IL92091A - Quinolonyl lactam esters and pharmaceutical compositions containing them - Google Patents

Quinolonyl lactam esters and pharmaceutical compositions containing them

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IL92091A
IL92091A IL9209189A IL9209189A IL92091A IL 92091 A IL92091 A IL 92091A IL 9209189 A IL9209189 A IL 9209189A IL 9209189 A IL9209189 A IL 9209189A IL 92091 A IL92091 A IL 92091A
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bond
hydrogen
alkyl
heterocyclic ring
alkenyl
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IL9209189A
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IL92091A0 (en
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Procter & Gamble Pharma
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92091/2 ΠΓΠΝ D^Dan rnnpn ΤΪΟΠΙ n vw ηκν m imp Quinolonyl lactam esters and pharmaceutical compositions containing them PROCTER & GAMBLE PHARMACEUTICALS, INC.
C: 78868/7 92091/2 - 1 BACKGROUND OF THE INVENTION This invention relates to novel antimicrobial compounds and compositions. The compounds of this invention contain a quinolone moiety and a lactam-containing moiety, in a new chemical entity.
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, ansamacrol ides, beta-lactams (including penicillins and cephalosporins), lincos-aminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described in Antibiotics, Chemotheraoeutics. and Antibacterial Agents for Disease Control (H. 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 or more 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 it can act. For example, bacterial resistance to beta-lactam antlbacterlals 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 antlbacterlals 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., IP 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 hydro! zed by beta-lactamase. Nobashery et al., 108 vL 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: 92091/2 -4- wherein (A) R is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, RlOa_o- , R Oa H=N-, (RlO) (Rll)N- , Rl2-C(=CHRl5)-C(=0)NH-, R12.C(»NO-R14)-C(-0)NH-, or R13- (CH2)M-C(-0) H- , preferably alkyl, alkenyl, R12-C(-N0-R14)-C(»0)NH-, or R13-(CH2)m-C(»0)NH-; where (1) m is an integer from 0 to 9, preferably from 0 to 3; (2) RlO and Rll are, independently, R^i where RlO* ]s hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring substituent; or R 0 and RH together comprise a heterocyclic ring including the nitrogen to which they are bonded; (3) R12 1s hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring, preferably alkyl, a carbocyclic ring or a heterocyclic ring; (4) Rl3 is Rl2, -Zl, or -CH(∑2) (Rl2) ; (5) Rl4 is Rl2, arylalkyl, heteroaryl alkyl , -C(Rl7)(Rl8)COOH, -C(-0)0-Rl2, or -C(-0)NH-Rl2, preferably l or -C(Rl7)(Rl8)C00H; where l7 and are, Independently, R12 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which R^7 and Rl8 are bonded; (6) l5 iS R14, halogen, -Z*. or -CH(Z2)(Rl2) , preferably Rl* or halogen; (7) Zl is -C(-0)0Rl6, -C(-0)Rl6, -N(R19)R16, -S(0)pR24, or -0R24; and Z2 is Z^ or -OH, -SH, or -SO3H; (a) p is an integer from 0 to 2, preferably 0; (b) Rl9 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroaikenyi; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(=0)R20; or, when Rl3 is -CH(Z2)(Rl2) and Z2 is - (R19)R16, R19 may comprise a moiety bonded to Rl6 to form a heterocyclic ring; and (c) R20 is R-12, NH(Rl2), N(R12)(R21), 0(R21), or S(R21), preferably Rl2, NH(Rl2), or N(R12)(R21); where 21 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R20 is N(R12)(R21) R21 may be a moiety bonded to Rl2 to form a heterocyclic ring; and (8) Rl6 is R * or hydrogen, preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring; where R 4 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroaikenyi; heteroaryl alkyl ; a carbocyclic ring; a heterocyclic ring; or, when Zl is N(R19)R16 and Rl6 is R24, R16 and . Rl9 may together comprise a heterocyclic ring including the nitrogen atom to which R19 is bonded; R2 is hydrogen, halogen, alkoxy, or R22C(»0)NH-, preferably hydrogen or alkoxy; where R22 is hydrogen or alkyl; bond "a" 1s 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-, preferably -C(Rl°a)-; where R23 is -C(RlOa), -0-, or -N-, and R 3 is directly bonded to N' in Formula (I) to form a 5-membered ring; except, if bond "a" is nil, then R3 is (1) -C(RlO*)(Z3)-, where (i) Z3 is -Rl6; -OR25; -S(0)rR25, where r is an integer from 0 to 2, preferably 0; -OC(=0)R25; or -N(R25)R26; (ii) R25 and R25 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R2S and R26 together comprise a heterocyclic ring including the nitrogen atom to which R25 and 26 are bonded; or (2) -CH2-27-; where 2? is -C(Rl°a)(Rl°) , -o-, or -NR10a/ and R27 is directly bonded to N' in Formula (I) to form a 5-mejnbered 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 a R2 moiety; where R8 is hydrogen or COOH, preferably COOH, and C* is linked to 32 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, -PO(OR29JOH, .OSO3H, -CH(R30)C00H, or -0CH(R29)C00H; preferably -SO3H, or -C(0)NHS02N(R29)(R30); where 'R29 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R30 is hydrogen, alkyl, alkenyl, or -NHR10a; or, if R4 is -C(0)NHS02N(R29)(R30), R29 and R30 may together comprise, a heterocyclic ring including the nitrogen to which 9 and R0 are bonded; and (F) (1) if bond "a" or bond "b" is nil, then R5 is Y; (2) if bond "a" and "b" are single bonds, R5 is -XZ-C-'-Ci lOaj.Sl.y., „r -X2-C"'(R32).R31.Y 0r (3) if bond "a" is a single bond and bond "b" is a double bond, R5 is -C(Rl0a)(R33)-x2-C"'-R31-Y-; -Xl-C(Rl0a)(R33)-C"'-R31-Y-; or -X2-C"'-R31-Y-; where (a) Xl is 0 or CH(R33),where R33 is hydrogen, alkyl or alkoxy; (b) χ s 0; S(0)s, where s is an integer from 0 to 2; or CH(R33), 92091/3 - 7 - (c) R31 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; (d) 32 iS hydrogen; alkyl; alkenyl; -COOH; or, if R4 is -C*(R28), R32 may be linked to C* to form a 3-membered carbocyclic ring; (e) Y is 0 or Z -R3 -0, where (1) Z4 is -0-; -S(0)f. where t is an integer of 0 to 2; or -NRlO*-; ana- (2) R34 is alkyl, alkenyl, heteroalkyl, heteroalkenyl , a carbocyclic ring, or a heterocyclic ring; and (3) Y is directly bonded to C (f) C" is bonded to R4 to form a 5- or 6-membered ring; (1) A1 is N or C(R40); where R40 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R1°)(RH), preferably hydrogen or halogen; (2) A2 is N or C{≠), preferably C(R6); where R6 is hydrogen or halogen? (3) A3 is N or C(R 1), preferably C( 41) ; where R41 is hydrogen; (4) R8 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R10)(RH), preferably alkyl or a carbocyclic 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(R1°)(RU), preferably hydrogen; and that (1) when Al 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 - 7a - (3) when A3 is C(R41) , R8 and may together comprise a heterocyclic ring including N" and the adjacent carbon to which R^l is bonded; and pharmaceutical ly-acceptable salts and biohydrolyzabl e esters thereof, and hydrates thereof.
It has been found that the compounds of this invention, and compositions containing these compounds, are effective antimicrobial agents against a broad range of pathogenic microorganisms. These compounds provide advantages versus antimicrobial agents among those knovm in the art, including (for example) the spectrum of antimicrobial activity, potency, the avoidance of microbial resistance, reduced toxicity, and improved pharmacology. ηίςπιΐΤΐθΝ OF THE INVENTION The present Invention encompasses certain novel quinolonyl lactam esters, methods for their manufacture, dosage forms, and methods of administering the quinolonyl lactam esters to a human or other animal subject. Specific compounds and compositions to be used in the invention must, accordingly, be pharmaceutically acceptable. As used herein, such a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
Quinolonyl Lactam Esters The compounds of this invention, herein referred to as "quinolonyl lactam esters", encompass any of a variety of lactam-contalning moieties linked, by an ester linkage, 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 carbocycllc ring, a heterocyclic ring, RlOa.fl-, R10aCH-N-, (RlO)(Rll)N-, Rl2.c(-CHRl5)-C(-0)NH-, or (preferably) Rl2-C(»N0-Rl4)-C(-O)NH-, or R13-(CH2)a-C(-0)NH-; where (1) n s an nteger from 0 to 9 (preferably 0 to 3); (2) RlO and R" are, Independently, RlOa whee Rl°a is hydrogen, alkyl, alkenyl, a carbocycllc ring, or a heterocyclic ring substituent; or RlO and R11 together comprise a heterocyclic ring including the nitrogen to which they are bonded; (3) R12 is hydrogen, alkyl, alkenyl, heteroalkyi, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl, a carbocyclic ring, or a heterocycl ic ring) ; (4) Rl3. is Rl2, -Zl, or -CH(∑2) (R12} ; (5) R14 is R12, arylalkyl, heteroarylalkyl, -C(Rl7)(Rl8)C00H, -C(-0)0-Rl2, or -C(=0)NH-Rl2, where R17 and R18 are, independently, Rl 2 0r together comprise a. carbocyclic ring or a heterocyclic ring including the carbon atom to which R ? and Rl8 ar8 bonded (preferably R* or -C(Rl7) (Rl8)C00H; (6) l5 is Rl*, halogen, -Zl, or -CH(Z2)(Rl2) (preferably Rl4 or halogen) ; (7) Z is -C(-0)0Rl6, -C(-0)R16, -N(Rl9)Rl6, -S(0)pR24, or -OR24; and Z2 is Z or -OH, -SH, or -SO3H; (a) p is an integer from 0 to 2 (preferably 0); (b) Rl9 is hydrogen; alkyl; alkenyl; heteroalkyi; heteroalkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(=0)R20; or, when Rl3 is -CH(Z )(Rl2) and Z2 is -N( 19)R 6, Rl9 may comprise a moiety bonded to Rl6 to form a heterocyclic ring; and (c) R20 is Rl2, NH(Rl2), N(R12)(R21 , 0(R21), or S(R21) (preferably R^, NH(Rl2), N(R1 ) (R21) ) ; where R 1 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 fo m a heterocyclic ring; and (8) Rl6 is R24 or hydrogen; where R24 is alkyl; alkenyl; arylalkyl; heteroalkyi; heteroalkenyl; heteroarylalkyl; a carbocyclic ring; a heterocyclic ring; or, when Z1 is N(R19)R16 and R16 JS R24, R16 and R*9 may together comprise a heterocyclic ring including the nitrogen -10- atom to which R19 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 $ hydrogen or alkyl (preferably hydrogen); 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(Rl°a)-, or -CH2-R23- (preferably -C(RlOa)-); where 23 is . RlOa), -0-, or -N-, and 23 is directly bonded to N' in Formula (I) to form a 5-membered ring; except, if bond "a". is nil, then R3 is (1) (preferably) -C(RlOa) (Z3) - , where (i) Z3 is -Rl6, -OR25, -S(0)rR25-f where r is an integer from 0 to 2 (preferably 0), -OC(=0)R25, or -N(R25)R26 ; (ii) R25 and R26 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R 5 and R26 together comprise a