CN115677679A - Oxazolidinone compound containing biaryl hydrazone structure and preparation method and application thereof - Google Patents

Oxazolidinone compound containing biaryl hydrazone structure and preparation method and application thereof Download PDF

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CN115677679A
CN115677679A CN202110843141.XA CN202110843141A CN115677679A CN 115677679 A CN115677679 A CN 115677679A CN 202110843141 A CN202110843141 A CN 202110843141A CN 115677679 A CN115677679 A CN 115677679A
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acid
compound
pharmaceutically acceptable
hydrogen
oxazolidin
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赵燕芳
侯云雷
齐银良
刘玖玉
王昆
宫平
刘亚婧
秦铭泽
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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Abstract

The invention relates to the field of medicinal chemistry, in particular to an oxazolidinone compound containing a biaryl hydrazone structure, or an optical isomer, a pharmaceutically acceptable salt and/or a solvate thereof, and a preparation method and application thereof. Compound (I)Is a compound shown as a general formula, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, wherein a substituent R 1 、R 2 、R 3 、R 4 、R 5 And ring A has the meaning given in the description. The invention also relates to the application of the compounds and the pharmaceutically acceptable salts, solvates or prodrugs thereof as antibacterial agents in treatment, in particular to the application in treatment of gram-positive bacterial infection, gram-negative bacterial infection and tubercle bacillus infection.

Description

Oxazolidinone compound containing biaryl hydrazone structure and preparation method and application thereof
The technical field is as follows:
the invention relates to the field of medicinal chemistry, in particular to an oxazolidinone compound containing a biaryl hydrazone structure, or an optical isomer, a pharmaceutically acceptable salt and/or a solvate thereof, and a preparation method and application thereof.
The background art comprises the following steps:
in recent years, widespread use and even abuse of antibacterial drugs has led to a dramatic increase in the mortality rate of infectious diseases. Clinically, the drug resistance of bacteria is becoming more serious, so that the curative effect of some antibacterial drugs is reduced or even ineffective, such as methicillin-resistant staphylococcus aureus (MRSA), methicillin-resistant staphylococcus epidermidis (MRSE) and vancomycin-resistant enterococcus pneumoniae (VRE). Some nonpathogenic bacteria become opportunistic bacteria such as proteus, pseudomonas aeruginosa, etc. The development and development of all these resistant strains presents great difficulties for clinical treatment. The existing antibacterial drugs can not meet the clinical needs, so the development of novel anti-drug-resistant antibacterial drugs, especially antibacterial drugs with novel action mechanisms, is urgent.
The oxazolidinone antibacterial drug is a chemical fully-synthesized antibacterial drug with a brand-new structure after sulfonamide and quinolone antibacterial drugs. Oxazolidinones are inhibitors of bacterial protein synthesis and have no effect on the normal function of DNA and RNA. The antibacterial drug mainly inhibits the initiation, elongation and termination of the protein peptide chain translated by the bacterial tRNA for 3 stages. The oxazolidinone antibacterial agent can be combined with bacterial ribosome 50S methylene, so that the synthesis of bacterial protein is inhibited, and cross resistance with other antibacterial agents rarely occurs. In 1987, duPont reported 2 completely new oxazolidinone antibacterial compounds DuP721 and DuP105. The two compounds are representative of novel oxazolidinone antibacterial drugs, but in phase I clinical tests, the research and development are stopped due to toxicity and safety reasons, but the two compounds lay a foundation for the research of early structure-activity relationship and the further development of the compounds. On the basis, the first oxazolidinone antibacterial drug Linezolid (Linezolid) successfully developed by the american pekoe company, which was approved for marketing in the united states 4 months in 2000 and used for treating infection caused by multiple gram-resistant positive bacteria. Tedizolid (Tedizolid) is the second oxazolidinone antibacterial marketed for the treatment of skin infections as approved by the FDA in the us 6 menses year 2014. Radezolid (Rx-1741) is a diaryloxazolidinone developed by Rib-X pharmaceutical company. The inhibitor has excellent inhibitory activity to gram-positive bacteria and better inhibitory action to gram-negative bacteria. The treatment of uncomplicated skin and skin structure infections (uSSSI), as well as community-acquired pneumonia (CAP), with this compound has entered phase ii clinical studies in 2008.
Figure BDA0003179783750000011
However, since the market, with their widespread use, the problem of drug resistance has appeared, and further optimization is needed to design more novel compounds to overcome the drug resistance. No oxazolidinone compound containing a biaryl hydrazone structure is prepared in the prior art.
The invention content is as follows:
the invention mainly aims to provide a hydrazon structure-containing biaryl oxazolidinone compound serving as an antibacterial agent, a preparation method thereof and application of the hydrazon structure-containing biaryl oxazolidinone compound serving as the antibacterial agent in preparation of drugs for treating infectious diseases.
In order to realize the purpose, the invention adopts the technical scheme that:
an oxazolidinone compound containing biaryl hydrazone structure, which is a compound shown in a general formula, a stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof or a prodrug thereof,
Figure BDA0003179783750000021
wherein the content of the first and second substances,
R 1 and R 2 Are each identical or different and are selected from hydrogen, halogen or (C) 1 -C 6 ) A haloalkyl group;
R 3 is selected from-NHCOCH 3 or-OH;
the A ring is 1-3R 6 Substituted aryl or heteroaryl, said heteroaryl containing 1-3 heteroatoms, which are N, O or S;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure BDA0003179783750000022
Figure BDA0003179783750000023
R 6 Selected from hydrogen, hydroxy, halogen, nitro, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group, an amino group which is unsubstituted or substituted with at least one group selected from the group consisting of 1 -C 6 ) Alkylamido, carboxyl, (C) 1 -C 6 ) Alkylsulfinyl (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 6 ) Alkyl acyl or (C) 1 -C 6 ) Alkyl ammoniaA formyl group; the following groups are hydroxyl, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Alkoxy, di (C) 1 -C 6 Alkyl groups);
R 7 、R 8 、R 9 、R 10 each of which is the same or different and is selected from the group consisting of hydrogen, hydroxy, nitro, cyano, amino, (C) 1 -C 6 ) Alkylsulfinyl (C) 1 -C 6 ) Alkylsulfonyl, (C) 1 -C 6 ) Alkanoyl, unsubstituted or substituted by at least one hydroxy, amino or halogen (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) An alkoxy group.
Preferably, the compound is a compound shown as a general formula, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Each of which is the same or different and is selected from hydrogen or halogen; and, R 1 And R 2 At least one of which is halogen;
R 3 is selected from-NHCOCH 3 or-OH;
the A ring is 1-3R 6 Substituted aryl or heteroaryl, said heteroaryl containing 1-3 heteroatoms, which are N, O or S;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure BDA0003179783750000031
R 6 Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group;
R 7 、R 8 、R 9 、R 10 each of which may be the same or different and is selected from the group consisting of hydrogen, hydroxy, nitro, cyano, amino, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group.
Further preferably, the compound is a compound shown as a general formula, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Are each the same or different and are selected from hydrogen or fluorine, and, R 1 And R 2 At least one of which is fluorine;
R 3 is-NHCOCH 3 ；
The A ring is optionally substituted by 1-3R 6 Substituted phenyl or 5-6 membered aromatic heterocyclic group, wherein the heteroaryl group contains 1-2 heteroatoms, and the heteroatoms are N, O or S;
R 6 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) An alkoxy group;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure BDA0003179783750000032
R 7 、R 8 、R 9 、R 10 Each of which is the same or different and is selected from hydrogen, hydroxy, nitro, cyano or amino.
Still more preferably, the compound is a compound represented by the general formula (VII), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Are each the same or different and are selected from hydrogen or fluorine, and, R 1 And R 2 At least one of which is fluorine;
R 3 is-NHCOCH 3 ；
R 4 Is selected from H or CH 3 ；
The A ring is any 1-3R 6 Substituted phenyl, pyridyl, furyl or thienyl;
R 5 is selected from
Figure BDA0003179783750000033
R 6 Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An alkoxy group.
