WO2012176909A1 - Dérivé de tripropeptine ou sel pharmacologiquement acceptable de celui-ci, et agent antibactérien - Google Patents

Dérivé de tripropeptine ou sel pharmacologiquement acceptable de celui-ci, et agent antibactérien Download PDF

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WO2012176909A1
WO2012176909A1 PCT/JP2012/066077 JP2012066077W WO2012176909A1 WO 2012176909 A1 WO2012176909 A1 WO 2012176909A1 JP 2012066077 W JP2012066077 W JP 2012066077W WO 2012176909 A1 WO2012176909 A1 WO 2012176909A1
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group
compound
general formula
carbon atoms
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世平 廣沢
高橋　良昭
秀樹 橋爪
良彦 古林
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公益財団法人微生物化学研究会
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a tripropeptin derivative or a pharmacologically acceptable salt thereof, and an antibacterial agent.
  • Methicillin-resistant Staphylococcus aureus is not only resistant to methicillin but also resistant to many antibiotics such as aminoglycosides, tetracyclines, beta-lactams, quinolones, and macrolides. Vancomycin was useful as an antibacterial agent against methicillin-resistant Staphylococcus aureus.
  • tripropeptins having a specific structure exhibiting antibacterial activity against Gram-positive bacteria including multidrug-resistant bacteria (such as methicillin-resistant Staphylococcus aureus) have been proposed (see Patent Document 1).
  • this proposed technique has antibacterial activity but is not sufficiently soluble in water, and therefore has a problem in formulation design and evaluation as a single unit.
  • the present invention is a tripropeptin derivative having excellent antibacterial activity against bacteria, particularly multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and having excellent solubility in water, or a pharmacologically acceptable product thereof.
  • an antibacterial agent containing the tripropeptin derivative or a pharmacologically acceptable salt thereof is an antibacterial agent containing the tripropeptin derivative or a pharmacologically acceptable salt thereof.
  • R 1 represents an organic group having 1 to 20 carbon atoms.
  • the above-mentioned problems can be solved and the object can be achieved, and an excellent antibacterial property against bacteria, particularly multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.
  • a tripropeptin derivative or a pharmacologically acceptable salt thereof that exhibits activity and is excellent in solubility in water and an antibacterial agent containing the tripropeptin derivative or a pharmacologically acceptable salt thereof can be provided.
  • tripropeptin derivative or a pharmacologically acceptable salt thereof The tripropeptin derivative of the present invention or a pharmacologically acceptable salt thereof may be abbreviated as a tripropeptin derivative represented by either the following general formula (1) or the following general formula (2) (hereinafter referred to as “tripropeptin derivative”). Or a pharmacologically acceptable salt thereof.
  • R 1 represents an organic group having 1 to 20 carbon atoms.
  • R 2 represents an organic group having 1 to 20 carbon atoms.
  • the R 1 in the general formula (1) is not particularly limited as long as it is an organic group having 1 to 20 carbon atoms, and can be appropriately selected according to the purpose.
  • a group represented by the general formula (1-1) and a group represented by the following general formula (1-2) are preferable.
  • R 10 , R 11 , and R 12 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or a substituent having 1 to 8 carbon atoms.
  • R 13 and R 14 each independently represents a hydrogen atom or an optionally substituted alkyl group having 1 to 8 carbon atoms
  • an optionally substituted carbon atom having 1 to 8 carbon atoms Represents any of 12 nitrogen-containing heterocyclic groups
  • R 16 and R 17 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • Examples of the alkyl group having 1 to 8 carbon atoms in R 10 , R 11 , R 12 , R 13 , and R 14 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and isobutyl. Group, tert-butyl group, pentyl group, hexyl group and the like.
  • Examples of the alkoxy group having 1 to 8 carbon atoms in R 10 , R 11 , and R 12 include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, and a tert-butoxy group. Is mentioned.
  • Examples of the alkylthio group having 1 to 8 carbon atoms in the R 10 , the R 11 , and the R 12 include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, and a tert-butylthio group. Is mentioned.
  • substituent for the alkylthio group having 1 to 8 include an amino group, a halogen atom, and a hydroxyl group.
  • the halogen atom include a fluorine atom and a chlorine atom.