heterocyclic ring including the nitrogen atom to which R25 and 26 are bonded; or (2) -CH2-R27-; where R 7 is -0-, or -NRlO, and R27 is directly bonded to * 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 R-3i to form a 3-membered ring; (2) if bond "b" is a double bond, * is -C(R28)-.; or (3) if bond "b" is nil, R* is hydrogen, -SO3H, -PO(OR29)OH, -C(O)NHSO2N(R29)(R30), -OSO3H, -CH(R30)COOH, or -0CH(R29)C00H (preferably -SO3H or -C(O)NHS02N(R29)(R30)); where R29 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R30 is hydrogen, alkyl, alkenyl, or -NHRlO*; or -11- (preferably), if R4 is -C(0)NHS02N(R29) (R30) , R29 and R30 may together comprise a heterocyclic ring including the nitrogen to which R2 an(j R30 are bonded; and (F) (1) if bond "a" or bond "b" is nil, then R¾ i s Y; (2) if bond "a" and "b" are single bonds, R5 is -X2-C"'=C(Rl0a).R3I.Y.t or -χ2_ο" ' (R32) _ 31 -y.. or (3) (preferably) if bond "a" is a single bond and bond "b" is a double bond, R5 is -C(Rl°a) (R33) -X2-C" -R31-Y- ; or (preferably) -Xl-C(RlOa) (R33) -C" -R31-Y- ; or -X2-C"'-R31-Y-, where (a) X1 is 0 or CH(R33)5where R33 is hydrogen, alkyl or alkoxy; (b) X2 is 0; S(0)s, when* s is an integer from 0 to 2 (preferably 0); or CH(R33); (c) R31 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; '(d) R3 is hydrogen; alkyl; alkenyl; -C00H; or, if R4 is -C*(R28), R32 may be linked to C* to form a 3-membered carbocyclic ring; (e) Y is 0 or Z -R3 -0, where (1) Z4 is -0-; -S(0)t-» where t is an integer of 0 to 2 (preferably 0); or -NRl°a- ; and (2) R34 is alkyl, alkenyl, heteroalkyl, heteroalkenyl , a carbocyclic ring, or a heterocyclic ring (preferably alkyl or alkenyl); and (3) Y is directly bonded to C (f) C"' is bonded to R4 to form a 5- or 6-membered ring; (6) (1) A1 is N or C(R*0); where R40 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R1°)(RH) (preferably hydrogen or halogen), and (2) A2 is N or (preferably) C(R6); where ≠ is hydrogen or halogen; (3) A3 is N or (preferably) C(R41); where R*l is hydrogen; 92091/2 -12- (4) R8 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R10)(R11) (preferably hydrogen or a carbocycl ic ring) ; (5) R7 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring (preferably a heterocyclic ring); and (6) : R9 is hydrogen, halogen, nitro, or N(R10)(R11); (H) and that ' (1) when A^ is C(R40), R8 and R40 may together comprise a heterocyclic ring including N'' and A ; (2) when 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 A^ is C(R41), R8 and R4 may together comprise a heterocyclic ring including N" and the adjacent carbon to which R41 is bonded; and pharmaceutically-.acceptable salts and biohydrolyzabie esters thereof, and hydrates thereof.
Definitions and Usage of Terms: The following is a list of definitions for terms used herein.
"Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.
"Alkyl" is an unsubstituted or substituted, saturated hydrocarbon chain radical having from 1 to 8 carbon atoms, preferably from 1 to 4 c&rbon atoms. Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.
"Heteroalkyl" is an unsubstituted or substituted saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms. -13- "Alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond.
"Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocycl c rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
"Cycloalkyl" is a saturated carbocyclic ring radical.
Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.
"Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
"Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.
"Heteroaryl" is an aromatic heterocyclic ring radical. Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridlnyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolonyl, and tetrazolyl.
"Alkoxy" Is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain 1s an alkyl or alkenyl (I.e., -0- alkyl or -0-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
"Alkyl ami no" 1s an amino radical having one or two alkyl substltuents (I.e., -N-alkyl).
"Aryl alkyl" 1s an alkyl radical substituted with an aryl group. Preferred aryl alkyl groups Include benzyl and phenyl ethyl. -14- "Arylamino" 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 alkylacyl groups include (for example) acetyl, formyl , and propionyl.
"Acyloxy" is an oxygen radical having an acyl substituent (i.e., -0-acyl); for example, -0-C(*0)-alkyl .
"Acyl ami no" 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 "pharmaceutical ly-acceptable salt" is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein). Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium). Preferred anionic salts include the halides (such as chloride salts).
A "biohydrolyzable ester" Is an ester of a quinolonyl lactam ester 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 antlmlcroblaily-actlve quinolonyl lactam ester. Such esters Include those that do not Interfere with the biological activity of qui no lone antimicrobials or beta -lac tarn antimicrobials (cephems, for example). Many such esters are known In the art, as described in World Patent Publication 87/05297, Johnston et al., published * -15- September 11, 1987, (incorporated by reference herein). Such esters include lower alkyi esters, lower acyloxy-alkyl esters (such as acetoxymethyl , acetoxyethyl , aminocarbonyloxymethyl , pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthal idyl esters), lower alkoxy -acyloxyalkyl esters (such as methoxycarbonyloxymethyl , ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and alkyi acylamino alkyi 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. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein. Preferred substituents include (for example) alkyi, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxy aceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrol idinyl , etc.), imino, thioxo, hydroxyal kyl , aryloxy, arylalkyl, 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 1s also Incorporated Into the definition of other substituents (such as R3, R8, and R9). As used herein, such a radical 1s Independently selected each time it is used (e.g., R10A need not be alkyi in all occurrences In defining a given compound of this Invention).
Lactam-contalnlno moieties: Groups It3, R4, and R5, together with bonds "a" and "b", form any of a variety of lactam-contalnlng moieties known in 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 bicyclic. -16- Pref erred lactam moieties include the oxacephems carbacephems of the representative formula: wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -C(RlOa)-, where R * is hydrogen; R« is -CH(R28), where R28 is COOH; and R* is -Xl-C(Rl0a)(R33)-C"'R31-Y-, where R * and R 3 are hydrogen, R31 is methylene, and X1 is 0 (for oxacephems) or C(R33) (for carbacephems).
Other preferred lactam moieties include the Isocephems and iso-oxacephems of the representative formula: wherein bond "a" Is a single bond; bond "b" s a double bond; R3 Is -C(RlO» where R">a is hydrogen; R* Is -C(R28), where R28 Is COOH; and 5 is -C(Rl0a)(p33)-x2-C"-R31-Y- ^ere Rloa and R33 are each hydrogen, R31 Is methylene, and X2 is S (for Isocephems) or 0 (for Iso-oxacephems).
Other preferred lactam-contalnlng moieties Include the penems, carbapenems and clavems, of the representative formula: -17- wherein bond Ma" Is a single bond; bond "b" is a double bond; R3 is -C(RlOa), where R10a is hydrogen; R4 is -CfR28)-, where R28 is COOH; and R* is -X2-C"'-R31-Y-, where 31 is methylene, and X2 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. NcCombie et al., "Synthesis and In Vitro Activity of the Penem Antibiotics", 8 Medicinal Researc Reviews 393 (1988).
Other preferred lactam-containing moieties of this Invention include the penicillins of the representative formula: wherein bond "a" Is a single bond, bond "b" Is a single bond; R3 Is -C(RlOa).( where R">* Is hydrogen; R< Is -CH( 28). where R28 1s COOH; and 5 is -x2-C"'(R32)-R31.y. where R32 is methyl, R31 Is methylene, and X2 Is S. -18- Other preferred lactam-containing 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°*)-, where RlO is hydrogen; R5 is Y; and R4 is -SO3H (for a monobactam), -PO(OR34)OH (for a monophospham) ; -C(0)NHS02N(R34)(R3S) (for a monocarbam) , -OSO3H (for a monosulfactam), -CH(R35)COOH (for nocardicins), or -OCH(R34)COOH. Such lactam moieties are described in C. Cimarusti 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: wherein bond "a" Is nil, bond "b" Is a single bond; R3 Is -C(Rl0a)(R29). where both lOa and R29 are hydrogen; and R5 Is Y. -19- Other preferred lactam moieties include the clavams representative formula: wherein bond "a" is a single bond; bond "b" is a single bond; 3 is -C(Rl°a) -, where R * is hydrogen; R* is -CH(R28) - , where R28 is COOH; and R5 is x2-C" ' -C-(Rl0a) -R31-Y- , where RlOa is hydrogen and R31 is methylene, and X? is 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" 1s a single bond; R3 Is -C(RlOa)-, where lO* Is hydrogen; R* 1s -C*(R28). where R28 Is COOH; and R5 is X2-C" (R32)-R31-Y-. where R31 is nil , R?2 Is l inked to C* to form a 3-raembered carbocycl ic ring, and X2 is C(R33) or sulfur.
Lactam moieties of this Invention also include the lactivicin analogs of the representative formula: -20- wherein bond "a" is nil; bond "b" is a single bond; R3 is -CH2-R27, where R27 0; R4 is -CH(R28)-, where R 8 is C00H; and R5 is Y.
Other lactam moieties include the pyrazol idinones of the representative formula: wherein bond "a" is a single bond; bond "b" is a double bond; R3 is -CH2-R23- where R23 is -N-; R* is -C(R28)-, where R28 is COOH; and R5 is x2-c"'-R31-Y-, where R31 is methylene, and χ2 is C(R33).
Other lactam moieties include the gaaraa-lactarns of the representative formula: 92091/2 •21- wherein bond "a" is a single bond; bond "b" is nil; R3 is -CH2-R23-, where R23 is -C(RlO«) and R * is hydrogen; R4 is -SO3H, -P0(OR29)OH, C(0)NHS02N(R29)(R30) . -OSO3H, - CHCR^COOH, Preferred lactam-containing moieties include cephems, isocephems, iso-oxacephems, oxacephems, carbacephems, penicillins, penems, carbapenems, and monocyclic beta-lactams.
Particularly preferred are cephems, penems, carbapenems and monocyclic beta-lactams.
R1 is any radical that may be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of an antimicrobially-active lactam. (As used herein, the term "antimicrobially-active lactam" refers to a lactam-containing compound, without a quinolonyl substituent moiety, which has antimicrobial activity.) This "active" position is beta (i.e., 7 -beta) for cephems, oxacephems and carbacephems (for example). The active position is alpha for penems, carbapenems, clavems and clavams.