Most preferably, the compound is
(S) -N- [ (3- {4- [6- (guanidinoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- ({ 3- [4'- (guanidinoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- [ (3- {4- [5- (guanidinoiminoethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- {4- [6- (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- ({ 3- [4'- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazole-2-hydrazinoethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- [ (3- {4- [6- (thioureidoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- {4- [5- (guanidinoiminomethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide;
(S) -2- [ (5- {4- [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2-fluorophenyl } pyridin-2-yl) methylene ] hydrazine-1-carboxamide;
(S) -N- ({ 3- [4'- (thioureidoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- (3- {4- [5- (thioureidoiminomethyl) pyridin-2-yl ] -3-fluorophenyl-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-1, 1' -biphenyl-4-yl ] methylene) hydrazine-1-carboxamide;
(S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2', 3-difluoro-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide;
(S) -2- [ (6- {4- [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2-fluorophenyl } pyridin-3-yl) methylene ] hydrazine-1-carboxamide;
(S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-3-hydroxy-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide;
(S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide;
(S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-3-methyl-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide.
The compound of the general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and an acid form a salt, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric 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, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.
The application of the compound shown in the general formula I, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or the application of the salt formed by the compound in preparing a medicament for treating microbial infection.
A pharmaceutical composition characterized by: the composition contains a compound shown in a general formula I, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a salt formed by the compound.
Use of a pharmaceutical composition for the manufacture of a medicament for the treatment of a microbial infection.
A composition preparation comprises active ingredients and pharmaceutically acceptable auxiliary agents; wherein, the active ingredient is a compound shown in a general formula I, a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, or a salt formed by the compound, or one or more of the compositions; the active component accounts for 0.1-99% of the preparation.
A composition formulation for use in the manufacture of a medicament for the treatment of a microbial infection.
The microbial infection is a bacterial infection.
The bacterial infection is a gram-positive coccal infection, a gram-negative coccal infection or a tubercle bacillus infection.
The invention also includes solvates of the compounds of formula I, such as ethanol, water, and the like, wherein various amounts of water, such as a monohydrate, a hemihydrate, a dihydrate, or a trihydrate, may be present.
The compounds of formula I of the present invention may be combined with an acid to form pharmaceutically acceptable salts thereof according to conventional methods in the art to which the present invention pertains. The acid may comprise an inorganic or organic acid, with salts with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric 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, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, and aspartic acid.
The invention also includes prodrugs of the compounds of formula I. Prodrugs, according to the present invention, are derivatives of compounds of formula i which may themselves have poor or even no activity, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form.
The invention also includes racemates, optically active isomers, polymorphic forms or mixtures thereof of the compounds of formula I which possess the useful properties described herein. The compounds of general formula i according to the invention contain a chiral centre (C-5 position of the oxazolidinone ring) and thus exist as two enantiomers or as a racemic mixture of the two. The invention relates to two enantiomers of useful nature and to mixtures containing the two isomers.
The term "alkyl" as used herein, unless otherwise indicated, refers to straight or branched chain alkyl groups; "alkoxy" refers to straight or branched chain alkoxy; "alkenyl" means straight or branched chain alkenyl; "alkynyl" refers to straight or branched chain alkynyl groups; the 5-to 10-membered heteroaryl group includes a group containing one or more hetero atoms selected from N, O and S, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic, the ring system is aromatic, and contains 5 to 10 atoms in total, and examples thereof include pyridyl, furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoquinolyl, indolyl, naphthyl and the like.
"or hydroxylated, aminated or halogenated" means that one or more hydrogen atoms in a substituent are replaced by hydroxyl, amino or halogen.
The following scheme A describes the preparation of the compounds of general formula I according to the invention, all starting materials being prepared by the methods described in these schemes, by methods well known to those skilled in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these synthetic routes are as defined below or in the claims.
Figure BDA0003179783750000071
Route A Synthesis of Compound I
In the route A, substituted aniline and methyl chloroformate are acylated to prepare an intermediate L1, then the intermediate L1 and (S) -N-acetyl-2-acetoxyl-3-chloropropylamine react in the presence of lithium tert-butoxide to prepare an intermediate L2, and the intermediate L2 and boronic acid pinacol ester react to generate an intermediate L3. Reacting the intermediate L3 with different substituted aldehydes or ketones to obtain an intermediate L4, and reacting the intermediate L4 with different substituted R 5 -NH 2 Reacting to obtain I.
The invention also comprises a pharmaceutical composition which comprises the compound of the general formula I and pharmaceutically acceptable salts and/or solvates thereof as active ingredients and pharmaceutically acceptable carriers; the compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects, such as allergic reactions.
The amount of active ingredient, i.e. the compound according to the invention, in the pharmaceutical composition and unit dosage form thereof may vary depending on the particular application, the potency of the particular compound and the desired concentration. Generally, the active ingredient will be present in an amount of between 0.5% and 90% by weight of the total composition.
Carriers for the pharmaceutical compositions of the present invention are of the usual type available in the pharmaceutical art and include: binders, lubricants, disintegrating agents, solubilizing agents, diluents, stabilizers, suspending agents, non-coloring agents, flavoring agents, and the like for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The invention also includes the use thereof for the preparation of a medicament for the treatment of microbial, in particular bacterial, infections in mammals. The method of use provides an effective amount of a compound of formula I which may be administered to a mammal orally, parenterally, transdermally or topically in a pharmaceutical composition.
The oxazolidinone compound with the general formula I has antimicrobial infection and especially antibacterial activity. Further, the oxazolidinone compounds of the general formula I of the present invention can exhibit potent antibacterial activity against human and animal pathogens including gram-positive bacteria such as staphylococci (Staphylococi), enterococci (Enterococci) and streptococci (Streptococci), anaerobic bacteria such as Bacteroides fragilis (Bacteroides fragilis) and Mycobacterium tuberculosis (Mycobacterium tuberculosis). Thus, it may be used as a medicament for the treatment of bacterial infections in mammals and the compounds according to the invention may be used as active ingredients in the preparation of a method for the treatment of bacterial infections in mammals, comprising administering to a patient suffering from, or susceptible to, such a condition a therapeutically effective amount of a compound according to the invention.
The precise amount of a compound of the invention required to treat a microbial, particularly bacterial, infection will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the condition being treated, the particular compound used and the mode of administration, e.g., route and frequency of administration, and the like. An appropriate effective amount can be determined by one of ordinary skill in the art using no more than routine experimentation.
The amount of the compound to be administered may be from about 0.1 to 100mg/kg body weight per day, preferably 1 to 50mg/kg body weight per day. It will be appreciated that the dosage may vary with the requirements of the patient, the severity of the bacterial infection being treated and the particular compound being used. Furthermore, it will be appreciated that the initial dose administered may be increased beyond the upper limit in order to reach the desired blood level rapidly, or the initial dose may be less than optimal and the daily dose may be increased gradually over the course of the treatment, depending on the particular situation. If desired, the daily dose may also be divided into multiple doses, for example 2-4 times per day.
Mammal means a human or an animal.
In combination therapy, the compound of the present invention and the other compound may be administered simultaneously or at intervals, and in the case of simultaneous administration, the compound of the present invention and the other compound may be combined in a single pharmaceutical composition or in separate compositions.
The invention has the advantages that:
the compound and the pharmaceutically acceptable salt, solvate or prodrug thereof have outstanding effects in treating gram-positive bacterial infection, gram-positive coccal infection and tubercle bacillus infection, and have better antibacterial activity, lower MAO-A inhibition and better safety compared with the existing medicaments of linezolid and raltegrazol.
