WO2010098365A1 - Antibiotique de type nucléoside - Google Patents

Antibiotique de type nucléoside Download PDF

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Publication number
WO2010098365A1
WO2010098365A1 PCT/JP2010/052902 JP2010052902W WO2010098365A1 WO 2010098365 A1 WO2010098365 A1 WO 2010098365A1 JP 2010052902 W JP2010052902 W JP 2010052902W WO 2010098365 A1 WO2010098365 A1 WO 2010098365A1
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substituted
alkyl
compound
unsubstituted
mmol
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PCT/JP2010/052902
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Japanese (ja)
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彰 松田
聡 市川
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塩野義製薬株式会社
国立大学法人北海道大学
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Publication of WO2010098365A1 publication Critical patent/WO2010098365A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a substance having antibacterial activity.
  • Nucleosides are one of the most important biological substances. These are not only the components of DNA and RNA that control the storage and expression of genetic information, but also function as coenzymes and intracellular signaling substances, and are involved in intracellular metabolism and energy supply. Have a role to play. Nucleosides have long been recognized as a good lead for conducting drug discovery chemistry research, and various nucleoside compounds have been clinically used.
  • nucleoside natural products can be good leads for drug development.
  • nucleoside derivatives there are several problems to be overcome in the method for synthesizing nucleoside derivatives.
  • nucleobase which is a nitrogen-containing aromatic ring
  • the reagents that can be used are limited due to its high coordination ability, and aldehydes and ketone bodies that are used as raw materials for the carbon increase reaction to the sugar part
  • it is unstable under various reaction conditions.
  • the inventors have conducted synthetic studies on antibacterial nucleosides having a novel mechanism of action.
  • MraY intracellular membrane enzyme translocase I
  • the MraY inhibitor that can be a cell wall synthesis inhibitor has recently attracted attention as a new target for the development of antibacterial agents, and is expected to lead to the creation of drugs that are widely effective against bacteria including drug-resistant bacteria.
  • MraY inhibitors are resistant to drug-resistant bacteria such as MRSA and VRE. It is expected to lead to the creation of drugs that are broadly effective against bacteria containing them (see Non-Patent Document 1 and Non-Patent Document 2).
  • FR-900493 is a natural product of nucleoside having a broad antibacterial spectrum isolated from Bacillus subtilis by Fujisawa Pharmaceutical Co., Ltd. in 1989 (see Patent Documents 1 and 2).
  • Murraymycins are natural products isolated by Wyeth in 2002 and showed excellent therapeutic effects in a strong MraY inhibitory activity and in vivo activity test using S. aureus infected mice. Moreover, no side effects such as toxicity have been reported in in vivo experiments, and it is expected as a lead for the development of new antibacterial agents (see Patent Documents 3 to 6, Non-Patent Documents 3 and 4).
  • Examples of other nucleoside compounds having an antibacterial action include those described in Patent Documents 3 to 20 and Non-Patent Documents 5 to 9.
  • An object of the present invention is to provide a compound having antibacterial activity. More preferably, the present invention provides an antibacterial nucleoside compound that exhibits antibacterial activity by inhibiting the action of MraY, particularly a novel derivative of Muramycin that is a MraY inhibitor.
  • R 1 is C6-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl;
  • R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl;
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted carbocyclic group, or A substituted or unsubstituted heterocyclic group,
  • R 5 is hydrogen, or substituted or unsubstituted lower alkyl,
  • R 6 is hydrogen, substituted or unsubstituted lower alkyl, or —C
  • (Item 3A) The compound according to item (1A) or (2A), wherein R 1 is aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or C2-C10 alkenyl, or a pharmaceutically acceptable salt thereof Salts or solvates thereof.
  • (Item 4A) The compound according to any one of items (1A) to (3A), wherein R 1 is C11-C20 alkyl, or C9-C20 alkenyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 2 is hydrogen, lower alkyl, carbocyclic group, or carbocyclic alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, or substituted or unsubstituted heterocyclic group
  • (Item 7A) The compound according to any one of items (1A) to (6A), wherein R 5 is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (Item 8A) The compound according to any one of items (1A) to (7A), wherein R 6 is hydrogen, or —C ( ⁇ O) —NH—CR 7 R 8 —CO ( ⁇ O) R 9 , or a pharmaceutically acceptable salt thereof Salts or solvates thereof.
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, or substituted or unsubstituted heterocyclic group
  • (Item 10A) The compound according to any one of items (1A) to (9A), wherein R 9 is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (Item 11A) A pharmaceutical composition comprising the compound according to any one of items (1A) to (10A), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (Item 12A) The pharmaceutical composition according to item (11A) having MraY inhibitory action.
  • (Item 13A) The pharmaceutical composition according to item (11A) or (12A) having antibacterial activity.
  • (Item 14A) The compound according to any one of items (1A) to (10A), a pharmaceutically acceptable salt thereof or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria Use of things.
  • (Item 15A) The compound according to any one of items (1A) to (10A), a pharmaceutically acceptable salt thereof or a solvate thereof for the treatment and / or prevention of various diseases caused by pathogenic bacteria.
  • (Item 16A) Treatment of various diseases caused by pathogenic bacteria, and / or administration of a compound according to any one of items (1A) to (10A), a pharmaceutically acceptable salt thereof, or a solvate thereof, and / or Or prevention methods.
  • (Item 17A) A pharmaceutical composition according to any of items (11A) to (13A), which treats various diseases caused by pathogenic bacteria described below: respiratory tract infection, Urinary tract infection, respiratory infection, sepsis, nephritis, cholecystitis, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection, etc.
