HU211973A9 - Antimicrobial quinolonyl 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, that is, 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, polyethers, 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 Antibiotic Action, 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 differences between classes of antimicrobial agents (and within the same class) in their effectiveness against different types of microorganisms and their tendency to develop microbial 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) in 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 concern 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 particular 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 it 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 antibacterial 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., 10 Antimicrobial Agents and Chemotherapy, 245 (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 211 973 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, halo, alkyl, alkenyl, heteroalkyl, a carbocyclic ring, a heterocyclic ring, R ^10a -O-, R ^10a CH = N-, (R '°) (R ^1I) N-, ^R12 -C (= ^CH-R15) -C (= O) NH-, R ¹² (C (= NO-R ^I4) -C (= O) NH- or ^{R 3} - (CH _{2) m} C (= O) NH-, where (1) m is 0 , 1, 2, 3,4, 5, 6, 7, 8 or 9;

(2) R ¹⁰ and R ¹¹ are each independently R ^10a , wherein R ^10a is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituent; obsession

R ¹⁰ and R "together form a heterocyclic ring that includes the nitrogen atom to which R ¹⁰ and R ¹¹ is bound;

(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 ^2, arylalkyl, heteroarylalkyl, -C (R ^I7) (R ¹⁸⁾ COOH, -C (= O) ^OR12 or -C (= O) NH-R ¹² 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;

(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 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, 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 ^{(R? 2) (R21);}

-O (R ²¹ ) or -S (R ²¹ ) where R ²¹ is alkyl, alkenyl, carbocyclic ring, heterocyclic ring or when R ²⁰ is -N (R ² ) (R ²¹ ) then R ²¹ may be a group which when bonded to R ¹² forms 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;

(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" denotes 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 -; 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 (1) Z ³ is -R ¹⁶ ; -OR ^25; -SfO / 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; or R25 _{and R2O} £ j _e i _en Designation together form a heterocyclic ring that includes the nitrogen atom to which R ²⁵ and R ²⁶ is bound; 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);

(E) (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 a R ³² group, when R ²⁸ is hydrogen or - The COOH group, C *, when attached to R ³² , 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, -PO (OR ²⁹ ) OH, -C (O) NHSO 2 N (R ²⁹ ) (R ³⁰ ) - OSO is ₃ H, -CH (R ³⁰ ) COOH, or -OCH (R ²⁹ ) COOH; wherein R ²⁹ is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring; and R ³⁰ is hydrogen, alkyl, alkenyl

A9 or -NHR ^10a ; or when R ⁴ is

-C (O) NHSO ₂ N (R ²⁹ ) (R ³⁰ ) then 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) when 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 ) ^-R3I- 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 ³ '-Y, -X'-C ^(1Oa R) ( R ³³ ) -C '' - R ³¹ -Y- or X ² -C '' - R ^3] -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 ⁴ is -C * (R ²⁸ ) then 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; 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 ¹¹ '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 ⁴¹ ) =; wherein R ⁴¹ is hydrogen;

H (4) R ⁸ is H, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or -N (R ^IO) a group of formula (R ');

(5) R ⁷ is hydrogen, halogen, alkyl, carbocyclic ring or heterocyclic ring; and (7) R ⁹ is hydrogen, halogen, nitro, or -N (R ⁰ ) (R ');

(H) except that (I) 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 taken} together may form a group -O (CH ₂ ) "- O- wherein n is 1, 2, 3 or 4;

(3) when A ³ is -C (R ⁴ ') =, then R ⁸ and R ⁴ ' may form a heterocyclic ring which includes N 'and the adjacent carbon atom to which R ^{41 is} bonded. .

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 invention have, among other things, significant advantages over compounds known in the art in terms of antimicrobial activity, 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 otherwise referred to herein as quinolonyl lactam esters, include any variation of the actam-containing groups that bind to the 3-carboxy group of a quinolone moiety through an ester linkage. These compounds include compounds of formula (I), pharmaceutically acceptable salts and biologically hydrolysable esters thereof, and hydrates of compounds wherein (A) R 'is hydrogen, halo, alkyl, alkenyl; , heteroalkyl, carbocyclic ring, heterocyclic ring, R ' ^0a- O-, R ^10a CH = N (R' °) (R ') N -, R' ² -C (= CH-R ¹⁵ ) -C (= O) NH-, or (preferably) ^R12 (C (= NO-R ^I4) -C (= O) NH- or R ³ - (CH _{2) m} 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 '° and R "are independently R ^10a, wherein R ^IOA is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocik4

A9 Lus ring ring substituent; or R ¹⁰ and R together form a heterocyclic ring containing the nitrogen to which R ¹⁰ and R are attached;

(3) R ¹² is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring or heterocyclic ring (preferably alkyl, 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 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 ² or -C (R ^'7) (R ¹⁸⁾ group of the formula 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 of the formula; 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 ) (R ¹² ) and Z ² is -N (R ¹⁹ ) R ¹⁶ , then R ¹⁹ may be a moiety that is linked to R ⁶ . bonded to form a heterocyclic ring; and (c) ^R20 is ^R12, -NH ^(R12), N ^{(Rl2) (R21),} -O ^(R21) -S (R ²¹⁾ group of the formula [R ¹² is preferably, -NH ^(R12), N (R ¹²⁾ (R ²¹⁾ group of the formula] ^R21 is alkyl, alkenyl, carbocyclic ring, heterocyclic ring or (preferably) when ^R20 is-N ^(Rl2) ( R @ ²¹⁾ group of the formula, R ²¹ is a group of an ^I2 -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 ¹⁹ ) R ¹⁶ and R ¹⁶ is R ²⁴ then R ¹⁶ and R ^{19 taken} together may form a heterocyclic ring containing the nitrogen atom to which R ^{19 is} attached ( preferably hydrogen, alkyl, carbocyclic or heterocyclic);

(B) R ² is hydrogen, halogen, alkoxy, or R ^{22 is} C (= O) NH -, 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 is bonded directly to the N 'of formula (I). except that when bond "a" is absent, R ³ is a group of formula (1) -C (R ^{, Oa} ) (Z ³ ) wherein (i) Z ³ is - R ¹⁶ ; -OR ^25: -S 10 -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; or R ²⁵ and R ²⁶ taken 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 bonded directly to the Forms a five membered ring for N 'of formula II;

