CN112898361A - 5-O-mycylamine glycosyl tylosin lactone derivative and preparation method and application thereof - Google Patents

5-O-mycylamine glycosyl tylosin lactone derivative and preparation method and application thereof Download PDF

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CN112898361A
CN112898361A CN202110137010.XA CN202110137010A CN112898361A CN 112898361 A CN112898361 A CN 112898361A CN 202110137010 A CN202110137010 A CN 202110137010A CN 112898361 A CN112898361 A CN 112898361A
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吴春丽
王庆
罗春迎
武小虎
严作廷
陈小让
王焕焕
张会
曹亚权
杨璞
张烁
翟洪进
杨莹雪
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Abstract

The invention belongs to the field of pharmaceutical chemistry and discloses a broader-spectrum 5-O-mycaminosugatylactone derivatives (I), preparation method and application thereof. To the use of said derivatives or compositions for the treatment and/or prophylaxis of antibacterial anti-mycoplasma anti-porcine virus; to the use of said derivatives or compositions for the treatment and/or prevention of bacterial mycoplasma and porcine reproductive and respiratory virus infections in animals; relates to the use of said derivatives or compositions for the treatment and/or prophylaxis of the animal bacterial mycoplasma blueEar virus infection. It has the following structural general formula:

Description

5-O-mycylamine glycosyl tylosin lactone derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a novel macrolide compound, in particular to a novel 5-O-mycaminosugatylolactone derivative; to a veterinary pharmaceutical composition comprising any of the derivatives; relates to a preparation method and a structure of the derivative; to a method for the treatment and/or prophylaxis of a bacterial infection in an animal, wherein the method comprises administering any one of said derivatives or compositions; to a method for the treatment and/or prophylaxis of mycoplasma infections in animals, wherein said method comprises administering any one of said derivatives or compositions; to a method for the treatment and/or prophylaxis of a porcine reproductive and respiratory syndrome infection, wherein said method comprises administering any one of said derivatives or compositions; and to the use of said derivatives for the manufacture of a medicament for the treatment and/or prevention of bacterial, mycoplasma, blue-ear infections in animals.
Background
Macrolides are a large group of antibiotics with a 12-22 carbon lactone ring chemical structure, and the number of varieties developed so far is over 100. However, the prior veterinary anti-mycoplasma macrolides medicines comprise hexadecylic tylosin, tilmicosin, acetylisovaleryl tylosin, tildipirosin, pentadecylic tylosin and gamithromycin. The macrolide antibiotics have wide antibacterial spectrum and are active to partial anaerobes, mycoplasma, chlamydia, legionella, spirochetes and rickettsia. In addition, macrolide antibiotics, which exert an anti-inflammatory effect by inhibiting the synthesis of inflammatory mediators by monocytes, have been demonstrated to be expressed by increasing NF-. kappa.B-mediated ICAM-1 receptors, and inhibit NF-. kappa.B activation by reducing the number of ICAM-1 receptor expressions, thereby reducing viral adhesion to the respiratory mucosa and exhibiting an antiviral effect. Is an rare good medicine for treating mixed infection caused by mycoplasma. Optimizing the structure of macrolide and developing new generation macrolide medicine are also the development direction of new veterinary medicine.
Figure BDA0002927087740000011
The sixteen-membered ring macrolide antibiotics such as tylosin, acetylisovaleryl tylosin, tilmicosin and tildipirosin are used as special antibiotics for animals to mainly prevent and treat respiratory infectious diseases of pigs, cattle, poultry and the like caused by sensitive bacteria such as haemophilus parasuis, actinobacillus pleuropneumoniae, pasteurella multocida, Mannheim haemolytica, staphylococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, corynebacterium pyogenes, porcine reproductive and respiratory syndrome viruses and mycoplasma of livestock and poultry. These drugs have a good effect on gram-positive bacteria, but have a poor effect on gram-negative bacteria, particularly on E.coli. Therefore, our research efforts have focused on developing a broader spectrum of tylosin derivatives, particularly against gram-negative bacteria such as E.coli.
5-O-mycaminosugatylactone (hereinafter named OMT) is obtained by taking tylosin as a raw material and hydrolyzing to remove allose and mycotose, is also a precursor of tylosin biosynthesis in the biosynthesis process, and is an excellent method for placing bacterial amino acid or peptide residues in vacant sites in a ribosome space stereo structure of the bacterial amino acid or peptide residues in the action mechanism.
Figure BDA0002927087740000021
Tylonolide is one of the important OMT derivatives, and the european union pharmaceutical commission for veterinary use (CVMP) approved in 2011 a market approval application of sterile injection (trade name zurrevo) containing tylonolide as a main ingredient by the intein corporation, which will be subsequently approved for sale in european union countries and approved in china as a new veterinary drug class ii. Therefore, the development of novel tylosin derivatives using OMT as a lead compound is an important research direction. Patent WO2014/187957A1 and document DOI 10.1038/ja.2017.61 report the antibacterial activity of 5-O-mycaminosugatolactone derivatives partially introduced with quinoline groups on gram-positive or negative bacteria, drug-sensitive bacteria and drug-resistant strains, wherein the compounds YT709(2k), YT650(2f), YT769 and YT770 show better antibacterial activity, the MICs for drug-sensitive bacteria Staphylococcus aureus are respectively 0.125. mu.g/mL, 0.25. mu.g/mL and 0.25. mu.g/mL, and the MICs for Escherichia coli standard strains are respectively 16. mu.g/mL, 4. mu.g/mL and 4. mu.g/mL. However, the compound with good antibacterial activity to mycoplasma, porcine reproductive and respiratory syndrome virus and gram-negative bacteria is not reported in the documents, the strain variety used in the document DOI:10.1038/ja.2017.61 is narrow in range, and the activity to pasteurella, mycoplasma and porcine reproductive and respiratory syndrome virus is not detected. The patent CN201910939085.2 applied by the subject group protects the derivative synthesized by using OMT as a raw material and the activity thereof. With the development of studies on the modification of the structure of OMT at positions 20 and 23, a number of broader compounds were found.
