One day before the start of the experiment, pick a single colony of the desired bacteria into a shaker tube, add 4 ml of culture medium (NB medium for Staphylococcus epidermidis, and MH medium for Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Bacillus subtilis), mix well, and place in a shaker at 37°C for 24 hours to prepare a bacterial suspension.

[0040] Preparation of stock solutions: For compounds spiramycin-I, I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-9, I-10, I-11, I-12, I-13, I-14, and I-15, and positive control compounds linezolid and vancomycin, weigh 3-5 mg of each compound and dissolve them in DMSO solution (calculate the required volume of DMSO based on molecular weight and mass). After thorough dissolution, prepare 100 mM stock solutions for later use.

[0041] Compound concentration preparation: The compound concentration gradient preparation method was adopted in this experiment. Therefore, the volume corresponding to the maximum working solution concentration of all compounds should be increased by 2 times to facilitate subsequent gradient dilution. After preparing all compound concentrations (128, 64, 32, 16, 8, 4, 2, 1, 0.5 μM), 100 μl of each was added to a 96-well plate.

[0042] Concentration and volume calculation: Based on the required compound concentration and corresponding volume, calculate the required volume according to C1V1 = C2V2. Assuming a 64 μM compound working solution is needed, add 100 μl to each well. For a double-parallel experiment, two replicates are required, resulting in a total volume of 200 μl. The calculated required stock solution volume is 0.128 μl.

[0043] Minimum inhibitory concentration (MIC) determination: Pipette 200 μl of bacterial suspension into a clean 96-well plate and measure the OD using a microplate reader. 600 Value. Dilute the bacteria with the appropriate culture medium to OD value. 600The value was 0.05. 100 μL was added to each well of a 96-well plate. The experimental group consisted of 100 μL bacterial culture + 100 μL of different concentrations of the test compound solution, and the Blank group consisted of 100 μL bacterial culture + 100 μL of the corresponding blank culture medium. After incubation at 37°C for 20 hours, the OD was measured using a microplate reader. 600 Value, OD 600 The lowest concentration less than 0.1 is the minimum inhibitory concentration (MIC).

[0044] The test results (Table 1) show that most acylated spiramycin derivatives exhibited strong antibacterial activity against all four strains (MIC 2–32 μM). Compared to spiramycin-I, all compounds showed a 2–8 fold increase in MIC against methicillin-resistant Staphylococcus aureus (MRSA), a 2–16 fold increase in MIC against Staphylococcus epidermidis, and a 2–16 fold increase in MIC against Bacillus subtilis. Against Staphylococcus aureus, except for compounds I-6 and I-9, the MICs of the other compounds were also increased by 4–16 times. In particular, the n-butylcarbamoyl compound I-13 showed the strongest antibacterial activity against all four strains, especially against Staphylococcus epidermidis and Bacillus subtilis, with I-13 even reaching a MIC of 1 μM, comparable to that of the positive control compounds linezolid or vancomycin.

[0045] Table 1. Minimum inhibitory concentrations (MICs, μg / mL, [μM]) of spiramycin acylated derivatives against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, and Bacillus subtilis.

[0046]

Claims

1. The application of a spiramycin acylated derivative, characterized in that, Spiramycin acylated derivatives can be used as anti-Gram-positive bacteria drugs or bactericides, or spiramycin acylated derivatives can be used as active ingredients in anti-Gram-positive bacteria drugs or bactericides, or spiramycin acylated derivatives can be used as active ingredients in the preparation of anti-Gram-positive bacteria drugs or bactericides; wherein, the spiramycin acylated derivatives refer to one or more of the spiramycin derivatives shown in general formula I: Among them, R 1 R 2 ArR, independently a CO-, R b CO- or R c R d NR e One or more of CO-; Here, Ar represents a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic aryl group, and the substituents on the substituted phenyl group or the substituted heterocyclic aryl group are independently F, Cl, -CF3, -OCH3, C, respectively. 1-5 One or more of the alkyl groups; R a It refers to any one or more of the chemical bonding bonds -, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH=CH-. In R 1 In the middle, R b It refers to C 5-15 Alkyl or C 3-15 One or more of the cycloalkyl groups; In R 2 In the middle, R b It refers to C 1-15 Alkyl or C 3-15 One or more of the cycloalkyl groups; R c R d NR e CO-Chinese R c and R d H and C are independent of each other. 1-5 Alkyl or C 3-6 Cycloalkyl, C 2-5 alkenyl, C 2-5 One or more of the following: alkynyl group, substituted or unsubstituted phenyl group, and substituted or unsubstituted benzoyl group; wherein the substituents on the substituted phenyl group or the substituted benzoyl group independently refer to C1. 1-5 One or more of alkyl, F, -OCH3, and -CF3; R e It refers to one or more of the following chemical bonding bonds: -, -CH2-, and -CH2CH2-.

