WO1994010163A1 - Derives antimicrobiens de 5-hydrazino-quinolone - Google Patents

Derives antimicrobiens de 5-hydrazino-quinolone Download PDF

Info

Publication number
WO1994010163A1
WO1994010163A1 PCT/US1993/010091 US9310091W WO9410163A1 WO 1994010163 A1 WO1994010163 A1 WO 1994010163A1 US 9310091 W US9310091 W US 9310091W WO 9410163 A1 WO9410163 A1 WO 9410163A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
heterocyclic ring
hydrogen
alkyl
quinolone
Prior art date
Application number
PCT/US1993/010091
Other languages
English (en)
Inventor
Thomas Prosser Demuth, Jr.
Ronald Eugene White
Original Assignee
The Procter & Gamble Company
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 The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to RU95110762A priority Critical patent/RU2126000C1/ru
Priority to AU54097/94A priority patent/AU687018B2/en
Priority to EP93924393A priority patent/EP0666853A1/fr
Priority to JP6511167A priority patent/JPH08502750A/ja
Priority to KR1019950701690A priority patent/KR950704301A/ko
Priority to BR9307347A priority patent/BR9307347A/pt
Priority to SK547-95A priority patent/SK54795A3/sk
Priority to PL93308671A priority patent/PL178094B1/pl
Publication of WO1994010163A1 publication Critical patent/WO1994010163A1/fr
Priority to FI952049A priority patent/FI952049A0/fi
Priority to NO951640A priority patent/NO951640L/no