Figure BDA0002927087740000022
The novel 20-position 20-1H-1,2, 3-triazole-5-O-myclobutanil derivative containing quinolyl and 23 tertiary amine groups opens up a new way for researching new drug-resistant antibiotics with wide antibacterial spectrum, and has important significance for developing self-owned intellectual property medicines.
Disclosure of Invention
The invention aims to provide a 5-O-mycaminosugatalactone derivative and an acid salt thereof, which can effectively prevent and/or treat bacterial, mycoplasma and porcine reproductive and respiratory syndrome virus infection. Another object of the present invention is to provide a method for synthesizing the same.
The invention further aims to provide application of the compound in preparing antibacterial, mycoplasma and porcine reproductive and respiratory syndrome medicines.
In order to realize the purpose of the invention, the technical scheme is as follows:
the structural general formula of the 5-O-mycaminosugatylactone derivative containing quinoline at the 20-position and amino or other substituent at the 23-position is as follows:
including pharmaceutically acceptable salts, esters, prodrugs or solvate thereof,
Figure BDA0002927087740000031
R1selected from i or ii or iii or iv:
i is hydrogen, a straight chain alkyl group containing 1 to 3 carbon atoms or a straight chain alkyl group containing a substituent;
ii is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, Cl, Br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino and methoxy;
iii is a mono-or poly-nitrogen containing unsaturated five-or six-membered heterocyclic group; or substituted single-nitrogen or multi-nitrogen unsaturated five-membered or six-membered heterocyclic group, wherein the substituent is single substituent or double substituent, and the substituent is selected from F, Cl, Br, I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino and methoxy;
iv is a five-membered or six-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen-oxygen, or nitrogen-sulfur unsaturation; or substituted five-membered or six-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen-oxygen or nitrogen-sulfur unsaturation, the substituent is mono-substituent or bi-substituent, the substituent is selected from F, Cl, Br, I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy, hydroxyethyl;
R2selected from v or vi or vii:
v is hydroxy, iodo;
vi is a saturated or unsaturated secondary amine group, or a substituted saturated or unsaturated secondary amine group,
Figure BDA0002927087740000032
wherein the nitrogen atom is part of a carbocyclic ring system selected from a saturated monocyclic ring containing 5 to 16 carbon atoms or a saturated bicyclic or saturated tricyclic ring system containing 8 to 20 carbon atoms; or a carbocyclic ring system as described above in which one or more carbon atoms are substituted by a group selected from straight or branched chain alkyl of 1 to 3 carbon atoms or hydroxy;
vii is
Figure BDA0002927087740000033
Wherein R is3And R4Each selected from straight or branched chain alkyl groups containing 1 to 6 carbon atoms; a linear or branched alkenyl group having 1 to 6 carbon atoms; or cycloalkyl containing 3 to 6 carbon atoms.
The following substituent compounds are preferred:
R1selected from i or ii or iii or iv:
i is hydrogen, straight chain alkyl containing 1 to 3 carbon atoms;
ii is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, Cl, Br, I or straight chain or branched chain alkyl with 1-3 carbon atoms or hydroxyl, nitryl, acetamido, methoxyl;
iii is a mono-or di-nitrogen containing unsaturated six-membered heterocyclic group;
iv is a five-membered heterocyclic group containing single oxygen, single sulfur, nitrogen oxygen and nitrogen sulfur unsaturated; or substituted five-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen oxygen and nitrogen sulfur, wherein the substituent is a single substituent and is selected from hydroxyethyl;
R2selected from v or vi or vii:
v is hydroxy;
vi is a saturated secondary amine group or a substituted saturated secondary amine group,
Figure BDA0002927087740000034
wherein the nitrogen atom is part of a carbocyclic ring system selected from saturated monocyclic rings containing 5 to 10 carbon atoms; or a carbocyclic ring system as described above in which one or more carbon atoms are substituted with a group selected from straight chain alkyl of 1 to 3 carbon atoms or hydroxy;
vii is
Figure BDA0002927087740000041
Wherein R is3And R4Each selected from straight or branched chain alkyl groups containing 1 to 6 carbon atoms; or cycloalkyl containing 3 to 6 carbon atoms.
More preferred are the following specific compounds:
Figure BDA0002927087740000042
the preparation method of the compound provided by the invention is realized through the following reaction route:
Figure BDA0002927087740000043
dissolving 5-O-mycaminosugal tylonolide (OMT) in an organic solvent, and adding a compound of a general formula 1, acetic acid, a water removing agent and a reducing agent to obtain a white or yellow target 2.