(Ε) (1) when bond "b" is a single bond, then R ⁴ is (preferably) -CH (R ²⁸ ) -; or when bond "a" is absent, -C (O) NHSO ₂ -; or -C (R ²⁸ ) -, wherein 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,

-PO (OR ²⁹ ) OH, -C (O) NHSO 2 N (R ²⁹ ) (R ³⁰ ), -OSO 3 H, -CH (R ³⁰ ) 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 a group of formula -NHR ^IOA; 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 are} attached. ; and

GB 211 973 A 9 (F) (1) where "a" is a bond or bond "b" is not present, then R ⁵ is Y;

(2) when 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 ^3, -Y- or (preferably) -X'-C (R ^10a ) (R ³³ ) -C "'- R ³¹ -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 (preferably 0); or C (R ³³ );

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

(d) R ³² is hydrogen, alkyl, alkenyl, -COOH; or when R ⁴ is -C '(R ²⁸ ) then 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 alkenyl); 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 (R ¹⁰ ) (R ') (preferably hydrogen or halo); and (2) A ² is nitrogen or (preferably) C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen;

(3) ^A3 is N or preferably C (R ^4I) = radical; wherein R ⁴ '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, halogen, nitro, or -N (R ¹⁰ ) (R ');

(H) except that (I) 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 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 ^4I) = group of the formula then form a ^R8 and ^R41 is a heterocyclic ring that includes N '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" refers to an optionally substituted radical having from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms. Preferred alkyl groups include, but are not limited to, 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 systems. 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 contain from 3 to 9 carbon atoms, preferably 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" is an aromatic hydrocarbon 6

HU 211 973 A9 is a group of gene rings. Preferred aryl groups include, but are not limited to, phenyl, tolyl, xylyl, coumolyl 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 RC (= 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", "diaogen" 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 cationic salt formed at an acidic (e.g. carboxyl) group or an anionic salt formed at a basic (e.g. amino) group. A large number of such salts are known in the art, as disclosed, for example, in International Patent Application Publication No. 87/05297 (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 hydrolysable 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 organism 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. 87/05297 (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 pivaloyloxyethyl). esters), lactonyl esters (e.g., phthalidyl esters and thiophthalidyl esters), lower alkoxy acyloxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, and isopropoxycarbonyloxy) 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 A., 1979, 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, alkoxy acyl (e.g. ethoxycarbonyl, 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, the substituent R ^10a is defined as a potential substituent on the group R ¹ , but is also included in the definition of other groups (such as R ³ , R ^8, and R ⁹ ). In the context of the present application, such a group is selected individually for each use (e.g., when defining a particular compound of the invention, the R ^10a group need not necessarily be an alkyl group at all occurrences).

Molecular fractions containing lactam

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. Those parts of the molar that

A9 in which bond "a" or "b" is absent (i.e., does not exist) are monocyclic; if both bonds exist, the structures are bicyclic.

Preferred lactam-containing compounds include oxacephems of formula IA and carbacephems, i.e. 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 ^, -C (R ^{, Oa} ) (R ³³ ) -C '' R ^3, -Y-, wherein R ^10a and R ³³ are hydrogen, R ³¹ is methylene, and X ¹ is (for oxacephem) is oxygen or (for carbacephem) C (R ³³ ).

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

Also preferred lactam-containing compounds include penem, carbapenems and clavems of formula (IC), that is, compounds of formula (I) wherein bond "a" represents a single bond; Bond "b" represents a double bond; R ³ is -C ^{(R, Oa)} - group, wherein R is hydrogen ^IOA; 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 (in the case of penem) sulfur, (in the case of carbapenems ) C (R ³³ ) or oxygen (in the case of clavems). Lactam derivatives of this type are disclosed in the following literature; R. Wise, J. Vitro and Pharmacokinetic Properties of Carbapenems, 30, Antimicrobial Agents and Chemotherapy, 343 (1986); and S. McCombie et al., "Synthesis and In Vitro Activation of the 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, Oa)} - group, wherein R is hydrogen ^IOA; R ⁴ is -CH (R ²⁸ ) - wherein R ²⁸ is -COOH; and R ⁵ is -X ² -C '' (R ³² ) R ³¹ -Y-, wherein R ³² is methyl, R ³¹ is methylene, and X ² is sulfur.

Likewise, preferred lactam-containing compounds include monocyclic beta-lactams of formula (IE), i.e., compounds of formula (I) wherein bond "a" represents a single bond; Bond "b" is not present; R ³ is a group of the general formula -C (R ^10a ) wherein R ^10a is hydrogen; R ⁵ is Y; R ⁴ is (for monobactam) -SO, H, (for monophospham) -PO (OR ³⁴ ) OH, (for monocarbamate) C (O) NHSO 2 N (R ³⁴ ), (for monosulfactam) -OSO 3 H, (for nocardicins) -CH (R ³⁵ ) COOH or -OCHIR 1-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 represents

-C (R ^10a ) (R ²⁹ ) - wherein R ^10a and R ²⁹ are each hydrogen; and R ⁵ is Y.

Likewise, 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 R ⁵ is -X ² -C '' = C- (R ^{1 (a)} -R ³¹¹ -Y-, wherein R ^10a is hydrogen, R ³¹ is methylene, and X ² is oxygen.

Also preferred lactam-containing compounds include 2,3-methylenepenams and capapenams of formula (IH), i.e. compounds of formula (I) wherein bond "a" represents a single bond, bond "b" represents a single bond; R ³ is -C (R> °) _ group, wherein R is hydrogen ^IOA; R ⁴ is -C (R ²⁸ ) wherein R ²⁸ is -COOH; and R ⁵ is -X ² -C '' (R ³² ) -R ³¹ -Y-, wherein R ³¹ is absent, R ^32, when attached to C *, forms 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.

Similarly, 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 represents

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-CH ₂ -R ²⁸ - wherein R ²⁸ is nitrogen: 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 ³ H, -POfOR 4, OH, -C (O) NHSO 2 N (R ³⁴ ) (R ³⁵ ), -OSO 3 H, -CH (R ³⁵ ) COOH, or -OCH (R ³⁴ ) COOH. a group of the formula; 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 the compound in the position of the active stereoisomer 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 quinolonyl substituent that exhibits antimicrobial activity.) This "active" position, for example, is the beta position for cephems, oxacephem, and carbacephem (i.e., 7- 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 the 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 16, 1986); and International Patent Application Publication No. 87/05297 (PCT) (Johnston et al., published September 11, 1987).