Links

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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to novel antimicrobial compounds, compositions, and methods of treatment.
  • the compounds of this invention comprise a quinolone or related heterocyclic moiety.
  • antimicrobial i.e., capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria.
  • antibacterlals include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds.
  • aminoglycosides ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nltrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides.
  • antibacterials and other antimicrobials are described in Antibiotics. Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981), both incorporated by reference herein.
  • beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis.
  • PBPs penicillin binding proteins
  • quinolones act by inhibiting synthesis of bacterial DNA, thus preventing the bacteria from replicating.
  • the pharmacological characteristics of antibacterials and other antimicrobials also vary considerably.
  • the classes of antimicrobials may vary in their relative efficacy against different types of microorganisms, and their susceptibility to development of microbial resistance.
  • These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial (or other antimicrobial) in any given clinical situation can be a complicated analysis of many factors, including the type of organism involved, the desired method of administration, and the location of the infection to be treated.
  • the pharmaceutical literature is replete with attempts to develop improved antimicrobials (i.e., compounds that have a broader scope of activity, greater potency, improved pharmacology, and/or less susceptibility to resistance development.)
  • improved antimicrobials i.e., compounds that have a broader scope of activity, greater potency, improved pharmacology, and/or less susceptibility to resistance development.
  • one group of antimicrobials that has been developed relatively recently for clinical use is the quinolones. These compounds include, for example, nalidixic acid, difloxacin, enoxacin, fleroxacin, norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin, and pefloxacin. See, C. Marchbanks and M. Dudley, "New Fluoroquinolones", 7 Hospital Therapy 18 (1988); P.
  • quinolones often show reduced effectiveness against certain clinically important pathogens (for example, gram positive bacteria and/or anaerobic bacteria).
  • pathogens for example, gram positive bacteria and/or anaerobic bacteria.
  • the quinolones also have limited water solubility limiting their bioavailability and suitability for parenteral dosing. They may also produce adverse side effects, such as gastrointestinal disturbance and central nervous system effects (such as convulsions). See, M. Neuman and A.
  • the present invention provides compounds of the general structure:
  • R 1 is alkyl; alkenyl; a carbocyclic ring; a
  • heterocyclic ring or -N(R 6 )(R 7 ), where R 6 and R 7 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R 5 and R 7 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and
  • R 2 is hydrogen, halogen, lower alkyl, or lower alkoxy
  • R 1 and R 2 may together comprise a six-membered heterocyclic ring that includes N' and the carbon atom to which R 2 is bonded;
  • R 3 is a heterocyclic ring or a carbocyclic ring
  • R 4 and R 5 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded;
  • the compounds of this invention are effective antimicrobial agents against a broad range of pathogenic microorganisms.
  • Applicants have also discovered that, surprisingly, compounds of this invention offer significantly increased water solubility at physiological pH in comparison to related antimicrobials known in the art. This surprising property may allow for, among other things, improved pharmacology, including increased serum levels upon administration, ease of formulation, and a more flexible dosing regimen.
  • the present invention encompasses certain novel quinolones, methods for their manufacture, dosage forms, and methods of administering the quinolones to a human or other animal subject.
  • Specific compounds and compositions to be used in the invention must, accordingly, be pharmaceutically acceptable.
  • a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
  • 5-(N-heterosubstituted amino) quinolones encompass any of a variety of quinolones (and related heterocyclic moieties) having an N-heteroamino substituent at the 5-position of the quinolone moiety.
  • the 5-(N-heterosubstituted amino) quinolones of this invention include compounds of the general structure:
  • heterocyclic ring or -N(R 6 )(R 7 ) (preferably alkyl or a carbocyclic ring), where R 6 and R 7 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R 6 and R 7 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and
  • R 2 is hydrogen, halogen, lower alkyl, or lower alkoxy (preferably halogen); or
  • R 1 and R 2 may together comprise a six- membered heterocyclic ring that includes N' and the carbon atom to which R 2 is bonded;
  • R 3 is a heterocyclic ring or a carbocyclic ring
  • R 4 and R 5 are, independently, hydrogen; lower alkyl
  • R 4 and R 5 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof.
  • Heteroatom is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
  • Alkyl is an unsubstituted or substituted saturated hydrocarbon chain radical having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms.
  • Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.
  • Heteroalkyl is an unsubstituted or substituted saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms.
  • Alkenyl is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond
  • Carbocyclic ring is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical.
  • Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems.
  • Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms.
  • Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • Cycloalkyl is a saturated carbocyclic ring radical.
  • Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.
  • Heterocyclic ring is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring.
  • Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems.
  • Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms.
  • Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
  • Aryl is an aromatic carbocyclic ring radical.
  • Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.
  • Heteroaryl is an aromatic heterocyclic ring radical.
  • Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl.
  • Alkoxy is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl).
  • Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
  • Alkyl amino is an amino radical having one or two alkyl substituents (i.e., -N-alkyl).
  • Arylalkyl is an alkyl radical substituted with an aryl group.
  • Preferred arylalkyl groups include benzyl and phenylethyl.
  • Arylamino is an amine radical substituted with an aryl group (i.e., -NH-aryl).
  • Aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
  • Preferred alkyl acyl groups include (for example) acetyl, formyl, and propionyl.
  • Halo is a chloro, bromo, fluoro or iodo atom radical. Chloro and fluoro are preferred halides.
  • a “lower” hydrocarbon moiety is a hydrocarbon chain comprised of from 1 to 6, preferably from 1 to 4, carbon atoms.
  • a "pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group.
  • Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium).
  • Preferred anionic salts include the halides (such as chloride salts).
  • a “biohydrolyzable ester” is an ester of a 5-(N-heterosubstituted amino) quinolone that does not essentially interfere with the antimicrobial activity of the compounds, or that are readily converted in vivo by a human or lower animal subject to yield an antimicrobially-active 5-(N-heterosubstituted amino) quinolone.
  • Such esters include those that do not interfere with the biological activity of quinolone antimicrobials. Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987, (incorporated by reference herein).
  • esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
  • lower alkyl esters such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters
  • lactonyl esters such as phthal