A compound of the general formula 1: r1Selected from i or ii or iii or iv.
The reducing agent is one or two of sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride;
the used water removing agent is one or two of anhydrous magnesium sulfate or anhydrous sodium sulfate;
the organic solvent is one or two of dichloromethane or 1, 2-dichloroethane.
Wherein the compound of formula 1 is according to DOI:10.1038/ja.2017.61, the aldehyde compound, propargylamine and 3-aminoquinoline are commercially available, and OMT is obtained by hydrolyzing mycose and allose in acid solution with tylosin.
Figure BDA0002927087740000044
Dissolving the compound shown in the general formula 2 in an organic solvent, and adding triphenylphosphine and iodine particles to obtain a white target 3. (synthesized according to the method shown in patent US20160108077a 1).
A compound of the general formula 2: r1Selected from i or ii or iii or iv.
The organic solvent is one or two of pyridine or N, N-dimethylformamide.
Figure BDA0002927087740000051
Dissolving the compound of the general formula 3 in an organic solvent, adding an acid-binding agent and a compound containing R2To obtain the target compound shown in the general formula 4 (synthesized according to the method shown in the patent US20160108077A 1).
A compound of the general formula 4: r2Selected from v or vi or vii:
a compound of the general formula 3: r1Selected from i or ii or iii or iv.
The acid-binding agent is one or two of anhydrous sodium carbonate or anhydrous potassium carbonate;
the organic solvent is one or two of tetrahydrofuran or acetonitrile.
The synthetic methods of the present invention include, but are not limited to, the addition or removal of an appropriate protecting group before or after the above steps to obtain the compounds of the present invention. In addition, it is also within the scope of the synthetic methods of the present invention to alter the order of the reaction steps to obtain the compounds of the present invention.
The salt-forming acid selected by the invention is organic acid or inorganic acid, the organic acid comprises baicalin, caffeic acid, shikimic acid, citric acid, lactic acid, citric acid, tartaric acid and the like, and the inorganic acid comprises hydrochloric acid, phosphoric acid and methanesulfonic acid.
The compounds of the invention are useful for treating or preventing diseases in animals caused by infection, the bacteria or mycoplasma or viruses causing the infection including staphylococcus, streptococcus, lactobacillus, enterococcus, enterobacter, erwinia, pasteurella, actinobacillus, bifidobacterium, peptostreptococcus, rickettsia, treponema, legionella, campylobacter, brucella, mycoplasma, ureaplasma, escherichia, listeria, bacillus, clostridium, DNA viruses, RNA viruses.
Specifically, the compounds of the present invention can treat livestock and poultry diseases caused by staphylococcus, streptococcus, lactobacillus acidophilus, mycobacterium tuberculosis, pasteurella, enterococcus faecalis, enterococcus faecium, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, klebsiella pneumoniae, streptococcus gallic acid, escherichia coli, pseudomonas aeruginosa, mannheimia, mycoplasma pneumoniae, mycoplasma gallisepticum, mycoplasma synoviae, blue-ear virus, influenza virus, etc.
The bacterial or viral infection and the diseases caused by the infection include, but are not limited to, the following diseases: respiratory infections caused by streptococcus pneumoniae, haemophilus influenzae, staphylococcus aureus, streptococcus digestions, pseudomonas, mycoplasma pneumoniae, chlamydia pneumoniae. Soft tissue infection, abscess, postpartum hyperpyrexia and mastitis caused by staphylococcus aureus, staphylococcus haemolyticus, streptococcus agalactiae, escherichia coli and the like. Urinary tract infections caused by staphylococci and enterococci. There are toxic diseases caused by infection of staphylococcus aureus and streptococcus. Ulcers caused by helicobacter pylori.
Useful for treating or preventing such disorders in animals include, but are not limited to, the following: arthritis and tenosynovitis of chicken caused by mycoplasma synoviae. Porcine reproductive and respiratory syndrome (PPRS) caused by the porcine reproductive and respiratory syndrome. Bovine respiratory diseases caused by pasteurella haemolytica, pasteurella multocida, mycoplasma bovis. Bovine intestinal disease caused by E.coli. Mastitis in dairy cows is caused by Staphylococcus aureus, Streptococcus uberis, Streptococcus agalactiae, Streptococcus dysgalactiae, Corynebacterium or enterococcus. Porcine respiratory disease caused by actinobacillus pneumoniae, pasteurella multocida, or mycoplasma. The invention is especially effective to respiratory diseases of farm animals such as pigs, cattle and chickens.
The amount of the present invention to be expressed in terms of treating or preventing a bacterial or viral infection is expressed as a "therapeutically effective amount" and may vary depending on the size, body weight, specific surface area of the animal or the compound of the present invention.
The effective amount of the present invention may be increased or decreased in proportion to the degree of urgency of the disease.
The use of the compounds of the invention and pharmaceutically acceptable salts, esters, prodrugs or solvate thereof: the active ingredient is combined with at least one pharmaceutically acceptable carrier, adjuvant or diluent to prepare a pharmaceutical composition or a veterinary drug composition, and the pharmaceutical composition or the veterinary drug composition is used for producing biological medical products and treating diseases such as respiratory infectious diseases, arthritis, mastitis and the like of livestock and poultry.