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

With the exception of penems, carbapenems, clavems and clavams, the R ¹ groups are preferably amides, for example acetylamino substituted with aryl, heteroaryl, aryloxy, heteroarylthio and lower alkylthio groups. -group; preferably an arylglycylamino group substituted with heteroarylcarbonyl and cycloheteroalkylcarbonyl; arylcarbonyl-amino; heteroaryl-carbonyl-amino; and preferably lower alkoxyiminoacetylamino substituted with aryl or heteroaryl. Particularly preferred R ¹ groups include those R ^l3 - (CH2) _m C (= O) NH-, amides, wherein R ¹³ is R ^12th Such preferred R * groups include, but are not limited to, [(2-amino-5-halo-4-thiazolyl) acetyl] amino; [(4-amino-2-pyridinyl) acetyl] amino; [[2- (aminomethyl) phenyl] acetyl] amino;

[(17 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 'is R ¹³ - (CH ₂ ) _m C (C = O) NH- and R ¹³ is -Z ¹ , preferred R ¹ groups include, for example: [( sulfamoyl-phenyl) -acetyl-amino;

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

[[(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 include - 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;

(? /) - [(amino-phenyl) -acetyl] amino;

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

(R) - [amino- (1,4-cyclohexadien-1-yl) acetyl] amino;

A9 [(hydroxyphenyl) acetyl] amino;

(R) - [[[[(4-ethyl-2,3-dioxo-l-piperazinyl) -karboni1] amino] - (4-hydroxyphenyl)] - acetyl] amino;

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

(R) - [[[[(4-Hydroxy-6-methyl-3-pyridyl) carbonyl] amino] (4-hydroxyphenyl)] acetyl] amino;

(? /) - [(phenyl-sulfonyl) acetyl] amino;

(2 / ?, 3S) - [2 - [(4-ethyl-2,3-dioxo-l-piperazinyl) carbonyl] amino] -3-hydroxy-l-oxobutyl] amino;

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

(? /) - [[amino-3 - [(ethylsulfonyl) amino] phenyl] -acetyl] amino;

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

(? 7) - [amino- (2-naphthyl) acetyl] amino;

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

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

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

This type of preferred R ^J groups also includes (ba), (bb), (on), (bd), (on), (bf), (bg), (bh), (bi), (bj) , (bk), (b1), (bm), (bn), (bo), (bp), (bq), (br) and (bs).

Another preferred substituent for R ¹ is R ¹² C (= CHR ^{, 5} ) -C (= O) NH-. This group includes, for example, the formulas (ca) and (eb).

In case of lactam-containing moieties other than penemektől, karbapenemektől, klavémektől klavámoktól and the preferred ^R1 substituents include R ^{I 2} C (= ^{NO-R 4)} C (= O) NH-. Examples of preferred classes of R ¹ include, but are not limited to, the following:

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) - [(1-carboxymethoxy) imino] acetyl] amino;

[(2-amino-4-thiazolyl) - [(1H-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-dihydroxy-phenyl)) - penta-imino] 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 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 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 form various quinolones, naphthyridines or related heterocyclic groups known in the art which possess 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); PB Fernandes et al., In 22 Ann. Rep. Med. Chem. 117 (DM Baily, editor, 1987); R. Albrecht, 21 Prog. Drug Research 9 (1977); and PB Fernandes et al., 23 Ann. Rep. Med. Chem. (RC Allen, 1987).

Preferred kinolonrészek include those compounds where A ¹ is -C ^(R40) = group of the formula, A ² is C (R ⁶⁾ = group of the formula and A ³ is C (R ^4I) = 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 ¹ is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴¹ ) = (i.e. quinolones); and where A ¹ is nitrogen, A ² jelentées -C ^(R6) = a group of formula and A ³ is C (R ^4I) = group of the formula (i.e., naphthyridines). Particularly preferred quinolone moieties are those wherein A ¹ is C (R ⁴⁰ ) =, A ² is

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-C (R ⁶ ) = and A ³ is -C (R ⁴¹ ) = (ie quinolones).

Preferably, R ⁸ is alkyl, aryl, cycloalkyl and alkylamino groups. More preferably, ^R8 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-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 4,599,334 (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 heptan, diazabicyclo [2.2.1) heptane, diazabicyclo [3.2.1 octane, thiazolidine, imidazolidine, pyrrole and thiomorpholine, and the following particularly preferred R ⁷ groups are: piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N, N-dimethylaminomethylpyrrolidine, N-methylaminomethylpyrrolidine, 'ethylaminomethylpyrrolidine, pyridine, N-methylpiperazine and 3,5-dimethylpiperazine.

Preferred quinolonyl 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 ^4I) = radical; and A ¹ 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-quinolecarboxylic acid;

7- (3-Amino-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;

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

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

ethyl 6-fluoro-1,4-dihydro-7- (4-methyl-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), (fi), (fm), (fn), (fo), (fp), (fq), (fr), (fs), (ft), (fii), (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 nitrogen; ^{2 is} -C (R ⁶ ) =; and A ³ is -C (R ⁴¹ ) =. Preferred examples of such quinolone moieties include, but are not limited to, the following;

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-naphthyridine-3-carboxylic acid.

Further examples of such preferred quinolone moieties include (ha), (hb), (he), (hd), (he), (hl), (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. compounds of formula I wherein A ¹ is -C (R ⁴⁰ ) -; A ² is -C (R ⁶ ) =; A ³ is -C (R ⁴¹ ) =; 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-2 H -pyrido [1,2,3-b] phenyl] -1. , 4-benzoxazine-6-carboxylic acid, and groups (ia), (ib), (ic), (id), (ie), (if), (ig), (ih) and (ii). group.

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-lactam 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.

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1) Ester-bonded penem quinolones, such as compounds of 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 group; ^R5 -SC "'- CH 2 -O group; 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 -S-C "'CH2-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 group; R ⁵ is -S-C "'CH2-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 group; 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).

2) Ester-bonded penem quinolones, such as compounds of 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 -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 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 -S-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 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) -; and the quinolone moiety has a structure wherein A ² is -CF-; A ³ is -CH; R ⁹ is hydrogen; A '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.

