HU211676A9 - Antimicrobial quinolonyl lactam esters - Google Patents

Description

BACKGROUND OF THE INVENTION

The present invention relates to novel antimicrobial compounds and compositions. The compounds of the present invention contain a quinolone moiety and a lactam moiety in a novel chemical composition.

There are numerous compounds in the chemical and medical literature that are claimed to have antimicrobial properties, i.e., compounds that are capable of killing microorganisms, such as bacteria, and inhibiting their growth or reproduction. Antimicrobial agents include a variety of naturally occurring (antibiotic), synthetic or semi-synthetic compounds. Antibacterial agents (for example) can be classified into the following classes: aminoglycosides, ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides, polypeptides, quinolones, tetracyclines and sulfonamides.

Such and other antimicrobial agents are described, for example, in Antibiotics, Chemotherapeutics, and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of AntibioticAction, 2nd edition (1981). ).

The mechanism of action of these antimicrobial agents is variable. At the same time, however, they all generally fall into one or more of the following four pathways: inhibit cell wall synthesis or cell wall repair; alter the permeability of the cell wall; inhibit protein synthesis; or inhibit the synthesis of nucleic acids. For example, the effect of beta-lactam antibacterial agents is to inhibit essential penicillin binding proteins (PBSs) responsible for cell wall synthesis in bacteria. Quinolones, on the other hand, act by inhibiting bacterial DNA synthesis, thereby preventing bacterial replication.

Not surprisingly, the pharmacological profile of antibacterial and other antimicrobial agents, as well as their suitability for a particular purpose, differ significantly between clinical applications. For example, there may be a difference between classes of antimicrobial agents (and substances of the same class) in their efficacy against different types of microorganisms and their tendency to develop antimicrobial resistance. Said antimicrobial agents may differ in their pharmacological properties, such as their bioavailability and biodistribution. In view of the foregoing, it is readily apparent that the selection of the appropriate antibacterial agent (or other antimicrobial agent) for a particular clinical situation may require complex analysis of a number of factors, such as the particular organism, the desired route of administration, and the site of infection.

Antimicrobial resistance, which is a growing problem in medicine, is an important factor in the selection of a suitable antimicrobial (and especially antibacterial) agent. Such "resistance" can be defined as the existence of organisms within a population of a given microbial species that are less sensitive to the action of a particular antimicrobial agent. These resistant strains can upset the mechanism of action of a particular antimicrobial agent or chemically degenerate the antimicrobial agent before the agent can exert its effect. For example, the development of bacterial resistance to beta-lactam antibacterial agents occurs through the development of bacterial strains that produce beta-lactamase enzymes that break down the anti-bacterial agent.

As a result of extensive use of antibacterial agents over a long period of time, many highly resistant bacterial strains have now developed. This is of particular concern in environments such as hospitals and sanatoriums, where infections are relatively high and antimicrobial agents are frequently used. See, for example, W. Sanders, Jr. et al., "Inductible Beta-lactamases: Clinical and Epidemiologic Implications for Use of Newer Cephalosporins", 10 Reviews of Infectious Diseases, 830 (1988). The development of resistant bacterial strains has led to the development of pathogenic bacteria which are completely resistant to the most recently developed antimicrobial agents.

The literature reports numerous attempts to enhance the efficacy of antimicrobial agents and to overcome antimicrobial resistance. Many attempts have been made to co-administer antimicrobial agents. For example, Thabaut et al. Describe the combination of quinolone-like perfloxacin with cefotaxime and cefsulodin beta-lactams (Thabaut et al., Presse Med., 1987, 2167). Lenoc et al. Report the use of cephems with aminoglycosides and quinolones [Lenoc et al., 36 Path. Biol., 762 (1988)]. Japanese Patent Publication No. 60 / 06,617, issued Jan. 14, 1985, also discloses compositions containing beta-lactams and quinolones. O'Callaghan et al. Report a mercaptopyridine-substituted cephem which, according to the authors, liberates an active antimicrobial agent upon hydrolysis of cephalosporin by beta-lactamase (O'Callaghan et al., 1976)]. Mobashery et al. Propose the in situ application of a bacterial beta-lactamase that allows the release of an antibacterially active leaving group from position 10 of a cephem.

However, many attempts to produce improved antimicrobial agents have yielded uncertain results. In fact, only a few antimicrobial agents have been developed that are clinically acceptable in terms of antimicrobial activity spectrum, avoidance of microbial resistance, and pharmacology.

HU 211 676 A9

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I, pharmaceutically acceptable salts and biologically hydrolysable esters thereof, and hydrates of compounds wherein (A) R ¹ is hydrogen, halogen, alkyl, alkenyl, heteroalkyl, carbocyclic. ring, a heterocyclic ring, R ^l0A -O-, R ^IOA CH = N-, (R '°) (R ") N-, R ⁱ² -C (= CH-R ⁵⁾ -C (= O) NH , R ¹² (C (= NO-R ⁴ ) -C (= O) NH - or R ¹³ - (CH ₂ ) _m C (= O) NH - wherein (1) m is 0, 1 , 2, 3,4, 5, 6, 7, 8 or 9;

(2) R ¹⁰ and R ¹⁰ 'are independently R ^10a , wherein R ^10a is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituent; obsession

R ^l0 and R ¹¹ together form a heterocyclic ring that includes the nitrogen atom; to which R '° and R' are attached;

(3) R ¹² is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring or heterocyclic ring;

(4) R ¹³ is R ¹² , -Z ^1, or -CH (Z ² ) (R ¹² );

(5) R ¹⁴ is R ¹² , arylalkyl, heteroarylalkyl, -C (R ¹⁷ ) (R ¹⁸ ) COOH, -C (= O) OR ¹² or -C (= O) NH-R ^{12 in} general wherein R ¹⁷ and R ¹⁸ are each independently R 2 _{or taken} together to form a carbocyclic ring or heterocyclic ring containing the carbon atom to which R ¹⁷ and R ^{18 are} attached;

(6) R ¹⁵ is R ¹⁴ , halogen, -Z ^1, or -CH (Z ² ) (R ¹² );

(7) ^Z1 is -C (= O) OR ^16, -C (= O) R ^16, -N (R ^{I9) R16,} -S (O) _p R ²⁴ vagp -OR ²⁴ radical; and

Z ² is Z ¹ or -OH, -SH or -SO ₃ H;

(a) p is 0, 1 or 2;

(b) R ¹⁹ is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring, heterocyclic ring,

-SO ₃ H, -C (= O) R ²⁰ ; or when R ¹³ is -CH (Z ²⁾ group ^(R12) of formula, and Z ² is -N (R ^I9) R ¹⁶ radical, R ¹⁹ may comprise a portion which binds to the R ^l6 forms a heterocyclic ring; and (c) ^R20 is ^R12, -NH ^(R12), N ^{(Rl2) (R21),} -O ^(R21) -S (R ²¹⁾ group wherein R ²¹ represents alkyl -, alkenyl, carbocyclic ring, heterocyclic ring, or when R ²⁰ is -N ^{(R 2)} wherein (R ^21), R ²¹ is a group of an R ⁱ² -höz bind to form a heterocyclic ring; and (8) R ¹⁶ is R ²⁴ or hydrogen; wherein R ²⁴ is alkyl, alkenyl, arylalkyl, heteroalkyl, heteroalkenyl, heteroarylalkyl, carbocyclic ring, heterocyclic ring; or when Z ¹ is -N (R ⁹ ) R ¹⁶ and R ¹⁶ is R ²⁴ then R ¹⁶ and R ¹⁹ together may form a heterocyclic ring containing the nitrogen atom to which R ^{19 is} attached;

(B) R ² is hydrogen, halogen; alkoxy or R ^{22 is} C (= O) NH-, wherein R ²² is hydrogen or alkyl;

(C) bond "a" represents a single bond or is absent;

Bond "b" represents a single bond, a double bond, or is absent;

but at least a 41 "or" b "bond is present in the molecule;

(D) R ³ is -C (R ^10a ) - or -CH ₂ -R ²³ -; wherein R ²³ is -C (R ^10a ), -O-, or -N-, and R ^{23, when} directly bonded to N 'of formula I, forms a five membered ring; except that when bond "a" is absent, R ³ is (1) -C (R ^10a ) (Z ³ ) - wherein (i) Z ³ is -R ¹⁶ ; -OR ²⁵ ; -S (O) _r R ²⁵ wherein r is 0, 1 or 2; -OC (= O) R ²⁵ or N (R ²⁵ ) R ²⁶ ;

(ii) R ²⁵ and R ²⁶ are each independently alkyl, alkenyl, carbocyclic or heterocyclic ring substituents; obsession

R ²⁵ and R ²⁶ together are a heterocyclic ring containing the nitrogen atom to which R ²⁵ and R ^{26 are} attached; or (2) -CH ₂ -R ²⁷ - wherein R ²⁷ is -C (R ^10a ) (R ¹⁶ ), -O- or -NR ^10a , and R ^{27 is} directly bonded to Forms a five membered ring for N in formula (I);

(Ε) (1) when bond "b" is a single bond then R ⁴ is -CH (R ²⁸ ) -; or when bond a is absent, -C (O) NHSO ² - or -C * (R ²⁸ ) -, and when R ⁵ contains an R ³² group, when R ²⁸ is hydrogen or -COOH, L and C * when attached to R ³² form a three membered ring;

(2) when bond "b" is a double bond then R ⁴ is -C (R ²⁸ ) =; or (3) when bond "b" is absent, R ⁴ is hydrogen, -SO ₃ H, PO (OR ²⁹ ) OH, -C (O) NHSO ² N (R ³ °), -OSO ₃ H , CH (R ³⁰ ) COOH or -OCH (R ²⁹ ) COOH; wherein R ²⁹ is hydro 3

GB 211 676 A9 atom, alkyl, alkenyl, carbocyclic ring or heterocyclic ring and R ³⁰ is hydrogen, alkyl, alkenyl, or a group of formula -NHR ^IOA; or when R ⁴ is -C (O) NHSON (R ³⁰ ), R ²⁹ and R ³⁰ together may form a heterocyclic ring containing the nitrogen atom to which R ²⁹ and R ^{30 are} attached; and (F) (1) if bond "a" or bond "b" is not present then R ⁵ is Y;

(2) if bond "a" and bond "b" are single bonds, then R ⁵ is -X ² -C "'= C (R ^10a ) R ³ ' -Y- or -X ² -C '" ( R ³² ) -R ³ '-Y-; or (3) where "a" bond is a single bond and bond "b" is a double bond, then R ⁵ is -C ^{(R, Oa)} R ³¹ -Y, -X ¹ -C (R ^10a) (R ³³ ) -C '' - R ^3, -Y- or X ² -C '' - R ³¹ -Y-; wherein (a) X ¹ is oxygen; or C (R ³³ ) wherein R ³³ is hydrogen, alkyl or alkoxy;

(b) X ² is O or S (O) _s wherein s is 0, 1 or 2;

(c) R ³¹ is nothing, alkyl, alkenyl, carbocyclic ring or heterocyclic ring;

(d) R ³² is hydrogen, alkyl, alkenyl, -COOH; or when R ⁹ is -C *, R ³² may be attached to C * to form a three membered ring;

(e) Y is O or Z ⁴ -R ³⁴ -O- wherein (1) Z ⁴ is O; -S (O) - wherein t is 0, 1 or 2; or ^-NR10a -; and (2) R ³⁴ is alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring or heterocyclic ring; and (3) Y binds directly to C ';

(f) C '' is attached to R ^{4 to} form a five or six membered ring and (G) (1) A ¹ is N or -C (R ⁴⁰ ) =; wherein R ⁴⁰ is hydrogen, hydroxy, alkoxy, nitro, cyano, halo, alkyl, or -N 1 R 1 X R ¹¹ ); and (2) A ² is N or -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen;

(3) A ³ is N or -C (R ⁴ ') =; wherein R ⁴¹ is hydrogen;

(4) R ⁸ is hydrogen, alkyl, carbocyclic ring, heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N (R ¹⁰ ) (R ⁿ );

(5) R ⁷ is hydrogen, halogen, alkyl, carbocyclic ring or heterocyclic ring; and (7) R ⁹ is hydrogen, halogen, nitro, or -N f R 1 X R ¹¹ ;

(H) except that (1) when A ¹ is -C ¹ R ⁴⁰ ) 4, R ⁸ and R ^{40 taken} together may form a heterocyclic ring containing N 'and A';

(2) when A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 taken} together may form a group -O- (CH ₂ ) _n -O- wherein n is 1, 2, 3 or 4;

(3) when A ³ is -C (R ⁴¹ ) =, then R ⁸ and R ⁴¹ may form a heterocyclic ring containing N 'and the adjacent carbon atom to which R ^{41 is} bound.

It has now been found that the compounds of the present invention and compositions containing them are effective antimicrobial agents against a wide range of pathogenic microorganisms. The compounds of the present invention have, among other things, significant advantages over compounds known in the art in terms of antimicrobial activity spectrum, potency and improved pharmacological properties.

DESCRIPTION OF THE INVENTION

The present invention relates to certain novel quinolonyl lactam esters, processes for their preparation, dosage forms, and methods of administering quinolonyl lactam esters to a human or other animal subject. The individual compounds and compositions to be used in the present invention should be pharmaceutically acceptable. As used herein, the term "pharmaceutically acceptable" refers to a component that is suitable for use in humans and / or animals without undesirable side effects (such as toxicity, irritation and allergic responses) and with a reasonable benefit / risk ratio.

