阅读说明：本技术 N-苯甲酰苯胺类衍生物、其制备方法和用途 (N-benzoylaniline derivatives, preparation method and application thereof ) 是由 李松 肖军海 袁波 林凤 郑志兵 钟武 李行舟 周新波 曹瑞源 樊士勇 肖典 于 2019-04-04 设计创作，主要内容包括：本发明涉及式I所示的N-苯甲酰苯胺类衍生物、其制备方法和用途。本发明涉及式I所示化合物、其药学可接受的盐、溶剂合物、水合物,含有该化合物的药物组合物具有抑制细菌AI-2型群体感应作用,可用于预防和/或治疗细菌感染所致的相关疾病。<Image he="365" wi="540" file="DSA0000181381470000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to N-benzanilide derivatives shown in a formula I, and a preparation method and application thereof. The invention relates to a compound shown in formula I, and pharmaceutically acceptable salts, solvates and hydrates thereof, and a pharmaceutical composition containing the compound has the effect of inhibiting bacterial AI-2 type quorum sensing, and can be used for preventing and/or treating related diseases caused by bacterial infection.)

1. N-benzanilide derivatives shown in formula I, racemates or optical isomers thereof, pharmaceutically acceptable salts, solvates or hydrates thereof,

wherein R is₁Is Br atom or phenyl; r₂Is Br or H atom; r₃Is hydroxyl or phenolic ester group; r4 is nitro or carboxyl or ester group, R5 is Br or H atom; r6 is halogen or alkyl; r7 is a carbonate chain.

2. The benzanilide derivative of claim 1 wherein R is R, a racemic or optical isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof₁Is Br atom or phenyl; r₂Is Br or H atom; r₃Is hydroxyl or phenolic ester group; r4 is nitro or carboxyl or ester group, R5 is Br or H atom; r6 is halogen or alkyl; r7 is a carbonate chain.

3. The benzanilide derivative of the formula I, a racemic or optical isomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof according to claim 1 or 2, which is selected from the group consisting of:

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl) carbamoyl) phenylacetate (compound 1);

3, 5-dibromo-N- (2-bromo-4-nitrophenyl) -4-hydroxybenzamide (compound 2);

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl (methyl octyl carbonate)) phenyl acetate (compound 3);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid methyl ester (compound 4);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 5);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 6);

ethyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 7);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid (compound 8);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromo-5-methylbenzoic acid methyl ester (compound 9);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoic acid (compound 10);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoate (compound 11);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-chlorobenzoic acid methyl ester (compound 12);

3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 13);

methyl 3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 14);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-fluorobenzoic acid methyl ester (compound 15);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 16);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 17);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 18);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 19);

5- ((2-bromo-4-nitrophenyl) carbamoyl) - [1, 1' -biphenyl ] -2-yl acetate (Compound 20).

4. A process for the preparation of benzanilide derivatives of the formula I, their racemates or optical isomers, their pharmaceutically acceptable salts, solvates or hydrates as claimed in any one of claims 1 to 3, which comprises the steps of: reacting the intermediate shown in the formula e with aniline shown in the formula f, and then reacting with iodocarbonate chain shown in the formula h to obtain the N-benzanilide derivative, the racemate or the optical isomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof or the hydrate thereof according to any one of claims 1 to 3,

wherein R is_1-6Is as defined inThe method of any one of claims 1-2.

5. A pharmaceutical composition comprising the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts, solvates or hydrates thereof according to any one of claims 1 to 3, and optionally one or more pharmaceutically acceptable carriers or excipients.

6. The pharmaceutical composition of claim 5, further comprising at least one antibiotic.

7. Use of the benzanilide derivatives, the racemates or optical isomers thereof, the pharmaceutically acceptable salts, solvates or hydrates thereof as set forth in any one of claims 1 to 3 for the preparation of a medicament as an inhibitor of bacterial quorum sensing.

8. Use of the benzanilide derivatives, the racemates or optical isomers thereof, the pharmaceutically acceptable salts, solvates or hydrates thereof according to any one of claims 1 to 3 for the preparation of a medicament for the prophylaxis and/or treatment of diseases caused by bacterial infections.

9. Use according to claim 8, wherein the bacterium is a gram-positive or gram-negative bacterium, preferably a gram-negative bacterium.