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention. The NMR of the compound was measured by Bruker ARX-600, and the mass spectrum was measured by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Figure BDA0003179783750000081
TABLE 1
Figure BDA0003179783750000091
Figure BDA0003179783750000101
Figure BDA0003179783750000111
Example 1 (S) -N- [ (3- {4- [6- (guanidinoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
1.1 (S) -N- [ (3- {4- [6- (guanidinoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
1.1.1 Preparation of methyl (4-bromo-3-fluorophenyl) carbamate
Dissolving 30.00g (158.76 mmol) of 4-bromo-3-fluoroaniline in 150mL of dry DCM, slowly adding 12.54g (158.76 mmol) of pyridine dropwise under ice salt bath, and stirring for 10min; 20.58g (190.52 mmol) of methyl chloroformate is added dropwise, the temperature is controlled to be lower than 5 ℃, the dropwise addition is completed within 30min, and the reaction is carried out for 4h at room temperature. After completion of the reaction, 300mL of water was added to the reaction mixture, followed by liquid separation, extraction of the aqueous layer twice with DCM (100 mL × 2), combination of the organic layers, washing twice with 1M hydrochloric acid (100 mL × 2), separation of the organic layer, drying over anhydrous sodium sulfate, and evaporation to dryness to obtain 40.27g of a white solid with a yield of 97.2%. MS (ESI) m/z (%): 248.28[ M + H ]] + 。
1.1.2 Preparation of (S) -N- { [3- (4-bromo-3-fluorophenyl) -2-oxo-1, 3-oxazolidin-5-yl ] methyl } acetamide
40.00g (153.27 mmol) of methyl (4-bromo-3-fluorophenyl) carbamate and 36.82g (459.80 mmol) of lithium tert-butoxide are added to 300mL of dry DMF, and the mixture is stirred at 35 ℃ for 1 hour. The reaction solution was cooled to 5 to 10 ℃ and 14.12g (306.53 mmol) of anhydrous methanol was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. Slowly put into the reaction solution59.17g (306.53 mmol) of (S) -1-acetylamino-3-chloropropan-2-yl acetate in 50mL of DMF was added dropwise thereto, and the mixture was reacted at room temperature for 20 hours. After the reaction is finished, cooling the reaction liquid to 0-5 ℃, dropwise adding 40mL of saturated ammonium chloride aqueous solution into the reaction liquid, controlling the dropwise adding speed to ensure that the temperature does not exceed 10 ℃, stirring for 2h at 0-5 ℃ after the dropwise adding is finished, and separating out white solid. The mixture was poured into 600mL of water, stirred for 30min, filtered, the filter cake washed with water, dried, the resulting solid added to 40mL of DCM, stirred at room temperature for 2h, filtered, and dried to give 42.08g of a white solid with 83.2% yield. MS (ESI) m/z (%): 353.4[ M ] +Na ]] +
1.1.3 Preparation of N- ({ (5S) -3- [ 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
19.8g (60 mmol) of (S) -N- { [3- (4-bromo-3-fluorophenyl) -2-oxo-1, 3-oxazolidin-5-yl are reacted at room temperature]Methyl } acetamide, 30.5 (120 mmol) of the bis-pinacol boronate and 17.7g (180 mmol) of potassium acetate were added successively to 400mL of anhydrous 1, 4-dioxane, degassed, and 2.1g (3 mmol) of Pd (PPh) 3 ) 2 Cl 2 And heating to 90 ℃ for reaction for 15h. After the reaction, the reaction solution pad is filtered by suction while being hot, the filter cake is washed by 200mL of hot 1, 4-dioxane, and the filtrate is concentrated under reduced pressure. 60ml of ether was added to the residue, stirred at room temperature for 30min, filtered, the filter cake was washed with ether and dried to give 33.09g of a white solid with a yield of 72.2%. MS (ESI) m/z (%): 401.3[ 2 ], [ M + Na ]] + 。
1.1.4 Preparation of (S) -N- ({ 3- [ 3-fluoro-4- (6-formylpyridin-3-yl) phenyl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
1g (2 mmol) of N- ({ (5S) -3- [ 3-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl at room temperature]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide, 0.73 (3.9 mmol) 5-bromo-2-pyridinecarboxaldehyde and 1.1g (8 mmol) sodium carbonate were added in succession to a mixed solution of DMF/water (10 mL/1 mL), degassed, N 2 0.09g (0.13 mmol) Pd (PPh) was added under protection 3 ) 2 Cl 2 And reacting at 90 ℃ for 12h. After the reaction, the reaction mixture was cooled to room temperature, 100mL of water was added thereto, DCM (15 mL. Times.3) was added thereto for extraction, the organic phases were combined, washed with saturated brine, and anhydrous sulfuric acidSodium drying, concentrating the organic phase, and performing column chromatography to obtain light yellow solid 0.5g with yield of 40.5%. MS (ESI) m/z (%): 358.3, M + H] + 。
1.1.5 Preparation of (S) -N- [ (3- {4- [6- (guanidinoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
0.1g (0.28 mmol) of (S) -N- ({ 3- [ 3-fluoro-4- (6-formylpyridin-3-yl) phenyl]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide, 0.03g (0.28 mmol) aminoguanidine hydrochloride, adding into absolute ethanol in sequence, reacting at 80 ℃ for 6h, after the reaction, filtering to obtain 0.092g solid product with yield of 80%. MS (ESI) m/z (%): 414.5, M + H] + 。 1 H NMR(600MHz,DMSO)δ12.53(s,1H),8.83(s,1H),8.29(t,1H),8.25(s,1H),8.14(d,J＝8.5Hz,1H),7.74(t,J＝8.8Hz,1H),7.67(dd,J＝13.5,2.1Hz,1H),7.48(dd,J＝8.6,2.1Hz,1H),4.79(dt,J＝11.6,5.4Hz,1H),4.20(t,J＝9.0Hz,1H),3.82(dd,J＝9.2,6.4Hz,1H),3.78(s,4H),3.46(t,J＝13.0,7.3Hz,1H),1.85(s,1H).
EXAMPLE 2 preparation of (S) -N- ({ 3- [4'- (guanidinoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromobenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -N- ({ 3- [4'- (guanidinoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl) is synthesized with aminoguanidine hydrochloride according to the synthesis method of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 285.0-287.4 deg.c; MS (ESI), m/z (%): 413.30[ 2[ M ] +H] + . 1 H NMR(600MHz,DMSO)δ12.03(s,1H),8.31(t,J＝5.8Hz,1H),8.23(s,1H),7.97(d,J＝8.4Hz,2H),7.66(d,J＝9.0Hz,2H),7.64–7.60(m,2H),7.44(dd,J＝8.6,2.1Hz,2H),4.78(dt,J＝11.6,5.3Hz,1H),4.18(t,J＝9.0Hz,1H),3.81(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.85(s,3H).
EXAMPLE 3 preparation of (S) -N- [ (3- {4- [5- (guanidinoiminoethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
2-bromo-5-acetylpyridine is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in the example 1, and the key intermediate is obtained according to the stepsSynthesis of (S) -N- [ (3- {4- [5- (guanidinoiminoethyl) pyridin-2-yl) with aminoguanidine hydrochloride in example 1, method 1.1.5]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]An acetamide. M.p. 267.1-270.3 deg.c; MS (ESI), m/z (%): 462.00[ 2[ M-H ]] - 。 1 H NMR(600MHz,DMSO)δ11.68(s,1H),8.85(s,1H),8.56(d,J＝8.4Hz,1H),8.33(t,J＝5.8Hz,1H),8.22(d,J＝8.1Hz,1H),7.77(t,J＝8.8Hz,1H),7.68(dd,J＝13.6,2.0Hz,1H),7.49(dd,J＝8.6,2.0Hz,1H),4.87–4.70(m,1H),4.20(t,J＝9.0Hz,1H),3.83(dd,J＝9.1,6.4Hz,1H),3.45(t,J＝5.7Hz,2H),2.49(s,3H),1.85(s,3H).