Quinolonyl lactam esters

The compounds of the present invention, or as also referred to herein as quinolonyl lactam esters, include any variation of the actam-containing groups which bind to the 3-carboxy group of a quinolone moiety through an ester bond. These compounds include compounds of formula (I), pharmaceutically acceptable salts and biologically hydrolysable esters thereof, and hydrates of compounds wherein (A) R ¹ is hydrogen, halogen, alkyl, alkenyl; , heteroalkyl, carbocyclic ring, heterocyclic ring, R 10 -O-, R ^10a CH = N-, (R ¹⁰

HU 211 676 A9

R ⁱ² -C (= ^CH-R15) -C (= O) NH-, or (preferably) ^R12 -C (= ^NO-R14) -C (= O) NH- or R ¹³ - (CH ₂ ) _{m is} -C (= O) NH-, wherein (1) m is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9 (preferably 0, 1, 2 or 3). ;

(2) R ¹⁰ and R ¹⁰ 'are independently R ^10a , wherein R ^10a is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituent; obsession

R ¹⁰ and R ¹¹ together form a heterocyclic ring containing the nitrogen atom to which R ¹⁰ and R ^{11 are} attached;

(3) R ¹² is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl; a carbocyclic ring or a heterocyclic ring (preferably an alkyl group, a carbocyclic ring or a heterocyclic ring);

(4) R ¹³ is R ¹² , -Z ^1, or -CH (Z ² ) (R ¹² );

(5) ^R14 is ^R12, arylalkyl, heteroarylalkyl, -C (R ^{I7), (I8} R) COOH, -C (= O) ^OR12 or -C (= O) ^NH-R12 general wherein R ¹⁷ and R ¹⁸ are each independently R ¹² or taken together to form a carbocyclic ring or heterocyclic ring containing the carbon atom to which R ¹⁷ and R ^{18 are} attached [preferably R ¹² or -C (R ^{I7) (R18)} COOH);

(6) R ¹⁵ is R ¹⁴ , halogen. -Z ¹ or -CH (Z ² ) (R ¹² ) (preferably R ¹⁹ or halogen);

(7) Z ¹ is -C (= O) OR ¹⁶ . -C (= O) R ^16, -N (R ^{I9) R16,} -S (O) _p R ²⁴ or -OR ²⁴ radical; and

Z ² is Z ¹ or -OH, -SH or -SO ₃ H;

(a) p is 0, 1 or 2 (preferably 0);

(b) R ¹⁹ is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring, heterocyclic ring, SO ₃ H, -C (= O) R ²⁰ ; or when R ¹³ is -CH (Z ²⁾ group ^(R12) of formula, and Z ² is N (R ⁱ⁹⁾ R ¹⁶ radical, R ¹⁹ may comprise a portion which binds to ^R16 to form a heterocyclic forms a ring; and (c) R ²⁰ is R ¹² , -NH (R ¹² ), -N (R ¹² ) (R ²¹ ),

-O (R ²¹ ) or -S (R ²¹ ) (preferably R ¹² , -NH (R ¹² ), N (R ¹² ) (R ²¹ )) wherein R ²¹ is alkyl, alkenyl carbocyclic ring, heterocyclic ring or (preferably) when ^R20 is -N ^{(R12) (R21)} radical, R ²¹ is a group of an ^l2 -höz binds to R form a heterocyclic ring; and (8) R ¹⁶ is R ²⁴ or hydrogen; wherein R ²⁴ is alkyl, alkenyl, arylalkyl, heteroalkyl, heteroalkenyl, heteroarylalkyl, carbocyclic ring, heterocyclic ring; or when Z ¹ is -N (R ^{I9) R16} group of formula and R ¹⁶ is R ^24, R ¹⁶ and R ¹⁹ may together form a heterocyclic ring that includes the nitrogen atom to which ^R19 is bonded ( preferably hydrogen, alkyl, carbocyclic ring or heterocyclic ring);

(B) R ² is hydrogen, halogen, alkoxy or R ^{22 is} C (= O) NH- (preferably hydrogen or alkoxy) wherein R ²² is hydrogen or alkyl (preferably hydrogen);

(C) bond "a" represents a single bond or is absent;

Bond "b" represents a single bond, a double bond, or is absent;

but at least bond "a" or "b" is present in the molecule;

(D) R ³ is -C (R ^10a ) - or -CH ₂ -R ²³ - (preferably -C (R ^10a ) -); wherein R ²³ is -C (R ^10a ), -O-, or -N-, and R ^{23, when} directly bonded to N 'of formula I, forms a five membered ring; except that when bond a is absent, R ³ is (1) (preferably) -C (R ^10a ) (Z ³ ) - wherein (i) Z ³ is -R ¹⁶ ; -OR ²⁵ , -S (O) _r R ²⁵ wherein r is 0, 1 or 2 (preferably 0); -OC (= O) R ²⁵ or N (R ²⁵ ) R ²⁶ ;

(ii) R ²⁵ and R ²⁶ are each independently alkyl, alkenyl, carbocyclic or heterocyclic ring substituents; obsession

R ²⁵ and R ²⁶ taken together are a seven-membered ring containing the nitrogen to which R ²⁵ and R ^{26 are} attached; or (2) -CH ₂ -R ²⁷ - wherein R ²⁷ is -C (R ^10a ) (R ¹⁶ ), -O- or -NR ^10a , and R ^{27 is} directly bonded to Forms a five membered ring for N 'of formula II;

(E) (1) when bond "b" is a single bond, then R ⁴ is (preferably) -CHCR ²⁸ ) -; or when bond a is absent, -C (O) NHSO ₂ -; or -C * (R ²⁸ ) -; when R ⁵ contains an R group; wherein R ²⁸ is hydrogen or (preferably) -COOH, and C *, when attached to R, forms a three membered ring;

(2) when bond "b" is a double bond then R ⁴ is -C (R ²⁸ ) =; or (3) when bond "b" is absent, R ⁴ is hydrogen, -SO ₃ H,

HU 211 676 A9

-PO (OR ²⁹ ) OH, -C (O) NHSO (R ³⁰ ), -OSO 3 H, -CH (R ^W ) COOH or -OCH (R ²⁹ ) COOH [preferably -SO 3 H or -C (O) NHSO ₂ N (R ²⁹ ) (R ³⁰ )]; wherein R ²⁹ is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring; and R ³⁰ is hydrogen, alkyl, alkenyl, or -NHR ^10a ; or (preferably) when R ⁴ is -C (O) NHSON (R ³⁰ ), R ²⁹ and R ^{30 taken} together may form a heterocyclic ring containing the nitrogen to which R ²⁹ and R ³⁰ bound; and (F) (1) if bond "a" or bond "b" is not present then R ⁵ is Y;

(2) if bond "a" or bond "b" is a single bond then R ⁵ is -X ² C '' = C (R ^10a ) -R ³¹ -Y- or -X ² -C "'(R ³² ) -R ³¹ Y-; or (3) (preferably) when bond "a" is a single bond and bond "b" is a double bond, then R ⁵ is -C (R ^10a ) (R ³³ ) -X ² -C '' - R ³¹ - Y or (preferably) -X ^ R ^ XR ^ -C '^' ^ - or -X ² -C '"- R ^3I-Y- group; wherein (a) X ¹ is oxygen; or C (R ³³ ) wherein R ³³ is hydrogen, alkyl or alkoxy;

(b) X ² is O or S (O) _s wherein s is 0, 1 or 2 (preferably 0); or C (R ³³ );

(c) R ³¹ is absent or alkyl. alkenyl, carbocyclic ring or heterocyclic ring;

(d) R ³² is hydrogen, alkyl. alkenyl, -COOH: or when R ⁴ is -C * (R ²⁸ ), R ³² may be attached to C 'to form a three membered ring;

(e) Y is O or Z ⁴ -R ³⁴ -O- wherein (1) Z ⁴ is O; -S (O) _t - wherein t is 0, 1 or 2 (preferably 0); or ^-NR10a ; and (2) R ³⁴ is alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring or heterocyclic ring (preferably alkyl or (3) Y) is directly attached to C ';

(f) C '' is attached to R ^{4 to} form a five or six membered ring and (G) (1) A ¹ is N or -C (R ⁴⁰ ) =; wherein R ⁴⁰ is hydrogen, hydroxy, alkoxy, nitro, cyano, halo, alkyl or -N (R ¹⁰ ) (R ^H ) (preferably hydrogen or halo); and (2) A ² is nitrogen or (preferably) -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen;

(3) Ar is nitrogen or preferably -C (R ⁴¹ ) =; wherein R ⁴¹ is hydrogen;

(4) R ⁸ is hydrogen, alkyl, carbocyclic ring, heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl or -N (R ¹⁰ ) (R ^H ) (preferably hydrogen or carbocyclic ring); );

(5) R ⁷ is hydrogen, halogen, alkyl, carbocyclic ring or heterocyclic ring (preferably heterocyclic ring); and (7) R ⁹ is hydrogen, halo, nitro, or -NR 1 - X R ¹¹ );

(H) except that (1) when A ¹ is -C (R ⁴⁰ ) =, R ⁸ and R ^{40 taken} together may form a heterocyclic ring containing N 'and A';

(2) when A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 may be taken} together to form -O- (CH ₂ ) _n O- wherein n is 1, 2, 3 or 4; and (3) when A ³ is -C (R ^4I) = group of the formula then form a ^R8 and ^R41 is a heterocyclic ring which includes Nl and the adjacent carbon atom to which R ⁴¹ binds.

Definitions and use of terms The following is a list of definitions of terms used in this specification.

The term "heteroatom" refers to nitrogen, sulfur or oxygen. Groups containing one or more heteroatoms may contain different heteroatoms.

The term "alkyl" means an optionally substituted radical having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms. Preferred alkyl groups include, for example, methyl. ethyl, propyl, isopropyl and butyl.

The term "heteroalkyl" refers to the radical of an optionally substituted, 3-8 membered, saturated chain formed of carbon atoms and one or two heteroatoms.

The term "alkenyl" refers to an optionally substituted C2-C8, preferably C2-C4, hydrocarbon chain having at least one olefinic double bond.

The term "carbocyclic ring" refers to a group consisting of an optionally substituted, saturated, unsaturated or aromatic hydrocarbon ring. Carbocyclic rings can be monocyclic rings or fused, bridged or spiro polycyclic ring systems6

HU 211 676 A9 no. Monocyclic rings contain from 3 to 9 carbon atoms, preferably from 3 to 6 carbon atoms, while polycyclic rings contain from 7 to 17 carbon atoms, preferably from 7 to 13 carbon atoms.

The term "cycloalkyl" refers to a group consisting of a saturated hydrocarbon ring. Preferred cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl and cyclohexyl.

The term "heterocyclic ring" refers to a group consisting of an optionally substituted, saturated, unsaturated or aromatic ring, which is composed of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings can be monocyclic rings or fused, bridged or spiro polycyclic ring systems. Monocyclic rings have from 3 to 9 carbon atoms. preferably containing from 3 to 6 carbon atoms. Polycyclic rings contain from 7 to 17 carbon atoms, preferably from 7 to 13 carbon atoms.

The term "aryl" refers to a group consisting of an aromatic hydrocarbon ring. Preferred aryl groups include, but are not limited to, phenyl. tolyl. xylyl, cumolyl and naphthyl.

The term "heteroaryl" refers to a group consisting of an aromatic heterocyclic ring. Preferred heteroaryl groups include, but are not limited to, thienyl, furyl; pyrrolyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl and tetrazolyl.

The term "alkoxy" refers to an oxygen radical having a hydrocarbon substituent wherein the hydrocarbon chain is an alkyl or alkenyl group (i.e., a group -O-alkyl or -O-alkenyl). Preferred alkoxy groups include, but are not limited to, methoxy. ethoxy, propoxy and allyloxy.

The term "alkylamino" refers to an amino group having one or two alkyl groups (i.e., a group -N-alkyl).

The term "arylalkyl" means an alkyl group substituted by an aryl group. Preferred arylalkyl groups include, but are not limited to, benzyl and phenylethyl.

The term "arylamino" refers to an amino group substituted with an aryl group (i.e., a group -NH-aryl).

The term "aryloxy" refers to an oxygen radical having an aryl substituent (i.e., a group -O-aryl).

The term "acyl group" or "carbonyl group" refers to a radical which can be formed by removing a hydroxy group from a carboxylic acid (i.e., a group of formula R-C (= O) -). Preferred alkyl acyl groups include, but are not limited to, acetyl, formyl and propionyl.

The term "acyloxy" refers to an oxygen radical substituted with an acyl group (i.e., a group -O-acyl); for example, a group of the formula -OC (= O) -alkyl.

The term "acylamino" refers to an amino group substituted with an acyl group (i.e., a group -N-acyl); such as, for example, -NH-C (= O) -alkyl.

The term "halo", "halogen" or "halide" means a chlorine, bromine, fluorine or iodine atom. Chlorine and fluorine are preferred halogens.

As used herein, the term "lower" hydrocarbon (e.g., "lower" alkyl) means a hydrocarbon chain of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

The term " pharmaceutically acceptable salt " refers to a conionic salt formed with an acidic (e.g., carboxyl) group and an anionic salt formed with a basic (e.g., amino) group. A large number of such salts are known in the art, such as, for example, U.S. Patent No. 87/05297. International Patent Publication No. PCT (Johnston et al., issued September 11, 1987). Preferred cationic salts include alkali metal salts (e.g., sodium and potassium salts) and alkaline earth metal salts (e.g., magnesium and calcium salts). Preferred anionic salts include halide salts (e.g., chloride salts).

The term "biologically hydrolyzable ester" refers to an ester of a dithiocarbamoylquinolone that does not substantially alter the antimicrobial activity of the compounds or is readily metabolized by a human or animal body to produce a dithiocarbamoylquinolone having antimicrobial activity. Such esters include those which do not adversely affect the biological activity of quinolone antimicrobial agents. A large number of such esters are known in the art, as disclosed, for example, in International Patent Application Publication No. 87/05,297 (Johnston et al., Published September 11, 1987). Such esters include, for example, lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxy). ethyl esters), lactonyl esters (e.g., phthalidyl esters and thiophthalidyl esters), lower alkoxy acyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyl). oxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylaminoalkyl esters (e.g. acetamidomethyl esters).

As defined above, substituent groups may themselves be substituted. Such substitution may be single or multiple substitution. Substituents of this type include, for example, those listed in C. Hansch and Leo C., Substituent Constants for Correlation Analysis in Chemistry and Biology (1979). Preferred substituents include, but are not limited to, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyacyl (e.g. ethoxycarbonyl)

A9, etc.), mercapto, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g. piperidyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy , arylalkyl, and combinations thereof.

As has been seen in the determination of the structure of the compounds of the invention, a single moiety may be present at multiple sites as a substituent. For example, R ^10a is defined as a potential substituent on R ¹ , but is also included in the definition of other groups (such as R ³ , R ^8, and R ⁹ ). For the purposes of the present application, such a group is selected individually for each use (for example, in the definition of a particular compound of the invention, the R ^10a group need not necessarily be an alkyl group at all occurrences).

Lactam-containing moieties

The groups R ³ , R ⁴ and R ^5, together with the bonds "a" and "b", represent various variants of lactam-containing moieties known in the art having antimicrobial activity. The moieties in which the "a" or "b" bond is absent (i.e., do not exist) are monocyclic; if both bonds exist, the structures are bicyclic.

Preferred lactam-containing compounds include oxacephems of formula IA and carbacephems. that is, compounds of formula I wherein bond "a" represents a single bond; Bond "b" represents a double bond; R ³ is -C (R ^10a ) -; wherein R ^10a is hydrogen; R ⁴ is -CH (R ²⁸ ) wherein R ²⁸ is -COOH; and R ⁵ is -X ¹ -C (R ^10a ) (R ³³ ) -C '' R ^3, -Y-, wherein R ^10a and R ³³ are hydrogen, R ³¹ is methylene, and X ¹ is ( for oxacephems) oxygen or (for carbacephems) C (R ³³ ).