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 Bioloov of b-Lactam Antibiotics (R. Horin et al., editors, 1987); "The Cephalosporin Antibiotics: Seminar- in- Print", 34 Drugs (Supp. 2) 1 (J. Williams, editor, 1987); fis Beta-Lactam Antibiotics: A Review from Chemistry of -22- 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 Anoew. Chem. Int. Ed. Enal . 180 (1985); G. Rolinson, "Beta-Lactam Antibiotics", 17 vh 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 Rl 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: acetylamino, preferably substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio substituents; arylglycylamino, preferably N-substituted with heteroarylcarbonyl and cycloheteroalkylcarbonyl substituents; arylcarbonylamino; heteroarylcarbonylami o; and lower alkoxyimlnoacetyamino, 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 1s R12. Examples of such preferred R* groups Include: [(2-am1no-5-halo-4-thiazolyl)acetyl]amino; [(4-am1nopyridin-2-yl)acetyl]amino; [[(3,5-dichloro-4-oxo-l(4H)-pyridinyl)acetyl]am1no]; [[[2-(aminomethy1)phenl]acetl]amino] ; [(lH-tetrazol-1-ylacetyl)amino]; I(cyanoacetyl)amino]; [(2-thlenylacetyl)amino]; [[(2-amino-4-th1azoyl)acetyl]amino]; and sydnone, 3-[-2-am1no]-2-oxoethyl .
The following are other such preferred R1 groups.  -25- When Rl is Rl3-(CH2)ra-C(C-0)NH-, and l3 is -Zl, preferred 1 groups include the following: [sulfamo 1phenylacetyl]amino; [[(4-pyridinylth1o)acetyl]am1no]; [[[(cyanomethyl)thio]acetyl]amino]; (S)-[[[(2-amino-2-carboxyethy1)th1o]acetyl]amino]; [[[(trifluoromethyl)th1o]acetyl]aa1no]; and (E)-[[[(2-am1nocarbony1-2-fluoroetheny1)thio]acety1]am1o].
The following are other such preferred Rl groups. -27- When Rl 1$ Rl3.(CH2)m-C(-0)MH-. and R« is -CH(Z2)(Rl2), preferred R1 groups include the following: [carboxyphenylacetyl]amino; [(phenoxycarbonyl)phenylacetyl]amino; [4-nethyi-2,3-d1oxo-l-p1peraz1necarbony1-D-phenylglycy1]- anino; -28- C[[3-(2-furylmethyleneamino)-2-oxo-l-imidazol idinyl )- carbonyl ] ami no] phenyl ] acetyl ] ami no; (R)-[ (ami nophenyl acetyl ) amino]; ( R ) - [ [ m i no ( - hydroxypheny 1 ) acetyl ] ami no ] ; ( R) - [ ( ami no - 1 , 4 -cycl ohexad i en - 1 -yl acetyl ) ami no ] ; [(hydroxy phenyl acetyl ) ami no] ; (R)-[[[[(4-ethyl-2,3-dioxo-l-piperazinyl Jcarbonyl Jamino]- (4-hydroxyphenyl)acetyl]amino] ; (R)-[[[[(5-carboxy-lH-imidazol-4-yl)carbonyl]amino]phenyl- acetyl]amino]; (R)-[[[[(4-hydroxy-6-methyl-3-pyridinyl)carbonyl]amino](4- hydroxyphenyl ) acetyl ] ami no] ; (R) - [ (phenyl sul foacetyl ) amino] ; (2R,3S)-[[2-[[(4-ethyl-2,3-dioxo-l-piperazinyl)carbonyl]- amino]-3-hydroxy-l-oxobuty1]amino]; [[carboxy(4-hydroxyphenyl)acetyl]amino]; (R)-i[amino[3-[(ethylsu1fonyl)amino]phenyl]acetyl]amino]; (R)- [[amino(benzo[b]thien-3-yl ) acetyl ] amino] ; (R)-[[amino(2-naphthyl ) acetyl ] ami no] ; (R)-[[am1no(2-amino-4-thiazolyl)acetyl]ainino]; [ [ [ [ ( 6 , 7 -d 1 hydrox - 4 - oxo - 4H - 1 - benzopy ran - 3 -yl ) carbonyl ] - amino] (4 -hydroxyphen 1 )acetyl ] ami no] ; ( R , R) - [ [ 2 - [ 4 - [ 2 - ami no-2 -carboxyethyl oxycarbony 1 ] ami nophen - yl]-2-hydroxyacetyl]amino]; and (S) - [ [ (5-hydroxy-4-oxo-l (4H) -pyridin-2-yl ) carbonyl ami no(2- araino-4-thiazolyl ) acetyl ] ami no] .
The following are other such preferred Rl groups. -34- Another class of preferred Rl groups (for lactam-containing moieties other than penems, carbapenems, clavems and clavams) include those of the formula: Rl2-C(=NO-Rl«)-C(-0)NH-.
Examples of this preferred class of Rl groups include: 2-phenyl -2-hydroxyiminoacetyl ; 2-thienyl -2-methoxyiminoacetyl ; and 2-[4-(gamma-D-glutamyloxy)phenyl J-2-hydroxyiminoacetyl .
(Z)[[(2-amino-4-thiazo1yl)(methoxyimino)acetyl]amino]; [[(2-furanyl (methoxyimino)acetyl]amino] ; (Z)-[[(2-amino-4-thiazolyl)[(l-carboxy-l-methyl)ethoxyim- ino]acetyl]amino]; (Z)-[[(2-amino-4-thiazolyl)(l-carboxymethoxyimino)acetyl]amino]; [[(2-amino-4-thiazolyl)[(lH-imidazol-4-ylmethoxy)imino]acet- yl]amino]; (Z)-[[(2-amino-4-thia2olyl-3-oxide)(methoxyi/nino)acetyl ]am- ino]; and (S,Z)-[[(2-amino-4-thiazolyl)[carboxy(3,4-dihydroxyphen- yl)methoxyimino]acetyl]amino].
Other preferred l groups include the following structures.  -38- Sui table R2 groups are among those well-known in the art, including those defined 1n 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. Enol. 180 (1985); 6. 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, -39-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 R9 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 sL Med Chem. 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. lopman 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. Reo. Med. Chem. 145 (D. M. Baily, editor, 1986); J. B. Cornett et al., in 21 Ann. Reo. Med. Chem. 139 (D. M. Bailey, editor, 1986); P. B. Fernandes et al., in 22 Ann. Reo. Med. Chem. 117 (D. M. Bailey, editor, 1987); R. Albrecht, 21 Proa. 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 A is C(R40), A2 IS C(R6), and A3 is C(R*1) (i.e., quinolones); Al is nitrogen, A2 IS C(R6), and A3 is C(R*1) (i.e., naphthyridines); A^ is C(R40), A is C(R6), and A3 is nitrogen (i.e., cinnoline add derivatives); and where Al is nitrogen, A2 IS nitrogen, and A3 1s C(R41) (I.e., pyridopyrimidine derivatives). More preferred quinolone moieties are those where Al Is C(R40), A2 is C(R6), and A3 is C(R41) (I.e., quinolones); and where Al Is nitrogen, A is CIRC), and A3 Is C(R41) (I.e., naphthyrldines). Particularly preferred quinolone moieties are where A is C(R*°), A2 IS C(R6), and A31s C(R*1) (I.e., quinolones).
R8 Is preferably alkyl, aryl, cycloalkyl and alky!amino. More preferably, R8 is ethyl, 2-fluoroethyl, 2-hydroxyethyl , t-butyl, 4-fluorophenyl, 2,4-dlfluorophenyl, methylamino and -40-cyclopropyl. Cyclopropyl is a particularly preferred R8 group. Preferred quinolone moieties also Include those where A1 is C(R40) and R8 and R40 together comprise a 6-membered heterocyclic ring containing an oxygen or sulfur atom.
R6 is preferably hydrogen or halo. More preferably R6 is chlorine or fluorine. Fluorine is a particularly preferred R6 group.
Preferred R? groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from 5 to 8 members. The heterocyclic ring may contain additional heteroatoms, such as oxygen, sulfur, or nitrogen, preferably nitrogen. Such heterocyclic groups are described in U.S. Patent 4,599,334, Petersen et al., issued July 8, 1986; and U.S. Patent 4,670,444, Grohe et al . , issued June 2, 1987 (both incorporated by reference herein). Preferred R7 groups include unsubstituted or substituted pyridine, piperi-dine, orpholine, diazabicyc1o[3.1.1]heptane, diazabicyclo [2.2.1]heptane, diazabicyclo[3.2.1]octane, diazabicyclo[2.2.2] octane, thiazolidine, imidazol idine, pyrrole and thiamorpholine, as well as the following particularly preferred R7 groups include piperazine, 3-methylpiperazine, 3-aminopyrrol idine, 3 - ami nomethyl p rrol idine, N , N-d i meth l ami nomethyl p rrol idine, N-methylaminomethyl pyrrolidine, N-ethyl ami nomethyl pyrrol idine, pyridine, N -methyl piperazine, and 3, 5-d1methyl piperazine.
Preferred quinolonyl lactam esters Include those having a 6- fluoroquinolone moiety or an 8-halo-6-fluoroquinolone moiety, of formula: -41- wherein A2 is C(R6) and ≠ is F ; A3 is C(R41 ) ; and A1 i s C(R40) where R*0 is hydrogen, fluorine or chlorine. Preferred exampl es of such quinolone moieties include: l-cyclopropyl -6-fluoro-l ,4-dihydro-4-oxo-7-(l-piperazinyl )- 3- quinol inecarboxyl ic acid; 7-(3-aminopyrrol idinyl )-l-cyclopropyl -6-fluoro-l ,4-dihydro- 4- oxo-3-quinol inecarboxyl ic acid; 7-[(3-aminomethyl )pyrrol idinyl ]-l-cyclopropyl -6-f1uoro-l ,4- dihydro-4-oxo-3-quinol inecarboxyl ic acid; 7-(3-aminopyrrol idinyl)-8-chloro-l-cyclopropyl -6-fluoro-I ,4- d hydro - 4 - oxo - 3 - qu i nol i necarboxy l ie acid; 7-(3-am1nopyrrol id1nyl )-l-cyclopropyl-6,8-difluoro-l ,4- dihydro-4-oxo-3-quinol inecarboxyl ic acid; 7 - [( 3 - ami nomethy 1 ) pyrrol id i nyl ] - 1 -cycl opropy 1 -6,8-difluoro- 1, -d1hydro-4-oxo-3-quinol inecarboxyl ic acid; 6 , 8-di f 1 uoro- 1 - ( 2 - f 1 uoroethyl ) - 1 , 4-d i hydro- 7 - (4 -methyl - 1 - piperazlnyl )-4-oxo-3-quinol inecarboxyl ic acid; 1 -ethyl -6-f 1 uoro- 1 ,4-d1hydro-4-oxo-7- ( 1 -piperazlnyl ) -3- quinol Inecarboxyl ic acid; l-ethyl-6-fluoro-l,4-d1hydro-7-(4-methyl -l-piperaz1nyl )-4- oxo-3-quinol Inecarboxyl ic add; 6 - f 1 uoro - 1 , -d i hydro - 1 -meth 1 am 1 no - 7 - ( - met h 1 - 1 - piperazlnyl )-4-oxo-3-quinol Inecarboxyl ic acid; and 1 -cycl oprop 1 -7- [3- (dimethyl amlnomethyl ) - 1 -pyrrol Id!nyl ] - 6,8-difluoro- l,4-d1hydro-4-oxo-3-quino Inecarboxyl Ic acid; -43- -44- 35  Al so preferred are quinolonyl lactam esters having a 1 ,8-naphthyridine moiety, of formula: wherein A* is N; A¾ is C(R6) and A3 IS C(R41) . Preferred examples of such qui no lone moieties Include: 7-(3-aminopyrrol idlnyl ) - 1 - (2, 4-dl fluorophenyl ) -6-fluoro- 1 ,4- d1hydro-4-oxo-lt8-naphthyr1d1ne-3-carboxyl 1c acid; and l-ethyl-6-fluoro-l ,4-d1hydro-4-oxo-7-(l-p1peraz1ny1)-l,8- naphthyr1d1ne-3-carboxyl 1c acid. -55- Also preferred are quinolonyl lactam esters having a pyridobenzoxazine or pyridobenzthiazine moiety, of formula: wherein A* is C(R40); A* is C{R6); A3 is C(R 1); and R ° and R8 together comprise a linking moiety between N' and A to form a 6-membered, oxygen-containing, heterocyclic ring where X (in this formula) is oxygen or sulfur. Preferred examples of such quinolone moieties include 9-fluoro-4,7-dihydro-3-methyl-10-(4-methyl-l-piperazinyl )-7-oxo-2H-pyrido[l,2,3-deJ-l,4-benzoxazine-6-carboxylic acid; and the following structures. 35 -58- The specific physical, chemical, and pharmacological properties of the quinolonyl lactam esters of this invention may depend upon the particular combination of the integral lactam-containing moiety, quinolone moiety and linking moiety comprising the compound. For example, selection of particular integral moieties may affect the relative susceptibility of a quinolonyl lactam ester to bacterial resistance mechanisms, (e.g. , beta-lactamase activity).