  • Examples of the halogen atom in R 10 , R 11 , and R 12 include a fluorine atom and a chlorine atom.
  • Examples of the NR 13 R 14 include an amino group (—NH 2 ), a dimethylamino group [—N (CH 3 ) 2 ], a diethylamino group [—N (C 2 H 5 ) 2 ], and the like.
  • Examples of the nitrogen-containing heterocyclic group having 1 to 12 carbon atoms that may have the substituent in R 10 , R 11 , and R 12 include the following structural formulas (1-1) to (1 And the group represented by -5).
  • Examples of the alkyl group having 1 to 6 carbon atoms in R 16 and R 17 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • the R 2 in the general formula (2) is not particularly limited as long as it is an organic group having 1 to 20 carbon atoms, and can be appropriately selected according to the purpose. It is preferably any one of a group represented by the general formula (2-1), a group represented by the following general formula (2-2), and a group represented by the following structural formula (2-1).
  • R 20 and R 21 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which may have a substituent.
  • R 22 is a methylene group, an oxygen atom, a sulfur atom, NR 23 (the R 23 is a hydrogen atom, and optionally has 1 to 1 carbon atoms) 8), and CH—NR 24 R 25 (wherein R 24 and R 25 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). R 24 and R 25 may be bonded to each other to form a ring structure.
  • Examples of the alkyl group having 1 to 8 carbon atoms that may have a substituent in R 20 , R 21 , and R 23 include a methyl group, an ethyl group, Examples include propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group and the like.
  • Examples of the substituent of the alkyl group having 1 to 8 carbon atoms that may have a substituent include an amino group, a halogen atom, a hydroxyl group, an alkoxy group, and a vinyl group.
  • Examples of the amino group include a dimethylamino group, a diethylamino group, and a diisopropylamino group.
  • Examples of the alkoxy group include an alkoxy group having 1 to 6 carbon atoms. Examples of the alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, and a tert-butoxy group.
  • Examples of the NR 20 R 21 include an amino group having 0 to 18 carbon atoms.
  • Examples of the amino group having 0 to 18 carbon atoms include amino group (—NH 2 ), dimethylamino group [—N (CH 3 ) 2 ], diethylamino group [—N (C 2 H 5 ) 2 ], dibutyl Amino group [—N (C 4 H 9 ) 2 ], ethylmethylamino group [—N (CH 3 ) (C 2 H 5 )], bis [2- (N, N-diisopropylamino) ethyl] amino group [ —N [CH 2 CH 2 N (CH (CH 3 ) 2 ) 2 ] 2 ], —N (CH 3 ) (CH 2 CH 2 N (CH 3 ) 2 ), —N (CH 3 ) (CH 2 CH 2 OCH 3 ), —N (CH 3 ) (CH 2 CH ⁇ CH 2 ), and the like.
  • Examples of the NR 23 in the R 22 include NCH 3 , NC 2 H 5 , NCH 2 CH 2 N (CH 3 ) 2 , NCH 2 CH 2 N (C 2 H 5 ) 2 and the like.
  • Examples of the alkyl group having 1 to 6 carbon atoms in R 24 and R 25 include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • Examples of the tripropeptin derivative represented by the general formula (1) include compounds 1 to 10 and compounds 16 to 20 represented by the following structural formulas.
  • Examples of the tripropeptin derivative represented by the general formula (2) include compounds 11 to 15 and compounds 21 to 31 represented by the following structural formulas.
  • “Me” represents a methyl group.
  • “Et” represents an ethyl group.
  • “Bu” represents an n-butyl group.
  • the pharmacologically acceptable salt of the tripropeptin derivative is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a salt with an organic base, a salt with a metal, an addition salt with an organic acid examples include addition salts with inorganic acids.
  • Examples of the salt with the organic base include a quaternary ammonium salt.
  • Examples of the salt with the metal include a salt with an alkali metal such as a sodium salt.
  • As an addition salt with the said organic acid, acetate etc. are mentioned, for example.
  • As an addition salt with the said inorganic acid, hydrochloride etc. are mentioned, for example.
  • a method for producing the tripropeptin derivative is not particularly limited and may be appropriately selected depending on the intended purpose. However, there is a method for producing a tripropeptin C by reacting a compound with tripropeptin C (hereinafter sometimes abbreviated as “TPPC”). preferable.