Also preferred lactam-containing compounds include isocephem and isoxacephem of formula IB. that is, compounds of formula I wherein bond "a" represents a single bond; Bond "b" represents a double bond; R ³ is C (R ^10a ) -, wherein R ^10a is hydrogen; R ⁴ is -C (R ²⁸ ) wherein R ²⁸ is -COOH; and R ⁵ is -C (R ^10a ) (R ³³ ) -X ² -C '' - R ³¹ -A wherein R ^10a and R ³³ are each hydrogen, R ³¹ is methylene, and X ² is (in the case of isocephem) or sulfur or (in the case of isoxacephem) oxygen.

Also preferred lactam-containing compounds include penems of formula (IC), carbapenems and clavems, i.e. compounds of formula (I) in which bond "a" represents a single bond; Bond "b" represents a double bond; R ³ is -C (R ^10a ) wherein R ^10a is hydrogen; R ⁵ is -C (R ²⁸ ) =. wherein R ²⁸ is -COOH; and R ⁵ is -X ² -C'-R ³¹ -Y-, wherein R ³¹ is methylene, and X ² is (for penem) sulfur, (for carbapenem) is C (R ³³ ) or (in the case of clavems) an oxygen atom. Lactam derivatives of this type are described in R. Wise, "In Vitro and Pharmacokinetic Properties of Carbapenems," 30 Antimicrobial Agents and Chemotherapy, 1986, 343; and S. McCombie et al., "Synthesis and In Vitro Activity of Penem Antibiotics," 8 Medical Research Reviews, 393 (1988).

Also preferred lactam-containing compounds include penicillins of formula (ID), i.e., compounds of formula (I) wherein the bond "a" represents a single bond; Bond "b" represents a single bond; R ³ is -C (R ^10a ) - wherein R ^10a is hydrogen; R ⁴ is -CH (R ²⁸ ) - wherein R ²⁸ is -COOH; and ^R5 is -X ² C "^'(R32) R ^3I-Y- group wherein ^R32 is methyl, ^R31 is methylene and X ² is sulfur.

Likewise, preferred lactam-containing compounds include the monocyclic beta-lactams of the formula (LE), that is, the compounds of the formula (I) wherein the bond "a" represents a single bond; Bond "b" is not present; R ³ is -C (R ^10a ) - wherein R ^10a is hydrogen; R ⁵ is Y; R ⁴ is (for monobactam) -SO 3 H, (for monophospham) is -PO (OR ³⁴ ) OH, (for monocarbamate) is C (O) NHSO 2 N (R ³⁴ ), (for monosulfactam) -OSO ₃ H, (for nocardicins) -CH (R ³⁵ ) COOH or -OCH (R ³⁴ ) COOH. Lactam derivatives of this type are described in C. Cimarusti et al., "Monocyclic 8-Lactam Antibiotics", 4 Medical Research Reviews. 1 (1984).

Also preferred lactam-containing compounds include the monocyclic beta-lactams of formula (IF), i.e. compounds of formula (I) in which bond "a" is absent, bond "b" being a single bond; R ³ is C (R ^10a ) (R ²⁹ ) - wherein R ^10a and R ²⁹ are each hydrogen; and R ⁵ is Y.

Similarly, preferred lactam-containing compounds include clavams of formula (IG), i.e. compounds of formula (I) wherein bond "a" represents a single bond, bond "b" represents a single bond; R ³ is -C (R ^10a ) - wherein R ^10a is hydrogen; R ⁴ is -CH (R ²⁸ ) - wherein R ²⁸ is -COOH; and ^R5 is -X ² C "'= C- (R ^IOA) -R ^3l Y- group wherein R ^IOA is hydrogen, ^R31 is methylene and X ² is oxygen.

Also preferred lactam-containing compounds include 2,3-methylenepenams and carbapenams of formula (IH), i.e. compounds of formula (I) wherein the "a" bond is

A9 represents a single bond, bond "b" represents a single bond; R ³ is -C (R ^10a ) - wherein R ^10a is hydrogen; R ⁴ is -C * (R ²⁸ ) wherein R ²⁸ is -COOH; and ^R5 is -X ² -C "'(R ³²⁾ -R ^3I-Y- group wherein ^R31 is absent, ^R32 bound to C * to form a three-membered carbocyclic ring, and X ² is C R ³³ or S.

Also included in the lactam derivatives of the invention are lactivicin analogs of formula II, i.e. compounds of formula I in which bond "a" is absent, bond "b" being a single bond; R ³ is -CH ₂ -R ³² wherein R ³² is oxygen; R ⁴ is -CH (R ²⁸ ) - wherein R ²⁸ is -COOH; and R ⁵ is Y.

Likewise, preferred lactam-containing compounds include pyrazolidinone derivatives of formula IJ, i.e. compounds of formula I wherein bond "a" represents a single bond, bond "b" represents a double bond; R ³ is CH ₂ -R ²⁸ - wherein R ²⁸ is N; R ⁴ is -C (R ²⁸ ) - wherein R ²⁸ is -COOH; and R ⁵ is -X ² -C '' - R ³¹ -Y-, wherein R ³¹ is methylene and X ² is C (R ³³ ).

Also preferred lactam-containing compounds include gamma-lactams of formula (IK), that is, compounds of formula (I) wherein bond "a" represents a single bond, bond "b" is absent; R ³ is -CH 2 -R ²⁸ - wherein R ²⁸ is -C (R ^10a ) and R ^10a is hydrogen; R ⁴ is -SO, H, -PO (OR ³⁴ ) OH, C (O) NHSO 2 N (R ³⁴ ) (R ³⁵ ), OSO _? H, -CH (R ³⁵ ) COOH, or OCH (R ³⁴ ) COOH; and R ⁵ is Y.

Preferred lactam-containing moieties include cephem, isocephem, isooxacephem, oxacephem, carbacephem, penicillin, penem, carbapenem, and monocyclic beta-lactams. Particularly preferred are cephem, penem, carbapenem and monocyclic beta-lactams.

The substituent R ¹ may be any group which may substitute for the compound in the active stereoisomer position of a 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 that exhibits antimicrobial activity.) This "active" position, for example, is the beta position for cephems, oxacephem and carbacephem beta status). The active position for penems, carbapenems, clavems and clavams is the alpha position.

Suitable R ¹ groups are well known to those skilled in the art. Many such R ¹ groups have been described in the art, for example in Cephalosporins and Penicillins, Chemistry and Biology (E. Flynn, editor, 1972); Chemistry and Biology ofb-Lactam Antibiotics (R. Morin et al., Editors, 1987); The Cephalosporin Antibiotics: Seminar-in-Print, 34 Drugs (Supp. 2) 1 (J. Williams, editor, 1987); New Beta-Lactam Antibiotics: A Review of Clinical Efficacy of New Cephalosporins (H. Neu, editor, 1982); M. Sassiver et al., In Structure Activity Relationships among Semi-synthetic Antibiotics (D. Perlman, editor, 1977); W. Druckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics," 24 Angew. Chem. Int. Ed. Engl., 180 (1985); G. Rolinson, Beta-Lactam Antibiotics, 17 J. Antimicrobial Chemotherapy, 5 (1986); European Patent Application 187,456 (Jung, published June 1986)

16); and International Patent Publication No. 87/05 297 (PCT) (Johnston et al., published September 11, 1987).

In the case of penems, carbapenems, clavems and clavams, R ¹ is preferably lower alkyl or lower alkyl substituted by hydroxy. Particularly preferred R ¹ groups include hydrogen, hydroxymethyl, ethyl, 1 (R) -hydroxyethyl, 1 (R) - [(hydroxysulfonyl) oxy] ethyl, and 1-methyl -1-hydroxy-ethyl.

With the exception of penems, carbapenems, clavems and clavams, in other cases, the R ¹ groups are preferably amides, for example, preferably acetylamino substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio groups. group; preferably N-substituted arylglycylamino substituted with six-heteroarylcarbonyl and cycloheteroalkylcarbonyl; arylcarbonyl-amino; heteroaryl-carbonyl-amino; and preferably lower alkoxyiminoacetylamino substituted with aryl or heteroaryl. Particularly preferred R ¹ groups include amides of the formula R ¹³ - (CH ₂ ) _m C (= O) NH - wherein R ¹³ is R ¹² . Such preferred R ¹ groups include, but are not limited to, the following:

[(2-amino-5-halo-4-thiazolyl) acetyl] amino;

[(4-amino-2-pyridinyl) acetyl] amino;

[[2- (aminomethyl) phenyl] acetyl] amino;

[(1 H -tetrazol-1-yl) acetyl] amino; (Cyanomethyl) amino group;

(2-thienyl-acetyl) amino;

sidnone, 3- (2-amino) -2-oxoethyl.

This type of preferred R ¹ groups also includes (aa), (ab), (ac), (ad), (ae), (af), (ag), (ah), (ai), (aj). , (k) and (al).

When R ¹ is R ¹³ - (CH ₂ ) _m C (C = O) NH-; and R ¹³ is -Z ¹ then preferred R ¹ groups include, for example, [(sulfamoylphenyl) acetyl] amino;

[[(4-pyridinyl) thio] acetyl] amino;

HU 211 676 A9 [((cyanomethyl) thio) acetyl] amino;

(S) - [[(2-amino-2-carboxyethyl) thio] acetyl] amino;

[[(Trifluoromethyl) thio] acetyl] amino;

(£) - [[[2- (aminocarbonyl) -2-fluoro-ethenyl] thio] acetyl] amino.

This type of preferred R ¹ groups also includes (am), (an), (ao), (ap), (aq), (ar), (as), (at), (au) and (av). ).

When R ¹ is R ¹³ - (CH ₂ ) _m C (C = O) NH-, and R ¹³ is -CH (Z ² ) (R ¹² ), the preferred R ¹ groups are others. besides - include, for example:

[(Carboxyphenyl) acetyl] amino;

[[(Phenoxycarbonyl) phenyl] acetyl] amino;

[[(4-methyl-2,3-dioxo-l-piperazinyl) carbonyl] -D-phenylglycyl] amino;

[[[[[3 - [[(2-furyl) -methylene] amino] -2-oxo-l-imidazolidinyl] carbonyl] amino] phenyl] acetyl] amino;

(R) - [(amino-phenyl) -acetyl] amino;

(R) - [amino- (4-hydroxyphenyl) acetyl] amino;

(? /) - [amino- (l, 4-cyclohexadiene-l-yl) acetyl] amino;

[(Hydroxy-phenyl) -acetyl] amino;

(R) - [[[[(4-ethyl-2,3-dioxo-l-piperazinyl) carbonyl] amino] - (4-hydroxyphenyl)] - acetyl) amino;

(R) - [[[[(5-carboxy-l / 7-imidazole-4-yl) carbonyl] amino] phenyl] acetyl] amino;

(? /) - [[[[(4-hydroxy-6-methyl] -3-pyridinyl) carbonyl] - amino] (4-hydroxyphenyl)!] - acetyl] amino;

(R) - [(phenylsulfo) acetyl] amino-c;

(2 H, 3 S) - [2 - [(4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl] amino] -3-hydroxy-1-oxobutyl] amino;

[Carboxy- (4-hydroxyphenyl) acetyl] amino;

(R) - [[amino-3 - [(ethylsulfonyl) amino] phenyl] acetyl] amino;

(? /) - [amino- (3-benzo [d] thienyl) acetyl] amino;

(R) - [amino (2-naphthyl) acetyl] amino;

(? /) - [amino- (2-amino-4-thiazolyl) acetyl] amino;

f [[(6,7-dihydroxy-4-oxo-4/7-l-benzopyran-3-yl) carbonyl] amino] - (4-hydroxyphenyl) acetyl] amino;

(R, R) - [2- [4 - [[[(2-amino-2-carboxyethyl) oxy] carbonyl] amino] phenyl] -2-hydroxyacetyl] amino; and (5) - [[[(5-hydroxy-4-oxo-1 (4H) -pyridin-2-yl) carbonyl] amino] - (2-amino-4-thiazolyl) acetyl] amino. .

Preferred R ¹ groups of this type include the (ba), (bb), (in), (bd), (in), (bf), (bg), (o), (bi), (bj) , (bk), (b1), (bm), (bn), (bo), (bp), (bq), (br) and (bs).

Another preferred substituent for R ¹ is R ¹² C (= CHR ¹⁵ ) -C (= O) NH-. This group includes, for example, the formulas (ca) and (cb).

In case of lactam-containing moieties other than penemektől, karbapenemektől, klavémektől klavámoktól and the preferred ^R1 substituents include R ^{I 2} C (= NO-R ^I4) -C (= O) NH-. Examples of this preferred class of R ¹ groups include, but are not limited to:

2-phenyl-2- (hydroxyimino) acetyl;

2-thienyl-2- (methoxyimino) acetyl; and

2- [4- (gamma-D-oxy-glutanil) phenyl] -2- (hydroxyimino) acetyl;

(Z) - [(2-amino-4-thiazolyl) - (methoxyimino) acetyl) amino;

[(2-furanyl) - (methoxyimino) acetyl] amino;

(Z) - [(2-amino-4-thiazolyl) - [(l-carboxy-l-methyl) ethoxyimino] acetyl] amino;

(Z) - [(2-amino-4-thiazolyl) - [(l-carboxy-methoxy) imino) acetyl] amino;

[(2-amino-4-thiazolyl) - [(l // - imidazol-4-yl) methoxyimino] acetyl] amino;

(Z) - [(2-amino-4-thiazolyl-3-oxide) - (methoxyimino) acetyl] amino;

(S, Z) - [(2-amino-4-thiazolyl) - [carboxy (3,4-dihydroxyphenyl) methoxyimino] acetyl] amino group.

Other preferred substituents R ¹ are (da), (db), (de), (dd), (de), (df), (dg), (dh), (di), (dj), (dk). , (dl), (dm) and (dn).

Other types, but also the preferred ^R1 group (ea), (eb) (ec) and (ed) R.

Suitable R ² groups include those known in the art. Such are described, for example, in W. Druckheimer et al., "Recent Developments in the Field of Beta-Lactam Antibiotics," 24 Angevv. Chem. Int. Ed. Engl., 180 (1985); G. Rolinson, Beta-Lactam Antibiotics, 17 J. Antimicrobial Chemotherapy, 5 (1986); European Patent Application 187,456 (Jung, published June 16, 1986). Preferred ^R2 substituents include the following: hydrogen, methoxy, ethoxy, propoxy, thiomethyl, halogen, cyano, formyl and formylamino group. Particularly preferred R ² substituents include hydrogen, methoxy, halogen, and formylamino group.