  • (Item 18A) A nucleic acid antibiotic containing the compound according to any one of items (1A) to (10A), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, or C1-C20 alkyl, C2 -C20 alkenyl, C2-C20 alkynyl or aryl substituted with substituted aryl;
  • R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl;
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted carbocyclic group, or A substituted or unsubstituted heterocyclic group,
  • R 1 is substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, substituted or unsubstituted C3-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl, C2
  • the compound according to item (1B) which is aryl substituted with C20 alkynyl or substituted aryl, or a pharmaceutically acceptable salt or solvate thereof.
  • R 1 is substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, or aryl substituted with C1-C10 alkyl, C2-C10 alkenyl or substituted aryl
  • (Item 5B) The compound according to any one of items (1B) to (4B), wherein R 1 is substituted C1-C10 alkyl, or aryl substituted with substituted aryl, or a pharmaceutically acceptable salt thereof, or a solvate thereof .
  • (Item 6B) The compound according to any one of items (1B) to (5B), wherein R 2 is hydrogen, lower alkyl, carbocyclic group, or carbocyclic alkyl, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, or substituted or unsubstituted heterocyclic group
  • (Item 11B) The compound according to any one of items (1B) to (10B), wherein R 9 is hydrogen, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (Item 12B) The compound according to any one of items (1B) to (11B), or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 is a carboxy protecting group.
  • (Item 13B) A pharmaceutical composition comprising the compound according to any one of items (1B) to (12B), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • (Item 14B) The pharmaceutical composition according to item (13B) having an MraY inhibitory action.
  • (Item 15B) The pharmaceutical composition according to items (13B) and (14B) having antibacterial activity.
  • (Item 16B) The compound according to any one of items (1B) to (12B), a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic and / or prophylactic agent for various diseases caused by pathogenic bacteria Use of things.
  • (Item 17B) The compound according to any one of items (1B) to (12B), a pharmaceutically acceptable salt thereof or a solvate thereof for the treatment and / or prevention of various diseases caused by pathogenic bacteria.
  • (Item 18B) Treatment of various diseases caused by pathogenic bacteria, and / or administration of a compound according to any one of items (1B) to (12B), a pharmaceutically acceptable salt thereof, or a solvate thereof, and / or Or prevention methods.
  • (Item 19B) A pharmaceutical composition according to any of items (13B) to (15B), which treats various diseases caused by pathogenic bacteria described below: respiratory tract infection, Urinary tract infection, respiratory infection, sepsis, nephritis, cholecystitis, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection, etc.
  • (Item 20B) A nucleic acid antibiotic containing the compound according to any one of items (1B) to (12B), a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound according to the present invention has good intracellular migration and exhibits strong antibacterial activity. Further, the compound according to the present invention has resistance to enzymes such as esterase in blood. Further, preferred compounds have MraY inhibitory action. Preferred compounds are also effective against resistant bacteria such as VRE and MRSA.
  • alkyl includes a linear or branched monovalent hydrocarbon group having 1 to 8 carbon atoms.
  • C1-C6 alkyl is used. More preferred is C1-C4 alkyl.
  • lower alkyl includes linear or branched alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n -Butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like.
  • substituted or unsubstituted lower alkyl may be substituted with one or more groups selected from substituent group ⁇ .
  • the substituent group ⁇ is halogen, hydroxy, lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, guanidino, hydroxyimino, A group consisting of lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, cyano and nitro.
  • lower alkoxy “hydroxy lower alkyl”, “hydroxy lower alkoxy”, “lower alkoxycarbonyl”, “lower alkylamino”, “lower alkoxy lower alkoxy”, “lower alkylcarbamoyl”, “hydroxy lower
  • the lower alkyl part of “alkylcarbamoyl”, “lower alkoxyimino”, “lower alkylthio”, “lower alkylsulfonyl”, “lower alkylsulfonyloxy”, “lower alkylsulfamoyl”, and “lower alkylsulfinyl” is also referred to as “lower alkyl”. Is the same.
  • lower alkenyl means 2 to 15 carbon atoms having one or more double bonds at any position, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably. Includes straight-chain or branched alkenyl having 2 to 4 carbon atoms.
  • lower alkynyl is a straight chain or branched chain having 2 to 10, preferably 2 to 8, more preferably 3 to 6 carbon atoms having one or more triple bonds at any position. Includes branched alkynyl. Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. These may further have a double bond at an arbitrary position.
  • “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, non-aromatic fused carbocyclic group and the like.
  • cycloalkyl is a carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, Examples include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • cycloalkenyl includes those having one or more double bonds at any position in the ring of the cycloalkyl, specifically cyclopropenyl, cyclobutenyl. , Cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, cyclohexadienyl and the like.
  • aryl includes phenyl, naphthyl, anthryl, phenanthryl and the like, and phenyl is particularly preferable.
  • non-aromatic fused carbocyclic group is a group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed. Specific examples include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
  • halogen includes fluorine, chlorine, bromine and iodine. Preferred are fluorine, chlorine and bromine.
  • halogen part of “halo lower alkyl” and “halo lower alkoxy” is the same as the above “halogen”.
  • arbitrary positions on the alkyl group of “lower alkyl” and “lower alkoxy” may be substituted with the same or different halogen atoms.
  • substituted C1-C5 alkyl “substituted C1-C10 alkyl”, “substituted or unsubstituted C6-C20 alkyl”, “substituted or unsubstituted C11-C20 alkyl”, “substituted or unsubstituted”
  • Substituents such as “substituted C2-C20 alkynyl”, “substituted or unsubstituted C9-C20 alkenyl”, “substituted or unsubstituted C2-C20 alkynyl”, “substituted or unsubstituted C3-C20 alkynyl” formula:
  • R x is halogen, lower alkyl, lower alkoxy, halo lower alkyl, halo lower alkoxy, lower alkyl or aryl-substituted amino, or lower alkyl or arylthio
  • m is an integer from 0 to 3
  • R x may be the same or different).
