CN107151264B - Novel glycopeptide antibiotic derivative, pharmaceutical composition, preparation method and application thereof - Google Patents
Novel glycopeptide antibiotic derivative, pharmaceutical composition, preparation method and application thereof Download PDFInfo
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- C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
- C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
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Abstract
The invention discloses glycopeptide antibiotic derivatives shown as a general formula (I), pharmaceutically acceptable salts thereof and a preparation method thereof, wherein R1Is a substituted or unsubstituted benzene ring or biphenyl ring, and the substituent of the substituted benzene ring or biphenyl ring is halogen, hydroxyl, amino, C with one or more1～C9Alkoxy, nitro, or isopropyl; r2Is H. In addition, the invention also provides a pharmaceutical composition containing the glycopeptide antibiotic derivative and pharmaceutically acceptable salts thereof as active ingredients and application thereof. The compound and the pharmaceutical composition provided by the invention have good antibacterial activity and have important significance for development of new antibacterial drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to novel glycopeptide antibiotic derivatives, pharmaceutically acceptable salts thereof, a preparation method and application.
Background
Glycopeptide antibiotics are the first choice drugs for clinical treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection. However, empirical therapy of glycopeptide antibiotics as MRSA has led to the development of bacterial resistance, for example, MRSA has a reduced sensitivity to vancomycin, which poses a serious threat to clinical anti-infective therapy, and thus, the search for novel glycopeptide antibiotics that are effective against resistant strains is urgent.
Chinese patent 200910053906.9 reports a novel glycopeptide compound, the structure of which is shown as the compound (II) of the invention, the glycopeptide compound has antibacterial activity, the novelty is that the four-position hydroxyl of the six-position amino acid glycosyl of the peptide skeleton is an upright bond, and the research on the structural modification is not reported in documents.
Disclosure of Invention
The invention aims to provide various glycopeptide derivatives shown in a general formula (I) and pharmaceutically acceptable salts thereof:
wherein R is1Is C3～C9Saturated aliphatic hydrocarbon group, decylaminomethyl or aromatic group, the aromatic group is unsubstituted or substituted benzene ring, biphenyl ring or naphthalene ring, and the substituent of the benzene ring, the biphenyl ring or the naphthalene ring is halogen, hydroxyl, amino, C with one or more1～C9Alkoxy, nitro, or isopropyl; r2Is H or CH2-R3，R3Is C3～C9A saturated aliphatic hydrocarbon group.
Preferably, R1Is phenyl, 4-chlorophenyl, 4-bromophenyl, 4-isopropylphenyl, 4-methoxyphenyl, 4-nitrophenyl, biphenyl, 4' -chloro-biphenyl, 2-chlorophenyl, 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 2, 4-dichlorophenyl, 3, 4-dimethoxyphenyl, 2,4, 5-trifluorophenyl, 4-n-nonyloxyphenyl, 4-n-octyloxyphenyl, 4-n-hexyloxyphenyl, 1-naphthyl, 2-naphthyl, n-nonyl, n-octyl, n-heptyl, n-hexyl, n-pentyl, n-butyl, n-propyl, decylaminomethyl.
Preferably, R2Is hydrogen, n-decyl, n-nonyl, n-octyl, n-heptyl, n-hexyl, n-pentyl, n-butyl.
In the present invention, the pharmaceutically acceptable salt is preferably an alkali metal salt, an alkaline earth metal salt or a salt with an acid. Wherein, the alkali metal is preferably sodium or potassium; the alkaline earth metal is preferably calcium or magnesium; the acid is preferably an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid or methanesulfonic acid, or an acidic amino acid such as aspartic acid or glutamic acid.
The invention also relates to a pharmaceutical composition, which comprises a therapeutically effective amount of the glycopeptide derivative or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In the present invention, the pharmaceutically acceptable carrier refers to a pharmaceutical carrier that is conventional in the pharmaceutical field, such as diluents, excipients (e.g., water, etc.), binders (e.g., cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.), fillers (e.g., starch, etc.), and disintegrating agents (e.g., calcium carbonate, sodium bicarbonate). In addition, other adjuvants such as flavoring agents and sweeteners can be added to the composition.
