ANTI-GRAM-NEGATIVE-BACTERIA AGENT, THERAPEUTIC AND PROPHYLACTIC AGENT AGAINST GRAM-NEGATIVE BACTERIAL INFECTIONS CONTAINING SAME, AND DISINFECTANT AGAINST GRAM-NEGATIVE BACTERIA
|Posted date||Nov 11, 2016|
|International application number||2016JP058659|
|International publication number||WO 2016152764|
|Date of international filing||Mar 18, 2016|
|Date of international publication||Sep 29, 2016|
|Title||ANTI-GRAM-NEGATIVE-BACTERIA AGENT, THERAPEUTIC AND PROPHYLACTIC AGENT AGAINST GRAM-NEGATIVE BACTERIAL INFECTIONS CONTAINING SAME, AND DISINFECTANT AGAINST GRAM-NEGATIVE BACTERIA|
|Abstract||The problem to be solved by the present invention is to provide a low-molecular compound that demonstrates an antibacterial effect against gram-negative bacteria, and particularly against multidrug-resistant gram-negative bacteria, even when used alone, without combination with other agents. This anti-gram-negative bacteria agent is characterized by comprising a compound represented by formula (I) (R11, R12, R13, R14, R15, R21, R22, R23, R24, R25 and R31 each individually represent a hydrogen atom or a predetermined substituent).|
|Outline of related art and contending technology||
In the world's first penicillin antibiotics after been invented, a large number of antibiotics is found, an improvement of natural antibiotics have been developed various synthetic antibacterial agent, a treatment for bacterial infections has made a remarkable progressed (hereinafter, referred to herein as antibiotics and synthetic antimicrobial agents are collectively referred to as antimicrobial agent). However, as a result of the antimicrobial agent is often used, acquires a resistance bacteria and antimicrobial agents, drug resistant bacteria that appear, then the plurality of anti-microbial agent is resistant to multi-drug resistant bacteria appear (multi-drug resistant) but become a major problem, with the recent further, pan-resistant to most of the antimicrobial agent to the multi-drug resistant bacteria has been (pan-drug resistant) appearance. Mention may be made of multi-drug resistance, multidrug resistant Pseudomonas aeruginosa (multiple-drug-resistant Pseudomonas aeruginosa: MDRP), multidrug resistant Acinetobacter (multiple drug-resistant Acinetobacter: MDRA) and the like, the main of nosocomial infections caused by bacteria and the clinical trial as a serious problem. For example P. aeruginosa is, such as a decrease in the resistance force upon infection by the hospitalized patients, pneumonia, urinary tract infection, surgical wound infection, bacteremia can cause such as, in particular multidrug resistant Pseudomonas aeruginosa infection in the case of difficult to treat. Such multi-drug resistant bacteria in order to cope, different from the conventional antimicrobial agents act on the new target molecule also multi-drug resistance which is effective, a need to develop new agents are.
Gram negative bacteria, the outer membrane of the separation membrane, the drug by the enzyme modification, the conformational change of the drug to the target molecule, such as the medicament outlet pump to the outside of cells by the action of the antimicrobial agent is weakened, multidrug resistance is believed to be gained. In particular, multi-drug resistance such as P. aeruginosa and greatly contribute to the acquisition of, various agents could be discharged by the drainage pump is a multifunctional agent, pump RND(resistance nodulation division) family. Therefore, the directionality of the one of the development of new drugs, an agent that inhibits the RND family of pump function has been considered to develop.
On the other hand, the outer membrane of gram-negative bacteria, outer membrane channel protein multi-ejector pump (for example in Pseudomonas aeruginosa OprM) protein such as β - in order to insert the transportation of the barrel, BAM (β -barrel assembly machinery) complex is responsible for the necessary functions are known, it has been elucidated that the tertiary structure are also. Only BAM complex present in the gram-negative bacteria, as long as the developing drugs that inhibit the function of, gram-negative bacteria such as Pseudomonas aeruginosa can be sterilized selectively only. 5 BAM complex is made up of two subunits, BamA, BamB, BamC, and since a BamE BamD, inhibits the interaction between the proteins in their normal the complex cannot be formed, it is believed that because of the dysfunction. Therefore, the development of new drugs as one of the additional directional, BAM complex sub-unit of an agent that inhibits protein-protein interactions has also been proposed to develop.
To the directionality of the development of new drugs instead of two of the above-listed 2 may be considered various types not, so far the present inventors, mentioned above on the basis of the two grain-oriented 2, anti-gram-negative bacteria agent as described below are proposed.
Patent Document 1 is (WO2007/091395 pamphlet), which is one of the pump RND family, MexA, MexB and OprM 3 sub-units of one MexAB-OprM pump configured target, site specific to the particular OprM that act on the agent to inhibit the function of the above-described pump, for example an antibody that binds to a specific site specific, as well as the drug (antibody) and an antimicrobial agent containing P. aeruginosa infection such as a therapeutic agent is disclosed. Embodiment, the predetermined and producing monoclonal antibodies having the activities, is an antimicrobial agent when used in combination with aztreonam (AZT) to, P. aeruginosa exert a bactericidal action is illustrated.