Preferred quinolonyl lactam esters include compounds having the following specific combinations of lactam-containing moieties, quinolone moieties and linking moieties. 1) Ester-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)-; R5 is -S-C"'-CH2-0-; and - the quinolone moiety is a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring b) where - the lactam-containing moiety is a penem, wherein bond "a" 1s a single bond; bond "b" is a double bond; R1 Is (1-hydroxyethyl) ; R2 is -H; R3 is -CH-; R4 is -C(C02H)-; Re Is -S-C"'-CH2-0-; and the quinolone moiety 1s a 6- fluoroquinolone moiety, wherein A* Is -C(R39)-; A2 1s -CF-; A3 is -CH-; and R7 Is a heterocyclic ring c) where - the lactam-containing moiety Is a penem, wherein referring to the formula, wherein bond "a" is a single bond; bond "b" is a double bond; R3 Is -CH-; R4 IS -C(C02H)-; R5 Is -S-C'-C^-O-; -59- the quinolone moiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring d) 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)-; R5 is -S-C"'-CH2-0-; and the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R9 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-1-pyrrol dinyl group, a 4-methyl-l-piperaz1nyl group, a 3-aminomethyl-l-pyrrol idinyl group, a 3-ethylaminomethyl-l-pyrrol idinyl group or a l-piperazinyl group Ester-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 3) Ester-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; 3 is -CH-; R* is -C(C(>2H)-; R* is -S-C-S-CH2CH2-O-; and the quinolone moiety is a structure, wherein A? Is -CF-; A31s -CH-; and R71s a heterocyclic ring b) where - the lactam-containing moiety 1s a penem, wherein bond "a" Is a single bond; bond "b" is a double bond; R3 1S -CH-; R* is -C(C02H)-; R* 1s -S-C-S-CH2CH2-O-; and -60- the quinolone moiety is a 6-fluoroquinolone moiety, wherein A1 is -C(R39)-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring c) 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)-; R¾ is -S-C"'-S-CH2CH2-0-; and the quinolone moiety is a naphthyridinone, wherein Al is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring 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-; R* is -C(C02H)-; and the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R9 is -H; A* is -CH-, -CF-, -CC1-, or -N-; R^ is cyclopropyl, ethyl, 2, -di fluorophenyl , 4-fluorophenyl , or t- butyl; and R7 is a 3-amino-l-pyrrolidinyl group, a 4-methyl-l-piperazinyl group, a 3-aminomethyl - 1 -pyrrol idinyl group, a 3 -ethyl ami nomethyl-1 -pyrrol idinyl group or a 1-piperazinyl group Ester-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 4} Ester-linked 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 is -CH-; R* is -C(C(>2H)-; 5 is -CH(R33)-C"'-CH2-0-; and -61- the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring b 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"'-CH2-0-; and the quinolone moiety is a 6- fluoroquinolone moiety, wherein A1 is -C(R39)-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R is -CH-; R* is -C(C02H)-; R5 is -CH(R33)-C"'-CH2-0-; and the quinolone moiety is a naphthyridinone, wherein A* is -N-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring d) where the lactam-containing moiety 1s a carbapenem, wherein bond "a" Is a single bond; bond "b" is a double bond; R1 Is (1-hydroxyethyl); R2 is -H; R3 1s -CH-; R* Is -C(C(>2H)-; R* is -CH(R33)-C"'-CH2-0-; R33 is -H or -Me; and the quinolone moiety 1s a structure, wherein A2 Is -CF-; A3 Is -CH-; R* 1s -H; A* IS -CH-, -CF-, -CC1-, or -N-; R8 Is cyclopropyl, ethyl, 2, 4 -di fluorophenyl, 4- fluorophenyl, or t-butyl; and R7 s a 3-am1no-l -pyrrol idinyl group, a 4-methyl-l-p1peraz1nyl group, a 3 -ami nomethyl-1 -pyrrol Idinyl group, a 3 -ethyl ami nomethyl-1 -pyrrol Idinyl group or a l-p1perazinyl group -62- Ester-1 inked carbapenem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 5) Ester-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-CH2CH2-0-; and the quinoione moiety is a structure, wherein A? is -CF-; A3 is -CH-; and 9 is a heterocyclic ring the lactam-containing moiety 1s a carbapenem, wherein bond "a" 1s a single bond; bond "b" is a double bond; R3 is -CH-; R* is -C(C02H)-; R* is -CH(R33)-C"'-S-CH2CH2-0-; and the quinoione moiety is a 6-fluoroquinolone moiety, wherein A* is -C(R39)-; A2 is -CF-; A3 is -CH-; and R7 is a heterocyclic ring c) where - the lactam-containing moiety 1s a carbapenem, wherein bond "a" is a single bond; bond "b" is a double bond; R Is -CH-; R* is -C(C(>2H)-; R5 is -CH(R33)-C"'-S-CH2CH2-0-; and the quinoione moiety 1s a naphthyridinone, wherein Al s -N-; A2 is -CF-; A 1s -CH-; and R7 Is a heterocyclic ring d) where - the lactam-containing moiety is a carbapenem, wherein bond "a" is a single bond; bond "b" 1s a double bond; Rl Is (1-hydroxyethyl); R2 S -H; R3 Is -CH-; R* Is -C(C(>2H)-; R* is -CH(R33)-Ce -S-CH2CH2-0-; R3 is -H or -Me; and -63- the quinolone moiety is a structure, wherein A2 is -CF-; A3 is -CH-; R9 is -H; A1 is -CH-, -CF-, -CC1-, or -N-; R8 is cyclopropyl, ethyl, 2 ,4-di fluorophenyl , 4-fluorophenyl , or t-butyl; and R7 is a 3-amino-l-pyrrol idinylgroup, a 4-methyl-l-piperazinyl group, a 3-aminomethyl-l-pyrrol idinyl group, a 3-ethylaminomethyl-l-pyrrolidinyl group or a 1-piperazinyl group.
Ester-linked penem quinolones of the classes (b), (c) and (d) are preferred; compounds of class (d) are particularly preferred. 6) Ester-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; R is -CH-; R4 is -C(C02H)-; R5 is -0-CH2-C"'-CH2-0-; · the quinolone moiety is a structure, wherein A2 1s -CF-; A3 is -CH-; and R7 is a heterocyclic ring. 7) Ester-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"'-CH2-0-; and - the quinolone moiety Is a structure, wherein A2 Is -CF-; A3 1$ -CH-; and R7 is a heterocyclic ring. 8) Ester-1 Inked iso-oxacephem quinolones, such as compounds of the class where -64- 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)-; R5 is -CH2-0-C"'-CH2-0-; and the quinolone moiety is a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring. 9) Ester- linked carbacephem qui nol ones, 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)-; R5 is -CH2-CH2-C"'-CH2-0-; and the quinolone moiety is a structure, wherein A? is -CF-; A3 is -CH-; and R7 is a heterocyclic ring. 10) Ester-linked monobactam qui nol ones, such as compounds of the following classes. a) where - the lactam-containing moiety is a monobactam, wherein bond "a" 1s a single bond; bond "b" is nil; R3 is -CH- and is bonded directly to X; R* is nil; X Is -CH2O-; and the quinolone moiety 1s a structure, wherein A? Is -CF-; A3 is -CH-; and R7 is a heterocyclic ring b) where - the lactam-containing moiety Is a monobactam, wherein bond "a" 1s a single bond; bond "b" is nil; R3 Is -CH- and 1s bonded directly to X; R5 is nil; X is -0-; and the quinolone moiety 1s a structure, wherein A? 1s -CF-; A31s -CH-; and R7 1s a heterocyclic ring Quinolonyl lactans esters of this Invention include (for example) the following compounds. -65- [6R- (6α, 7β) ] ] - 7- [ [ [ (01 f 1 uoromethyl ) thiojacetyl ]am1 no] -7-methoxy ] - 3-[t[l-cyclopropyl -6-fl uoro-l,4-dihydro-4-oxo-7-(l-pi peraz inyl) -- 3quinol1nyl]carbonyloxy]methyl]-8-oxo-5-oxa-l-azabicyclo[4.2.0]- oct-2-ene-2-carboxylic acid [6R-(6a,7^)]-7-[[[(2-Aminocarbonyl-2-fluoroethenyl)thio]acetyl] amino]-3-[[[[9-fluoro-3,7-dihydro-3-methyl-10-(4-methyl-l- piperazinyl)-7-oxo-2H-pyrido[l,2,3-de]-l,4-benzoxazin-6-yl]- carbonyl]oxy]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene- 2-carboxylic acid -66- [6R-[6e,7^]]-7-[[Carboxy(4-hydroxyphenyl)acety1]amino]-3-[[[l- ethyl-6-fluoro-l,4-d1hydro-7-(4-methyl-l-p1peraz1nyl)-4-0X0-3- quinolinyl]carbonyloxy]methyl]-8-oxo-5-th1a-l-azab1cyc1o[4.2.0] oct-2-ene-2-carboxylic acid [5R-[5o,6ttJ]-3-I[[7-(3-Aminopyrrol1d1n-l-y1)-8-chloro-l-cyclo- propyl-6-f1uoro-l,4-dihydro-4-oxo-3-qu1nol1nyl]carbonyloxy]- methy1J-6-[(R)-l-hydroxyethyl]-7-oxo-4-th1a-l-azabicyclo[3.2.0]- hept-2-ene-2-carboxy11c acid -67- [5R-[5e,6ttJ]-3-[[[l-Ethyl-l,4-d1hydro-6-methy1 -4-oxo-l, 8-naphthyridin-3-yl Jcarbonyloxy Jmethy ] -6- [ (R) - 1 -hydroxyethyl ] - 7 ■ oxo-4-th1a-l-azabicyclo[3.2.0]hept-2-ene-2-carboxy11c acid [5R-[5o,6e]]-3-[[[l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-( 1 -plperazinyl ) -3-qulnol 1 nyl jcarbonyl ox Jmethyl J -6- [ (R) - 1 -hydroxyethyl ]-7-oxo-4-thia-l -azabicyclo[3.2.0]oct-2-ene-2-carboxylic acid -68- (3S)-2-[[l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piper- az1nyl)-3-qu1noHnyl]carbonyloxy]-3-[[[[[(R)-4-ethyl-2,3-dioxo-l- piperazinyl]carbony1]am1no](4-hydroxyphenyl )acetylJamino]-4-oxo- 1-azetldinesulfonlc acid sodium salt (3S)-3-[[(2-Amino-4-thiazo1yl)(methoxyimino)acetylamino]-2-[[l- ethy1-6-f1uoro-l,4-d1hydro-4-oxo-7-(l-p1perazinyl)-l,8-naph- thyridin-3-yl]carbonyloxy] -4-oxo- 1-azetidinesulfonic acid sodium salt -69- (3S)-2-[[5-Ethy1-5,8-d1hydro-8-oxo-l,3-d1oxolo[4,5-g]7-quino- 