IL92031A - Quinolonyl lactams and pharmaceutical compositions containing them - Google Patents

Description

92031/2 ΏΏΊ Quinolonyl lactams and pharmaceutical compositions containing them PROCTER & GAMBLE PHARMACEUTICALS, INC.

C : 78804/2 92031/2 BACKGROUND OF THE INVENTION This invention relates to novel antimicrobial compounds and compositions. The compounds of this invention contain, as integral substltuents, a quinolone moiety and a lactam-containing 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. In particular, antibacterials include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds. They may be classified (for example) as the aminoglycosides, ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincos-aminides, macrolides, nltrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazlnes, polyenes, polyethers, qulnolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described In Antibiotics. Chemotheraoeutics. 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.

The mechanism of action of these antibacterials vary. However, each can be generally classified as functioning in one of four ways: by inhibiting cell wall synthesis or repair; by altering cell wall permeability; by Inhibiting protein synthesis; or by inhibiting synthesis of nucleic acids. For example, beta-lactam antibacterials act through inhibiting the essential penicillin binding proteins (PBPs) in bacteria, which are responsible for cell wall synthesis. On the other hand, quinolones act by inhibiting synthesis of bacterial ONA, thus preventing the bacteria from replicating.

Not surprisingly, the pharmacological characteristics of antibacterials and other antimicrobials, and their suitability for any given clinical use, also vary considerably. For example, the classes of antimicrobials (and members within a class) 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 development of microbial resistance is one factor in the selection of an appropriate antimicrobial (particularly antibacterials), which is of increasing concern in medical science. This "resistance" can be defined as existence of organisms, within a population of a given microbial species, that are less susceptible to the action of a given antimicrobial agent. Such resistant strains may subvert the mechanism of action of a particular antimicrobial, or chemically degrade the antimicrobial before 1t can act. For example, bacterial resistance to beta-lactam antibacterials has arisen through development of bacterial strains that produce beta-lactamase enzymes, which degrade the antibacterial.

In part as a result of the Intense use of antibacterials over extended periods of time, many highly resistant strains of bacteria have evolved. This Is of particular concern In environments such as hospitals and nursing homes, which are characterized by relatively high rates of infection and intense use of antibacterials. See, e.g., W. Sanders, Jr. et al., "Inductible Beta-lactamases: Clinical and Epidemiologic Implications for Use of Newer Cephalosporins", 10 Reviews of Infectious Diseases 830 (1988). Indeed, the development of resistant bacterial strains has led to a concern that pathogenic bacteria may be produced that are essentially resistant to even the newest developed antibacterial agents.

The literature describes many attempts to enhance the efficacy of antimicrobials, and to overcome the development of microbial resistance. Many such attempts involve the combination of antimicrobials. For example, Thabaut et al., 16 Presse Med. 2167 (1987) describes combinations of pefloxacin (a quinolone) with the beta-lactams cefotaxime and cefsulodin. Lenoc et al., 36 Path. Biol. 762 (1988), describes combined use of cephems with aminoglycosides, and with quinolones. Japanese Patent Publication 60/06,617, published January 14, 1985, also describes compositions containing beta-lactams and quinolones. O'Callaghan et al., 10 Antimicrobial Agents and Chemotherapy 245 (1976), describes a mercapto pyridine-substituted cephem, which is said to liberate an active antimicrobial agent when the cephalosporin is hydrolyzed by beta-lactamase. Mobashery et al., 108 sL American Chemical Society 1684 (1986), presents a theory of employing bacterial beta-lactamase in situ to release an antibacterially-active leaving group from the 10-position of a cephem.

However, many such attempts to produce improved antimicrobials yield equivocal results. Indeed, few antimicrobials are produced that are truly clinically-acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology.

SUMMARY OF THE INVENTION The present Invention provides compounds of the formula: 92031/2 -4- wherein (A) Rl is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, Rl°a-0-, Rl°aCH=N-, (RlO)(Rll)N-, Rl2-C(-CHRl5)-C(-0)NH-, R12.C(»N0-R14)-C(-0)NH-, or R13-(CH2)m-C(-0)NH- ; where (1) m is an integer from 0 to 9; (2) R10 and R11 are, independently, R10a where R10A is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring substituent; or R° and R1 together comprise a heterocyclic ring including the nitrogen to which they are bonded; (3) Rl2 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl , a carbocyclic ring, or a heterocyclic ring; (4) Rl3 is Rl2, -Zl, or -CH(Z2) ( l2) ; (5) Rl4 is R12, aryl lkyl, heteroarylalkyl , -C(R17)(R18)C00H, -C(-0)0-Rl2, or -C(«0)NH-Rl2, where Rl7 and R18 are, independently, R12 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which R17 and R18 are bonded; (6) Rl5 is Rl4, halogen, -Z^ , or -CH(Z2)(Rl2) ; (7) Zl is -C(-0)0Rl6, -C(«0)Rl6, -N(R*9)R16, -S(0)pR24, or -0R24; and ∑2 is Z* or -OH, -SH, or -SO3H; (a) p is an integer from 0 to 2; 92031/2 -5- (b) R19 is hydrogen; alkyl ; alkenyl; heteroalkyl; heteroalkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(«0)R20; or, when Rl3 is -CH(Z2)( l2) and ∑2 is -N(R19)R16, R19 may comprise a moiety bonded to R15 to form a heterocyclic ring; and (c) R20 is Rl2, NH(Rl2), N(R12)(R21)> 0(R21), or S(R21); where R21 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R20 is N(Rl2) (R21) R21 may be a moiety bonded to R12 to form a heterocyclic ring; and (8) Rl6 is R 0r hydrogen; where R24 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroaryl lkyi; a carbocyclic ring; a heterocyclic ring; or, when is N(Rl9)Rl6 and R16 is R24, R16 and R9 may together comprise a heterocyclic ring including the nitrogen atom to which R 9 is bonded; R2 is hydrogen, halogen, alkoxy, or R22C(-0)NH- , where R22 is hydrogen or alkyl ; 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; R3 is .c(RlOa)., or -CH2-R23-; where R23 is -C(RlOa), -0-, or -N-, and R23 |s directly bonded to N' in Formula (I) to form a 5-membered ring; except, if bond "a" is nil, then R3 is (1) -C(Rl0a)(Z3)-, where (i) Z3 is -Rl6, -0R25; -S(0)rR25; where r is an integer from 0 to 2; -0C(-0)R25; or -N(R25)R26 ; (ii) R5 and R26 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R25 and R26 together comprise a heterocyclic ring including the nitrogen atom to which R5 and R26 are bonded; or (2) -CH2- 27-; where 27 ,s -C(RlOaj ( 16J , _o-, 0r -NRlO, and R27 is directly bonded to N' in Formula (I) to form a 5-membered ring; (E) (1) if bond "b" is a single bond, R4 is -CH(R28).; OR> F bond "a" is nil; -C(0)NHS02-; or -C*(R28).; if R5 contains an R^2 moiety; where R 8 is hydrogen or COOH, and C* is linked to ^2 o form a 3Tmembered ring; (2) if bond "b" is a double bond, R4 is -C(R28)=; or (3) if bond "b" is nil, R4 is hydrogen, -SO3H, -PO(OR29)OH, -C(O)NHSO2N(R29)(R30)I -OSO3H, -CH(R30)COOH, or -OCH(R29)COOH; where R 9 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R30 is hydrogen, alkyl, alkenyl, or -NHRl°a; or, if R4 is -C(O)NHSO2N(R29)(R30), R29 AND R30 may together comprise a heterocyclic ring including the nitrogen to (F) (1) (2) -W-C"'(R32).R31.24.r34 C.;. or (3) if bond "a" is a single bond and bond "b" is a double bond, R5 is (a) (b) R3 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; (c) R32 iS hydrogen; alkyl; alkenyl; -COOH; or, if R4 is -C*(R28), R32 may be linked to C* to form a 3-membered carbocyclic ring; (d) (1) Z4 1s -0-; -S(0)f, where t is an integer of 0 to 2; or -NR36-; (2) X' is oxygen, sulfur, or R35-NR36; (3) R34 is alkyl, alkenyl, heteroalkyl, heteroalkenyl , a carbocyclic ring, or a heterocyclic ring; 920.31/3 -7- (4) R35 is nil, N(R36), 0r oxygen; (5) R36 is hydrogen, alkyl, : ^alkenyl, a carbocyclic ring, or a heterocyclic ring; (e) C"' is bonded to R4 to form a 5- or 6-membered ring; (G) (1) if X' is sulfur or R 5-NR36, Y is oxygen or Y'; or (2) if X' is oxygen, Y is Y'; where Y' is sulfur or -NR 9; where R3^ is hydrogen, alkyl, oxygen, sulfur, or (RlOa), or if A3 is C(R 1), then R3^ and R4 may together comprise a heterocyclic ring; (H) (1) A is N or C(R40); where R40 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or (R1°)(RH); (2) A2 is N or C(R6); where is hydrogen or halogen; (3) A3 is N or C(R41); where R41 is hydrogen; (4) R8 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, aryl alkyl, or N(R10)(R11); (5) R? is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring; and (7) R9 is hydrogen, halogen, nitro, or N(R10)(RH); (I) except that (1) when A* is C(R40), R8 and R40 may together comprise a heterocyclic ring including N**and A ; (2) when A2 is C(R6), R6 and R7 may together comprise -0-(CH2)n-°-> where n is an integer froa 1 to 4; and (3) when A3 is C(R41), R8 and R41 may together comprise a heterocyclic ring including N" and the adjacent carbon to which R4* is bonded; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

DESCRIPTION OF THE INVENTION The present invention encompasses certain novel quinolonyl lactams, methods for their manufacture (although such methods are not claimed), , dosage forms, and methods of administering the quinolonyl lactams to a human or other animal subject. Specific compounds and compositions to be used 92031/2 -8- in the invention must, accordingly, be pharmaceutically acceptable. As used herein, such a "pharmaceutical ly-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.

Quinolonyl Lactams The compounds of this invention, herein referred to as "quinolonyl lactams", encompass any of a variety of lactam-containing moieties linked, by a non-ester linking moiety, to the 3-carboxy group of a quinolone moiety. These compounds include those of the formula: wherein (A) R1 is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring,~~a heterocyclic ring, Rl°a-0-, Rl°aCH-N-, (R10)(RH)N-, Rl2-C(-CHRl5)-C(-0)NH-, or (preferably) Rl2-C(-NO-Rl4)-C(«0)NH-, or Rl3-(CH2)m-C(«0)NH-; where (1) ra is an integer from 0 to 9 (preferably 0 to 3); (2) RlO and R" are, independently, R*0a where R10* is hydrogen, alkyl, alkenyl, carbocyclic ring, or heterocyclic ring substituents; or RlO ad Rll together comprise a heterocyclic ring Including the nitrogen to which they are bonded; (3) Rl2 iS hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl, a carbocyclic ring, or a heterocyclic ring); 92031/2 - 9 - (4) Rl3 is Rl2, -Zl; or -CH(Z2) (Rl2) ; (5) ' R 1 * is l2, arylalkyl, heteroaryl al kyl , -C(Rl7)(Rl8)C00H, -C(«0)0-Rl2, or -C{«0)NH-Rl2, where RT nd are, independently, R 2 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which R 7 and R 8 are bonded (preferably Rl2 or -C(R17)(R18)C00H ) ; ( 6 ) Rl5 is R 4, halogen, -Z*, or -CH(Z2)(Rl2) (preferabl R1* or halogen); (7) Zl is -C(-0)0Rl6., - C(-0)Rl6, - { R19 ) 16 , -S(0)pR24, 0r -OR24; and Z is Z or -OH, -SH, or - SO3H ; (a) p is an integer from 0 to 2 (preferably 0); (b) Rl5 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroal kenyl ; a carbocyclic ring; a heterocyclic ring; - SO3H ; - C(-0)R20; or, when Rl3 is -CH(Z2)(Rl2) and ∑ is -N ( R19 ) R16 , R1 9 may comprise a moiety bonded to R*6 to form a heterocyclic ring; and (c) R0 is Rl2, NH(Rl2), N(R12)(R21), 0(R21), or S(R21) (preferably Rl2, NH(Rl2), N(R*2) (R21J J ; where R21 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or (preferably) when R20 is N (R12)(R21) R21 may be a moiety bonded to Rl2 to form a heterocyclic ring; and (8) R16 is R2* or hydrogen; where R2 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroal kenyl ; heteroaryl al kyl ; a carbocyclic ring; a heterocyclic ring; or, when Z1 is N(R19)R16 and Rl6 js R24} R16 and Rl9 may together comprise a heterocyclic ring including the nitrogen atom to which R9 is bonded (preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring); R2 is hydrogen, halogen, alkoxy, or R22c(-0)NH- (preferably hydrogen or alkoxy), where R22 is hydrogen or alkyl (preferably hydrogen); bond "a" is a single bond or is nil; and bond Hb" is a single bond, a double bond, or is nil; except bond "a" and bond "b" are not both nil; R3 is -C(RlOa)-, or -CH2-R23- (preferably -C(RlO*)-); where R23 is -C(RlOa), -0-, or -N-, and R23 ,s directly bonded to N' in Formula (I) to form a 5-membered ring; except, if bond "a" is nil, then R is (1) (preferably) -C(Rl0a)(Z3)-, where (i) Z3 is - l6; -OR25; .s(0)rR25, where r is an integer from 0 to 2 (preferably 0); -OC(»0)R25; 0r -N(R25)R26; (ii) R25 and R26 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R25 and R26 together comprise a heterocyclic ring including the nitrogen atom to which R25 and R26 are bonded; or (2) -CH2-R27-; where R27 is -C(RlO«) (R16) , -0-, or -NRlO, and R27 is directly bonded to N' in Formula (I) to form a 5-membered ring; (1) if bond "b" is a single bond, R4 is (preferably) -CH(R28)-; or, if bond "a" is nil; -C(0)NHS02-; or -C*(R28)-; if R5 contains a R32 moiety; where R28 is hydrogen or (preferably) COOH, and C* is linked to R32 to form a 3-membered ring; (2) if bond "b" is a double bond, R* is -C(R28)-; or (3) if bond "b" is nil, R* is hydrogen, -SO3H, -P0(0R29)0H, -C(0)NHS02N(R29)(R30), -OSO3H, -CH(R30)C00H, or -0CH(R29)C00H (preferably -SO3H or -C(0)NHS02N(R29)(R30)); wnere R29 Is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R30 is hydrogen, alkyl, alkenyl, or - HR^a; or (preferably), if R* 1s -C(0)NHS02N(R29)(R30), R29 and R30 may together comprise a heterocyclic ring including the nitrogen to which R29 and R30 are bonded; and (F) (1) if bond "a" or bond "b* is nil, than R6 is X' or Z4-R34-X'; (2) (3) if bond "a" is a single bond and bond "b" is a double bond, R5 is (a) (b) R31 is nil, alkyl, alkenyl, a carbocycl c ring, or a heterocyclic ring; (c) R32 is hydrogen; alkyl; alkenyl; -C00H; or, if R4 fs -C*(R28), R32 ma be linked to C* to form a 3-membered carbocyclic ring; (1) Z4 is -0-; -S(0)t-, where t is an integer of 0 to 2 (preferably 0); or -N 36- ; (2) X' is oxygen, sulfur, or R35-NR 6; (3) 3* is alkyl, alkenyl, heteroalkyl, heteroalkenyl , a carbocyclic ring, or a heterocyclic ring (preferably alkyl or alkenyl ) ; (4) R35 is nil, N(R36), or oxygen; (5) R36 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; (e) C' is bonded to R4 to form a 5- or 6-membered ring; (G) (1) if X' is sulfur or R 5-N 36, γ is γ* 0r (preferably) oxygen; or (2) if X' is oxygen, Y is Y'; where Y' is sulfur or (preferably) -NR39; where 39 is hydrogen, alkyl, oxygen, sulfur, or N(RlO*}, or if A3 is C(R41), then R39 and R may together comprise a heterocyclic ring; (H) (1) Al is N or C(R n); where R ° is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R1°)(RH) (preferably hydrogen or halogen); -12- (2) A2 is N or (preferably) C(R6); where R6 is hydrogen or halogen; (3) A3 is N or (preferably) C(R41); where R41 is hydrogen; (4) R8 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R10)(RU) (preferably alkyl or a carbocycl ic ring) ; (5) R7 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring (preferably a heterocyclic ring); and (7) R9 is hydrogen, halogen, nitro, or N(RlO) (R^) (preferably hydrogen) ; (I) except that (1) when A* is C(R40), R8 and R40 may together comprise a heterocyclic ring including N" and A*; (2) when A2 is C(R6), R6 and R7 may together comprise -0-(CH2)n-0-> where n is an integer from 1 to 4; and (3) when A3 is C(R41), R8 and R41 may together comprise a heterocyclic ring including N" and the adjacent carbon to which R4 is bonded; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

Definitions and Usaoe of Terms: The following is a list of definitions for terms used herein.