  • the “lower alkyl or aryl-substituted amino” includes a secondary to tertiary amino group or a quaternary ammonio group substituted with lower alkyl or aryl, and includes, for example, methylamino, ethylamino, propylamino (Eg, n-propylamino, isopropylamino), butylamino (eg, n-butylamino, isobutylamino, s-butylamino, and t-butylamino), pentylamino, hexylamino, dimethylamino, diethylamino, dipropyl Amino, diisopropylamino, dibutylamino, trimethylammonio, triethylammonio, tripropylammonio, tributylammonio, allylamino, diallylamino, triallylammonio, e
  • aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl means aryl substituted with alkyl, alkenyl or alkynyl having the number of carbon atoms within the range. And the aryl moiety is the same as the above “aryl”.
  • Preferred embodiments are phenyl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl.
  • a more preferred embodiment is phenyl substituted with C1-C10 alkyl or C2-C10 alkenyl.
  • substituent of the “substituted aryl” moiety in “aryl substituted by substituted aryl” is selected from halogen, lower alkyl, lower alkoxy, halo lower alkyl, halo lower alkyloxy.
  • Carboxy protecting group includes protecting groups described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), and the like. For example, methyl, ethyl, t-butyl, benzyl, paramethoxybenzyl and the like can be mentioned.
  • carbocyclic part of “carbocyclic alkyl” is the same as the above “carbocyclic group”.
  • heterocyclic group is a heteroaryl, non-aromatic heterocyclic group or bicyclic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
  • heterocyclic groups such as tricyclic fused heterocyclic groups.
  • heteroaryl refers to pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiazolyl And 5- to 6-membered aromatic cyclic groups.
  • the ⁇ non-aromatic heterocyclic group '' means dioxanyl, thiylyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, Piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroaze
  • bicyclic fused heterocyclic group means indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl , Benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzoxiazolyl, benzisothiazolyl, benzothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Zolyl, thienopyridyl, thienopyrrolyl, thienopyrazolyl, thienopyr
  • tricyclic fused heterocyclic group examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl, imidazoquinolyl, tetrahydrocarbazolyl and the like.
  • heterocyclic group is a 5- to 6-membered heteroaryl or non-aromatic heterocyclic group.
  • substituent of “substituted or unsubstituted carbocyclic group” and “substituted or unsubstituted heterocyclic group” is one or more selected from the group consisting of lower alkyl and substituent group ⁇ . The group of is mentioned.
  • heterocyclic portion of “heterocyclic alkyl” is the same as the above “heterocyclic group”.
  • the “solvate” includes, for example, a solvate with an organic solvent (for example, an alcohol (eg, ethanol) solvate), a hydrate and the like.
  • an organic solvent for example, an alcohol (eg, ethanol) solvate
  • a hydrate When forming a hydrate, it may be coordinated with any number of water molecules.
  • prodrug any form known in the art can be adopted.
  • Prodrugs take the metabolic mechanism of the body in reverse, and in their original form do not show drug action or only show very weak activity, but they show pharmacological activity only after being metabolized in vivo Or it has been modified to increase its pharmacological activity.
  • salts and solvates, esters, amides and the like can also be mentioned as examples of prodrugs.
  • the compounds of the present invention include pharmaceutically acceptable salts.
  • alkali metals such as lithium, sodium or potassium
  • alkaline earth metals such as magnesium or calcium
  • ammonium salts with organic bases and amino acids, or inorganic acids (hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphorus Acid or hydroiodic acid) and organic acids (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, Benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like).
  • hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable.
  • the compounds of the present invention are not limited to specific isomers, and all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ) And racemates.
  • One of the characteristics of the compound according to the present invention is that C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2- is substituted for R 1 in formula (I). This is a point in which intracellular migration and antibacterial activity are improved by applying aryl substituted with C20 alkynyl.
  • R 1 is aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl.
  • R 1 is aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or C2-C10 alkenyl.
  • R 1 is C11-C20 alkyl or C9-C20 alkenyl.
  • Another feature of the compounds according to the present invention is that, for R 1 in formula (I), substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl Applying substituted or unsubstituted C2-C20 alkynyl, or C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or aryl substituted with substituted aryl to improve intracellular migration and antibacterial activity This is the point.
  • R 1 Preferred embodiments of R 1 include substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, substituted or unsubstituted C3-C20 alkynyl or C1-C20 alkyl, C2- C20 alkenyl, C2-C20 alkynyl or aryl substituted with substituted aryl.
  • R 1 More preferred embodiments of R 1 are substituted with substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, or C1-C10 alkyl, C2-C10 alkenyl or substituted aryl. Is aryl.
  • R 1 is aryl R 1 is substituted with substituted C1-C10 alkyl or substituted aryl.
  • Method for producing the compound of the present invention A general method for producing the compound of the present invention is illustrated below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the synthesis of the compound of the present invention can be carried out in consideration of a technique known in the art.
  • the raw material compounds are commercially available compounds, those described in Non-Patent Documents 5 and 6, those described in the present specification, and those described in other references cited in the present specification, and In addition, known compounds can be used.
  • Some of the compounds of the present invention may have tautomers, positional isomers and optical isomers, but the present invention includes all possible isomers and mixtures thereof, including these. To do.