11nyl]carbonyloxy] -4-0X0-3- [(phenoxyacetyl )am1no]azetidinesul - fonic acid sodium salt [6R-[6e,7^)]]-3-[[[7-(3-Am1no-l-pyrrolid1nyl)-l-(2,4-d1fluor- ophenyl)-6-fluoro-l,4-d1hydro-4-oxo-l,8-naphthyridin-3-y1]carbon- yloxy Jmethyl ] -7- [ [ (5-hydroxy-4-oxo- 1 (4H) -pyr1d1n-2-yl Jcarbonyl - amino] (2-am1no-4-th1azolyl)acetylam1no]-8-oxo-l-azab1cyclo [4.2.0]oct-2-ene-2-carboxyl1c acid -70- [6R-[6e,7^)]J-3-[[[7-(3-Amino-l-pyrro1id1nyl)-8-chloro-l-cyclo- propyl-6-fluoro-l,4-dihydro-4-oxo-3-quinol1ny1 ]carbonyloxy]- methyl]-7-[[[[[(R)-4-ethy1-2,3-dioxo-l-piperaz1ny11carbonyl]- amino](4-hydroxyphenyl) acetyl ] ami no] -8-oxo- l-azab1cyclo[4.2.0] oct-2-ene-2-carboxylic acid [6R-[6o,7^)]]-3-[[[l-Cyclopropyl-6-fluoro-l,4-d1hydro-4-oxo-7- (l-pfperazinyl)-3-quinolinyl]carbonyloxy]methyl]-7-[[phenoxy acetyl ]am1no] -8-oxo- 1 -azab1cyclo[4.2.0]oct-2-ene-2-carboxyl ic acid -71- [5R,(5e,6e)]-3-[[[[7-[3-(Afliinomethyl)-l-pyrroHd1nyl]-l-cyclopropyl -6, 8-difluoro-l,4-d1hydro-4-oxo-3-quinol inyljcarbonyl ] oxy JmethylJ-6-[(R)- 1-hydroxyethyl] -7-oxo-l -azabicyclo(3.2. OJhept-2-ene-2-carboxy1 ic acid [5Rl(5e,6o)]-3-[[[6,8-D1fluoro-l-(2-fluoroethyl)-l,4-dihydro-4-oxo-7- (4-methyl -1-piperazlnyl )-3-quinol inyl Jcarboxyl ]oxy]methyl ] -6-[(R)-l-hydroxyethyl]-40-methyl-7-oxo-l-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid -72- [5R,(5a,6e)]-3-[[[[8-Ethyl-5,8-d1hydro-5-oxo-2-(l-piperazinyl) pyr1do[2,3-dlpyr1m1d1nyl Jcarbonyljoxyjmethyl 1-6- [(R)-l -hydroxy ethy1]-7-oxo-l-azab1cyc1o[3.2.0]hept-2-ene-2-carboxyl 1c add [5R,[5e,6eJ]-3-[[[l-Cyclopropyl-6-nuoro-l,4-d1hydro-7-(l-pipera-z1nyl)-4-oxo-3-3-quinolinyl]carbonyloxy]methyl J -6-[(R)-l -hydroxy ethyl]-7-oxo-l-azab1cyclo[3.2.0[hept-2-ene2-carboxylic add [6R- [6α, 7β] ] -7- [ [Carboxy(4-hydroxyphenyl ) acetyl ] ami no] -3- [ [ [ 1 -cyclopropy1-6-f1uoro-l,4-d1hydro-7-(l-p1peraz1nyl)-4-oxo-3-qu1noHny1]carbonyloxy]methyl-8-oxo-5-th1a-l-azab1cyclo[4.2.0] oct-2-ene-2-carboxyl1c acid -73- Other preferred quinolonyl lactam esters are exemplified by the following structures.    -80- Hethods of Manufacture The quinolonyl lactam esters of thi s Invention may be made using any of a variety of synthetic techniques known In the art . Manufacture of quinolonyl lactam esters general ly Involves the preparation of a lactam-containlng moiety, a quinolone moiety and a procedure or set of procedures for l inking the lactam-contalning and quinolone moieties. Procedures for making a broad variety of lactam-contalning moieties and quinolone moieties are well known in the art. For example, procedures for preparing lactam-contalning moieties, and related compounds, are described In the following references, all Incorporated by reference herein (including articles cited within these references ) : Cephalosporins and Penicill ins.- ChWllS rY W4 Biology (E. H. Flynn, ed, 1972) Chapters 2, 3, 4, 5, 6, 7, 15 and Appendix I ; Recent Advances In the Chemistry of -Lactam Antibiotics (A.G. Brown and S. M. Roberts, ed. , 1985) ; Tonics in Antibiotic Chemistry. Vol . 3, (Part B) and Vol . 4, (P. Sommes, -81-ed., 1980); Recent Advances 1n the Chemistry of θ-lactam Antibiotics (J. Elks, ed., 1976); Structure-Activity Relationships Amono the Semisynthetic Antibiotics (0. 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 (K. B. Morin and M. Gorman, eds, 1982); 4 Medicinal Research Reviews 1-24 (1984); 8 Medicinal Research Review 393-440 (1988); 24 Anaew. Chem. Int. Ed. Engl. 180-202 (1985); 40 J. Antibiotics 182-189 (1987); European Patent Publication 266,060; 42 Also, for example, procedures for preparing quinolones useful In the methods of this Invention are described n the following references, all Incorporated by reference herein -82- (including articles listed within these references); 21 Progress in Drug Research. 9-104 (1977); 31 J. Med. Chem.. 503-506 (1988); 32 J. Med. Chem.. 1313-1318 (1989); 1987 Liebias Ann. Chem.. 871-879 (1987); 14 Druos Exotl. Clin. Res..379-383 (1988); 31 vL 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 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 JL. Med. Chem.. 1586-1590 (1988); 31 J. Med. Chem.. 1598-1611 (1988); and 23 J. Med. Chem.. 1358-1363 (1980).
The quinolonyl lactam esters of this invention may be made by the following general reaction sequence: Lact-CH2-X + M+"0C(-0)-Quin —> Lact-CH2-0C(-0)-Quin where X is a reactive leaving group (such as halo, a sulfonate ester or other activated hydroxyl functionality), "Lact" generically represents an appropriately protected lactam-contalnlng moiety (such as a penem, carbapenem, oxacephem, or carbacephem) and "Quin" represents an appropriately protected quinolone moiety. The reaction can be envisioned as a nucleophlllc displacement of the reactive X substltuent from the lactam by the quinolone carboxyllc acid or salt, to form an ester coupled conjugate of the lactam and qulnolone.
For Lact and Qu1n, certain functional groups contained In the structures (such as carboxyl, hydroxyl, and amino) may need to be blocked In order to prevent undesired competing side reactions from occurring with X. For example, suitable protecting groups for carboxyl substtuents include esters; -83- protecting groups for hydroxyl substltuents Include ethers , esters , and carbonates ; and protecting groups for amino substltuents Include carbamates and amides , if such protecting groups are employed, then appropriate deprotecting chemi stry, that Mi l l not decompose the ester coupled conjugate, may be required to obtain antimicrobial ly-active products .
If the l actam-containing moiety i s a monocycl ic beta- l actam, an al ternative coupl ing strategy may be employed as outl ined by the fol lowing sequence, where X is a heteroatom (0, S, halo, etc . ) substituent l inked to the lactam.
This sequence involves amide formation between the lactam and the quinolone, rearrangement displ acing X and l iberation of the ester by hydrolysis. The lactam containing structure may Initial ly be mono- or bicycl ic. The ester coupled product wi l l be monocycl ic.
Compositions The compositions of this invention comprise: (a) a safe and effective amount of a quinolonyl lactam ester; and (b) a pharmaceutical ly-acceptable carrier.
A "safe and effective amount" of a quinolonyl lactam ester 1s an amount that 1s effective, to nhibit 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, rritation, 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 -84-to be used, the carrier employed, the solubility of the quinolonyl lactam esters therein, and the dosage regimen desired for the composition.
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 ester that is suitable for administration to a human or lower animal subject, in a single dose, according to good medical practice. These compositions preferably contain from about 30 mg to about 20,000 mg, more preferably from about 50 mg (milligrams) to about 7000 mg, more preferably from about 500 mg to about 1500 mg, of a quinolonyl lactam ester.
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 quinolonyl lactam ester. The amount of carrier employed in conjunction with the quinolonyl lactam ester is sufficient to provide a practical quantity of material for administration per unit dose of the quinolonyl lactam ester. 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 administration Include sugars, starches, cellulose and Its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic add, phosphate buffer solutions, emuls1f1ers, Isotonic saline, and pyrogen-free water. -85- Preferred carriers for parenteral admini stration incl ude propylene glycol , ethyl oleate, pyrrol idone, ethanol , and sesame oi l . Preferably, the pharmaceuticaHy-acceptable carrier, in compositions for parenteral admini stration, compri ses at least about 90% by weight by the total composition.
Various oral dosage forms can be used, including such sol id forms as tablets, capsules, granules and bul k powders. These oral forms compri se a safe and effective amount, usual ly at least about 5%, and preferably from about 25% to about 50%, of the quinolonyl l actam ester. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, fl avoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emul sions, 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 al so be administered topically to a subject, i .e. , by the direct laying on or spreading of the composition on the epidermal or epithel ial tissue of the subject. Such compositions Include, for example, lotions, creams, solutions, gels and sol ids. 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 ester. 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 1s organic n nature and capable of having dispersed or dissolved therein the quinolonyl lactam ester. The carrier may Include -86-pharmaceuti cal l - acceptable emol ients, emul si fiers, thickening agents, and solvents .