The pharmaceutical composition of the present invention may be administered to a patient in need of treatment by intravenous injection, subcutaneous injection or oral administration. For oral administration, it can be prepared into conventional solid preparations such as tablet, powder or capsule; for injection, it can be prepared into injection. The various dosage forms of the pharmaceutical composition of the invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredients is 0.1-99.5% (weight ratio). In the preparation, the weight content of the compound is 0.1-99.5%, and the preferable content is 0.5-90%.
The general dosage of the pharmaceutical composition applied to a patient in need of treatment can be referred to the existing dosage of vancomycin and norvancomycin, for example, an adult can be 0.1-2.0 g/d, and the dosage can be changed according to the age, the disease condition and the like of the patient. The compounds of the invention can be salified by conventional methods, for example as the hydrochloride salt.
It is a further object of the present invention to provide a process for the preparation of the compounds of the above general formula.
The compounds of the invention of the general formula (I) can be prepared by the following synthetic routes:
wherein R is1And R2Is as defined above
The specific method comprises the following steps:
the method A comprises the following steps: when R is2＝H，R1As defined in claim 1:
1. condensation: a compound of the formula (II) with an aldehyde R1-CHO reacting in a suitable solvent and at a suitable temperature to produce the intermediate Schiff base. Wherein the molar ratio of the aldehyde to the compound represented by the general formula (II) is 2:1 to 0.9:1, preferably 1.1:1 to 1.5: 1; the suitable solvent may be selected from dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), C1～C4Preferably the solvent is DMF, C1～C4More preferred solvents are DMF/methanol (1: 1); the suitable temperature may be from 0 ℃ to 100 ℃, preferably from 60 ℃ to 70 ℃.
2. Reduction: the product of the condensation reaction is directly reacted with a reducing agent without separation and purification to obtain the compound shown in the general formula (I). Among them, the reducing agent may be sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, pyridine/borane, etc., and the preferred reducing agent is sodium cyanoborohydride.
The method B comprises the following steps: when R is1And R2Is CH2-R3And R is3As defined in claim 1:
1. condensation: a compound of the formula (II) with an aldehyde R3-CHO reacting in a suitable solvent and at a suitable temperature to produce the intermediate Schiff base. Wherein the molar ratio of aldehyde to compound of formula (II) is from 2:1 to about 3:1, preferably 2.5: 1. The suitable solvent may be selected from dimethyl sulfoxide (DMSO), N-Dimethylformamide (DMF), C1～C4Preferably the solvent is DMF, C1～C4More preferred solvents are DMF/methanol (1: 1); the suitable temperature may be from 0 ℃ to 100 ℃, preferably from 60 ℃ to 70 ℃.
2. Reduction: the product of the condensation reaction is directly reacted with a reducing agent without separation and purification to obtain the compound shown in the general formula (I). Among them, the reducing agent may be sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, pyridine/borane, etc., and the preferred reducing agent is sodium cyanoborohydride.
It is a further object of the present invention to provide the use of the above compounds in the manufacture of a medicament for combating bacterial infections. The positive progress effect of the invention is that the derivatives of the compound shown as the general formula (I) and the pharmaceutically acceptable salts thereof have good antibacterial action.
Detailed Description
To further illustrate the invention, a series of examples are given below. It is to be noted that these embodiments are purely illustrative. These examples are given for the purpose of fully illustrating the meaning and content of the invention, and are not therefore to be considered as limiting the invention to the scope of the described examples.
In the following examples, the following abbreviations have the following meanings. Undefined abbreviations have their commonly accepted meaning, unless otherwise stated, all room temperatures refer to temperatures of 20 ℃ to 30 ℃.
DMF N, N-dimethylformamide
HPLC high performance liquid chromatography
Minimum Inhibitory Concentration (MIC)
The data relating to some of the exemplary compounds of formula (I) are shown in Table 1.