10. The use of claim 8, wherein said bacteria include, but are not limited to, Vibrio harveyi, Escherichia coli, Klebsiella pneumoniae, Proteus proteus, Shigella dysenteriae, Brucella, Haemophilus influenzae, Hemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Bordetella parapertussis, Parahaemophilus parahaemolyticus, Legionella pneumophila, Vibrio cholerae.

11. The use of claim 8, wherein said diseases caused by bacterial infection include, but are not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, sepsis, etc.

12. Use of the benzanilide derivatives, the racemates or optical isomers thereof, the pharmaceutically acceptable salts, solvates or hydrates thereof according to any one of claims 1 to 3 for the preparation of a medicament for the prevention and/or treatment of diseases caused by bacterial quorum sensing.

13. The use of claim 12, wherein said diseases caused by bacterial quorum sensing include, but are not limited to, various diseases caused by gram-negative bacteria such as escherichia coli, pneumophilus, proteus, shigella, brucella, bacillus influenzae (haemophilus), parainfluenza (haemophilus), catarrh (moraxella), acinetobacter, yersinia, pasteurella, shigella, bordetella pertussis, parapertussis, haemophilus parahaemolyticus, legionella pneumophila, vibrio cholerae, including, but not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, sepsis, etc.; preferably, the disease is a disease caused by the antibiotic-insensitive above-mentioned drug-resistant bacteria.

14. Use of the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof according to any one of claims 1 to 3 as a tool for studying inhibition of bacterial quorum sensing.

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to N-benzanilide derivatives, a preparation method thereof, and application thereof in preparing a medicament for preventing and/or treating diseases caused by gram-negative bacteria.

Background

During the growth of the flora, bacteria can continuously generate chemical signal molecules (also called autoinducers) and secrete the chemical signal molecules into the surrounding environment, when the concentration of the signal molecules reaches a certain threshold value, the expression of genes related to thalli, such as bioluminescence, formation of a biological back membrane, release of virulence factors, expression of virulence genes and the like, can be regulated or started to adapt to the change of the environment, and the regulation system is called a Quorum Sensing (QS) signal system of the bacteria.

The signal molecules are roughly divided into four types according to different population effects: (1) the LuxI/LuxR type signal system of gram-negative bacteria, mediated by AHL (acylated homoserine lactone); (2) a small molecule polypeptide (AIP) mediated signaling system for gram-positive bacteria; (3) a LuxS/AI-2 type signal system; (4) AI-3/epinephrine/norepinephrine type signaling system.

The QS system was first discovered in marine vibrio fischeri (v. fischeri), and when the density of the bacteria is high, the bacteria produce a bioluminescence phenomenon to capture food, avoid natural enemies, and the like. Through research on the mechanism, it is found that in v.fischeri, N-Acetyl Homoserine Lactones (AHL) synthesized by LuxI proteins can be combined with the amino residue of AHL receptor proteins encoded by LuxR to form a specific conformation, so that the carboxyl terminal is combined with a target DNA sequence, thereby activating transcriptional expression of a light-emitting gene. In gram-positive bacteria, oligopeptides are mainly used as signal molecules to mediate population effect, the signal molecules are obtained by processing and modifying longer precursor peptides, and due to different compositions and lengths of the precursor peptides, the formed signal molecules are relatively large in difference, and AlP signal molecules cannot freely pass through cell membranes and need to be transported to the outside of cells through a transporter ABC or other transporters to play a role. The AI-2 signal molecule was first discovered in the gram-negative bacterium Vibrio harveyi in 1990. When a strain lacking AHL is discovered, the strain can still produce bioluminescence, experiments prove that AI-2 can be produced, and then people put Vibrio harveyi into culture solution of other bacteria and can also produce bioluminescence, and a series of experiments show that a large amount of bacteria can produce and utilize AI-2, such as escherichia coli and salmonella typhimurium. Subsequent experiments demonstrated that AI-2 is widely present in both gram-positive and gram-negative bacteria, for a total of about 70 species, which is also referred to as "universal autoinducer". In gram-negative bacteria enterohemorrhagic escherichia coli (EHEC) O157: h7 discloses a novel signal molecule AI-3, the synthesis and structure of which is not yet clear, but studies have shown that epinephrine and norepinephrine can act in place of AI-3.