  • the compound of the present invention when obtaining a salt of the compound of the present invention, if the compound of the present invention is obtained in the form of a salt, it can be purified as it is, and if it is obtained in a free form, it can be dissolved in an appropriate organic solvent. Alternatively, it may be suspended and an acid or base is added to form a salt by a conventional method.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof may exist in the form of adducts (hydrates or solvates) with water or various solvents, and these adducts are also included in the present invention. Is included.
  • a typical general synthesis method of the compound of the present invention is shown below.
  • the compounds described in the examples were synthesized generally according to these, but are not particularly limited to these methods.
  • Reaction solvents, bases, reducing agents and the like that can be used in the production of the compounds are described below.
  • preferred ones are shown, but the present invention is not particularly limited thereto.
  • Reaction solvent N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), aromatic hydrocarbons (example) , Toluene, benzene, xylene, etc.), saturated hydrocarbons (eg, cyclohexane, hexane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (eg, tetrahydrofuran, diethyl) Ethers, dioxane, 1,2-dimethoxyethane, etc.), esters (eg, methyl acetate, ethyl acetate, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.
  • metal hydride eg, sodium hydride
  • metal hydroxide eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide
  • metal carbonate eg, sodium carbonate
  • potassium carbonate eg, sodium carbonate
  • potassium t-butoxide e.g.
  • metal alkoxide eg, sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • sodium bicarbonate metallic sodium
  • organic amine eg, triethylamine, diisopropylethylamine, dia) Zabicycloundecene (DBU), 2,6-lutidine, etc.
  • pyridine alkyl lithium (n-butyl lithium (n-BuLi), sec-butyl lithium (sec-BuLi), tert-butyl lithium (tert-BuLi) )etc.
  • Reducing agent supported metal such as Pd carbon used in H 2 atmosphere, sodium borohydride, lithium borohydride, sodium triacetoxyborohydride, borane complex, diisobutylaluminum hydride, sodium borohydride sodium Bis (2-methoxyethoxy) aluminum sodium hydride (Red-Al TM ), lithium aluminum hydride and the like.
  • Compound (I) according to the present invention can be produced by the following method.
  • R a 1 , R a 2 , R a 3 , R a 4 and R a 5 are each independently substituted or unsubstituted lower alkyl, and Pg 1 and Pg 2 are tert-butoxycarbonyl
  • An amino-protecting group such as a (t-Boc) group or a benzyloxycarbonyl (Cbz) group
  • Pg 3 represents a carboxy such as a methyl (Me) group, an ethyl (Et) group, or a tert-butyl (t-Bu) group;
  • a protecting group, and other symbols are as defined above
  • First Step A compound (A1) that is commercially available or can be prepared by a known method is mixed with a base such as Ba (OH) 2 in toluene, chloroform, tetrahydrofuran, water, or a mixed solution thereof, 0 ° C. to 150 ° C., preferably 0
  • Compound (A2) can be
  • the compound (A2) is mixed with Pg 3 OC ( ⁇ NH) CCl 3 and Lewis acid (boron fluoride / diethyl ether complex (BF 3 / OEt 2 ), trimethylsilyl in a solvent such as toluene, chloroform, dichloromethane, tetrahydrofuran and the like. Trifluoromethanesulfonate (TMSOTf), etc., preferably in the presence of BF 3 ⁇ OEt 2 at 0 ° C. to 150 ° C., preferably below 0 ° C., for 0.5 to 24 hours, preferably 1 to 12 hours. To obtain compound (A3) (see J. Org. Chem. 2008, 73, 569.).
  • First Step The compound (A5) is reduced in a solvent such as tetrahydrofuran, methanol, ethanol, water or a mixed solvent such as ethanol-water under reducing conditions using, for example, a metal such as zinc and NH 4 Cl.
  • Compound (A6) can be obtained by reacting at 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours.
  • Second Step Compound (A6) is dissolved in 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclocarbodiimide, bis (2-oxo-3-oxazolidinyl) phosphoric acid in a solvent such as toluene, dichloromethane, chloroform, tetrahydrofuran and the like.
  • the compound (0) is subjected to a condensation reaction with formic acid in the presence of a condensing agent such as nick chloride at 0 ° C. to 150 ° C., preferably 0 ° C., for 0.5 to 24 hours, preferably 1 to 12 hours.
  • A7 can be obtained.
  • Compound (A7) is mixed with triphosgene in a solvent such as toluene, chloroform, dichloromethane, tetrahydrofuran or the like in the presence of a base such as Et 3 N at ⁇ 80 ° C. to 50 ° C., preferably at ⁇ 78 ° C. for 0.1 to 24 hours.
  • Compound (A8) can be obtained by reacting preferably for 0.5 to 12 hours.
  • Compound (B1) is added in a solvent such as tetrahydrofuran, methanol, ethanol, water or a mixed solvent such as ethanol-water in the presence of a base such as potassium carbonate at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.
  • the compound (B2) can be obtained by reacting for 0.5 to 24 hours, preferably 1 to 12 hours.
  • R c 1 is substituted or unsubstituted lower alkyl
  • Pg 6 is an amino-protecting group such as t-Boc group and Cbz group, and other symbols are as defined above).
  • the compound (C1) is subjected to R C 1 -X 1 (X 1 is a halogen or a suitable leaving group in the presence of a base such as KHCO 3 in a solvent such as toluene, chloroform, dichloromethane, tetrahydrofuran or DMF.
  • the compound (C2) can be obtained by reacting at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
  • Second Step Compound (C2) is mixed with a reducing agent such as LiBH 4 in a solvent such as tetrahydrofuran, methanol, ethanol, water and the like at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. for 0.1 hour to 48 hours.