Quinolone moieties

The groups A ¹ , A ² , A ³ , R ⁸ , R ⁷ and R ⁹ are various quinolones. naphthyridines or related heterocyclic groups known in the art having antimicrobial activity. Such groups are well known in the art. They are described, for example, in J. Wolfson et al., The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Activity in Vitro, 28, Antimicrobial Agents and Chemotherapy (1985) 581; and T. Rosen et al., 31 J. Med. Chem. 1586 (1988); T. Rosen et al., 31 J. Med. Chem. 1598 (1988); G. Klopman et al., 31 Antimicrob. Agents Chemother. 1831 (1987); 31: 1831-1840; JP Sanchez et al., 31 J. Med. Chem. 983 (1988); JM Domagalia et al., 31 J. Med. Chem. 991 (1988); Μ. Wentland P. et al., 20 Ann. Rep. Med. Chem. 145 (DM Baily, editor, 1986); JB Comett et al .. in 21 Ann. Rep. Med. Chem. 139 (DM Baily, editor, 1986); Ρ. Fernandes et al., In 22 Ann. Rep. Med. Chem. 117 (DM Baily, editor, 1987); R. Albrecht, 21 Prog. Drug Research 9 (1977); and Ρ. B

HU 211 676 A9

Fernandes et al., 23 Ann. Rep. Med. Chem. (R. C. Allen, editor, 1987).

Preferred quinolone moieties include those wherein A ¹ is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴¹ ) = General. a group of formula (i.e., quinolones); A ¹ is nitrogen, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴¹ ) = (i.e., naphthyridines); A ¹ is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is nitrogen (i.e., the cinnolic acid derivatives); and wherein A ¹ is nitrogen, A ² is nitrogen, and A ³ is -C (R ⁴¹ ) = (i.e., pyridopyrimidine derivatives). More preferred quinolone moieties are those wherein A * is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴ ) = ( i.e., quinolones); and where A ¹ is nitrogen, A ² is C (R ⁶⁾ = group of the formula and A ³ is C (R ^4I) = group of the formula (i.e., naphthyridines). Kinolonrészek particularly preferred are those where ^A1 is C ^(R40) = group of the formula, A ² is C (R ⁶⁾ = group of the formula and A ³ is C (R ^4I) = group of the formula (i.e. quinolones).

Preferably, R ⁸ is alkyl, aryl, cycloalkyl and alkylamino groups. More preferably, R ⁸ is ethyl, 2-fluoroethyl, 2-hydroxyethyl, tert-butyl, 4-fluorophenyl. 2,4-difluorophenyl, methylamino and cyclopropyl. The cyclopropyl group is a particularly preferred R ⁸ group. Also preferred quinolone moieties include those wherein A ¹ is -C (R ⁴⁰ ) = and R ⁸ and R ⁴⁰ together form a six membered heterocyclic ring containing oxygen or sulfur.

Preferably R ⁶ is hydrogen or halogen. More preferably ^R6 is chlorine or fluorine. A fluorine atom is a particularly preferred example of R ⁶ .

Preferred R ⁷ groups include nitrogen-containing heterocyclic rings. Particularly preferred are 5-8 membered nitrogen-containing heterocyclic rings. The heterocyclic ring may also contain further heteroatoms, such as oxygen, sulfur or nitrogen, preferably nitrogen. Such heterocyclic groups are disclosed in U.S. Patent No. 4,599,334 to Petersen et al., Issued July 8, 1986; and U.S. Patent No. 4,670,444 to Grohe et al., issued June 2, 1987. Preferred R ⁷ groups include optionally substituted pyridine, piperidine, morpholine, diazabicyclo [3.1.1] heptane, diazabicyclo [2.2. l-heptane, diazabicyclo [3.2.1] octane, diazabicyclo [2.2.2] octane, thiazolidine. imidazolidine from red and thiomorpholine and the following particularly preferred R ⁷ groups: piperazine,

3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N, N-dimethylaminomethylpyrrolidine, N-methylaminomethylpyrrolidine, A-ethylaminomethylpyrrolidine, pyridine , N-methylpiperazine and 3,5-dimethylpiperazine.

Preferred linolonyl lactam esters include compounds of formula (IL) having a 6-fluoroquinolone moiety or an 8-halo-6-fluoroquinolone moiety, i.e., compounds of formula I wherein A ² is -C (R ⁶ ) = and R ⁶ is fluoro; A ³ is C (R ⁴¹ ) =; and A is C (R ⁴⁰ ) = wherein R ⁴⁰ is hydrogen, fluoro, or chloro.

Preferred examples of such quinolone moieties include, but are not limited to:

1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid;

7- (3-Amino-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

7- [3- (aminomethyl) pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

7- (3-amino-pirzolidinil) -8-chloro-l-cyclopropyl-6-fluoro-4-dihydro-4-oxo-3-quinolinecarboxylic acid;

7- [3- (aminomethyl) pyrrolidinyl] -1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

7- [3- (aminomethyl) pyrrolidinyl] -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid;

l-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (l-piperazinyl) -3-quinolinecarboxylic acid;

ethyl 6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid;

6-fluoro-1,4-dihydro-1- (methylamino) -7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid; and 1-cyclopropyl-7- [3 - [(dimethylamino) methyl] -1-pyrrolidinyl] -6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

Further preferred examples of such quinolone moieties include (fa), (fb), (fc), (fd), (fe), (ff), (fg), (fh), (fi), ( fj), (fk), (fl), (fm), (fn), (fo), (fp), (fq), (fr), (fs), (ft), (fú), (fv) , (fw), (fx), (fy), (fz), (ga), (gb), (gc), (gd), (ge), (gf), (gg), and (gh) groups.

Also preferred quinolonyl lactam esters include 1,8-naphthyridines of formula (IM), i.e. compounds of formula (I) wherein A ¹ is N; A ² is -C (R ⁶ ) =; and A ³ is C (R ^4I) = group of the formula. Preferred examples of quinolone moieties of this type include, but are not limited to:

7- (3-Amino-pyrrolidinyl) -1- (2,4-difluoro-phenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid; and

-ethyl 6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -1,8-naphthyrid n-3-carboxylic acid.

Further examples of such preferred quinolone moieties include (ha), (hb), (he), (hd), (he), (hf), (hg), (hh), (hi), (hj) , (hk), (hl) and (hm).

Also preferred are the quinolonyl lactam esters of formula (IN) having a pyridobenzoxazine or pyridobenzthiazine moiety, i.e., a compound of formula (I).

Compounds of formula A9 wherein A ¹ is -C (R ⁴⁰ ) =; A ² is -C (R ⁶ ) =; A ³ is -C (R ⁴ ) =; and R ⁴⁰ and R ⁸ together form a bond between N 'and A to form a six-membered heterocyclic ring in which X is -O- or -S- in formula (IN). Preferred examples of such quinolone derivatives include 9-fluoro-4,7-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2H-pyrido [1,2,3-de] -1 , 4-bezoxazine n-6-carboxylic acid and the following groups; (ia), (ib), (ic), (id), (ie), (if), (ig), (ih) and (ii).

The specific physical, chemical and pharmacological properties of the quinolonyl lactam esters of the present invention may depend to a large extent on the unique combination of the integral, i.e., essential lactam-containing, quinolone and binding moieties. For example, the choice of specific integral moieties may affect the individual susceptibility of quinolonyl lactam esters to bacterial resistance mechanisms (e.g., beta-lactamase activity).

Preferred quinolonyl lactam esters include, but are not limited to, compounds having the following unique combinations of lactam-containing moieties, quinolone moieties and binding moieties.

1) Ester bonded penem quinolones such as compounds of the following classes,

(a) in which the lactam-containing moiety is a penem in which 'the bond is a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -SC '' - CH 2 -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(b) in which the lactam-containing moiety is a penem wherein the bond "a" represents a single bond; bond b represents a double bond; R ¹ is 1-hydroxyethyl; R ² is hydrogen; R ³ is -CH; R ⁴ is -C (CO 2 H) -; R ⁵ is -SC '' - CH 2 -O-; and the quinolone moiety is a 6-fluoroquinolone wherein A ¹ is -C (R ³⁹ ) -; A ² is -CF-: A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(c) in which the lactam-containing moiety is a penem having the formula "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H); R ⁵ is -SC '' - CH 2 -O-; and the quinolone moiety is a naphthyridinone wherein A ¹ is nitrogen; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(d) wherein the lactam-containing moiety is a penem wherein bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO ₂ H) -; R ⁵ is -SC "'- CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; R ⁹ is hydrogen; A ¹ is -CH-, -CF-, -CC 1 - or a nitrogen atom; R ⁸ is cyclopropyl, ethyl, 2,4-difluorophenyl, 4-fluorophenyl or tert-butyl; and R ⁷ is 3-amino-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -1- pyrrolidinyl or 1-piperazinyl.

The ester bonded penem quinolones of classes (b), (c) and (d) are preferred. Particularly preferred are compounds of the class (d).

3. Ester-linked penem quinolones, such as the following classes,

(a) in which the lactam-containing moiety is a penem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -SC "'- S-CH ₂ CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(b) in which the lactam-containing moiety is a penem wherein the bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -SC '' - S-CH ₂ CH ₂ -O-; and the quinolone moiety is a 6-fluoroquinolone wherein A ¹ is -C (R ³⁹ ) -; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(c) in which the lactam-containing moiety is a penem having the formula "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁷ is -C (CO 2 H) group; R ⁵ is -SC "'- S-CH ₂ CH ₂ -O; and the quinolone moiety is a naphthyridinone wherein A ¹ is nitrogen; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

(d) wherein the lactam-containing moiety is a penem wherein bond "a" represents a single bond; bond b represents a double bond; R ¹ is 1-hydroxyethyl; R ² is hydrogen; R ³ is -CH; R ⁴ is -C (CO 2 H) -; R ⁵ is -SC "'- S-CH ₂ CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; R ⁹ is hydrogen; ¹ is -CH-,

HU 211 676 A9

-CF-, -CC1- or N; R ⁸ is cyclopropyl, ethyl, 2,4-difluorophenyl, 4-fluorophenyl or tert-butyl; and R ⁷ is 3-amino-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -1- pyrrolidinyl or 1-piperazinyl.

The ester bonded penem quinolones of classes (b), (c) and (d) are preferred. Particularly preferred are compounds of the class (d).

4. Ester-linked carbapenem quinolones, including compounds of the following classes,

(a) wherein the lactam-containing moiety is a carbapenem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -CH (R ³³ ) -C '' - CH 2 -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

b) wherein the lactam-containing moiety is a carbapenem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (C 2 H) -; R ⁵ is CH (R ³³ ) -C '' - CH 2 -O-; and the quinolone moiety is a 6-fluoroquinolone wherein A ¹ is -C (R ³⁹ ) -; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

c) wherein the lactam-containing moiety is a carbapenem wherein the bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is C (CO 2 H) -; R ⁵ is -CH (R ³³ ) C "-CH 2 -O-; and the quinolone moiety is a naphthyridinone wherein A ¹ is nitrogen; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

d) wherein the lactam-containing moiety is a carbapenem wherein bond "a" represents a single bond; bond b represents a double bond; R ¹ is 1-hydroxyethyl; R ² is hydrogen; R ³ is -CH-; R ⁴ is -C (CO 2) -; R ⁵ is -CH (R ³³ ) -C '' - CH 2 -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; R ⁹ is hydrogen; A ¹ is -CH-, -CF-, -CC 1 - or a nitrogen atom; R ⁸ is cyclopropyl, ethyl, 2,4-difluorophenyl, 4-fluorophenyl or tert-butyl; and R ⁷ is 3-amino-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -1- pyrrolidinyl or 1-piperazinyl.

The ester-linked carbapenem quinolones of classes (b), (c) and (d) are preferred. Particularly preferred are compounds of the class (d).

5. Ester-linked carbapenem quinolones, including compounds of the following classes,

(a) wherein the lactam-containing moiety is a carbapenem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R4 is -C (CO2fl) -; R ⁵ is -CH (R ³² ) -C '' - S-CH ₂ CH ₂ -O-; and the quinolone moiety has a structure wherein A is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

b) wherein the lactam-containing moiety is a carbapenem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -CH (R ³³ ) -C '' - S-CH ₂ CH ₂ -O-; and the quinolone moiety is a 6-fluoroquinolone wherein A ¹ is -C (R ³⁹ ) -; A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

c) wherein the lactam-containing moiety is a carbapenem wherein the bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is C (CO 2 H) -; R ⁵ is -CH (R ³³ ) C '' - S-CH ₂ CH ₂ -O-; and the quinolone moiety is a naphthyridinone wherein A ¹ is nitrogen; A ² is -CF-, A ³ is -CH-; and R ⁷ is a heterocyclic ring;

d) wherein the lactam-containing moiety is a carbapenem wherein bond "a" represents a single bond; bond b represents a double bond; R ¹ is 1-hydroxyethyl; R ² is hydrogen; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -CH (R ³³ ) -C '' - S-CH 2 CH 2 O -; R ³³ is hydrogen or methyl; and the quinolone moiety has a structure wherein A ² is

-CF-; A ³ is -CH-; R ⁹ is hydrogen; A ¹ is -CH-, -CF-, CC 1 - or nitrogen; R ⁸ is cyclopropyl, ethyl, 2,4-difluorophenyl, 4-fluorophenyl or tert-butyl; and R ⁷ is 3-amino-1-pyrrolidinyl, 4-methyl-1-piperazinyl, 3- (aminomethyl) -1-pyrrolidinyl, 3 - [(ethylamino) methyl] -1- pyrrolidinyl or 1-piperazinyl.

Esters of classes (b), (c) and (d) are preferred

A9-linked carbapenem quinolones. Particularly preferred are compounds of the class (d).

6. Ester-bonded oxacephem quinolones, such as compounds of the following class, wherein the lactam-containing moiety is an oxacephem, wherein bond a represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -OCH 2 -C '' - CH ₂ -O- and the quinolone moiety is structured in which A ² is -CF-; A ³ is -CH-;

and R ⁷ is a heterocyclic ring.

7. Ester-bonded isocephem quinolones, such as compounds of the following class, wherein the lactam-containing moiety is an isocephem in which bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; ^R5 is -CH2-SC "'- CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring.

8. Ester-linked isooxacephem quinolones, including compounds of the following class. wherein the lactam-containing moiety is an isoxacephem, wherein bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO2H) ~ group; R ⁵ is -CH 2 -OC "- CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring.