Methods of Admini tration This invention also provides methods of treating or preventing an infectious disorder in a human or other animal subject, by admini stering a safe and effective amount of a quinolonyl l actam ester to said subject. As used herein, an "infectious disorder" i s any disorder characterized by the presence of a microbial infection. Preferred methods of thi s 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 quinolonyl lactam esters and compositions of this invention can be administered topically or systemically. Systemic appl ication Includes any method of Introducing the quinolonyl lactam ester into the tissues of the body, e.g. , intrathecal , epidural , intramuscular, transdermal , intravenous, Intraperitoneal , subcutaneous, subl ingual , 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 quinolonyl lactam ester used, the resistance pattern of the Infecting organism to the quinolonyl lactam ester used, the abil ity of the quinolonyl lactam ester to reach minimum nhibitory concentrations at the site of the nfection, the nature and extent of other Infections -87- ( i f any) , the personal attributes of the subject (such as weight) , compl iance with the treatment regimen, and the presence and severity of any side effects of the treatment .
Typical ly, for a human adul t (weighing approximately 70 ki lograms) , 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 quinolonyl l actam ester are administered per day. Treatment regimens preferably extend from about 1 to about 56 days, more preferably from about 7 to about 28 days , in duration . Prophylactic regimens (such as avoidance of opportuni stic infections in immunocompromi sed patients) may extend 6 months, or longer, according to good medical practice .
A preferred method of parenteral admini stration i s through intramuscular injection. As is known and practiced in the art, al l formul ations for parenteral admini stration must be steri le. For mammal s, especial ly humans, (assuming an approximate body weight of 70 ki lograms) individual doses of from about 100 mg to about 7000 mg, preferably from about 500 mg to about 1500 mg, are acceptable.
A preferred ethod of systemic administration is oral .
Individual doses of from about 100 mg to about 2500 mg, preferably from about 250 mg to about 1000 mg are preferred.
Topical administration can be used to del iver the quinolonyl lactam ester systemlcal ly, or to treat a local nfection. The amounts of quinolonyl lactam ester to be topically administered depends upon such factors as skin sensitivity,, type and location of the tissue to be treated, the composition and carrier ( if any) to be administered, the particular quinolonyl lactam ester to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local ) effects are desired.
The following non-1 i itlng examples illustrate the compounds, compositions, processes, and uses of the present Invention. -88- IMMELJ [5RJ[5a,6a]]-3-[[7-[(3-am1no-l-pyrrolidinyl)-6-nuoro-l-(2,4-d1fluorophenyl)-l,4-dihydro-4-oxo-3-(l,8-naphthyridiny1 )] carbonyloxy]methyl ] -6- ( 1 (R) -hydroxyethyl ) - 7 -oxo-4- thi a- 1 -aza-bicyclo[3.2.0Jhept-2-ene-2-carboxylic acid, according to this invention is made by the following general reaction sequence. -89- Approximately 0.28 nvnol (0.112 g) of [5R] [5a,6a]] -3-hydroxymethyl -6- (l (R)-t-butyld1methyl siloxyethyl ) -7-oxo-thi -l-azabicyclo[3.2.0]hept-2-ene-2-carboxyl ic acid, al lyl ester (made according to U.S. Patent 4,631 , 150, Batti stini et al . , issued December 23, 1986, incorporated by reference herein) i s dissolved in approximately 10 ml THF (tetrahydrofuran) . Under a nitrogen blanket, at approximately 22'C (72*F) , approximately 0.32 m ol of d i ethyl azodicarboxy late, 0.32 mmol of 6-fluoro-l- (2,4-di fluor-ophenyl ) -l,4-dihydro-4-oxo-7-[3-[3- (l-propenyl )oxycarbonyl ]amino-l-pyrrol idinyl ] -3-(l ,8-naphthyridine) -carboxyl ic acid and 0.32 mmol P h3 (triphenyl phosphine) are sequentially added with stirring. After approximately 15 minutes, 10 ml phosphate buffer (0.5 M, pH 7.0) is added, the THF is rapidly evaporated, and the aqueous residue is extracted with dichloromethane. Drying and removal of the solvent in vacuo yields the crude Product ( I) which is further purified by flash chromatography.
Approximately 0.15 g of Product ( I) (0.18 mmol ) is dissolved in 20 ml THF. Then 40 microl iters of glacial acetic acid and 60 mg of tetrabutyl ammonium fluoride are added and the reaction is al lowed to stand approximately 24 hours at ambient temperature. The THF Is evaporated and the residue Is taken up in dichloromethane. Extraction with aqueous bicarbonate, and solvent reduction, yields product (II) .
Approximately 60 mg of Product (II) (0.08 mmol ) 1s then dissolved In 15 ml THF at ambient temperature, and 5 mg PPtvj, 44 mg sodium ethyl hexanoate and 5 mg Pd(PPh3)a are added with stirring. Within several minutes a precipitate forms and 1s collected by filtration. The solid final product (III) Is purified to analytical purity by repeated trituration.
Similarly, the following quinolonyl lactam esters are prepared according to the general procedure of this Example, with substantially similar results. -90- using the quinolone 7-(3-an»inopyrrol1dinyl)-l-cyclopropyl-6,8- difluoro-l,4-dihydro-4-oxo-3-qu1nol1necarboxylic acid (prepared according to J. P. Sanchez, et al., J. Ned. Chem., 1988, 31, 983) using the quinolone 6-fluoro-l,4-d1hydro-l-methylam1no-7-(4-methy1-l-p1peraz1nyl)-4-oxo-3-qu1no11ne carboxyilc acid (prepared according to N.P. Went land, et al., J. Ned. Chem. 1984, 27, 1103) using the naphthyrldlnone 7-(2,5-d1azab1cyc1o[2.2.1]heptan-2 -y 1 ) - 1 - ( 1 , 1 -dimethyl ethyl ) -6-fl uoro- 1 , 4-d1 hydro-4-oxo- 1,8-naphthyrldlne-3-carboxyllc acid (prepared according to A. Weber, et al., Eur. Pat. Appl. EP 266576) -91- using the quinolone 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro- 4-0X0-7-(4-methyl-l-piperaz1ny1)-3-quinolinecarboxylic acid (prepared according to T. Iridura, Aust. Pat. Specif. AU 537813) using the quinolone 9-fluoro-4,7-d1hydro-3-methyl-lO-(4-methyl-l-p1peraz1nyl)-7-oxo-2H-pyrido[l,2,3-de]-l,4-benzoxaz1ne-6-carboxyllc add (prepared according to I. Hagakaa et al., Chem. Phann Bull. 1984, 32, 4907) using the quinolone 7-(3-am1nopyrro11d1ny1)«8-chloro-l-cyclopropyl-6-fluoro-l,4-d1hydro -4-oxo-3-qu1nolinecarboxyl1c acid (prepared according to J. P. Sanchez, et al., J. Ned. Chea., 1988, 31, 983) and the B-lactam [5R-[40,5a,6aJ]-6-[(R)-l-(t-butyldlmethyls1lyloxy)ethyl]-2-(hydroxymethyl)-4-methyl-7-oxo-I-azabicyclo(3.2.0]hept-2-ene-2-carboxyl1c add allyl ester -92- (prepared according to B.6. Chrlstensen et al., Eur. Pat. Appl . EP 185315 Al, 1986) using the qulnolone l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- (l-piperazinyl)-3-quinolinecarboxy1ic acid (prepared according to K. Grohe et al., Ger. Offen. OE 3142854 ) and the B-lactam [5R-[4^,5a,6a]]-6-[(R)-l-(t-buty1dimethy1s11y1oxy)ethyl]-2- (hydroxymethyl)-4-methyl-7-oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxyllc acid allyl ester (prepared according to B.G. Chrlstensen et al., Eur. Pat. Appl. EP 185315 Al, 1986).
According to the general procedure of Example 1, the following quinolonyl lactam ester is made: using the qulnolone 7-(3-am1nopyrrol1d1nyl)-l-cyclopropyl-6-fluoro-l,4-d1hydro -4-oxo-3-qu1noHnecarboxylic acid (prepared according to J. P. Sanchez, et al., J. Med. Chem., 1988, 31, 983).
Similarly, the following quinolonyl lactam ester is prepared according to the general procedure of this Example, with substantially similar results. -93- using the B-lactam [5R-[40,5of6er]]-6-[( )-l-(t- butyldimethylsilyloxy)ethy ]-2-(hydroxymethyl)-4-methyl-7-oxo-1- azabicyclo[3.2.0]hept-2-ene-2-carboxy11c acid allyl ester (prepared according to B.G. Chrlstensen et al., Eur. Pat. Appl. EP 185315 Al, 1986).
EXAMPLE 3 According to the general procedure of Example 1, the following quinolonyl lactam ester is made: using the naphthyrdnone 7-(3-am1nopyrrol1dinyl)-l-cyclopropyl-6-fluoro-l,4-d1hydro -4-oxo-l,8-naphthyr1d1ne-3-carboxy11c add (prepared according to J. P. Sanchez, et al., J. Ned. Chem., 1988, 31, 983).
Similarly, the following quinolonyl lactam ester Is prepared according to the general procedure of this Example, with substantially similar results. -94-using the B- lactam [5R-[4^,5a,6o]]-6-[(R)-l-(t-butyl dimethyl si ly1oxy)ethyl J -2- (hydroxymethyl ) -4-methyl -7-oxo- 1 -azabicyclo[3.2.0]hept-2-ene-2-carboxyl1c acid allyl ester (prepared according to B.G. Christensen et al., Eur. Pat. Appl . EP 185315 Al , 1986) EXAMP 4 [5R-[5or,6e]]-3-[[[l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7- ( 1 -piperazinyl ) -3-quinol 1 nyl Jcarbonyl oxyjmethyl ] -6- [ (R) - 1 - hydroxyethyl ]-7-oxo-4-thia- l-azabicyc1o[3.2. OJhept- 2-ene-2-carboxylic Acid -95- A mixture of approximately 5.0 g of ciprofloxacin I in 175 ml of water at approximately O'C is adjusted to approximately pH 12 by adding IN NaOH. To this solution Is added approximately 44 ml of acetone followed by the dropwise addition of approximately 2.7 g of allylchloroformate in 33 ml of acetone. The reaction is stirred approximately one hour in the cold while maintaining the mixture at pH 10-12 by addition of more IN NaOH. Then the reaction is concentrated to approximately 125 ml and is extracted twice with ether. The aqueous layer is cooled In an ice bath, acidified with 10% HC1 and is extracted three times with ethyl acetate. The extract Is washed with water, dried over NagSOa, filtered, and the filtrate Is concentrated to dryness to give II. To a solution of approximately 6 g of II In CH2CI2 at approximately O'C Is added dropwise a solution of approximately 0.73 g of NaOH In 5 ml of methanol. The mixture 1s stirred for one hour at ambient temperature, and concentrated to dryness. The residue Is triturated in ether and the sodium salt III 1s collected by filtration.