  • Compound (C3) can be obtained by reacting preferably for 12 to 24 hours.
  • Compound (C3) is sulfamoyl halide and -80 ° C. to 50 ° C., preferably -20 ° C. to 20 ° C. in a solvent such as tetrahydrofuran, methanol, ethanol, water and the like for 0.1 hour to 24 hours, preferably Can be reacted for 0.5 to 12 hours to give compound (C4).
  • a solvent such as tetrahydrofuran, methanol, ethanol, water and the like for 0.1 hour to 24 hours, preferably Can be reacted for 0.5 to 12 hours to give compound (C4).
  • a mixture of compounds (C5-d) and (C5-u) can be obtained by reacting preferably at 20 ° C. to 100 ° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • Compound (C7) can be obtained by reacting at 50 ° C., preferably ⁇ 20 ° C. to 20 ° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
  • First Step Compound (C7) is mixed with a metal halide such as HgBr 2 in a solvent such as ethyl acetate, toluene, chloroform, dichloromethane, tetrahydrofuran, acetonitrile and the like, in the presence of a base, at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C.
  • the compound (C8) can be obtained by reacting at 0.1 to 24 ° C. for 0.1 to 24 hours, preferably 0.5 to 12 hours.
  • Second Step Compound (C8) is mixed with a quaternary ammonium salt represented by Bu 4 NOPg 5 in a solvent such as toluene, chloroform, tetrahydrofuran, acetonitrile or the like under acidic conditions at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C.
  • Compound (C9) can be obtained by reacting at -20 ° C for 0.1-24 hours, preferably 0.5-12 hours.
  • the compound (D1) is heated at 0 ° C. to 150 ° C. under hydrogenation reaction conditions using, for example, Pd carbon as a catalyst in a solvent such as tetrahydrofuran, methanol, ethanol, water or a mixed solvent such as ethanol-water.
  • Compound (D2) can be obtained by reacting preferably at 20 ° C. to 100 ° C. for 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
  • X 2 represents halogen or a suitable leaving group
  • a metal halide such as HgBr 2
  • a solvent such as ethyl acetate, toluene, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, etc.
  • Compound (D3) can be obtained by reacting for 1 to 24 hours, preferably 0.5 to 12 hours.
  • the compound (E1) is added at 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C., for 0.5 hours to 24 hours, preferably 1 hour to Compound (I) can be obtained by reacting for 12 hours.
  • the aldehyde used for the synthesis of the compound of the present invention can be prepared by the following method.
  • a solvent such as ethyl acetate, toluene, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, sulfur trioxide / pyridine complex, sulfur trioxide / triethylamine complex, Dess-Martin periodinane (Des-Martin
  • R 1 ′ represents one having two carbon chains shorter than R 1
  • Pg 8 represents a carboxy protecting group.
  • the compound (F5) can be obtained by converting the compound (F3) into an ester of the compound (F4) and further reducing it.
  • the compound (F6) is reduced to 0 ° C. to 150 ° C. under reducing conditions using a borane / dimethyl sulfide complex, borane / tetrahydrofuran complex, borane / triethylamine complex in a solvent such as ethyl acetate, toluene, chloroform, dichloromethane, tetrahydrofuran, acetonitrile and the like.
  • the compound (F2) can be obtained by reacting at 20 ° C. to 100 ° C. for 0.1 hour to 24 hours, preferably 0.5 hour to 12 hours.
  • R 1 includes C6-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or a group which is aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. It is done.
  • R 1 is preferably a group which is aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. Can be mentioned.
  • R 1 is more preferably a group that is C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or aryl substituted with C2-C10 alkenyl.
  • R 1 is most preferably a group which is C11-C20 alkyl or C9-C20 alkenyl.
  • R 1 includes substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, or C1-C20 Examples include groups that are aryl substituted with alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl.
  • R 1 is preferably substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, substituted or unsubstituted C3-C20 alkynyl or C1-C20 Examples include groups that are aryl substituted with alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl.
  • R 1 is more preferably substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, or C1-C10 alkyl, C2-C10 alkenyl or substituted And groups that are aryl substituted with aryl.
  • R 1 is most preferably a group which is a substituted C1-C10 alkyl or an aryl substituted with a substituted aryl.
  • R 2 includes a group which is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl.
  • R 2 is preferably a group that is hydrogen, lower alkyl, carbocyclic group, or carbocyclic alkyl.
  • R 2 is more preferably hydrogen.
  • R 3 and R 4 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted And a group that is a carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 3 and R 4 are preferably each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, or substituted or non-substituted A group which is a substituted heterocyclic group.
  • R 5 includes a group that is hydrogen or a substituted or unsubstituted lower alkyl.
  • R 5 is preferably hydrogen.
  • R 6 is hydrogen, substituted or unsubstituted lower alkyl, —C ( ⁇ O) —NH—CR 7 R 8 —CO ( ⁇ O) R 9 , or —C ( ⁇ O) —.
  • a group which is OR 10 is mentioned.
  • R 6 is preferably a group that is hydrogen, —C ( ⁇ O) —NH—CR 7 R 8 —CO ( ⁇ O) R 9 , or —C ( ⁇ O) —OR 10. It is done.
  • R 7 and R 8 are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, substituted or unsubstituted And a group that is a carbocyclic group or a substituted or unsubstituted heterocyclic group.
  • R 7 and R 8 are preferably each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted carbocyclic alkyl, substituted or unsubstituted heterocyclic alkyl, or substituted or non-substituted A group which is a substituted heterocyclic group.