In the examples, preparative HPLC purification conditions: chromatographic column Sepax BR-C1821.2X 100mm (5 μm), gradient elution, mobile phase composition:
| time (min) | Methanol | 0.1% formic acid |
| 0 | 5 | 95 |
| 20 | 30 | 70 |
The detection wavelength was 240 nm. And (3) decompressing the required fraction to remove the organic solvent, adjusting the pH to 6-7 by using saturated sodium bicarbonate, extracting by using n-butyl alcohol, washing by using water, decompressing and steaming to remove butanol, and drying to obtain the product. The yield in the present invention means a molar yield.
TABLE 1
And annotating: cl element analysis: theoretical 9.62%, found 9.27%
Example 1: synthesis of Compound 1
Dissolving the compound (500mg, 0.31mmol) shown in the general formula (II) in 10ml of DMF/methanol (1:1) at room temperature, adding 4-bromobenzaldehyde (63mg, 0.34mmol), heating and stirring the reaction solution at 60 ℃ for 2 hours, cooling to room temperature, adding sodium cyanoborohydride (40mg, 0.62mmol), stirring at room temperature for 2 hours, evaporating the methanol from the reaction solution under reduced pressure, pouring the residue into 70ml of acetone to precipitate, performing suction filtration, washing with acetone, and purifying by preparative HPLC to obtain 100mg of the final product (compound 1) with the yield of 18.4%.
Example 2: synthesis of Compound 1
The compound represented by the general formula (II) (300mg, 0.19mmol) was dissolved in 6ml of DMF/methanol (1:1), 4-bromobenzaldehyde (70mg,0.38mmol) was added, the reaction mixture was stirred at 0 ℃ for 3 hours, sodium cyanoborohydride (24mg, 0.38mmol) was added, stirring was carried out at room temperature for 2 hours, the reaction mixture was evaporated under reduced pressure to remove methanol, the residue was poured into 50ml of acetone to precipitate, suction filtration and acetone washing were carried out, and purification was carried out by preparative HPLC to obtain 50mg of the final product (compound 1), with a yield of 14.7%.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):7.81(2H),7.59-7.23(8H),6.79(3H),6.50(1H),6.35(2H),5.86-5.13(7H),4.95-4.20(10H),3.55-2.50(6H),2.45-2.00(4H),1.90-0.95(15H),0.89-0.84(6H)。
Example 3: synthesis of Compound 10
The compound represented by the general formula (II) (500mg, 0.31mmol) was dissolved in 10ml of DMF/methanol (1:1), 4' -chloro-biphenylcarboxaldehyde (100mg, 0.46mmol) was added, the reaction solution was heated and stirred at 65 ℃ for 2 hours, then cooled to room temperature, sodium cyanoborohydride (40mg, 0.62mmol) was added, stirred at room temperature for 2 hours, the reaction solution was evaporated under reduced pressure to remove methanol, the residue was poured into 70ml of acetone to precipitate, suction filtration, acetone washing, and purification by preparative HPLC was carried out to obtain 130mg of the final product (compound 10), with a yield of 23.5%.
Example 4: synthesis of Compound 10
The compound represented by the general formula (II) (300mg, 0.19mmol) was dissolved in 6ml of DMF/methanol (1:1), 4' -chloro-biphenylcarboxaldehyde (37mg, 0.17mmol) was added, the reaction solution was heated and stirred at 65 ℃ for 2 hours, then cooled to room temperature, sodium cyanoborohydride (12mg, 0.19mmol) was added, stirred at room temperature for 2 hours, the reaction solution was evaporated under reduced pressure to remove methanol, the residue was poured into 70ml of acetone to precipitate, suction filtration, acetone washing, and purification by preparative HPLC was carried out to obtain 60mg of the final product (compound 10), with a yield of 17.4%.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):7.90-7.82(2H),7.66-7.00(12H),6.79-6.34(6H),5.77-5.05(8H),4.95-4.25(9H),3.36-2.55(5H),2.35-2.28(7H),1.89-1.08(15H),0.89-0.84(6H)。
Example 5: synthesis of Compound 16
Dissolving a compound (300mg, 0.19mmol) shown in a general formula (II) in 3ml DMSO, adding 1-naphthaldehyde (39mg, 0.25mmol), heating and stirring a reaction solution at 70 ℃ for 1.5 hours, cooling to room temperature, adding sodium cyanoborohydride (24mg, 0.38mmol), stirring at room temperature for 2 hours, pouring the reaction solution into acetone to separate out a precipitate, performing suction filtration, washing with acetone, and purifying by preparative HPLC to obtain a final product (compound 16)90mg, wherein the yield is 27.4%.
