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WO1998018807A1 - Derives de l'erythromycine a - Google Patents

Derives de l'erythromycine a Download PDF

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Publication number
WO1998018807A1
WO1998018807A1 PCT/JP1997/003683 JP9703683W WO9818807A1 WO 1998018807 A1 WO1998018807 A1 WO 1998018807A1 JP 9703683 W JP9703683 W JP 9703683W WO 9818807 A1 WO9818807 A1 WO 9818807A1
Authority
WO
WIPO (PCT)
Prior art keywords
erythromycin
acid
derivative
compound
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1997/003683
Other languages
English (en)
Japanese (ja)
Inventor
Toshifumi Asaka
Akiko Matsuura
Masato Kashimura
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU44726/97A priority Critical patent/AU4472697A/en
Publication of WO1998018807A1 publication Critical patent/WO1998018807A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • 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

Definitions

  • the present invention relates to novel derivatives of the antibiotic erythromycin A.
  • Erythromycin A is an antibiotic widely used as a treatment for infectious diseases caused by gram-positive bacteria, mycoplasma, and the like.
  • erythromycin A has the disadvantage that it is degraded by acid in the stomach because it is unstable to acid, and its pharmacokinetics is not constant.
  • Many erythromycin A derivatives have been produced to date to improve such biological or pharmacodynamic properties.
  • a 6-0-methylerythromycin A derivative (US Pat. No. 4,331,803) is reported to have improved acid stability and better in vivo antibacterial activity when administered orally than erythromycin A. Have been.
  • An object of the present invention is to provide an erythromycin A derivative or a salt thereof, which is a new macrolide antibiotic having a strong antibacterial activity, and a composition containing the same as an active ingredient.
  • Another object of the present invention is to provide a use of the erythromycin A derivative or a salt thereof for the treatment of bacterial infection, which comprises applying an effective amount of the erythromycin A derivative or a salt thereof to a patient. To provide.
  • the present inventors have conducted various studies on the antibacterial activity of the erythromycin A derivative, and as a result, have found that a compound having a specific group introduced at the 6-position has strong antibacterial activity, and completed the present invention.
  • the present invention provides a compound of the formula (I)
  • R represents an alkyl group having 3 to 5 carbon atoms or an alkyl group having 3 to 5 carbon atoms substituted with a hydroxyl group.
  • the alkyl group having 3 to 5 carbon atoms is linear or branched, and examples thereof include a propyl group, an isopropyl group, a butyl group, a pentyl group, and an isopentyl group.
  • the alkyl group having 3 to 5 carbon atoms substituted by a hydroxyl group is linear or branched and includes a 2,3-dihydroxypropyl group, a 2,3-dihydroxy-3-methylbutyl group, and the like. be able to.
  • pharmaceutically acceptable salts refer to salts used in chemotherapy and prevention of bacterial infections.
  • acids such as hydrogenic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, penden
  • the compound of the present invention can be produced, for example, as follows.
  • the method for producing the compound of the present invention is not limited to the method shown below.
  • Step (2) The compound (a) is hydrogenated by a conventional method to obtain a compound of the present invention represented by the formula (b) (wherein R 1 is the same as described above).
  • Step (3) The compound represented by the formula (c) (where R 'is the same as described above) is obtained by subjecting the compound (a) to a normal diolation reaction using osmium tetroxide. The compounds of the invention can be obtained.
  • the erythromycin A derivative of the present invention is administered orally or parenterally, and is 50 to 2000 mg when treating an adult, and is administered in 2 to 3 times a day. This dosage may be adjusted appropriately according to the age, weight and condition of the patient.
  • the compound of the present invention can be used in various pharmaceutical forms for the purpose of application due to its pharmacological action.
  • the pharmaceutical compositions of the present invention can be prepared by uniformly mixing an effective amount of the compound of the present invention in the form of the free or acid addition salt as an active ingredient with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • composition of the present invention for oral administration, excipients, binders, lubricants, antioxidants, coating agents, surfactants, plasticizers, coloring agents, flavoring agents, etc. are mixed. Preparations include powders, granules, capsules, tablets and the like, and for parenteral administration, preparations such as injections and infusions. When formulating, a usual formulation method can be used.
  • Example 1-one Provides professional reerythromycin A
  • Step (1) 2 4 "— 0-bis (trimethylsilyl) erythromycin A 9— ⁇ 0— [1- (1-methylethoxy) cyclohexyl] oxime ⁇ (37.8 g, 0.037 mol) and prenyl bromide
  • the reaction was carried out in the same manner as in the step (1) of Example 1 using amide (16.36 g) and potassium hydroxide (4.28 g) to obtain 6-0-prenylerythromycin A (10.16 g).
  • Step (2) Using the compound (0.30 0.37 ⁇ 01) obtained in the above step (1) and 10% palladium carbon (50! 3 ⁇ 4 wet, 0.06 g), react in the same manner as in step (2) of Example 1. The title compound (0.157 g, crystallized from methanol) was obtained.
  • the compound (l.Og, 1.29 dl) obtained in Step (1) of Example 1 was dissolved in tetrahydrofuran (5 ml).
  • N-methylmorpholine N-oxide (0.908 g) and osmium tetroxide solution (3.64 ml) were added, and the mixture was stirred at room temperature under a nitrogen stream for 15 hours.
  • a saturated aqueous sodium sulfite solution (10 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate.
  • the in vitro antibacterial activity of the compound obtained in Example 1 against various test bacteria was measured using a medium for susceptible discs (manufactured by Eiken Chemical Co., Ltd.) according to the MIC assay method of the Japan Society of Chemotherapy did.
  • the results were expressed as MIC values (minimum inhibitory concentration of microbial growth / g / m 1) and are shown in Table 1.
  • the compound obtained in Example 1 showed strong antibacterial activity.
  • the compounds of the present invention have strong antibacterial activity and are useful as antibacterial agents. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterial infections in humans and animals (including farm animals).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de l'érythromycine représentés par la formule générale (I) ou des sels pharmaceutiquement acceptables de ceux-ci, et présentant une activité antibactérienne puissante. Dans ladite formule, R représente alkyle C3-5 éventuellement hydroxylé.
PCT/JP1997/003683 1996-10-31 1997-10-14 Derives de l'erythromycine a Ceased WO1998018807A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU44726/97A AU4472697A (en) 1996-10-31 1997-10-14 Erythromycin a derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8289498A JP2000198795A (ja) 1996-10-31 1996-10-31 エリスロマイシンａ誘導体
JP8/289498 1996-10-31

