Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
  • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• the present invention relates to a novel 5-aminoquinocarboxylic acid derivative or a salt thereof having an excellent antibacterial activity against Gram-positive bacteria including Gram-negative bacteria and resistant bacteria, and an antibacterial agent containing the same as an active ingredient.
• synthetic antibacterial agents such as nalidixic acid and pyromidic acid have been known as therapeutic agents for infectious diseases.
• they have a drawback that they are less effective against intractable diseases such as Pseudomonas aeruginosa infection.
• quinolone carboxylic acid derivatives substituted with a fluorine atom at the 6-position such as norfloxacin, ofloxacin, ciprofloxacin, and sufloxacin, have been developed, and these have strong antibacterial activity against Gram-negative bacteria. Widely used in clinical practice.
• an object of the present invention is to provide an antibacterial agent which has a strong antibacterial activity against Gram-positive bacteria including Gram-negative bacteria and resistant bacteria and has good absorbability.
• the present inventors synthesized a large number of quinolone derivatives and examined their antibacterial activity and absorption into the living body.
• the 5-aminoquinolone carboxylic acid derivative represented by the following general formula (1) and its derivative were obtained. It has been found that the salt maintains the antibacterial activity against Gram-negative bacteria, and the antibacterial activity against Gram-positive bacteria, especially resistant bacteria, is remarkably enhanced as compared to conventional quinolonecarbonic acid derivatives, and has excellent absorbability.
• the present invention has been completed.
• the present invention provides the following general formula (1)
• R 1 is a hydrogen atom, an amino group, a linear or branched alkyl group having 1 to 5 carbon atoms, or an alkylamino group having a linear or branched alkyl group having 1 to 5 carbon atoms.
• R 2 represents a hydrogen atom or a linear or branched alkyl group having 1 to 5 carbon atoms
• X represents a halogen atom
• Y represents CH 2 , NH, CHR 3 , NR 3
• R 3 represents a linear or branched alkyl group having 1 to 5 carbon atoms
• Z represents an oxygen atom or two hydrogen atoms.
• the 5-aminoquinolone carboxylic acid derivative of the present invention is represented by the general formula (1), wherein the linear or branched alkyl group having 1 to 5 carbon atoms is, for example, methyl Group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, is0-butyl group, tert-butyl group, II-pentyl group and the like.
• the salt of the compound (1) of the present invention include metal salts of inorganic acids, inorganic acid salts, and organic acid salts. More specifically, the alkali metal salts include lithium salts, sodium salts, potassium salts, and the like.
• the inorganic acid salts include hydrochlorides, sulfates, nitrates, hydrobromides, and phosphates. And organic salts such as acetate, fumarate, maleate, lactate, tartrate, citrate, malate, oxalate, methanesulfonate, and benzenesulfonate. Salts, p-toluenesulfonic acid salts and the like.
• the compound (1) of the present invention is compounded with a compound (2) according to, for example, the following reaction formula. It can be produced by reacting (3).
• the starting compound (2) used in the above method is a known compound.
• the method described in JP-A-62-18969 or JP-A-62-187549 is used. Therefore, it can be manufactured.
• Compound (3) can also be produced according to a known method, for example, the method described in Journal of American Chemicals Society, Vol. 106, pp. 630 (1989).
• the compound (1) of the present invention In order to produce the compound (1) of the present invention from the compound (2) and the compound (3), 1 to 5 mol of the compound (3) is used per 1 mol of the compound (2), and acetonitrile and dimethyl are used.
• the reaction may be carried out in a solvent such as sulfoxide, dimethylformamide, hexamethylphosphoric triamide, pyridine, or 1-methyl-1-pyrrolidone at room temperature or under reflux for 1 to 10 hours.
• the precipitate is collected by filtration or the solvent is distilled off to obtain a crude product, which is purified by silica gel gel chromatography or recrystallization to obtain a pure compound (1) of the present invention.
• the thus-obtained compound (1) of the present invention can be further converted into a salt such as an alkali metal salt, an inorganic acid salt or an organic acid salt as described above by a conventional method, if necessary.
• a salt such as an alkali metal salt, an inorganic acid salt or an organic acid salt as described above by a conventional method, if necessary.
• the compound (1) obtained in this way is used as an antibacterial agent, its dosage depends on the patient's weight, age, sex, administration method, physical condition, medical condition, etc.
• An appropriate dose is 100 to 80 Omg, and about 5 to 4 Omg per day for parenteral administration.
• Compound (1) of the present invention can be prepared in the usual manner using tablets, granules, powders, capsules, Various antibacterial agents such as suspending agents, injections, and suppositories can be prepared.
• compound (1) is added to excipients, and if necessary, binders, disintegrants, lubricants, coloring agents, flavoring agents, bulking agents, coating agents, sugar coatings, etc.
• tablets, granules, powders, capsules, suppositories and the like are preferably prepared by a conventional method.
• the compound (1) When preparing an injection, the compound (1) may be previously dissolved, dispersed, emulsified, or the like in an aqueous carrier of distilled water for injection, or may be made into a powder for injection, and dissolved at the time of use.
• Administration methods for injections include intravenous administration, intraarterial administration, intraportal administration, intraperitoneal administration, intramuscular administration, and subcutaneous administration.
• Tables 1 to 3 The bacteria shown in Tables 1 to 3 were measured according to the following conditions according to the Japanese Society of Chemotherapy MIC measurement method. In addition, spafloxacin was used as a control. The results are shown in Tables 1 to 3.
• Dilution of sample Make up to 1,000 xg / with 25% dimethyl sulfoxide, then dilute twice with sterile purified water to make 100 / xg to 0.000. After that, dilute it 10 times with the medium to make a plate.
• Staphylococcus aureus FDA 209P 0.012 0.006 0.012 0.024
• Streptococcus faecal is I FO 12964 0.20 0.20 0.20 0.39
• MRSA Methicillin-resistant Staphylococcus aureus
• the 5-aminoquinocarboxylic acid derivative of the present invention exhibits a strong antibacterial activity against Gram-positive bacteria including resistant bacteria while maintaining its antibacterial activity against Gram-negative bacteria, and has good absorption into the living body. It is useful for prevention and treatment of various infectious diseases in Japan.

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• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Organic Chemistry (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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• 1993
  • 1993-05-25 WO PCT/JP1993/000694 patent/WO1993024460A1/ja not_active Ceased
  • 1993-05-25 EP EP19930910391 patent/EP0601197A4/en not_active Withdrawn
  • 1993-05-25 CA CA002102196A patent/CA2102196A1/en not_active Abandoned
  • 1993-05-25 TW TW082104099A patent/TW222272B/zh active
  • 1993-05-25 US US08/185,898 patent/US5430028A/en not_active Expired - Fee Related

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