"Heteroatom" 1s 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" 1s an unsubstltuted or substituted saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms.

"Alkenyl" 1s an unsubstltuted 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 unsubstltuted 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" 1s a saturated carbocyclic ring radical. Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.

"Heterocyclic ring" is an unsubstltuted 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) thlenyl, furyl, pyrrolyl, pyrldinyl, pyrazlnyl, thlazolyl, pyr1m1dinyl, quinolonyl, and tetrazolyl.

"Alkoxy" Is an oxygen radical having a hydrocarbon chain substHuent, where the hydrocarbon chain Is an alky1 or alkenyl (i.e., -0-alkyl or -0-alkenyl). Preferred alkoxy groups Include (for example) methoxy, ethoxy, propoxy and allyloxy.

"Alkylamlno" 1s an amino radical having one or two alkyl substltuents (I.e., -N-alkyl).

"Arylalkyl" Is an alkyl radical substituted with an aryl group. Preferred aryl alkyl sgroups Include benzyl and phenyl ehtyl .

"Aryl ami no" is an amine radical substituted with an aryl group (i.e., -NH-aryl).

"Aryloxy" is an oxygen radical having a aryl substituent (i.e., -0-aryl).

"Acyl" or "carbonyl" is a radical formed by removal of the hydroxy from an carboxylic acid (i.e., R-C(»0)-). Preferred alkyl acyl groups include (for example) acetyl, foryl, and propionyl .

"Acyloxy" is an oxygen radical having an acyl substituent (i.e., -0-acyl); for example, -O-C(-O) -al kyl .

"Acyl amino" is an amino radical having an acyl substituent (i.e., -N-acyl); for example, -NH-C(»0) -alkyl .

"Halo", "halogen", or "halide" is a chloro, bromo, fluoro or iodo atom radical. Chloro and fluoro are preferred halides.

Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower" alkyl) is a hydrocarbon chain comprised of from 1 to 6, preferably from 1 to 4, carbon atoms.

A "pharmaceutica ly- cceptable 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 choride salts).

A "blohydrolyzable ester" Is an ester of a qulnolonyl lactam that does not essentially Interfere with the antimicrobial activity of the compounds, or that are readily metabolized by a human or lower animal subject to yield an antimicrobial ly-active quinolonyl lactam. Such esters include those that do not Interfere with the biological activity of quinol one antimicrobials or beta- lactam antimicrobials (cephems, for example). Many such esters are known in the art, as described In World Patent Publication 87/05297, Johnston et al., published September 11, 1967, (incorporated by reference herein). Such 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).

As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansen and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorported 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., piperidlnyl, morpholinyl, pyrrolidinyl , etc.), imino, thloxo, hydroxyalkyl , aryloxy, aryl alkyl, and combinations thereof.

Also, as used In defining the structure of the compounds of this Invention, a particular radical may be defined for use as a substituent in multiple locations. For example, the R10a substituent Is defined as a potential substituent of R1, but is also Incorporated Into the definition of other substituents (such as R3, R8, and R9). As used herein, such a radical is Independently selected each time It Is used (e.g., R10a need not be alkyl In all occurrences In defining a given compound of this Invention).

Lactam-contalnlng moieties: Groups R3, R*, and R5, together with bonds "a" and "b", form any of a variety of lactam-contalnlng moieties known n the art to have antimicrobial activity. Such moieties wherein either bond "a" or bond"b" are nil (I.e., do not exist) are monocyclic; If both bonds exist, the structures are blcyclic.

Preferred lactam moieties Include the cephems, oxacephems, and carbacephems of the representative formula: wherein bond "a" is a single bond; bond "b" 1s a double bond; R3 is -C(RlOa).t where RlOa Is hydrogen; R* Is -CH(R28), wnere R*8 Is COOH; and R* 1s -W-C(Rl°a)(R33)-C"'R31-X-, where RlOa and R33 are hydrogen, R31 is methylene, and V is S (for cephems), 0 (for oxacephems), or C(R33) (for carbacephems).

Other preferred lactam moieties Include the Isocephems and 1so-oxacephems of the representative formula: wherein bond "a" 1s a single bond; bond "b" Is a double bond; R3 is -C(RlOa) where Rl°» is hydrogen; R* is -C(R28), where R** 1s COOH; and R* is -C(Rl°«)(R33)-*-<:■'-31-X- where ^t and 33 are each hydrogen, 1 is methylene, and W Is S (for Isocephems) or 0 (for Iso-oxacephems) .

Other preferred lactam-containlng moieties Include the penems, carbapenems and clavems, of the representative formula: wherein bond "a" is a single bond; bond "b" Is a double bond; R3 1s -C(RiOa), where RlO* Is hydrogen; R* is -C(R28)-f where R28 is COOH; and R5 Is -¼-C"'-R31-X-, where R^l IS methylene, and W is S (for penems), C(R33) (for carbapenems), or 0 (for clavems). Such lactam moieties are described In the following articles, all incorporated by reference herein: R. Wise, "In Vitro and Pharmacokinetic Properties of the Carbapenems", 30 Antimicrobial Agents and Chemotherapy 343 (1986); and S. McCombie et al., "Synthesis and In Vitro Activity of the Penem Antibiotics", 8 Medicinal Research Reviews 393 (1988).

Other preferred lactam-containlng moieties of this invention include the penicillins of the representative formula: COOH wherein bond "a" Is a single bond, bond "b" 1s a single bond; R3 1s -C(Rla)., Where RlOa is hydrogen; R* Is -CH(R28). where 28 is COOH; and R5 is -W-C"'(R32)-R31-X- where R2 is methyl, R31 iS methylene, and is S.

Other preferred lactam-contalnlng moieties Include the monocyclic beta-lactams, of the representative formula: wherein bond "a" Is a single bond; bond "b" Is nil; R3 is -C(Rl°a)-, where R*0a Is hydrogen; R5 is X; and R* Is -SO3H (for a monobactam), -PO(0R3)0H (for a monophospham); -C(0)NHS02M(R34)(R35) (for a monocarbam), -OSO3H (for a monosulfactam), -CH(R35)C00H (for nocardicins), or -0CH(R3*)C00H. Such lactam moieties are described In C. Cimarustl et al., "Monocyclic 8-lactam Antibiotics", 4 Medicinal Research Reviews 1 (1984), Incorporated by reference herein.

Other preferred lactam moieties Include the monocyclic beta-lactams of the representative formula: whereln bond "a" Is nil, bond "b" is a single bond; 3 Is -C(Rl0a)(R29). where both R a and R* are hydrogen; and 5 Is X.

Other preferred lactam moieties Include the clavams of the representative formula: wherein bond "a" 1s a single bond; bond "b" 1s a single bond; R3 1s -C(RlOa)., where Rl a Is hydrogen; R* 1s -OU **)-, where *8 is COOH; and R5 1S W-C"'-C-(Rl0a)-R31-x-, where RlOa is hydrogen and R31 Is methylene, and W 1s 0.

Other preferred lactam moieties include the 2,3-methyleno-penams and -carbapenams of the representative formula: wherein bond "a" Is a single bond; bond "b" Is a single bond; R3 1s -C(RlOa)., where RlOa Is hydrogen; R« Is -C*(R28)» where R** 1s COOH; and 5 Is H-C'tRSij-RSl-X-, where R31 IS nil, R32 is linked to C* to form a 3-membered carbocycllc ring, and M Is C(R33) or sulfur.

Lactam moieties of this Invention also nclude the lactlvlcln analogs of the representative formula: wherein bond "a" Is nil; bond "b" 1s a single bond; 3 Is -CH2-R32, where R 2 is 0; R« is -CH(R28)-, where R 8 Is COOH; and R5 IS X.

Other lactam moieties Include the pyrazolldlnones of the representative formul : wherein bond "a" Is a single bond; bond "b" Is a double bond; R3 Is -CH2-R28-, where R28 Is -N-; R* Is -C(R28J-, where R28 is COOH; and R* Is W-C"-R31-X-, where 31 Is methylene, and W 1s C(R33).

Other lactam moieties Include the gamma-actams of the representative formula: wherein bond "a" is a single bond; bond "b" I s nil; R i s -CH2-R28-, where R2* is -C(RlO» and RlO* is hydrogen; R* i s -SO3H, -P0(0R34)0H, -C(0)NHS(>2N(R34)(R35), -OSO3H, -CH(R35)COOH, or -0CH(R34)C00H; and R51$ X.

Preferred lactam-containlng moieties include cephems, isocephems, 1so-oxacephems, oxacephems, carbacephems, penicillins, penems, carbapenems, and monocyclic beta-lactams. Particularly preferred are cephems, penems, carbapenems and monocyclic beta-lactams.

R1 IS any radical that may be substituted at the active stereolsomerlc position of the carbon adjacent to the lactam carbonyl of an antimicrobia y-actlve lactam. (As used herein, the term "antimicrobially-actlve lactam" refers to a lactam-containlng compound, without a qulnolonyl substituent moiety, which has antimicrobial activity.) This "active" position 1s beta (I.e., 7-beta) for cephems, oxacephems and carbacephems (for example). The active position is alpha for penems, carbapenems, clavems and clavams.

Appropriate R1 groups will be apparent to one of ordinary skill In the art. Many such R1 groups are known In the art, as described In the following documents (all of which are Incorporated by reference herein): Cephalosporins and Penicillins: Chemistry and Biology (E. Flynn, editor, 1972); Chemistry and Bloloov of b-Lactam Antibiotics (R. Morln et al., editors, 1987); "The Cephalosporin Antibiotics: Sem1nar-1n-Pr1nt", 34 Drugs (Supp. 2) 1 (J. Williams, editor, 1987); New Beta-Lactam Antibiotics: A Review from Chemistry of Clinical Efficacy of the New Cephalosporins (H. Neu, editor, 1982); M. Sassiver et al., in Structure Activity Relationships amono the Semi -synthetic Antibiotics (D. Perlman, editor, 1977). W. Ourckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics", 24 Anaew. Chem. Int. Ed. Enal . 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 JL Antimicrobial Chemotherapy 5 (1986); European Patent Publication 187,456, Jung, published July 16, 1986; and World Patent Publication 87/05297, Johnston et al., published September 11, 1987.

For penems, carbapenems, clavems and clavams, R1 is preferably lower alkyl, or hydroxy- substituted lower alkyl. Particularly preferred R groups include hydrogen, hydroxymethyl, ethyl, [l(R)-hydroxyethyl], [l(R)-[(hydroxysulfonyl)oxyethyl]], and [1-methyl-l-hydroxyethyl].

Except for penems, carbapenems, clavems and clavams, preferred R* groups are amides, such as: acetyl ami no, preferably substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio substituents; arylglycylamino, preferably N- substituted with heteroaryl carbonyl and cycloheteroalkylcarbonyl substituents; aryl carbonyl ami no; heteroaryl carbonyl mi no; and lower alkoxylmlnoacetyl mino, preferably substituted with aryl and heteroaryl substituents. Particularly preferred R1 groups Include amides of the general formula Rl3-(CH2)m-C(-0)NH- and R13 Is Rl2. Examples of such preferred R1 groups include: [(2-am1no-5-halo-4-thiazolyl)acetyl]am1no; [ ( 4 - ami nopy r 1 d 1 n - 2 -y 1 ) acet 1 ] ami no ; [[(3,5-dichloro-4-oxo-l(4H)-pyr1d1nyl)acetyl]am1no]; [[[2-(am1nomethyl)phenyl]acetyl]amino]; [(lH-tetrazol-l-yl acetyl) mi no]; [ (cyanoacetyl ) ami no] ; [(2-th1enyl acetyl ) amino] ; [[(2-amino-4-thiazoyl)acetyl]ara1no]; and sydnone, 3-[-2-am1no]-2-oxoethy1.

When Rl . 1t Rl3-(CH2)B-C(C-0)NH- , and R^ 1$ -Z*. preferred R1 groups Include the following: [sul faraoyl phenyl acetyl ]aof no; [[(4-pyr1d1nylth1o)acetyl ]am1no] ; [ [ [ (cyanomethyl )th1o)acetyl ] ami no] ; ( S) - { ti (2-aa>tno-2-carboxyethyl ) t 1 o] acetyl ]am1 no] [[[(tr1fluoronethy1)th1o]acety1]an1no] ; and (E)-[[[(2-aminocarbonyl -2-fluoroethenyl )th1o] acetyl ] ami no J .

When Rl Is Rl3-(CH2)m-C(-0)HH-, and is -CH(Z2)(Rl2), preferred R1 groups Include the following: [carboxyphenylacetyl]anino; [(phenoxycarbonyl)pheny1acety1]mino; ( -methyl-2,3-dloxo-l-piperazlnecarbonyl-D-phenylglycyl]- aolno; I[[3-(2-furylmethyleneamlno)-2-oxo-l-ImldazoHdinyl]- carbonyl]amino]phenyl]acetyl]mino; (R)-[(amlnophenylacetyl)amino]; (R)-[[amino( -hydroxyphenyl)acetyl]amino]; (R)-[(amino-1,4-cyclohexadien-1-ylacetyl)amino] ; [(hydroxyphenylacetyl)amino]; (R)-([l[(4-ethyl-2,3-dioxo-l-piperazinyl)carbonyl]mino]- (4-hydroxyphenyl)acetyl]amino]; (R)-([[[(5-carboxy-lH-imidazol -4-yl)carbonyl]amino]phenyl acetyl]amino]; (R)-[[[I(4-hydroxy-6-methy1-3-pyridinyl)carbony1]amino](4 hydroxyphenyl)acetyl]amino]; (R)-[(phenylsulfoacetyl)amino]; (2R,3S)-[[2-[[(4-ethy1-2,3-dioxo-l-piperaz1ny1)carbonyl]- amlno]-3-hydroxy-1-oxobuty1]amino]; [[carbox (4-hydroxyphenyl)acetyl]amino]; (R)-[[amino[3-[(ethylsulfonyl)amino]phenyl]acetyl]amino] ; (R)-[[amino(benzo[b]thien-3-yl)acety1]amino]; (R)-[[amino(2-naphthyl)acety1]am1no]; (R)-[[amino(2-am1no-4-thiazolyl)acety1]am o]; [[[[(6»7-dihydroxy-4-oxo-4H-1-benzopyran-3-y1)carbony1]- amino](4-hydroxyphenyl)acetyl]amino]; (R,R)-[[2-[4-[2-am1no-2-carboxyethyloxycarbonyl]aminophen yl]-2-hydroxyacetyl]am1no]; and (S)-(((5-hydroxy-4-oxo-l(4H)-pyrid1n-2-yl)carbonylam1no(2 am1no-4-thiazolyl)acetyl]amino].

The following are other such preferred R1 groups.

Another preferred R* group is R12-C(«CHR15)-C(»0)NH-groups include (for example) the following structures.

Another class of preferred Rl groups (for lactam-containing moieties other than penems, carbapenems, clavems and clavams) include those of the formula: Rl2-C(-N0-Rl4)-C(-0)NH-.

Examples of this preferred class of R1 groups include: 2-phenyl-2-hydroxyiminoacetyl ; 2-thienyl -2-methoxyiminoacetyl ; and 2-[4-(gamma-D-glutamyloxy)phenyl]-2-hydroxyiminoacetyl .

(Z)[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino] ; [[(2-furanyl (ethoxyimino)acetyl ]amino] ; (Z)-[[(2-amino-4-thiazolyl)[(l-carboxy-l-methyl )ethoxyim- ino]acetyl]amino]; (Z)-[[(2-amino-4-thiazolyl)(1-carboxymethoxyimino)acetyl]amino]; [[(2-amino-4-thiazolyl)[(lH-imidazol-4-ylmethoxy)imino]acet- yl]amino]; (Z)-[[(2-amino-4-thiazolyl-3-oxide)(methoxyimino)acety1]am- ino] ; and (S,Z)-[[(2-amino-4-thiazolyl)[carboxy(3,4-dihydroxyphen- yl)methoxyimino]acetyl]amino].