  • TPPC tripropeptin C
  • TPPC Tripropeptin C
  • the TPPC is a compound represented by the following structural formula (3), and is produced, for example, from the Lysobacter sp. BMK333-48F3 strain, which is a strain belonging to the genus Lysobacter, as described in WO 01/074850.
  • Lysobacter sp. BMK333-48F3 strain is the National Institute of Advanced Industrial Science and Technology, Biotechnology Institute of Technology (currently Japan Institute for Product Evaluation Technology, Patent Microorganism Depositary Center, East of Tsukuba City, Ibaraki, Japan 305-8586, Japan. 1-chome 1-address 1 center 6) was entrusted as FERM P-17741 on February 22, 2000, and transferred on March 2, 2001 under the terms of the Budapest Treaty. It is entrusted to the same office with an accession number.
  • the TPPC is produced as a main component in the production from the strain of Lysobacter sp. BMK333-48F3, which belongs to the genus Lysobacter (H. Hashizumi et al., THE JOURNAL OF ANTIBIOTICS, VOL. 54, NO. 12, DEC. 2001 (1054-1059)).
  • TPPC shows the best therapeutic effect among a group of tripropeptins in a mouse S. aureus systemic infection model (H. Hashizumi et al., THE JOURNAL OF ANTIBIOTICS, VOL. 57, NO. 6, JUNE 2004). 394-399)).
  • the TPPC can also be selectively produced by adding leucine to the medium using a biosynthetic pathway (H. Hashizumi et al., Issue in Honor of Prof. Atta-ur-Rahman, ARKIVOC). 2007 (vii) 241-253).
  • the tripropeptin derivative represented by the general formula (1) includes, for example, the TPPC and ⁇ -ketoester (R 15 —CO—CH 2 —COOR; R 15 is the same group as R 1 in the general formula (1), Alternatively, R 1 represents a group protected with a protecting group, and R represents an alkyl group such as a methyl group or an ethyl group, for example.
  • R 15 represents a group protected with a protecting group
  • R represents an alkyl group such as a methyl group or an ethyl group, for example.
  • a pyrimidone structure is formed by a cyclization reaction between the guanidyl group and the ⁇ -ketoester in the TPPC, thereby being represented by the general formula (1).
  • Tripropeptin derivatives can be produced.
  • “Me” represents a methyl group.
  • the reaction in the reaction formula (1) is not particularly limited as long as it can generate a pyrimidone structure by a cyclization reaction between a guanidyl group and a ⁇ -ketoester, and can be appropriately selected according to the purpose.
  • a cyclization reaction between a guanidyl group and a ⁇ -ketoester for example, H. et al. Bredereck et al. , Chem. Ber. , 97, 61-73, 1964.
  • the reaction temperature in the reaction formula (1) is not particularly limited and may be appropriately selected depending on the intended purpose. It is preferably 40 ° C. to 100 ° C., more preferably 50 ° C. to 80 ° C.
  • the reaction time in the reaction formula (1) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1 hour to 100 hours, and more preferably 20 hours to 90 hours.
  • the solvent used in the reaction formula (1) is not particularly limited and may be appropriately selected depending on the intended purpose, but pyridine is preferable.
  • tripropeptin derivative represented by the general formula (2) is, for example, the TPPC and N, N-dialkylformamide dialkylacetal [R 20 R 21 N—CH (OR ′)] as shown in the following reaction formula (2). 2 ] can be reacted.
  • “Me” represents a methyl group.
  • R ′ represents an alkyl group having 1 to 8 carbon atoms. Examples of R ′ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • the reaction temperature in the reaction formula (2) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 40 ° C to 100 ° C.
  • the reaction time in the reaction formula (2) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1 hour to 10 hours.
  • the solvent used in the reaction formula (2) is not particularly limited and may be appropriately selected depending on the intended purpose, but pyridine is preferable.
  • reaction in the reaction formula (2) is, for example, H. Bredereck et al. , Chem. Ber. , 97, 61-73, 1964.
  • reaction formula (3) the product obtained by the reaction formula (2) is reacted with a nitrogen-containing heterocyclic compound or the like so that the R 2 can be represented by the general formula ( A tripropeptin derivative represented by the general formula (2), which is a group represented by 2-2), can be produced.