By "veterinary composition" is meant a composition comprising said compounds in a proportion varying from 0.1 to 99.5%.
An "acceptable carrier" is an acceptable ingredient disclosed in the pharmaceutical field, and is a solid or liquid filler, excipient, solvent, diluent, etc., which helps transport, absorption and distribution of the drug to be tested in the body, and must not be harmful to the patient.
The preparation of the invention includes but is not limited to final sterilized injection, non-final sterilized injection, powder injection, tablet, granule, capsule, soluble powder and powder.
The term "animal" as used herein generally includes, but is not limited to, humans, cattle, pigs, chickens, ducks, goats, sheep, dogs, cats, rats, mice, rabbits, ducks, etc., especially farm animals cattle, pigs, chickens, ducks.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
The invention has the innovation points and advantages that: the C-20 site and the C-23 site of OMT are structurally modified, 5-O-mycaminosugatalactone derivatives containing quinoline at the 20 site and amino at the 23 site are designed and synthesized, and the broad-spectrum antibacterial activity evaluation is carried out on the compound, wherein the evaluation comprises gram-positive standard strains, gram-negative standard strains, cow mastitis pathogens, mycoplasma and blue-ear viruses. The compound of the invention shows excellent inhibitory activity against staphylococcus aureus standard bacteria, escherichia coli standard bacteria and the like (see table 1). 4-7b, 4-7c and 4-7g showed broad-spectrum inhibitory activity (see tables 1-3). The broad-spectrum antibacterial effects of the compounds 4-7b, 4-7c and 4-7g are more obvious than those of contrast drugs YT709, YT650, YT769, YT770, tylonolide, tilmicosin, gamithromycin, tulathromycin and the like. In addition, the compounds 4-7b, 4-7c and 4-7g of the present invention showed strong inhibitory effects against Mycoplasma hyopneumoniae, Mycoplasma gallisepticum, Pasteurella haemolytica and the porcine reproductive and respiratory virus (see tables 3-4). The synthesis method is simple, high in yield and beneficial to production implementation and conversion. Opens up a new way for researching new broad-spectrum drug-resistant antibiotics and has important significance for developing drug-resistant drugs for the owner of intellectual property rights.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1: preparation of the derivative (2-1) shown by the Compound of formula 2
Dissolving N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 86%.
Example 2: preparation of the derivative (2-2) shown by the Compound of formula 2
Dissolving N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 83%.
Example 3: preparation of the derivatives (2-3) shown by the Compounds of formula 2
Dissolving N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 84%.
Example 4: preparation of derivatives (2-4) shown by Compounds of formula 2
Dissolving N-p-trifluoromethylbenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 87%.
Example 5: preparation of the derivatives (2-5) shown by the Compounds of formula 2
Dissolving N-p-bromobenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 85%.
Example 6: preparation of derivatives (2-8) shown by Compounds of formula 2
Dissolving N-p-nitrobenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 84%.
Example 7: preparation of derivatives (2-9) shown by Compounds of formula 2
Dissolving N- (3-methoxy-4-hydroxy) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 84%.
Example 8: preparation of the derivatives (2-10) shown by the Compounds of formula 2
Dissolving N- (4-pyridyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 87%.
Example 9: preparation of the derivatives (2-11) shown by the Compounds of formula 2
Dissolving N- (3-pyridyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 90%.
Example 10: preparation of derivatives (2-12) shown by Compounds of formula 2
Dissolving N- (2,4, 6-trimethoxy) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 87%.
Example 11: preparation of the derivatives (2-13) shown by the Compounds of formula 2
Dissolving N-p-acetamido benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 85%.
Example 12: preparation of the derivatives (2-14) shown by the Compounds of formula 2
Dissolving N- (2-thienyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 82%.
Example 13: preparation of the derivatives (2-15) shown by the Compounds of formula 2
Dissolving N- (3-thienyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 88%.
Example 14: preparation of the derivatives (2-16) shown by the Compounds of formula 2
Dissolving N- (5-thiazolyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 83%.
Example 15: preparation of the derivatives (2-17) shown by the Compounds of formula 2
Dissolving N- (2-thiazolyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 81%.
Example 16: preparation of the derivatives (2-18) shown by the Compounds of formula 2
Dissolving N- (5-pyrimidyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 86%.
Example 17: preparation of derivatives (2-19) shown by Compounds of formula 2
Dissolving N-p-methylbenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by using a silica gel chromatographic column to obtain the target product with the yield of 93%.
Example 18: preparation of the derivatives (2-20) shown by the Compounds of formula 2
Dissolving N-p-ethylbenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 85%.
Example 19: preparation of the derivatives (2-21) shown by the Compounds of formula 2
Dissolving N-p-isopropylbenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting at room temperature for 2 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 83%.
Example 20: preparation of the derivatives (2-22) shown by the Compounds of formula 2
Dissolving N- (5-hydroxyethyl 2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine and OMT in 1, 2-dichloroethane, stirring uniformly, dropwise adding acetic acid, adding anhydrous magnesium sulfate, stirring for 30 minutes, then adding sodium triacetoxyborohydride, reacting for 2 hours at room temperature to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 84%.
Example 21: preparation of the derivative (3-1) shown by the Compound of formula 3
Dissolving 20-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin amine sugar tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 87%.