  • a “solvate” is a complex formed by the combination of a solute (e.g., a 5-(N-heterosubstituted amino) quinolone) and a solvent (e.g., water).
  • a solute e.g., a 5-(N-heterosubstituted amino) quinolone
  • a solvent e.g., water
  • Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the quinolone antimicrobials (e.g., water, ethanol, acetic acid, N,N-dimethyl formamide).
  • substituent groups may themselves be substituted. Such substitution may be with one or more substituents.
  • substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein.
  • Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
  • alkyl alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl
  • R 1 , R 2 , and R 3 form any of a variety of quinolone moieties known in the art to have antimicrobial activity. Such moieties are well known in the art, as described in the following articles, all incorporated by reference herein: J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", 28 Antimicrobial Agents and Chemotherapy 581 (1985); and T. Rosen et al., 31 J. Med Chem. 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. Klopman et al., 31 Antimicrob. Agents Chemother.
  • R 1 is preferably alkyl, alkenyl, aryl, cycloalkyl, a heterocyclic ring, or alkylamino. More preferably, R 1 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, methylamino, 3-oxetanyl, 2-fluorocyclopropyl, bicyclo [1.1.1] pentane, vinyl, or cyclopropyl.
  • Cyclopropyl, 2-fluorocyclopropyl, t-butyl, 2-fluorocyclopropyl, and 2,4-difluorophenyl are particularly preferred R 1 groups.
  • Preferred 5-(N-heterosubstituted amino) quinolones also include those where R 1 and R 2 together comprise a 6-membered heterocyclic ring, according to the formula:
  • X is O, S, or CH 2 .
  • R 2 is preferably chlorine, fluorine, methoxy, or methyl. Fluorine and chlorine are particularly preferred R 2 groups.
  • Preferred R 3 groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from 5 to 8 members.
  • the heterocyclic ring may contain additional heteroatoms, such as oxygen, sulfur, or nitrogen, preferably nitrogen.
  • Such heterocyclic groups are described in U.S. Patent 4,599,334, Petersen et al., issued July 8, 1986; and U.S. Patent 4,670,444, Grohe et al., issued June 2, 1987 (both incorporated by reference herein).
  • R 3 groups include unsubstituted or substituted pyridine, piperidine, morpholine, diazabicyclo[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabicyclo[2.2.2] octane, imidazolidine, and 5-amino-3-azabicyclo[4.2.0]heptane, as well as particularly preferred R 3 groups which include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminomethylpyrrolidine, N-ethyl aminomethylpyrrolidine, 3,5-dimethylpyridine, N-methylpiperazine and 3,5-dimethylpiperazine.
  • R 4 and R 5 groups include those where R 4 and R 5 together comprise a heterocyclic ring containing the nitrogen atom to which they are bonded, those where both R 4 and R 5 are lower alkyl, those where one of R 4 or R 5 is hydrogen and the other is lower alkyl, and those where both R 4 and R 5 are hydrogen. More preferred groups are where one of R 4 or R 5 is hydrogen and the other is alkyl and those where both R 4 and R 5 are hydrogen. Particularly preferred groups are where both R 4 and R 5 are hydrogen.
  • Preferred compounds of the present invention include those having both an R 3 group that contains a basic nitrogen atom (including, for example, pyridine, piperidine, diazabicyclo-[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabiclyo[2.2.2]octane, and imidazolidine) and R 4 and R 5 groups that allow the nitrogen atom to which they are bonded to be basic (including, e.g., where R 4 and R 5 together comprise a heterocyclic ring containing the nitrogen to which they are bonded, both R 4 and R 5 are lower alkyl, one of R 4 and R 5 are lower alkyl and the other is hydrogen, or both R 4 and R5 are hydrogen).
  • a basic nitrogen atom including, for example, pyridine, piperidine, diazabicyclo-[3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicy
  • Particularly preferred compounds are those where the R 3 group is one of piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminopyrrolidine, N-ethyl aminomethylpyrrolidine, N-methylpiperazine, or 3,5-dimethylpiperazine; and both R 4 and R 5 are hydrogen.
  • a "basic nitrogen atom” is one where the nitrogen atom possesses a lone pair of electrons that can be involved in ionic bonding with any of a variety of cations. It is understood in the art that the basicity of a nitrogen atom of a given moiety will depend on the nature of that nitrogen atom's covalent bonding. See, e.g., A. Streitwieser and C. Heathcock, Introduction to Organic Chemistry, 2d edition, pp. 734-40 (1981), incorporated by reference herein.
  • Preferred 5-(N-heterosubstituted amino) quinolones include:
  • lactam-quinolones encompass any of a variety of lactam moieties linked, by a linking moiety, to a quinolone moiety at the 5-position of the quinolone.
  • Lactam-quinolones include compounds having the general structure:
  • R 7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R 8 )(R 9 ) (preferably hydrogen or halogen), and
  • R 8 and R 9 are, independently, R 8a , where R 8a is hydrogen, alkyl, alkenyl, carbocyclic ring, or heterocyclic ring substituents; or R 8 and R 9 together comprise a heterocyclic ring including the nitrogen to which they are bonded;
  • a 2 is N or C(R 2 ) (preferably C(R 2 )); where R 2 is hydrogen or halogen;
  • a 3 is N or (preferably) C(R 5 ); where R 5 is hydrogen;
  • R 1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R 8 )(R 9 ) (preferably alkyl or a carbocyclic ring);
  • R 3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring (preferably a heterocyclic ring);
  • R 4 is hydroxy
  • R 6 is R 15 or R 16 X; where R 15 is a substituent moiety of L and is nil, alkyl, heteroalkyl, or alkenyl; R 16 is a substituent moiety of L and is alkyl, alkenyl, a carbocyclic ring or a heterocyclic ring; and X is alkyl, heteroalkyl, alkenyl, oxygen, sulfur, or NH;
  • R 1 and R 7 may together comprise a heterocyclic ring including N' and A 1 ;
  • R 2 and R 3 may together comprise -O-(CH 2 ) n -O-, where n is an integer from 1 to 4;
  • R 4 and R 5 may together comprise a heterocyclic ring including the carbon atoms to which R 4 and R 5 are bonded and the carbon atom of Formula (I) to which said carbon atoms are bonded;
  • R 1 and R 5 may together comprise a heterocyclic ring including N' and the adjacent carbon to which R 5 is bonded;
  • (II) B is a structure according to Formula (II), where L is bonded to R 14 :
  • m is an integer from 0 to 9 (preferably from 0 to 3);
  • R 17 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl, a carbocyclic ring, or a heterocyclic ring);
  • R 18 is R 17 , -Y 1 , or -CH(Y 2 )(R 17 );
  • R 22 and R 23 are bonded (preferably R 17 or -C(R 22 )(R 23 )COOH)
  • R 20 is R 19 , halogen, -Y 1 , or -CH(Y 2 )(R 17 ) (preferably R 19 or halogen);
  • (a) p is an integer from 0 to 2 (preferably 0);
  • R 24 may comprise a moiety bonded to R 21 to form a heterocyclic ring;
  • R 25 is R 17 , NH(R 17 ), N(R 17 )(R 26 ), O(R 26 ), or S(R 26 ) (preferably R 17 , NH(R 17 ) or N(R 17 )(R 26 )).
  • R 26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring or (preferably) when R 25 is N(R 17 )(R 26 ), R 26 may comprise a moiety bonded to R 17 to form a heterocyclic ring; and
  • R 21 is R 29 or hydrogen; where R 29 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroarylalkyl; a carbocyclic ring; a heterocyclic ring; or, when Y 1 is N(R 24 )R 21 and R 21 is R 29 , R 21 and R 24 may together comprise a heterocyclic ring including the nitrogen atom to which R 24 is bonded (preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring);
  • bond "a” is a single bond or is nil; and bond “b” is a single bond, a double bond, or is nil; except bond “a” and bond “b” are not both nil;
  • R 12 is -C(R 8a )-, or -CH 2 -R 28 - (preferably -C(R 8a )-); where R 28 is -C(R 8a ), -O-, or -N-, and R 28 is directly bonded to N" in Formula (II) to form a 5-membered ring; except, if bond "a" is nil, then R 12 is
  • X 1 is -R 21 ; -OR 30 ; -S(O) r R 30 , where r is an
  • R 30 and R 31 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R 30 and R 31 together comprise a heterocyclic ring including the nitrogen atom to which R 30 and R 31 are bonded; or