Separately, to a solution of approximately 5.0 g of [5R-[5a,6l]]-3-hydroxymethyl-6-(1-(R)-t-butyldimethylslloxyethyl)-7-oxo-4-th1a-l-azab1cyclo[3.2.0]hept-2-ene-2-carboxyl1c add allyl ester and 1.7 ml of tr1ethylamine in 30 ml of CH2CI2 at approximately -40'C Is added approximately 1.1 ml of mesyl chloride. The reaction Is stirred for approximately 10 minutes, then washed with 10X aqueous NaHC03 and water. The organic phase is dried over Na2S0a, filtered, and the filtrate is concentrated to dryness to give IV. To a solution of approximately 4.3 g of the mesylate IV In 30 ml of DMF at approximately O'C Is added -96- approximately 3.9 g of III and the reaction is stirred cold for approximately four hours and at ambient temperature for approximately one hour. The reaction Is concentrated to dryness in vacuo and the residue is dissolved in CH2CI2 and washed with water. The organic phase is dried over N 2S04, filtered and the filtrate is concentrated to dryness. The residue is purified by flash chromatography (silica gel) to give V. To a mixture of approximately 2.6 g of V and 2 ml of glacial acetic acid in 30 ml of THF at room temperature 1s added approximately 3.5 g of tetra-n-butyl mmonium fluoride tri hydrate. The mixture is stirred for approximately 30 hours, then concentrated to dryness and residue is purified by flash chromatography (silica gel) to give VI. To a mixture of approximately 1.3 g of VI, 0.19 ml of water and 0.027 g of bis(tripheny1phosph1ne)pa1ladium chloride in approximately 36 ml of CH2CI2 at approximately 19*C is added approximately 1.1 ml of tributyltinhydride. The mixture is rapidly stirred for approximately 10 minutes and the precipitate is collected by filtration. The solid is triturated in acetone and is collected by filtration to afford the title compound VII.
Similarly, the following qulnolonyl lactam esters are prepared according to the general procedure of this Example, with substantially similar results. using the qui no lone 7-(3-aa1nopyrro11d1ny1)-8-chloro-l-cyclopropyl-6-fluoro-l,4-d1hydro -4-oxo-3-qu1no11necarboxyl1c acid (prepared according to J. P. Sanchez, et al., J. Med. Chem., 1988, 31, 983) -97- using the quinolone l-ethyl-6-fluoro-l,4-dihydro-4-oxo-7-(l- piperaz1nyl)-3-qu1noline carboxyllc acid (prepared according to H. Koga, et al., J. Ned. Chem., 1980, 23, 1358) using the quinolone 6-fluoro-l-(4-fluorophenyl)-l,4-dihydro-7- (4-methyl-l-piperazinyl) 4-oxo-3-quinol1necarboxyl fc acid (prepared according to D.T.W. Chu et al., J. Med. Chem. 1985, 28, 1558) using the quinolone 7-(3-am1nopyrrol1d1nyl)-l-cyc1opropyl-6,8-d1fluoro-l,4-d1hydro-4-oxo-3-qu1nol1necarboxy11c acid (prepared according to J. P. Sanchez, et al., J. Ned. Chen., 1988, 31, 983) and the B- lactam [5R-[4?,5o,6o]]-6-[( )-l-(t-butyld1methylsilyl -oxy) ethyl J-2- (hydroxymethyl ) -4 -methyl -7-oxo- 1 -azab1cyclo[3.2.0] -98- hept-2-ene-2-carboxy1 ic acid al lyl ester (prepared according to B.6. Chri stensen et al . , Eur. Pat . Appl . EP 185315 Al , 1986) .
EXAMPLE 5 Product I I I , according to thi s invention, 1 s made by the fol lowing general reaction sequence.
Approximately 1.26 g of ciprofloxacin and 1.59 g NaHC03 Is suspended In approximately 25 ml of water and stirred for approximately 1 hour. Approximately 0.72 g of 2-(tr1methy1s11y1) ethyl chloroformate (made according to 38 Zhur obschel Khl . 1179 (1968)) In approximately 10 ml of tetrahydrofuran 1s added dropwlse to the stirring aqueous solution. After approximately 1 hour the mixture Is poured Into 150 ml of chloroform and acidified with 150 ml of cold 0.1H HC1. The aqueous phase Is extracted with chloroform again and the combined chloroform -99- layers are washed successively with cold O.IN HCl, water, and saturated aqueous sodium chloride. The chloroform solution is dried over NagSO.}, filtered, and concentrated. The residue is triturated with ether to provide product I after filtration.
A mixture of approximately 0.16 g of product I, 0.20 g of product II (prepared as above), and 0.040 g of NaHC03 are combined in approximately 1 ml of dimethylformamide under an inert atmosphere. The mixture 1s heated at approximately 70*C for 8 hours and then cooled to room temperature. The addition of approximately 0.50 g of tetra-n-butylammonium fluoride trihydrate is followed by stirring for approximately 16 hours at room temperature. The mixture is then eluted through a OowexR 50x4 (Na cycle) column with deionized water. The appropriate fractions are partially concentrated In vacuo, then lyophilized to give the final product III.
Similarly, the following quinolonyl lactam esters are prepared according to the general procedure of this Example, with substantially similar results. using the qulnolone 7-(3-am1nopyrrol1d1nyl)-l-cyclopropyl-6,8-d1f1uoro-l,4-d1hydro-4-oxo-3-qu1no11necarboxy11c acid (prepared according to J. P. Sanchez, et al., J. Ned. Chen., 1988, 31, 983) -100- uslng the qulnolone 7-(3-am1nopyrrol idinyl)-8-chloro-l- cyclopropyl-6-fluoro-l,4-dihydro -4-oxo-3-quino1 Inecarboxyl ic acid (prepared according to J. P. Sanchez, et al., J. Med. Chem., 1988, 31, 983) using the qulnolone 7-(3-aminopyrrolid1nyl)-l-cyclopropyl-6- fluoro-l,4-dihydro -4-oxo-3-qunolInecarboxyl1c add (prepared according to J. P. Sanchez, et al., J. Ned. Chem., 1988, 31, 983) using the naphthyrldlnone 7-(3-am1nopyrrol1d1nyl)-l-cyclopropyl-6-fluoro-l,4-d1hydro -4-oxo-l,8-naphthyr1d1ne-3-carboxy11c acid (prepared according to J. P. Sanchez, et al., J. Ned. Chem., 1988, 31, 983).
The following other quinolonyl lactam esters are made by the general procedures of this Example and Examples 1 - 4, with substantially similar results.  -102- 35 -104- EX AMPLE 6 [3S-(2b,3b)]-2-[[l-Cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-7-(l-piperaz1nyl)-3-quinol1nyl]carbonyloxy]-3-[(phenoxyacetyl )anri-no]-4-oxo-l-azetidinesulfon1c acid sodium salt, according to this invention, Is made by the following general reaction sequence. - 105- An anhydrous solution of approximately 20 g 1 -ethyl -6-fluoro-l ,4-dihydro-4-oxo-7- [4-[2-propenyloxy)carbonyl ]-l-p1pera-z1nyl ] -3-qu1nol 1necarboxy11c acid sodium sal t and 6.4 ml of tri ethy amine In 100 ml of dioxane and 20 ml of acetone I s cooled to 0_C (32_F) . To this stirred solution Is added 4.4 ml of ethyl chloroformate dropwlse keeping the temperature at 2*C (36*F) . This solution Is stirred at O'C (32'F) for 45 minutes . A cooled solution of 7.8 g of 6-am1nopen1c1l lan1c acid potassium salt ( I) , 4.2 ml of tri ethyl amine and 9.6 ml of water 1s added all at once to the above mixed anhydride solution and stirred at room temperature until reaction Is complete as per TLC (thin layer chromatography. The reaction mixture 1s washed with dlchloromethane then the aqueous layer 1s acidified to pH 2 with IN HC1. The aqueous layer Is extracted with dlchloromethane and the combined organic extracts are washed with water, dried over sodium sulfate and concentrated 1n vacuo to yield Product (II) .
Approximately 13.0 g of Product ( II) Is added to a stirred solution of mercury( II) acetate (12.8 g) In acetic acid (200 ml ) , at room temperature. Acetone Is mixed with the resulting gel and -106-the insoluble material filtered off and washed with acetone and ether to give Product (III). An excess of diazomethane in ether is added to a stirred suspension of 11.9 g of the salt Product (III) in dimethyl sulfoxide (45 ml). After 2 hours the mixture is diluted with dichloromethane, filtered and washed with water. The organic layer is dried (sodium sulfate) and concentrated to give a mixture of products with the desired Product (IV) isolated by chromatography. This thiol (IV) (4.4 g) and mercury (II) acetate (1.08 g) in dimethyl sulfoxide (80 ml) are stirred for 18 hours. The mixture is then diluted with dichloromethane, filtered and washed with water. The organic layer is dried over sodium sulfate and evaporated to yield Product (V).
Approximately 2.95 g of Product (V) is dissolved in acetone (35 ml), and approximately 0.95 g of p-toluene sulfonic acid monohydrate is added. The mixture Is stirred for 20 minutes at 18'C (64'F). The solvent is then evaporated to leave Product (VI), which is triturated. To a solution of 2.3 g of Product (VI) in dichloromethane (20 ml) is added 0.52 ml of phenoxyacetyl chloride with Ice-bath cooling. This mixture is stirred and a solution of 0.55 ml of pyridine in dichloromethane (4 ml) is added during a period of 30 minutes. After stirring an additional 30 minutes, the mixture 1s concentrated, and the residue dissolved in dichloromethane, washed with dilute HC1, water, saturated sodium bicarbonate, and brine, and dried over sodium sulfate and evaporated to give Product (VII).
Product (VII) (approximately 0.91 g) 1s dissolved In 15 ml of acetone with 0.26 ml of acetic acid and cooled to 0'C (32*F). Approximately 0.25 g of potassium permanganate, dissolved In 10 ml of water, Is added keeping the temperature at approximately 2*c (36*F). When the addition is complete, the mixture Is warmed to room temperature and allowed to stir for 3 hours. The solid is then filtered, and washed with dichloromethane. The filtrate Is diluted with water and the layers separated. The organic layer Is washed with saturated sodium bicarbonate solution and water, dried and evaporated to give Product (VIII). -107- An anhydrous solution of approximately 0.46 g Product (VI II) in 4 ml of DMF is made, and approximately 0.95 g of DMF · SO3 complex i s added. Thi s is allowed to stir 2 hours or until the reaction is complete as shown by TLC. The mixture Is then diluted with 20 ml of dichloromethane and 20 ml of 0.5 N potassium hydrogen phosphate solution with stirring. The pH is adjusted to 6 with I N NaOH and 0.25 g of tetrabutyl ammonium hydrogen sul fate is added. The layers are separated and the organic layer is washed with water, dried and concentrated to yield Product (IX) .
The product (IX) is taken up in approximately 10 ml of dichloromethane, 30 ml of water and 5 mg of bis(triphenylphos-phine) palladium chloride. The mixture is treated with approximately 150 microl iters of tri butyl tin hydride while maintaining a temperature of approximately 21*C (70*F) . After rapid stirring for approximately 5 minutes, the deprotected product 1s isolated by filtration. This is then taken up in water and methanol , filtered, and washed with water. The filtrate is concentrated to yield final Product (X) which is purified by trituration..