EXAMPLE 4 preparation of (S) -N- [ (3- {4- [6- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
(S) -N- [ (3- {4- [6- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) pyridin-3-yl) was synthesized according to the synthesis method of 1.1.5 in example 1, starting from 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]And (3) acetamide. M.p 282.7-283.1 ℃; MS (ESI), m/z (%): 440.14[ M ] +H] + . 1 H NMR(600MHz,DMSO)δ12.53(s,1H),8.83(s,1H),8.29(t,1H),8.25(s,1H),8.14(d,J＝8.5Hz,1H),7.74(t,J＝8.8Hz,1H),7.67(dd,J＝13.5,2.1Hz,1H),7.48(dd,J＝8.6,2.1Hz,1H),4.79(dt,J＝11.6,5.4Hz,1H),4.20(t,J＝9.0Hz,1H),3.82(dd,J＝9.2,6.4Hz,1H),3.78(s,4H),3.46(t,J＝13.0,7.3Hz,1H),1.85(s,1H).
Example 5 (S) -N- ({ 3- [4'- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Synthesis of (S) -N- ({ 3- [4'- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-1, 1' -biphenyl-4-yl from 4-bromobenzaldehyde as starting material by the synthesis of key intermediate according to the synthesis method 1.1.4 in example 1 and then with 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide according to the synthesis method 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 249.8-254.5 deg.c; MS (ESI), m/z (%): 473.03[ M-H ]] - 。 1 H NMR(600MHz,DMSO-d 6 )δ12.73(s,1H),8.33(dd,J＝12.6,6.6Hz,2H),7.93(d,J＝8.4Hz,2H),7.64(dd,J＝20.1,11.0Hz,4H),7.44(dd,J＝8.6,2.1Hz,1H),4.78(td,J＝11.4,5.4Hz,1H),4.18(t,J＝9.0Hz,1H),3.82(dd,J＝9.1,6.4Hz,1H),3.75(s,4H),3.44(t,J＝5.5Hz,2H),1.85(s,3H).
Example 6 (S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazol-2-hydrazinoethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
Synthesis of (S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazol-2-hydrazinoethyl) pyridin-2-yl from 2-bromo-5-acetylpyridine as starting material by following the synthesis of 1.1.4 in example 1 to the key intermediate and 1.1.4 in example 1 to the 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]An acetamide. M.p. 309.2-312.3 ℃; MS (ESI), m/z (%): 454.25[ M ] +H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ11.49(s,1H),8.82(s,1H),8.49(d,J＝8.4Hz,1H),8.28(t,J＝5.8Hz,1H),8.08(d,J＝8.7Hz,1H),7.73(t,J＝8.8Hz,1H),7.66(dd,J＝13.5,2.2Hz,1H),7.48(dd,J＝8.6,2.1Hz,1H),4.79(dt,J＝11.6,5.4Hz,1H),4.19(t,J＝9.0Hz,1H),3.86–3.80(m,1H),3.79(d,J＝4.9Hz,4H),3.45(dd,J＝8.1,3.4Hz,2H),2.43(s,3H),1.84(s,3H)。
Example 7 (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromo-2-fluorobenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl) is synthesized according to the synthesis method of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 284.5-286.5 deg.c; MS (ESI), m/z (%): 457.09[ M ] +H] + . 1 H NMR(600MHz,DMSO-d 6 )δ12.42(s,1H),8.43(s,1H),8.28(t,J＝5.9Hz,1H),8.22(t,J＝7.9Hz,1H),7.70(t,J＝8.9Hz,1H),7.64(dd,J＝13.7,2.2Hz,1H),7.55(s,1H),7.53(s,1H),7.45(dd,J＝8.7,2.2Hz,1H),4.78(dt,J＝11.6,9.0,5.3Hz,1H),4.19(t,J＝9.0Hz,1H),3.80(dd,J＝9.2,6.4Hz,1H),3.77(s,4H),3.44(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 8 (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Synthesis of (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl) from 4-bromo-2-fluorobenzaldehyde as starting material by the synthesis of key intermediate according to 1.1.4 of example 1 and 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide according to 1.1.5 of example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 284.5-286.5 ℃; MS (ESI), m/z (%): 457.09[ M ] +H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ12.42(s,1H),8.43(s,1H),8.28(t,J＝5.9Hz,1H),8.22(t,J＝7.9Hz,1H),7.70(t,J＝8.9Hz,1H),7.64(dd,J＝13.7,2.2Hz,1H),7.55(s,1H),7.53(s,1H),7.45(dd,J＝8.7,2.2Hz,1H),4.78(dt,J＝11.6,9.0,5.3Hz,1H),4.19(t,J＝9.0Hz,1H),3.80(dd,J＝9.2,6.4Hz,1H),3.77(s,4H),3.44(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 9 (S) -N- [ (3- {4- [6- (thioureidoiminomethyl) pyridin-3-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
According to the synthesis method of 1.1.5 in the embodiment 1, the (S) -N- [ (3- {4- [6- (thioureidoiminomethyl) pyridin-3-yl ] is synthesized by taking the thioaminoguanidine as the raw material and reacting the thioaminoguanidine with the obtained intermediate of 1.1.4]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]An acetamide. M.p 259.1-262.5 ℃; MS (ESI), m/z (%): 429.11[ M-H ]] - ；452.93[M+Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ11.70(s,1H),8.76(s,1H),8.39(d,J＝8.1Hz,2H),8.27(t,J＝5.9Hz,1H),8.24(s,1H),8.14(s,1H),8.02(d,J＝8.5Hz,1H),7.72(t,J＝8.8Hz,1H),7.66(dd,J＝13.5,2.1Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),4.78(td,J＝11.5,5.2Hz,1H),4.19(t,J＝9.0Hz,1H),3.81(dd,J＝9.1,6.4Hz,1H),3.45(t,J＝5.5Hz,2H),1.85(s,3H)。
Example 10 (S) -N- [ (3- {4- [5- (guanidinoiminomethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
2-bromo-5-aldehyde pyridine is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in the example 1, and then (S) -N- [ (3- {4- [5- (guanidinoiminomethyl) pyridin-2-yl) is synthesized according to the synthesis method of 1.1.5 in the example 1]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]An acetamide. M.p. 278.4-282.3 deg.C; MS (ESI), m/z (%): 414.24, M + H] + 。 1 H NMR(600MHz,DMSO-d 6 )δ12.19(s,1H),9.12(d,J＝1.8Hz,1H),8.41(dd,J＝8.4,2.1Hz,1H),8.31(t,J＝5.8Hz,1H),8.28(s,1H),8.09(t,J＝8.9Hz,1H),7.87(d,J＝7.8Hz,1H),7.65(dd,J＝14.2,2.0Hz,1H),7.48(dd,J＝8.8,2.0Hz,1H),4.79(dt,J＝11.6,5.4Hz,1H),4.20(t,J＝9.0Hz,1H),3.83(dd,J＝9.1,6.5Hz,1H),3.45(t,J＝5.5Hz,2H),1.85(s,3H).