Example 22: preparation of the derivative (3-2) shown by the Compound of formula 3
Dissolving 20-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin glucosamine tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 83%.
Example 23: preparation of the derivatives (3-3) shown by the Compounds of formula 3
Dissolving 20-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin glucosamine tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 85%.
Example 24: preparation of the derivatives (3-4) shown by the Compounds of formula 3
Dissolving 20-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin glucosamine tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 25: preparation of the derivatives (3-5) shown by the Compounds of formula 3
Dissolving 20-deoxy-20- { N-p-bromobenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin glucosamine tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 84%.
Example 26: preparation of the derivatives (3-6) shown by the Compounds of formula 3
Dissolving 20-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -5-O-carbomycin glucosamine tylosin lactone in anhydrous pyridine, uniformly stirring, adding triphenylphosphine and iodine, stirring at room temperature for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 27: preparation of the derivative (4-1a) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazol-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting in a sealed tube at 120 ℃ for 5 hours to obtain the product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 78%.
Example 28: preparation of the derivative (4-1b) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain the target product, wherein the crude product is separated by a silica gel chromatographic column to obtain the target product, and the yield is 74%.
Example 29: preparation of the derivative (4-1c) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 79%.
Example 30: preparation of the derivatives (4-1d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazol-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the crude product is separated by a silica gel chromatographic column to obtain the target product, and the yield is 84%.
Example 31: preparation of the derivative (4-1e) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding 3, 5-dimethylpiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the crude product is separated by a silica gel chromatographic column to obtain the target product, and the yield is 88%.
Example 32: preparation of the derivatives (4-1f) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazol-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile and water, uniformly stirring, adding anhydrous potassium carbonate, adding dimethylamine hydrochloride, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 85%.
Example 33: preparation of derivatives (4-1g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (4-N, N-dimethylamino) benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodo-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, and reacting in a sealed tube at 120 ℃ for 5 hours to obtain the product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 81%.
Example 34: preparation of the derivative (4-2a) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a target product with the yield of 83%.
Example 35: preparation of the derivative (4-2b) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 81%.
Example 36: preparation of the derivative (4-2c) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 78%.
Example 37: preparation of the derivatives (4-2d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 84%.
Example 38: preparation of the derivative (4-2e) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding 3, 5-dimethylpiperidine, sealing in a tube, reacting at 120 ℃ for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 39: preparation of derivatives (4-2g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-methoxybenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, reacting for 5 hours at 120 ℃ in a sealed tube to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 82%.
Example 40: preparation of the derivative (4-3a) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain the product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 78%.
Example 41: preparation of the derivative (4-3b) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 81%.
Example 42: preparation of the derivatives (4-3c) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the crude product is separated by a silica gel chromatographic column to obtain the target product, and the yield is 87%.
Example 43: preparation of the derivatives (4-3d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, sealing in a tube, reacting at 120 ℃ for 5 hours to obtain the product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 44: preparation of the derivatives (4-3e) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding 3, 5-dimethylpiperidine, and reacting for 5 hours in a sealed tube at 120 ℃, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 75%.
Example 45: preparation of the derivatives (4-3f) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile and water, uniformly stirring, adding anhydrous potassium carbonate, adding dimethylamine hydrochloride, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 77%.
Example 46: preparation of derivatives (4-3g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N- (2-furyl) methylene-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, reacting for 5 hours at 120 ℃ in a sealed tube to obtain the product, and separating a crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 47: preparation of the derivative (4-4a) shown by the Compound of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 81%.
Example 48: preparation of the derivatives (4-4b) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting at 120 ℃ for 5 hours in a sealed tube to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 77%.
Example 49: preparation of the derivatives (4-4c) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting at 120 ℃ for 5 hours in a sealed tube to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 79%.
Example 50: preparation of the derivatives (4-4d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, and reacting at 120 ℃ for 5 hours in a sealed tube to obtain the target product, wherein the crude product is separated by a silica gel chromatographic column to obtain the target product, and the yield is 77%.
Example 51: preparation of derivatives (4-4g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-p-trifluoromethyl benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, and separating the crude product by a silica gel chromatographic column to obtain the target product with the yield of 83%.
Example 52: preparation of the derivatives (4-5a) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-4-bromobenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting for 5 hours at 120 ℃ in a sealed tube to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 86%.
Example 53: preparation of the derivatives (4-5b) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-4-bromobenzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile and water, uniformly stirring, adding anhydrous potassium carbonate, adding dimethylamine hydrochloride, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 75%.
Example 54: preparation of the derivatives (4-6a) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding piperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 55: preparation of the derivatives (4-6b) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a target product with the yield of 75%.
Example 56: preparation of the derivatives (4-6c) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 79%.
Example 57: preparation of the derivatives (4-6d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 74%.
Example 58: preparation of the derivatives (4-6e) shown by the Compounds of formula 2
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding 3, 5-dimethylpiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 85%.
Example 59: preparation of the derivatives (4-6f) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile and water, uniformly stirring, adding anhydrous potassium carbonate, adding dimethylamine hydrochloride, reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, and separating the crude product by a silica gel chromatographic column to obtain a target product with the yield of 82%.