9. Ester-linked carbacephem quinolones, including compounds of the following class. wherein the lactam-containing moiety is a carbacephem, wherein bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -CH ₂ -CH ₂ -C '' CH ₂ -O-; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring.

10. Ester-linked oxacephem quinolones, including compounds of the following classes,

(a) in which the lactam-containing moiety is a monobactam in which the bond "a" represents a single bond; bond "b" is absent; R ³ is -CH- and is bonded directly to X; R ⁵ is absent; X is -CH ₂ -; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring;

b) wherein the lactam-containing moiety is a monobactam in which bond "a" represents a single bond; bond "b" is absent; R ³ is -CH- and is bonded directly to X; R ⁵ is absent; X is O; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH-; and R ⁷ is a heterocyclic ring.

Quinolonyl lactam esters of the invention include, but are not limited to, the following:

[6 R - (6a, 7P)] - 7 - [[[(difluoromethyl) thio] acetyl] amino] -7-methoxy-3 - [[[1-cyclopropyl-6-fluoro-1,4 -dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinyl] carbonyl-oxy] methyl] -8-oxo-5-oxa-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid [Compound 1.1];

[6 /? - (6a, 73)] - 7 - [[[2- (aminocarbonyl) [-2-fluoro-ethenyl] thio] acetyl] amino] -3 - [[[9-fluoro- 3,7-Dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2 H -pyrido [1,2,3- b] -1,4-benzoxazine-6 -yl] -carbonyloxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (compound of formula 1.2);

[6R- (6a, 7P)] - 7 - [[Carboxy- (4-hydroxy-phenyl) -acetyl] -amino] -3 - [[[1-ethyl-6-fluoro-1,4-dihydro-7 - (4-Methyl-1-piperazinyl) -4-oxo-3-quinolinyl] carbonyloxy] methyl] 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid (compound of formula 1.3);

[5R- (5a, 6a)) - 3 - [[[7- (3-amino-l-pyrrolidinyl) -8-chloro-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-3-quinolinyl ] carbonyloxy] methyl] -6 - [(R) -1-hydroxyethyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid [ Compound (1.4)];

[5R - (5α, 6α)] - 3 - [[[1-Ethyl-1,4-dihydro-6-methyl-4-oxo-1,8-naphthyridin-3-yl] carbonyloxy] methyl ] -6 - [(R) -1-hydroxyethyl] -7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept2-ene-2-carboxylic acid (Compound 1.5);

[5R - (5α, 6α)] - 3 - [[[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinyl] carbonyloxy] methyl 1] -6 - [(R) -1-hydroxyethyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] oct-2-ene-2-carboxylic acid [(1.6) compound of the formula];

sodium (3S) -2 - [[1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinyl] carbonyloxy] -3 [[[[ (R) -4-Ethyl-2,3-dioxo-1-piperazinyl] carbonyl] amino] - (4-hydroxy-phenyl) -acetyl] -amino] -4-oxo-lazetidinesulfonate (Compound 1.7) ];

sodium (3S) -3 - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -2 - [[l-ethyl-6-fluoro-l, 4-dihydro-4 -oxo-7- (1-piperazinyl) -1,8-naphthyridin-3-yl] carbonyloxy] 4-oxo-1-azetidine sulfonate (Compound 1.8);

sodium (3Y) -2 - [[5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5g] -7-quinolinyl] carbonyloxy] -4-oxo-3 - [(phenoxyacetyl) amino] azetidine sulfonate (Compound 1.9);

[6 / -? (6?, 7?)] - 3 - [[[7- (3-amino-l-pyrrolidinyl) -] - (2,4-difluorophenyl) -6-fluoro-l, 4-dihydro-4 oxo-l, 8-naphthyridin-3-yl] carbonyloxy] methyl] -7 - [[[5-hydroxy-4-oxo-l (4 //) - 2-pyridyl] carbonylamino] - (2-amino-4-thiazolyl) acetylamino] -8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (Compound 1.10);

[6α- (6α, 7β)] - 3 - [[[7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinyl] carbonyloxy] methyl] -7 - [[[[[(/?) - 4-ethyl-2,3-dioxo-l-piperazinyl] carbonyl] amino] - (4-hydroxyphenyl) acetyl] -amino] -8-oxo-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid (Compound 1.11);

HU 211 676 A9 [6R - (6α, 7β)] - 3 - [[[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinyl] - carbonyloxy] methyl] -7 - [[phenoxyacetyl] amino] -8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (Compound 1.12);

[5R- (5a, 6a)] - 3 - [[[7- [3- (aminomethyl) -2-pyrrolidinyl] -l-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3 -quinolinyl] -carbonyloxy] -methyl] -6 - [(R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid [( Compound 1.13];

[5R - (5α, 6a)] - 3 - [[[6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7- (4-methyl- 1-piperazinyl) -3-quinolinyl] carbonyloxy] methyl] -6 - [(trans) -1-hydroxyethyl] -4P-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (compound of formula 1.14);

[5R- (5a, 6a)] - 3 - [[[8-ethyl-5,8-dihydro-5-oxo-2- (l-piperazinyl) pyrido [2,3-d] pyrimidinyl] carbonyl oxy] methyl] -6 - [(R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid [1.15] ];

[5R- (5a, 6a)] -3 - [[[1-Cyclopropyl-6-fluoro-1,4-dihydro-7 (1-piperazinyl) -4-oxo-3-quinolinyl] carbonyloxy] methyl thi 1] -6 - [(R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (Compound 1.16);

[6 /? - (^ 6)] - 7 - [[carboxy (4-hydroxyphenyl) acetyl] amino] -3 - [[[l-cyclopropyl-6-fluoro-l, 4-dihydro- 7- (1-piperazinyl) -4-oxo-3-quinolinyl] carbonyloxy] methyl] 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2 carboxylic acid (1.17).

Other examples of preferred quinolonyl lactam esters include compounds of formula (1.18) to (1.60).

Production procedures

The quinolonyl lactam esters of the present invention can be prepared using various synthetic methods known in the art. Generation of quinolonyl lactam esters generally involves the preparation of a lactam-containing moiety and a quinolone moiety, and a process or sequence of methods for linking the lactam-containing moiety to the quinolone moiety. Methods for preparing a wide variety of lactam-containing moieties and quinolone moieties are well known in the art. For example, methods for preparing lactam-containing moieties and related compounds are disclosed in, and referenced in, Cephalosporins and Penicillins: Chemistry and Biology (EH Flynn, editor, 1972), Chapters 2, 3, 4, 5, 6 , 7, 15 and Appendix 1; Recent Advances in Chemistry of fi-Lactam Antibiotics (A. G. Brown and S. M. Roberts, editors, 1985); Topics in Antibiotic Chemistry, Vol. 3, (Part B) and Vol. 4, (P. Sommes, editor, 1980); Recent Advances in Chemistry of $ -Lactam Antibiotics (J. Elks, editor, 1976); Structure-Activity Relationships among Semisynthetic Antibiotics (D. Perlman, editor, 1977). Chapters 1,2,3,4; Antibiotics, Chemotherapeutics and Antibacterial Agents for Disease Control (M. Grayson, editor, 1982); Chemistry and Biology of $ -Lactam Antibiotics,

Volumes 1-3 (K. B. Morin and M. Gorman, editors, 1982); 4 Medical Research Reviews, 1-24 (1984); 8 Medical Research Reviews, 393-440 (1988); 24 Angew. Chem. Int. Ed. Engl., 1985, 180-202; 40 J. Antibiotics, 182-189 (1987); European Patent Application 266,060; 427. Antibiotics, 993 (1989); U.S. Patent No. 4,742,053; 35 Chem. Pharm. Bull., 1903-1909 (1987); 32

7. Med. Chem., 601-604 (1989); U.S. Patent No. 4,791,106; Japanese Patent Publication No. 62/158,291; 31 7. Med. Chem., 1987-1993 (1988); 7. Med. Chem., 1987, 514-522; 28 Tetrahedron Letters, 285-288 (1987); 28 Tetrahedron Letters, 289-292 (1987); 52 7. Org. Chem., 1987, 4007-4013; 407. Antibiotics, 370384 (1987); 407. Antibiotics, 1636-1639 (1987); 37 7. Antibiotics, 685-688 (1984); 23 Heterocycles, 22552270; 27 Heterocycles: 49-55; 33 Chem. Pharm. Bull., 4371-4381 (1985); 28 Tetrahedron Letters 5103-5106 (1987); 53 7. Org. Chem., 1988, 4154-4156; 38 7. Antibiotics, 1351-1355 (1986); 59 Pure and Appl. Chem., 467-474 (187); 1987 7. C. S. Chem. Comm .; 44 Tetrahedron, 3231-3240 (1988); 28 Tetrahedron Letters, 2883-2886 (1987); 40 J. Antibiotics, 1563-1571 (1987); 33 Chem. Pharm. Bull., 4328-4394 (1985); 37

7. Antibiotics, 1984, 57-62; United States Patent 4,631,150; 34 Chem. Pharm. Bull., 999-1014 (1986); 52 7. Org. Chem., 1987, 4401-4403; 39 Tetrahedron: 2505-2513 (1983); 38 7. Antibiotics, 1382-1400 (1985); European Patent Application No. 053 815; 40 7. Antibiotics, 1563-1571 (1987); 7. Antibiotics, 1716-1732 (1987); 47 7. Org. Chem., 5160-5167 (1981); U.S. Patent 4,777,252; U.S. Patent No. 4,762,922; European Patent Application 287,734; U.S. Patent No. 4,762,827; European Patent Application 282,895; European Patent Application 282,365; U.S. Patent No. 4,777,673.

Methods for preparing quinolones for use in the methods of the invention are also described in the following literature (including references cited therein): 21 Progress in Drug Research, 1977, 9-104; 31 7. Med. Chem. 503-506 (1988); 32 7. Med. Chem., 1313-1318. (1989); 1987 Liebigs Ann. Chem., 1987, 871879; 14 Drug Exptl. Clin. Res., 379-383 (1988); Chem. Chem. 983-991 (1988); 32 7. Med. Chem. 537-542 (1989); 787. Pharm. Sci., 1989, 585-588; 26 7. Week. Chem., 1989; 24 7. Week. Chem., 181-185 (9187); U.S. Patent 4,599,334; 35 Chem. Pharm. Bull., 2281-2285 (1987); 29 7. Med. Chem., 2363-2369 (1986); 31 7. Med. Chem., 991-1001. (1988); 25 7. Week. Chem., 479-485 (1988); European Patent Application 266,576; European Patent Application No. 251,308; 36 Chem. Pharm. Bull., 1223-1228 (1988); European Patent Application 227 088; 227,039.

European Patent Application No. 211,676 A9; European Patent Application 228,661; 31 J. 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 the invention may be prepared, for example, by the following reaction:

Lacto-CH ₂ -X + M ⁺ -OC (= O) -Kin -> Lacto-CH ² OC (= O) -Kin where X is a reactive leaving group (e.g., halogen, sulfonate ester or other activated hydroxy group), "Lakt" is generally means a suitably protected lactam moiety (e.g., penem, carbapenem, ocacephem or carbacephem) and "Kin" means a suitably protected quinolone moiety. The reaction is conceivable by replacing the reactive group X of the lactam with a quinolone carboxylic acid or a salt of the quinolone carboxylic acid by a nucleophilic pathway to form an ester linked conjugate of lactam and quinolone.

In the case of Lakt and Kin, it may be necessary to block certain functional groups (such as carboxyl, hydroxyl and amino groups) in the molecular structure of Lakt and Kin in order to prevent possible undesirable side reactions with X. For example, protecting groups capable of blocking carboxyl groups include, but are not limited to, esters; ethers, esters and carbonates are suitable for protecting hydroxyl groups; while protected amino groups include carbamates and amides. If such types of protecting groups are used, chemical methods of deprotection that do not disrupt the conjugate linker ester should be used later to produce antimicrobially active products. When the lactam-containing malecular moiety is a monocyclic beta-lactam, an alternative reaction sequence of Scheme [A] may also be used; in Scheme [A], X represents a heteroatom substituent (oxygen, sulfur, halogen, etc.) which is bonded to the lactam.

In the reactions of Scheme [A], an amide formation occurs between the lactam and the quinolone, followed by rearrangement with the substitution of X, and finally the ester is liberated by hydrolysis. The lactam-containing structure may initially be mono- or bicyclic. The ester bonded product will be monocyclic.

compositions

Compositions of the invention include:

(a) a harmless and effective amount of a quinolonyl lactam ester; and (b) a pharmaceutically acceptable carrier.

A "harmless and effective amount" of a quinolonyl lactam ester is an amount that effectively inhibits microbial growth at the site of infection in a human or inferior animal subject, at a reasonable benefit-risk ratio and without undesirable side-effects. (for example, toxicity, imitation, and allergic reactions). It is clear that the specific value of "safe and effective amount" depends on a number of factors; factors such as the condition to be treated, the duration of the treatment, the nature of any subsequent treatments, the particular dosage form to be used, the solubility of the carrier, the solubility of the quinolonyl lactam esters in the carrier, and the particular composition. dosing instructions.

The compositions of the invention are preferably formulated in dosage units. As used herein, the term "dosage unit form" refers to a composition of the present invention containing an amount of quinolonyl lactam esters which, in accordance with good medical practice, is suitable for administration in a single dose to a human or inferior animal. The compositions preferably contain from about 30 mg to about 20,000 mg, more preferably from about 50 mg (milligram) to about 7,000 mg, more preferably from about 500 mg to about 1500 mg, of a quinolonyl lactam ester.

The compositions of the present invention may be in any form suitable for oral, rectal, topical or parenteral administration. Depending on the mode of administration, if desired, various pharmaceutically acceptable carriers well known in the art may be used. These include solid and liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Optionally, other pharmaceutically active substances that do not substantially alter the antimicrobial activity of the quinolonyl lactam ester may be included. The amount of carrier used in combination with the quinolonyl lactam ester should be such that it is possible to administer the quinolonyl lactam ester per dosage unit. Methods and compositions for preparing dosage forms useful in the treatment methods of the present invention are described, for example, in: 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, 2nd Edition (1976).

In particular, pharmaceutically acceptable carriers for systemic administration include, but are not limited to, sugars, starches, cellulose and cellulose derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, solutions, emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration

A9 includes, but is not limited to, propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil. In compositions for parenteral administration, the pharmaceutically acceptable carrier is preferably present in an amount of at least about 90% by weight of the total composition.