  • R 2 can be represented by the general formula ( A tripropeptin derivative represented by the general formula (2), which is a group represented by 2-2)
  • “Me” represents a methyl group.
  • R 22 in the nitrogen-containing heterocyclic compound and nitrogen-containing heterocyclic group in the reaction formula (3) is the same as R 22 in the general formula (2-2).
  • both R 20 and R 21 are preferably methyl groups.
  • the reaction temperature in the reaction formula (3) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10 ° C to 60 ° C.
  • the reaction time in the reaction formula (3) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 1 hour to 20 hours.
  • the solvent used in the reaction formula (3) is not particularly limited and may be appropriately selected depending on the intended purpose, but pyridine is preferable.
  • the tripropeptin derivative represented by the general formula (2) is obtained by reacting the TPPC with Me 2 N—CH (OMe) 2 as shown in the following reaction formula (4), for example. Via A, it can be further produced by reacting with HR 2 (R 2 is the same as R 2 in the general formula (2)).
  • R 2 is the same as R 2 in the general formula (2).
  • the synthesis according to the reaction formula (4) may be superior in yield compared to the synthesis according to the reaction formula (2) and the synthesis according to the reaction formula (3).
  • “Me” represents a methyl group.
  • “Me” represents a methyl group.
  • the reaction temperature in the reaction formula (4) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 10 ° C. to 60 ° C. through two stages.
  • the reaction time in the reaction formula (4) is not particularly limited and may be appropriately selected depending on the intended purpose, but is preferably 5 hours to 40 hours through two steps.
  • pyridine is described as the solvent, but the solvent in the reaction formula (4) is not limited to pyridine.
  • the antibacterial agent of the present invention contains at least the tripropeptin derivative of the present invention or a pharmacologically acceptable salt thereof, and further contains other components as necessary.
  • the antibacterial action of the “antibacterial agent”, that is, the microorganism that is the target of the action of suppressing the generation, growth, and proliferation of microorganisms includes bacteria.
  • Gram positive bacteria containing a drug resistant microbe are preferable.
  • the bacterium include methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-sensitive Staphylococcus aureus Enterococcus (VRE), vancomycin-sensitive enterococcus (VSE), pneumococci, hemolytic streptococci and the like.
  • the dosage form and administration method of the antibacterial agent are not particularly limited, and can be appropriately selected according to the administration subject such as mammals including humans, animals such as poultry and fish. When administered to humans, it can be administered orally or parenterally, and it is for oral use such as tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, etc. Formulations; injections; external preparations such as solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays; suppositories and other desired dosage forms.
  • a pharmaceutical carrier that is pharmaceutically acceptable, for example, a filler, a bulking agent, a binder, a disintegrant, a dissolution accelerator, a wetting agent, an excipient, a lubricant, etc.
  • a pharmaceutical carrier that is pharmaceutically acceptable, for example, a filler, a bulking agent, a binder, a disintegrant, a dissolution accelerator, a wetting agent, an excipient, a lubricant, etc.
  • stabilizers, preservatives, isotonic agents, solubilizing agents and the like can be blended in the preparation.
  • the injection solution can be stored in a storage container and then solidified by lyophilization to provide an injection preparation prepared at the time of use.
  • one dose can be stored in one container, and multiple doses can be stored in one container.
  • a suspending agent, an emulsifier and the like can be blended.
  • the administration method is, for example, a method of oral administration directly or mixed or dissolved in feed or drinking water, injection, intrarectal administration And parenteral administration such as intramammary administration, drug bath (used in the case of fish), and the like.
  • parenteral administration such as intramammary administration, drug bath (used in the case of fish), and the like.
  • powders, fine granules, soluble powders, syrups, solutions, injections, suppositories, breast injections and the like can be obtained.
  • Tripropeptin C (TPPC) was produced according to the method described in WO 01/074850. Details are as follows.
  • Lysobacter sp. BMK333-48F3 strain (FERM BP-7477) was added to agar slant medium [meat extract agar medium; polypeptone (manufactured by Wako Pure Chemical Industries, Ltd.) 1% by mass, meat extract (manufactured by Kyokuto Pharmaceutical Co., Ltd.) 1% by mass, Sodium chloride (Wako Pure Chemical Industries, Ltd.) 0.2 mass% and agar (Wako Pure Chemical Industries, Ltd.) 1.4 mass% were dissolved in distilled water and then the pH was adjusted to 7.0. 48 hours at 27 ° C).