Suitable R2 groups are among those well-known 1n the art, including those defined In the following documents (all incorporated by reference herein). W. Durckheimer et al . , "Recent Developments in the Field of Beta-Lactam Antibiotics", 24 Anoew, Chem. Int. Ed. Engl. 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 J. Antimicrobial Chemotherapy 5 (1986); and European Patent Publication 187,456, Jung, published July 16, 1986. Preferred R2 groups Include hydrogen, methoxy, ethoxy, propoxy, thiomethyl, halogen, cyano, formyl and formylamino. Particularly preferred R2 groups include hydrogen, methoxy, halogen, and formylamino.

Quinolone Moieties: Groups Al, A2, A3, R8, R7, and R^ form any of a variety of quinolone, naphthyridine or related heterocyclic 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 «L Med Chem. 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. Klopman et al., 31 Antimicrob. Aoents Chemother. 1831 (1987); 31:1831-1840; J. P. Sanchez et al., 31 J. Med. Chem.983 (1988); J. M. Domagala et al., 31 J. Med. Chem.991 (1988); M. P. Wentland et al., In 20 Ann, R.«, He^, Chffl, 145 (D. M. Baily, editor, 1986); J. B. Cornett et al., n 21 Ann. Reo. Med. Chem. 139 (D. M. Bailey, editor, 1986); P. B. Fenandes et al., In 22 An, RW. fte, Cnentt 117 (D. M. Bailey, editor, 1987); R. Albrecht, 21 Proo. Drug Research 9 (1977); and P. B. Fernandes et al., In 23 Ann. Reo. Med. Chem. (R. C. Allen, editor, 1987).

Preferred quinolone moieties Include those where A1 s C(R*), A2 IS C(R6), and A3 Is C(R**) ( .e., qulnolones); Al Is nitrogen, A2 is C(R6), and A3 is C(ft") ( .e., naphthyrldlnes); Al 1s C(R40), A21S C(R6), and A3 is nitrogen (I.e., cnnollne acid derivatives); and where Al Is nitrogen, A21s nitrogen, and A3 IS C(R41) (I.e., pyridopyrimldlne derivatives). More preferred qulnolone moeltles are those where A1 is C(R4°), A is C(R6), and A3 IS C(R*1) (I.e., quinolones); and where A is nitrogen, A∑ is C(R6), and A3 is C(R*1) (i.e., naphthyridines) . Particularly preferred qulnolone moieties are where A* is C(R4°), A2 is C(R6), and A3 is C(R*1) (I.e., quinolones).

R8 is preferably alkyl, aryl, cycloalkyl and alkyl ami no. More preferably, R8 is ethyl, 2-fluoroethyl , 2-hydroxyethyl , t-butyl, 4- fluorophenyl, 2,4-dlfluorophenyl , methylamino and cyclopropyl. Cyclopropyl is a particularly preferred R8 group. Preferred quinolone moieties also include those where Al is C(R4°) and R8 and *° together comprise a 6-membered heterocyclic ring containing an oxygen or sulfur atom.

R6 S preferably hydrogen or halo. More preferably R^ is chlorine or fluorine. Fluorine is a particularly preferred R6 group.

Preferred 9 groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from S 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). Preferred R7 groups include unsubstHuted or substituted pyridine, pi peri -dine, morphoHne, d1azabicyclo[3.l.l]heptane, dlazablcy-clo[2.2.1]heptane, dlazabcyclo [3.2.1] octane, d1azab1cyclo[2.2.2] octane, thlazolldlne, ImdazoUd ne, pyrrole and thiamorphol ine, as well as the following particularly preferred R7 groups nclude p1peraz1ne, 3-methylp1perazine, 3-am1nopyrrol1dine, 3 - mi nomethyl pyrrol 1 d i ne , N , N-d 1 methyhl ami nomethyl pyrrol d 1 ne , N-methyl ami nometh l pyrrol 1d1 ne , N-ethyl ami nomethyl yrrol 1 d 1 ne , pyridine, N-methylp1peraz1ne, and 3,5-dlmethylpiperazine.

Preferred quinolonyl lactams Include those having a 6- luoroquinolone moiety or an 8-halo-6-fluoroqu1nolone moiety, of formula: wherein A¾ is C(R6) and R* is F; A3 is C(R*1); and A1 is C(R4<>) where R*° is hydrogen, fluorine or chlorine. Preferred examples of such quinolone moieties Include: l-cyclopropyl-6-f1uoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-- 3- quino1inecarboxyl1c acid; 7-(3-aminopyrrol1d1nyl)-l-cyclopropyl-6-fl uoro-l,4-dihydro- - oxo - 3 - qu 1 no 1 i necarbox 11c ac 1 d ; 7-[(3-am1nomethyl)pyrro11d1nyl]-l-cyclopropyl-6-fluoro-l,4- d1hydro-4-oxo-3-qu1noHnecarboxyl 1c acid; 7-(3-ara1nopyrrol1dinyl)-8-chloro-l-cyclopropyl-6-f1uoro-l,4- dihydro-4-oxo-3-quinol 1 necarboxy 11c acid; 7- (3-am1 nopyrrol 1 d 1 n 1 ) - 1 -cycl opropyl -6 , 8-d 1 f 1 uoro- 1 , 4- dihydro-4-oxo-3-qu1nol 1 necarbox 11c acid; 7-[(3-afflinomethyl ) pyrrol Idinyl ]-l -cycl opropyl -6,8-d1fluoro÷ l,4-d1hydro-4-oxo-3-quinol1necarboxyl1c acid; 6,8-dl f luoro-1 - (2-f luoroethyl ) -1 , -dihydro-7- (4-methyl -1 - p i peraz 1 ny 1 ) - 4 -oxo - 3 - qu 1 nol 1 necarbox 11c ac 1 d ; l-ethy1-6-fluoro- -d1hydro-4-oxo-7-(I-p1peraz1nyl)-3- quinolinecarboxyllc acid; l-ethy1-6-fluoro-l,4-d1hydro-7-(4-methy1-l-p1peraz1nyl)-4- oxo-3-quinoHnecarboxylic add; 6-fluoro-l,4-d1hydro-l-methylam1no-7-(4-«oethyl-l- p1perazinyl)-4-oxo-3-quinol1necarboxyl1c acid; and l-cyclopropyl -7-[3- (dimethyl aminomethyl ) -l -pyrrol idinyl ]- 6,8-difluoro- 1 ,4-dihydro-4-oxo-3-quinol inecarboxyl ic acid.

The following are other examples of such preferred quinolone moieties.

 Also preferred are qulnolonyl lactams having a 1 ,8-naphthyrldine moiety, of formula: wherein A* s N; A2 I S C< 6) and A3 1s C(R*1) . Preferred examples of such qui nol one moieties Include: 7- (3-a*1nopyrro1 Idlnyl) -1- (2 ,4-dl f 1 uorophenyl ) -6- f 1 uoro- 1 , - d1hydro-4-oxo-l ,8-naphthyr1d1ne-3-carboxy11c acid; and 1 -ethyl -6- 1 uoro- 1 ,4-d1hydro-4-oxo-7- ( 1 -pi peraz nyl ) - 1 ,8- naphthyr1d1ne~3-carboxyl1c acid.

Also preferred are qutnolonyl lactams having a pyridobenzoxazlne or pyrldobenzthlazne moiety, of formula: wherein Al IS C(R*<>); A2 is C(R6); A3 IS C(R«1); and R*0 and ≠ together comprise a linking moiety between h" and A to form a 6-membered, oxygen-containing, heterocyclic ring where X (in this formula) 1s oxygen or sulfur. Preferred examples of such qulnolone moieties Include 9-fluoro-4,7-dihydro-3-methy1-10-(4-methyl-l-piperaz1nyl)-7-oxo-2H-pyrido[l,2,3-de]-l,4-benzoxazlne-6-carboxylic acid; and the following structures.

Also preferred are qul olonyl lactams having an Isothla-zoloqulnoHnedlone or tsoxazoloqulno lnedtone moiety, of formula: wherein R5 Is depicted as R1 and O1 in this formula; A* is C(R40); A2 IS C(R6); A is C(R*1); Y is NR39, and R 9 and R<1 together comprise a moiety forming a 5-membered, substituted, heterocyclic ring.

Preferred examples of such quinolone moieties include 9-cyclopropyl-6-fluoro-2,3,4,9-tetrahydro-7-(l-piperazinyl)iso-thiazolo[5,4-b]quino1 ine-3,4-dione; and: Linking Moieties: Group Y, together with the X subst tuent of Group R5 and C* , form a variet of linking moieties between the Vactam-contalnlng structure and the qulnolone structure of the qulnolonyl lactams. Representative structures for Unking groups are set forth below. (In these structures, R3, R4, R5, and bonds •a" and "b" comprise a cephem or pene structure, for purposes of exemplification only. The linking moieties depicted may be used with any of the lactam-contalning moieties of this Invention.) Thioester linking moiety: wherein X is S, and Y Is oxygen.

Another thioester Unking moiety Is exemplified by the following structure: wherein X Is Z«-R34-X1; ∑♦ Is S, R34 IS ethyl, X* 1s S, and Y Is 0.

Imidate, linking moiety: wherein X s 0, anil V Is NR39, A3 S C(R«), and R39 and R«l together comprise a heterocyclic r ng.

Amide linking moiety: wherein X is R35-N(R36), R35 iS nil, and R36 is hydrogen and Y is oxygen.

Hydrazide linking moiety: wherein X is 35-N(R36), R35 iS N(R36), and R36 iS hydrogen In both occurrences, and Y Is oxygen.

Preferred linking moieties include thloester and amide containing moieties.

The specific physical, chemical, and pharmacological properties of the quinolonyl lactams of this Invention may depend upon the particular combination of the Integral lactam-contalning moiety, qui no lone moiety and Unking moiety comprising the compound. For example, selection of particular Integral moieties may affect the relative susceptibility of the quinolonyl lactam to bacterial resistance mechanisms (e.g., beta- lactamase activity).