  • R 32 is -C(R 8a )(R 21 ), -O-, or -NR 8a , and R 32 is directly bonded to N" in Formula (II) to form a 5-membered ring;
  • R 33 is hydrogen or COOH (preferably COOH), and C* is linked to
  • R 36 to form a 3-membered ring
  • R 13 is hydrogen, -SO 3 H, -PO(OR 34 )OH, -C(O)NHSO 2 N(R 34 )(R 35 ), -OSO 3 H, -CH(R 35 )COOH, or -OCH(R 34 )COOH (preferably -SO 3 H, or -C(O)NHSO 2 N(R 34 )(R 35 );
  • R 34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R 35 is hydrogen, alkyl, alkenyl, or -NHR 8a ; or (preferably), if R 13 is -C(O)NHSO 2 N(R 34 ) (R 35 ), R 34 and R 35 may together comprise a heterocyclic ring including the nitrogen to which R 34 and R 35 are bonded; and
  • R 14 is -C(R 8a )(R 38 )-W-C"'-R 37 -; or
  • W is 0; S(O) s , where s is an integer from 0 to 2 (preferably 0); or C(R 38 ), where R 38 is hydrogen, alkyl or alkoxy;
  • R 36 hydrogen; alkyl; alkenyl; -COOH; or, if R 13 is -C*(R 33 ), R 36 may be linked to C* to form a 3-membered carbocyclic ring;
  • R 37 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring;
  • t and u are, independently, 0 or 1;
  • R 39 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl or alkenyl);
  • X 2 is oxygen, or S(O) v , where v is an integer from 0 to 2 (preferably 0); (4) X 3 is nitrogen; N(R 40 ); N+(R 41 )(R 42 ); or R 43 -N(R 41 ); and is linked to R 14 by a single or double bond; or, if R 14 is nil, X 3 is linked to B by a single or double bond (preferably X 3 is nitrogen, N(R 40 ) or N+(R 41 )(R 42 )); where
  • R 41 and R 42 are, independently, hydrogen; alkyl; alkenyl; carbocyclic rings; heterocyclic rings; or, if R 6 is R 16 X, then R 41 and R 42 together with
  • Q may comprise a heterocyclic ring as R 16 ;
  • R 43 is N(R 41 ), oxygen or sulfur
  • X 4 is oxygen, sulfur, NR 40 , or R 43 -NR 41 (preferably oxygen, sulfur or NR 40 );
  • Y 3 is oxygen, sulfur, NR 40 or N+(R 41 )(R 42 );
  • Y 4 is oxygen or NR 41 (preferably oxygen);
  • Z is nil, oxygen, sulfur, nitrogen, NR 40 , or N(R 41 )-R 43 (preferably oxygen, sulfur, nitrogen or NR 40 );
  • lactam-containing moieties include cephems, isocephems, iso-oxacephems, oxacephems, carbacephems, penicillins, penems, carbapenems, and monocyclic beta-lactams. Particularly preferred are cephems, penems, carbapenems and monocyclic beta-lactams.
  • R 10 in formula (II), is any radical that may be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of an antimicrobially-active lactam.
  • antimicrobially-active lactam refers to a lactam-containing compound, without a quinolonyl substituent moiety, which has antimicrobial activity.
  • This "active" position is beta (i.e., 7-beta) for cephems, oxacephems and carbacephems (for example).
  • the active position is alpha for penems, carbapenems, clavems and clavams.
  • 5-(N-heterosubstituted amino) quinolones can be prepared by the following procedure:
  • reaction sequence can be envisioned as a nucleophilic aromatic displacement of the quinolone 5-halogen substituted by
  • 5-(N-heterosubstituted amino)quinolones can be prepared by the following procedure:
  • the reaction sequence can be envisioned as a selective nucleophilic aromatic displacement of the quinolone 5-halogen substitutent by (R 4 )(R 5 )N-NH 2 to form the 5-(N-heterosubstituted amino)quinolones.
  • the reaction can preferably be carried out in a nonpolar aprotic solvent, preferably benzene, toluene, xylene, etc., at an elevated temperature, preferably 50°C to reflux.
  • compositions of this invention comprise:
  • a “safe and effective amount" of a 5-(N-heterosubstituted amino) quinolone is an amount that is effective, to inhibit microbial growth at the site of an infection to be treated in a human or lower animal subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
  • the specific "safe and effective amount” will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the 5-(N-heterosubstituted amino) quinolone therein, and the dosage regimen desired for the composition.
  • compositions of this invention are preferably provided in unit dosage form.
  • a "unit dosage form” is a composition of this invention containing an amount of a 5-(N-heterosubstituted amino) quinolone that is suitable for administration to a human or lower animal subject, in a single dose, according to good medical practice.
  • These compositions preferably contain from about 30 mg to about 20,000 mg, more preferably from about 50 mg (milligrams) to about 7000 mg, more preferably from about 500 mg to about 3500 mg, of a 5-(N-heterosubstituted amino) quinolone.
  • compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical or parenteral administration.
  • a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances.
  • Optional pharmaceutically-active materials may be included, which do not substantially interfere with the antimicrobial activity of the 5-(N-heterosubstituted amino) quinolone.
  • the amount of carrier employed in conjunction with the 5-(N-heterosubstituted amino) quinolone is sufficient to provide a practical quantity of material for administration per unit dose of the 5-(N-heterosubstituted amino) quinolones.
  • Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker & Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
  • pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.
  • Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil.
  • the pharmaceutically-acceptable carrier, in compositions for parenteral administration comprises at least about 90% by weight by the total composition.
  • oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the 5-(N-heterosubstituted amino) quinolone. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
  • Preferred carriers for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil.
  • compositions of this invention can also be administered topically to a subject, i.e., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject.
  • Such compositions include, for example, lotions, creams, solutions, gels and solids.
  • These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1%, and preferably from about 1% to about 5%, of the 5-(N-heterosubstituted amino) quinolone.
  • Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water.
  • the carrier is organic in nature and capable of having dispersed or dissolved therein the 5-(N-heterosubstituted amino) quinolone.
  • the carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, and solvents.
  • This invention also provides methods of treating or preventing an infectious disorder in a human or other animal subject, by administering a safe and effective amount of a 5-(N-heterosubstituted amino) quinolone to said subject.
  • an "infectious disorder” is any disorder characterized by the presence of a microbial infection.
  • Preferred methods of this invention are for the treatment of bacterial infections.
  • infectious disorders include (for example) central nervous system infections, external ear infections, infections of the middle ear (such as acute otitis media), infections of the cranial sinuses, eye infections, infections of the oral cavity (such as infections of the teeth, gums and mucosa), upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients (such as patients receiving cancer chemotherapy, or organ transplant patients).
  • central nervous system infections for example, central nervous system infections, external ear infections, infections of the middle ear (such as acute otitis media), infections of the cranial sinuses, eye infections, infections of the oral cavity (such as infections of the teeth, gums and mucosa), upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections,
  • the 5-(N-heterosubstituted amino) quinolones and compositions of this invention can be administered topically or systemically.
  • Systemic application includes any method of introducing the 5-(N-heterosubstituted amino) quinolone into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration.
  • the specific dosage of antimicrobial to be administered, as well as the duration of treatment, are mutually dependent.