  • the culture broth thus obtained was centrifuged to separate it into a culture filtrate and cells. After the cells were extracted with 10 L of methanol, the extract was concentrated under reduced pressure. The obtained concentrated solution was combined with the culture filtrate, and 50 L of this mixed solution was mixed with an aromatic synthetic adsorbent Diaion HP-20 (Mitsubishi Chemical Corporation) column (6 L), which is a porous polystyrene-divinylbenzene copolymer. ).
  • the column was sequentially eluted with 18 L each of distilled water, 50% by mass methanol water, and 65% by mass acetone water.
  • the eluate of 65% by mass acetone, which is the active fraction, was concentrated to dryness under reduced pressure, thereby obtaining 30 g of a solid extract containing tripropeptins.
  • the solid crude product containing tripropeptins thus obtained was placed on a silica gel (Merck) column (1,500 mL), and chloroform: methanol: water (10: 5: 1 (volume ratio)) (4 , 500 mL) and butanol: methanol: water (4: 1: 2 (volume ratio)) (4,500 mL).
  • the active fraction of the eluate was collected to obtain 10.8 g of a crude product containing tripropeptins. This was dissolved in 50% by mass methanol water and adsorbed on an aromatic synthetic adsorbent Diaion CHP20P (Mitsubishi Chemical Corporation) column (250 mL), 20% by mass acetone water, 30% by mass acetone water, 35% by mass. Elution was successively carried out with acetone water, 40 mass% acetone water, 45 mass% acetone water, 50 mass% acetone water, 55 mass% acetone water, and 60 mass% acetone water (750 mL each).
  • the 45 mass% acetone water elution fraction and the 50 mass% acetone water elution fraction were concentrated to obtain 1.0 g of tripropeptin C.
  • ethyl 4-chloro-3-oxobutyrate (Tokyo Kasei Kogyo Co., Ltd.) 1.10 g / toluene 2.2 mL solution was added dropwise so as to keep the liquid temperature at ⁇ 2 ° C. or lower, and the mixture was allowed to react overnight. It was. Acetic acid (0.42 mL) was added under ice cooling, and the mixture was concentrated under reduced pressure. 46 mL of toluene was added, and the mixture was washed with 25 mL of saturated aqueous sodium bicarbonate. The aqueous layer was extracted 3 times with 25 mL of chloroform, and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure.
  • the target compound was obtained as a brown liquid (1.16 g, 68% yield).
  • Example 1 ⁇ Synthesis of Compound 1> Compound 1 represented by the following structural formula was synthesized according to the following reaction formula. 138 mg of tripropeptin C (TPPC) is dissolved in 5 mL of pyridine, and 129 ⁇ L of methyl acetoacetate (methyl 3-oxobutanoate, manufactured by SIGMA-ALDRICH Co., Ltd.) and 82.8 mg of potassium carbonate (potassium carbonate) are added thereto. The mixture was reacted at 60 ° C. for 20 hours under a nitrogen stream. After the reaction, the mixture was centrifuged, and the lysate was concentrated under reduced pressure.
  • TPPC tripropeptin C
  • 129 ⁇ L of methyl acetoacetate methyl 3-oxobutanoate, manufactured by SIGMA-ALDRICH Co., Ltd.
  • potassium carbonate potassium carbonate
  • Example 2 ⁇ Synthesis of Compound 2> Compound 2 represented by the following structural formula was synthesized according to the following reaction formula. 115 mg of TPPC was dissolved in 2 mL of pyridine, and 276 mg of ethyl 3-oxo-4,4,4-trifluorobutyrate (ethyl 3-oxo-4,4,4-trifluorobutanoate, manufactured by SIGMA-ALDRICH) and potassium carbonate 138 mg was added and reacted at 70 ° C. for 70 hours under a nitrogen stream. After the reaction, the mixture was centrifuged, and the lysate was concentrated under reduced pressure.