Pre erred qulnolonyl lactams include compounds wherein (A) (1) if bond "a" or bond "b" is nil, then R$ is X; (2) if bond "a" and "b" are single bonds, R5 is -W-C"'«C(Rl0a)-R31-X-, or -W-C"'(R32)-R31.X.; 0r (3) if bond "a" is a single bond and bond "b" is a double bond, R5 is -C(Rl0a)(R33)-w-C"'-R31-x-; -W-C(R10»)(R33)-C"'-R31-X"-; -W'-C(Rl°a)(R33)-C"'-R31-X-; W».C(Rl0a)(R33).c"'-R31-S-; or -W-C"' -R31-X- ; where W is 0, or C(R33); W" is sulfur, and X" is oxygen or R35-NR36; and (B) (1) if R5 is -C(Rl0a)(R33)-w-C"'-R31-X-; -W-C(Rl0a)(R33)-C"'-R31-X"-; ; or -W-C"'-R31-X-, Y is oxygen or N-R39; or (2) if R5 is -W"-C(Rl0a)(R33)-C"'.R31.s-, Y is N-R39. Other preferred quinolonyl lactams include compounds having the following specific combinations of lactam-containing moieties, quinolone moieties and linking moieties. 1) Amide-linked cephem quinolones, such as compounds of the following classes. the lactam-containing moiety is a cephem, wherein bond "a" Is a single bond; bond "b" Is a double bond; R is -CH-; R* is -C(C(>2H)-; R5 is -S-CH2-C"'-CH2-NH-; the quinolone moiety Is a structure, wherein A? is -CF-; A3 Is -CH-; and R7 1s a heterocyclic ring; and Y Is oxygen the lactam-containing moiety Is a cephem, wherein bond "a" 1s a sngle bond; bond "b" Is a double bond; R3 1S -CH-; R* Is -C(C02H)-; 5 IS -S-CH2-C"'-CH2-NH-; the qulnolone moiety 1s a 6 -fluoroquinolone, wherein A* 1s -C(R«0)-; A2 is -CF-; A is -CH-; and R7 1s a heterocyclic ring; and Y is oxygen the lactam-containlng moiety is a cephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -S-CH2-C"-CH2-NH-; the quinolone moiety is a naphthyridinone, wherein A* is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen the lactam-containing moiety Is a cephem, wherein bond "a" is a single bond; bond "b" Is a double bond; R2 is -H or -OMe; R* 1S -CH-; R< is -C(C02H)-; R5 is -S-CH2-C"'-CH2-NH-; and Rl is [[(2-thienyl )acetyl]amino], [[(2-amino-4-thia-zolyl )(methoxyimino) acetyl ]amino], [[(4-pyri-dy 1 thio) acet l ] ami no ] , [( phenoxy) acetyl ] ami no ] , [[(2-am1no-4-th1azolyl)acetyl]am1no], [[(2-amino-4-th azolyl )[[(3,4-d1hydroxyphenyl )carbonyl ] ami o] acetyl ] ami no] ; the qulnolone moiety 1s a structure, wherein A? 1s -CF-; A3 IS -CH-; R* 1s -H; A* Is -CH-, -CF-, -CC1-, or -H-; R8 Is cyclopropyl, ethyl, 2, 4 -d1 fluorophenyl, 4- fluorophenyl, or t-buty ; and R7 s a 3-am1no-l -pyrrol 1d1nyl group, a 4-methyl-l-p1peraz1nyl group, a 3-anlnomethyl-l-pyrrol dlnyl group, a 3-ethylamihoroethyl-l-pyrrol Idlnyl group or a l-p1peraz1nyl group; and Y 1s oxygen Amide-linked cephem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. (2) Amide-linked penem quinolones, such as compounds of the following classes. a) where the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; is -C(C02H)-; R5 is -S-C"'-CH2-NH-; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen b) where the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; Rl is (1-hydroxyethyl); 2 is -H; R3 is -CH-; R* is -C(C02H)-; R5 IS -S-C"'-CH2-NH-; the quinolone moiety is a 6-fluoroquinolone, wherein A* Is -C(R4(>)-; A∑ is -CF-; A Is -CH-; and R7 is a heterocyclic ring; and Y is oxygen c) where the lactam-containing moiety is a penem, wherein bond "a" 1s a single bond; bond "b" Is a double bond; R3 is -CH-; R* 1s -C(C02H)-; R* is -S-C"'-CH2-NH-; quinolone moiety Is a naphthyridinone, wherein A1 Is -N-; A? Is -CF-; A3 is -CH-; and ? is a heterocyclic ring; and Y Is oxygen d) where the lctam-containing moiety is a penem, wherein bond "a" 1s a single bond; bond "b" Is a double bond; R* 1S -CH-; R« Is -C(C02H)-; R* is -S-C"'-CH2-NH-; the quinolone moiety 1s a structure, wherein A is -CF-; A3 is -CH-; R9 is -H; A* is -CH-, -CF-, -CC1-, or -N-; R8 1S cyclopropyl, ethyl, 2,4-difluorophenyl , 4- fluorophenyl , or t-butyl; and R7 is a 3-amino-l-pyrrol idinyl group, a 4-methyl -1-piperazinyl group, a 3- ami nomethyl-1 -pyrrol idinyl group, a 3-ethyl ami nomethyl-1 -pyrrol idinyl group or a 1-piperazinyl group; and Y is oxygen Amide-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 3) Amide-linked penem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* Is -C(C02H)-; R* is -S-C"'-S-CH2CH2-NH-; the quinolone moiety is a structure, wherein A 1s -CF-; A3 is -CH-; and is a heterocyclic ring; and Y Is oxygen b) where - the lactam-contalning moiety Is a penem, wherein bond "a" is a single bond; bond "b" Is a double bond; ≠ 1s -CH-; R« 1s -C(C02H)-; 5 IS -S-C"'-S-CH2CH2-NH-; the quinolone moiety is a ^-fluoroquinolone, wherein A* Is -C(R*0) A2 IS -CF-; A3 1S -CH-; and is a heterocyclic ring; and Y is oxygen the lactam-containing moiety is a penem, wherein bond "a" 1s a single bond; bond "b" is a double bond; R3 is -CH-; R4 is -C(C02H)-; R5 is -S-C"-S-CH2CH2-NH-; the quinolone moiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A is -CH-; and R? is a heterocyclic ring; and Y is oxygen d) where the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R1 is (1-hydroxyethyl ) ; R2 is -H; R3 is -CH-; R4 is -C(C02H)-; R5 is -S-C'-S-C^C^-NH-; the quinolone moiety is a structure, wherein A is -CF-; A3 is -CH-; R* is -H; A is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2,4-difluorophenyl , 4-fluorophenyl , or t-butyl ; and R7 is a 3-amino-l-pyrrolidinyl group, a 4-methyl-l-piperazinyl group, a 3-aminomethyl-l-pyrrolidinyl group, a 3-ethylaminomethyl-l-pyrrolidinyl group or a 1-piperazinyl group; and Y is oxygen Amide-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 4) Amide-linked carbapenem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety Is a carbapenem, wherein bond "a" Is a single bond; bond "b" Is a double bond; R3 IS -CH-; R* Is -C(C02H)-; R$ 1s -CH(R33)-C"'-CH2-NH-; the quinolone moiety 1s a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen the lactam-containlng moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R« is -C(C02H)-; R5 is -CH(R33)-C"'-CH2-NH-; the quinolone moiety is a 6-fluoroquinolone, wherein A* is -C(R40)-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R* is -CH(R33)-C"'-CH2-NH-; the quinolone moiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen the lactam-containlng moiety Is a carbapenem, wherein bond "a" 1s a single bond; bond "b" Is a double bond; Rl is (1-hydroxyethyl); R2 is -H; R3 1S -CH-; R* 1s -C(C02H)-; R* IS -CH(R33)-C"'-CH2-NH-; 33 is -H or -Me; the quinolone moiety Is a structure, wherein A2 is -CF-; A3 is -CH-; R3 IS -H; A* IS -CH-, -CF-, -CC1-, or -N-; 1$ cyclopropyl, ethyl, 2,4-difluorophenyl, 4-fluorophenyl, or t-butyl; and R7 is a 3-am1no-l-pyrrol1d1nyl group, a 4-methyl-l-p1peraz1nyl group, a 3-arainomethyl-l-pyrrolidlnyl group, a 3-ethylam1nomethyl-l-pyrrolidinyl group or a 1-plperazlnyl group; and Y is oxygen Amide-linked carbapenem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 5) Amide-linked carbapenem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C-'-S-CH2CH2-NH-; the quinolone moiety is a structure, wherein A is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen b) where - the lactam-containi g moiety is a carbapenem, . wherein bond "a" 1s a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C" ' -S-CH2CH2-NH- ; the quinolone moiety Is a 6- fluoroquinolone, wherein Al Is -C(R*0)-; A¾ 1s -CF-; A3 is -CH-; and R7 Is a heterocyc ic ring; and Y is oxygen c) where · the lactam-containing moiety is a carbapenem, wherein bond "a" s a single bond; bond "b" Is a double bond; R3 IS' -CH-; R* IS -C(C<>2H)-; R5 1S -CH(R33) -C" ' -S-CH2CM2-MH- ; the quinolone moiety Is a naphthyrldinone, wherein A* 1s -«-■;■ A2 IS -CF^; A3 1S -CH-; and R7 Is a heterocyclic ring; and Y is oxygen the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R1 is (1-hydroxyethyl ) ; R2 is -H; R3 is -CH-; R4 is -C(C02H)-; R5 is -CH(R33)-C"'-S-CH2CH2-NH-; R 3 is -H or -Me; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R* is -H; A* is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2,4-difluorophenyl , 4 -fluorophenyl , or t-butyl ; and R7 is a 3-amino-l-pyrrol idinyl group, a 4-methyl-l-piperazinyl group, a 3-aminomethyl-l-pyrrolidinyl group, a 3-ethylaminomethyl-l-pyrrol idinyl group or a 1-piperazinyl group; and Y is oxygen Amide-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 6) Amide-linked oxacephem quinolones, such as compounds of the class where the lactam-containing moiety is a oxacephem, wherein bond "a" is a single bond; bond "b" Is a double bond; R3 1s -CH-; R* is -C(C02H)-; R5 is -0-CH2-C"'-CH2-NH-; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; and R7 Is a heterocyclic ring; and Y 1s oxygen 7) Amide-linked isocephem quinolones, such as compounds of the class where - the lactam-containing moiety Is a Isocephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 IS -CH-; R« is -C(C02H)-; R5 is -CH2-S-C"'-CH2-NH-; the quinolone moiety is a structure, wherein A2 Is -CF-; A3 1s -CH-; and R7 is a heterocyclic ring; and Y is oxygen 8) Amide- linked iso-oxacephem qui nol ones, such as compounds of the class where the lactam-containing moiety is a iso-oxacephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R* is -CH2-0-C"'-CH2-NH-; the quinolone moiety is a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen 9) Amide-linked carbacephem quinolones, such as compounds of the class where the lactam-containing moiety is a carbacephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R* is -CH2-CH2-C"'-CH2-NH-; the quinolone moiety Is a structure, wherein A2 is -CF-; A3 1s -CH-; and R7 is a heterocyclic ring; and Y Is oxygen 10) Amide-linked monobactam quinolones, such as compounds of the class where the lactam-containing moiety s a monobactam, wherein bond "a" Is a single bond; bond "b" 1s nil; R3 1$ -CH- and Is bonded directly to X; R5 is nil; X 1$ -CH2NH-; the quinolone moiety Is a structure, wherein A2 1s -CF-; A3 is -CH-; and R? is a heterocyclic ring; and Y is oxygen 11) Thioester-1 inked cephem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety is a cephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; * is -C(C02H)-; R5 is -S-CH2-Cn'-CH2-S-; the quinolone moiety is a structure, wherein A? is -CF-; A3 1s -CH-; and R? is a heterocyclic ring; and Y is oxygen b) where - the lactam-containing moiety 1s a cephem, wherein bond "a" is a single bond; bond "bN is a double bond; R3 is -CH-; R* is -C(C02H)-; R* is -S-CH2-C"'-CH2-S-; the quinolone moiety 1s a 6-fluoroquinolone, wherein A* is -C(R*0)-; A2 is -CF-; A3 is -CH-; and R71S a heterocyclic ring; and Y is oxygen c) where - the lactam-containing moiety is a cephem, wherein bond "a" 1s a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -S-CH2-C"'-CH2-S-; the quinolone moiety is a naphthyrldlnone, wherein Al is -N-; A2 is -CF-; A3 Is -CH-; and 9? is a heterocyclic ring; and Y is oxygen d) where the l ctam-containing moiety is a cephem, wherein bond "a" Is a single bond; bond "b" is a double bond; R2 is -H or -OMe; R3 is -CH-; R* is -C(C02H)-; R5 is -S-CH2-C" -CH2-S-; and, Rl is [[(2-thienyl)acetyl]am no], [[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino- ] , [[(4-pyridylthio)acetyl ]amino], [(phenoxy)acetyl]amino], [[(2-amino-4-thiazolyl)acetyl]amino], [[(2-amino-4-thiazolyl)[[(3,4-dihydroxyphenyl )car- bonyl] amino]acetyl]amino] ; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R9 is -H; A* is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2,4-difluorophenyl , 4-fluorophenyl , or t-butyl; and R7 is a 3-amino-1-pyrrolidinyl group, a 4-methyl-l-piperazinyl group, a 3-ami omethyl-l-pyrroldinyl group, a 3-ethylaminomethyl-l-pyrrolidinyl group or a l-piperazinyl group; and Y s oxygen Thioester-1inked cephem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 12) Thioester-1Inked penem quinolones, such as compounds of the following classes. a) where - the lactara-containing moiety is a penem, wherein bond "a" Is a single bond; bond "b" is a double bond; R3 is -CH-; R« 1$ -C(C02H)-; R* Is -S-C"-CH2-S-; the quinolone moiety Is a structure, wherein A is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen b) where - the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C(>2H)-; 5 is -S-CM'-CH2-S-; the quinolone moiety 1s a structure, wherein A? is -CF-; A3 is -CH-; R9 is -H; A* is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2, 4-di fluorophenyl , 4- fluorophenyl , or t-butyl; and R7 is a 3 - ami no- 1- pyrrol idinyl group, a 4-methyl -1-piperazinyl group, a 3-aminomethyl-l -pyrrol idinyl group, a 3 -ethyl ami nomethyl-1 -pyrrol idinyl group or a 1-piperazinyl group; and Y is oxygen Thioester-1 inked penem quinolones of the class (b) are preferred. 13) Thioester-1 inked penem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety 1s a penem, wherein bond "a" Is a single bond; bond "b" 1s a double bond; R Is -CH-; R< is -C(C02H)-; R5 is -S-C"'-S-CH2CH2-S-; the quinolone moiety s a structure, wherein A? is -CF-; A3 1s -CH-; and R7 is a heterocyclic ring; and Y 1s oxygen b) where - the lactam-containing moiety Is a penem, wherein bond "a" 1s a single bond; bond "b" Is a double bond; 3 1S -CH-; * Is -C(C¾H)-; R* is -S-C"'-S-CH2CH2-S-; the quinolone moiety Is a 6-fluoroqu1nolone, wherein Al 1s -( W)-; A2 is -CF-; A3 Is -CH-; and R? is a heterocyclic ring; and Y is oxygen the lactam-containlng moiety 1s a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R is -CH-; R* is -C(C02H)-; R5 is -S-C"'-S-CH2CH2-S-; the quinolone moiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen the lactam-containing moiety is a penem, wherein bond "a" is a single bond; bond "b" is a double bond; R1 is (1-hydroxyethyl); R2 is -H; R3 is -CH-; R* is -C(C02H)-; R5 is -S-C"'-S-CH2CH2-S-; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R^ is -H; Al is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2,4-difluorophenyl , 4-fluorophenyl , or t-butyl; and R7 is a 3-amino-l-pyrrolidinyl group, a 4-methyl-l-piperazinyl group, a 3-aminomethyl-1-pyrrolidinyl group, a 3-ethylaminomethyl-1-pyrrolidinyl group or a 1-piperazinyl group; and Y is oxygen Thioester-1inked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 14) Thioester-1Inked carbapenem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety is a carbapenem, wherein bond "a" 1$ a single bond; bond "b" is a double bond; 3 Is -CH-; R* 1$ -C(C02H)-; R5 is -CH(R33)-e*'-CH2-$-; the quinolone moiety is a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen b) where - the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R1 is (1-hydroxyethyl ) ; R2 is -H; R3 is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C"'-CH2-S-; R33 is -H or -Me; and, the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R* is -H; A* is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2, -difluorophenyl, 4-fluorophenyl , or t-butyl; and R7 is a 3-amino-l-pyrrolidinyl group, a 4-methyl -1-piperazinyl group, a 3-aminomethyl -1-pyrrol idinyl group, a 3-ethylaminomethyl-1-pyrrol idinyl group or a 1-piperazinyl group; and Y is oxygen Thioester-linked carbapenem quinolones of the class (b) are preferred. 15) Thioester-1 inked carbapenem quinolones, such as compounds of the following classes. a) where - the lactam-containing moiety 1s a carbapenem, wherein bond "a" Is a single bond; bond "b" Is a double bond; R3 s -CH-; R4 is -C(C0?H)-; R5 1s -CH(R33)-C"'-$-CH2CH2-S-; the quinolone moiety Is a structure, wherein A2 s -CF-; A3 1s -CH-; and R7 Is a heterocyclic ring; and Y s oxygen b) where - the lactatn-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C"'-S-CH2CH2-S-; the quinolone moiety is a 6-fluoroquinolone, wherein A* is -C(R<0)-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen c) where · the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C"'-S-CH2CH2-S-; the quinolone noiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen d) where - the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R1 is (1-hydroxyethyl); R2 is -H; R3 is -CH-; R* is -C(C02H)-; R* is -CH(R33)-C"'-S-CH2CH2-S-; R 3 is -H or -Me; the quinolone noiety is a structure, wherein A2 is -CF-; A is -CH-; R* is -H; Al is -CH-, -CF-, -CC1-, or -H-; R8 is cyclopropyl, ethyl , 2,4-di fluorophenyl , 4- fluorophenyl, or t-butyl; and R7 is a 3-amino-l-pyrroHdlnyl group, a 4-methyl-l-piperazinyl group, a 3-aminomethyl-l-pyrrolidlnyl group, a 3-ethylaminomethyl-l-pyrrolidinyl group or a 1-piperazinyl group; and Y is oxygen Thioester- linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 16) Thioester-1 inked oxacephem quinolones, such as compounds of the class where the lactam-containing moiety is a oxacephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -0-CH2-C"'-CH2-S-; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen 17) Thioester-1 inked isocephem quinolones, such as compounds of the class where the lactam-containing moiety is a isocephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R5 is -CH2-S-C"'-CH2-S-; the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen 18) Thioester-1 inked iso-oxacephem quinolones, such as compounds of the class where the lactam-contalning moiety 1s a so-oxacephem, wherein bond "a" Is a single bond; bond "b" 1s a double bond; R3 is -CH-; R* 1s -C(C02H)-; R5 1s -CH2-0-C"'-CH2-S-; the quinolone moiety Is a structure, wherein A2 Is -CF-; A Is -CH-; and R7 Is a heterocyclic ring; and Y s oxygen 19) Thioester-1 Inked carbacephen quinolones, such as compounds of the class where the lactam-contalning moiety Is a carbacephem, wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH-; R4 s -C(C02H)-; R5 s -CH2-CH2-C"'-CH2-S-; the quinolone moiety is a structure, wherein A is -CF-; A3 is -CH-; and R7 is a heterocyclic ring; and Y is oxygen 20) Thioester-1 inked monobactam quinolones, such as compounds of the class where the lactam-containing moiety is a monobactam, wherein bond "a" is a single bond; bond "b" is nil; R3 is -CH- and is bonded directly to X; R5 Is nil; X is -S-; the quinolone moiety is a structure, wherein A is -CF-; A3 is -CH-; and R? is a heterocyclic ring; and Y is oxygen Quinolonyl lactams of this Invention Include (for example) the following compounds. [6R-(6a,7£)]-7·[[Carboxy(4-hydroxypheny1)acet 1]amino]-3-[[l-ethyl-6-fluoro-l»4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinyl]carbonylamino]-7-methoxy-8-oxo-5-oxa-l-azabtcyclo[4.2.0]oct-2-ene-carboxyl1c add disodlum salt [6R-(6a,7b)]-3-[[[7-(3-Aeino-l-pyrrolidinyl)-8-chloro-l- cyclopropyl-6-fluoro-l,4,dihydro-4-oxo-3-quinoliny1]carbonyl - thio]methyl]-7-[[(difluoromethylthio)acetyl ]amino]-7-methoxy-8- oxo-5-oxa-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyl ic acid sodium salt [5R-[5a,6a]]-3-[[[7-(3-amino-l-pyrrol idinyl)-l-(2,4-di- fluorophenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-napthyridin-3-yl]- carbonylthio]methyl]-6-[(R)-l-hydroxyethyl]-7-oxo-4-thia-l-azabi- cyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt [6R-(6a,7b)l-7-[(R)-[([(5-carboxy-lH-1midazol-4- yl)carbonyl]amino]hydroxyphenyl)acetyl ]amino]-3-[[[5-ethyl- 5,8-dihydro-8-oxo-l,3-dioxolo[4,5-g]quinolin-7-yl- carboxyl]amino]methyl]-8-oxo-5-thia-l-azabicyc1o[4.2.0]oct-2-ene-2-carboxyl ic acid disodium salt [6R-(6a,7b)J-3-[[[[l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l p1peraziny1)-l,8-naphthyr1din-3-y1]carbonyl]thio]methyl]-7-[[[[(R)-(4-ethyl -2,3-dioxo-l-piperazinyl )carbonyl ]amino](4-hydroxyphenyl)acetyl]ainino]-8-oxo-5-th1a-l-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt [6R-(6a,7b) ]-7-[[(2-amino-4-thiazo1yl )[(l-carboxy-l -methyl ) - ethoxyimino]acetyl]amino]-3-[[[[l-cyclopropyl-6-fluoro-l,4-di- hydro-4-oxo-7-(l-piperazinyl)-3-quinol inyl Jcarbonyl ]thio]-methyl ]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyl ic acid disodium salt [6R-[6a,7b]]-3-[[[7-(3-am1no-l-pyrrol1dinyl)-8-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinyl]carbonylamino]methyl]-7-[[[[(R)-6,7-dihydroxy-4-oxo-(4H)-1-benzopyran-3-yl Jcarbonylamino]-4-hydroxyphenylacet 1 ]aminoJ-8-oxo-5-1hi -1-azabicyclo[4.2.0]oct-2-ene-2-carboxyl ic acid sodium salt [6R-[6a,7b]]-7-[[(R)-am1no(hydroxyphenyl)acetyl]amino]-3- [[[7-(3-amino-l-pyrrolidlnyl)-l-difluorophenyl -6-fluoro-l,4-di-hydro-4-oxo-l-8-naphthyridin-3-yl]carbonylthio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyl ic acid sodium salt [6R-[6a,7b]]-7-[[(R)-amino(2-naphthalenyl)acetyl]amino]-3-[[[(1-ethyl-1,4-dihydro-7-methyl-4-oxo-3-quinol inyl)carbonyl-amino]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.01oct-2-ene-2-car-boxylic acid sodium salt (3S)-2-[[[l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-pipera- 2lnyl)-3-quinol1nyl]carbonyl]th1o]-3-[[[t[(R)-4-ethyl-2,3-dioxo- l-piperazinyl]carbonyl]amino](4-hydroxyphenyl)acetyl ]araino]-4-oxo-l-azetinesulfonic add sodium salt (3S)-3-[[(2-amino-4-thiazoly1)(methoxyimino)]acetyl]amino]-2-[[[9-fluoro-4,7-dihydro-3-n»ety1-10-(4-methy]-l-piperazinyl)-7-oxo-2H-pyrido[l,2,3-de]-l,4-benzoxaz1n-6-yl]carbonyllthio]-4-oxo-l-azetidinesulfonic acid sodium salt [6R-[6a,7b]-7-[[(2-amino-4-thia2olyl)(raethoxyimino)[acetyl] amino]-3-I[[9-cyclopropyl -6-fluoro-4,9-dihydro-7-(4-methyl-l-plperazinyl)-4-0X0-3-i$othiazolo[5,4-b]quinoliny]]oxy]methy1]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyl ic acid sodium salt [5R- I 5a,6a]]-3[[t[l-cyclopropyl-6-f1uoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinolinyl]carbonyl]amino]methyl]-6-[(R)-l-hydroxyethyl 1-7-0X0-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-car-boxyllc acid sodium salt [5R-[5a, 6a]] -3-[[l[7-(3-anrinomethyl-l -pyrrol idinyl )-l -cyclo- propyl-6,8-difluoro-l,4-dihydro-4-oxo-3-quinolinyl]carbonyl]- aro1no]methyl]-6-[(R)-l-hydroxyethyl]-7-oxo-l-azabicyclo[3.2.0] hept-2-ene-2-carboxylic acid sodium salt [5R-[5a,6a]-3-[[[[(3-amino-l-pyrrolidinyl)-l-(2,4-difluoro-phenyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridin-3-yl]car-bonyl ] am1no]methyl ] -6- [ (R) - 1 -hydroxyethyl ] -7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxyl ic acid sodium salt Other preferred quinolonyl lactams are exemplified by the following structures.  -87-  -90- -92- -93- -94- -95- -96-  Methods of Manufacture The quinolonyl lactams of this invention may be made using any of a variety of synthetic techniques known In the art . Manufacture of quinolonyl lactam generally Involves the preparation of a lactam-containlng moiety, a quinolone moiety and a procedure or set of procedures for l inking the lactam-containlng and quinolone moieties. Procedures for making a broad variety of l actam-containlng moieties and quinolone moieties are wel l known In the art. For example, procedures for preparing lactam-containlng moieties are described In the following references, al l incorporated by reference herein (Including articles cited within these references) : Cephalosporins and PenKW Ins; emis ry and Biology (E. H. Flynn, ed, 1972) Chapters 2, 3, 4, 5, 6, 7, 15 and Appendix I ; Recent Advances in the Chemistry of θ-Lactam Antibiotics (A.G. Brown and S. M. Roberts, ed., 1985); Topics in Antibiotic Chemistry. Vol. 3, (Part B) and Vol. 4, (P. Sommes, ed., 1980); Recent Advances in the Chemistry of θ-lactam Antibiotics (J. Elks, ed., 1976); Structure-Activity Relationships Among the Semisynthetic Antibiotics (D. Perlman, ed, 1977); Chapts. 1, 2, 3, 4; Antibiotics. Chemotheraoeutics and Antibacterial Agents for Disease Control (M. Grayson, ed, 1982); Chemistry and Biology of ^-Lactam Antibiotics, Vols 1-3 ( . B. Morin and M. Gorman, eds, 1982); 4 Medicinal Research Reviews 1-24 (1984); 8 Medicinal Research Review 393-440 (1988); 24 Anoew. Chem. Int. Ed. Engl. 180-202 (1985); 40 J. Antibiotics 182-189 (1987); European Patent Publication 266,060; 42 JL. Antibiotics 993 (1989); U.S. Patent 4,742,053; 35 Chem. Pharm. Bull. 1903-1909 (1987); 32 J. Med. Chem.. 601-604 (1989); U.S. Patent 4,791,106; Japanese Patent Publication 62/158291; 31 J. Med. Chem. 1987-1993 (1988); 30 J. Med. Chem.. 514-522 (1987); 28 Tet. Let. 285-288 (1987); 28 Tet. Let. 289-292 (1987); 52 jL Pro. Chem.. 4007-4013 (1987); 40 J. Antibiotics. 370-384 (1987); 40 J. Antibiotics. 1636-1639 (1987); 37 J. Antibiotics. 685-688 (1984); 23 Heterocvcles. 2255-2270; 27 Heterocvcles. 49-55; 33 Chem. Pharm. Bull. 4371-4381 (1985); 28 Tet. Let. 5103-5106 (1987); 53 J. Pro. Chem.. 4154-4156 (1988); 39 J, ftntlfrHttel, 1351-1355 (1986); 59 Pure and Aool . Chem.. 467-474 (1987); 1987 J.C.S. Chem. Comm.: 44 Tetrahedron. 3231-3240 (1988); 28 IsL. kfii^, 2883-2886, (1987); 40 J. Antibiotics. 1563-1571 (1987); 33 Chem. Pharm. Bull.. 4382-4394 (1985); 37 J. Antibiotics. 57-62 (1984); U.S. Patent 4,631,150; 34 Chem. Pharm. Bull.. 999-1014 (1986); 52 J. Pro. Chem.. 4401-4403 (1987); 39 Tetrahedron. 2505-2513 (1983); 38 J. Antibiotics. 1382-1400 (1985); European Patent Application 053,815; 40 J. Antibiotics. 1563-1571 (1987); 40 J. Antibiotics. 1716-1732 (2987); 47 J, Qq, Cheffl., 5160-5167 (1981); U.S. Patent 4,777,252; U.S. Patent 4,762,922; European Patent Publication 287,734; U.S. Patent 4,762,827; European Patent Publication 282,895; European Patent Publication 282,365; U.S. Patent 4,777,673.