  • the dosage and treatment regimen will also depend upon such factors as the specific 5-(N-heterosubstituted amino) quinolone used, the resistance pattern of the infecting organism to the 5-(N-heterosubstituted amino) quinolone used, the ability of the 5-(N-heterosubstituted amino) quinolone to reach minimum inhibitory concentrations at the site of the infection, the nature and extent of other infections (if any), the personal attributes of the subject (such as weight), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
  • Treatment regimens preferably extend from about 1 to about 56 days, preferably from about 7 to about 28 days, in duration.
  • Prophylactic regimens may extend 6 months, or longer, according to good medical practice.
  • a preferred method of parenteral administration is through intramuscular injection.
  • all formulations for parenteral administration must be sterile.
  • individual doses of from about 100 mg to about 7000 mg, preferably from about 500 mg to about 3500 mg, are acceptable.
  • a preferred method of systemic administration is oral. Individual doses of from about 100 mg to about 2500 mg, preferably from about 250 mg to about 1000 mg are preferred.
  • Topical administration can be used to deliver the 5-(N-heterosubstituted amino) quinolone systemically, or to treat a local infection.
  • the amounts of 5-(N-heterosubstituted amino) quinolone to be topically administered depends upon such factors as skin sensitivity, type and location of the tissue to be treated, the composition and carrier (if any) to be administered, the particular 5-(N-heterosubstituted amino) quinolone to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) effects are desired.
  • a solution of approximately 207 g of pentafluorobenzoyl chloride II (0.90 mole) and 250 ml of dioxane is cooled to 15-20°C with an ice water bath and a solution of approximately 126 g of I and 90.9 g of triethylamine (0.90 mole) in 300 ml of dioxane is added dropwise over 5.5 hours.
  • the addition funnel is rinsed with an additional 50 ml of dioxane and the reaction is stirred at 20°C overnight.
  • the mixture is then vacuum filtered and the precipitate is washed twice with 100 ml portions of dioxane.
  • the filtrate is vacuum stripped at 25°C and 1000 ml of hexane is added to the residue. More precipitate is collected and added to the first batch.
  • the combined product is then resuspended in 1500 ml of hexane, stirred briefly, filtered and vacuum dried to give III.
  • the mixture is neutralized to pH 7 with approximately 5 ml of acetic acid and is extracted three times with chloroform.
  • the dried chloroform extracts are evaporated to give a slurry which is triturated with 400 ml of boiling ethanol.
  • the resulting solids are filtered at room temperature.
  • An additional wash with 100 ml of cold ethanol followed by vacuum drying gives IV.
  • a mixture of IV (22g. 0.070 mole) and 2N H 2 SO 4 (600 ml) is stirred at 100°C for 20 hours and allowed to cool to room temperature.
  • the product V is collected by filtration, washing with water.
  • a mixture of VI (4.0g, 0.0086 mole), acetonitrile (120 ml) and hydrazine monohydrate (4.0 ml, 0.082 mole) is refluxed for 2.5 hours with a solution forming.
  • the solution is diluted with acetonitrile (100 ml) and stirred for 2 hours at room temperature.
  • the precipitate is collected by filtration and heated in acetonitrile (150 ml). Some undissolved material is removed by filtration and the filtrate is stored at room temperature overnight.
  • the product VII is collected by filtration washing with acetonitrile.
  • Monoethyl hydrogenmalonate (13.2g, 0.10 mol) is dissolved in tetrahydrofuran (260 ml) and cooled to -65°C. Then 2M n-butyl lithium (100 ml, 0.20 mol) is added dropwise to maintain a temperature below -50°C. The reaction is warmed to -5°C and recooled to -65°C. Pentafluorobenzoyl chloride 1 (7.20 ml, 0.05 mol) is dissolved in tetrahydrofuran (32 ml) and is added dropwise to keep the temperature below -50°C. After the addition, the reaction was warmed to -35°C and stirred for 1 hr.
  • Aqueous HCl (13%, 316 ml) is added to the solution and stirred for 30 min.
  • the mixture is extracted with CH 2 Cl 2 and washed with aqueous NaHCO 3 followed by water.
  • the organic layer is dried with Na 2 SO 4 and concentrated to give the product 2, which exists as a mixture of keto-enol tautomers in solution.
  • Pentafluorobenzoyl acetic acid ethyl ester 2 (10g, 0.035 mol) is added to acetic anhydride (8.5 ml, 0.09 mol) and triethylortho-formate (10 ml, 0.06 mol). The reaction is heated to 110°C for 2.25 hrs. The reaction is concentrated. The product is dissolved in ethanol (250 ml) and cooled to 0°C. Then 2,4-difluoroaniline (4.7 ml, 0.046 mol) is slowly added and the ice bath is removed. The reaction is stirred overnight and concentrated to dryness under reduced pressure. The residue is triturated in petroleum ether and the product is collected by filtration to give 3 as a mixture of cis-trans isomers.
  • the vinylogous amide 3 (9.43g, 0.022 mol) is dissolved in dimethyl formamide (57.0 ml) and K 2 CO 3 (9.46g, 0.068 mol) is added. The reaction is stirred overnight and then concentrated. Methylene chloride is added and the solution is washed with water. The organic phase is dried over Na 2 SO 4 , concentrated, and vacuum dried to give the quinolone 4.
  • the ester 4 (8.49g, 0.021 mol) is placed in a solution of 8:6:1 acetic acid/water/H 2 SO 4 (309 ml) and is heated to 100oC until the reaction is complete. The solution is poured into ice water, and the precipitate is filtered. The product is recrystallized by dissolving in CH 2 Cl 2 and precipitating out with hexane. The solid is collected to afford the acid 5. The filtrate is concentrated and the residue is purified as previously from CH 2 Cl 2 to give a second crop.
  • the quinolone 5 (10g, 0.027 mol) is dissolved in dimethylformamide (60 ml) and (3S)-t-butoxycarbonyl amino
  • a mixture of methyl propiolate (983 g, 11.7 mole) and 500 ml of tetrahydrofuran is cooled to 5°C and cyclopropylamine (667 g, 11.7 mole) dissolved in 1000 ml of tetrahydrofuran is added over approximately one hour from an addition funnel at a rate to keep the temperature at 3-7°C.
  • the mixture is stirred for an additional hour at 5°C and the ice bath is removed.
  • the reaction is stirred for approximately one hour at 20-25°C at room temperature for 3 hours and is allowed to stand for about 2.5 days at room temperature.
  • the solvent is removed under reduced pressure and the residue is vacuum distilled to give I.
  • a solution of approximately 207 g of pentafluorobenzoyl chloride II (0.90 mole) and 250 ml of dioxane is cooled to 15-20°C with an ice water bath and a solution of approximately 126 g of I and 90.9 g of triethylamine (0.90 mole) in 300 ml of dioxane is added dropwise over 5.5 hours.
  • the addition funnel is rinsed with an additional 50 ml of dioxane and the reaction is stirred at 20°C overnight.
  • the mixture is then vacuum filtered and the precipitate is washed twice with 100 ml portions of dioxane.
  • the filtrate is vacuum stripped at 25°C and 1000 ml of hexane is added to the residue. More precipitate is collected and added to the first batch.
  • the combined product is then resuspended in 1500 ml of hexane, stirred briefly, filtered and vacuum dried to give III.
  • An antimicrobial composition for parenteral administration comprising: Component Amount
  • the above ingredients are mixed, forming a suspension.
  • Approximately 2.0 ml of the suspension is systemically administered, via intramuscular injection, to a human subject suffering from a lower respiratory tract infection, with Streptococcus pneumonia present. This dosage is repeated twice daily, for approximately 14 days. After 4 days, symptoms of the disease subside, indicating that the pathogen has been substantially eradicated.
  • An enteric coated antimicrobial composition for oral administration is made comprising the following core tablet:
  • the components are admixed into a bulk mixture.
  • Compressed tablets are formed, using tabletting methods known in the art.
  • the tablet is then coated with a suspension of methacrylic acid/methacrylic acid ester polymer in isopropanol/acetone.
  • a human subject having a urinary tract infection with Escherichia coli present, is orally administered two of the tablets, every 8 hours, for 14 days. Symptoms of the disease then subside, indicating substantial eradication of the pathogen.