Example 11 (S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) pyridin-2-yl ] -3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl ] acetamide
2-bromo-5-aldehyde pyridine is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then the key intermediate and 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide are synthesized into (S) -N- [ (3- {4- [5- (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) pyridin-2-yl) pyridine according to the synthesis method of 1.1.5 in example 1 and 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide]-3-fluorophenyl } -2-oxo-1, 3-oxazolidin-5-yl) methyl]An acetamide. M.p. 272.3-277.2 ℃; MS (ESI), m/z (%): 440.20[ m ] +H] + ；438.25[M-H] - ；462.00[M+Na] + 。 1 H NMR(600MHz,DMSO-d 6 )δ12.40(s,1H),9.03(d,J＝1.8Hz,1H),8.28(dd,J＝8.4,2.1Hz,1H),8.23–8.20(m,2H),8.02(t,J＝8.9Hz,1H),7.83(d,J＝7.8Hz,1H),7.58(dd,J＝14.2,2.0Hz,1H),7.42(dd,J＝8.8,2.1Hz,1H),4.72(dt,J＝11.7,5.4Hz,1H),4.13(t,J＝9.0Hz,1H),3.75(dd,J＝9.1,6.5Hz,1H),3.70(s,4H),3.38(t,J＝5.5Hz,2H),1.78(s,3H)。
Example 12 (S) -2- [ (5- {4- [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2-fluorophenyl } pyridin-2-yl) methylene ] hydrazine-1-carboxamide
According to the synthesis method of 1.1.5 in the example 1, (S) -2- [ (5- {4- [5- (acetamidomethyl) -2-oxo-1, 3-oxazolidin-3-yl) is synthesized by using semicarbazide as a raw material and the intermediate obtained in 1.1.4]-2-fluorophenyl } pyridin-2-yl) methylene]Hydrazine-1-carboxamide. M.p is 199.3-211.2 ℃; MS (ESI), m/z (%): 415.69 2[ M ] +H] + ；436.93[M+Na] + ；413.11[M-H] - 。 1 H NMR(600MHz,DMSO-d 6 )δ10.97(s,1H),8.83(s,1H),8.36(s,2H),8.31(t,J＝5.6Hz,1H),8.00(s,1H),7.78(t,J＝8.8Hz,1H),7.69(dd,J＝13.6,2.1Hz,1H),7.50(dd,J＝8.6,2.1Hz,1H),4.79(td,J＝11.4,5.5Hz,1H),4.20(t,J＝9.0Hz,1H),3.82(dd,J＝9.0,6.5Hz,1H),3.45(t,J＝5.7Hz,2H),1.85(s,3H)。
Example 13 (S) -N- ({ 3- [4'- (thioureidoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromobenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -N- ({ 3- [4'- (thioureidoiminomethyl) -2-fluoro-1, 1' -biphenyl-4-yl is synthesized with aminoguanidine according to the synthesis method of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p 299.1-301.5 deg.c; MS (ESI), m/z (%): 429.93[ 2M + H ]] + ；428.10[M-H] - 。 1 H NMR(600MHz,DMSO-d 6 )δ11.50(s,1H),8.26(dd,J＝12.5,6.5Hz,2H),8.09(s,1H),8.05(s,1H),7.90(d,J＝8.4Hz,2H),7.62(dt,J＝21.3,8.5Hz,4H),7.43(dd,J＝8.6,2.1Hz,1H),4.77(dt,J＝11.5,5.2Hz,1H),4.18(t,J＝9.0Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.85(s,3H)。
Example 14 (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromo-2-fluorobenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2,3' -fluoro-1, 1' -biphenyl-4-yl) is synthesized with aminoguanidine according to the synthesis method of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 263.1-268.4 ℃; MS (ESI), m/z (%): 448.02, M + H] + ；446.06[M-H] - 。 1 H NMR(600MHz,DMSO-d 6 )δ11.61(s,1H),8.33(t,J＝8.0Hz,2H),8.30(s,1H),8.27(t,J＝5.9Hz,1H),8.14(s,1H),7.69(t,J＝8.9Hz,1H),7.62(dd,J＝13.7,2.2Hz,1H),7.47(d,J＝12.1Hz,1H),7.44(dd,J＝8.6,1.9Hz,2H),4.77(dt,J＝11.5,5.2Hz,1H),4.18(t,J＝9.0Hz,1H),3.80(dd,J＝9.2,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 15 (S) -N- (3- {4- [5- (thioureidoiminomethyl) pyridin-2-yl ] -3-fluorophenyl-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
2-bromo-5-aldehyde pyridine is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in the embodiment 1, and then the key intermediate and the aminoguanidine are synthesized into (S) -N- (3- {4- [5- (thioureidoiminomethyl) pyridin-2-yl) according to the synthesis method of 1.1.5 in the embodiment 1]-3-fluorophenyl-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 301.7-303.1 deg.C; MS (ESI), m/z (%): 431.00[ m ] +H] + ；429.05[M-H] - 。 1 H NMR(600MHz,DMSO-d 6 )δ11.64(s,1H),9.03(d,J＝1.8Hz,1H),8.36(dd,J＝8.4,2.1Hz,1H),8.32(s,1H),8.27(t,J＝5.8Hz,1H),8.17(s,1H),8.09(dd,J＝15.9,6.9Hz,2H),7.82(d,J＝7.6Hz,1H),7.64(dd,J＝14.2,2.0Hz,1H),7.47(dd,J＝8.8,2.0Hz,1H),4.86–4.72(m,1H),4.19(t,J＝9.0Hz,1H),3.81(dd,J＝9.1,6.5Hz,1H),3.45(t,J＝5.4Hz,2H),1.85(s,3H)。
Example 16 (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Synthesis of (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl) from 4-bromo-2-hydroxybenzaldehyde as starting Material according to the Synthesis method 1.1.4 in example 1 and Synthesis of a Key intermediate according to the Synthesis method 1.1.4 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 281.3-284.6 ℃; MS (ESI), m/z (%): 429.68[ 2 ] M + H] + . 1 H NMR(600MHz,DMSO-d6)δ11.95(s,1H),10.35(s,1H),8.47(s,1H),8.30(t,J＝5.8Hz,1H),8.07(d,J＝8.2Hz,1H),7.60(dd,J＝13.5,2.3Hz,1H),7.57(d,J＝8.9Hz,1H),7.43(dd,J＝8.6,2.2Hz,1H),7.15(s,1H),7.05(d,J＝8.2Hz,1H),4.77(dt,J＝11.6,5.3Hz,1H),4.17(t,J＝9.0Hz,1H),3.78(dt,J＝46.4,23.3Hz,1H),3.45(t,2H),1.85(s,3H)。
Example 17 (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromo-2-hydroxybenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method 1.1.4 in the example 1, and then the synthesis method and the synthesis method 1.1.5 in the example 1 are carried outSynthesis of (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl) with thioaminoguanidine]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p is 282.2-289.3 ℃; MS (ESI), m/z (%): 444.11[ M-H ]] - . 1 H NMR(600MHz,DMSO-d6)δ11.43(s,1H),10.07(s,1H),8.39(s,1H),8.26(t,J＝5.8Hz,1H),8.14(s,1H),8.04(d,J＝8.1Hz,1H),7.96(s,1H),7.60(dd,J＝10.6,3.1Hz,1H),7.58(dd,J＝8.1,5.6Hz,1H),7.42(dd,J＝8.6,2.1Hz,1H),7.08(s,1H),7.01(d,J＝8.2Hz,1H),4.77(dt,J＝11.5,5.3Hz,1H),4.17(t,J＝9.0Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.85(s,3H)。
Example 18 (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Synthesis of (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-3 ' -hydroxy-1, 1' -biphenyl-4-yl) starting from 4-bromo-2-hydroxybenzaldehyde, following the synthesis of key intermediates according to the synthesis method 1.1.4 in example 1 and the synthesis of 2-hydrazino-4, 5-dihydro-1 imidazole hydrobromide according to the synthesis method 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 264.4-267.3 ℃; MS (ESI), m/z (%): 455.01[ M ] +H] + ；453.06[M-H] - .1H NMR(600MHz,DMSO-d6)δ12.17(s,1H),10.21(s,1H),8.45(s,1H),8.22(t,J＝5.8Hz,1H),7.92(d,J＝8.2Hz,1H),7.54(dd,J＝10.0,3.7Hz,1H),7.52(t,J＝6.3Hz,1H),7.36(dd,J＝8.6,2.1Hz,1H),7.07(s,1H),7.01(d,J＝8.2Hz,1H),4.71(dt,J＝9.1,5.3Hz,1H),4.11(t,J＝9.0Hz,1H),3.73(dd,J＝9.0,6.5Hz,1H),3.67(s,4H),3.37(t,J＝5.5Hz,2H),1.78(s,3H)。
Example 19 (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-1, 1' -biphenyl-4-yl ] methylene) hydrazine-1-carboxamide
4-bromobenzaldehyde is used as a raw material, key intermediates are synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl) is synthesized with semicarbazide according to the synthesis method of 1.1.5 in example 1]-2 '-fluoro-1, 1' -biphenyl-4-yl]Methylene) hydrazine-1-carboxamide. M.p 299.1-301.5 deg.c; MS (ESI), m/z (%): 429.93[ 2M + H ]] + ；428.10[M-H] - . 1 H NMR(600MHz,DMSO-d6)δ11.50(s,1H),8.26(dd,J＝12.5,6.5Hz,2H),8.09(s,1H),8.05(s,1H),7.90(d,J＝8.4Hz,2H),7.62(dt,J＝21.3,8.5Hz,4H),7.43(dd,J＝8.6,2.1Hz,1H),4.77(dt,J＝11.5,5.2Hz,1H),4.18(t,J＝9.0Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.85(s,3H)。