Example 60: preparation of derivatives (4-6g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-benzyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, reacting for 5 hours at 120 ℃ in a sealed tube, and separating a crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 61: preparation of the derivatives (4-7b) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding hexamethyleneimine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 62: preparation of the derivatives (4-7c) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding heptamethylene imine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 84%.
Example 63: preparation of the derivatives (4-7d) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin glucosamine tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding p-hydroxypiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain a crude product, wherein the crude product is separated by a silica gel chromatographic column to obtain a target product, and the yield is 86%.
Example 64: preparation of the derivatives (4-7e) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding 3, 5-dimethylpiperidine, and reacting at 120 ℃ in a sealed tube for 5 hours to obtain the target product, wherein the target product is obtained by separating a crude product through a silica gel chromatographic column, and the yield is 87%.
Example 65: preparation of derivatives (4-7g) shown by Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding diethylamine, reacting for 5 hours at 120 ℃ in a sealed tube, and separating a crude product by a silica gel chromatographic column to obtain a target product with the yield of 82%.
Example 66: preparation of the derivatives shown by the Compounds of formula 4 (4-7h)
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding di-N-propylamine, reacting for 5 hours at 120 ℃ in a sealed tube, and separating a crude product by a silica gel chromatographic column to obtain a target product with the yield of 81%.
Example 67: preparation of the derivatives (4-7i) shown by the Compounds of formula 4
Dissolving 20-deoxy-23-deoxy-20- { N-methyl-N- [ (1- (3-quinolyl) -1H-1,2, 3-triazole-4-yl) methylamine } -23-iodine-5-O-carbomycin ammonia sugar tylosin lactone in acetonitrile, uniformly stirring, adding anhydrous potassium carbonate, adding di-N-butylamine, reacting for 5 hours at 120 ℃ in a sealed tube, and separating a crude product by a silica gel chromatographic column to obtain a target product with the yield of 85%.
Example 68: in vitro standard strain and clinical strain antibacterial screening test of compound of the invention
Add 200. mu.L of the stock solution to column 1 of the 96-well plate, set two multiple wells, add 100. mu.L of MHB medium to columns 2-10, add 200. mu.L of the stock solution to column 11, and add 200. mu.L of the medium to the last column. Diluting sequentially from row 1 to row 10 by a microsyringe to obtain dilution of the rest liquid, discarding the rest liquid, and adding 100 μ L of the bacteria liquid to rows 1-10 to obtain 10 concentrations of 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125 and 0.0625 μ g/mL. And (3) culturing for 17h in a constant temperature box at 37 ℃, taking out, observing the good growth of bacteria in the negative control group by naked eyes, and obtaining the minimum concentration of the sample, which is the Minimum Inhibitory Concentration (MIC) of the sample, wherein the minimum concentration of the sample, which is observed that the bacteria can not grow, in the sample adding hole.
TABLE 15 inhibitory Activity of O-mycaminosugatylactone derivatives and control drugs against gram-positive and gram-negative standard bacteria (MIC: μ g/mL)
Figure BDA0002927087740000121
Figure BDA0002927087740000131
As can be seen from antibacterial experiments, the compounds of the present invention exhibited excellent activity against staphylococcus aureus, in which the MIC values of the compounds 2-3, 2-10, 2-14, 4-7b, 4-7c and 4-7g were the smallest, with a MIC of 0.125 μ g/mL, which was superior to control drugs such as vancomycin (MIC equal to 0.25 μ g/mL), YT709(MIC equal to 0.25 μ g/mL), YT770(MIC equal to 0.25 μ g/mL), OMT (MIC equal to 0.5 μ g/mL), YT769(MIC equal to 0.5 μ g/mL), tilmicosin (MIC equal to 1 μ g/mL), linezolid (MIC equal to 2 μ g/mL), YT650(MIC equal to 2 μ g/mL); compounds 2-1, 2-2, 2-8, 2-15, 4-3a and 4-6g had MICs for Staphylococcus aureus of 0.25. mu.g/mL, comparable to vancomycin, YT709, YT 770. In addition, the compounds such as 2-16, 2-17, 4-2a, 4-2b, 4-2g, 4-3f, 4-5b and the like also have stronger activity of inhibiting staphylococcus aureus than tilmicosin and YT 650. In the compound, only 4-7b, 4-7c and 4-7g have strong killing effect on escherichia coli and klebsiella pneumoniae standard bacteria, and the MIC value is 1-2 mu g/mL. 4-7b, 4-7c and 4-7g (MIC ═ 1 μ g/mL) had the strongest inhibitory activity against e.coli compared to the control drugs tylonolide, YT770 and YT769(MIC ═ 2 μ g/mL). The inhibitory activity of 4-7b, 4-7c and 4-7g (MIC ═ 1 ug/mL) on Klebsiella pneumoniae is better than that of YT769 and YT770(MIC ═ 2 ug/mL). In conclusion, 4-7b, 4-7c and 4-7g have obvious inhibitory effect on staphylococcus aureus and have excellent inhibitory activity on gram-negative bacteria such as escherichia coli and klebsiella pneumoniae. Therefore, 4-7b, 4-7c and 4-7g can be used as preferred compounds for the next screening of the activity against clinical pathogens of cow mastitis, Mycoplasma hyopneumoniae, Mycoplasma gallisepticum, Pasteurella haemolytica and porcine reproductive and respiratory syndrome virus.