Landscapes

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

Abstract

On décrit des composés antimicrobiens à base de 5-(N-amino hétérosubstitué) quinolone de formule générale (I), où (1) R?1, R2 et R3¿ forment l'une quelconque des variétés de quinolone et de structures hétérocycliques apparentées similaires à celles connues des spécialistes pour présenter une activité antimicrobienne; et (2) a) R4 et R5 représentent chacun hydrogène, alkyle inférieure, cycloalkyle, hétéroalkyle ou-C(=O)-X-R8, où X représente une liaison covalente, N, O ou S, et où R8 représente alkyle inférieur, alcényle inférieur, arylalkyle, un cycle carbocyclique ou un cycle hétérocyclique; ou bien b) R4 et R5 représentent ensemble un cycle hétérocyclique qui inclut l'atome d'azote auquel ils sont liés. On décrit aussi certains de leurs sels et de leurs esters biohydrolysables qui sont pharmaceutiquement acceptables ainsi que certains solvats de ces derniers.
PCT/US1993/010091 1992-10-30 1993-10-22 Derives antimicrobiens de 5-hydrazino-quinolone WO1994010163A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
RU95110762A RU2126000C1 (ru) 1992-10-30 1993-10-22 Производные 5-гидразинохинолона, композиция для лечения или профилактики инфекционного заболевания, способ лечения или профилактики
AU54097/94A AU687018B2 (en) 1992-10-30 1993-10-22 Antimicrobial 5-hydrazino-quinolone derivatives
EP93924393A EP0666853A1 (fr) 1992-10-30 1993-10-22 Derives antimicrobiens de 5-hydrazino-quinolone
JP6511167A JPH08502750A (ja) 1992-10-30 1993-10-22 抗菌５−ヒドラジノ−キノロン誘導体
KR1019950701690A KR950704301A (ko) 1992-10-30 1993-10-22 항미생물제 5-히드라지노-퀴놀론 유도체(antimicrobial 5-hydrazino-quinolone derivatives)
BR9307347A BR9307347A (pt) 1992-10-30 1993-10-22 Derivados de 5-hidrazino-quinolina antimicrobianos
SK547-95A SK54795A3 (en) 1992-10-30 1993-10-22 Antimicrobial 5-hydrazino-quinoline derivatives
PL93308671A PL178094B1 (pl) 1992-10-30 1993-10-22 Nowe pochodne 5-hydrazynochinolonu o działaniu przeciwdrobnoustrojowym
FI952049A FI952049A0 (fi) 1992-10-30 1995-04-28 Antimikrobiset 5-hydratsino-kinolonijohdannaiset
NO951640A NO951640L (no) 1992-10-30 1995-04-28 Antimikrobielle 5-hydrazinokinolonderivater