Example 6: synthesis of Compound 16
The compound represented by the general formula (II) (300mg, 0.19mmol) was dissolved in 5ml DMSO, 1-naphthaldehyde (39mg, 0.25mmol) was added, the reaction solution was heated and stirred at 100 ℃ for 1 hour, then cooled to room temperature, sodium cyanoborohydride (36mg, 0.57mmol) was added, stirred at room temperature for 3 hours, the reaction solution was poured into acetone to precipitate, suction filtration, acetone washing, and purification by preparative HPLC was carried out to obtain 42mg of the final product (compound 16) with a yield of 12.6%.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):8.20-8.00(2H),7.86-7.74(3H),7.60-7.23(8H),6.80-6.60(3H),6.59-6.55(1H),6.35(2H)，5.95-5.17(7H),5.00-4.60(3H),4.59-3.85(5H),3.20-2.95(3H),2.44-2.10(6H),2.05-1.11(16H),0.89-0.84(6H)。
Example 7: synthesis of Compound 18
Dissolving a compound (400mg, 0.25mmol) shown in the general formula (II) in 50ml of methanol, adding 3, 4-dichlorobenzaldehyde (53mg, 0.30mmol), heating and stirring the reaction solution at 65 ℃ for 2 hours, cooling to room temperature, adding sodium cyanoborohydride (19mg, 0.30mmol), stirring at room temperature for 2 hours, concentrating the reaction solution under reduced pressure, pouring the residue into acetone to precipitate, performing suction filtration, washing with acetone, and purifying by preparative HPLC to obtain a final product (compound 18) of 130mg with a yield of 29.6%.
Example 8: synthesis of Compound 18
The compound represented by the general formula (II) (500mg, 0.31mmol) was dissolved in 50ml of methanol, 3, 4-dichlorobenzaldehyde (75mg, 0.43mmol) was added, the reaction solution was heated and stirred at 65 ℃ for 2 hours and then cooled to room temperature, sodium triacetoxyborohydride (131mg, 0.62mmol) was added, stirring at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, the residue was poured into acetone to precipitate, suction filtration, acetone washing, and purification by preparative HPLC was carried out to obtain 100mg of the final product (compound 18) with a yield of 18.4%.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):7.81-7.70(1H),7.60-7.22(7H),6.79-6.34(7H),5.65-5.07(7H),4.94-3.90(8H),3.50-2.90(9H),2.40-2.10(6H),2.00-1.05(15H),0.89-0.84(6H)。
Example 9: synthesis of Compound 19
Dissolving the compound (300mg, 0.19mmol) shown in the general formula (II) in 6ml of DMF/methanol (1:1) at room temperature, adding n-decanal (33mg, 0.21mmol), heating and stirring the reaction solution at 60 ℃ for 1 hour, cooling to room temperature, adding sodium cyanoborohydride (24mg, 0.38mmol), stirring at room temperature for 1 hour, evaporating the methanol from the reaction solution under reduced pressure, pouring the residue into 50ml of acetone to precipitate, performing suction filtration, washing with acetone, and purifying by preparative HPLC to obtain the final product (compound 19)110mg with the yield of 33.7%.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):7.82-7.10(7H),6.95-6.36(5H),5.70-5.16(9H),4.95-3.90(11H),3.20-2.85(2H),2.44-1.97(7H),1.95-1.06(32H),0.90-0.82(9H)。
The synthesis of compounds 2 to 9, 11 to 15, 17 and 20 to 28 was the same as in method example 1 except that 4-chlorobenzaldehyde, diphenylformaldehyde, benzaldehyde, 2, 4-dichlorobenzaldehyde, 4-methoxybenzaldehyde, 3, 4-dimethoxybenzaldehyde, 2-bromobenzaldehyde, 3-bromobenzaldehyde, 4-isopropylbenzaldehyde, 2,4, 5-trifluorobenzaldehyde, 2-chlorobenzaldehyde, 3-chlorobenzaldehyde, 4-nitrobenzaldehyde, 2-naphthaldehyde, n-decanal, n-nonanal, n-octanal, n-heptanal, n-hexanal, n-pentanal, n-butanal, 4-n-nonanoxybenzaldehyde, 4-n-octoxybenzaldehyde and 4-n-hexyloxybenzaldehyde were used instead of 4-bromobenzaldehyde, respectively.