TABLE 2 inhibitory Activity of preferred Compounds and controls against clinical pathogenic bacteria of cow mastitis (MIC: μ g/mL)
Figure BDA0002927087740000141
Note: staphylococcus aureus ATCC25923 and Escherichia coli ATCC25922 are standard strains, and the rest are clinical mastitis isolate milk samples. The clinical isolates tested were more or less resistant to the initial isolation and analysis of the strain information.
TABLE 3 inhibitory Activity of preferred Compounds of the invention and controls on Mycoplasma hyopneumoniae, Pasteurella haemolytica (MIC: μ g/mL)
Figure BDA0002927087740000142
Figure BDA0002927087740000151
TABLE 4 minimum drug concentration (μ g/mL) of preferred compounds of the invention and control drugs for porcine reproductive and respiratory syndrome virus
Figure BDA0002927087740000152
As can be seen from Table 2, the inhibitory activity of the preferred compounds against clinical pathogenic bacteria of cow mastitis shows the strongest inhibitory activity against a broad spectrum of antibacterial activity, as compared with control drugs and compounds of various known structures, preferably compounds 4-7b, 4-7c and 4-7 g. Preferably, the compounds 4-7b, 4-7c and 4-7g have broad-spectrum antibacterial activity, which is much higher than that of the commercially available control drugs such as tylosin, gamithromycin, tulathromycin and the like. Wherein the inhibitory activities of 4-7b, 4-7c and 4-7g on Escherichia coli are stronger than those of control compounds YT650, YT769 and YT 770. As can be seen from Table 3, the preferred compounds 4-7b, 4-7c and 4-7g all enhanced the anti-hemolytic Pasteurella activity over the control drug or compound. Preferably, the compounds 4-7b, 4-7c, 4-7g and the control drug have better activity level on mycoplasma hyopneumoniae and mycoplasma gallisepticum. As can be seen from Table 4, the preferred compounds, 4-7b, 4-7c and 4-7g, have a superior killing effect on porcine reproductive and respiratory syndrome virus over the control compounds. As described above, the compounds 4-7b, 4-7c and 4-7g are preferable as lead compounds for drug development.
4-7b, 4-7c and 4-7g can be used as active ingredients or combined with other medicines, and can be prepared into a medicinal preparation for resisting bacteria or mycoplasma according to the requirements of conventional pharmaceutical methods and processes after being mixed with auxiliary and/or additive ingredients acceptable in pharmacy.
Example 69: study on preparation of Tildipirosin oral liquid containing 10% (W/V) of preferred Compound 4-7b
Adding water 60-70% of the total volume of the oral liquid into a preparation tank, stirring, and adjusting the pH value to 5.7-6.3 by using concentrated phosphoric acid with the mass percentage concentration of 85%. Preferred compounds 4-7b are added in amounts. And then the pH value is adjusted to 5.5-6.0 by using concentrated phosphoric acid with the mass percentage concentration of 5% -100%, so that the materials are completely dissolved and clear. Adding 30 mass percent of propylene glycol, stirring to dissolve, and heating to 50-60 ℃. Adding water to 100ml, and filtering through a 0.45 micron filter membrane to obtain the veterinary tylonolide oral liquid.
Example 70: study on preparation of Tildipirosin oral liquid containing 10% (W/V) of preferred Compound 4-7b
Preferably 4-7b10g (calculated as 4-7b), adding propylene glycol to 40ml, adjusting to be clear with tartaric acid, adding water to a proper volume, adjusting the pH value to 5.8 with tartaric acid, and finally adjusting to be 100ml to prepare the veterinary tylonolide oral liquid.
Figure BDA0002927087740000153
Figure BDA0002927087740000161
Figure BDA0002927087740000171
Figure BDA0002927087740000181
Figure BDA0002927087740000191
Figure BDA0002927087740000201
Figure BDA0002927087740000211
Figure BDA0002927087740000221
Figure BDA0002927087740000231
Figure BDA0002927087740000241
Figure BDA0002927087740000251
Figure BDA0002927087740000261
Figure BDA0002927087740000271
Figure BDA0002927087740000281
Figure BDA0002927087740000291
Figure BDA0002927087740000301

Claims (8)

  1. A5-O-mycaminosugatylactone derivative containing quinoline at the 1-position and amino or other substituent at the 23-position or a salt thereof, characterized by having the following general structural formula:
    Figure FDA0002927087730000011
    R1selected from i or ii or iii or iv:
    i is hydrogen, straight chain alkyl containing 1 to 3 carbon atoms;
    ii is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, Cl, Br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino and methoxy;
    iii is a mono-or poly-nitrogen containing unsaturated five-or six-membered heterocyclic group; or substituted single-nitrogen or multi-nitrogen unsaturated five-membered or six-membered heterocyclic group, wherein the substituent is single substituent or double substituent, and the substituent is selected from F, Cl, Br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino and methoxy;
    iv is a five-membered or six-membered heterocyclic group containing single oxygen, single sulfur, nitrogen oxygen and nitrogen sulfur; or substituted five-membered or six-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen oxygen and nitrogen sulfur unsaturation, wherein the substituent is mono-substituent or di-substituent, and is selected from F, Cl, Br or I, or straight chain or branched chain alkyl or hydroxyl with 1-3 carbon atoms, nitro, trifluoromethyl, acetamido, N, N-dimethylamino, methoxy and hydroxyethyl;
    R2selected from v or vi or vii:
    v is hydroxy, iodo;
    vi is a saturated secondary amine group or a substituted saturated secondary amine group,
    Figure FDA0002927087730000021
    wherein the nitrogen atom is part of a carbocyclic ring system selected from saturated monocyclic rings containing 5 to 16 carbon atoms; or a saturated bicyclic or saturated tricyclic ring system containing 8 to 20 carbon atoms; or a carbocyclic ring system as described above in which one or more carbon atoms are substituted with a group selected from straight chain alkyl of 1 to 3 carbon atoms or hydroxy;
    vii is
    Figure FDA0002927087730000022
    Wherein R is3And R4Each selected from straight or branched chain alkyl groups containing 1 to 6 carbon atoms; a linear or branched alkenyl group having 1 to 6 carbon atoms; or cycloalkyl containing 3 to 6 carbon atoms.