The mechanism of action is shown in that when the density of the bacterial population is low, a small amount of self-induced signals can be generated, and the signals diffuse to the outside of the cells and are immediately diluted by the surrounding environment. When the density of the bacterial population continuously rises and the concentration reaches a certain threshold value, the signal molecules enter the cells and are combined with corresponding transcription regulatory proteins to form a transcription regulatory protein signal molecule polymer, and the polymer can regulate the transcription and translation of the population effect regulatory protein and the synthesis of the signal molecules. Although this communication of information between bacteria has been proposed for a long time, the systematic research has been mainly focused on the last decade, and this effect has now been demonstrated to exist among various bacteria.

At the end of the 70's of the 20 th century, scientists discovered that the use of natural or synthetic quorum sensing regulators (including agonists or inhibitors) could interfere with the signaling system and regulate the expression of undesirable genes in bacteria. The bacterial quorum sensing inhibitor does not interfere normal physiological functions of cells in vivo, only can be used for regulating the expression of harmful genes of pathogenic bacteria so as to lose pathogenic capability, and therefore, the bacterial quorum sensing inhibitor is regarded as a new direction for the development of antibacterial drugs, wherein the bacterial quorum sensing inhibitor can be used in combination with antibiotics, so that the sensitivity of pathogenic bacteria to the antibiotics is improved, the curative effect of the drugs is enhanced, and various diseases caused by various gram-negative bacteria such as endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, septicemia and the like are mainly treated. The aim of the present invention is to find new AI-2 bacterial quorum sensing inhibitors for the prevention and/or treatment of diseases caused by gram-negative and positive bacteria, in particular drug-resistant gram-negative and positive bacteria.

Disclosure of Invention

The first aspect of the invention relates to the derivatives of N-benzanilide shown in the formula I, the racemic body or the optical isomer thereof, the pharmaceutically acceptable salt, the solvate or the hydrate thereof,

wherein R is₁Is Br atom or phenyl; r₂Is Br or H atom; r₃Is hydroxyl or phenolic ester group; r₄Is nitro or carboxyl or ester group, R₅Is Br or H atom; r₆Is halogen or alkyl; r₇Are carbonate chains.

The benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates according to any one of the first aspect of the present invention are selected from the group consisting of:

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl) carbamoyl) phenylacetate (compound 1);

3, 5-dibromo-N- (2-bromo-4-nitrophenyl) -4-hydroxybenzamide (compound 2);

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl (methyl octyl carbonate)) phenyl acetate (compound 3);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid methyl ester (compound 4);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 5);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 6);

ethyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 7);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid (compound 8);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromo-5-methylbenzoic acid methyl ester (compound 9);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoic acid (compound 10);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoate (compound 11);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-chlorobenzoic acid methyl ester (compound 12);

3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 13);

methyl 3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 14);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-fluorobenzoic acid methyl ester (compound 15);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 16);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 17);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 18);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 19);

5- ((2-bromo-4-nitrophenyl) carbamoyl) - [1, 1' -biphenyl ] -2-yl acetate (compound 20);

the second aspect of the present invention relates to the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof according to any one of the first aspect of the present invention can be prepared by the following reaction scheme:

wherein R is_1-7Is as defined in any of the first aspects of the invention, d_a、e_aIs an intermediate obtained by taking a as a raw material, d_b，e_bIs an intermediate obtained by taking b as a raw material.

The third aspect of the invention relates to a pharmaceutical composition, which comprises the benzanilide derivative, the racemate or the optical isomer thereof, the pharmaceutically acceptable salt, the solvate or the hydrate thereof, and one or more pharmaceutically acceptable carriers or excipients.

The pharmaceutical composition according to any one of the third aspect of the invention, further comprising at least one antibiotic.

The pharmaceutical composition according to any one of the third aspect of the present invention, wherein the antibiotic includes, but is not limited to, β -lactams (meropenem, cephalexin, ceftazidime, cefpirome, etc.), aminoglycosides (e.g., amikacin, streptomycin, tobramycin, isepamicin, etc.), glycopeptides (e.g., vancomycin, teicoplanin, polymyxin, etc.), macrolides (e.g., roxithromycin, clarithromycin, azithromycin, etc.), tetracyclines (e.g., doxycycline, minocycline, tigecycline, etc.), quinolones (e.g., norfloxacin, ciprofloxacin, gatifloxacin, pazufloxacin, etc.), and the like.