(WO2010/147145 pamphlet) is Patent Document 2, (corresponding to the complex BAM) YaeT complex by inhibiting the formation of, exert a bactericidal action against gram - negative bacteria such as anti-gram-negative bacteria agent has been proposed. Such anti-gram-negative bacteria agent 1 as the first embodiment, includes an amino acid sequence represented by at least LTLR, preferably C-terminus is amidated are, YfgL YaeT (corresponding BamA) and inhibiting the binding of (corresponding BamB) described in the peptide molecule. Is LTLR, included in the amino acid sequence of YfgL, interacts with the binding YaeT amino acid sequence of the region. In addition, as the first embodiment 2, or comprises the amino acid sequence represented by IRLH FIRL, preferably C-terminus is amidated, and YfiO YaeT (corresponding BamA) of inhibiting the binding of (corresponding BamD) described in the peptide molecule. Embodiment, polymyxin B is an antimicrobial agent, ofloxacin (OFLX) or aztreonam (AZT) to pseudomonas aeruginosa itself does not affect the survival of when to coexist at low concentrations, Pseudomonas aeruginosa (standard strains and highly multidrug resistant strains) and shown to be bactericidal against E. Coli illustrated. Further embodiment, multidrug resistant Pseudomonas aeruginosa infection by the rabbit cornea ulcer model and the above-described predetermined time of administration of the peptide molecule OFLX, infection of mice with P. aeruginosa pneumonia model with respect to the above-mentioned predetermined peptide molecule and to the time of administration of colistin sulfate administration, an excellent therapeutic effect of the infection the illustrated may be observed.
Patent Document 3 (Japanese Patent Application JP-2011-178674) is, LXLR represented by (X is T or S) comprising the amino acid sequence at least 4 amino acids peptide molecule, a hydrophobic group on its C-terminus (for example β - naphthylamine) is bonded to the modified peptide molecule, are included as well as the modified peptide molecule, an antimicrobial agent and the peptide molecule A therapeutic drug is disclosed. This modified peptides, as described above C-terminus is modified with a hydrophobic group for improving the permeability by the film, as well as gram-negative bacteria Gram-positive bacteria shown to be sterilized, in particular multidrug resistant Pseudomonas aeruginosa and methicillin-resistant staphylococcus aureus (MRSA) agent such as the invention is effective against the resistant strains, antibiotics and the like of the conventional modified peptide alone without combination with a bactericidal action is shown in, for example in the outer membrane of gram-negative bacteria to an antibacterial agent to enhance the permeability of the combined use of the further improvement of bactericidal action is described. Embodiment, an anti-deterioration effect the cell membrane (polymyxin B) survival of the pseudomonas aeruginosa itself is not affected when to coexist at low concentrations, β - naphthylamine C (hydrophobic group) in the above-mentioned predetermined end has been modified with a peptide molecule, Pseudomonas aeruginosa (standard strains and highly multidrug resistant strains), E. coli, and Staphylococcus aureus (methicillin-sensitive and methicillin-resistant strains) exhibit bactericidal action with respect to the illustrated.
(Japanese Patent Application JP-2012-180302) Patent Document 4 is, XXLR (XX LT is, or LS FS) of the repeating unit represented by the amino acid sequence and contains at least 2, the C-terminus amidated peptide molecules containing anti-gram-negative bacteria agent is disclosed. The anti-gram-negative bacteria agent, in combination with other antimicrobial agents used alone without a sufficient sterilization even if shown to be described. Embodiment, the antimicrobial agent is absent or (OFLX) was added and the solution added to, the above-mentioned predetermined peptide (standard strain) Pseudomonas aeruginosa Acinetobacter and exhibit bactericidal action with respect to the illustrated.
|Scope of claims||
式（I）中、R 11、R 12、R 13、R 14、R 15、R 21、R 22、R 23、R 24、R 25およびR 31はそれぞれ独立して、水素原子、ハロゲン原子、炭素原子数が1～4個のアルキル基（－R）、ヒドロキシル基（－OH）、炭素原子数が1～4個のアルコキシ基（－OR）、メルカプト基（－SH）、炭素原子数が1～4個のチオアルコキシ基（－SR）、カルボキシル基（－COOH）、炭素原子数が2～5個のカルボン酸エステル基（－COO－R）、末端の窒素原子に結合した水素原子が炭素原子数が1～4個のアルキル基で置換されていてもよいカルボン酸アミド基（－COO－NH 2）、炭素原子数が2～5個のアシル基（－CO－R）、末端の窒素原子に結合した水素原子が炭素原子数が1～4個のアルキル基で置換されていてもよいカルバモイル基（－CO－NH 2）、窒素原子に結合した水素原子が炭素原子数が1～4個のアルキル基で置換されていてもよいアミノ基（－NH 2）、末端の窒素原子に結合した水素原子が炭素原子数が1～4個のアルキル基で置換されていてもよいウレイド基（－NH－CO－NH 2）、ニトロ基（－NO 2）またはシアノ基（－CN）を表す。
（i）R 11、R 12、R 13、R 14またはR 15が、炭素原子数が1～4個のアルキル基である；
（iv）R 11、R 12、R 13、R 14およびR 15のうち、水素原子以外の置換基であるものの数が2以下である；
（v）R 21、R 22、R 23、R 24およびR 25のうち、水素原子以外の置換基であるものの数が2以下である。
|IPC(International Patent Classification)|
National States: AE AG AL AM AO AT AU AZ BA BB BG BH BN BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IR IS JP KE KG KN KP KR KZ LA LC LK LR LS LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PA PE PG PH PL PT QA RO RS RU RW SA SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW KM ML MR NE SN ST TD TG
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