  • R 9 includes hydrogen or a group that is lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl.
  • R 9 is preferably hydrogen.
  • R 10 includes a carboxy protecting group.
  • R 1 is any one of (A1-1) to (A1-8); R 2 is any one of (A2-1) to (A2-3); R 3 is any one of (A3-1) to (A3-2); R 4 is any one of (A3-1) to (A3-2); R 5 is any one of (A5-1) to (A5-2); R 6 is any one of (A6-1) to (A6-2), R 7 is any one of (A7-1) to (A7-2); R 8 is any one of (A7-1) to (A7-2); R 9 is any one of (A9-1) to (A9-2); A compound wherein R 10 is (A10-1).
  • R 1 is a group that is C6-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl;
  • R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl;
  • One of R 3 and R 4 is hydrogen and the other is
  • R 7 and R 8 are hydrogen and the other is —CH 2 CH (CH 3 ) 2 or
  • R 1 is substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, or C1 A group that is an aryl substituted with a C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl;
  • R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl;
  • One of R 3 and R 4 is hydrogen and the other is
  • R 6 is —C ( ⁇ O) —NH—CR 7 R 8 —CO ( ⁇ O) R 9 ;
  • One of R 7 and R 8 is hydrogen and the other is —CH 2 CH (CH 3 ) 2 or
  • R 1 is substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, or C1 A group that is an aryl substituted with a C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl;
  • R 2 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl;
  • One of R 3 and R 4 is hydrogen and the other is
  • R 6 is —C ( ⁇ O) —OR 10 ; Compounds in which R 10 is a carboxy protecting group are preferred.
  • the following embodiment may also be one preferred embodiment.
  • R 1 includes C6-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or a group that is aryl substituted with C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. It is done.
  • R 1 is preferably a group which is an aryl substituted with C11-C20 alkyl, C9-C20 alkenyl, C3-C20 alkynyl or C1-C20 alkyl, C2-C20 alkenyl or C2-C20 alkynyl. Can be mentioned.
  • R 1 is more preferably C11-C20 alkyl, C9-C20 alkenyl, or C1-C10 alkyl, or a group that is aryl substituted with C2-C10 alkenyl.
  • R 1 is most preferably a group which is C11-C20 alkyl or C9-C20 alkenyl.
  • R 1 includes substituted C1-C5 alkyl, substituted or unsubstituted C6-C20 alkyl, substituted or unsubstituted C2-C20 alkenyl, substituted or unsubstituted C2-C20 alkynyl, or C1-C20 Examples include groups that are aryl substituted with alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl.
  • R 1 is preferably substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, substituted or unsubstituted C3-C20 alkynyl or C1-C20 Examples include groups that are aryl substituted with alkyl, C2-C20 alkenyl, C2-C20 alkynyl or substituted aryl.
  • R 1 is more preferably substituted C1-C10 alkyl, substituted or unsubstituted C11-C20 alkyl, substituted or unsubstituted C9-C20 alkenyl, or C1-C10 alkyl, C2-C10 alkenyl or substituted And groups that are aryl substituted with aryl.
  • R 1 is most preferably a group which is a substituted C1-C10 alkyl or an aryl substituted with a substituted aryl.
  • R 2 includes groups that are hydrogen, lower alkyl, lower alkenyl, lower alkynyl, carbocyclic group, heterocyclic group, carbocyclic alkyl, or heterocyclic alkyl.
  • R 2 is preferably a group which is hydrogen, lower alkyl, carbocyclic group, or carbocyclic alkyl.
  • R 2 is preferably hydrogen.
  • R 3 and R 4 one of R 3 or R 4 is hydrogen, and the other is a substituent described in Table 1 below (hereinafter R 3 or R 4 represents A-1 to A-20 and To do).
  • R 7 and R 8 As R 7 and R 8 , one of R 7 or R 8 is hydrogen and the other is a substituent described in Table 2 below (hereinafter, R 7 or R 8 is B-1 to B-19 and To do).
  • R 1 is any one of (B1-1) to (B1-8);
  • R 2 is any one of (B2-1) to (B2-3),
  • R 3 and R 4 are any of (B3) (that is, one is hydrogen and the other is any one of A-1 to A-20).
  • R 7 and R 8 are any one of (B7) (that is, one is hydrogen and the other is any one of B-1 to B-19).
  • the compound of the present invention or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. In addition, these pharmaceutical preparations are used for animals and humans.
  • the compound according to the present invention is a nucleic acid antibiotic.
  • the compounds of the present invention have a broad spectrum of antibacterial activity, and various diseases caused by pathogenic bacteria in various mammals including humans, such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis It can be used for prevention or treatment of oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
  • the compound according to the present invention is particularly effective against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Staphylococcus pneumoniae (PRSP), vancomycin-resistant enterococci (VRE), vancomycin-resistant Staphylococcus aureus (VRSA) and the like. High antibacterial activity. It also exhibits antibacterial activity against gram-negative bacteria including Pseudomonas aeruginosa, Escherichia coli, Haemophilus influenzae and the like.
  • MRSA methicillin-resistant Staphylococcus aureus
  • PRSP penicillin-resistant Staphylococcus pneumoniae
  • VRE vancomycin-resistant enterococci
  • VRSA vancomycin-resistant Staphylococcus aureus
  • a compound having an inhibitory effect on MraY acts at a position upstream in the biosynthetic pathway relative to the target of ⁇ -lactam antibiotics, and therefore, bacteria having resistance to ⁇ -lactam antibiotics, such as ⁇ -lactam resistant Pseudomonas aeruginosa, are used. It is expected to be effective against bacteria.