The fourth aspect of the present invention relates to the use of the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof according to any one of the first aspect of the present invention for the manufacture of a medicament for use as an inhibitor of bacterial quorum sensing.

In an embodiment of the present invention, a compound selected from the group consisting of racemates or optical isomers thereof, pharmaceutically acceptable salts, solvates or hydrates thereof, may be used for the preparation of a medicament for use as a bacterial quorum sensing inhibitor,

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl) carbamoyl) phenylacetate (compound 1);

3, 5-dibromo-N- (2-bromo-4-nitrophenyl) -4-hydroxybenzamide (compound 2);

2, 6-dibromo-4- ((2-bromo-4-nitrophenyl (methyl octyl carbonate)) phenyl acetate (compound 3);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid methyl ester (compound 4);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 5);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 6);

ethyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 7);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromobenzoic acid (compound 8);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-bromo-5-methylbenzoic acid methyl ester (compound 9);

3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoic acid (compound 10);

methyl 3-bromo-4- (3, 5-dibromo-4-hydroxybenzoylamino) -5-methylbenzoate (compound 11);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-chlorobenzoic acid methyl ester (compound 12);

3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 13);

methyl 3-chloro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 14);

4- (4-acetoxy-3, 5-dibromobenzamido) -3-fluorobenzoic acid methyl ester (compound 15);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 16);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 17);

3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoic acid (compound 18);

methyl 3-fluoro-4- (3, 5-dibromo-4-hydroxybenzamido) benzoate (compound 19);

5- ((2-bromo-4-nitrophenyl) carbamoyl) - [1, 1' -biphenyl ] -2-yl acetate (compound 20);

the fifth aspect of the present invention relates to the use of the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof according to any one of the first aspect of the present invention for the preparation of a medicament for the prevention and/or treatment of diseases caused by bacterial infections.

The use according to any of the fifth aspects of the invention, wherein the bacterium is a gram-positive or gram-negative bacterium, preferably a gram-negative bacterium.

The use according to any of the fifth aspect of the invention, wherein said gram-negative bacteria is selected from the group consisting of vibrio harveyi, escherichia coli, pneumobacillus, proteus, shigella dysenteriae, brucella, haemophilus influenzae, parainfluenza, catarrh, acinetobacter, yersinia, pasteurella, shigella, pertussis, parapertussis, haemophilus parahaemolyticus, legionella pneumophila, vibrio cholerae.

The use according to any one of the fifth aspect of the invention, wherein the diseases caused by bacterial infection include, but are not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, septicemia and other diseases; preferably, the disease is a disease caused by the antibiotic-insensitive drug-resistant strain described above.

The sixth aspect of the present invention relates to the use of the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof according to any one of the first aspect of the present invention for the preparation of a medicament for the prevention and/or treatment of diseases caused by quorum sensing.

The use according to any of the sixth aspect of the present invention, wherein the diseases caused by bacterial quorum sensing include, but are not limited to, various diseases caused by gram-negative bacteria such as Vibrio harveyi, Escherichia coli, Klebsiella pneumoniae, Proteus, Shigella dysenteriae, Brucella, Haemophilus influenzae, Hemophilus parainfluenzae, Morta, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Bordetella parapertussis, Parahemolytic bacilli, Legionella pneumophila, Vibrio cholerae, including, but not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, pyothorax, septicemia, etc.; preferably, the disease is a disease caused by the antibiotic-insensitive drug-resistant strain described above.

The seventh aspect of the invention relates to the use of the benzanilide derivatives, racemates or optical isomers thereof, pharmaceutically acceptable salts, solvates or hydrates thereof according to the first aspect of the invention as a tool for studying quorum sensing regulation.

The eighth aspect of the present invention relates to a method for preventing and/or treating a disease caused by bacterial infection, which comprises the step of administering a prophylactically and/or therapeutically effective amount of the benzanilide derivative, the racemate or the optical isomer thereof, the pharmaceutically acceptable salt, the solvate or the hydrate thereof according to the first aspect of the present invention to a subject in need thereof.