Also, for example, procedures for preparing quinolones useful in the methods of this invention are described in the following references, all Incorporated by reference herein (including articles listed within these references); 21 Progress in Druo Research.9-104 (1977); 31 J. Med. Chem.. 503-506 (1988); 32 J. Med. Chem.. 1313-1318 (1989); 1987 Liebios Ann. Chem.. 871-879 (1987); 14 Drugs Exotl . Clin. Res.. 379-383 (1988); 31 J. Med. Chem.. 983-991 (1988); 32 J. Med. Chem.. 537-542 (1989); 78 J. Pharm. Sci.. 585-588 (1989); 26 J. Het. Chem.. (1989); 24 J. Het. Chem.. 181-185 (1987); U.S. Patent 4,599,334, 35 Chem. Pharm. Bull.. 2281-2285 (1987); 29 J. Med. Chem.. 2363-2369 (1986); 31 J. Med. Chem.. 991-1001 (1988); 25 J. Het. Chem.. 479-485 (1988); European Patent Publication 266,576; European Patent Publication 251,308, 36 Chem. Pharm. Bull.. 1223-1228 (1988); European Patent Publication 227,088; European Patent Publication 227,039; European Patent Publication 228,661; 31 «L Med. Chem.. 1586-1590 (1988); 31 J. Med. Chem.. 1598-1611 (1988); and 23 J. Med. Chem.. 1358-1363 (1980).

Procedures for linking the lactam-containing moiety and quinolone moieties may vary according to the type of linking group desired. For example, quinolonyl lactams having a thioester linking moiety may be made by the following general reaction sequence: RSH + HO (+0)-Quin HSC(-0)-Qu1n + Lact-CH2-X ---> Lact - CH2-SC(«0)-Qu1n where X Is a reactive leaving group (such as halo, a sulfonate ester, acetate, thlobenzoate or other activated hydrox 1 functionality. Lact generically represents an appropriately protected lactam-containing moiety (such as a penem, carbapenem, cephem, monocyclic beta-lactam, oacephem, or carbacephem), and "Quln" represents an appropriately protected quinolone moiety. The sequence can be Invisloned as formation of the Intermediate quinolone thoacld, followed by nucleophilic displacement of the lactam X substltuent to form a thioester coupled conjugate of the lactam and quinolone.

Quinolonyl lactams having a hydrazone or hydrazide linking moiety may be made by the following general reaction sequence: H2NNHC(«0)-Quin + Lact-CHO ---> Lact-CH-NNHC(-O)-Quin Lact-CH2NHNHC(=0)-Quin where "Lact" generically represents an appropriately protected lactam-containing moiety (such as a penem, carbapenem, cephem, monocyclic beta-lactam, oxacephem, or carbacephem) and Quin represents an appropriately protected quinolone moiety. The sequence can be envisioned as the condensation of the quinolone hydrazide with a lactam aldehyde or ketone to form the hydrazone coupled lactam quinolone conjugate. Subsequent reduction yields the corresponding hydrazide coupled lactam quinolone conjugate.

Quinolonyl lactams having an amide linking moiety may be made by the following general reaction sequence: Lact-CH2-NH2 + X-C(-0)-Quin — Lact-CH2-NHC(-0)-Quin where X Is a reactive leaving group (such as halo, an HOBt ester, mixed anhydride or other activated carboxyl functionality), "Lact" generically represents an appropriately protected lactam containing structure (such as penem, carbapenem, cephem, oxacephem, or carbacephem),, and "Quin" represents an appropriately protected quinolone. The reaction can be envisioned as an acylatlon of the lactam amio substltuent with the activated quinolone carboxyl group, to form an amide coupled conjugate of the lactam and quinolone.

In the reaction sequences described herein, certain functional groups contained in the Lact and Quin structures (such as carboxyl, hydroxy1, and amino groups) may need to be blocked In order to prevent undesired, competing side reactions. Suitable protecting groups for carboxyl substituents include esters; protecting groups for hydroxyl substituents Include ethers, esters, and carbonates; and protecting groups for amino substituents include carbamates and amides. If such protecting groups are employed, then appropriate deprotecting chemistry, that will not decompose the coupled conjugate, may be required to obtain antimicrobially active products.

Compositions: The compositions of this invention comprise: (a) a safe and effective amount of a quinolonyl lactam; and (b) a pharmaceutically-acceptable carrier.

A "safe and effective amount" of a quinolonyl lactam 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 quinolonyl lactam therein, and the dosage regimen desired for the compostion.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a quinolonyl lactam 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 g (milligrams) to about 7000 mg, more preferably from about 500 mg to about 1500 mg, of a quinolonyl lactam.

The compositions of this Invention may be In any of a variety of forms, suitable (for example) for oral, rectal, topical, or parenteral administration. Depending upon the particular route of administration desired, 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 quinoionyl lactam. The amount of carrier employed in conjunction with the quinoionyl lactam is sufficient to provide a practical quantity of material for administration per unit dose of the quinoionyl lactam. 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).

In particular, pharmaceutically-acceptable carriers for systemic adminstration 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 admin straton include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight by the total composition.

Various 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 quinoionyl lactam. 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.

The 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 quinolonyl lactam. 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. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the quinolonyl lactam. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, and solvents.

Methods of Administration: 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 quinolonyl lactam to said subject. As used herein, 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. Such 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.

The quinoionyl lactams and compositions of this invention can be administered topically or systemically. Systemic application includes any method of introducing the quinoionyl lactam 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 quinoionyl lactam used, the resistance pattern of the infecting organism to the quinoionyl lactam used, the ability of the quinoionyl lactam 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.

Typically, for a human adult (weighing approximately 70 kilograms), from about 75 mg to about 30,000 mg, more preferably from about 100 mg to about 20,000 mg, more preferably from about 500 mg to about 3500 mg, of quinoionyl lactam are administered per day. Treatment regimens preferably extend from about 3 to about 56 days, preferably from about 7 to about 28 days, in duration. Prophylactic regimens (such as avoidance of opportunistic infections In immunocompromised patients) may extend 6 months, or longer, according to good medical practice.

A preferred method of parenteral administration Is through Intramuscular Injection. As 1s known and practiced In the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kilograms) Individual doses of from about 100 mg to about 7000 mg, preferably from about 500 mg to about 1500 mg, are acceptable.

A preferred method of systemic administration i s oral . Individual doses of from about 100 mg to about 2500 mg, preferably from about 250 mg to about 1000 mg are preferred.

Topical admini stration can be used to del iver the quinolonyl lactam systemical ly, or to treat a local infection. The amounts of quinolonyl l actam to be topical ly administered depends upon such factors as skin sensitivity, type and location of the ti ssue to be treated, the composition and carrier ( if any) to be administered, the particular quinolonyl lactam to be administered, as wel l as the particular disorder to be treated and the extent to which systemic (as distinguished from local ) effects are desired.

The following non-l imiting examples il lustrate the compounds, compositions, processes, and uses of the present Invention.

EXAMPLE 1 [5R-[5a,6a]]-3-[[[l-Cyclopropyl -6,8-d1f1uoro-l ,4-dihydro-4-oxo-7- (3-aminomethyl -l -pyrrol idinyl )-3-quinol inyl ]carbonyl amino] methyl ]-6-[(R)-l-hydroxyethyl ]-7-oxo-4-thia-l-azabicyclo[3.2.0] -hept-2-ene-2-carboxyl ic acid, according to this Invention, i s made by the following general reaction sequence.

Approximately 0.73 9 (1.5 mllHmoles) of l-(cyclopropyl)-6,8-d1f1uoro-l,4-d1hydro-4-oxo-7-[3-[(2-propeny1)oxycarbonyl]-amlnomethyl ]-l -pyrrol 1d1nylJ-3-qu1nol1ne carboxylic acid, sodium salt, (I) Is dissolved n 30 ml anhydrous dtoxane, and 1.1 equivalent of sodium bicarbonate and 6 ml of acetone are added. Compound (I) prepared from l-cyclopropy1-6,8-d1fluoro-l,4-d1hydro-4-oxo-7-(3-am1nomethy1-l-pyrro11d1ny1)-3-qu1no11ne carboxylic acid (J. Sanchez, et al., 31 J. Med. Cham.9383 (1988) by standard methods.) The reaction solution is cooled to approximately O'C (32*F) and 1.1 equivalent of isobutylchloro- formate is added slowly with stirring. The reaction is maintained at approximately 2*C (36*F) for approximately 1 hour.

Approximately 1 mmol (244 mg) of [5R-[5a,6a]]-3-aminomethyl - 6-I(R)-l-hydroxyethylJ-7-oxo-4-thia-l-azabicyclo[3.2.01hept-2- ene-2-carboxylic acid (II, made according to 69 Helv. Chim. Acta 1576 (1986), is dissolved in 10 ml of 30% aqueous dioxane, containing 1 additional mmol of sodium bicarbonate. This solution is added to the above reaction mixture, and the mixture stirred for an additional 60 min. at approximately 2*C. The reaction is quenched with the addition of 1.3 mmol sodium bicarbonate in 70 ml ice water. After extracting with ether, the aqueous layer is acidified to approximately pH 2 and is exhaustively extracted with methylene chloride. The solid Product (III) is then obtained.

Approximately 350 mg (0.5 mmol) of Product (III) is dissolved in 20 ml THF (tetrahydrofuran) containing 0.5 mmol sodium bicarbonate. At room temperature, under a nitrogen blanket, 14 mg of trlphenylphosphine, 122 mg of sodium ethylhexa-noate, and 14 mg of tetrakis(tr1phenylphosphine)pa11adium are added. The reaction mixture Is stirred for approximately 1 hr during which time a precipitate forms. The solid final product (IV) is collected by filtration and purified by repeated trituration with acetone.