  • ethyl 3-oxo-4,4,4-trifluorobutyrate ethyl 3-oxo-4,4,4-trifluorobutanoate, manufactured by SIGMA-ALDRICH
  • Example 4 ⁇ Synthesis of Compound 4> Compound 4 represented by the following structural formula was synthesized according to the following reaction formula. TPPC (173 mg) was dissolved in pyridine (5 mL), and this was mixed with ethyl 4- (tert-butoxycarbonylamino) -3-oxobutyrate (Ethyl 4- (tert-butoxycarbonyl) -3-oxobutanoate, A. Nudelman et al., Tetrahedron, 60). , 1731-1748, 2004.) 147 mg and 62 mg of potassium carbonate were added, and the mixture was reacted at 60 ° C. for 80 hours under a nitrogen stream.
  • TPPC TPPC (173 mg) was dissolved in pyridine (5 mL), and this was mixed with ethyl 4- (tert-butoxycarbonylamino) -3-oxobutyrate (Ethyl 4- (tert-butoxycarbonyl) -3-oxobut
  • Example 9 ⁇ Synthesis of Compound 9> Compound 9 represented by the following structural formula was synthesized according to the following reaction formula. 290 mg of TPPC was dissolved in 8 mL of pyridine, and the ethyl 4- [4- (dimethylamino) methyl-1 H- 1,2,3-triazol-1-yl] -3-oxobutyrate synthesized in Production Example 2 was added thereto. (Ethyl 4- [4- (dimethylamino) methyl-1 H- 1,2,3-triazol-1-yl] -3-oxobutanoate) (635 mg) and potassium carbonate (200 mg) were added, and the mixture was reacted at 60 ° C. under a nitrogen stream. It was.
  • Example 11-2 ⁇ Synthesis of Compound 11>
  • Compound 11 represented by the following structural formula was synthesized according to the following reaction formula. 267 mg of TPPC was dissolved in 2.3 mL of pyridine, and 110 mg of N, N-dimethylformamide dimethylacetal (N, N-dimethylformamide dimethylacetal, manufactured by Tokyo Chemical Industry Co., Ltd.) was added thereto and reacted at room temperature under a nitrogen stream. After 3 hours, 28 mg of N, N-dimethylformamide dimethylacetal was added, and the mixture was further reacted for 2 hours.
  • N, N-dimethylformamide dimethylacetal manufactured by Tokyo Chemical Industry Co., Ltd.
  • Example 12 ⁇ Synthesis of Compound 12> Compound 12 represented by the following structural formula was synthesized according to the following reaction formula.
  • Example 13 ⁇ Synthesis of Compound 13> Compound 13 represented by the following structural formula was synthesized according to the following reaction formula.
  • Example 14 ⁇ Synthesis of Compound 14> Compound 14 represented by the following structural formula was synthesized according to the following reaction formula.
  • Compound 11 (142 mg) obtained in Example 11-1 was dissolved in 1.5 mL of pyridine, and 1- [2- (dimethylamino) ethyl] piperazine (1- [2- (dimethylamino) ethyl] piperazine, 222 mg (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the mixture was reacted at room temperature for 20 hours under a nitrogen stream.
  • Example 15 ⁇ Synthesis of Compound 15> Compound 15 represented by the following structural formula was synthesized according to the following reaction formula.
  • Compound 11 (100 mg) obtained in Example 11-1 was dissolved in 1 mL of pyridine, and N, N, N ′′, N ′′ -tetraisopropyldiethylenetriamine (N, N, N ′′, N ′′ -tetraisopropylethyleneethylenetrimine, Tokyo, Japan) (Made by Kasei Kogyo Co., Ltd.) 261 mg was added, and it was made to react at 100 degreeC under nitrogen stream for 48 hours.
  • TPPC 100 mg of TPPC was dissolved in 0.87 mL of pyridine, and 42 mg of N, N-dimethylformamide dimethyl acetal was added thereto and reacted at room temperature under a nitrogen stream. After 3 hours, 10 mg of N, N-dimethylformamide dimethylacetal was added, and the mixture was further reacted for 2 hours. After the reaction, azeotropy with toluene was performed, and the resulting colorless solid was dissolved in 1.8 mL of pyridine. To this, 138 mg of dibutylamine (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred at room temperature while stirring under a nitrogen stream. For 29 hours.
  • dibutylamine manufactured by Tokyo Chemical Industry Co., Ltd.
