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.
• the chemical and medical literature describes a myriad of compounds that are said to be 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), lincos- aminides, macrolides, nltrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides.
• antibacterials and other antimicrobials are described in Antibiotics. Chemotheraoeutics. and Antibacterial Aoents 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-lacta 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 icrobial 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. Marchba ⁇ s 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.
• 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. It has been found that the compounds of this invention, and compositions containing these compounds, 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. DESCRIPTION OF THE INVENTION
• 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- and R 7 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and (b) R 2 is hydrogen, halogen, lower alkyl, or lower alkoxy (preferably halogen); or (2) (Preferably) Rl and R 2 may together comprise a six- membered heterocyclic ring that includes N' and the carbon atom to which R is bonded; (B) R3 is a heterocyclic ring or a carbocyclic ring
• R 4 and R5 are, independently, hydrogen; lower alkyl; cycloalkyl; heteroalkyl; or -C(»0)-X-R 8 (preferably hydrogen or lower alkyl), where X is a covalent bond, N, 0, or S, and R 8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or (2) (Preferably) R 4 and R- together comprise a hetero ⁇ cyclic 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 ilkenyl (i.e., -0-alkyl or -0-alkenyl).
• Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
• Alkylamino 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., -0-aryl).
• Preferred alkylacyl groups include (for example) acetyl, formyl, and propionyl.
• Acylamino is an amino radical having an acyl substituent (i.e., -N-acyl); for example, -NH-C(-O)-alkyl .
• "Halo”, “halogen”, or “halide” 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. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al . , published September 11, 1987 (incorporated by reference herein).
• 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-hetero- substituted 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 , pivaloylox- ymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthal idyl and thiophthal idyl 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 , pivaloylox- ymethyl and pivaloyloxyethyl
• 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-di ethylformamide) .
• 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, a inoalkyl (e.g., a inomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl , heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrol idinyl , etc.), imino, thioxo, hydroxyalkyl , aryloxy, arylalkyl, and combinations thereof.
• a inoalkyl e.g., a inomethyl, etc.
• cyano halo
• carboxy alkoxyaceyl
• thiol e.g., aryl, cycloalkyl, heteroaryl , heterocycloal
• Groups Rl, 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 Che . 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. Klopman et al . , 31 Antimicrob. Agents Chemother.
• Rl is preferably alkyl, alkenyl, aryl, cycloalkyl, a heterocyclic ring, or alkylamino. More preferably, Rl is ethyl, 2-fluoroethyl, 2-hydroxyethyl , t-butyl, 4-fluorophenyl, 2, -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 Rl groups.
• Preferred 5-(N-heterosubstituted amino) quinolones also include those where Rl and R together comprise a 6-membered heterocyclic ring, according to the formula:
• R is preferably chlorine, fluorine, methoxy, or methyl. Fluorine and chlorine are particularly preferred R 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, piperi- dine, morpholine, diazab " icyclo[3.1.1]heptane, diazabicy- clo[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-ethylaminomethylpyrrolidine, 3,5-dimethylpyridine, N-methylpiperazine and 3,5-dimethylpiper- azine.