  • the compound according to the present invention has good intracellular migration and exhibits strong antibacterial activity.
  • muraymycin is known as a compound having a long alkyl chain among the existing nucleic acid antibiotics.
  • this alkyl chain is cleaved by an enzyme such as esterase in the blood because it has an ester bond.
  • the blood concentration is expected to decrease.
  • the compound according to the present invention has resistance to an enzyme such as esterase in blood since an alkyl chain is introduced without an ester bond. From this, an improvement in in vivo activity accompanying the extension of the blood half-life is expected.
  • the compound according to the present invention has advantages such as high metabolic stability, high solubility, high oral absorption, good bioavailability, and a long half-life, and can be an excellent pharmaceutical product.
  • the dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 0.1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day. In the case of parenteral administration, it is usually 1 ⁇ g to 10 g / day, preferably 0.1 to 2 g / day.
  • the number of administration is preferably once a day or divided.
  • the administration route is preferably the most effective for treatment, and can be oral or parenteral, for example, rectal, buccal, subcutaneous, intramuscular, intravenous and the like.
  • Administration forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections, and the like.
  • Liquid preparations such as emulsions and syrups suitable for oral administration are water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, propylene glycol, oils such as sesame oil, olive oil, soybean oil And preservatives such as p-hydroxybenzoates, and flavors such as strawberry flavor and peppermint.
  • excipients such as lactose, glucose, sucrose and mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyl It can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, and a plasticizer such as glycerin.
  • Formulations suitable for parenteral administration preferably comprise sterile aqueous preparations containing the active compound that is isotonic with the blood of the recipient.
  • a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution or a mixture of salt water and a glucose solution.
  • Topical formulations are prepared by dissolving or suspending the active compound in one or more media such as mineral oil, petroleum, polyhydric alcohol and the like or other bases used in topical pharmaceutical formulations.
  • a preparation for enteral administration is prepared using a normal carrier such as cacao butter, hydrogenated fat, hydrogenated fatty carboxylic acid and the like, and is provided as a suppository.
  • the compound of the present invention is a compound having utility as a medicine.
  • it has a strong antibacterial activity because of its improved intracellular translocation, and is resistant to enzymes such as esterases in the blood, has a small clearance, or is halved. It includes points that are long enough for the period to have a medicinal effect.
  • the underline in the NMR data in the examples indicates that the peak is a part with an underline.
  • Lithium borohydride (LiBH 4 ) (3.6 g, 164 mmol) was added to an ethanol (1.5 L) solution of the obtained crude methyl ester compound and treated at 0 ° C. for 24 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 1 mol / L hydrochloric acid.
  • the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an alcohol form.
  • the catalyst was removed with amino silica gel (6 ⁇ 20, 25% ethyl acetate-hexane) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6 ⁇ 20, 0.3% methanol-chloroform), and compound (2) (3.15 g, 7.34 mmol, 32%) and compound (3) (1.57 g, 3.66 mmol, 16%) was obtained as a white solid.
  • Acetic acid (AcOH) 106 ⁇ L, 1.84 mmol
  • tetrabutylammonium acetate Bu 4 NOAc
  • ethyl acetate 15 ml
  • hydrochloric acid 15 ml
  • Example 6-1 (4S) -4- (1S-benzyloxycarbonylamino-2-hydroxy) ethyl-2-N- (2,2,2-trichloroethoxysulfonyl) iminotetrahydropyrimidine (compound (6-1) )
  • N-methylmorpholine 340 ⁇ L, 3.1 mmol
  • S tert-butyl N- (methylthiocarbonyl) valinate
  • HgBr 2 Mercury bromide
  • NaClO 2 sodium chlorite
  • NaClO sodium hypochlorite
  • the mixture was concentrated under reduced pressure.
  • the residue was purified by HPLC (YMCJ'sphere ODS M80, 4.6 ⁇ 150 mm, 0.1% TFA 23% methanol-water, 7.2 min-epi-muraymycin D2, 20.0 min-muraymycin D2), and muraymycin D2 (15) (2.6 mg, 0.0028 mmol, 52%) and epi-muraymycin D2 (16) (2.4 mg, 0.0026 mmmol, 48%) were obtained as white foam.
  • the protecting group on the guanidino group in L-Arg of compound (21) can be deprotected under acidic conditions after performing the so-called Ugi reaction described in General Synthesis Method E, Example 14 or 15.
  • acidic conditions include an approximately 80% aqueous trifluoroacetic acid solution.
  • Example 4-1 compound (4-2) (120 mg, 84%) was obtained as a colorless syrup from compound (2) (100 mg, 0.23 mmol).
  • Example 8-1 compound (7-2) (292 mg, 62%) was obtained as a white foam from compound (6-2) (450 mg, 0.827 mmol).
  • Triphosgene (740 mg, 2.5 mmol) was added to a tetrahydrofuran solution (50 mL) of (S) -valine tert-butyl ester hydrochloride (1.57 g, 7.5 mmol) and N-methylmorpholine (2.75 mL, 25.0 mmol). The mixture was stirred for 1 hour at ° C. A DMF solution (20 mL) of N- ⁇ -Boc ornithine (1.16 g, 5.0 mmol) was added dropwise with a cannula, and the reaction mixture was further stirred at room temperature for 12 hours. The reaction was stopped and the mixture was poured into 1 mol / L hydrochloric acid and extracted with AcOEt.
  • Example 6-1 compound (8-1) (42.7 mg, 0.073 mmol), compound (13) (56.9 mg, 0.073 mmol), hexadecanal (89.8 mg, 0.37 mmol), 2,4- Compound (18) (1.5 mg, 35%) and compound (19) (1.5 mg, 35%) were obtained as white foam from dimethoxybenzylamine (53.9 ⁇ L, 0.37 mmol).