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

3) 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 group; R ⁵ is -CH (R ³³ ) -C '' - CH 2 -O-; and

A9 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 (CO 2) H group; 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 bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH; R ⁴ is -C (CO 2) H group; 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 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; 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).

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 group; R ⁵ is -CH (R ³³ ) -C '' - S-CH ₂ CH ₂ -General; 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 (CO 2) H group; R ⁵ is -CH (R ³³ ) -C 1 ^, -S-CH ₂ CH ₂ -General; 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 bond "a" represents a single bond; bond "b" represents a double bond, R ³ is -CH; R ⁴ is -C (CO 2) H group; R ⁵ is -CH (R ³³ ) -C '' - S-CH ₂ CH ₂ -General; 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; R2 is hydrogen; R3 is -CH-; R4 is -CH (R33) -C '' - S-CH2CH2-O-; R33 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.

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

5) Ester-bonded oxacephem quinolones, such as compounds of the following classes, wherein the lactam-containing moiety is an oxacephem in which 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 -OCH 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.

6) Ester-bonded isocephem quinolones, such as compounds of the following classes, wherein the lactam-containing moiety is an isocephem in which bond "a" represents a single bond; bond b is double

A 219 represents a bond; R ³ is -CH-; R ⁴ is -C (CO 2 H) -; R ⁵ is -CH 2 -S-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.

7) Ester-bonded isooxacephem quinolones, such as the compounds of the following classes, wherein the lactam-containing moiety is an isooxacephem wherein bond "a" represents a single bond; bond b represents a double bond; R ³ is -CH-; R ⁴ is -C (CO 2) H group; R ⁵ is -CH 2 -O-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.

8) Ester-bonded carbacephem quinolones, such as compounds of the following classes, wherein the lactam-containing moiety is a carbacephem 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 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.

9) Ester-bonded oxacephem quinolones, including compounds of the following classes,

(a) in which 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 directly attached to X; R ⁵ is absent; X is -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 monobactam in which bond "a" represents a single bond; bond "b" is absent; R ³ is -CH- and is directly attached 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, 7β)] - 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 of formula 1.1);

[6 / -? (6?, 7?)] - 7 - [[[[2- (aminocarbonyl) -2-fluoro-ethenyl] thio] acetyl] amino] -3 - [[[9-fluoro- 3,7-dihydro-3-methyl-10 (4-methyl-l-piperazinyl) -7-oxo-2 // - pyrido [2,3-df] -l, 4benzoxazine-6-yl] carbonyl oxy] methyl-8-oxo-5-thiala-azabicyclo [4.2.0] oct-2-enecarboxylic acid (compound of formula 1.2);

[67? - (6?, 7?)] - 7 - [[carboxy (4-hydroxyphenyl) acetyl] amino] -3 - [[[l-ethyl-6-fluoro-l, 4-dihydro- 7- (4-methyl-l-piperazinyl) -4-oxo-3-quinolinyl] carbonyloxy] methyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid (compound of formula 1.3);

[57? - (5a, 6a)] - 3 - [[[7- (3-amino-l-pyrrolidinyl) -8-chloro-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3- quinolinyl] -carbonyloxy] -methyl] -6 - [(R) -1-hydroxyethyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-en-2 carboxylic acid (compound of formula 1.4);

[5R- (5a, 6a)] - 3 - [[[l-ethyl-l, 4-dihydro-6-methyl-4-oxo-l, 8-naphthyridin-3-yl] carbonyloxy] methyl »- 6 - [(R) -1-Hydroxyethyl] -7-oxo-4-thia-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid (Compound 1.5);

[5 /? - (5a, 6a)] - 3 - [[[l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7- (l-piperazinyl) -3-quinolinyl] carbonyloxy] -methyl] 6- [(?) -1-hydroxy-ethyl] -7- oxo-4-thia-1-aza-bicyclo [3.2.0] oct-2-ene-2-carboxylic acid (Formula 1.6) compound]; Na (35) -2 - [[l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxo-7- (l-piperazinyl) -3-quinolinyl] carbonyloxy] -3 [[[[[ (R) -4-Ethyl-2,3-dioxo-1-piperazinyl] carbonyl] amino] - (4-hydroxyphenyl) acetyl] amino] -4-oxo-1-azetidine sulfonate [(1.7) compound of the formula];

sodium (3 S) -3 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2 - [[1-ethyl-6-fluoro-1,4-dihydro-4 -oxo-7 (1-piperazinyl) -1,8-naphthyridin-3-yl] carbonyloxy] -4-oxo-azetidinesulfonate (Compound 1.8); sodium (3S) -2 - [[5-ethyl-5,8-dihydro-8-oxo-l, 3-dioxolo [4,5-g] -7-quinolinyl] carbonyl] -4-oxo -3 - [(phenoxyacetyl) amino] azetidine sulfonate (Compound 1.9); [6 R - (6a, 7P)] - 3 - [[[7- (3-Amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4 -oxo-1,8-naphthyridin-3-yl] carbonyloxy] methyl] -7 - [[[5-hydroxy-4-oxo-1 (4 H) -2-pyridyl] carbonylamino] - ( 2-amino-4-thiazolyl) -acetylamino] -8-oxo-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (compound of formula 1.10);

[6R- (6a, 73)] - 3 - [[[7- (3-amino-l-pyrrolidinyl) -8-chloro-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinyl ] carbonyloxy] methyl] -7 - [[[[[(/ f) -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 of formula 1.11);

[67R - (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); [57? - (5a, 6a)] - 3 - [[[(7- [3-amino-methyl) -2-piiTolidinil] -1-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);

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

[5 / f- (5a, 6a)] - 3 - [[[8-ethyl-5,8-dihydro-5-oxo-2- (l-pipe14

HU 211,973 A9 Razinyl) pyrido [2,3-b] pyrimidinyl] carbonyloxy] methyl] 6 - [(R) -1-hydroxyethyl] -7-oxo-1-aza-bicyclo [3.2. .0] hept2-ene-2-carboxylic acid (compound of formula 1.15); [5 /? - (5a, 6a)] - 3 - [[[l-cyclopropyl-6-fluoro-4-carbonyloxy-dihydro-7- (l-piperazinyl) -4-oxo-3-quinolinyl] ] methyl] 6 - [(R) -1-hydroxyethyl] -7-oxo-1-azabicyclo [3.2.0] hept2-ene-2-carboxylic acid (compound of formula 1.16); [6R- (6a, 7 (i)] - 7 - [[carboxy (4-hydroxyphenyl) acetyl] amino] -3 - [[[l-cyclopropyl-6-fluoro-l, 4-dihydro 7- (l-piperazinyl) -4-oxo-3-quinolinyl] carbonyloxy] methyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2- carboxylic acid (compound of formula 1.17).