Example 10: synthesis of Compound 29
Dissolving a compound (500mg, 0.31mmol) shown in a general formula (II) in 10ml of DMF/methanol (1:1), adding N-Fmoc-2- (N-decylamino) -acetaldehyde (168mg, 0.40mmol), heating and stirring a reaction solution at 65 ℃ for 1.5 hours, cooling to room temperature, adding sodium cyanoborohydride (40mg, 0.62mmol), stirring at room temperature for 2 hours, evaporating the methanol from the reaction solution under reduced pressure, pouring the residue into acetone to separate out a precipitate, performing suction filtration, washing with acetone, performing vacuum drying, uniformly dispersing a crude product by using 10ml of DMF, stirring at room temperature, adding 1ml of diethylamine, stirring the reaction solution at room temperature for 1 hour, pouring into 100ml of acetone to separate out a precipitate, performing suction filtration, washing with acetone, and purifying by using reverse phase HPLC to obtain a final product (compound 29)80mg, wherein the yield is 14.5%.
1H-NMR(400MHz,CD3OD)δ(ppm):7.75-7.65(3H),7.36-7.16(3H),7.02-6.80(3H),6.64-6.41(3H),5.68-5.29(6H),5.10-4.83(3H),4.60-4.55(1H),4.21-4.14(3H),3.98-3.31(6H),3.29-3.18(2H),3.00-2.20(14H),2.10-1.10(33H),0.97-0.87(9H)。
Example 11: synthesis of Compound 30
The compound represented by the general formula (II) (300mg, 0.18mmol) was dissolved in 6ml of DMF/methanol (1:1), n-decanal (70mg, 0.45mmol) was added, the reaction mixture was heated at 65 ℃ under stirring for 2 hours and then cooled to room temperature, sodium cyanoborohydride (28mg, 0.45mmol) was added thereto, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was cooled and then methanol was evaporated under reduced pressure, and the residue was poured into 50ml of acetone to precipitate. The precipitate is filtered off with suction, washed with a little acetone and dried in vacuo. Purification by reverse phase HPLC gave 180mg of the final product (compound 30) in 53.3% yield.
Example 12: synthesis of Compound 30
The compound represented by the general formula (II) (300mg, 0.18mmol) was dissolved in 4ml of DMF/methanol (1:1), n-decanal (56mg, 0.36mmol) was added, the reaction mixture was heated at 65 ℃ under stirring for 1.5 hours, then cooled to room temperature, sodium cyanoborohydride (34mg, 0.54mmol) was added, the reaction mixture was stirred at room temperature for 2 hours, after cooling, methanol was evaporated under reduced pressure, and the residue was poured into 50ml of acetone to precipitate. The precipitate is filtered off with suction, washed with a little acetone and dried in vacuo. Purification was performed by reverse phase HPLC to obtain 150mg of the final product (Compound 30) in 44.4% yield.
Example 13: synthesis of Compound 30
The compound represented by the general formula (II) (500mg, 0.31mmol) was dissolved in 10ml of DMF/methanol (1:1), n-decanal (145mg, 0.93mmol) was added, the reaction mixture was heated at 65 ℃ under stirring for 1 hour and then cooled to room temperature, sodium cyanoborohydride (59mg, 0.93mmol) was added thereto, the reaction mixture was stirred at room temperature for 1 hour, the reaction mixture was cooled and then methanol was evaporated under reduced pressure, and the residue was poured into 60ml of acetone to precipitate. The precipitate is filtered off with suction, washed with a little acetone and dried in vacuo. Purification was performed by reverse phase HPLC to obtain 160mg of the final product (Compound 30) in 27.4% yield.