The method according to any one of the eighth aspect of the invention, wherein the bacterium is a gram-positive or gram-negative bacterium, preferably a gram-negative bacterium.

The method according to the eighth aspect of the present invention, wherein the diseases caused by bacterial infection include, but are not limited to, various diseases caused by gram-negative bacteria such as Vibrio harveyi, Klebsiella pneumoniae, Proteus proteus, Shigella dysenteriae, Brucella, Haemophilus influenzae, Hemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Bordetella parapertussis, Parahemolytic bacilli, Legionella pneumophila, Vibrio cholerae, including, but not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, septicemia, etc.; preferably, the disease is a disease caused by the antibiotic-insensitive drug-resistant strain described above.

The ninth aspect of the present invention relates to a method for preventing and/or treating a disease caused by bacterial quorum sensing, which comprises the step of administering a prophylactically and/or therapeutically effective amount of the benzanilide derivative, the racemate or the optical isomer thereof, the pharmaceutically acceptable salt, the solvate or the hydrate thereof according to the first aspect of the present invention to a subject in need thereof.

The method according to any one of the ninth aspect of the present invention, wherein the diseases caused by bacterial quorum sensing include, but are not limited to, various diseases caused by gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Proteus proteus, Shigella dysenteriae, Brucella, Haemophilus influenzae, Hemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter, Yersinia, Pasteurella, Shigella, Bordetella pertussis, Bordetella parapertussis, Parahemolytic bacilli, Legionella pneumophila, Vibrio cholerae, etc., including, but not limited to, endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, septicemia, etc.; preferably, the disease is a disease caused by the antibiotic-insensitive drug-resistant strain described above.

Detailed Description

Various phrases and terms used herein have the same general meaning as commonly understood by one of ordinary skill in the art, but are specifically defined herein to control the meaning defined herein.

R as used herein_1-7Represents R₁、R₂、R₃、R₄、R₅、R₆、R₇。

As used herein, the term "halogen" has the general meaning well known in the art and typically includes F, Cl, Br, I, and also includes isotopic forms thereof, preferably F, Cl, Br in the present invention.

As used herein, the term "alkyl" refers to a straight, branched or cyclic alkyl group containing 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

As used herein, the groups represented by the following terms have the general meaning well known in the art: nitro, methyl, phenolic ester, carbonate chain.

As used herein, the terms "racemate" and "optical isomer" have their common meaning as is well known in the art.

According to the present invention, the present invention relates to suitable pharmaceutically acceptable salts or hydrates of the compounds of formula I or stereoisomers thereof, wherein the pharmaceutically acceptable salts include, but are not limited to, salts of the compounds of formula I with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, phosphorous acid, hydrobromic acid and nitric acid, and salts with various organic acids such as maleic acid, malic acid, fumaric acid, succinic acid, tartaric acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, p-toluenesulfonic acid, palmitic acid and the like. The present invention includes those stoichiometric solvates, including hydrates, as well as compounds containing variable amounts of water that are formed when prepared by a low pressure sublimation drying process.

In accordance with the present invention, stereoisomers of the compounds of formula I according to the present invention are meant to indicate that some of the compounds of the present invention may exist as optical isomers or as tautomeric isomers, and the present invention includes all existing forms thereof, particularly pure isomers, the different isomeric forms may be separated or resolved from other forms of isomers by various conventional means, or certain isomers may be obtained by various conventional synthetic methods or stereospecific or asymmetric syntheses. These less pure products contain at least 1%, more suitably 5%, and even more suitably at least 10% of the compound of formula I or a pharmaceutically acceptable derivative thereof.

According to the present invention, the above compounds of formula I may be prepared by the following typical exemplary process comprising the steps of:

1) 1g of acetic anhydride (10.1mmol) is dissolved in 40mL of dichloromethane, the mixture is placed in a 250mL flask, the mixture is stirred and dissolved, 1g (3.4mmol) of 3, 5-dibromo-4-hydroxybenzoic acid is added, concentrated sulfuric acid is added dropwise for 2d, oil bath at 35 ℃ is refluxed for 5h, and the reaction is completed. Adding 50mL of saturated NaCl solution, stirring for 20min, pouring into a separating funnel, standing for layering, taking an organic phase, washing the organic phase to be neutral by using the saturated NaCl solution, drying for 5h by using anhydrous sodium sulfate, and spin-drying to obtain an intermediate d_a1.2g of white solid, yield 100%.