Other examples of preferred quinolonyl lactam esters include compounds of formula (1.18) to (1.55).

Production procedures

The quinolonyl lactam esters of the present invention can be prepared using various synthetic methods known in the art. The preparation of quinolonyl lactam esters generally includes 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 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 (H. Flynn, 1972), Chapters 2,3,4, 5,6,7,15 and Appendix 1; Recent Advances in Chemistry of 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 fi-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); 24An £ W. Chem. Int. Ed. Engl., 1985, 180-202; 40 J. Antibiotics, 182-189 (1987); European Patent Application 266,060; 42 J. Antibiotics, 993 (1989); U.S. Patent No. 4,742,053; 35 Chem. Pharm. Bull., 1903-1909 (1987); 32 J. Med. Chem., 601-604 (1989); U.S. Patent 4,791,106; Japanese Patent Publication No. 62/158,291; 31 J. Med. Chem., 1987-1993 (1988); 30: Med. Chem. 514-522 (1987); 28 Tetrahedron Letters, 285-288 (1987); 28 Tetrahedron Letters, 289-292 (1987); 52 /. Org. Chem., 1987, 4007-4013; 40 /. Antibiotics, 370-384 (1987); 40 /. Antibiotics, 1636-1639 (1987); 37 /. Antibiotics, 1984, 685-688; 23 Heterocycles, 2255-2270; 27 Heterocycles, 49-55; 33 Chem. Pharm. Bull., 4371-4381 (1985); 28 Tetrahedron Letters 5103-5106 (1987); 53 /. Org. Chem., 4154-4156 (1988); 38 /. Antibiotics, 1986, 1351-1355; 59 Pure and Appl. Chem. 467-174 (1987); 1987 /. C. S. Chem. Comm .; 44 Tetrahedron, 3231-3240 (1988); 28 Tetrahedron Letters, 2883-2886 (1987); 40 /. Antibiotics, 1563-1571 (1987); 33 Chem. Pharm. Bull., 4328-4394 (1985); 37 /. Antiphol., 57-62 (1984); U.S. Patent No. 4,631,150; 34 Chem. Pharm. Bull., 999-1014 (1986); 52 /. Org. Chem., 1987, 4401-4403; 39 Tetrahedron, 1983, 2505-2513; 38 /. Antibiotics, 1382-1400 (1985); European Patent Application 053 815; 40 /. Antibiotics, 1563-1571 (1987); 40 /. Antibiotics, 1716-1732 (1987); 47 /. 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, 9-104 (1977); 31 /. Chem. 503-506 (1988); 32 /. Med. Chem., 1313-1318 (1989); 1987 Liebigs Ann. Chem. 871-879 (1987); 14 Drug Exptl. Clin. Res., 379-383 (1988); 31 /. Chem. 1988, 983-991; 32 /. Chem., 1989, 537-542; 78 /. Pharm. Sci., 1989, 585-588; 26 /. Seven. Chem., 1989; 24 /. Seven. Chem., 181-185 (1987); U.S. Patent 4,599,334; 35 Chem. Pharm. Bull., 2281-2285 (1987); 29 /. Med. Chem., 2363-2369 (1986); 31 /. Med. Chem., 991-1001 (1988); 25 /. Seven. Chem., 479-4485 (1988); European Patent Application 266,576; European Patent Application 251,308; 36 Chem. Pharm. Bull., 1223-1228 (1988); European Patent Application 227,088; European Patent Application No. 227,039; European Patent Application 228,661; 31 /. Med. Chem., 1586-1590 (1988); 31 /. Med. Chem., 1598-1611 (1988); and 23 /. Med. Chem., 1358-1363 (1980).

The quinolonyl lactam esters of the invention may be prepared, for example, by the following reaction:

Lact-CH ₂ -X + M ⁺ -OC (= O) -Kin ->

-> Lact-CH ₂ -OC (= O) -Kin wherein X is a reactive leaving group (e.g., halogen, sulfonate ester or other activated hydroxy group), "Lact" is generally a suitably protected lactam-containing moiety (e.g., penem, carbapenem, oxacephem or carbacephem) and "Kin" means a suitably protected moiety of quinolone. 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, prevention of possible undesirable side reaction with group X15 is worthwhile

A9 may require blocking of certain functional groups (such as carboxyl, hydroxyl and amino groups) in the molecular structure of Laki and Kin. 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. If the lactam moiety is a monocyclic beta-lactam, the alternative reaction sequence of Scheme [A] may also be used; in Scheme [A], X represents a heteroatom substituent (oxygen, sulfur, halogen, etc.) that binds to actam 1.

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 in a human or inferior animal subject at the site of infection, at a reasonable benefit / risk ratio and without undesirable side effects. (for example, toxicity, irritation 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 further treatments, the particular dosage form to be used, the solubility of the carrier, the solubility of the quinolone lactam esters in the carrier, and the dosage regimen for the particular composition. standards.

The compositions of the invention are preferably formulated in dosage units. As used herein, the term "unit dosage form" refers to a composition of the invention containing an amount of a quinolonyl lactam ester which, in accordance with good medical practice, is suitable for administration in a single dose to a human or inferior animal. Preferably the compositions are about 30 mg to about 20 mg

They contain a quinolonyl lactam ester in an amount of from about 000 mg, more preferably from about 50 mg (milligram) to about 7000 mg, more preferably from about 500 mg to about 1500 mg.

The compositions of the 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 methods of treatment of the present invention are described, for example, in Modem Pharamceutics, 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 include, but are 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 suitable solvents, preservatives, emulsifiers.

Aqueous solutions of emulsifiers, suspending agents, diluents, sweeteners, bulking agents, coloring agents and flavoring agents, emulsions, suspensions and / or suspensions of non-effervescent granules and 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 general, the carrier is organic and suitable for dispersing and / or dissolving the quinolonyl lactam ester. Carriers may include pharmaceutically acceptable plasticizers, emulsifiers, thickeners, and solvents.

