Classifications

• • 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
• • 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 subject of the present invention is new quinolones and more particularly quinolones substituted by a piperidine cycle.
• R is hydrogen or fluorine
• R 1 represents hydrogen, a radical (lower alkyl optionally hydroxylated), an acyl radical derived from an organic carboxylic acid, an alkyl carbonic acid, or an aryl sulfonic acid, or an arylamino carbonyl radical of the form:
• Ar represents an aromatic radical, mono or bicyclic, optionally substituted by one, two or three substituents chosen from lower alkyl, halogens and trifluoromethyl
• T oxygen or sulfur
• X represents hydrogen or fluorine
• Y represents hydrogen or fluorine
• R 3 is chosen from the group consisting of an isopropyl radical, a terbutyl radical, a cyclopropyl radical, a (cyclopropyl) alkyl radical, a phenyl radical or a phenyl radical substituted by one, two or three substituents defined as above
• R 2 represents an oxygen atom linked by a semi-polar bond
• n 0 or 1
• R 1 represents hydrogen, a linear or branched lower alkyl radical, optionally substituted by a hydroxyl or an acyl radical defined as above
• R, R 2 and n are defined as above
• R 3 is a cyclopropyl radical, the amino derivatives of formula IB
• R 1 represents hydrogen, a lower alkyl radical, linear or branched, optionally substituted by a hydroxyl or an acyl radical derived from a carboxylic, carbonic or arylsulfonic acid
• R 3 is a terbutyl radical
• R 3 represents an isopropyl radical
• R 3 represents a phenyl radical, optionally substituted by one, two or three substituents
• R 3 represents a (cyclopropyl) alkyl radical in which the alkyl residue has from 1 to 3 carbon atoms
• the compounds for which ZR 1 is a ureido function are those which are currently preferred.
• R and R 3 have the meanings previously provided
• T oxygen or sulfur
• W is a group ⁇ C-H or ⁇ N
• B is hydrogen or a 5- or 6-membered aromatic structure
• V is hydrogen, a lower alkyl radical, a radical trifluoromethyl or halogen
• the compounds for which ZR 1 is a ureido function are those which are currently preferred.
• the compounds according to the invention can be salified by adding a mineral or organic base.
• the main salts which can be used are those of alkali metals, alkaline earth metals, ammonium, iron, aluminum, alkylamine salts, hydroxyalkylamine salts, phenylalkylamine salts, pyridylalkylamine salts, salts of cyclany lamines, dicyclanylalkoylamine salts ...
• the sodium, lithium, ammonium, N.methylglucamine and tromethanol salts are those presently preferred.
• These compounds can also be salified with a strong mineral or organic acid, when R 1 represents hydrogen, a lower alkyl radical or a lower (hydroxyalkyl) radical.
• R 1 represents hydrogen, a lower alkyl radical or a lower (hydroxyalkyl) radical.
• hydrochlorides, methane sulfonates, lactates or acetates are preferred examples.
• the compounds according to the invention have very marked antibacterial properties, in particular against Gram positive bacteria. They also have the property of being moderately absorbed generally so that their elimination is essentially fecal.
• They can therefore be used effectively as drugs for bacterial infections of the digestive tract, for the treatment of bacterial dysentery, travelers' diarrhea, or intestinal infections. They can also be used topically for the treatment of eye infections or ear canal infections.
• the compounds according to the invention will be used in the form of pharmaceutical compositions in which the active principle of general formula I or one of its salts, is added or mixed with an excipient or an inert non-toxic pharmaceutically acceptable vehicle.
• the most suitable pharmaceutical forms are those intended for administration by the digestive route such as oral solutions or suspensions, granules, capsules, bare or coated tablets, dragees, sachets of powdered flavored or not, sweetened or not, pills or cachets.
• the average dosage depends mainly on the severity of the infection and the sensitivity of the microbial germ to the antibacterial agent.
• the unit dosage ranges from 100 to 600 mg per dose.
• the daily dosage ranges from 200 to 1200 mg divided into 2 to 4 doses.
• the invention also relates to a process for obtaining the compounds of general formula I which consists in reacting a 6-fluoro 7-halo 1-R 3 4-oxo 1, 4-dihydroquinoleine 3-carboxylic acid.
• formula E
• Hal represents an easily exchangeable halogen atom
• R 3 and R have the meanings provided previously
• the invention also relates to a process for converting the amino compound of formula IV into urea or thiourea which consists in subjecting the compound of formula IV to the action of an isocyanate or isothiocyanate of formula
• R, R 3 , T and Ar are defined as above.
• the crystals formed are taken up in 50 cm of edianol and the precipitate is filtered off.
• the precipitate is suspended in 50 cm 3 of water for 30 min then drained, washed with water, with ethanol and dried. 2 g of melting crystals are thus collected (in the Koffler block) above 260 ° C (the yield is 50% of theory).
• the IR spectrum and micro-analysis are in agreement with an anhydrous product.
• the hydrochloride formed by taking up with IN hydrochloric acid (30 cm 3 ) is also above 260 ° C.
• the hydrochloride is in the form of pale yellow crystals, sparingly soluble in water.
• the minimum inhibitory concentrations were measured by a microdilution technique (*) in a liquid medium (Mueller-Hinton broth) in a volume of 100 ⁇ l and for a concentration range from 128 to 0.06 mg / L, prepared from a stock solution of antibiotic grading 512 mg / L.
• the preparation of these mother solutions carried out varied according to the molecules as a function of the solubility criteria.
• the inoculation is done by adding to each well 10 ⁇ l of a physiological water dilution of an 18 H broth in heart / brain broth such that each well contains approximately 106 bacteria / ml.
• the minimum inhibitory concentration is read as the first concentration of non-culture-giving antibiotic, macroscopically visible after 18 H of incubation at 37 °.

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

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• 1992
  • 1992-05-26 FR FR9206404A patent/FR2692577B1/fr not_active Expired - Lifetime
• 1993
  • 1993-05-25 EP EP93913065A patent/EP0598089A1/fr not_active Withdrawn
  • 1993-05-25 JP JP6500257A patent/JPH06509589A/ja active Pending
  • 1993-05-25 CA CA002114132A patent/CA2114132A1/fr not_active Abandoned
  • 1993-05-25 US US08/185,918 patent/US5478841A/en not_active Expired - Fee Related
  • 1993-05-25 HU HU9400211A patent/HUT67679A/hu unknown
  • 1993-05-25 WO PCT/FR1993/000505 patent/WO1993024479A1/fr not_active Application Discontinuation
• 1994
  • 1994-01-24 OA OA60462A patent/OA09881A/fr unknown
  • 1994-01-25 FI FI940357A patent/FI940357A/fi not_active Application Discontinuation
  • 1994-01-25 NO NO940250A patent/NO940250L/no unknown

Non-Patent Citations (1)

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