2. The application as described in claim 1, characterized in that, ArR a In CO-, Ar is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic aryl group, and R is a substituted or unsubstituted heterocyclic aryl group. a This refers to any one or more of the following: chemical linkage, -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH=CH-; here, the substituent on the substituted phenyl or substituted heterocyclic aryl group refers to one or two or more of the following substituents that are substituted at any position on the phenyl or heterocyclic aryl group: methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, tert-butyl, -OCH3, -OCH2CH3, F, Cl, and -CF3; Furthermore, ArR a In CO-, Ar is a substituted or unsubstituted phenyl group, and R... a This refers to one or more of the chemical bonds -, -CH2-, -CH2CH2-, and -CH=CH-; here, the substituent on the substituted phenyl group refers to one or two or more of the substituents methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, tert-butyl, -OCH3, F, Cl, and -CF3 that are substituted at any position on the phenyl group. Preferred, ArR a CO- is one or more of benzoyl, 4-butylbenzoyl, 4-tert-butylbenzoyl, 4-tert-butylphenylacetyl, 4-CF3-benzoyl, and 4-CF3-phenylacryloyl.

3. The application as described in claim 1, characterized in that, R b R in CO- b In R 1 In the middle, it refers to the C of a straight chain or a branch chain. 5-15 One or more of alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, and cyclohexyl; further, R b It refers to one or more of the following: pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; preferably, R b It refers to one or more of the following: pentyl, hexyl, heptyl, and cyclohexyl. And / or, R b R in CO- b In R 2 In the middle, it refers to the C of a straight chain or a branch chain. 1-15 One or more of alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl, and cyclohexyl; further, R b It refers to one or more of the following: methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, and cyclohexyl; preferably, R b It refers to one or more of methyl, ethyl, and propyl.

4. The application as described in claim 1, characterized in that, R c R d NR e CO-Chinese R c and R d Each of the following groups can be independently selected from one or more of H, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, propargyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzoyl: substituted phenyl or substituted benzoyl groups can be methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, F, -OCH3, -CF3, R. e It refers to one or more of the following chemical bonding bonds: -, -CH2-, and -CH2CH2-. Furthermore, R c R d NR e CO-Chinese R c and R d Each and every one is independently one or more of the following: H, methyl, ethyl, propyl, butyl, pentyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, propyne, substituted or unsubstituted phenyl, substituted or unsubstituted benzoyl. The substituents on the substituted phenyl or substituted benzoyl groups refer to methyl, butyl, tert-butyl, -CF3, R. e It refers to one or more of the following chemical bonding bonds: - and -CH2-. Preferred, R c R d NR e CO- is One or more of them.

5. The application as described in claim 1, characterized in that, Preferred compounds of spiramycin acylated derivative I are shown below:

6. The application as described in any one of claims 1-5, characterized in that, The antibacterial agent has one or more of the following as active ingredients: spiramycin acylated derivative I, or spiramycin acylated derivative I and a pharmaceutically acceptable acid salt. These acids are one or more of the following: HCl, HBr, sulfuric acid, formic acid, acetic acid, succinic acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, tartaric acid, camphorsulfonic acid, citric acid, benzoic acid, and gluconic acid. The compounds also include one or more of their respective diastereomer mixtures, diastereomer monomers, enantiomer mixtures, and enantiomer monomers, as well as one or more of their pharmaceutically acceptable salts, solvates, hydrates, or various crystal forms.

7. The application as described in claim 1, characterized in that, The spiramycin acylated derivative I is effective against Gram-positive bacteria, such as Staphylococcus, Streptococcus, Streptococcus pneumoniae, Bacillus anthracis, Corynebacterium diphtheriae, Clostridium tetani, etc., one or more of these bacteria. The spiramycin acylated derivative I can be used to treat infectious or inflammatory diseases caused by Gram-positive bacteria, such as respiratory tract infections, purulent tonsillitis, bronchitis, pneumonia, gastrointestinal diseases, reproductive system diseases, and infections of the skin and surgical incisions, one or more of these diseases.

8. A pharmaceutical composition or bactericidal composition comprising one or more of the spiramycin acylated derivative I or a pharmaceutically acceptable salt, solvate, hydrate or crystalline form of the thereof as an active ingredient, according to any one of claims 1-6.

9. The composition according to claim 8, characterized in that, A pharmaceutical composition or bactericidal composition comprising one or more of the spiramycin acylated derivative I or a pharmaceutically acceptable salt thereof as described in any one of claims 1-6, one or more of any pharmaceutically acceptable excipients, and / or one or more of other active compounds.

10. The use of a pharmaceutical composition according to claim 8 or 9, characterized in that, The pharmaceutical composition or bactericidal composition is used to prepare a drug for treating or alleviating diseases caused by Gram-positive bacteria.

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