• R 4 and R5 groups include those where R 4 and R- together comprise a heterocyclic ring containing the nitrogen atom to which they are bonded, those where both R 4 and R5 are lower alkyl, those where one of R 4 or R5 is hydrogen and the other is lower alkyl, and those where both R 4 and R5 are hydrogen. More preferred groups are where one of R 4 or R5 is hydrogen and the other is alkyl and those where both R 4 and R5 are hydrogen. Particularly preferred groups are where both R 4 and R5 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, diazabic- yclo[3.2.1]octane, diazabiclyo[2.2.2]octane, and imidazolidine) and R 4 and R- groups that allow the nitrogen atom to which they are bonded to be basic (including, e.g., where R 4 and R- 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, diaza
• Particularly preferred compounds are those where the R 3 group is one of piperazine, 3-methylpiperazine, 3-amino- pyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylamino- pyrrolidine, N-ethylaminomethylpyrrolidine, 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: Q - L - B wherein Q, L and B are defined as follows: (I) Q is a structure according to Formula (I)
• R 7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R 8 )(R 9 ) (preferably hydrogen or halogen), and (ii) R 8 and R 9 are, independently, R 8a , where R 8a -j S 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; (2) A2 is N or C(R2) (preferably C(R2)); where R is hydrogen or halogen;
• a 3 is N or (preferably) C(R5); where R$ is hydrogen;
• Rl 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 5 or Rl ⁇ X; where R 5 is a substituent moiety of L and is nil, alkyl, heteroalkyl, or alkenyl; Rl ⁇ 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;
• Rl and R 7 may together comprise a heterocyclic ring including N' and Al;
• R and R 3 may together comprise -0-(CH2)n-0- . 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 R5 are bonded and the carbon atom of Formula (I) to which said carbon atoms are bonded;
• Rl and R 5 may together comprise a heterocyclic ring including N' and the adjacent carbon to which R5 is bonded;
• (II) B is a structure according to Formula (II), where L is bonded to Rl 4 :
• m is an integer from 0 to 9 (preferably from 0 to 3);
• Rl7 i hydrogen, alkyl, alkenyl, heteroalkyl, hetero- alkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl, a carbocyclic ring, or a heterocyclic ring);
• Rl8 is Rl 7 , -Yl, or -CH( ⁇ 2)(Rl 7 );
• Rl 9 is Rl 7 , arylalkyl, heteroarylalkyl , -C(R22)(R23)C00H, -C(-0)0-Rl 7 , or -C(-0)NH-Rl 7 , where R22 and R23 are, independently, Rl 7 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which
• R22 and R 23 are bonded (preferably Rl or -C(R22)(R23)C00H)
• R20 is Rl9, halogen, -Yl, or -CH( ⁇ 2)(Rl 7 ) (preferably R or halogen); (6) ⁇ l is -C(»0)0R21, -C( «0)R21, -N(R2 4 )R21, 0 r -S(0) p R29 or -0R29; and ⁇ is Yl or -OH, -SH, or -SO3H;
• (a) p is an integer from 0 to 2 (preferably 0);
• R is hydrogen; alkyl; alkenyl; heteroalkyl; hetero- alkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(-0)R25; or, when Rl8 is
• R24 may comprise a moiety bonded to R21 to form a heterocyclic ring
• R25 is RI 7 , NH(Rl 7 ), N(Rl 7 )(R26), 0(R26), 0 r S(R26) (preferably Rl 7 , NH(Rl 7 ) or N(R1 7 )(R26J) .
• w ere R26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring or (preferably) when R25 is N(R1 7 )(R26).
• R26 ma y comprise a moiety bonded to R 7 to form a hetero ⁇ cyclic ring; and (7) R 1 is R 9 or hydrogen; where R 29 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl ; heteroarylalkyl ; a carbocyclic ring; a heterocyclic ring; or, when ⁇ l is N(R24)R21 and R 2 1 is R 29 , R21 an( j R24 m ay 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 ;
• Rl 2 is -C(R 8 a)-, or -CH2-R 28 - (preferably -C(R 8 a)-); where R 28 is -C(R ⁇ a), -0-, 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 Rl 2 is (1) (preferably) -C(R 8 a)( ⁇ l)-, where
• R 33 is hydrogen or COOH (preferably COOH), and C* is linked to
• R 3( 5 to form a 3-membered ring; (2) if bond "b" is a double bond, Rl 3 is -C(R 33 ) ; or (3) if bond "b” is nil, Rl 3 is hydrogen, -SO3H, -P0(0R )0H, -C(0)NHS0 2 N(R 34 )(R 3 5), -OSO3H, -CH(R 35 )C00H, or -0CH(R 3 )C00H (preferably -SO3H, or -C(0)NHS02N(R 3 )(R 35 ); where R 34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R-- is hydrogen, alkyl, alkenyl, or -NHR 8a ; or (preferably), if R 3 is -C(0)NHS02N(R 34 ) (R 5), R 34 and R 35 may together comprise a heterocyclic
• Rl 4 is -C(R 8a )(R 38 )-W-C"'-R 37 -;