Example 20 (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2', 3-difluoro-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide
4-bromo-2-fluorobenzaldehyde is used as a raw material, a key intermediate is synthesized according to the synthesis method of 1.1.4 in example 1, and then (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl is synthesized with semicarbazide according to the synthesis method of 1.1.5 in example 1]-2', 3-difluoro-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide. M.p. 281.4-284.8 ℃; MS (ESI), m/z (%): 430.06[ M-H ]] - . 1 H NMR(600MHz,DMSO-d6)δ10.46(s,1H),8.26(t,J＝5.9Hz,1H),8.21(t,J＝8.1Hz,1H),8.07(s,1H),7.67(t,J＝8.9Hz,1H),7.62(dd,J＝13.7,2.1Hz,1H),7.47-7.44(m,1H),7.44-7.40(m,2H),4.77(td,J＝11.4,5.3Hz,1H),4.18(t,J＝9.0Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 21 (S) -2- [ (6- {4- [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2-fluorophenyl } pyridin-3-yl) methylene ] hydrazine-1-carboxamide
Taking 2-bromo-5-aldehyde pyridine as a raw material, synthesizing a key intermediate according to the synthesis method of 1.1.4 in example 1, and synthesizing (S) -2- [ (6- {4- [5- (acetamidomethyl) -2-oxo-1, 3-oxazolidin-3-yl) with semicarbazide according to the synthesis method of 1.1.5 in example 1]-2-fluorophenyl } pyridin-3-yl) methylene]Hydrazine-1-carboxamide. M.p is 271.3-272.9 ℃; MS (ESI), m/z (%): 415.25[ 2[ M ] +H] + ；413.11[M-H] - . 1 H NMR(600MHz,DMSO-d6)δ10.56(s,1H),9.02(s,1H),8.39(d,J＝6.1Hz,1H),8.30(t,J＝5.8Hz,1H),8.06(t,J＝8.9Hz,1H),7.92(s,1H),7.87(d,J＝8.3Hz,1H),7.66(dd,J＝14.1,2.0Hz,1H),7.49(dd,J＝8.8,2.1Hz,1H),4.90–4.68(m,1H),4.19(t,J＝9.0Hz,1H),3.82(dd,J＝9.1,6.5Hz,1H),3.45(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 22 (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-3-hydroxy-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide
4-bromo-2-hydroxybenzaldehyde as a raw material, key intermediates were synthesized according to the synthesis method of 1.1.4 in example 1, and (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl) was synthesized with semicarbazide according to the synthesis method of 1.1.5 in example 1]-2 '-fluoro-3-hydroxy-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide. M.p. 296.4-306.7 ℃; MS (ESI), m/z (%): 430.06[ M ] +H] + ；428.10[M-H] - ,452.05[M+Na] + . 1 H NMR(600MHz,DMSO-d6)δ10.24(s,1H),8.26(t,J＝5.9Hz,1H),8.16(s,1H),7.88(d,J＝8.1Hz,2H),7.59(dd,J＝11.2,2.4Hz,1H),7.57(dd,J＝9.6,5.6Hz,1H),7.41(dd,J＝8.6,2.2Hz,1H),7.06(s,1H),7.01(d,J＝8.1Hz,1H),6.44(s,3H),4.77(dt,J＝11.5,5.2Hz,1H),4.17(t,J＝9.0Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),1.84(s,3H)。
Example 23 (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Synthesis of (S) -N- ({ 3- [4' - (guanidinoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl) from 4-bromo-2-methylbenzaldehyde as starting material and aminoguanidine hydrochloride according to the synthesis of 1.1.4 in example 1 as key intermediate and 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 251.6-255.4 deg.C; MS (ESI), m/z (%): 427.03f [ M ] +H] + . 1 H NMR(600MHz,DMSO-d6)δ11.97(s,1H),8.49(s,1H),8.30(t,J＝5.8Hz,1H),8.17(d,J＝8.1Hz,1H),7.63(d,J＝9.1Hz,1H),7.61(dd,J＝9.6,4.0Hz,1H),7.45(d,J＝11.2Hz,2H),7.43(dd,J＝8.7,2.0Hz,1H),4.77(td,J＝11.5,5.4Hz,1H),4.18(t,J＝9.0Hz,1H),3.81(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),3.34(s,3H),1.85(s,3H)。
Example 24 (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazole-2-hydrazinomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
Using 4-bromo-2-methylbenzaldehyde as raw materialSynthesis of 1.1.4 in example 1 Key intermediates were synthesized and (S) -N- ({ 3- [4' - (4, 5-dihydro-1H-imidazol-2-hydrazinomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl) was synthesized with 2-hydrazino-4, 5-dihydro-1-imidazole hydrobromide following the synthesis of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p. 277.9-280.5 ℃; MS (ESI), m/z (%): 453.37[ m ] +H] + ；451.17[M-H] - . 1 H NMR(600MHz,DMSO-d6)δ12.28(s,1H),8.51(s,1H),8.28(t,J＝5.7Hz,1H),8.10(d,J＝8.7Hz,1H),7.63(d,J＝8.9Hz,1H),7.61(dd,J＝10.4,3.3Hz,1H),7.47(d,J＝6.7Hz,2H),7.43(dd,J＝8.6,1.9Hz,1H),4.77(td,J＝11.4,5.5Hz,1H),4.18(t,J＝9.0Hz,1H),3.80(dd,J＝9.0,6.5Hz,1H),3.75(s,4H),3.44(t,J＝5.4Hz,2H),2.49(s,3H),1.84(s,3H)。
Example 25 (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl ] -2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide
4-bromo-2-methylbenzaldehyde as a raw material, a key intermediate was synthesized according to the synthesis method of 1.1.4 in example 1, and (S) -N- ({ 3- [4' - (thioureidoiminomethyl) -2-fluoro-3 ' -methyl-1, 1' -biphenyl-4-yl) was synthesized with aminoguanidine according to the synthesis method of 1.1.5 in example 1]-2-oxo-1, 3-oxazolidin-5-yl } methyl) acetamide. M.p is 276.3-280.8 ℃; MS (ESI), m/z (%): 443.98[ 2[ M ] +H] + ；442.09[M-H] - ；465.91[M+Na] + . 1 H NMR(600MHz,DMSO-d6)δ11.39(s,1H),8.42(s,1H),8.26(t,J＝5.9Hz,1H),8.23(s,1H),8.15(d,J＝8.2Hz,1H),7.95(s,1H),7.64-7.58(m,2H),7.42(dd,J＝7.0,3.7Hz,2H),7.40(d,J＝8.3Hz,1H),4.77(td,J＝11.4,5.3Hz,1H),3.79(dd,J＝9.1,6.4Hz,1H),3.44(t,J＝5.5Hz,2H),2.44(s,3H),1.84(s,3H)。
Example 26 (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl ] -2' -fluoro-3-methyl-1, 1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide
4-bromo-2-methylbenzaldehyde as a raw material was synthesized into a key intermediate according to the synthesis method of 1.1.4 in example 1, and then (S) -2- ({ 4' - [5- (acetylaminomethyl) -2-oxo-1, 3-oxazolidin-3-yl) was synthesized with semicarbazide according to the synthesis method of 1.1.5 in example 1]-2' -fluoro-3-methyl-1,1' -biphenyl-4-yl } methylene) hydrazine-1-carboxamide. 278.7 to 283.1 ℃; MS (ESI), m/z (%): 426.09[ 2[ M-H ]] - 。 1 H NMR(600MHz,DMSO-d6)δ10.24(s,1H),8.26(t,J＝5.8Hz,1H),8.16(s,1H),8.03(d,J＝8.1Hz,1H),7.69–7.49(m,1H),7.41(dt,J＝18.1,7.0Hz,1H),6.47(s,1H),4.77(td,J＝11.4,5.4Hz,1H),4.17(t,J＝9.0Hz,1H),3.79(dd,J＝9.0,6.5Hz,1H),3.44(t,J＝5.4Hz,2H),2.43(s,3H),1.84(s,3H)。
EXAMPLE 27 preparation of a tablet (250 mg/tablet) containing the Compound of example 8 as an active ingredient
Taking 250g of the compound of example 8, 30g of starch, 80mL of HPMC aqueous solution 2%, 15g of sodium carboxymethyl starch, and 2g of magnesium stearate, according to the following steps:
a. preparing an appropriate amount of HPMC solution for later use according to the percentage 2;
b. drying the raw materials and the auxiliary materials properly, and respectively sieving the dried raw materials and the auxiliary materials by a 100-mesh sieve for later use;
c. weighing raw materials and auxiliary materials according to the prescription amount. Mixing the compound of example 1, starch and carboxymethyl starch sodium uniformly, adding 2% HPMC solution to make into soft mass, and making into wet granule with 20 mesh sieve;
d. drying wet granules at 55 deg.C for about 3 hr, cooling, adding magnesium stearate, and sieving with 20 mesh sieve; measuring the content and calculating the weight of the tablets;
e. pressing with 10mm concave punch to obtain 1000 tablets;
f. and (5) inspecting the finished product, and packaging and warehousing after the finished product is qualified.