A variety of oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. These oral forms contain the quinolonyl lactam ester in a safe and effective amount, usually at least about 5%, preferably about 25% to about 50%. Tablets containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-forming agents and bulking agents may be compressed, powdered, enteric coated, sugar coated, film coated, film coated. Liquid oral dosage forms include aqueous solutions containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, bulking agents, coloring agents and flavoring agents, emulsions, suspensions and / or non-effervescent granules. Preferred carriers for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil.

The compositions of the invention may also be administered topically to the subject, i.e., the composition may be applied directly to the patient's epidermal or epithelial tissue by lubrication or spraying. Such compositions include, but are not limited to, lotions, creams, solutions, gels and solids. Such topical compositions contain the quinolonyl lactam ester in a safe and effective amount, usually in an amount of at least about 0.1%, and preferably in the range of about 1% to about 5%. Suitable carriers for topical administration preferably remain as a continuous film on the skin and prevent swelling or immersion of the active ingredient in water. In general, the carrier is organic and suitable for dispersing or dissolving the quinolonyl lactam ester. Carriers may include pharmaceutically acceptable plasticizers, emulsifiers, thickeners, and solvents.

Admission procedures

The present invention also encompasses methods of treating or preventing an infectious disorder in a human or animal body comprising administering to a subject a safe and effective amount of a quinolonyl lactam ester. As used herein, the term "infectious disorder" refers to any disorder characterized by the presence of a microbial infection. Such infectious disorders include, but are not limited to: central nervous system infections, external ear infections, middle ear infections (e.g., acute otitis media), cranial sinus infections, eye infections, oral cavity infections (e.g., teeth, oral infections), upper respiratory tract infections, lower respiratory tract infections, urinary tract infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin infections, bacterial endocarditis, bacterial endocarditis, bacterial endocarditis, antibacterial prophylaxis in immunosuppressed patients (for example, those receiving or receiving chemotherapy for cancer or organ transplantation).

The quinolonyl lactam esters and compositions of the invention may be administered topically or systemically. Systemic applications include all methods suitable for the introduction of quinolonyl lactam ester into body tissues and include, but are not limited to, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, and oral administration. The individual dose of antimicrobial agent to be administered and the duration of treatment are interrelated. The dose and treatment regimen will also depend on other factors such as the particular quinolonyl lactam ester used, the resistance of the infectious organism to the quinolonyl lactam ester used, the minimal inhibition of the quinolonyl lactam ester at the site of infection. concentration, where appropriate the nature and extent of other infections, the individual characteristics of the subject being treated (e.g., body weight), the stage of the treatment program, and the presence and severity of any side effects of the treatment.

In an adult human subject (assuming a weight of approximately 70 kg), dithiocarbamoylquinolone will typically be present in an amount of about 75 mg to about 30,000 mg per day, preferably about 100 mg to about 20,000 mg, more preferably about 500 mg to about 3500 mg. Preferably, the treatment program is from about 1 day to about 56 days, more preferably from about 7 days to about 28 days. A prophylactic program (for example, to prevent possible infections in immunologically compromised patients) can last up to 6 months or more, according to good medical practice.

One preferred method of parenteral administration is intramuscular injection. As is well known, all formulations for parenteral administration should be sterile. For mammals, particularly human organisms (assuming a body weight of about 70 kg), individual doses of about 100 mg to about 7000 mg, preferably about 500 mg to about 1500 mg, are acceptable.

HU 211 676 A9

A preferred method of systemic administration is the oral route. Individual doses are preferably in the range of about 100 mg to about 2500 mg, more preferably in the range of about 250 mg to about 1000 mg.

Topical administration may be used to systemically disperse the quinolonyl lactam ester or to treat a local infection. The amount of topical application of quinolonyl lactam ester will depend on a number of factors, including skin sensitivity, the type and location of tissue to be treated, the composition of the composition to be administered and the carrier employed, the particular quinolonyl lactam to be administered and the individual disorder to be treated. and the extent to which systemic (i.e., non-distinctly local) effects are desired.

The following non-limiting examples illustrate the compounds, compositions, methods, and uses of the present invention.

EXAMPLE 1

The [5 R - (5a, 6a) J 3 - [[7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1- 4-Dihydro-4-oxo-3- (1,8-naphthyridinyl) carbonyloxy] methyl] -6- [1 (R) -hydroxyethyl] -7-oxo-4-thia-1-aza Bicyclo [3.2.0] hept-2-ene-2-carboxylic acid is prepared according to the reaction sequence in Scheme [B].

An allyl of formula (Ia) prepared according to the Battistini process (Battistini et al., U.S. Patent No. 4,631,150; published December 23, 1986). )] - 3- (hydroxymethyl) -6- [l (/?) - [(tert-butyldimethylsilyl) oxy] ethyl] -7-oxo-4-thia-l-azabicyclo [3.2.0 About 0.28 mmol (0.112 g) of hept-2-ene-2-carboxylate are dissolved in about 10 mL of tetrahydrofuran (THF). With stirring, under nitrogen, at about 22 ° C (72 ° F), about 0.32 mmol diethyl azodicarboxylate, 0.32 mmol 6-fluoro-1 (2,4-difluorophenyl) -1,4- dihydro-4-oxo-7- [3- [3- (1-propenyl) oxycarbonyl] amino-1-pyrrolidinyl] -3- (1,8-naphthyridine) carboxylic acid, and 0.32 mmol of triphenylphosphine (PPh ₃ ) was added to the solution. After about 15 minutes, 10 ml of phosphate buffer (0.5 M, pH 7.0) was added, the tetrahydrofuran was evaporated rapidly, and the aqueous residue was extracted with dichloromethane. After drying and removal of the solvent, the crude compound of formula (Ib) is obtained. which is further purified by flash chromatography.

About 0.15 g (0.18 mmol) of the product of formula (1b) is dissolved in 20 ml of tetrahydrofuran. Thereafter, 40 microliters of glacial acetic acid and 60 mg of tetrabutylammonium fluoride were added to the solution, and the reaction mixture was allowed to stand at ambient temperature for about 24 hours. The tetrahydrofuran was evaporated and the residue was dissolved in dichloromethane. The solution was washed with aqueous sodium bicarbonate solution and the solvent removed. As a result, the product of formula (1c) is obtained.

About 60 milligrams (0.08 mmol) of compound (1c) is dissolved in 15 ml of tetrahydrofuran at ambient temperature, followed by stirring with 5 mg of triphenylphosphine, 44 mg of sodium ethylhexanoate and 5 mg of tetrakis (triphenylphosphine) palladium [ Pd (PPh ₃ ) ₄ ] is added to the solution. Within minutes, a precipitate formed. The precipitate was filtered off. The solid final product (1.61) is made analytically pure by repeated trituration.

The following quinolonyl lactam esters were prepared in substantially the same manner as in the general procedure of Example 1.

The compound of formula (1.62) was prepared according to the method of Sanchez (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983), 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl. 6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is prepared using quinolone.

The compound of formula (1.63) is prepared from 6-fluoro-1,4-dihydro-1- (4-dihydro-1- (Wentland, et al., J. Med. Chem., 1984, 27, 1103). methylamino) 7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid using quinolone.

7- (2,5-Diazabicyclo [2.2.1] heptan-2-yl) prepared according to Weber's method (A. Weber, et al., European Patent Application 266,576). ) -1-tert-Butyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is prepared using naphthyridinone.

The compound of formula (1.65) is prepared from 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-, prepared according to the method of Iridura (T. Iridura, et al., Australian Patent Application 537,813). Prepared using 4-oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid quinolone.

The compound of formula (1.66) is prepared from 9-fluoro-4,7-dihydro-3-methyl-10 by the method of Hagakawa (I. Hagakawa, et al., Chem. Pharm. Bull., 1984, 32, 4907). - (4-Methyl-1-piperazinyl) -7-oxo-2H-pyrido [1,2,3-b] -1,4-benzoxazine-6-carboxylic acid is prepared using quinolone.

7- (3-Amino-1-pyrrolidinyl) -8-chloro-1-one prepared according to the method of Sanchez (JP Sanchez et al., J. Med. Chem., 1988, 31, 983). cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid quinolone and the Christensen method [B. G. Christensen et al., European Patent Application 185,315 (1986)] prepared from allyl [5 R, 5a, 6a]] - 6 - [(R) -1 - [(tert-butyl). -dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxolazabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam live.

The compound of formula (1.68) is prepared from 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1-cyclopropyl-6-fluoro-1,4-dihydro 7- (1-piperazinyl) -3-quinolinecarboxylic acid quinolone and Christensen's method [B. G. Christensen et al., European Patent Application 185,315 (1986)], 3ΐ1ί1- [5Λ- (4β, 5α, 6α)] - 6 - [(R) -1 - [(tert-butyldimethyl) silyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam.

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EXAMPLE 2

According to the general procedure, the following quinolonyl lactam ester is prepared.

7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl, prepared according to the method of Sanchez (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983). 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was prepared using quinolone.

In a manner similar to the general procedure of Example 2, the following quinolonyl lactam ester was prepared with substantially similar results.

The compound of formula 1.70 is prepared according to the method of Christensen [B. Allyl [5 R - (4 P, 5 A, 6 A)] - 6 - [(7 R) -1 - [(tert-Butyl) prepared according to European Patent Application 185 185, G. Christensen et al. using dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam we produce it.

EXAMPLE 3

Following the general procedure of Example 1, the following quinolonyl lactam ester was prepared.

The compound (1.71) was prepared according to the method described by Sanchez (JP Sanchez et al., J. Med. Chem., 1988, 31, 983), 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl. 6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is prepared using naphthyridinone.

In a manner similar to the general procedure of Example 3, the following quinolonyl lactam ester was prepared with substantially similar results.

The compound of formula 1.72 is prepared according to the method of Christensen [B. Allyl [5 R - (4β, 5α.6α)] - 6 - [(R) -1 - [(tert-butyl) prepared according to European Patent Application 185 185, G. Christensen et al. -dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam .

EXAMPLE 4

[5Λ- (5α, 6α)] 3 - [[[1-Cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) -3 quinolinyl] carbonyloxy] methyl] -6 - [(7?) - l-hydroxyethyl] -7-oxo-4-thia-l-azabicyclo [3.2.0] hept-2-ene -2-Carboxylic acid is prepared according to the reaction sequence of Scheme [C].

A pH of about 5.0 g of a mixture of ciprofloxacin of formula (4a) and 175 ml of water is adjusted to about 12 by addition of 1 M sodium hydroxide solution at about 0 ° C. To this solution was first added approximately 44 mL of acetone, followed by the dropwise addition of a solution of allyl chloroformate (2.7 g) in 33 mL of acetone to the above mixture. The reaction mixture was stirred cold for one hour while maintaining the pH of the mixture by addition of 1M sodium hydroxide solution to 10-12. The mixture was then concentrated to about 125 ml and extracted twice with diethyl ether. The aqueous layer was cooled in an ice bath, acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The extract was washed with water, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness. As a result, the compound of formula (4b) is obtained.

Dissolve 6 g of compound (4b) in dichloromethane at about 0 ° C and add a solution of sodium hydroxide (0.73 g) in methanol (5 ml) dropwise to the former. The mixture was stirred for one hour at ambient temperature and then evaporated to dryness. The residue is triturated under diethyl ether and the sodium salt of formula (4, c) is filtered off.

Notwithstanding the above steps, about 5.0 g of allyl- [5 R - (5a, 6a)] - 3-hydroxymethyl-6 - [(R) -1 - [(tert-butyldimethylsilyl) oxy] -ethyl] -7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylate and 1.7 ml of triethylamine in 30 ml of dichloromethane at about 40 ° C. at a temperature of about ml mesyl chloride. The reaction mixture was stirred for about 10 minutes and then washed with 10% aqueous sodium bicarbonate and water. The organic phase is dried over sodium sulfate, filtered and the filtrate is evaporated to dryness. As a result, the compound of formula (4d) is obtained.

To a solution of about 4.3 grams of mesylate (4d) in 30 ml of N, N dimethylformamide at about 0 ° C is added about 3.9 g of compound (4c) and the reaction mixture is first stirred for about 9 hours. and then stirred at ambient temperature for about one hour. The reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in dichloromethane and the solution is washed with water. The organic phase is dried over sodium sulfate, filtered, and the filtrate is evaporated to dryness. The residue was purified by flash chromatography on silica gel to give 4e.

To a mixture of about 2.6 g of compound (4e), 2 ml of glacial acetic acid and 30 ml of tetrahydrofuran is added about 3.5 g of tetra (n-butyl) ammonium fluoride trihydrate at room temperature. The reaction mixture is stirred for about 30 hours and then evaporated to dryness. The residue was purified by flash chromatography on silica gel to give 4f.

To a mixture of about 1.3 g of compound (4f), 0.19 ml of water, 0.027 g of bis (triphenylphosphine) palladium chloride and about 36 ml of methylene chloride at about 19 ° C, about 1.1 ml of tributyl -on-hydride is added. The reaction mixture is stirred rapidly for about 10 minutes and the precipitate is filtered off. The solid was triturated under acetone and filtered. As a result, the title compound (1.73) is obtained.

Following the general procedure of Example 4, the following quinolonyl lactam esters were prepared with substantially similar results.

The compound (1.74) was prepared according to the method of Sanchez (JP Sanchez et al., J. Med. Chem., 1988, 31, 983), 7- (3-amino-1-pyrrolidinyl) -8-chloro. 1-Cycloprogyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid using quinolone.

HU 211 676 A9

Compound (1.75) was prepared according to the method of Koga (H. Koga et al., J. Med. Chem., 1980, 23, 1358) as 1-ethyl-6-fluoro-1,4-dihydro-4-. oxo-7- (1-piperazinyl) 3-quinolinecarboxylic acid using quinolone.

The compound (1.76) was prepared from 6-fluoro-1- (4-fluorophenyl) -1, prepared according to the Chu procedure (DTW Chu et al., J. Med. Chem., 1985, 28, 1558). Prepared using 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid quinolone.

Compound (1.77) is prepared according to the method of Sanchez (J.

7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-1,4-dihydro-4, prepared according to P. Sanchez, et al., J. Med. Chem., 1988, 31, 983. -oxo-3-quinolinecarboxylic acid quinolone and Christensen's method [B. G. Christensen et al., European Patent Application 185,315 (1986)] prepared from allyl [5 R - (4β, 5α, 6α)] - 6 - [(R) -1 - [(tert-butyl). -dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-ozo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam live.

EXAMPLE 5

Compound (1.78) is prepared according to the general procedure of Scheme [D].