2) Taking an intermediate d_a1g (2.8mmol) and 10mL of thionyl chloride are placed in a 50mL flask, stirred and dissolved, 2 drops of DMF are added dropwise, oil bath at 70 ℃ is refluxed for 4 hours, the reaction is finished, and heating is stopped. Spin-drying to give intermediate e_a1.05g of white solid, yield 100%.

3) 1g (4.6mmol) of the starting material h and 0.8g (6.5mmol) of phenylboronic acid are dissolved in 12mL of 1, 4-dioxane, 3mL of water-soluble 3g K are added₂CO₃(21mmol), vacuumizing, adding 0.29g (0.25mmol) of palladium tetratriphenylphosphine under nitrogen atmosphere, refluxing at 100 ℃ for 10h, adding 50mL of water and dichloromethane respectively, stirring, adding 1N HCl to adjust the pH value to acidity, stirring for 10min, standing, taking a dichloromethane layer, extracting an aqueous layer with dichloromethane, spin-drying an organic phase, and carrying out column chromatography to obtain 0.15g of a white solid, namely an intermediate c.

4) Dissolving intermediate c 0.15g (0.7mmol) and acetic anhydride 0.21g (2.1mmol) in dichloromethane 7mL, dripping 4d concentrated sulfuric acid, refluxing at 40 deg.C for 3 hr, adding saturated NaCl solution 7mL, stirring, standing to obtain organic phase, washing the organic phase with saturated NaCl solution to neutrality, drying and spin-drying to obtain white solid 0.12g, i.e. intermediate d_b。

5) Taking an intermediate d_bDissolving 50mg in SOCl25mL, adding 2d DMF, refluxing at 70 deg.C for 3 hr, and spin-drying to obtain white solid 50mg, i.e. intermediate e_b。

6) The intermediate h is obtained by the following steps: under the ice bath condition, 5.7g (44.98mmol) of chloromethyl chloroformate is added into a reaction bottle, after 40mL of DCM is used for dissolution, 5.8g (44.98mmol) of 1-octanol is added, 4.55g (44.98mmol) of triethylamine is slowly and dropwise added, after ice bath reaction is carried out for 10min, the ice bath is removed, stirring is carried out for 21h at room temperature, the reaction product is washed to be neutral by 40mL of diluted hydrochloric acid, 40mL of saturated sodium bicarbonate and 40mL of distilled water in a separating funnel in sequence, an organic phase is dried by anhydrous sodium sulfate, after decompression and concentration, an oily product is obtained and is dried, and then the oily product is directly put into the next reaction (6.72g), and the yield is 67.3%. 4.76g (31.76mmol) of NaI was added to the reaction flask, 40mL of anhydrous acetonitrile was added thereto and the mixture was dissolved by stirring, 6.72g (30.26mmol) of the synthesized chloromethyl-1-octylcarbonate was added thereto, the mixture was stirred overnight in the dark, insoluble matter was removed by filtration, and the filtrate was concentrated and dried to obtain an intermediate h iodomethyl-1-octylcarbonate and directly charged into the next step.

7) E is to be_aOr e_bStirring the intermediate with the formula f at normal temperature under the basic condition of triethylamine to obtain a formula g, and generating a formula i by the formula g and the intermediate h under the action of NaH; when R4 is an ester group, the formula g is hydrolyzed under the action of NaOH to generate a formula j, and the formula j is hydrolyzed with methanol or ethanol in SOCl₂Reacting to generate formula k. Wherein the compounds of formula I in the case where formula g, formula I, formula j, formula k are R

Wherein R is_1-7The groups are as defined in any one of the first aspect of the invention.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula I and at least one pharmaceutically acceptable carrier or excipient. The compounds of formula I or pharmaceutically acceptable salts thereof may be used alone or in combination with pharmaceutically acceptable carriers or excipients in the form of a pharmaceutical composition, which when used in the form of a pharmaceutical composition, will generally be formulated in an appropriate administration form or dosage form by combining an effective amount of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof of the invention with one or more pharmaceutically acceptable carriers or diluents, which procedure comprises mixing, granulating, compressing or dissolving the components in a suitable manner.

