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WO1992016545A1 - Derive de 6-o-methylerythromycine ester - Google Patents

Derive de 6-o-methylerythromycine ester Download PDF

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Publication number
WO1992016545A1
WO1992016545A1 PCT/JP1992/000288 JP9200288W WO9216545A1 WO 1992016545 A1 WO1992016545 A1 WO 1992016545A1 JP 9200288 W JP9200288 W JP 9200288W WO 9216545 A1 WO9216545 A1 WO 9216545A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
methylerythromycin
ester derivative
ethyl acetate
compound
Prior art date
Application number
PCT/JP1992/000288
Other languages
English (en)
Japanese (ja)
Inventor
Toshifumi Asaka
Shigeo Morimoto
Katsuo Hatayama
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.
Publication of WO1992016545A1 publication Critical patent/WO1992016545A1/fr

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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

Definitions

  • the present invention relates to a derivative of 6-0-methylerythromycin ⁇ , and more particularly, to a 6-0-methylethyl sullomycin which has a markedly reduced bitterness when taken as a drug and has improved in vivo absorbability. It relates to the compound modified at the 2-position of Mycin A. Background art
  • Erythromycin or its derivatives used for chemotherapy of various bacterial infections generally have a characteristic bitter taste. Therefore, when these are used as oral medicines, there is a need to make capsules or coated tablets. Furthermore, for children and the elderly who have difficulty swallowing these drugs, it is desirable to make them into solutions or granules, in which case masking did not sufficiently reduce bitterness.
  • erythromycins which have no bitterness when the drug is administered and exhibit antibacterial activity by returning to the active substance in the living body at the time of absorption or after absorption.
  • the 2-position conductor of erythromycin is ethyl succinate [Antibiotics and Chemotherapy, Vol. 7, No. 9, No. 4] P. 87 (1957)], Probiotic acid ester lauryl sulfate [Journal of the Americas Pharmaceuticals, Inc. American Pharmaceutica IA ssociation), Vol. 48, No. 11, page 62, pp. 195]], aryl, ethyl and benzyl carbonate esters [antino, thiote Antiqueotics Ann- ua-ua I, Vol. 19533-1954, Vol. 500, page 950 (1954)].
  • An object of the present invention is to provide a new 2′-position derivative of 6-0-methylerythromycin A with significantly reduced bitterness when taken and improved in vivo absorbability. Disclosure of the invention
  • the invention relates to the formula
  • R represents a pyridyl group.
  • the pyridyl group means a viridyl-2-yl group, a virid-3-yl group, and a virid-4-yl group.
  • a pharmaceutically acceptable salt is defined as a contact with a human or a lower animal, such as a human or a lower animal, without undue toxicity, irritation, allergy, etc. within the scope of sound medical judgment. It means a salt that is suitable for use and that is effective for the intended use in chemotherapy and prevention of bacterial infections. They include, for example, acetic acid, propionic acid, succinic acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, cunic acid, stearinic acid, succinic acid, ethyl succinic acid, lactobionic acid, gluconic acid, glucoheptic acid.
  • Acid benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2 — hydro Kissene sulfonic acid, benzene sulfonic acid, noduletoluene sulfonic acid, raurylsulfuric acid, lingoic acid, aspartic acid, glutamic acid, adibic acid, cystine, hydrochloric acid, hydrobromic acid Salts with acids such as, but not limited to, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, viric acid, thiocyanic acid, pendecanoic acid, acrylic acid polymer and carboxyvinyl polymer Can be mentioned.
  • the compound of the present invention can be produced, for example, as follows.
  • 6 0—methyl erythromycin A in an inert solvent, in the presence of a dehydrochlorinating agent, 2—1 to 3 equivalents of vicoline neuzorechloride, nicotinoid zorechloride or isonicotinoyl laurel, Preferably, it can be produced by reacting with 1.5 equivalents.
  • the dehydrochlorinating agent it is possible to use sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium carbonate, sodium carbonate, triethylamine, or the like. Wear. These are used in an amount of 1 to 10 equivalents to 6-0-methylerythromycin A, and preferably 3 to 5 equivalents in the case of sodium hydrogencarbonate.
  • the inert solvent there can be used acetone, ethyl acetate, dichloromethan, cross-linked form, tetrahydrofuran, etc., and preferably, acetone, ethyl acetate, tetraethyl and the like. La Hydrofuran.
  • the reaction time is usually 4 to 8 hours at ambient temperature, but if the progress of the reaction is slow, the reaction is continued for another 2 to 4 days. In some cases, if the progress of the reaction is insufficient, the reaction can be continued by further adding a dehydrochlorinating agent and a compound of the formula i.
  • the compound of formula I of the present invention can be prepared in the form of tablets, capsules, powders, lozenges, soft Xu, suspensions, solutions and the like, and can be administered orally or parenterally.
  • Each of the above-mentioned preparations contains a commonly used excipient (eg, crystalline cellulose, starch, lactose, etc.), a binder (eg, hydroxypropyl cellulose, polyvinyl alcohol, etc.), a lubricant (eg, magnesium stearate, talc, etc.). Etc.), and can be manufactured by an ordinary method (for example, a method prescribed in the Japanese Pharmacopoeia, Revised 12th).
  • the dosage of the compound of formula I varies depending on the condition, age, weight, and the like of the patient, but is usually administered to adults in a dose of 50 to 200 mg once to four times a day.
  • a known ester of the compound of the present invention (samples 1 to 3) and 6-0-methyl erythrocyte mycin A (control samples 1 to 3) as control were suspended in 5% arabia gum water, Male ICR mice (12 mice per group) were orally administered at a dose of 100 mg Z kg. Thereafter, three mice were exsanguinated and killed at predetermined time intervals, and the amount of antibacterial activity in the serum was measured. The antibacterial activity was measured by a paper disk method using Micrococcus luteus / ATCCC 9341 as a test bacterium.
  • Control 1 6—0—methyl erythromycin A 2′-ethyl carbonate
  • Control 2 6—0-Methyl erythromycin A 2'—benzyl carbonate
  • Control 3 6—0—Methyl erythromycin A 2'—ethyl ethyl phosphate Availability
  • a macrolide antibiotic which significantly reduces bitterness when taken and has good bioabsorbability when orally administered.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un nouveau dérivé 2'-substitué de 6-O-méthylérythromycine A, représenté par la formule générale (I), qui constitue un antibiotique aux macrolides ayant une amertume considérablement réduite lors de l'administration et une absorbabilité in vivo accrue lors de son administration perorale, ou à un sel pharmaceutiquement acceptable de ce dérivé. Dans la formule (I), R représente pyridyle.
PCT/JP1992/000288 1991-03-14 1992-03-11 Derive de 6-o-methylerythromycine ester WO1992016545A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP12879791 1991-03-14
JP3/128797 1991-03-14