  • Example 30 ⁇ Synthesis of Compound 30> According to the following reaction formula, compound 30 represented by the following structural formula was synthesized. 100 mg of TPPC was dissolved in 0.87 mL of pyridine, and 42 mg of N, N-dimethylformamide dimethyl acetal was added thereto and reacted at room temperature under a nitrogen stream. After 3 hours, 10 mg of N, N-dimethylformamide dimethylacetal was added, and the mixture was further reacted for 2 hours.
  • Water solubility was measured by the following two methods (A: visual method, B: HPLC method). The results are shown in Table 1-1 and Table 1-2.
  • ⁇ A Visual method >> Distilled water (100 ⁇ L) was added to the measurement sample (1 mg), and whether or not dissolution was possible was visually confirmed after stirring. At this time, the solubility when a clear solution was obtained was defined as “> 10 mg / mL”. For TPPC, repeat the process of visually checking whether or not dissolution is possible after adding TPPC to distilled water (2 mL) slightly and stirring, so that the solubility can be determined from the amount immediately before saturation (turbidity or particles can be confirmed). Asked.
  • ⁇ B HPLC method >> Column: Shiseido, ODS, UG120, 4.6 mm ⁇ 150 mm, 2 ⁇ M Flow rate: 1 mL / min Column oven: 50 ° C
  • Mobile phase The concentration was varied linearly from 0 minutes (62 volume% 5 mM aqueous ammonium carbonate / 38 volume% acetonitrile) to 10 minutes (30 volume% 5 mM aqueous ammonium carbonate / 70 volume% acetonitrile).
  • Detection 210nm A sample obtained by completely dissolving a measurement sample with DMSO (dimethyl sulfoxide) was used as a standard solution.
  • a calibration curve of concentration / peak area was prepared. Saline (0.05 mL) is added to the measurement sample (2 mg), this solution is centrifuged (3,000 rpm ⁇ 10 min, 25 ° C.), and the resulting supernatant is subjected to HPLC (high performance liquid chromatography) under the above conditions. The concentration was determined from the analytical curve, and the maximum solubility of the measurement sample in physiological saline was determined. Since TPPC was not dissolved in physiological saline, distilled water was used instead of physiological saline.
  • ⁇ Test Example 1 >> Regarding the TPPC and the compound 1 obtained in Example 1, the minimum inhibitory concentration (MIC, ⁇ g / mL) for the strains shown in Table 2-1 and Table 2-2 was determined based on the Mueller It measured by the multiple dilution method on the Hinton agar medium (Difco). The results are shown in Table 2-1 and Table 2-2.
  • the VSE (2 strains) in Table 2-4 is the Ent. faecalis JCM5803 (VSE) and Ent. faecium is a JCM5804 (VSE).
  • the VRE (4 strains) in Table 2-4 are the Ent. faecalis NCTC 12201, 12203 (VRE) and Ent. faecium NCTC 12202, 12204 (VRE).
  • the compound 1 of the present invention S. aureus FDA 209P strain and S. aureus respect aureus Smith strain, was confirmed to exhibit the same antibacterial and TPPC and VCM.
  • the compound 1 of the present invention has S.I. aureus MSSA strains 1 to 10 and S. aureus It was confirmed that the aureus MRSA strains 1 to 10 exhibited antibacterial properties equivalent to or better than those of TPPC and VCM. From the results shown in Table 2-2, it was confirmed that Compound 1 of the present invention exhibited antibacterial properties for both VRE and VSE, and the antibacterial properties were equivalent to or better than TPPC.
  • Test Example 2 In the same manner as in Test Example 1, antibacterial properties of TPPC, compounds 1 to 10 and compounds 16 to 31 were measured against the strains described in Tables 3-1 to 3-8. The results are shown in Tables 3-1 to 3-8.
  • Test Example 3 In the same manner as in Test Example 1, antibacterial properties of TPPC and compounds 11 to 15 were measured against the strains described in Table 4. The results are shown in Table 4.
  • MSSA and MRSA used the same strains as those used in Test Example 1.
  • the dose ( ⁇ g / mouse) in Table 5-1 represents the amount of the sample in the total amount of drug solution (0.25 mL / mouse) injected into the mouse.
  • R 1 represents an organic group having 1 to 20 carbon atoms.