The pharmaceutical compositions of the present invention may be administered in any of the following ways: oral, aerosol inhalation, rectal, nasal, vaginal, topical, parenteral such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or infusion, or by means of an explanted reservoir, with oral, intramuscular, intraperitoneal or intravenous administration being preferred.

Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention include, but are not limited to: ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, carboxymethylcellulose hook, polyacrylates, beeswax, wool vinegar and the like. The carrier may be present in the pharmaceutical composition in an amount of from 1% to 98% by weight, typically about 80% by weight, for convenience local anesthetics, preservatives, buffers and the like may be directly dissolved in the carrier.

Oral preparations such as oral tablets and capsules may contain excipients such as binding agents, for example syrup, acacia, sorbitol, tragacanth, or polyvinylpyrrolidone, fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica, disintegrating agents such as potato starch, or acceptable wetting agents such as sodium lauryl sulfate.

The pharmaceutical compositions of the present invention in the form of oral liquids may be prepared as suspensions, solutions, emulsions, syrups or elixirs in water and oils, or may be prepared as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, sorbitol, cellulose methyl ether, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gelatin, hydrogenated edible fats and oils, emulsifying agents such as lecithin, sorbitan monooleate, gum arabic; or a non-aqueous carrier (which may comprise an edible oil), such as almond oil, an oil such as glycerol, ethylene glycol, or ethanol; preservatives, e.g. methyl or propyl p-hydroxybenzoates, sorbic acid. Flavoring or coloring agents may be added if desired. Suppositories may contain conventional suppository bases such as cocoa butter or other glycerides. For parenteral administration, liquid dosage forms are generally prepared from the compound and at least one sterile or aseptic carrier. The carrier is preferably water, and the compound can be dissolved in the carrier or made into suspension solution according to the difference of the selected carrier and drug concentration, and the compound is firstly dissolved in water when making injection solution, and then the solution is filtered and sterilized and filled into a sealed bottle or ampoule. When applied topically to the skin, the compounds of the present invention may be formulated in the form of a suitable ointment, lotion, or cream in which the active ingredient is suspended or dissolved in one or more carriers. Among the vehicles that may be used in the ointment formulation include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions and creams may employ carriers including, but not limited to: mineral oil, sorbitan monostearate, tween 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Depending on the mode of administration, the composition may contain 0.1% by weight, or more suitably 10-60% by weight of the active ingredient, but where the composition is in unit dosage form, it preferably contains 50-500 mg of the active ingredient per unit, depending on the route and frequency of administration, a suitable therapeutic dose for adults may be, for example, 100-3000 mg per day, such as 1500 mg per day.

It will be appreciated that the optimal dosage and interval for administration of a compound of formula I will be determined by the severity of the disease or condition, the nature of the compound and the conditions, such as the form, route and site of administration and the particular mammal being treated, and that such optimal dosage may be determined by a clinician.

Advantageous effects of the invention

The invention provides a series of novel quorum sensing inhibitors, which do not interfere normal physiological activities of cells, only inhibit the expression of harmful genes of pathogenic bacteria to enable the pathogenic bacteria to lose pathogenic capability, so the quorum sensing inhibitors are regarded as a new direction for the development of antibacterial drugs, can be used in combination with antibiotics, can be used for preventing and/or treating various diseases caused by various gram-negative bacteria, such as endocarditis, peritonitis, gastroenteritis, cholecystitis, cystitis, diarrhea, empyema, septicemia and the like, and is particularly suitable for preventing and/or treating diseases caused by drug-resistant gram-negative bacteria insensitive to the existing antibiotics.

Detailed Description

The invention is further illustrated by the following specific intermediates and examples, but it should be understood that these intermediates and examples are for illustrative purposes only and are not to be construed as limiting the invention in any way.

The materials used in the tests and the test methods are described generally and/or specifically herein. Although many materials and methods of operation are known in the art for the purpose of this invention, the invention is described herein in as much detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.

¹The H-NMR spectrum was measured by JNM-ECS-400 NMR. Mass spectra were determined by an API 3000 triple quadrupole tandem mass spectrometer.