About 1.26 g of ciproflaxin and 1.59 g of sodium bicarbonate are suspended in about 25 ml of water and the suspension is stirred for about one hour. To the stirred aqueous solution was added dropwise 38 Zhur. obschei Khim. (1986), a solution of about 0.72 grams of [2- (trimethylsilyl) ethyl] chloroformate in about 10 ml of tetrahydrofuran. After about one hour, the mixture was poured into 150 ml of chloroform and acidified with 150 ml of cold 0.1 M hydrochloric acid. The aqueous phase was repeatedly extracted with chloroform, and the combined chloroform layers were washed successively with cold 0.1 M hydrochloric acid, water, and saturated aqueous sodium chloride. The chloroform solution was dried over sodium sulfate, filtered and concentrated. The residue was triturated under diethyl ether. After filtration, the products of formula (5a) are obtained.

About 0.16 g of compound (5a), 0.20 g of compound (5b) (prepared as above) and 0.040 g of sodium bicarbonate under inert atmosphere of about 1 ml / V, dimethylformamide. The mixture was heated at about 70 ° C for about 8 hours and then cooled to room temperature. To the resulting mixture was added 0.50 g of tetra (n-butyl) ammonium fluoride trihydrate, followed by stirring at room temperature for about 16 hours. The mixture was then eluted with deionized water on a DowexR 50 x 4 (Na-cycle) column. The appropriate fractions were partially concentrated in vacuo and lyophilized. As a result, the final product of formula (1.78) is obtained.

The following quinolonyl lactam esters were prepared in substantially the same manner as in the general procedure of Example 5.

The compound (1.79) is prepared according to the method of Sanchez (JP Sanchez et al., J. Med. Chem., 1988, 31, 983), 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl. 6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was prepared using quinolone.

7- (3-Amino-1-pyrrolidinyl) -8-chloro (1.80) was prepared according to the method of Sanchez (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983). -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid using quinolone.

The compound of formula (1.81) was prepared according to the method of Sanchez (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983), 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl. 6-Fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was prepared using quinolone.

7- (3-Amino-1-pyrrolidinyl) -1-cyclopropyl, prepared according to the Sanchez method (JP Sanchez et al., J. Med. Chem., 1988, 31, 983). 6-Fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is prepared using naphthyridinone.

1-5. The quinolonyl lactam esters (1.83) to (1.96) are obtained in substantially the same manner as the general procedures of the example.

EXAMPLE 6

Sodium [3S (2β, 3β)] - 2 - [[1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-piperazinyl) -3-quinolinyl] according to the invention (1.97) ] -carbonyloxy] -3 - [(phenoxyacetyl) amino] -4-oxo-1-azetidine sulfonate was prepared according to the procedure of Scheme [E].

About 20 g of ethyl 6-fluoro-1,4-dihydro-4-oxo-7- [4 - [(2-propenyloxy) carbonyl] -1-piperazinyl] -3-quinolinecarboxylic acid sodium salt (6 (aa)] and anhydrous solution of triethylamine (6.4 ml) in dioxane (100 ml) and acetone (20 ml) were cooled to 0 ° C (32 ° F). Ethyl chloroformate (4.4 ml) was added dropwise to the stirred solution while maintaining the temperature at 2 ° C (32 ° F). To the resulting mixed anhydride solution was added simultaneously a cooled solution of 6.8 g of potassium salt of 6-amino-penicillanic acid (compound 6b), 4.2 ml of triethylamine and 9.6 ml of water, and and stirred at room temperature until the reaction is complete according to TLC (thin layer chromatography). The reaction mixture was then washed with dichloromethane and the aqueous layer was acidified to pH 2 with 1M hydrochloric acid. The aqueous layer was extracted with dichloromethane, and the combined organic extracts were washed with water, dried over sodium sulfate and evaporated in vacuo. As a result, the product of formula (6c) is obtained.

Approximately 13.0 grams of compound (6-c) is added at room temperature to a stirred solution of 12.8 g of mercury (II) acetate in 200 ml of acetic acid. The resulting gel is mixed with acetone and the insoluble material is filtered off and washed with acetone and diethyl ether. As a result, the product of formula (6d) is obtained.

To a stirred suspension of 11.9 grams of salt (6d) in 45 ml of dimethyl sulfoxide was added an excess of diazomethane in diethyl ether. After 2 hours, the mixture was diluted with dichloromethane, the diluted solution was filtered and washed with water. The organic phase is dried over sodium sulphate and then poured into ethyl acetate

EN 211 676 A9. From the product mixture thus obtained, the desired product of formula (6e) is isolated by chromatography.

A mixture of 4.4 g of thiol (6e), 1.08 g of mercury (II) acetate and 80 ml of dimethyl sulfoxide is stirred for 18 hours. The mixture was then diluted with dichloromethane, the diluted solution was filtered and washed with water. The organic layer was dried over sodium sulfate and concentrated. As a result, the product of formula (6f) is obtained.

About 2.95 g of compound (6, f) is dissolved in 35 ml of acetone and then about 0.95 g of p-toluenesulfonic acid monohydrate is added. The mixture was stirred at 18 'C (64' F) for 20 minutes. Removal of the solvent gave a residue of product (6g) which was triturated. 2.3 g of compound (6g) are dissolved in dichloromethane (20 ml) and phenoxyacetyl chloride (0.52 ml) is added while cooling in an ice bath. The mixture is stirred while a solution of 0.55 ml of pyridine in 4 ml of dichloromethane is added over 30 minutes. After stirring for an additional 30 minutes, the mixture was concentrated and the residue was dissolved in dichloromethane. The solution was washed with dilute hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. As a result, the product of formula (6h) is obtained.

About 0.91 g of compound (6h) is dissolved in a mixture of 15 ml of acetone and 0.26 ml of acetic acid and then cooled to 0 'C (32' F). To this solution is added a solution of 0.25 g of potassium permanganate in 10 ml of water while maintaining the temperature of the mixture at about 2 'C (36' F). When the addition was complete, the mixture was warmed to room temperature and stirred for an additional 3 hours. The solid is then filtered off and washed with dichloromethane. The filtrate was diluted with water and the phases were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and water, dried and evaporated. As a result, the product of formula (6i) is obtained.

To a dry solution of about 0.46 g of compound (6i) in 4 ml of N, N dimethylformamide is added about 0.95 g of DMF.SO. complex. The resulting mixture was stirred for 2 hours, or until the reaction was complete by TLC. The mixture is then diluted with 20 ml of dichloromethane and 20 ml of 0.17 M (0.5 N) potassium hydrogen phosphate solution with stirring. The pH was adjusted to 6 with 1M sodium hydroxide solution and 0.25 g of tetrabutylammonium hydrogen sulfate was added. The phases are separated and the organic layer is washed with water, dried and concentrated. As a result, the product of formula (6j) is obtained. Compound 6j is dissolved in about 10 mL of dichloromethane. 30 ml of water and 5 mg of bis (triphenylphosphine) palladium chloride. About 150 microliters of tributyltin hydride are added to the resulting mixture while maintaining the temperature at about 21 'C (70' F). After rapid agitation for about 5 minutes, the deprotected compound is filtered off. The filtered material was dissolved in a mixture of water and methanol, the solution was filtered and the filtered material was washed with water. The filtrate was concentrated to give the final product (1.97) which was then purified by trituration (trituration under solvent).

EXAMPLE 7

An antimicrobial composition for parenteral administration according to the invention is prepared having the following composition:

component Quantity [5 /? - (5a, 6a)] - 3 - [[7- (3-amino-l-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -l, 4-dihydro- 4-oxo-3- (1,8-naphthyridinyl) carbonyloxy] methyl] -6- [1 (R) -hydroxyethyl] -7-oxo-4-thia-laza-bicyclo [3.2.0] ] hept-2-ene-2-carboxylic acid ^l 100 mg / ml vehicle Carrier: Sodium citrate buffer containing (in percentage by weight of carrier): lecithin 0.48% (Carboxymethyl) -cellulose 0.53% povidone 0.50% methyl paraben 0.11% propyl paraben 0.011%

one ]. Example quinolone lactam ester

The above ingredients are mixed to form a suspension. Approximately 2.0 milliliters of the suspension is systemically administered intramuscularly to a human patient suffering from a lower respiratory tract infection caused by Streptococcus pnenmoniae. This dose is repeated twice daily for approximately 14 days. After four days, the symptoms of the disease have subsided, indicating that the pathogen is now virtually extinct.

EXAMPLE 8

An enteric coated antimicrobial composition for oral administration according to the present invention is prepared having the following tablet core composition:

component Quantity (Mg) [5R - (5a, 6a)] - 3 - [[7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro- 4-OX0-3-11,8-naphthyridinyl) carbonyloxy] methyl] -6- [1 (R) -hydroxyethyl] -7-oxo-4-thia-1-azabicyclo [3.2.0 ] hept-2-ene-2-carboxylic acid ¹ 350.0 starch 30.0 magnesium stearate 5.0 microcrystalline cellulose 100.0 colloidal silica 2.5 povidone 12.5

1: a quinolonyl lactam ester of Example 1

HU 211 676 A9

The components are mixed to form a blend. Compressed tablets are formed using tabletting techniques known in the art. The tablet is then coated with a suspension of a methacrylic acid / methacrylic acid ester polymer in a mixture of isopropanol / acetone. A human patient suffering from a urinary tract infection caused by Escherichia coli is orally given two tablets every eight hours for 14 days. The symptoms of the disease are then alleviated, indicating that the pathogen is essentially extinct.

Claims (29)