1H-NMR(400MHz,DMSO-d6+D2O)δ(ppm):7.78-6.95(7H),6.93-6.32(5H),5.80-5.18(8H),4.95-4.10(9H),3.64-2.80(12H),2.34-2.03(6H),1.96-1.06(44H),0.95-0.80(12H)。
Synthesis of Compounds 31 to 36 was carried out in the same manner as in method example 7 except that n-nonanal, n-octanal, n-heptanal, n-hexanal, n-pentanal, and n-butanal were used in place of n-decanal.
Example 14: synthesis of Compound 37
The compound represented by the general formula (II) (400mg, 0.25mmol) was dissolved in 8ml of DMF/methanol (1:1), n-decanal (50mg, 0.32mmol) was added, the reaction mixture was heated at 65 ℃ under stirring for 1 hour, then cooled to room temperature, sodium cyanoborohydride (32mg, 0.50mmol) was added thereto, the reaction mixture was stirred at room temperature for 1 hour, the methanol was distilled off under reduced pressure, and the residue was poured into 50ml of acetone to precipitate. Filtering, washing with acetone, purifying with preparative HPLC, collecting the required fractions, concentrating, adjusting pH to 6-7 with saturated sodium bicarbonate solution, extracting with n-butanol, washing the organic layer with water, adding 1ml of saturated HCl methanol solution, stirring at room temperature, removing the solvent under reduced pressure, adding acetone, stirring, filtering, washing, and drying to obtain the final product (compound 37)42mg with a yield of 9.1%. (Cl element analysis: theoretical 9.62%, found 9.27%).
Example 15: effects of the embodiment
The results of the in vitro antibacterial activity test of the target compounds of the present invention are shown in Table 2. The method comprises the following steps:
1. test strains
Staphylococcus aureus 26003(Staphylococcus aureus)
2. Test method
Sample preparation: the solid sample was dissolved in a small amount of DMSO and then diluted with sterile water to 0.5 mg/ml.
The determination method comprises the following steps: agar plate paper method. The bacterial load of the agar plate is 105CFU/ml. The diameter of the paper sheet was 6.0mm, and each paper sheet was loaded with 20. mu.l. Culturing in an incubator at 37 ℃ for 18 hours for observation,and measuring the diameter of the inhibition zone.
3. Activity description (see Table 2)
The + represents the diameter of the bacteriostatic zone larger than 13mm
+ represents the diameter of the bacteriostatic zone of 9-13mm
+ represents a bacteriostatic circle with a diameter of 7-9mm (including 9mm)
TABLE 2 results for antibacterial Activity of Compounds 1-37
As can be seen from table 2, the compounds of the present invention all showed antibacterial activity.
The agar paper sheet method has a relatively high requirement on the diffusion performance of the sample. Some compounds have poor diffusion due to the problems of solubility and the like, so that the inhibition zone of the compounds on related strains is influenced, and the antibacterial activity of the compounds cannot be completely measured by an agar paper sheet method. In order to accurately reflect the antibacterial activity of the compound, the Minimum Inhibitory Concentration (MIC) of the compound on a specific strain needs to be determined by an agar plate dilution method.
Example 16: effects of the embodiment
In vitro MIC results for some of the compounds of interest of the present invention are shown in table 3. The method comprises the following steps:
1. test strains
The total number of the plants is 4: staphylococcus aureus 26003(Staphylococcus aureus), diplococcus pneumoniae 31002(Streptococcus pneumoniae), Staphylococcus albus 260101(Staphylococcus albus), Enterococcus 32220(Enterococcus faecium), Streptococcus allergis 32206, Staphylococcus epidermidis 26069, Enterococcus faecium (e.faecium) ATCC35667, Enterococcus faecium (e.faecium) MEEA0039, Enterococcus faecalis (e.faecium) ATCC51299, Streptococcus pneumoniae (s.pneumoniae) ATCC 49619, and Streptococcus pneumoniae (s.pneumoniae) MSPN 0003.