SUBMISSION 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., tooth, mouth, infections), upper respiratory tract infections, lower respiratory tract infections, urinary and genital infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin infections, bacterial endocarditis, immunosuppressive, anti-bacterial wounds antibacterial prophylaxis in patients (eg receiving or receiving chemotherapy for cancer or transplantation).

The quinolonyl lactam esters and compositions of the invention may be administered topically or systemically. Systemic applications include all procedures suitable for the administration of quinolonyl lactam ester to body tissues and include, but are not limited to, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, , rectal 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 minimum inhibitory concentration of the quinolonyl lactam ester at the site of infection, 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 adverse reactions to 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. administered in an amount ranging from. 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.

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.

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Example 1

The [5R - (5α, 6α)] - 3 - [7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) - (1.56) according to the invention - 1,4-dihydro-4-oxo-3- (1,8-naphthyridinyl) carbonyloxy] methyl] -6- [1 (R) -hydroxyethyl] -7-oxo-4-thia-1 The azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid is prepared according to the reaction scheme in Scheme [B].

Allyl [5R- (5a, 6a)] prepared according to the Battistini process (Battistini et al., U.S. Patent No. 4,631,150, published December 23, 1986). 3- (hydroxymethyl) -6- [1 (R) - [(tert-butyldimethylsilyl) oxy] ethyl] -7-oxo-4-thia-1-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). While stirring, under nitrogen, at about 22 ° C (72'F), about 0.32 mmol of diethyl azodicarboxylate, 0.32 mmol of 6-fluoro-1- (2,4-difluorophenyl) , 4-dihydro-4-oxo-7- [3- [3- (1-propenyl) oxycarbonyl] amino-1-pyrrolidinyl] -3- (1,8-naphthyridine) carbonate, and , 32 mmol 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 (1) (b) is obtained, which is further purified by flash chromatography.

About 0.15 g (0.18 mmol) of the product of formula (1) (b) is dissolved in 20 ml of tetrahydrofuran. Thereafter, 40 microliters of glacial acetic acid and 60 mg of tetrabutylammonium fluoride were added 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) was 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 aprecipitate is filtered. The solid final product (1.56) is made analytically pure by repeated trituration.

Following the general procedure of Example 1, the following quinolonyl lactam esters were prepared with substantially similar results.

The compound of formula (1.57) is prepared according to the method described by 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl in the Sanchez method (JP Sanchez et al., J. Med. Chem., 1988, 31, 983). 6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was prepared using quinolone.

The compound of formula (1.58) is prepared from 6-fluoro-1,4-dihydro-1- (methyl), prepared according to the method of Wentland (P. P. Wentland, et al., J. Med. Chem., 1984, 27, 1103). (amino) 7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid using quinolone.

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

6,8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-4 was prepared according to the method of Iridura (T. Iridura, et al., Australian Patent Application 537,813). oxo-7- (4-methyl-1-piperazinyl) -3-quinolinecarboxylic acid using quinolone.

The compound of formula (1.61) was prepared by the 9-fluoro-4,7-dihydro-3-methyl-10-yl compound prepared according to the procedure of Hagakawa (I. Hagakawa, et al., Chem. Pharm. Bull., 1984, 32,4907). (4-Methyl-1-piperazinyl) -7-oxo-2H-pyrido [1,2,3-de] -1,4-benzoxazine-6-carboxylic acid is prepared using quinolone.

7- (3-Amino-1-pyrrolidinyl) -8-chloro-1 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 quinolone and Christensen's method [B. Allyl [5R- (4P, 5a, 6a)] -6 - [(R) -1 - [(tert-butyldimethylsilyl) prepared according to European Patent Application 185 185 (G. Christensen et al., 1986). ) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-ol-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam.

The compound of formula (1.63) is prepared from 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7 prepared according to the Grohe process (K. Grohe et al., German Patent Application 3,142,854). - (1-Piperazinyl) -3-quinolinecarboxylic acid quinolone and Christensen's method [B. Allyl [5R- (4P, 5a, 6a)] -6 - [(R) -1 - [(tert-butyldimethylsilyl) prepared according to European Patent Application 185 185 (G. Christensen et al., 1986). ) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam.

Example 2

According to the general procedure described in Example 1, the following quinolonyl lactam ester was prepared:

The compound of formula (1.64) was prepared according to the method of Sanchez (J, P. 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 using quinolone.

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

The compound of formula (1.65) is prepared according to the method of Christensen (BG Christensen et al., European Patent Application 185,315 (1986)) - 6 - [(/ ?) - l - ^[(phi, tert-butyl-dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-l-azabicyclo [3.2.0] hept -2-ene-2-carboxylate was prepared using beta-lactam.

Example 3

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

HU 211 973 A9

The compound of formula (1.66) 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 1.67 is prepared according to the method of Christensen [B. G. Christensen et al., European Patent Application 185,315 (1986)] prepared allyl [5 R - (4 [beta], 5 [alpha], 6 [beta])] - 6 - [(R) -1 - [(fezr-butyl). dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam live.

Example 4

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

A mixture of about 5.0 g of ciprofloxacin 4a and 175 mL of water is adjusted to about 12 by adding 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 (4, b) in methylene chloride 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 (4c) 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-azabicyclo [3.2.0] hept-2-ene-2-carboxylate and 1.7 ml triethylamine in 30 ml dichloromethane, At 40 ° C, about 1.1 ml of mesyl chloride is added. 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 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 (4, d) in 30 ml of AA-dimethylformamide at about 0 ° C is added about 3.9 g of compound (4c) and the reaction mixture is stirred for about 4 hours. and stirring at ambient temperature for about one hour. The reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in methylene chloride 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 4Ö, 0.19 ml of water, 0.027 g of bis (triphenylphosphine) palladium chloride and about 36 ml of methylene chloride at about 19 ° C in about 1.1 ml of tributyltin The reaction mixture is stirred rapidly for about 10 minutes and the precipitate is filtered off, the solid is triturated with acetone and filtered to give the title compound (1.68).

The following quinolonyl lactam esters were prepared in substantially the same manner as in the general procedure of Example 4.

The compound (1.69) 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-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid using quinolone.

The compound (1.70) was prepared according to Koga's method (1-Ethyl-6-fluoro-1,4-dihydro-4-one prepared according to Koga et al., J. Med. Chem., 1980, 23, 1358). oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid using quinolone.