EXAMPLE 28 preparation of capsules (125 mg/capsule) containing the Compound of example 8 as an active ingredient
125g of the compound of example 8, 15g of starch, 15g of lactose, 2% by volume of an HPMC aqueous solution of about 40mL, 7.5g of sodium carboxymethyl starch, 1g of magnesium stearate were taken. The method comprises the following steps:
a. preparing 2 percent of HPMC solution in proper amount for standby.
b. Drying the raw materials and the auxiliary materials properly, and respectively sieving the dried raw materials and the auxiliary materials by a 100-mesh sieve for later use.
c. Weighing the raw materials and the auxiliary materials according to the prescription amount. The compound of example 2, starch, lactose, sodium carboxymethyl starch were mixed well, 2% HPMC solution was added to make a soft mass, and wet granulation was performed with a 20 mesh sieve.
d. The wet granules were dried at 55 ℃ for about 3 hours, cooled slightly after drying, added with magnesium stearate, and sized with a 20 mesh sieve. Measuring the content and calculating the loading.
e. Filling the 2# capsule shell into granules to obtain 1000 capsules.
f. Polishing and removing dust from the capsule.
g. And (5) inspecting a finished product, and packaging and warehousing after the finished product is qualified.
EXAMPLE 29 preparation of dispersible tablets (250 mg/granule) with the Compound of example 8 as the active ingredient
The following ingredients, 250g of the compound of example 8, 50g of pregelatinized starch, 50g of microcrystalline cellulose, 20g of sodium carboxymethyl starch, 2% HPMC in water solution of about 90ml, 20g of silica gel micropowder, 18g of stevioside, 2g of magnesium stearate, were taken and prepared according to the following steps:
a. an appropriate amount of HPMC solution was prepared for use by 2%.
b. Drying the raw materials and the auxiliary materials properly, and respectively sieving the dried raw materials and the auxiliary materials by a 100-mesh sieve for later use.
c. Weighing the raw materials and the auxiliary materials according to the prescription amount. The compound of example 4, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, and rebaudioside were mixed well, then 2% HPMC solution was added to make a soft mass, and wet granulation was performed with a 20 mesh sieve.
d. Drying the wet granules at 55 deg.C for 3 hr, cooling, adding silica gel micropowder and magnesium stearate, and sieving with 20 mesh sieve. Measuring the content and calculating the weight of the tablet.
e. And (3) pressing by using a 11mm shallow concave punch to obtain 1000 tablets.
f. And (5) inspecting the finished product, and packaging and warehousing after the finished product is qualified.
Example 30 preparation of sodium chloride injection (100 mL: 250 mg) with the Compound of example 8 as the active ingredient
The following components are taken, 250g of the compound of example 8, 825g of sodium chloride, 6.5g of citric acid and water for injection are added to 100L, and the process is carried out according to the following steps:
a. the compound of example 4, sodium chloride and citric acid were weighed out in their prescribed amounts.
b. Dissolving the main and auxiliary materials in water for injection (about 80 deg.C) which accounts for about 90% of the total preparation amount, and stirring to completely dissolve.
c. Adding 0.05% of activated charcoal for injection activated at 120 deg.C for 2 hr, stirring, and standing for 15 min.
d. Filtering and decarburizing with 0.6 μm titanium rod filter, and adding water for injection to full dose.
The compound of the invention is studied for in vitro antibacterial activity, and the results are as follows:
the compounds prepared in the above examples were sterilized as test samples and then diluted to a range of concentrations, up to 128mg/L, in M-H broth. In each row of the 96-well dilution plate, 100. Mu.L of LM-H broth medium was added as a blank to the 12 th well, 50. Mu.L of LM-H broth was added to the 11 th well, and 50. Mu.L of the sample test solution was added sequentially from the 10 th well to the 1 st well in descending order.
Selecting a proper amount of test bacteria and standard strains, inoculating the test bacteria and the standard strains into Mueller-Hinton (M-H) nutrient broth culture medium suitable for growth of the test bacteria, culturing at 37 ℃ for 16-18H, correcting the concentration of the grown bacteria liquid to 0.5 McLeeb's ratio turbidity standard by using normal saline, and diluting the bacteria liquid by using M-H broth 1: 100 (v/v) to obtain the test bacteria liquid. Then 50 mul of test bacterial liquid is inoculated in the 1 st to 11 th holes, and the test bacterial liquid is placed in a square plate with a cover and covered by wet gauze after shaking and mixing, and cultured for 18 to 20 hours at the temperature of 37 ℃.
The observation result under the light source with black background shows that the bacteria growing holes have diffuse turbidity or the bottom of the holes are in button-like precipitation, and the bacteria growing holes have no phenomenon. The lowest concentration of drug contained in the aseptically grown wells was the Minimum Inhibitory Concentration (MIC). The test results are shown in Table 2.
TABLE 2 MIC ug/mL of the activity of some of the compounds of the examples on gram-positive bacteria and tubercle bacillus
Figure BDA0003179783750000221
AUREUS is standard Staphylococcus aureus (29213), MRSA is methicillin-resistant Staphylococcus aureus, LREF is linezolid-resistant enterococcus faecalis, VRE is vancomycin-resistant enterococcus faecium, GBS is Streptococcus agalactiae, steptococcus pneumoniae is Streptococcus pneumoniae
The compounds obtained in examples 8, 16 and 19 according to the invention were then tested for MAO-A inhibition (see Table 3).
TABE 3 MAO-A inhibition (30. Mu.M,%)
Compound (I) Inhibition rate
Example 8 52.9
Example 16 52.3
Example 19 63.5
Linezolid 68.3
Leidazolide 96.2
The results of the preliminary in vitro antibacterial activity tests in tables 2 and 3 show that the compound has better antibacterial activity than linezolid and raltegrazole, has obvious antibacterial activity to drug-resistant bacteriA, and simultaneously has lower MAO-A inhibition and better safety.