PATENT CLAIMS C 1-8 alkyl; C2-C8 alkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when R ²⁰ is-N ^{(Rl2) (R21)} radical, R ²¹ and R ¹² together form a C 1-8 alkyl; (C) s is 0, 1 or 2; (D) (1) A ¹ is N or -C (R ⁴⁰ ) =; wherein R ⁴⁰ is hydrogen, hydroxy, alkoxy, nitro, cyano, halo, C 1 -C 8 alkyl, or -N (R ¹⁰ ) (R); and (2) A ² is N or -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen; (1) m is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; C 1-8 alkyl; (C) R ²⁸ is hydrogen or -COOH; (D) s is 0, 1 or 2; (E) R ³¹ is nothing; C 1-8 alkyl; (1) m is 0, 1, 2, 3, 4, 5, 6, 7, 8 or 9; A compound of formula (Ia) wherein (A) R ¹ is hydrogen; halogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; R ^{10a is} -O-; R ^10a CH = N-; (R ¹⁰ ) (R) N-; R ² -C (= CH-R ¹⁵ ) C (= O) NH-; R ¹² - (C (= NO-R ¹⁴ ) -C (= O) NH- or R ¹³ -CH ₂ ) _m C (= O) NH-; wherein the heteroalkyl group is carbon atoms and one or two. it has a heteroatom selected from oxygen, sulfur or nitrogen; and wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (2) when A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 may be taken} together to form -O- (CH ₂ ) _n -O- wherein n is 1, 2, 3 or 4; and (3) when A ³ is -C (R ^4I) = group of the formula, then R ⁸ and R may form a ^41, 3 to 9 atoms, a monocyclic or polycyclic C 7-17 heterocycle comprising N 'and the adjacent carbon to which R ^{41 is} attached; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; and pharmaceutically acceptable salts and biologically hydrolysable esters of the compound. and hydrates thereof. (2) A ² is -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen; (2) ^R10 and ^R11 are independently selected from R ^'°. wherein R ^10a is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; A 3-9-membered monocyclic or 7-17-atom polycyclic carbocycle or a 3-9-atom monocyclic or 7-17-atom polycyclic heterocycle; obsession R ^{10 and} R ^{11 taken} together are one. They form a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle which includes the nitrogen to which R ¹⁰ and R are attached; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (2) when A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 may be taken} together to form -O- (CH ₂ ) _n -O- wherein n is 1, 2, 3 or 4; and (3) when A ³ is -C (R ⁴ ) =, then R ⁸ and R ⁴ 'may form a ^3- to 9-membered monocyclic or 7 to 17-atom polycyclic heterocycle containing N' -. t and the adjacent carbon to which R ^{41 is} attached; and pharmaceutically acceptable salts and biologically hydrolysable esters thereof, as well as hydrates thereof. (2) R ¹⁰ and R ¹¹ are independently R ^10a wherein R ^10a is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; A 3-9-membered monocyclic or 7-17-atom polycyclic carbocycle or a 3-9-atom monocyclic or 7-17-atom polycyclic heterocycle; obsession R ^{10 and} R together form a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle which includes the nitrogen to which R ¹⁰ and R are attached; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; A compound of formula (Ib) wherein (A) R ¹ is hydrogen; halogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; R ^{10a is} -O-; R ^10a CH = N-; (R ¹⁰ ) (R) N-; R ¹² -C (= CH-R ¹⁵ ) C (= O) NH-; R ¹² - (C (= NO-R ^I4) -C (= O) NH- or R ^l3 - (CH 2) _m C (= C)) NH-; wherein the heteroalkyl group is carbon atoms and one or two. it has a heteroatom selected from oxygen, sulfur or nitrogen; and wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; C2-C8 alkenyl; 3-9 atoms monocyclic or 7-17 atoms polycyclic carbocycles; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (F) Y is O or Z ⁴ -R ³⁴ -O- wherein (1) Z ⁴ is O; -S (O) _t - wherein t is 0, 1 or 2; or -NR ^{, Oa} -; and (2) R ³⁴ is C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; (2) ^R10 and ^R11 are independently selected from R ^'Oa, where R ^10a is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; A 3-9-membered monocyclic or 7-17-atom polycyclic carbocycle or a 3-9-atom monocyclic or 7-17-atom polycyclic heterocycle; obsession R ¹⁰ and R together are one. They form a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle which includes the nitrogen to which R ¹⁰ and R are attached; wherein the heterocycles are one or more. they have a heteroatom selected from oxygen, sulfur or nitrogen; 3-9 atoms monocyclic or 7-17 atoms polycyclic carbocycles; (3) A ³ is -C (R ^4I) = radical; wherein R ⁴¹ is hydrogen; GB 211 676 A 9 (4) ^R8 is C1-8 alkyl or They form a 3-9 atom monocyclic or a 7-17 atom heterocycle; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; 3-9 atoms monocyclic or 7-17 atoms polycyclic heterocycles! ring; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heteroalkenyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; (c) R ²⁰ is R ¹² , -NH (R ¹² ), -N (R ¹² ) (R ²¹ ); wherein R ²¹ is (3) R ¹² is C 1 -C 8 alkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; A compound according to claim 2, wherein R ¹³ is C 1 -C 8 alkyl or C 2 -C 8 alkenyl. (3) A ³ is N or -C (R ⁴¹ ) =; wherein R ⁴¹ is hydrogen; (3) R ¹² is hydrogen; (C 1 -C 8) alkyl; (C 2 -C 8) alkenyl; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein the heteroalkenyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (3) ^A3 is N or C (R ^4I) = group of the formula; wherein R ⁴¹ is hydrogen; 3-9 atoms monocyclic or 7-17 atoms polycyclic carbocyclic; or a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (G) (1) A ¹ is N or -C (R ⁴⁰ ) =; wherein R ⁴⁰ is hydrogen, hydroxy, alkoxy, nitro, cyano, halo, C 1 -C 8 alkyl, or N (R ¹⁰ ) (R); and (2) A ² is nitrogen or -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when R ²⁰ is N (R ⁱ²⁾ a group of formula (R ^21), then £ r2i _and r 2 together form a C 3-9 monocyclic heterocycle or 7-17 atoms; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; and (8) R ¹⁶ is R ²⁴ or hydrogen; wherein R ²⁴ is C 1-8 alkyl; C2-C8 alkenyl; Akil aryl group; 38-membered heteroalkyl; C3-C8 heteroalkenyl; heteroaryl-alkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when Z ¹ is -N (R ^{I9) R16} group of formula and R ¹⁶ is R ^24, R ¹⁶ and R ¹⁹ together form a 3-9 C 7-17 monocyclic or polycyclic heterocyclic ring atoms, which includes the nitrogen atom to which R ^{19 is} attached; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; wherein arylalkyl is C 1 -C 8 alkyl substituted with one or two heteroatoms substituted with oxygen, sulfur and nitrogen; wherein the heteroalkyl group is carbon atoms and one or two. it has a heteroatom selected from oxygen, sulfur or nitrogen; wherein the heteroalkenyl group is carbon atoms and one or two. it has a heteroatom selected from oxygen, sulfur or nitrogen; and wherein heteroarylalkyl is C 1 -C 8 alkyl substituted with one or two heteroatoms substituted with one or two heteroatoms selected from oxygen, sulfur and nitrogen; (B) R ² is hydrogen, halo, alkoxy, or R ^{22 is} C (= O) NH - wherein R ²² is hydrogen or (3) R ¹² is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein the heteroalkenyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (4) R ¹³ is R ¹² , -Z ^1, or -CH (Z ² ) (R ¹² ); 4-fluorophenyl, 2,4-difluorophenyl, methylamino or cyclopropyl. A compound according to claim 2, wherein R ² is hydrogen or alkoxy. (4) R ⁸ is hydrogen; C 1-8 alkyl; 3-9 atoms monocyclic or 717 atoms polycyclic carbocycles; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; alkoxy; OH; C2-C8 alkenyl; aryl-alkyl; or -N (R ¹⁰ ) (R '); wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the arylalkyl group is a C 1 -C 8 alkyl group substituted with one or two heteroatoms substituted with oxygen, sulfur and nitrogen; (4) R ¹³ is R ¹² , -Z ^1, or -CH (Z ² ) (R ¹² ); (4) R ⁸ is hydrogen; C 1-8 alkyl; 3-9 atoms monocyclic or 717 atoms polycyclic carbocycles; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; alkoxy; OH; C2-C8 alkenyl; aryl-alkyl; or -N (R ¹⁰ ) (R ¹¹ ); wherein the arylalkyl group is a C 1 -C 8 alkyl group substituted with one or two heteroatoms substituted with oxygen, sulfur and nitrogen; and wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (4) R ¹³ is R ¹² , -Z ^1, or -CH (Z ² ) (R ¹² ); (5) R ⁷ is C 3-9 monocyclic or polycyclic heterocycle Ί17 atoms; and (7) R ⁹ is hydrogen; (D) except that (1) when A ¹ is -C ¹ R ⁴⁰ ) 4, R ⁸ and R ^{41 taken} together are a 3- to 9-membered monocyclic group containing N 'and A'; 7 to 17 atoms may form a polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (5) ^R14 is ^R12 or C (R ^{I7), (I8} R) COOH; A compound according to claim 2, wherein A 'is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴¹ ) = general. a group of the formula; or ^A1 is nitrogen, ^A2 is C ^(R6) = a group of formula and A ³ is C (R ^4I) = group of the formula. (5) R ⁷ is hydrogen; halogen; C 1-8 alkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; or a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; and (7) R ⁹ is hydrogen, halogen, nitro or -N (R ¹⁰ ) (R); (E) except that (1) when A ¹ is -C (R ⁴⁰ ) =, then R ⁸ and R ^{40 taken} together form a 3- to 9-atom containing N 'and A' they may form a monocyclic or 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (5) R ¹⁴ is R ¹² , arylalkyl, heteroarylalkyl, -C (R ¹⁷ ) (R ¹⁸ ) COOH, -C (= O) OR ¹² or -C (= O) NH-R ^{12 in} general wherein R ¹⁷ and R ¹⁸ are each independently R ¹² or taken together to form a 3-9-membered monocyclic or 7-17-atom polycyclic carbocycle or a 3-9-atom monocyclic or 7-17-atom polycyclic heterocycle the carbon atom to which R * ⁷ and R ^{18 are} attached; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; wherein the arylalkyl group is a C 1 -C 8 alkyl group substituted with one or two heteroatoms substituted with oxygen, sulfur and nitrogen; and wherein heteroarylalkyl is C 1 -C 8 alkyl substituted with one or two heteroatoms substituted with one or two heteroatoms selected from oxygen, sulfur and nitrogen; (5) R ⁷ is hydrogen; halogen; C 1-8 alkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; or a 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (5) R ¹⁴ is R ¹² , arylalkyl, heteroarylalkyl, -C (R ¹⁷ ) (R ¹⁸ ) COOH, -C (= O) OR ¹² or -C (= O) NH-R ^{12 in} general wherein R ¹⁷ and R ¹⁸ are each independently R ¹² or taken together to form a 3-9-membered monocyclic or 7-17-atom polycyclic carbocycle or a 3-9-atom monocyclic or 7-17-atom polycyclic heterocycle the carbon atom to which R ¹⁷ and R ^{18 are} attached; wherein the arylalkyl group is a C 1 -C 8 alkyl group substituted with one or two heteroatoms substituted with oxygen, sulfur and nitrogen; wherein heteroarylalkyl is C 1 -C 8 alkyl substituted with one or two heteroatoms substituted with one or two heteroatoms selected from oxygen, sulfur and nitrogen; and wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (6) R ¹⁵ is R ¹⁴ or halogen; It contains a moiety of 6-fluoroquinolone, 8-halo-6-fluoroquinolone, pyridobenzoxazine, pyridobenzthiazine, isothiazolokinolindione or isoxazolokinolindione. A compound according to claim 2, wherein A ¹ is -Cf R ⁴⁰ ), A ^{2 is} present GB 211 676 A 9 of -C ^(R6) = a group of formula and A ³ is -C ^(R41) = group of the formula. (6) R ¹⁵ is R ¹⁴ , halogen, -X ^1, or CH (Z ² ) (R ¹² ); (6) R ¹⁵ is R ¹⁴ , halogen, -Z ^1, or -CH (Z ² ) (R ¹² ); (7) Z ¹ is -C (= O) OR ¹⁶ , -C (= O) R ¹⁶ , -N (R ¹⁹ ) R ¹⁶ , -S (O) _p R ²⁴ or -OR ²⁴ ; and Z ² is Z ¹ or -OH, -SH or -SO ₃ H; (a) p is 0; (b) R ¹⁹ is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; 38-membered heteroalkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; -SO ₃ H; -C (= O) R ²⁰ ; or when R ¹³ is -CH (Z ² ) (R ¹² ) and Z ² is -N (R ¹⁹ ) R ¹⁶ , then R ¹⁹ and R ¹⁶ together are A compound according to claim 6 which is a (7) ^Z1 is -C (= O) OR ^16, -C (= O) R ^16, N (R ^{I9) R16,} -S (O) _p R ²⁴ or -OR ²⁴ radical; and Z ² is Z ¹ or -OH, -SH or -SO ₃ H; (a) p is 0, 1 or 2; (b) R ¹⁹ is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; 38-membered heteroalkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; -SO ₃ H; -C (= O) R ²⁰ ; or when R ¹³ is -CH (Z ²⁾ group ^(R12) of formula, and Z ² is -N (R ^I9) R ¹⁶ radical, R ¹⁹ and R ¹⁶ together form a C 3-9 monocyclic or 7- 17 atoms form a polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heteroalkenyl group is carbon atoms and one or two is oxygen. has a heteroatom selected from sulfur or nitrogen; A9 (c) R ²⁰ is selected from the group consisting of R ¹² , -NH (R ¹² ), -N (R ¹² ) (R ²¹ ), O (R ²¹ ) or -S (R ²¹ ); wherein R ²¹ is C 1 -C 8 alkyl; C2-C8 alkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when R ²⁰ is -N (R ¹² ) (R ²¹ ), R ²¹ and R ^{12 taken} together form a 3- to 9-membered monocyclic or 7 to 17-atom heterocycle; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; and (8) R ¹⁶ is R ²⁴ or hydrogen; wherein R ²⁴ is C 1 -C 8 alkyl; C2-C8 alkenyl; Akil aryl group; 38-membered heteroalkyl; C3-C8 heteroalkenyl; heteroaryl-alkyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when Z ¹ is -N (R ¹⁹ ) R ¹⁶ and R ¹⁶ is R ²⁴ , then R ¹⁶ and R ^{19 taken} together may form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle the nitrogen atom to which R ^{19 is} attached; wherein the arylalkyl group is a C 1-8 alkyl group substituted with an aryl group; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; wherein heteroarylalkyl is C 1 -C 8 alkyl substituted with one or two heteroatoms substituted with one or two heteroatoms selected from oxygen, sulfur and nitrogen; wherein the heteroalkenyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (B) R ² is hydrogen, halo, alkoxy, or R ^{22 is} C (= O) NH - wherein R ²² is hydrogen or (7) R ⁹ is hydrogen, halogen, nitro or -N (R ¹⁰ ) (R ¹¹ ); (H) except that (1) when A ¹ is a group of formula -QR ⁴⁰ ^, then R ⁸ and R ^{40 taken} together are a 3- to 9-membered monocyclic group containing N 'and A'; -17 atoms may form a polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; A9 (2) When A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 may be taken} together to form -O- (CH 2) _n -O- wherein n is 1. , 2, 3 or 4; and (3) when A ³ is -C (R ⁴¹ ) =, then R ⁸ and R ^{41 may form} a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle containing N 'and the adjacent carbon to which R ^{41 is} attached; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; and pharmaceutically acceptable salts and biologically hydrolysable esters thereof, as well as hydrates thereof. (7) ^Z1 is -C (= O) OR ^16, -C (= O) R ^16, -N (R ^{I9) R16,} -S (O) _p R ²⁴ or -OR ²⁴ radical; and Z ² is Z ¹ or -OH, -SH or -SO, H; (a) p is 0, 1 or 2; (b) R ¹⁹ is hydrogen; C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; 38-membered heteroalkenyl; A 3-9-atom monocyclic or a 7-17-atom polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; -SO ₃ H; -C (= O) R ²⁰ ; or when R ¹³ is -CH (Z ²⁾ group ^(R12) of formula, and Z ² is -N (R ^{I9) R16} group of formula. then R ¹⁹ and R ¹⁶ together form a 3-9 atom monocyclic or 7-17 atom polycyclic heterocycle; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; wherein the heteroalkyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; and wherein the heteroalkenyl group has carbon atoms and one or two heteroatoms selected from oxygen, sulfur or nitrogen; (c) ^R20 is ^R12, -NH ^(R12), N ^{(Rl2) (R21);} HU 211 676 A9 -O (R ²¹ ) or -S (R ²¹ ); wherein R ²¹ is C 1 -C 8 alkyl; C2-C8 alkenyl; (8) R ¹⁶ is hydrogen; C 1-8 alkyl; 3-9 atoms monocyclic or 717 atoms polycyclic carbocycles; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (B) R ² is hydrogen or alkoxy; (C) (1) A ¹ is N or -C (R ⁴⁰ ) =; wherein R ⁴⁰ is hydrogen or halogen; A compound according to claim 6 wherein R ⁸ is C 1-8 alkyl, aryl, cycloalkyl or alkylamino. A compound according to claim 8 wherein R ⁸ is ethyl, 2-fluoroethyl, 2-hydroxyethyl, tert-butyl, A compound according to claim 8, wherein R ⁴⁰ is hydrogen or halogen. A compound according to claim 10, wherein R ⁴⁰ is chlorine or fluorine. A compound according to claim 10, wherein R ⁷ is a nitrogen-containing, 3 to 9-atom monocyclic or 7 to 17-atom polycyclic heterocycle. A compound according to claim 12, wherein R ⁷ is piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N-dimethylaminomethylpyrrolidine, A-methylamino -methylpyrrolidine. N-ethylamino-methylpyrrolidine. pyridine, N-methylpiperazine or 3,5-dimethylpiperazine. A compound according to claim 13, wherein R ⁸ is cyclopropyl and R ² is fluoro. A compound according to claim 14, wherein R ⁷ is piperazine. A compound of formula Ic wherein (A) R ¹ is C 1 -C 8 alkyl; C2-C8 alkenyl; ^{I 2} R - (C (= ^NO-R14) -C (= O) NH-, or R ^l3 -íCH _{2) m} C (= O) NH-; wherein (1) m is 0, 1, 2 or 3; A composition for treating or preventing an infectious disease in a human or other animal subject comprising (1) a safe and effective amount of a compound according to claim 1; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject, comprising (1) a safe and effective amount of a compound according to claim 2; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject, comprising (1) a safe and effective amount of a compound according to claim 6; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject, comprising (1) a safe and effective amount of a compound according to claim 13; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject, comprising (1) a safe and effective amount of a compound according to claim 15; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject, comprising (1) a safe and effective amount of a compound according to claim 16; and (2) a pharmaceutically acceptable carrier. A composition for treating or preventing an infectious disease in a human or other animal subject according to claim 17, which composition is suitable for parenteral administration. A composition for treating or preventing an infectious disease in a human or other animal subject according to claim 17, which composition is suitable for oral administration. 25. A method of preventing or treating an infectious disease in a human or animal subject comprising administering to the subject a safe and effective amount of a compound according to claim 1. 26. A method of preventing or treating an infectious disease in a human or animal subject comprising administering to the subject a safe and effective amount of a compound according to claim 2. 27. A method of preventing or treating an infectious disease in a human or animal subject comprising administering to the subject a safe and effective amount of a compound according to claim 12. 28. A method of preventing or treating an infectious disease in a human or animal subject comprising administering to the subject a safe and effective amount of a compound according to claim 15. 29. A method of preventing or treating an infectious disease in a human or animal subject comprising administering to the subject a safe and effective amount of a compound according to claim 16.