The compound of formula (1.71) is 6-fluoro-1- (4-fluorophenyl) -1, prepared according to the Chu process (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.

The compound of formula (1.72) is prepared using 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl, prepared according to the method of Sanchez (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983). Quinolone of 6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and Chirstensen's method [B. G. Christensen et al., European Patent Application 185,315 (1986)] prepared allyl [5 R (4β, 5α, 6α)] - 6 - [(R) -1 - [(tert-butyl). -dimethylsilyl) oxy] ethyl] -2- (hydroxymethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate beta-lactam we produce it.

HU 211 973 A9

Example 5

Compound 1.73 is prepared according to the general procedure of Scheme [D].

About 1.26 g of ciproflaxin and 1.59 g of sodium hydrogencarbonate 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. 1179 (1986), 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 product of formula (5a) is 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 of Λ, Λ-dimethyl -formamide. The mixture is 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 1.73 is obtained.

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

The compound of formula (1.74) 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. 6,8-Difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is prepared using quinolone.

The compound of formula (1.75) is 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-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid using quinolone.

The compound (1.76) is prepared according to 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1 (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983). Prepared using 4-dihydro-4-oxo-3-quinolinecarboxylic acid quinolone.

The compound of formula (1.77) was prepared according to 7- (3-amino-1-pyrrolidinyl) -1-cyclopropyl-6-fluoro-1 (JP Sanchez, et al., J. Med. Chem., 1988, 31, 983). 4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid is prepared using naphthyridinone.

1-5. The quinolonyl lactam esters (1.78) to (1.91) are obtained in substantially the same manner as in the general procedures of Example 1-1.

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 (1.92) ] -carbonyloxy] -3 - [(phenoxyacetyl) amino] -4-oxo] azetidine sulfonate is prepared according to the procedure of Scheme [E].

Approximately 20 g of sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- [4 - [(2-propenyloxy) carbonyl] -1-piperazinyl] -3-quinolinecarboxylic acid [( Compound 6a] and 6.4 ml triethylamine in 100 ml dioxane and 20 ml acetone 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 'Cos (32' F). To the resulting mixed anhydride solution was added simultaneously a cooled solution of 6.8 g of potassium salt of 6-aminopenicillanic acid (6.b), 4.2 ml of triethylamine and 9.6 ml of water, and the reaction mixture was added to the reaction mixture. 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 (6c) 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 layer was dried over sodium sulfate and concentrated. 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, 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.

Approximately 2.95 grams of the compound of formula (h) (f) are 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 20 ml of dichloromethane

Then, 0.52 ml of phenoxyacetyl chloride was added to the solution 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 methylene chloride. 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 the solution is cooled to 0 ° C (32 ° F). To this solution was 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 solution of about 0.46 g of compound (6i) in 4 ml of anhydrous Λ ', Λ'-dimethylformamide is added about 0.95 g of DFM SO ₃ complex. The resulting mixture is stirred for 2 hours, or until the reaction is 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 layers were separated and the organic layer was washed with water, dried and concentrated. As a result, the product of formula (6j) is obtained.

Compound (6j) was dissolved in a mixture of about 10 mL of dichloromethane, 30 mL of water and 5 mg of bis (triphenylphosphine) palladium chloride, and about 150 microliters of tributyl hydride were added while maintaining the temperature at about 21 ° C. After stirring for about 5 minutes, the compound liberated by deprotection is filtered off, the filtrate is dissolved in water and methanol, the solution is filtered and the filtrate is washed with water. concentrate the filtrate to give the final product (1.92) which is then purified by trituration (trituration with solvent).

Example 7

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

component Quantity [5- (5α, 6α)] - 3 - [[7- (3-amino-1-pyrrolidinyl) -6-fluoro-1- (2,4-difluorophenyl) -1,4-dihydro-4-oxo -3- (1,8-naphthyridinyl) carbonyl-oxy] methyl] -6- [1 (Z) -hydroxyethyl] 7-oxo-4-thia-1-aza-bicyclo [3.2.0] hept-2-ene-2-carboxylic acid ¹ 100 mg / ml vehicle Carrier: sodium citrate buffer, containing (in% by weight of carrier): lecithin 0.48% (Carboxymethyl) -cellulose 0.53% povidone 0.50% methyl paraben 0.11% propyl paraben 0.011%

a quinolonyl lactam ester of Example 1

The above ingredients are mixed to form a suspension. About 2.0 milliliters of the suspension is systemically administered intramuscularly to a human patient suffering from a lower respiratory tract infection caused by Streptococcus pneumoniae. 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) [5 /? - (5a, 6a)] - 3 - [[7- (3-amino-l-pyrrolidinyl) -6-fluoro-l- (2,4-difluorophenyl) -1,4-dihydro-4- oxo-3- (1,8-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

a quinolonyl lactam ester of Example 1

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. In a human patient with a urinary tract infection caused by Escherichia coli 14