Publications (1)

Publication Number Publication Date
WO1998018807A1 true WO1998018807A1 (fr) 1998-05-07

Family

ID=17744061

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/003683 Ceased WO1998018807A1 (fr) 1996-10-31 1997-10-14 Derives de l'erythromycine a

Country Status (3)

Country Link
JP (1) JP2000198795A (fr)
AU (1) AU4472697A (fr)
WO (1) WO1998018807A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011651A3 (fr) * 1997-09-02 1999-05-06 Abbott Lab Derives d'erythromycine 3-descladinose 6-o-substituee
WO2004039823A1 (fr) * 2002-10-29 2004-05-13 The Kitasato Institute Nouveaux derives de macrolides potentialisant une activite antifongique
WO2009019868A1 (fr) 2007-08-06 2009-02-12 Taisho Pharmaceutical Co., Ltd. Composé 10a-azalide réticulé en position 10a et en position 12

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS572298A (en) * 1980-06-04 1982-01-07 Taisho Pharmaceut Co Ltd Erythromycin derivative
WO1997042206A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Composes a base d'erythromycine 6-0 substituee et technique de production
WO1997042204A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Erythromycines 6-o substituees et leur procede de preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS572298A (en) * 1980-06-04 1982-01-07 Taisho Pharmaceut Co Ltd Erythromycin derivative
WO1997042206A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Composes a base d'erythromycine 6-0 substituee et technique de production
WO1997042204A1 (fr) * 1996-05-07 1997-11-13 Abbott Laboratories Erythromycines 6-o substituees et leur procede de preparation

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999011651A3 (fr) * 1997-09-02 1999-05-06 Abbott Lab Derives d'erythromycine 3-descladinose 6-o-substituee
WO2004039823A1 (fr) * 2002-10-29 2004-05-13 The Kitasato Institute Nouveaux derives de macrolides potentialisant une activite antifongique
WO2009019868A1 (fr) 2007-08-06 2009-02-12 Taisho Pharmaceutical Co., Ltd. Composé 10a-azalide réticulé en position 10a et en position 12

Also Published As

Publication number Publication date
JP2000198795A (ja) 2000-07-18
AU4472697A (en) 1998-05-22

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