2. Test method
Sample preparation: dissolving with DMSO, diluting with sterile water to appropriate concentration, and sequentially diluting to desired volume.
And (3) determination: agar plate dilution method. Using a multi-point inoculator to quantify, inoculating 10 per point5And (4) CFU. The result is observed after culturing in an incubator at 37 ℃ for 18-24 hours, and the Minimum Inhibitory Concentration (MIC) value is read.
3. The positive control drug is vancomycin hydrochloride
The MIC values for some of the compounds are shown in table 3.
TABLE 3 MIC (μ g/ml) of part of the compounds
As can be seen from Table 3, some of the compounds of the present invention have better anti-gram-positive bacteria activity than vancomycin hydrochloride.
Table 8 MIC (μ g/mL) of part of the compounds to e.faecium ATCC35667
As can be seen in table 8, the antibacterial activity of the compounds of the present invention against enterococcus faecium (e.faecium) ATCC35667 was superior to that of the positive control vancomycin hydrochloride, and the MICs of some of the compounds were much lower than those of vancomycin. For example, compounds 1, 9 and 11 have far superior antibacterial activity against ATCC35667 over vancomycin hydrochloride
TABLE 9 MIC (μ g/mL) of part of the compounds to E.faecium MEEA0039
As can be seen in table 9, the antibacterial activity of the compounds of the present invention against enterococcus faecium (e.faecium) MEEA0039 is superior to that of the positive control vancomycin hydrochloride, and the MICs of some compounds are much lower than those of vancomycin. For example, the antibacterial activity of the compounds 2 and 11 on MEEA0039 is far better than that of vancomycin hydrochloride
TABLE 10 MIC (μ g/mL) of part of the compounds for E.faecalis ATCC51299
As can be seen in table 10, the antibacterial activity of some of the compounds of the present invention against enterococcus faecalis e.faecalis ATCC51299 was superior to that of the positive control vancomycin hydrochloride, and the MICs of some of the compounds were much lower than those of vancomycin.
TABLE 11 MIC (μ g/mL) of part of the compounds for S.pneumoconiae ATCC 49619
As can be seen in table 11, the antibacterial activity of the partial compounds of the present invention against streptococcus pneumoniae (s. pneumoconiae) ATCC 49619 was superior to that of the positive control vancomycin hydrochloride, and the MICs of some compounds were much lower than those of vancomycin.
TABLE 12 MIC of part of the Compounds to S.pneumoconiae MSPN 0003 (. mu.g/mL)
As can be seen in table 12, the antibacterial activity of the partial compounds of the present invention against streptococcus pneumoniae (s. pneumoconiae) MSPN 0003 is superior to that of the positive control vancomycin hydrochloride, and the MICs of some compounds are much lower than those of vancomycin.
From the above list, we can conclude that the compounds of the present invention exhibit superior antibacterial activity against different gram-positive bacteria compared to vancomycin hydrochloride. It should be noted that the above summary and the detailed description are intended to demonstrate the practical application of the technical solutions provided by the present invention, and should not be construed as limiting the scope of the present invention. Various modifications, equivalent substitutions, or improvements may be made by those skilled in the art within the spirit and principles of the invention. The scope of the invention is to be determined by the appended claims.
Claims (16)
1. Glycopeptide antibiotic derivative shown in general formula (I) and pharmaceutically acceptable salt thereof,
wherein: r1Is 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-methoxyphenyl or 4-isopropylphenyl; r2Is H.
2. The glycopeptide antibiotic derivative according to claim 1, wherein the hydroxyl group at the four position of the six-amino acid glycosyl of the peptide backbone is an upright bond, and pharmaceutically acceptable salts thereof.
3. The glycopeptide antibiotic derivative according to any one of claims 1 to 2, wherein the pharmaceutically acceptable salt is an alkali metal salt, an alkaline earth metal salt, or a salt with an acid.
4. The glycopeptide antibiotic derivative according to claim 3, wherein the alkali metal is sodium or potassium; the alkaline earth metal is calcium or magnesium; the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, aspartic acid or glutamic acid.