Similarly, the following qulnolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. uslng the quinolone 7-(3-a»1nopyrrol1d1nyl)-l-cyclopropy1-6,8- d1f1uoro-l,4-d1hydro-4-oxo-3-qu1nol1ne carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrrol1d1nyl )-l-chloro-l cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-qu1no11ne carboxyli acid (prepared according to J. P. Sanchez, et. al., J. Hed. Chem. 1988, 31, 983) using the quinolone 7-(3-am1nopyrrol1d1nyl-l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-3-qu1nol1ne carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Hed. Chen., 1988, 31, 983) using the naphthyrldlnone 7-(3-a»1iHvyrrol d1nyl)-l-cyclopropyl-6-fluoro ,4-d1hydr«-4-ox0- -naph^ acid (prepared according to J.P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the quinolone l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinoline carboxylic acid (prepared according to H. oga, et. al., J. Med. Chem., 1980, 23, 1358) using the naphthyrldlnone 7-(3-aminopyrrol1d1ny1)-l-(2,4-difluorophenyl)-6-f1uorol,4-d1hydro-4-oxo-l,8-naphthyr1dine-3-carboxylic acid (prepared according to D.T.W. Chu, et. al., J. Med. Chen., 1986, 29, 2363) using the quinolone l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-7-(l-piperazinyl)-3-quinoline carboxyllc acid (prepared according to K. Grohe, et al., Ger. Offen.0E 3142854) using the quinolone 6-fluoro-l-(4-fluorophenyl)-l,4-dihydro-4- oxo-7-(l-piperazinyl)-3-quinoline carboxylic acid (prepared according to D.T.U. Chu, et. al., J. Med. Chem., 1985, 28, 1558) using the quinolone 9-fluoro-4,7-dihydro-3-methyl-10-(l piperazinyl)-7-oxo-2H-pyr1do[l,2,3-de]-l,4-benzoxazine-6-carboxylic add (prepared according to I. Hayakawa, et. al . Chen. Pharra. Bull., 1984, 32, 4907) using the naphthyrldlnone 7-(2,5-d1azabicyclo[2.2.1]heptan-2-yl)-l-(l,l-d1fflethylethyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyri-dlne-3- carboxyilc acid (prepared according to A. Weber, et. al., EP 266576) using the quinolone l-(2-fluoroethyl)-6,8-difluorp-l,4-dihydro-4-oxo-7-(4- methyl-l-piperazinyl)-3-quinoline carboxylic acid (prepared according to T. Irikura, Aust. Pat. Specif. AU 537813).

EXAMPE 2 According to the general procedure of Example 1, the following quinolonyl lactam is made: using the beta-lactam 3-(aa1nomethyl)-6-(l-hydroxyethy1)-4-methyl-7-oxo-l-azab1cyclo[4.2.0]hept-2-ene-2-carboxylic acid (prepared according to B.G. Christesen, et al., Eur. Pat. Appl. EP 292191) Similarly, the following quinolonyl lactam is prepared by the general procedure of this Example, with substantially similar results. uslng the quinolone l-(2-fluoroethy1)-6,8-difluoro-l,4-dihydro-4- oxo-7-(4-methyl-l-piperazinyl)-3-qu1noline carboxyiic acid (prepared according to T. Irikura, Aust. Pat. Specif. AU 537813).

EXAMPLE 3 According to the general procedure of Example 1, the following quinolonyl lactam is made: using the beta-lactam N-[2-(aminomethyl)-4-oxo-3-azetidinyl ]-2-phenoxy-acet amide (prepared according to J.6. Gleason, et. al., US 4,200,572) Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-anj1nopyrrol1d1nyl)-l-cyclopropy1-6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxyiic add (prepared according to J. P. Sanchez, et. al., J. Med. Chea., 1988, 31, 983) using the quinolone 7-(3-aminopyrrol Idinyl )-l-chloro-l- cyclopropyl -6-fluoro-l,4-dihydro-4-oxo-3-quinol ine carboxyl ic acid (prepared according to J.P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrro1Idinyl-1-cyclopropyl-6-f1uoro-l,4-d1hydro-4-oxo-3-quino11ne carboxy 1c acid (prepared according to J.P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the naphthyrldlnone 7-(3-am1nopyrrol1d1ny1)-l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-l,8-naphthyr1d1ne-3-carboxyl1c acid (prepared according to J.P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) EXAMPLE 4 [6R-[6a,7/J]]-3-[[(l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-7- ( 1-piperazinyl ) -3-quinol inyl )carbon lam1no]methyl ] -8-oxo-7- [ (2-thienyl acetyl ) amino] -5-thia- 1 -azabicyclo[4.2. O]oct- 2-ene-2-carboxylic Acid Sodium Salt To a solution of approximately 1.7 gm 1-cyclopropyl -6-fluoro-l,4-dihydro-4-oxo-7-(l-p1perazinyl)-3-quinoline carboxylic acid (I) in 20 ml water, 5 ml IN sodium hydroxide and 20 ml dioxane is added approximately 1.7 gm di-t-butyl carbonate. The reaction is stirred at room temperature for approximately 6 hours and is concentrated to approximately 5 ml in vacuo. The mixture is diluted with acetone and the product (II) is collected by filtration.

Separately, reactant (III) was prepared by heating a mixture of approximately 5.0 gm of commercial cephalothin sodium salt 1.06 gm sodium bicarbonate and 0.82 gm sodium azide in 75 ml water at approximately 50*C for 18 hours. The reaction is cooled to approximately 3-5*C, covered with ethyl acetate and slowly acidified with cold IN HC1. The mixture is extracted 3x with ethyl acetate and the combined organic layers are dried over sodium sulfate and concentrated to dryness.

This intermediate (3.0 gm) is combined with 3.0 gm 10% Pd/C, 4.5 gm sodium bicarbonate and 100 ml 50% methanol/water, and hydrogenated at 30-40 psi and room temperature until theoretical uptake of hydrogen 1s observed. The catalyst 1s removed by filtration and the filtrate Is concentrated to dryness. The residue 1s dissolved in water, acidified with cold IN HC1 and washed with methylene chloride. The aqueous phase is reduced in volume and added to a Oowex 50W-X4 ion exchange column. Elution with 2% pyr1d1ne/MeOH then affords reactant (III).

To 1.9 gm of product (II) n 75 ml anhydrous dioxane containing 0.41 gm sodium bicarbonate at 0-3*C s added 0.66 gm sobutyl chloroformate n 15 ml acetone slowly with stirring. The reaction 1s maintained at 0-3*C for approximately 2 hours. To this solution Is added 1.33 gm reactant (III) dissolved in 40 ml 30% aqueous dioxane containing 0.35 gm additonal sodium bicarbonate. The mixture Is allowed to come to room temperature during the addition and then stirred a further 2 hours. The reaction 1s then poured Into 100 ml ce water containing 0.5 gm sodium bicarbonate and extracted with ethyl acetate. The aqueous layer 1s the acidified and Is extracted Sx with an equal volume of methylene chloride. The organic phase is then dried over sodium sulfate and concentrated to dryness to obtain product (IV) after trituration with acetone/hexanes.

To a suspension of 1.2 gm of product (IV) in 30 ml methylene chloride is added 30 ml trifluoroacetic acid at room temperature. The reaction is stirred at room temperature for 4 hours and then concentrated to dryness. The residue is resuspended in methylene chloride and reconcentrated several times. The residue is then trituated with acetone to obtain product (V) after filtration.

Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-aminopyrrolid1nyl)-l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-qu1noline carboxylic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983) using the quinolone 7-(3-an»inopyrrolidinyl)-l-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinol1ne carboxylic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Chem., 1988» 31, 983) uslng the qu nolone 7-(3-aminopyrrol idinyl -1-cyclopropyl -6- fluoro-l,4-dihydro-4-oxo-3-qu1no ine carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the naphthyrldlnone 7-(3-am1nopyrrol1dinyl)-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyr1d1ne-3-carboxyl1c acid (prepared according to J. P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983) using the qulnolone l-ethyl-6-fluoro-l,4-d1hydro-4-oxo-7-(l-p1peraz1nyl)-3- quinollne carboxyllc acid (prepared according to H. oga, et. al., J. Med. Chen., 1980, 23, 1358) using the naphthyridinone 7-(3-aminopyrrolidinyl)-l-(2,4 di fluorophenyl ) -6- fluorol, 4-dihydro-4-oxo-l,8-naphthyridine-3- carboxylic acid (prepared according to O.T.W. Chu, et. al . , J Med. Chem., 1986, 29, 2363) using the quinolone 6-fluoro-l-(4-fluorophenyl)-l,4-dihydro-4-oxo-7-(l-piperazinyl)-3-quinoline carboxylic acid (prepared according to O.T.W. Chu, et. al., J. Ned. Chem., 1985, 28, 1558) using the quinolone 9-fluoro-4,7-dihydro-3-methyl-10-(l p1peraz1nyl)-7-oxo-2H-pyr1do[l,2,3-de]-lt4-benzoxazine-6-carboxylic acid (prepared according to I. Hayakawa, et. al. Chen. Pharn. Bull., 1984, 32, 4907) using the naphthyrldinone 7-(2,5-diazabicyclo[2.2. l]heptan-2-yl )- l-(l,l-dimethylethyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3- carboxylic acid (prepared according to A. Weber, et. al., EP 266576).

EXAMPLE § According to the general procedure of Example 4, the following quinolonyl lactam is made. using the beta- lactam 3-(acetyloxymethyl)-8-oxo-7-[(4-pyr1dylthioacetyl)am1no]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (prepared according to S. Crast, et. al., J. Med. Chem., 1973, 16, 1413) Similarly, the following quinolonyl lactam Is prepared by the general procedure of this Example, with substantially similar results. uslng the qulnolone 7-(3-am1nopyrrolidinyl)-l-cyclopropyl-6,8- d1fluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Med. C em., 1988, 31, 983).

EX MPLE 5 According to the general procedure of Example 4, the following quinolonyl lactam is made. using the beta-lactam 3-[[(aminocarbonyl)oxy]methyl]-7-[[2-furanylmethoxyimino) acetyl ]amino]-8-oxo-5-thi a- 1-azabicyclo [4.2.0]oct-2-ene-carboxyl1c acid (prepared according to N.C. Cook, et. al., US 3,974,153).

Similarly, the following quinolonyl lactam is prepared by the general procedure of this Example, with substantially similar results. using the qulnolone 7-(3-amtnopyrrol1d1nyl)-l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-qu1noline carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Ned. Chen., 1988, 31, 983).

EXAMPLE 7 According to the general procedure of Examp e 4, the following quinolonyl lactam 1$ made. using the beta-lactam 3- ( acetyl oxymethyl )-7-[[(2-amino-4-thiazolyl)acetyl] amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (prepared according to J. Org. Chem., 1970, 35, 2430).

Similarly, the following quinolonyl lactam is prepared by the general procedure of this Example, with substantially similar results. using the qui no! one 7-(3-aminopyrrol idinyl )-l-cyclopropyl -6,8-d1f1uoro-l,4-d1hydro-4-oxo-3-qu1no11ne carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983).

EXAMPLE 8 According to the general procedure of Example 4, the following quinolonyl lactam s made. uslng the beta-lactam 3-(acetyloxymethyl)-8-oxo-7- [(phenoxyacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxyllc acid (prepared according to R.B. Norin, et. al., J. Am. Chem. Soc, 1969, 91, 1401).

Similarly, the following quinolonyl lactam is prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-aminopyrrolidinyl)-l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-3-quinol1ne carboxylic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983).

EXAHP 9 According to the general procedure of Example 4, the following quinolonyl lactam is made. using the beta-lactan 3-(acetyloxymethyl)-7-methoxy-8-oxo-7-{(2-thienylacetyl)am1no]-5-th1a-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyllc add (prepared according to arady, et al., J. Am. Chem. Soc., 1972, 94, 1410).

Similarly, the following quinolonyl lactam Is prepared by the general procedure of this Example, with substantially similar results. using the qui no lone 7-(3-aminopyrrol idinyl )-l-cyclopropyl -6,8-difluoro-l,4-dihydro-4-oxo-3-quinoline carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983).

EXAMP IQ According to the general procedure of Example 5, the following qui nol only lactam is made. using the beta- lactam 3-[(acetyloxy)methyl]-7-[(2-anrino-4-thiazolyl)methoxyim1no)acetyl]amino]-8-oxo-5-th1a-l-azabicyclo [4.2.0]oct-2-ene-carboxyl ic add (prepared according to N. Ochiai, et al., US 4,098,888)).

Similarly, the following qulnolonyl lactams are prepared by the general procedure of this Example, with substantially similar resul ts . uslng the quinolone 7-(3-aminopyrro11dinyl)-l-cyclopropyl-6,8- d1fluoro-l,4-d1hydro-4-oxo-3-qu1noline carboxylic acid (prepared according to J. P. Sanchez, et. al . , J. Med. Chem., 1988, 31, 983) using the quinolone 7-(3-aminopyrrolidinyl)-l-chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinoline carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the quinolone 7-(3-arainopyrro 1d1nyl-l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-3-quino11ne carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the naphthyridinone 7-(3-am1nopyrrol1d1nyl)-l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-l,8-naphthyr1d1ne-3-carboxy1*c acid (prepared according to J.P. Sanchez, et. al., J. Hed. Chem., 1988, 31, 983) using the quinolone l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperazinyl)-3- quinoline carboxylic acid (prepared according to H. Koga, et. al., J. Med. Chem., 1980, 23, 1358) using the naphthyridinone 7-(3-arainopyrro1idinyl)-l-(2,4-dif1uorophenyl)-6-f1uorol,4-d1hydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (prepared according to O.T.W. Chu, et. al., J. Ned. Chen., 1986, 29, 2363). using the quinolone 6-fluoro-l-(4-fluorophenyl)-l,4-d1hydro-4-oxo-7-(l-p1peraz1nyl)-3-qu1noline carboxyllc acid (prepared accordlng to D.T.W. Chu, et. al., J. Med. Chem., 1985, 28, 1558) using the qulnolone 9-fluoro-4,7-d1hydro-3-methyl-10-(l- pperazinyl)-7-oxo-2H-pyr1do[1,2,3-de]-1,4-benzoxaz1ne-6- carboxyllc acd (prepared according to I. Hayakawa, et. al., Chem. Pharm. Bull., 1984, 32, 4907) using the naphthyrldlnone 7-(2,5-d1azabicyclo[2.2.1Jheptan-2-yl)-1-(1,1-dimethylethyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyr1d1ne-3- carboxyi1c acid (prepared according to A. Weber, et. al., EP 266576) using the qulnolone 7-(3-am1nopyrrol1d1nyl-l-cyclopropyl-6-f1uoro-l,4-d1hydro-4-oxo-3-qu1nol1ne carboxyi1c acid (prepared according to J.P. Sanchez, et. al . , J. Med. Chem., 1988, 31, 983).

The following other quinolonyl lactams are also prepared by the general procedure of this Example and Examples 1-9, with substantially similar results. -130- 35 -132- -133- EXAHPLE 11 [6R-6a , 7B] ] -3- [ [ 1 -Cycl opropyl -6-f 1 uoro- 1 , -d1hydro-4-oxo-7-(l-p1peraz1ny1 )-3-qu1nol 1nylcarbonyl ]hydraz1noiiiethyl ]-8-oxo-7-[(2-th1enylacetyl )am1nol-5-th1a-l-azab1cyclo[4.2.0]oct-2-ene-2-carboxyl lc acid sodium salt, according to this invention, made by the following general reaction sequence.

A solution of 3-(hydroxy*ethyl)-8-oxo-7-[(2-th1eny1acetyl)-amino]-5-th1a-l-azab1cyclo[4.2.0]oct-2-ene-2-carboxy1ic acid diphenylmethyl ester (I) (0.65g) In dlchloronethane (20ml) 1s added to a mixture of Dess-Nartln per1od1nane (0.59g) in dichloromethane (10ml). The reaction is stirred for 30 minutes and poured into a mixture of ether (30ml) and 10% aqueous sodium bicarbonate (50ml) containing a 7-fold excess of sodium thio-sulfate. The mixture is rapidly stirred for 12 minutes and the organic layer separated and washed with 10% sodium bicarbonate and water. The organic phase is dried over sodium sulfate, filtered and the filtrate is concentrated to dryness to yield product (II).

Separately, a solution of ciprofloxacin methyl ester (l.Og), hydrazine hydrate (1.45g) and DMF (dimethylformamide) (50ml) is heated at 40'C (105*F) for 16 hours and concentrated to dryness in vacuo. The residue is triturated with acetone and recrystallized from ethanol/DMF to give the hydrazide product (HI).