• W is 0; S(0) 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 Rl 3 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, heteroal enyl , a carbocyclic ring, or a heterocyclic ring (preferably alkyl or alkenyl);
• X 2 is oxygen, or S(0) v , where v is an integer from 0 to 2 (preferably 0); (4) X 3 is nitrogen; N(R 4 0); N+(R 1)(R 42 ) ; or R 43 -N(R 1); and is linked to R 4 by a single or double bond; or, if Rl 4 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 4 1)(R 42 )); where
• R 4 1 and R 4 2 are, independently, hydrogen; alkyl; alkenyl; carbocyclic rings; heterocyclic rings; or, if R 6 is Rl6 ⁇ , then R i and R 42 together with
• Q may comprise a heterocyclic ring as Rl ⁇ ;
• R 43 is N(R 4 1), oxygen or sulfur
• X 4 is oxygen, sulfur, NR 40 , or R 3 -NR 1 (preferably oxygen, sulfur or NR 40 ); (6) Y 3 is oxygen, sulfur, NR 40 or N+(R41)(R42) ;
• Y 4 is oxygen or NR 4 1 (preferably oxygen);
• Z is nil, oxygen, sulfur, nitrogen, NR 40 , or N(R 1)-R 43 (preferably oxygen, sulfur, nitrogen or NR 40 );
• Q' is said R 6 substituent of Q; and (10) Q" is Q'; or together with ⁇ , X 3 , Z or Z', is said R- substituent of Q; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.
• 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.
• RlO 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:
• R 4 and R- are previously defined and [5-Halo-Quinolone] is an appropriately protected 5-halogen substituted quinolone where the halogen is preferably chloro or fluoro (preferably fluoro).
• 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:
• R 4 and R- are previously defined and [5,7-Dihalo-Quinolone] is an appropriately protected 5- and 7- halogen substituted quinolone where the halogen at positions 5 and 7 is independently a chloro or fluoro (preferably fluoro).
• the reaction sequence can be envisioned as a selective nucleophilic aromatic displacement of the quinolone 5-halogen substitutent by (R 4 )(R 5 )N-NH2 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-hetero- substituted 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 phar aceutically-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, - _ib- 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-hetero- substituted 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-hetero- substituted 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 immuno- suppressed 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-hetero- substituted 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 H2SO4 (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.
• the solid is stirred in acetonitrile (180 ml) for 10 minutes and the product VI is collected by filtration, washing with acetonitrile (2 x 60 ml).
• 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 HC1 (13%, 316 ml) is added to the solution and stirred for 30 min.
• the mixture is extracted with CH2C12 and washed with aqueous NaHC ⁇ 3 followed by water.
• the organic layer is dried with Na2S04 and concentrated to give the product 2, which exists as a mixture of keto-enol tautomers in solution.
• Pentafluorobenzoyl acetic acid ethyl ester 2 (lOg, 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 dimethylformamide (57.0 ml) and K2CO3 (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 Na2S ⁇ 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/H2S04 (309 ml) and is heated to lOOOC until the reaction is complete. The solution is poured into ice water, and the precipitate is filtered.
• the quinolone 5 (lOg, 0.027 mol) is dissolved in dimethylformamide (60 ml) and (3S)-t-butoxycarbonylamino pyrrolidine (6.0g, 0.032 mol) was added. The reaction is heated to 55°C and triethylamine (7.5 ml, 0.054 mol) is added over 20 min. The reaction is complete in 45 min. as determined by TLC and the heat is removed. The product precipitates out of solution and is filtered. The solid is rinsed with ether. The product is dissolved in hot EtOAc and is precipitated out by the addition of hexanes. The solid is filtered and vacuum dried to afford 6.
• 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 is made comprising: Component Amount
• Carrier sodium citrate buffer witk (percent by weight of carrier): lecithin 0.48% carboxymethyleel1ulose 0.53 povidone 0.50 methyl paraben 0.11 propyl paraben 0.011
• 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.
• EXAMPLE 5 An enteric coated antimicrobial composition for oral administration, according to this invention, 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.

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