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96896092A 1992-10-30 1992-10-30
US07/968,960 1992-10-30

Publications (1)

Publication Number Publication Date
WO1994010163A1 true WO1994010163A1 (fr) 1994-05-11

Family

ID=25514997

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/010091 WO1994010163A1 (fr) 1992-10-30 1993-10-22 Derives antimicrobiens de 5-hydrazino-quinolone

Country Status (21)

Country Link
EP (1) EP0666853A1 (fr)
JP (1) JPH08502750A (fr)
KR (1) KR950704301A (fr)
CN (1) CN1064357C (fr)
AU (1) AU687018B2 (fr)
BR (1) BR9307347A (fr)
CA (1) CA2148003A1 (fr)
CZ (1) CZ282581B6 (fr)
EG (1) EG20543A (fr)
FI (1) FI952049A0 (fr)
HU (1) HUT72072A (fr)
IL (1) IL107323A (fr)
MX (1) MX9306814A (fr)
NO (1) NO951640L (fr)
NZ (1) NZ257470A (fr)
PL (1) PL178094B1 (fr)
RU (1) RU2126000C1 (fr)
SG (1) SG59979A1 (fr)
SK (1) SK54795A3 (fr)
WO (1) WO1994010163A1 (fr)
ZA (1) ZA938089B (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995029894A1 (fr) * 1994-04-28 1995-11-09 The Procter & Gamble Company Nouveaux antimicrobiens comprenant la quinolone 5-(n-heterosubstitue amino)
WO1996004286A1 (fr) * 1994-08-02 1996-02-15 The Procter & Gamble Company Procede d'obtention d'antimicrobiens a base de quinolonyle lactame et nouveaux composes intermediaires
WO1996004247A1 (fr) * 1994-08-02 1996-02-15 The Procter & Gamble Company Procede d'elaboration de composes antimicrobiens
WO1997029102A1 (fr) * 1996-02-09 1997-08-14 Toyama Chemical Co., Ltd. Derives de l'acide quinolonecarboxylique et leurs sels
WO2008115890A2 (fr) * 2007-03-19 2008-09-25 Takeda Pharmaceutical Company Limited Inhibiteurs de mapk/erk kinase
US7709498B2 (en) 2005-06-08 2010-05-04 Janssen Pharmaceutica N.V. Quinoline derivatives as antibacterial agents

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PT1901749T (pt) * 2005-05-18 2016-11-04 Raptor Pharmaceuticals Inc Fluoroquinolonas aerossolizadas e suas utilizações
US8546423B2 (en) 2005-05-18 2013-10-01 Mpex Pharmaceuticals, Inc. Aerosolized fluoroquinolones and uses thereof
EA010601B1 (ru) * 2005-06-09 2008-10-30 Янссен Фармацевтика Н.В. Производные хинолина в качестве антибактериальных агентов
CN101020647B (zh) * 2007-02-14 2011-03-30 杭州师范学院 一种β-环丙胺基丙烯酸(酯)的合成方法
EP3092901B1 (fr) * 2007-10-05 2020-04-29 Senhwa Biosciences, Inc. Analogues de quinolone et procédés associés
WO2009147616A1 (fr) * 2008-06-03 2009-12-10 Actelion Pharmaceuticals Ltd Dérivés de [4-(1-amino-éthyl)-cyclohexyl]-méthyl-amine et de [6-(1-amino-ethyl)-tétrahydro-pyran-3-yl]-méthyl-amine
MX345158B (es) 2008-10-07 2017-01-18 Raptor Pharmaceuticals Inc Formulaciones de fluoroquinolona en aerosol para farmacocinetica mejorada.
HUE050147T2 (hu) 2008-10-07 2020-11-30 Horizon Orphan Llc Tüdõgyulladás csökkentése levofloxacin belélegzése útján
AR076222A1 (es) * 2009-04-09 2011-05-26 Actelion Pharmaceuticals Ltd Derivados 2-hidroxietil-1h-quinolin-ona y sus analogos azaisotericos con actividad antibacteriana y composiciones farmaceuticas que los contienen
AU2010289326B2 (en) 2009-09-04 2015-09-24 Horizon Therapeutics U.S. Holding Llc Use of aerosolized levofloxacin for treating cystic fibrosis

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668680A (en) * 1985-12-12 1987-05-26 Warner-Lambert Company 5-amino-6,8-difluoroquinolones as antibacterial agents
EP0350733A2 (fr) * 1988-07-15 1990-01-17 Bayer Ag Dérivés d'acides 7-(1-pyrrolidinyl)-3-quinolone et -naphtyridone carboxyliques, procédé pour leur préparation
WO1991016327A1 (fr) * 1990-04-18 1991-10-31 Norwich Eaton Pharmaceuticals, Inc. Quinolonyle lactames anti-microbiens
WO1992009596A1 (fr) * 1990-11-30 1992-06-11 Warner-Lambert Company Stereoisomeres individuels de 7-[3-(aminoalkyl)-1-pyrrolidinyl]-quinolones et de naphtyridones utilises comme agents antibacteriens