Two tablets are administered orally every eight hours for 9 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, can form a 3 to 9 atoms, monocyclic or 7-17 membered heterocycle R ²¹ and R ¹² együettesen; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; C 1-8 alkyl; (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 1 R ¹¹ (R ¹¹ ); and (2) A ² is N or -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen; C 1-8 alkyl; (C) R ²⁸ is hydrogen or -COOH; (D) 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 '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-R14) -C (= O) NH-, or ^R13 - (CH2) _n, C (= O) NH-; wherein said heteroalkyl carbon atoms and one or has two heteroatoms 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 taken} together may form a group -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 ^{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 bioavailable bridge esters and hydrates of the compound. (2) A ² is nitrogen or -C (R ⁶ ) =; wherein R ⁶ is hydrogen or halogen; (2) R ¹⁰ and R ^10a are independently R, ^{R, Oa} 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 form a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle which includes the nitrogen to which R ¹⁰ and R ^{11 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 taken} together may form a group -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 ^4! bound; and pharmaceutically acceptable salts and biologically hydrolysable esters thereof, as well as hydrates thereof. (2) R ¹⁰ and R 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 ^{11 taken} together form a 3-9-membered monocyclic or 7-17-atom polycyclic heterocycle containing the nitrogen to which R ¹⁰ and R ^{11 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 ^{0a is} -O-; R ^10a CH = N-; (R '°) (R ⁿ⁾ N-; R ¹² -C (= CH-R ¹⁵ ) C (= O) NH-; R ¹² - (C (= ^{NO-R 4)} C (= O) NH-, or ^R13 - (CH2) _m C (= O) NH-; wherein said heteroalkyl carbon atoms and one or has two heteroatoms selected from oxygen, sulfur or nitrogen, and wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (Dm is 0, 1,2, 3, 4, 5, 6, 7, 8 or 9; (2) when A ² is -C (R ⁶ ) =, then R ⁶ and R ^{7 taken} together may form a group -O- (CH ₂ ) "- O- wherein n is 1.2, 3 or 4; and A9 (3) When ^A3 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 atom 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. 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; (E) R ³³ is hydrogen; alkyl or alkoxy; (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 ^-NR10a -; and (2) R ³⁴ is C 1-8 alkyl; C2-C8 alkenyl; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; (2) R ¹⁰ and R ¹¹ are independently R ^10a , wherein R ^10a is hydrogen; C 1-8 alkyl; C2-C9 alkenyl; A 3-9-atom monocyclic or 7-17-atom polycyclic carbocycle or a 3-8-atom monocyclic or 7-17-atom polycyclic heterocycle; obsession R ¹⁰ and R ^{11 taken} together form a 3- to 9-membered monocyclic or 7 to 17-atom polycyclic heterocycle containing the nitrogen to which R ¹⁰ and R ^{11 are} attached; wherein the heterocycles have one or more heteroatoms selected from oxygen, sulfur or nitrogen; (3) A ³ is N or -C (R ⁴¹ ) =; wherein R ⁴¹ is hydrogen; (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) ^A3 is N or C (R ^4I) = radical; wherein R ⁴¹ is hydrogen; 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 3-9 monocyclic or 7-17 membered 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 1-8 alkyl; C2-C8 alkenyl; aryl-alkyl; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; heteroaryl-alkyl; 39 atoms monocyclic or 7 to 17 atoms polycyclic carbocycles; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; or when Z '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-membered 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 ³³ is hydrogen, alkyl or alkoxy; (C) R ² is hydrogen, halo, alkoxy, or R ^{22 is} C (= O) NH - wherein R ²² is hydrogen or Form 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; 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 (R ^2), -N (R ¹²⁾ (R j ^2, -O ^(R21) or a group of formula -S ^(R21) wherein ^R21 is 1 C18 -C8 al24 HU 211 973 A9; C2-C8 alkenyl; (3) R ' ² 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; (3) A ³ is N or -C (R ⁴¹ ) =; wherein R ⁴¹ is hydrogen; 3-9 atoms monocyclic or 7-17 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; (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; C3-C8 heteroalkyl; C3-C8 heteroalkenyl; heteroaryl-alkyl; A 39-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) R ¹⁶ and wherein 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 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 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 3-9 atoms monocyclic or 7-17 atoms polycyclic carbocycles; 3-9 atoms monocyclic or 7-17 atoms polycyclic22 HU 211 973 A9 salt heterocycle; or when R ²⁰ is N (R ² ) (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 1-8 alkyl; C2-C8 alkenyl; aryl-alkyl; Form 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; 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 ), -O (R ²¹ ) or -S (R ²¹ ) wherein R ²¹ is 1- C8 alkyl; C2-C8 alkenyl; (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 ⁸ is hydrogen, C 1-8 al 26 HU 211 973 A9; 3-9 atoms monocyclic or 717 atoms polycyclic carbocycles; (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 -C 8) -alkyl, (C 3 -C 9) monocyclic or (C) 717 polycyclic carbocycle; A 3-9 atom monocyclic or a 7-17 atom polycyclic heterocycle; alkoxy; OH; C2-C8 alkenyl; aryl-alkyl; or -N (R ¹⁰ ) (R ^h ); 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 717 atoms; and (7) R ⁹ is hydrogen; (D) except that (1) when A ¹ is -C (R ⁴⁰ ) =, then R ⁸ and R ^{40 taken} together form a 3- to 9-membered monocyclic ring containing N 'and A' or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (5) ^R14 is ^R12 or C (R ^I7) (R ¹⁸⁾ COOH; A compound according to claim 2. wherein A ¹ is -C (R ⁴⁰ ) =, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴ ') =; or A ¹ is nitrogen, A ² is -C (R ⁶ ) =, and A ³ is -C (R ⁴ ) =. (5) R ⁷ is hydrogen, halo, 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 are a 3-9 monocyclic monocyclic ring containing N 'and A' or a 7-17 atom polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (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 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 heterocycle has 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; 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, halo, 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) ^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 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; 6. A compound according to claim 2, wherein A ¹ is -C ^(R40) = group of the formula, A ² is C (R ⁶⁾ = group of the formula and A ³ is C (R ^4I) = general group. HU 211 973 A9 (6) R ^{1 S} is R ^14, halogen, -Z ^1, or -CH (Z ²⁾ group of formula ^(R12); (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 ⁹ ) R ¹⁶ , then R ¹⁹ and R ^{16 taken} together are a 3 to 9 atom monocyclic or 7-17 atoms form a polycyclic heterocycle; 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 / 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 A compound according to claim 6, comprising a moiety of 6-fluoroquinolone, 8-halo-6-fluoroquinolone, pyridobenzoxazine, pyridobenzthiazine, isothiazolokinolindione or isoxazolokinolindione. (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; (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 (7) R ⁹ is hydrogen, halogen, nitro or -N (R ¹⁰ ) (R); (H) except that (1) when A ¹ is -C ¹ R ⁴⁰ ) 4, R ⁸ and R ^{40 taken} together are a 3- to 9-membered monocyclic group containing N 'and A' or 7 -17 atoms may form a polycyclic heterocycle; wherein the heterocycle has one or more heteroatoms selected from oxygen, sulfur or nitrogen; (7) Z> 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 ^{(Z2) (R12)} formula, and Z ² is -N (R ^I9) R ¹⁶ radical, R ¹⁹ and R ¹⁶ together form a (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, N-dimethylaminomethylpyrrolidine, (V-methyl- aminomethylpyrrolidine, N-methylaminomethylpyrrolidine, pyridine, (V-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 (1c) wherein (A) R ¹ is C 1 -C 8 alkyl; C2-C8 alkenyl; ^{I 2} R - (C (= ^NO-R14) -C (= O) NH-, or ^R13 - _{<CH2) 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 parenteral 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 6. 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 of claim 16.