  2. 2. The 5-O-mycaminosugatylactone derivative containing quinoline at the 20-position and amino or other substituent at the 23-position or a salt thereof according to claim 1, wherein R is1Selected from i or ii or iii or iv:
    i is hydrogen, straight chain alkyl containing 1 to 3 carbon atoms;
    ii is phenyl or substituted phenyl, the substituent is mono-substituent, di-substituent or tri-substituent, the substituent is selected from F, Cl, Br, I or straight chain or branched chain alkyl with 1-3 carbon atoms or hydroxyl, nitryl, acetamido, N, N-dimethylamino and methoxyl;
    iii is a mono-or di-nitrogen containing unsaturated six-membered heterocyclic group;
    iv is a five-membered heterocyclic group containing single oxygen, single sulfur, nitrogen oxygen and nitrogen sulfur unsaturated; or substituted five-membered heterocyclic group containing mono-oxygen, mono-sulfur, nitrogen oxygen and nitrogen sulfur, wherein the substituent is a single substituent and is selected from hydroxyethyl;
    R2selected from v or vi or vii:
    v is hydroxy;
    vi is a saturated secondary amine group or a substituted saturated secondary amine group,
    Figure FDA0002927087730000031
    wherein the nitrogen atom is part of a carbocyclic ring system selected from saturated monocyclic rings containing 5 to 10 carbon atoms; or a carbocyclic ring system as described above in which one or more carbon atoms are substituted with a group selected from straight chain alkyl of 1 to 3 carbon atoms or hydroxy;
    vii is
    Figure FDA0002927087730000032
    Wherein R is3And R4Each selected from straight or branched chain alkyl groups containing 1 to 6 carbon atoms; or
    Cycloalkyl containing 3 to 6 carbon atoms.
  3. 3. The 5-O-mycaminosugatylactone derivative containing quinoline at the 20-position and amino or other substituent at the 23-position or a salt thereof according to claim 1, which is one of the following compounds:
    Figure FDA0002927087730000033
    Figure FDA0002927087730000041
    Figure FDA0002927087730000051
    Figure FDA0002927087730000061
    Figure FDA0002927087730000071
    Figure FDA0002927087730000081
    Figure FDA0002927087730000091
    Figure FDA0002927087730000101
  4. 4. the 5-O-mycaminosugatylactone derivative containing quinoline at the 20-position and amino or other substituent at the 23-position or a salt thereof according to claim 3, characterized in that the following compounds are preferred:
    Figure FDA0002927087730000102
    Figure FDA0002927087730000111
  5. 5. the 5-O-mycaminosulfanyl tylactone derivative having quinoline in the 20-position and amino or other substituent in the 23-position or a salt thereof according to any one of claims 1 to 4, wherein the acid selected to form the salt is baicalin, caffeic acid, shikimic acid, citric acid, lactic acid, citric acid, tartaric acid, phosphoric acid, hydrochloric acid or an amino acid.
  6. 6. The use of a 5-O-mycaminosugatalolactone derivative containing quinoline at position 20 and amino or other substituents at position 23 or a salt thereof according to any one of claims 1 to 5 in the manufacture of a medicament, wherein the derivative is used as an active ingredient or in combination with other drugs, mixed with pharmaceutically acceptable auxiliary and/or additional ingredients, and then formulated into a pharmaceutical preparation for the treatment or prevention of bacterial infections, mycoplasma infections, and blue ear diseases by conventional pharmaceutical methods and processes.
  7. 7. The use of a 5-O-mycaminosugatalactone derivative having a quinoline in position 20 and an amino group or other substituent in position 23, or a salt thereof, in the manufacture of a medicament according to claim 6 for the treatment of chronic respiratory diseases in livestock and poultry, mycoplasma arthritis, porcine reproductive and respiratory syndrome, caprine pleuropneumonia, bovine mastitis, or porcine reproductive and respiratory syndrome, caused by infection with mycoplasma gallisepticum, mycoplasma synoviae, mycoplasma hyopneumoniae, mycoplasma bovis, staphylococcus aureus, streptococcus.
  8. 8. The use of a 5-O-mycaminosugatylactone derivative containing quinoline in the 20-position and amino or other substituents in the 23-position or a salt thereof in the manufacture of a medicament according to claim 6 or 7, wherein the derivative is formulated as an injection, powder for injection, tablet, granule, capsule, soluble powder or powder.
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