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0228178A (ja) * 1988-04-23 1990-01-30 Toyama Chem Co Ltd 新規なピリドンカルボン酸誘導体およびその塩並びにそれらの製造法
WO1991002526A1 (fr) * 1989-08-16 1991-03-07 Pfizer Inc. Acides azabicyclo quinolone carboxyliques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4668680A (en) * 1985-12-12 1987-05-26 Warner-Lambert Company 5-amino-6,8-difluoroquinolones as antibacterial agents
EP0350733A2 (fr) * 1988-07-15 1990-01-17 Bayer Ag Dérivés d'acides 7-(1-pyrrolidinyl)-3-quinolone et -naphtyridone carboxyliques, procédé pour leur préparation
WO1991016327A1 (fr) * 1990-04-18 1991-10-31 Norwich Eaton Pharmaceuticals, Inc. Quinolonyle lactames anti-microbiens
WO1992009596A1 (fr) * 1990-11-30 1992-06-11 Warner-Lambert Company Stereoisomeres individuels de 7-[3-(aminoalkyl)-1-pyrrolidinyl]-quinolones et de naphtyridones utilises comme agents antibacteriens

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995029894A1 (fr) * 1994-04-28 1995-11-09 The Procter & Gamble Company Nouveaux antimicrobiens comprenant la quinolone 5-(n-heterosubstitue amino)
WO1996004286A1 (fr) * 1994-08-02 1996-02-15 The Procter & Gamble Company Procede d'obtention d'antimicrobiens a base de quinolonyle lactame et nouveaux composes intermediaires
WO1996004247A1 (fr) * 1994-08-02 1996-02-15 The Procter & Gamble Company Procede d'elaboration de composes antimicrobiens
US5703231A (en) * 1994-08-02 1997-12-30 The Procter & Gamble Company Process for making antimicrobial compounds
US5801242A (en) * 1994-08-02 1998-09-01 The Procter & Gamble Company Process for making quinolonyl lactam antimicrobials and novel intermediate compounds
WO1997029102A1 (fr) * 1996-02-09 1997-08-14 Toyama Chemical Co., Ltd. Derives de l'acide quinolonecarboxylique et leurs sels
US7709498B2 (en) 2005-06-08 2010-05-04 Janssen Pharmaceutica N.V. Quinoline derivatives as antibacterial agents
WO2008115890A2 (fr) * 2007-03-19 2008-09-25 Takeda Pharmaceutical Company Limited Inhibiteurs de mapk/erk kinase
WO2008115890A3 (fr) * 2007-03-19 2009-04-30 Takeda Pharmaceutical Inhibiteurs de mapk/erk kinase
JP2010522191A (ja) * 2007-03-19 2010-07-01 武田薬品工業株式会社 Ｍａｐｋ／ｅｒｋキナーゼ阻害剤
US8063066B2 (en) 2007-03-19 2011-11-22 Takeda Pharmaceutical Company Limited MAPK/ERK kinase inhibitors

Also Published As

Publication number Publication date
CZ109795A3 (en) 1995-12-13
IL107323A (en) 2000-06-01
RU95110762A (ru) 1997-01-10
MX9306814A (es) 1994-07-29
NZ257470A (en) 1997-08-22
NO951640L (no) 1995-06-30
SG59979A1 (en) 1999-02-22
CA2148003A1 (fr) 1994-05-11
KR950704301A (ko) 1995-11-17
HUT72072A (en) 1996-03-28
FI952049A (fi) 1995-04-28
CN1092773A (zh) 1994-09-28
IL107323A0 (en) 1994-01-25
PL178094B1 (pl) 2000-02-29
PL308671A1 (en) 1995-08-21
BR9307347A (pt) 1999-05-25
ZA938089B (en) 1994-06-07
AU687018B2 (en) 1998-02-19
AU5409794A (en) 1994-05-24
EP0666853A1 (fr) 1995-08-16
CN1064357C (zh) 2001-04-11
HU9501237D0 (en) 1995-06-28
FI952049A0 (fi) 1995-04-28
NO951640D0 (no) 1995-04-28
CZ282581B6 (cs) 1997-08-13
SK54795A3 (en) 1995-12-06
RU2126000C1 (ru) 1999-02-10
EG20543A (en) 1999-07-31
JPH08502750A (ja) 1996-03-26

Similar Documents

Publication Publication Date Title
AU659996B2 (en) Antimicrobial quinolone thioureas
US5672600A (en) Antimicrobial dithiocarbamoyl quinolones
US5646163A (en) Quinolone 5-(N-heterosubstituted amino) antimicrobials
AU687018B2 (en) Antimicrobial 5-hydrazino-quinolone derivatives
CA2001205C (fr) Quinolonyl lactams antimicrobiens
US5180719A (en) Antimicrobial quinolonyl lactam esters
CA2001201C (fr) Quinolonyl lactams antimicrobiens esters
AU7764391A (en) Penicillan or cephalosporin derivatives of quinolonyl
HU211319A9 (hu) Mikrobaellenes kinolon-tiokarbamidok Az átmeneti oltalom az 1-22. igénypontokra vonatkozik.
IL92092A (en) Diethylcarbamoil quinolones and pharmaceutical preparations containing them
HU211332A9 (hu) Mikrobaellenes ditiokarbamoil-kinolonok Az átmeneti oltalom a(z) 1*29. igénypontra vonatkozik.
HU211676A9 (hu) Mikrobaellenes kinolonil-laktám-észterek

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CZ FI HU JP KP KR KZ LK LV MG MN MW NO NZ PL RO RU SD SK UA UZ VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1993924393

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 257470

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2148003

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 54795

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: PV1995-1097

Country of ref document: CZ

Ref document number: 952049

Country of ref document: FI

WWP Wipo information: published in national office

Ref document number: 1993924393

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1995-1097

Country of ref document: CZ

WWG Wipo information: grant in national office

Ref document number: PV1995-1097

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1993924393

Country of ref document: EP