EXAMPLE 7 An antimicrobial composition for parenteral administration, according to this Invention, Is made comprising: Component Ajsojio [5R] [5e,6a]-3-[(7-[(3-amino-l-pyrrol1d1nyl )-6-fluoro-l-(2,4-d1 fluorophenyl) -1,4 -di hydro- 4 -oxo-3-(1 ,8-naphthyr1d1nyl ) ]carbonyloxy]methyl ] -6- (l(R)-hydroxyethyl )- 7-0X0-4- th1 a- 1- azab1cyclo[3.2.0]hept-2-ene- 2- carboxyl 1e add* 100 tng/ml carrier -108- Carrier: sodium citrate buffer with (percent by weight of carrier) : lecithin carboxymethyl eel 1 ul ose povidone methyl paraben propyl paraben 1 ; a quinolonyl lactam ester, made according to Example 1 The above ingredients are mixed, forming a suspension. Approximately 2.0 ml of the suspension is syste ically 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.
EXAMPLE 8 An enteric coated antimicrobial composition for oral administration, according to this invention, is made comprising the following core tablet: Component AWMHt (mq) [5R][5a,6a]-3-[[7-[(3-an»1no-l-py r rol 1 d 1 ny 1 ) - 6 - f 1 uoro- 1 - ( 2 , 4 -di f 1 uorophenyl ) - 1 ,4-d1hydro-4-oxo-3-(1 ,8-naphthyr1d1nyl )]carbony1oxy]methy1 ] -6- ( 1 (R) -hydroxyethyl ) -7-oxo-4-thi a-l-azab1cyclo[3.2.0]hept-2-ene- 2-carboxyl 1c addl 350.0 starch 30.0 magnesium stearate 5.0 mi crocr stall 1ne cellulose 100.0 colloidal sil icon dioxide 2.5 povidone 12.5 a quinolonyl lactam ester, made according to Example 1 -109- The components are admixed into a bulk mixture. Compressed tablets are formed, using tabietting methods known in the art.
The tablets are coated with a suspension of methacrylate acid/methacrylate ester polymer in sopropanol /acetone. A human subject, having a urinary tract infection with Escherichia col i 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.
LS/ewl/N527R(PAl)

Claims (14)

92091/2 - 110 -
1. . A compound of the general formula R* wherein (A) Rl is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, l0a_o- , l0aCH=N-, (RlO) (Rn)N-, R12-C(=CHR15)-C(=0)NH-, R12-C(»N0-R1 )-C(-0)NH-, or Rl3-(CH2)M-C(«0)NH-, preferably alkyl, alkenyl, R12-C(- Q-R1^)-C(»0)NH-, or R13-(CH2)m-C(-0)NH-; where (1) m is an integer from 0 to 9, preferably from 0 to 3; (2) RlO and Rll are, independently, RIO* where R * is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring substituent; or RlO and Rll together comprise a heterocyclic ring including the nitrogen to which they are bonded; (3) Rl* Is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring, preferably alkyl, a carbocyclic ring or a heterocyclic ring; (4) Rl3 is Rl2, -Zl, or -CH(Z2)(Rl2) ; (5) Rl* is l , arylalkyl, heteroarylalkyl , -C(Rl7){Rl8)C0OH, -C(-0)0-Rl2, or -C(-0)NH-Rl2, preferably l2 0r -C(Rl7)(R18)COOH; where Rl7 and Rl8 are, independently, R12 or together comprise a - Ill - carbocyclic ring or a heterocyclic ring including the carbon atom to which Rl? and Rl8 are bonded; (6) Rl5 is Rl4, halogen, -Z*. or -CH(Z2)(Rl2), preferably Rl* or halogen; (7) Zl is -C(-0)0Rl6. -C(-OJRl6, -N(R19JR16, -S(0)pR24, 0r -0R24; and Z is Zl or -OH, -SH, or -SO3H; (a) p is an integer from 0 to 2, preferably 0; (b) Rl9 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroalkenyl; a carbocyclic ring; a heterocyclic ring; -SO3H; -C(»0)R20; 0r, when Rl3 is -CH(Z2){Rl2) and Z2 is -M RIER!*, Rl9 may comprise a moiety bonded to R^ to form a heterocyclic ring; and (c) 0 is Rl2, NH(Rl2), N(R12)(R21), 0(R21), or S(R21), preferably Rl2, NH(Rl2), or N(R12)(R21); where R21 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or when R20 is N(R12)(R21J R21 may be a moiety bonded to R 2 to form a heterocyclic ring; and (8) Rl6 is R 4 or hydrogen, preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring; where R24 1S alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroaryl al kyl ; a carbocyclic ring; a heterocyclic ring; or, when Zl is N(R19)R16 and Rl6 is R24, Rl6 and Rl9 may together comprise a heterocyclic ring including the nitrogen atom to which Rl9 is bonded; (B) R is hydrogen, halogen, alkoxy, or R22C(«0)NH-, preferably hydrogen or alkoxy; where R22 is hydrogen or alkyl; (C) 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; (D) R3 is -c(Rl0i)-f or -CH2-R23-, preferably -C(RlO*)-; where R23 is -C(RlOa), -0-, or -N-, and R23 is 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 92091/3 - 112 - (i) Z3 is -Rl6; -0R25; -S(0)rR25, wnere r is an integer from 0 to 2. preferably 0; -0C(=0)R25 ; or -N(R25) 26; (ii) R25 and R25 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 R 6 are bonded; or (2) -CH2-R27-; where 7 is -C(RlO*) (HIS) , -o-, or -NR10i, and R27 is directly bonded to N' in Formula (I) to form a S-membered ring; (E) (1) if bond "b" is a single bond, R4 is -CH(R28).; 0r, \f bond "a" is nil; -C(0)NHS02-; or -C*(R28)-; if R5 contains a R32 moiety; where R28 is hydrogen or COOH, preferably COOH, and C* is linked to R32 to form a 3-membered 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(0)NHS02N(R29)(R30), -OSO3H, -CH(R30)C00H, or -0CH(R29)C00H; preferably -SO3H, or -C(0)NHS02N(R29)(R30); where 'R29 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R30 is hydrogen, alkyl, alkenyl, or -NHR10a; or, if R4 is -C(0)NHS02N(R29)(R30)f R29 and R3° may together comprise, a heterocyclic ring including the nitrogen to which R 9 and 30 are bonded; and (F) (1) if bond "a" or bond "b" is nil, then R5 is Y; (2) if bond "a" and "b" are single bonds, R5 is -X2-C"'-C(Rl0a)-R31-Y-, or -X2-C"' (R32).R31.Y-; 0r (3) if bond "a" is a single bond and bond "b" is a double bond, R5 is -C(Rl0a)(R33)-x2-C"'-R31-Y-; -Xl-C(Rl0a)(R33).c"'-R31-Y-; 0r -X2-C"'-R31-Y-; where (a) Xl is 0 or CH(R33), where R33 is hydrogen, alkyl or alkoxy; (b) X2 is 0; S(0)s, where s is an integer from 0 to 2; or CH(R33), 92091/2 - 113 - (c) R31 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; (d) R32 is hydrogen; alkyl; alkenyl; -C00H; or, if R4 is -C*(R28), R32 may be linked to C* to form a 3-membered carbocyclic ring; (e) Y is 0 or Z -R3 -0, where (1) Z4 is -0-; -S(0)f. where t is an integer of 0 to 2; or -NRlOa.; and (2) R34 is alkyl, alkenyl, heteroalkyl. heteroalkenyl , a carbocyclic ring, or a heterocyclic ring; and (3) Y is directly bonded to C (f) C"' is bonded to R4 to form a 5- or 6-membered ring; (G) (1) Al is N or C(R40) ; where R 0 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R10)( H) , preferably hydrogen or halogen; (2) A2 is N or C(R6), preferably C(R6) ; where R6 is hydrogen or halogen? (3) A3 is N or C(R 1), preferably C(R 1) ; where R 1 is hydrogen; (4) R8 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R10)(R11), preferably alkyl or a carbocyclic 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(R10)(RU), preferably hydrogen; (H) and 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 92091/2 - 114 - (3) when A3 is C(R41)» R8 and R*l may together comprise a heterocyclic ring including N" and the adjacent carbon to which R41 is bonded; and phar aceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.
2. A compound, according to Claim 1, containing a lactam-containing moiety selected from the group consisting of: oxacephems, carbacephems, isocephems, iso-oxacephems, penems. carbapenems, clavems, penicillins, clavams, 2,3-methyleno-penems, 2,3-methyleno-carbapenems, and pyrazolidinones; preferably isocephems, oxacephems, carbacephems, penicillins, and carbapenems.
3. A compound, according to Claim 2, wherein said lactam-containing moiety is selected from the group consisting of penems and carbapenems.
4. A compound, according to Claim 1, containing a lactam-containing moiety selected from the group consisting of: monobactams, monophosphams, monocarbams, monosulfactams, nocardicins, lactivicin analogs, and gamma-lactams; preferably a monobactam.
5. A compound, according to Claim 2 or 4, wherein R2 is hydrogen or alkoxy and R3 is -C(Rl°a)-.
6. A compound according to Claim 1, wherein: A1 is nitrogen or C(R40), preferably nitrogen; A2 is C(R6); and A3 IS C(R41).
7. A compound according to Claim 6, containing a 6-fluoroquinolone moiety, a 8-halo-6-fluoroquinolone moiety, a pyridobenzoxazine moiety, a pyridobenthiazine moiety, a isothiazoloquinolinedione, or isoxazoloquinplinedione moiety. 92091/2 - 115 -
8. A compound, according to Claim 7, wherein: R8 is alkyl, aryl , cycloalkyl or alkylamino, preferably ethyl, 2-fluoroethyl , 2- hydroxyethyl , t-butyl, 4-fluorophenyl , 2,4-difluorophenyl . methyl amino or cylcopropyl; and R4^ is hydrogen, chlorine or fluorine.
9. A compound, according to Claim 8, wherein R7 is a nitrogen-containing heterocyclic ring, preferably piperazine, 3- methylpiperazine, 3-aminopyrrol idine, 3-aminomethyl pyrrol idine, Ν,Ν-dimethyl ami nomethyl pyrrol idine, N-methyl ami nomethyl pyrrol idine, N-ethyl ami nomethyl pyrrol dine, pyridine, N-methylpiperazine, or 3,5-dimethylpiperazine.
10. A compound, according to Claim 9, wherein R^ is cyclopropyl, is fluorine, and R? is piperazine.
11. A composition for treating or preventing an infectious disorder in a human or other animal subject, comprising: (1) a safe and effective amount of a compound of any of Claims 1 through 10; and (2) a pharmaceutical ly-acceptable carrier.
12. A composition for treating or preventing an infectious disorder in a human or other animal subject, according to Claim 11, wherein said composition is suitable for parenteral administration.
13. A composition for treating or preventing an infectious disorder in a human or other animal subject, according to Claim 11, wherein said composition is suitable for oral admini tration.
14. A compound according to any of claims 1 through 10 for use as a medicament for preventing or treating an infectious disorder in a human. For the Applicants, DR. REINttOLRCOHN AND PARTNERS Bv:
IL9209189A 1988-10-24 1989-10-23 Quinolonyl lactam esters and pharmaceutical compositions containing them IL92091A (en)

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