  • R 2 represents an organic group having 1 to 20 carbon atoms.
  • R 1 in the general formula (1) is any one of a group represented by the following general formula (1-1) and a group represented by the following general formula (1-2) Or a pharmacologically acceptable salt thereof.
  • R 10 , R 11 , and R 12 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, or a substituent having 1 to 8 carbon atoms.
  • R 16 and R 17 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • R 2 in the general formula (2) is a group represented by the following general formula (2-1), a group represented by the following general formula (2-2), and a structural formula (2-1) Or a pharmacologically acceptable salt thereof according to ⁇ 1>.
  • R 20 and R 21 each independently represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which may have a substituent.
  • R 22 is a methylene group, an oxygen atom, a sulfur atom, NR 23 (the R 23 is a hydrogen atom, and optionally has 1 to 1 carbon atoms) 8), and CH—NR 24 R 25 (wherein R 24 and R 25 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms). R 24 and R 25 may be bonded to each other to form a ring structure.
  • An antibacterial agent comprising the tripropeptin derivative according to any one of ⁇ 1> to ⁇ 3> or a pharmacologically acceptable salt thereof.
  • the compound of the present invention is excellent in water solubility, antibacterial property and infection treatment effect, and therefore, an antibacterial agent, preferably an antibacterial agent against Gram-positive bacteria, more preferably methicillin resistant Staphylococcus aureus, methicillin sensitive It can be suitably used as an antibacterial agent against Staphylococcus aureus, vancomycin-resistant enterococci and vancomycin-sensitive enterococci.
  • an antibacterial agent preferably an antibacterial agent against Gram-positive bacteria, more preferably methicillin resistant Staphylococcus aureus, methicillin sensitive It can be suitably used as an antibacterial agent against Staphylococcus aureus, vancomycin-resistant enterococci and vancomycin-sensitive enterococci.

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Abstract

L'invention concerne un dérivé de tripropeptine représenté par la formule (1) ou (2), ou un sel pharmacologiquement acceptable de celui-ci. Dans la formule générale (1), R1 représente un groupe organique ayant 1-20 atomes de carbone. Dans la formule générale (2), R2 représente un groupe organique ayant 1-20 atomes de carbone.
PCT/JP2012/066077 2011-06-24 2012-06-22 Dérivé de tripropeptine ou sel pharmacologiquement acceptable de celui-ci, et agent antibactérien WO2012176909A1 (fr)

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Publication number Priority date Publication date Assignee Title
JP2015105267A (ja) * 2013-12-03 2015-06-08 公益財団法人微生物化学研究会 併用抗メチシリン耐性黄色ブドウ球菌薬、及びβラクタム系抗生物質の抗菌活性増強剤

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2001074850A1 (fr) * 2000-03-30 2001-10-11 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Antibiotiques tripropeptines et leur procede de production

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001074850A1 (fr) * 2000-03-30 2001-10-11 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Antibiotiques tripropeptines et leur procede de production

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Title
HASHIZUME, H. ET AL.: "A New Type of Tripropeptin with Anteiso-branched Chain Fatty Acid from Lysobacter sp. BMK333-48F3.", THE JOURNAL OF ANTIBIOTICS, vol. 61, no. 9, 2008, pages 577 - 582 *
HASHIZUME, H. ET AL.: "Production of tripropeptins in media supplemented with precursors based on the biosynthetic pathway.", ARKIVOC, vol. 7, 2007, pages 241 - 253 *
HASHIZUME, H. ET AL.: "Tripropeptin C Blocks the Lipid Cycle of Cell Wall Biosynthesis by Complex Formation with Undecaprenyl Pyrophosphate.", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 55, no. 8, August 2011 (2011-08-01), pages 3821 - 3828 *
HIDEKI HASHIZUME: "Biseibutsu Taisha Sanbutsu kara no Shinki Ko Kansenshoyaku no Tansaku", SYMPOSIUM ON MICROBIAL SCIENCES SYMPOSIUM PAPERS, vol. 19TH, 2007, pages 22 - 23 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015105267A (ja) * 2013-12-03 2015-06-08 公益財団法人微生物化学研究会 併用抗メチシリン耐性黄色ブドウ球菌薬、及びβラクタム系抗生物質の抗菌活性増強剤

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