Publications (1)

Publication Number Publication Date
WO1992016545A1 true WO1992016545A1 (fr) 1992-10-01

Family

ID=14993679

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/000288 WO1992016545A1 (fr) 1991-03-14 1992-03-11 Derive de 6-o-methylerythromycine ester

Country Status (1)

Country Link
WO (1) WO1992016545A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034007A1 (fr) * 1995-04-27 1996-10-31 Laboratorios Aranda, S.A. De C.V. Derives de quinolonylcarboxyerythromycine et compositions pharmaceutiques les contenant

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61200998A (ja) * 1985-03-01 1986-09-05 Taisho Pharmaceut Co Ltd エリスロマイシンエステル誘導体

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61200998A (ja) * 1985-03-01 1986-09-05 Taisho Pharmaceut Co Ltd エリスロマイシンエステル誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 72, No. 19, pages 421-422. (1970), Abstract No. 101051j and 101054n, BOJARSKA-DAHLIG, H. et al. Abstract of the literature of "Erythromycin derivatives I. and II"; & ROCZ. CHEM. 1969, 12, p.2071-79 and idem, 1969, 12, p.2155-57. About the the point of esterifying the 2' order of erythromycin A with pyridine-carboxylic acid. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996034007A1 (fr) * 1995-04-27 1996-10-31 Laboratorios Aranda, S.A. De C.V. Derives de quinolonylcarboxyerythromycine et compositions pharmaceutiques les contenant

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