Approximately 0.50g of product (II) and approximately 0.33g of product (III) are mixed in DMF (25ml) stirred at room temperature for 6 hours and concentrated to dryness in vacuo. The hydrazone is purified by repeated trituration in acetone, and then dissolved in anisole (5ml). To this solution is added drop-wise trifluoroacetic acid at -15"C (5*F) and the reaction is stirred at ambient temperature for 20 minutes. The solution is concentrated to dryness in vacuo and the residue is triturated with ether. The solid 1s dissolved In DMF/H2O and treated with sodium bicarbonate (0.080g); then the solution Is concentrated to dryness in vacuo and the solid recrystallized from ethanol/water to give product (IV).

Approximately 0.18g of product IV Is then mixed with 10% Pd/C (0.18g) and 70% THF/H2O and subjected to hydrogenation for 16 hours, and filtered to remove the catalyst. The filtrate Is concentrated to dryness and the final Product (V) s purified by recrystallization from ethanol/water.

EXAMPLE 12 (3S)-1-[[7-(3-Am1no-1-pyrrolidlnyl)-1-cyclopropyl-6,8-difluoro-1, 4-dihydro-4-oxo-3-quinol1nyl]carbobylthio]-4-oxo-3- [{phenoxyacetyl)amino]-l-azet1dinesulfon1c acid sodium salt, according to this Invention, Is made by the following general reaction sequence.

Approxloately 1.9 g of 7- [3-anilno-l -pyrrol 1d1nylJ-l-cyclo-propyl-6,8-d1fluoro-l,4-d1hydro-4-oxo-3-qu1nol1ne carboxyllc acid (I) Is dissolved in approximately 54 ml of absolute methanol. Approximately 7.9 ml of thionyl chloride is added at approximately 6*C (43*F). The mixture is refluxed for approximately 15 hr and then concentrated to dryness. Cold sodium carbonate solution is added and the solution is is extracted with dichloromethane. The organic layer is dried and concentrated to yield product (II).

Approximately 0.02g of 60% NaH (dispersion in mineral oil) is added to a solution of 0.78 g of tri phenyl methyl mercaptan in approximately 20 ml of THF. Approximately 1.15 g of 4 Angstrom molecular sieves and 0.21 g of product (II) are then added. The mixture is stirred at room temperature for approximately 2.5 days, cooled, and approximately 0.1 ml of water is added, and the mixture filtered. The filtrate is concentrated to dryness and taken up in dichloromethane and washed with IN aqueous NaOH, then with water. The organic phase was concentrated to dryness and the residue recrystallized from ethyl acetate to yield product (HI).

A solution of 0.3 g of product (III) in 12 ml of glacial acetic acid is treated with 4 ml of 1 N HC1 solution. The solution is heated for approximately 1.5 hr and then the acid is evaporated. The residue is triturated with acetone and the product filtered to yield product (IV).

A mixture of 0.8 g of product (IV) and approximately 23 ml of water is cooled to 0*C (32'F), and a 1 N NaOH solution is added dropwlse to pH of 12. Approximately 6 ml of acetone is added followed by a dropwise addition of 0.35 g of allyl chloroformate in approximately 4 ml of acetone, maintaining a temperature of 0*C and pH 12 using additional IN sodium hydroxide. Stirring Is continued for approximately 60 m1n or until the pH drift ceases to change from pH 12. The acetone is removed by evaporation in vacuo and the aqueous layer 1s extracted with ether. The aqueous layer 1s cooled and 10% HC1 solution 1s added to adjust the pH to 2. This 1s extracted with dichloromethane, the organic layer washed with water, dried and concentrated and triturated with ether to yield product (V).

A solution of 1.2 g of product (V) In a mixture of 10 ml dloxane and 2.77 ml of 1 N sodium hydroxide solution, is stirred for approximately 20 min in an ice bath. Then 0.6 g of 4-(acetyloxy)-3-[(pheno* /acetyl)amino]-2-azetidinone, in approximately 10 ml of dioxane, is added slowly. The reaction is stirred in an ice bath then warmed to room temperature to complete the reaction. Product (VI) is isolated by filtration.

A solution of 0.25 g of product (VI) in 1 ml of DMF is made, and 0.5 g of DMF-S03 complex is added. The reaction mixture is stirred for approximately 2 hours after which the mixture is diluted with 10 ml of dichloromethane and 10 ml of 0.5 N potassium hydrogen phosphate solution. The pH is adjusted to 6 and 0.13 g of tetrabutylammoniumhydrogen sulfate is added. The layers are separated and the organic layer is washed with water., dried and concentrated to yield product (VII).

Approximately 0.59 g of product (VII) Is taken up in approximately 10 ml of dichloromethane, 60 ml of water and 9 mg of bis(triphenylphosphine)pa1lad1um chloride. The mixture is treated with approximately 300 microliters of tributyltinhydride while maintaining a temperature of approximately 21*C (70*F). After rapid stirring for approximately 15 minutes, the reaction is concentrated to dryness, triturated with diethylether, and the crude product 1s taken up In aqueous methanol and stirred with Oowex 50W (Na) for approximately 1 hour. The resin is filtered off and washed with water. The filtrate is concentrated and lyophlllzed to yield the product (VIII) as a powder. Final purification Is achieved by trituration in dichloromethane.

Similarly, the following quinolonyl lactam 1$ prepared by the general procedure of this Example, with substantially similar results. using the quinolone l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- (l-p1perazinyl)-3-quino)ine carboxylic acid (prepared according to K. Grohe, et al., Ger. Offen. DE 3142854).

EXAMPLE 13 [6R-[6a,70]]-3-[[l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- (l-piperazinyl)-3-quinolinyl]carbonylthio]methyl]-8-oxo-7- [(2-thienylacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic Acid Sodium Salt (II) R - OH* (ttl) ft - SPh, (VII) ft-CO,4llyl (VIII) R - H To approximately 3.3 gm of 1-cyclopropyl-6-fluoro-l,4-diydro-4-oxo-7-(l-piperazinyl)-3-quinoline-3-carboxylic acid (I, prepared according to K. Grohe, et al., Ger. Offen. DE 3142854) in 100 ml absolute methanol is added 14 ml of thionyl chloride. The reaction was refluxed for approximately 15 hours and then concentrated to dryness. The crude residue is then extracted with methylene chloride and aqueous sodium carbonate solution. The organic layer is dried over a2S04 and concentrated to yield product (II).

To approximately 2.5 gm of triphenylmethyl mercaptan in 75 ml of DMF is added 0.1 gm of NaH (60% in mineral oil). After 15 minutes, approximately 15 gm of 4 angstrom molecular sieves and 2.9 gm product (I) is added at room temperature. The mixture is then heated at 40-45*C for 18 hours. The reaction is cooled, 2 ml of water is added and then the mixture is filtered. The DMF is removed under vacuum and the crude residue is taken up in methylene chloride and extracted several times with IN aqueous NaOH solution. The organic layer is washed with brine solution, dried over sodium sulfate and concentrated to dryness. The crude product (III) is used as is for the next step.

To a solution of approximately 3.7 gm of product (III) in 50 ml galcial acetic acid is added 10 ml of 3N HC1 solution and the mixture is heated at 60*C for approximately 4 hours. The solution 1s concentrated to dryness and the crude residue is trituated with acetone to yield product (IV) after filtration.

To a solution of 1.9 gm of product (IV) in 75 ml of water at approximately 5*C Is added IN NaOH to adjust the pH to 12. Then approximately 12 ml of acetone 1s added followed by the dropwise addition of 0.9 gm allyl chloroformate In 10 ml acetone. During the addition, the pH Is maintained around 12 with the periodic addition of further IN NaOH and the reaction 1s maintained at approximately 5*C. After 30 minutes an additional 0.5 gm aliquot of allyl chloroformate in 5 ml acetone Is added. The reaction Is allowed to warm to room temperature over 3 hours and then the acetone Is removed by evaporation. The remaining solution Is then extracted with methylene chloride, the aqueous layer 1s acidified and then extracted 2x with methylene chloride. The organic layer is then dried with sodium sulfate, concentrated to dryness, and triturated with acetone/hexanes to give approximately 2 gm of solid. This product is then dissolved in methylene chloride and chilled to approximately 5*C, and a solution of 185 mg of sodium hydroxide in 0.5 ml methanol is added dropwise. After 1 hour the reaction mixture is evaporated to dryness and the residue is triturated with acetone to yield product (V).

Separately, reactant (VI) is prepared by suspending approximately 25 gm of commercial cephalothin sodium salt in 500 ml of 50% DMF/dioxane, which is cooled to 3-5*C. Allyl iodide (12.1 gm) is added and the reaction Is stirred in the dark at room temperature for approximately 46 hours. The reaction mixture is poured into brine solution and ethyl acetate and extracted. The aqueous layer was extracted with a second ethyl acetate wash, the organic layers were combined and then washed successively with brine, water, 10% sodium bicarbonate and water. The solution is then dried over sodium sulfate, filtered and evaporated to dryness. The residue 1s triturated with either to obtain a solid product.

To approximately 10 gm of this Intermediate in methylene chloride 1s added 8.4 ml t i methyl si lyl iodide. The reaction is stirred at room temperature In the dark for 2 hours, then cooled to approximately 5*C and slowly quenched with cold 10% aqueous sodium t osulfate. The resulting layers are separated and the organic phase Is washed with additional thiosulfate solution, then water, dried over sodium sulfate and filtered. The solution 1$ then evaporated to near dryness and the residue 1s treated with hexanes to precipitate reactant (VI).

Approximately 2.0 gm of product (V) s added portionwise over 5 minutes to a solution of 2.2 gm reactant (VI) in 40 ml 50% DNF/d1oxane at room temperature In the dark. The reaction 1$ allowed to proceed for 2 hours and then evaporated to dryness. The residue 1s then taken up In water and ethyl acetate, the organic layer collected and washed 5x with cold 0.14N aqueous sodlum hydroxide, then with water. The solution is dried over sodium sulfate, filtered and evaporated. The residue is triturated with acetone/hexanes to obtain solid product (VII).

Approximately 1.3 gm of product (VII) is dissolved in 30 ml methylene chloride containing approximately 0.15 ml water and 20 mg bis(triphenylphosphine) palladium chloride. Approximately 0.9 ml of tri butyl tin hydride is added dropwise over 1 minute while maintaining the reaction at approximately 20*C. The reaction is vigorously stirred for 10 minutes during which time a precipitate forms which is collected by filtration and dried. The precipitate is then suspended in water containing 1 equivalent sodium bicarbonate. Acetone is then added slowly causing a complete solution to initially form, followed by the precipitation of the product (VIII) which is collected by filtration.

Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-aminopyrrolidinyl)-l-cyclopropyl-6,8-d1fluoro-l,4-dihydro-4-oxo-3-quinoline carboxyllc acid (prepared according to J. P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrrol1d1ny1)-l-chloro-l- cydopropyl-6-fluoro-l,4-d1hydro-4-oxo-3-qu1no11ne carboxyl ic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrro11diny1-l-cyclopropy1-6- fluoro-l,4-d1hydro-4-oxo-3-qu1nol1ne carboxyllc acid (prepared according to J.P. Sanchez, et. al., J. Med. Chem., 1988, 31, 983) using the naphthyridinone 7-(3-am1nopyrrol1d1nyl)-l-cyclopropyl- 6-fluoro-l,4-d1hydro-4-oxo-l,8-naphthyr1d1ne-3-carboxyl1c acid (prepared according to J. . Sanchez, et. al., J. Ned. Chem., 1988, 31, 983). ΕΧΛΗΡίΕ 14 [5R-[5a,6a]]-2-[[2-[l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- (l-p1peraz1nyl)-3-qu1nolinyl]carbonyUhiolethylthio]-6-(i- hydroxyethyl)-3-methyl-7-oxo-l-azabicyclo[3.2.0]hept- 2-ene-2-carboxylic Acid Sodium Salt (V) B - H (III) R - H (vi) R - cut (IV) R - OP(0)(Ofti), Approximately 7.2 g of 2-(t-butyldimethylsilyloxy)-l- methylcarbaceph-2-em (prepared according to 53 J. Org. Chem., 4154 (1988)), 1.6 g NaHC03, 36 ml of 2-(trimethylsilyl)ethanol , and 1 ml of a 0.1% solution of Sudan III in CH2CI2 are combined in approximately 300 ml of CH2CI2. A stream of argon is bubbled through the solution while cooling to approximately -78*C. Ozone is bubbled through the solution until the red color disappears, then argon is bubbled through the solution as it is allowed to warm to room temperature. Approximately 7.1 ml of triethylamine and 9.6 ml of acetic anhydride are added to the solution and it Is allowed to stir for approximately 16 hours at room temperature. The mixture is diluted with approximately 400 ml of saturated aqueous ammonium chloride and the aqueous phase is extracted twice with approximately 400 ml of ether. The combined organic layers are washed with approximately 400 ml of saturated aqueous sodium chloride then dried over HgS04. After filtration and concentration most of the 2-(tr1methy1s11yl)ethanol Is removed by short path distillation at approximately 60'C/O.l mmHg. The resulting residue Is dissolved In approximately 600 ml of CH2CI2 under an argon atmosphere and approximately 8.2 g of 2,2'-d1pyridyl disulfide and 9.8 g of triphenylphosphine are added. After approximately 5 hours at room temperature the solution Is concentrated and purified by chromatography on silica gel to give the product II as a mixture of somers at the position alpha to the thloester carbonyl.

A solution containing approximately 3.0 g of product II In approximately 120 ml of tetrahydrofuran Is cooled to approximately -75*C under an argon atmosphere. Approximately 10.0 ml of a 1.0 M solution of sodium b1s(tr1methy1si1y1 )amide in tetra-hydrofuran is added dropwise over approximately 7 minutes while maintaining the reaction temperature below approximately -70*C. Approximately 3 minutes after completion of the addition approximately 30 ml of 1 M HC1 is added, the mixture is further diluted with approximately 180 ml of water, and extracted with approximately 40 ml of 1:1 ether:petroleum ether six times. The combined organic layers are washed with approximately 100 ml of water, then approximately 100 ml of saturated aqueous sodium chloride, and dried over MgSOij. Concentration of the solution provides product III as a mixture of isomers at the 4-position.

Approximately 0.90 ml of diphenyl chlorophosphate and 0.80 ml of Ν,Ν-diisopropylethylamine are added simultaneously in a dropwise fashion to a cold solution (ice bath) of approximately 2.8 g of product III dissolved in approximately 30 ml of dry acetonitrile under an argon atmosphere. The ice bath is removed and the mixture is allowed to stir approximately 30 minutes at room temperature before concentrating and purifying by chromatography on silica gel to provide product IV as a single isomer.

A solution containing approximately 1.3 g of product IV in approximately 4.5 ml of dry acetonitrile is cooled in an ice bath under an argon atmosphere. Approximately 0.53 ml of Ν,Ν-dlisopropylethylamine 1s added followed by the dropwise addition of approximately 0.20 ml of 2-mercaptoethanol . After stirring for approximately 10 minutes the ice bath is removed and the solution is stirred approximately 3 hours longer at room temperature. Concentration of the solution, followed by chromatography on silica gel, provides product V.

Approximately 0.80 g of the product V is dissolved In 8 ml of dichloromethane along with approximately 0.34 ml of tr1ethylamine, and the mixture Is cooled in an ice bath under an Inert atmosphere. Approximately 0.14 ml of methanesulfonyl chloride Is added dropwise, and the mixture Is stirred approximately 15 minutes longer. The reaction mixture 1s transferred to a separatory funnel along with approximately 40 ml of dlchloromethane used to rinse the reaction fl ask. The dlchloromethane solution 1 s washed sequential ly with Ice water, cold IN hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. After drying over Na2S04 and concentration of the solution product VI i s obtained.

Reactant VII i s prepared by adding IN NaOH to a sol ution of 1.9 gm l-cyclopropyl -6-fluoro-l ,4-dihydro-8-oxo-7- ( l -piperazinyl ) -3-quinol ine thiocarboxyl ic acid (prepared as described herein) in 75 ml of water at approximately 5'C to adjust the pH to 12. Then approximately 12 ml of acetone is added followed by the dropwise addition of 1.4 gm 2- (trimethyl silyl )ethyl chloroformate (made according to Zhur. obschei . him. 1968, 38, 1179) in 10 ml acetone. During the addition, the pH is maintained around 12 with the periodic addition of further IN NaOH and the reaction is maintained at approximately 5'C. After 30 minutes an additional 0.7 gm al iquot of 2- (trimethylsilyl )ethyl chloroformate in 5 ml acetone i s added. The reaction 1s al lowed to warm to room temperature over 3 hours and then the acetone is removed by evaporation. The remaining solution is then extracted with methylene chloride, the aqueous layer is acidified and then extracted 2x with methylene chloride. The organic layer is then dried with sodium sul fate, concentrated to dryness, and triturated with acetone/hexanes to give approximately 2 gm of sol id. This product is then dissolved in methylene chloride and chilled to approximately 5*C, and a solution of 185 mg of sodium hydroxide in 0.5 ml methanol is added dropwise. After 1 hour the reaction mixture is evaproated to dryness and the residue 1s triturated with acetone to yield reactant (VII) .