  • Example 6-1 compound (8-2) (113 mg, 0.194 mmol), compound (13) (150 mg, 0.194 mmol), hexadecanal (46.6 mg, 0.194 mmol), 2,4- By reacting dimethoxybenzylamine (29.1 ⁇ L, 0.194 mmol) in ethanol (2 mL) at 50 ° C, compound (30) (33.0 mg, 17%) and compound (31) (33.0 mg, 17% ) was obtained as a white foam.
  • Example 6-1 compound (21) (32.2 mg, 0.05 mmol), compound (13) (40 mg, 0.05 mmol), hexadecanal (12.4 mg, 0.05 mmol), 2,4-dimethoxybenzyl
  • compound (32) 7.5 mg, 15%
  • compound (33) 7.5 mg, 15%
  • Example 6-1 compound (22) (56.0 mg, 0.13 mmol), compound (13) (100 mg, 0.13 mmol), hexadecanal (31.2 mg, 0.13 mmol), 2,4-dimethoxybenzyl
  • compound (34) 33.0 mg, 25%
  • compound (35) 33.0 mg, 25%
  • Example 6-1 compound (8-1) (17.4 mg, 0.03 mmol), compound (13) (23.1 mg, 0.03 mmol), compound (26) (85.0 mg, 0.30 mmol), 2,4 -By reacting -dimethoxybenzylamine (45.0 ⁇ L, 0.3 mmol) in toluene (2 mL) at 50 ° C, compound (38) (5.1 mg, 16%) and compound (39) (5.1 mg, 16 %) was obtained as a white foam.
  • Example 6-1 compound (8-1) (17.4 mg, 0.03 mmol), compound (13) (23.1 mg, 0.03 mmol), compound (28) (84.6 mg, 0.30 mmol), 2,4 -Dimethoxybenzylamine (45.0 ⁇ L, 0.3 mmol) was reacted in toluene (2 mL) at 50 ° C to give compound (40) (4.8 mg, 15%) and compound (41) (4.8 mg, 15 %) Was obtained as a white foam.
  • Example 6-1 compound (8-1) (17.4 mg, 0.03 mmol), compound (13) (23.1 mg, 0.03 mmol), compound (29) (85.2 mg, 0.30 mmol), 2,4 -Dimethoxybenzylamine (45.0 ⁇ L, 0.3 mmol) was reacted in toluene (2 mL) at 50 ° C to give compound (42) (4.8 mg, 14%) and compound (43) (4.8 mg, 14 %) Was obtained as a white foam.
  • Test Example 1 In vitro measurement of antibacterial activity (test method) The minimum growth inhibitory concentration (MIC: ⁇ g / ml) was determined by a micro liquid dilution method in accordance with NCCLS.
  • the bacterial species used are as follows. (1) Staphylococcus aureus (2) Streptococcus pneumoniae (3) Enterococcus faecalis (4) Enterococcus faecium Brain Heart Infusion Agar was used for preculture of the bacteria used for MIC measurement, and blood agar (horse) was used for S. pneumoniae.
  • Muller Hinton Broth was used as a medium for MIC measurement.
  • the amount of inoculum for MIC measurement was 5 ⁇ 10 5 CFU / ml, and was determined after culturing at 35 ° C. for 20 hours.
  • the test results are shown in Table 3 below.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 10mg Lactose 90mg Microcrystalline cellulose 30mg CMC-Na 15mg Magnesium stearate 5mg 150mg
  • the compound represented by the formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
  • Formulation Example 4 The following components were heated and mixed and then sterilized to give an injection.
  • the compound according to the present invention has advantages such as high metabolic stability, high solubility, high oral absorption, good bioavailability, and a long half-life, and can be an excellent pharmaceutical product.

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Abstract

La présente invention concerne un composé ayant une activité antibactérienne et un de ses dérivés, de manière davantage préférée un composé de nucléoside antibactérien qui peut inhiber l'activité du MraY, afin d'exercer une activité antibactérienne et un dérivé du composé de nucléoside, en particulier un nouveau dérivé de Muraymycine qui est un inhibiteur du MraY. L'invention concerne spécifiquement un nouveau dérivé de Muraymycine ou un de ses sels pharmaceutiquement acceptables. Le composé présente de bonnes propriétés de pénétration intracellulaire et une activité antibactérienne puissante. Le composé présente également une résistance contre les enzymes telles que les estérases présentes dans le sang. Un mode de réalisation préféré du composé présente une activité inhibitrice du MraY. Le mode de réalisation préféré du composé est efficace contre les bactéries résistantes telles que les VRE et MRSA.
PCT/JP2010/052902 2009-02-25 2010-02-24 Antibiotique de type nucléoside WO2010098365A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085867A1 (fr) * 2001-04-25 2002-10-31 Wyeth Holdings Corporation Antibiotiques aa-896
WO2002085310A2 (fr) * 2001-04-25 2002-10-31 Wyeth Holdings Corporation Antibiotiques aa-896

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085867A1 (fr) * 2001-04-25 2002-10-31 Wyeth Holdings Corporation Antibiotiques aa-896
WO2002085310A2 (fr) * 2001-04-25 2002-10-31 Wyeth Holdings Corporation Antibiotiques aa-896

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LIN YANG-I ET AL.: "Muraymycins, novel peptidoglycan biosynthesis inhibitors: semisynthesis and SAR of Their derivatives", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 17, 2002, pages 2341 - 2344 *

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