5. A process for preparing a glycopeptide antibiotic derivative as claimed in any one of claims 1 to 4, and pharmaceutically acceptable salts thereof, which comprises: reacting a compound of the formula (II) with an aldehyde R1-CHO reacts in a polar solvent at a temperature of 0-100 ℃ to generate an intermediate Schiff base, and then the intermediate Schiff base reacts with a reducing agent at room temperature to obtain a compound shown in a general formula (I);
wherein: r1Is 4-bromophenyl, 3-bromophenyl, 2-bromophenyl, 4-methoxyphenyl or 4-isopropylphenyl; r2Is H.
6. The method according to claim 5, wherein the molar ratio of the aldehyde to the compound represented by the general formula (II) is 2:1 to 0.9: 1.
7. The method according to claim 6, wherein the molar ratio of the aldehyde to the compound represented by the general formula (II) is 1.1:1 to 1.5: 1.
8. The method according to claim 5, wherein the polar solvent is selected from the group consisting of dimethyl sulfoxide, N-dimethylformamide, and C1～C4One or more of alcohol, acetonitrile and water.
9. The method according to claim 8, wherein the polar solvent is N, N-dimethylformamide methanol-1: 1.
10. The method according to claim 5, wherein the temperature is 60 ℃ to 70 ℃.
11. The method of claim 5, wherein the reducing agent is sodium cyanoborohydride, sodium borohydride, sodium triacetoxyborohydride, or pyridine/borane.
12. Use of a glycopeptide antibiotic derivative as defined in any one of claims 1 to 4, and pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of bacterial infectious diseases.
13. A pharmaceutical composition with good antibacterial activity, wherein the pharmaceutical composition comprises a therapeutically effective amount of the glycopeptide antibiotic derivative as defined in any one of claims 1 to 4, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. The pharmaceutical composition according to claim 13, wherein the glycopeptide antibiotic derivative and pharmaceutically acceptable salts thereof as active ingredient comprises 0.1 wt.% to 99.5 wt.% of the active ingredient.
15. The pharmaceutical composition according to claim 14, wherein the pharmaceutical composition comprises 0.5 wt.% to 90 wt.% of the active ingredient.
16. Use of a pharmaceutical composition according to any one of claims 13 to 15 in the preparation of a medicament for the treatment of a bacterial infectious disease.
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| WO2018010476A1 (en) * | 2016-07-15 | 2018-01-18 | 上海来益生物药物研究开发中心有限责任公司 | Glycopeptides based derivative, pharmaceutically acceptable salt thereof, preparation method therefor and use thereof |
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| IT1098354B (en) * | 1977-07-01 | 1985-09-07 | Lilly Co Eli | PROCEDURE TO FACILITATE GENETIC EXCHANGE IN STREPTOMYCES |
| CN1803852A (en) * | 2005-12-21 | 2006-07-19 | 华侨大学 | Method for preparing organic solvent soluble amphiphilic N,N-dilong chain alkyl chitosan |
| CN101928331A (en) * | 2009-06-26 | 2010-12-29 | 上海来益生物药物研究开发中心有限责任公司 | New compound and application thereof |
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| EG18377A (en) * | 1986-09-19 | 1993-04-30 | Lilly Co Eli | Process for preparing glycopeptide antibiotics |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| IT1098354B (en) * | 1977-07-01 | 1985-09-07 | Lilly Co Eli | PROCEDURE TO FACILITATE GENETIC EXCHANGE IN STREPTOMYCES |
| CN1803852A (en) * | 2005-12-21 | 2006-07-19 | 华侨大学 | Method for preparing organic solvent soluble amphiphilic N,N-dilong chain alkyl chitosan |
| CN101928331A (en) * | 2009-06-26 | 2010-12-29 | 上海来益生物药物研究开发中心有限责任公司 | New compound and application thereof |
Non-Patent Citations (1)
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| 一种新糖肽抗生素LY333328的抗菌活性与作用机制;罗清平等;《国外医药抗生素分册，第25卷第5期，第221-225页》;20040930;第2.1节、图1表1 * |
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