A mixture of approximately 0.5 gm of product VI and 0.48 gm reactant VII were combined in 10 ml OMF and allowed to react at room temperature for 2 hours. The solvent Is removed in vacuo and the residue is dissolved in chilled methylene chloride and extracted with water, 3x with cold 10% sodium bicarbonate, then water and finally dried over sodium sulfate. The solution was concentrated to dryness to obtain product VIII.

To a solution of 0.25 gm product VIII In 10 ml OMF is added approximately 0.55 g of tetra-n-butylammonium fluoride and the mixture 1s stirred approximately 6 hours at room temperature. The reaction Is chilled and approximately 2 ml of cold saturated aqueous sodium bicarbonate 1s added. The mixture is eluted through a DowexR 50 x 4 (Na cycle) column with deionized water. The appropriate fractions are concentrated in vacuo, then lyophlllzed to give the final product IX.

Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-aminopyrrolid1ny1)-l-cyclopropyl-6,8-d1fluoro-l,4-dihydro-4-oxo-3-quinol1ne carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrrolidiny1-l-cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-3-qu1noline carboxylic acid (prepared according to J. P. Sanchez, et. al., J. Ned. Chen., 1988, 31, 983).

EXfflPLE IS [6R-[6a,7b]]-3-[[(l-cyc1opropyl-6-fluoro-l,4-d1hydro-4-oxo- 7-(l-p1perazinyl)-3-quinolinyl)carbonylth1o]methyll-8-oxo- 7-[(phenoxyacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid sodium salt A mixture of 1.0 gra 3-(acetyloxymethyl)-8-oxo-7- [(phenoxyacetyl)amino]-5-thia-l-azab1cyclo[4.2.0]oct-2-ene-carboxylic acid sodium salt (II, prepared according to R.B. Morln, et al., J. Am. Chem. Soc, 1969, 91, 1401) and 1.1 gm reactant (I, preparation described herein) In water adjusted to approximately pH 8 with sodium bicarbonate 1s stirred for 24 hr at approximately 40oC. The reaction mixture is cooled and the solvent removed In vacuo. The residue Is triturated with acetone/hexanes to obtain purified product (III).

To a solution of 0.8 gm of product (III) In approximately 20 ml methylene chloride containing 0.09 ml water and 12 mg bls(trlphenylphosphlne) palladium chloride. Then approximately 0.55 ml of trlbutyltln hydride Is added dropwlse while maintaining the reaction at approximately 20oC. The mixture is stirred vigorously for 10 in during which time a precipitate forms. The solid Is collected by filtration and resuspended in water containing 1 equivalent of sodium bicarbonate. Addition of a small amount of acetone Initially causes a solution to form, further addition repreclpltates the desired product (IV) which s collected and dried. using the beta-lactam 3-[[(aminocarbonyl)oxyJmethyl]-7-[[2- furanyl methoxyimino)acetyl ]amino]-8-oxo-5-thia- 1 -azabicyclo [4.2.0]oct-2-ene-carboxylic acid (prepared according to H.C. Cook, et. al.t US 3,974,153) using the beta-lactam 3-(acetyloxymethyl)-7-[[(2-araino-4-thiazolyl) acetyl] an1no]-8-oxo-5-th1a-l-azab1cyclo[4.2.0]oct-2-ene-2-carboxyllc acid (prepared according to J. Org. Chen., 1970, 35, 2430).

EXAMLE 1§ According to the general procedure of Example 15, the following qulnolonyl lactam Is made: using the beta-lactam 3- (( acetyl oxy)methyl ] -7- [(2-amino-4- thiazolyl) methoxyimino)acetyl]amino]-8-oxo-5-thia-l-azabicyclo [4.2.0]oct-2-ene-carboxylic acid (prepared according to M. Ochiai, et al . , US 4,098,888).

Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the quinolone 7-(3-am1nopyrrol1dinyl)-l-chloro-l- cyclopropy1-6-fluoro-l,4-d1hydro-4-oxo-3-quinol1ne carboxylic add (prepared according to J. P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983) using the quinolone 7-(3-am1nopyrrol d1nyl-l-cyclopropy1-6- fluoro- -d1hydro-4-oxo-3-qu1no11ne carboxylic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Cem., 1988, 31, 983) using the naphthyridinone 7-(3-aminopyrrolidiny1)-l-cyclopropyl- 6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyrid1ne-3-carboxylic acid (prepared according to J.P. Sanchez, et. al., J. Ned. Chem., 1988, 31, 983).

EXANPE 17 According to the general procedure of Example 16, the following quinolonyl lactam is made: using the qulnolone 7-(3-aminopyrrol1d1nyl)-l-cyclopropyl-6,8-d1fluoro-l,4-d1hydro-4-oxo-3-quinol1ne carboxyllc acid (prepared according to J. . Sanchez, et. al., J. Ned. Chen., 1988, 31, 983).

Similarly, the following quinolonyl lactams are prepared by the general procedure of this Example, with substantially similar results. using the beta-lactam 3-(acetyloxymethyl)-8-oxo-7-[(4-pyridylthioacetyl) amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (prepared according to S. Crast, et. al., J. Med. Chem., 1973, 16, 1413) using the beta-lactam 3-(acetyloxymethyl)-7-methoxy-8-oxo-7-[(2-thienylacetyl)amino]-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxyllc add (prepared according to Karady, et al., J. Am. Chem. Soc, 1972, 94, 1410).

The following other quinolonyl lactams are also prepared by the general procedure of this Example and Examples 12-16, with substantially similar results. -156- EMHP E 119 An antimicrobial composition for parenteral administration, according to this Invention, s made comprising: Component Amount [5R-[5a,6a]]-3-[[[l-cyclopropyl-6,8-d1fluoro-I,4-d1hydro-4-oxo-7-( 3 - ami noraethyl - 1 - pyrrol 1 d nyl ) -3-qu1no Inyl ]carbony1am1no]methy1 J-6-[(R)-l-hydroxyethylJ-7-oxo-4-th1a-l-azab1cyc1o[3.2.0]hept-2-ene-2-carboxyllc acid 100 mg/ml carrier Carrler: sodium citrate buffer with (percent by weight of carrier) : lecithin 0.48% carboxymethyl eel 1 ul ose 0.53 povidone 0.50 methyl paraben 0.11 propyl paraben 0.011 1 : a qulnolonyi lactam, made according to Example 1 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 pneumoniae 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. ΕΧΑΗΡ Ε 19 An enteric coated antimicrobial composition for oral administration, according to this Invention, is made compri sing the fol lowing tablet: Component romn* (rot)) ί 5R - f 5a , 6a ] ] - 3 - f [ ( 1 -cycl oprop 1 - 6,8-difluoro-l ,4-dihydro-4-oxo-7- (3-aminoroethyl -1 -pyrrol Idlnyl) -3-quinol iny ]carbony1am1no]methyl J-6-[(R)-l -hydroxyethyl )-7-oxo-4-th1a-l-azab1cyclo[3.2.0]hept-2-ene-2-carboxyl ic acid starch magnesium stearate mlcrocrystal l lne cellulose colloidal sil icon dioxide povidone a qulnolonyi lactam, made according to Example 1 The components are admixed into a bulk mixture. Compressed tablets are formed, using tabietting methods known in the art. The tablet is then coated with a suspension of methacrylic acid/methacrylate 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.

DLS/ewl/N528R(PA4) -156- -157- EXAMP 19 An antimicrobial composition for parenteral administrati according to this invention, is made comprising: Component Amount [5R-[5a,6a]]-3-[[[l-cyclopropyl-6,8-difluoro-l,4-dihydro-4-oxo-7-(3-amlnomethyl -1 -pyrrol idinyl ) -3-quinolinyl ]carbonylamino]methyl ] -6-((R)-l-hydroxyethyl]-7-oxo-4-thia-l-azab1cyclo[3.2.0Jhept-2-ene-2-carboxyllc acid 100 mg/ml carrier

Claims (1)

1. 60 C L A I A compound of the general formula wherein is a carbocyclic a heterocyclic or where m is a integer from 0 to and where is a carbocyclic or a heterocyclic ring or and together comprise a heterocyclic ring including the nitrogen to which they are a carbocyclic or a heterocyclic or is aryl heteroaryl alkyl or where or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which and are is or is and Z is or or p is an integer from 0 to 161 is a carbocyclic a heterocyclic E 13 and Z2 is R 19 comprise a moiety bonded to to form a heterocyclic and is N or S where is a carbocyclic a heterocyclic or when is N R21 may be a moiety bonded to to form a heterocyclic and is or where is a carbocyclic a heterocyclic when is and is R R16 and may together comprise a heterocyclic ring including the nitrogen atom to which is B is or where R2 2 is hydrogen or C bond is a single bond or is and bond is a single a double or is except bond and bond are not both is or where R is or and is directly bonded to in Formula to form a if bond is then R3 is where is where r is an integer from 0 to or and carbocyclic ring or heterocyclic ring substituents or R25 and together comprise a heterocyclic ring including the nitrogen atom to which and R are or 162 where 2 and R27 is directly bonded to in Formula to form a if bond is a single R4 is if bond is or contains an R32 where R28 is hydrogen or and is linked to to form a 3rmembered if bond is a double R4 is bond is R4 is or where is a carbocyclic or a heterocyclic and is or if R4 is R29 and may together comprise a heterocyclic ring including the nitrogen to which and are and if bond or bond Is than is or if bond and are if bond is a single bond and bond is a double R5 is W is where s an integer from 0 to or e or R31 a carbocyclic or a heterocyclic is hydrogen if R4 is R32 be linked to to form a carbocyclic is where t is an integer of 0 to or is or heteroalkenyl a carbocyclic or a heterocyclic 163 R35 is 0r R36 is a carbocyclic or a heterocyclic is bonded to R4 to form a or if is sulfur or Y is oxygen or or if is Y is where is sulfur or where is or or if A3 is then and may together comprise a heterocyclic A1 is N or where R40 is or is N or where R6 is hydrogen or A3 is N or C where R is R8 is a carbocyclic a heterocyclic aryl or R7 is a carbocyclic or a heterocyclic and is or except that when is R8 and may together comprise a heterocyclic ring including A when A2 is and R7 may together comprise where n is an integer 1 to and when A3 is R8 and may together comprise a heterocyclic ring including and the adjacent carbon to which R is and salts and biohydrolyzabie esters and hydrates A according to wherein bond 1s a single bond and bond is a single bond or a double forming a bicyclic A according to Claim wherein said moiety is selected from the group consisting of 1 and A according to Claim wherein either bond is or bond 1s forming a monocyclic A according to Claim wherein moiety selected from the group consisting of monophosphams and A according to Claim wherein said containing moiety 1s a A according to Claim wherein moiety 1s selected from the group consisting of and A according to Claim wherein said moiety 1s selected from the group consisting of cephe and A according to Claim wherein said moiety is selected from the group consisting of clavems and wherein said is or A according to Claim wherein said moiety is selected from the group consisting of pyrazol monosul and and is A according to wherein 1s A according to Claim wherein is A according to Claim wherein 1s A according to Claim wherein said moiety selected from the group consisting of pyrazol monosul lactivicin and lactams and ft1 is A according to Claim wherein said moiety is selected from the group consisting of pyrazol and and A according to Claim wherein 1s hydrogen or A compound according to Claim wherein R3 is A compound according to Claim is is and or A is is and is A compound according to Claim wherein A2 is and A compound according to Claim wherein Q is a a a pyrldobenzoxazine a a or A according to Claim wherein 1s or A according to Claim wherein is methyl no or A according to Claim wherein hydrogen or A according to Claim wherein 1 chlorine or A according to Claim wherein R7 a heterocyclic A according to Claim wherein R7 1s 3 pyrrol i di yrrol i ne nomethyl pyrrol nomethy or 167 A according to Claim wherein S and R2 1s A according to Claim wherein A according Claim wherein γ and comprise a Unking moiety selected from the group consisting of and hydrazida A according to wherein said linking moiety is a thioester wherein X 1s A according to Claim wherein said linking moiety is a thioester wherein X is and is A according to Claim wherein said linking moiety an amide A according to Claim if bond or bond is then is if bond and are single 1S if bond is a single bond bond is a double is or where is or is and is oxygen or and if is or Y is oxygen or if is Y is A compound of the general formula wherein is or where is an integer from 0 to and RlOa a carbocycTic or heterocyclic ring or together comprise a heterocyclic ring the nitrogen to which they are a carbocyclic or a RI3 or is or 14 is or and or or p is is heteroalkenyl a carbocyclic a heterocyclic when is and comprise a moiety bonded to to form a heterocyclic and where is a carbocyclic a heterocyclic or when may be a bonded to to form a heterocyclic and 1S a carbocyciic ring or a heterocyclic hydrogen or bond 1s a single bond or is and bond is a single a double or is except bond and bond are not both if bond is where is where r is or and R26 carbocyciic ring or heterocyclic ring or together comprise a heterocyclic ring including the nitrogen atom to which and are bond is a single is if bond is or contains a R32 where R28 is and 1s linked to to form a if bond 1s a double is 0r if bond is 1s or a or a heterocyclic and R3 if is and may together comprise a heterocyclic including the nitrogen to which and are and if bond or 1s then 1s 1f bond and are single R5 1s o or if bond is a single bond and bond is a double is 0r where is where s is or is alkyl or R31 is a carbocycl or a heterocyclic R32 if is R32 may be linked to to form a carbocyclic X 1S or Z 1s where t is or is or is alkyl or or R a carbocycl c or a heterocyc is bonded to to form a or if is sulfur or γ or if is Y is where V is where or or if then and may together comprise a N or where is hydrogen or A2 is where is hydrogen or where is alkyl or a carbocyclic R7 is a heterocyclic and is except that when is and may together comprise a heterocyclic ring inclLding and when is R6 and R7 may together comprise where n is an integer from to and when is and may together comprise a heterocyclic ring including and the adjacent carbon to which and pharmaceutical salts and esters and hydrates A according to Claim bond a sing e bond and bond a A composition for treating or preventing an disorder in a human or other animal a safe and effective amount of a compound of Claim and a acceptable A composition for treating or preventing an disorder in a human or other animal a safe and effective amount of a compound of Claim and a pharmaceutical A composition for treating or preventing an infectious disorder in a human or other animal a safe and effective amount of a compound of Claim a pharmaceutical A composition for treating or preventing an disorder in a human or other animal a safe and effective amount of a compound of and a pharmaceutical A composition for treating or preventing an infectious disorder in a human or other animal a safe and effective of a compound of Claim and a A composition for treating or preventing an infectious disorder in a human or other animal a safe and effective amount of a compound of Claim and a A composition for treating or preventing an disorder in a human or other animal a safe and effective amount of a compound of Claim and a A composition for treating or preventing an infectious disorder in a human or other animal a safe and effective amount of a compound of Claim and a A composition for treating or preventing an infectious disorder in a human or other animal a safe and effective of a compound of Claim and a A composition for treating or preventing an disorder 1n a human or other animal a safe and effective amount of a compound of Claim and a A composition for treating or preventing an Infectious disorder in a human or other animal according to Claim wherein said composition is suitable for parenteral 92031 2 173 A composition for treating or preventing an infectious disorder in a human or other animal according to claim wherein said composition is suitable for oral A compound of claim 1 for use as a medicament for preventing or treating an infectious disease in a human or animal A compound of claim 6 for use as a medicament for preventing or treating an infectious disease in a human or animal 50 A compound of claim 8 for use as a medicament for preventing or treating an infectious disease in a human or animal A compound of claim 25 for use as a medicament for preventmg or treating an infectious disease in a human or animal A compound of claim 28 for use as a medicament for preventing or treating an infectious disease in a human or animal A compound of claim 29 for use as a medicament for preventing or treating an infectious disease in a human or animal A compound of claim 33 for use as a medicament for preventing or treating an infectious disease in a human or animal A compound of claim 34 for use as a medicament for preventing or treating an infectious disease in a human or animal For the COHN AND PARTNERS insufficientOCRQuality