Claims (10)

1. An oxazolidinone compound containing a biaryl hydrazone structure is characterized in that: the compound is a compound shown in a general formula, a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
Figure FDA0003179783740000011
wherein the content of the first and second substances,
R 1 and R 2 Each of which is the same or different and is selected from hydrogen, halogen or (C) 1 -C 6 ) A haloalkyl group;
R 3 is selected from-NHCOCH 3 or-OH;
the A ring is 1-3R 6 Substituted aryl or heteroaryl, said heteroaryl containing 1-3 heteroatoms, which are N, O or S;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure FDA0003179783740000012
Figure FDA0003179783740000013
R 6 Selected from hydrogen, hydroxy, halogen, nitro, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) Alkoxy, amino which is unsubstituted or substituted by at least one of the following groups, (C) 1 -C 6 ) Alkylamido, carboxyl, (C) 1 -C 6 ) Alkylsulfinyl (C) 1 -C 6 ) Alkylsulfonyl group, (C) 1 -C 6 ) Alkyl acyl or (C) 1 -C 6 ) An alkylcarbamoyl group; the following groups are hydroxyl, (C) 1 -C 6 ) Haloalkyl, (C) 1 -C 6 ) Alkoxy, di (C) 1 -C 6 Alkyl);
R 7 、R 8 、R 9 、R 10 each of which may be the same or different and is selected from the group consisting of hydrogen, hydroxy, nitro, cyano, amino, (C) 1 -C 6 ) Alkylsulfinyl (C) 1 -C 6 ) Alkylsulfonyl group, (C) 1 -C 6 ) Alkanoyl, unsubstituted or substituted by at least one hydroxy, amino or halogen (C) 1 -C 6 ) Alkyl or (C) 1 -C 6 ) An alkoxy group.
2. A compound according to claim 1, characterized in that: the compound is a compound shown in a general formula, a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Each of which is the same or different and is selected from hydrogen or halogen; and, R 1 And R 2 At least one of which is halogen;
R 3 is selected from-NHCOCH 3 or-OH;
ring A is 1-3R 6 Substituted aryl or heteroaryl, said heteroaryl containing 1-3 heteroatoms, which are N, O or S;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure FDA0003179783740000021
R 6 Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group;
R 7 、R 8 、R 9 、R 10 each of which is the same or different and is selected from the group consisting of hydrogen, hydroxy, nitro, cyano, amino, (C) 1 -C 6 ) Alkyl, (C) 1 -C 6 ) An alkoxy group.
3. A compound according to claim 1, characterized in that: the compound is a compound shown in a general formula, a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Are each the same or different and are selected from hydrogen or fluorine, and, R 1 And R 2 At least one of which is fluorine;
R 3 is-NHCOCH 3 ；
A ringIs arbitrarily divided into 1-3R 6 Substituted phenyl or 5-6 membered aromatic heterocyclic group, wherein the heteroaryl contains 1-2 heteroatoms, and the heteroatoms are N, O or S;
R 6 selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 4 ) Alkyl, (C) 1 -C 4 ) An alkoxy group;
R 4 is H or (C) 1 -C 4 ) An alkyl group;
R 5 is selected from
Figure FDA0003179783740000022
R 7 、R 8 、R 9 、R 10 Each of which is the same or different and is selected from hydrogen, hydroxy, nitro, cyano or amino.
4. A compound according to claim 3, characterized in that: the compound is a compound shown in a general formula, a stereoisomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
in the formula (I), the compound is shown in the specification,
R 1 and R 2 Are each the same or different and are selected from hydrogen or fluorine, and, R 1 And R 2 At least one is fluorine;
R 3 is-NHCOCH 3 ；
R 4 Is selected from H or CH 3 ；
The A ring is any 1-3R 6 Substituted phenyl, pyridyl, furyl or thienyl;
R 5 is selected from
Figure FDA0003179783740000023
R 6 Selected from hydrogen, hydroxy, halogen, nitro, amino, cyano, (C) 1 -C 4 ) Alkyl or (C) 1 -C 4 ) An alkoxy group.
5. Compounds according to any of claims 1 to 4, characterized in that: the compound of the general formula I and a stereoisomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, and an acid form a salt, wherein the acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric 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, ethanesulfonic acid, isethionic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, trifluoroacetic acid, or aspartic acid.
6. The use of a compound of claim 5, wherein: the use of a compound of general formula i as claimed in any one of claims 1 to 4, and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, or a salt of a compound as claimed in claim 5, in the manufacture of a medicament for use in the treatment of microbial infections.
7. A pharmaceutical composition characterized by: a composition comprising a compound of formula i according to any one of claims 1 to 4 and a stereoisomer, a pharmaceutically acceptable salt, solvate or prodrug thereof, or a salt of a compound according to claim 5.
8. A pharmaceutical composition according to claim 7, wherein: use of the composition in the manufacture of a medicament for the treatment of a microbial infection.
9. A composition formulation characterized by: the preparation is active ingredients and pharmaceutically acceptable auxiliary agents; wherein, the active ingredient is one or more of the compounds of the general formula I in any one of the claims 1 to 4 and stereoisomers, pharmaceutically acceptable salts, solvates or prodrugs thereof, or salts formed by the compounds in the claim 5, or compositions in the claim 7; the active component accounts for 0.1-99% of the preparation.
10. A formulation of the composition of claim 9, wherein: the use of a formulation of said composition in the manufacture of a medicament for the treatment of a microbial infection.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1119647A (en) * 1994-07-20 1996-04-03 拜尔公司 6-membered nitrogen-containing heteroaryl-oxazolidinones
CN101429170A (en) * 2003-06-03 2009-05-13 瑞伯-X医药品有限公司 Biaryl heterocyclic compounds and methods of making and using the same
CN102131811A (en) * 2008-06-24 2011-07-20 财团法人乙卯研究所 Oxazolidinone derivative having fused ring
WO2016077818A1 (en) * 2014-11-14 2016-05-19 Melinta Therapeutics, Inc. Method for treating, preventing, or reducing the risk of skin infection
CN107033095A (en) * 2017-05-11 2017-08-11 沈阳红旗制药有限公司 The Jie Gou oxazolidinone compounds of hydrazone containing piperazine
CN107721943A (en) * 2017-10-26 2018-02-23 沈阳药科大学 Jie Gou oxazolidinone compounds of hydrazone containing biaryl and preparation method thereof
CN108976222A (en) * 2018-09-21 2018-12-11 沈阳药科大学 Biaryl Oxazolidinone compound containing heterocycle and preparation method thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1119647A (en) * 1994-07-20 1996-04-03 拜尔公司 6-membered nitrogen-containing heteroaryl-oxazolidinones
CN101429170A (en) * 2003-06-03 2009-05-13 瑞伯-X医药品有限公司 Biaryl heterocyclic compounds and methods of making and using the same
CN102131811A (en) * 2008-06-24 2011-07-20 财团法人乙卯研究所 Oxazolidinone derivative having fused ring
WO2016077818A1 (en) * 2014-11-14 2016-05-19 Melinta Therapeutics, Inc. Method for treating, preventing, or reducing the risk of skin infection
CN107205989A (en) * 2014-11-14 2017-09-26 梅琳塔治疗公司 The method for the treatment of, prevention or reduction skin infection risk
CN107033095A (en) * 2017-05-11 2017-08-11 沈阳红旗制药有限公司 The Jie Gou oxazolidinone compounds of hydrazone containing piperazine
CN107721943A (en) * 2017-10-26 2018-02-23 沈阳药科大学 Jie Gou oxazolidinone compounds of hydrazone containing biaryl and preparation method thereof
CN109574947A (en) * 2017-10-26 2019-04-05 沈阳药科大学 The Oxazolidinone derivative and preparation method thereof of the structure of hydrazone containing biaryl
CN108976222A (en) * 2018-09-21 2018-12-11 沈阳药科大学 Biaryl Oxazolidinone compound containing heterocycle and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YACHUANG WU，等: "Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues containing a hydrazone moiety as promising antibacterial agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 158, pages 247 - 258 *

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