CA2148003A1 - Antimicrobial 5-hydrazino-quinolone derivatives - Google Patents

Abstract

Antimicrobial 5-(N-heterosubstituted amino) quinolone compounds of general formula (I), wherein (1) R1, R2 and R3 form any of a variety of quinolone and related heterocyclic structures similar to those known in the art to have antimicrobial activity; and (2) (a) R4 and R5 are, independently, hydrogen; lower alkyl;
cycloalkyl; heteroalkyl; or -C(=O)-X-R8, where X is a covalent bond, N, O, or S, and R8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or (b) R4 and R5 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof.

Description

w O 94/101~3 ~ 0 ~ ~ Pcr/US9~/10091 .,'.':' Ant~m~crob1al 5-hydrazlno-qulnolone derlvatlYes ~Y5~ E_li ;YL~}~
This invention relates to novel anttmi~roblal~ compounds ~- ~ co~positions and methods of treatment. In particular the compounds of thts~ i nv~fltion compris~ a quinolone or related ~`
heterocyclic~moiety. ~
I0 The chem~cal and; medical;ltterature describes a~myri~d of compounds that are ~sai~d to be~ antimicrobial l.e~. capable of ~`;
destroying or `suppressing the growth or rcprotuc~ion of microorganisms such as ~acterta. In particular an~ibacter~als `` include a lar~e variety of naturally-ocourring ~ant~btotk) 15 ~ synthetic or semi-synthetic compounds. They~may be classtfied (for ~ ex~a~ple) as the ~aminoglycosides ~ ansa~acroltdes beta~-lactams~ (includlng`p~nicillins and cephal~ospor;ins) lincos~
a`minides macrolides ~nttrofùrans nucleosides~ ol~igosaccharltes pept1des ~and polypept~des1~ phenazines ~polyenes polyeth~rs 20 quinolones tetracyclines. and~sul~onami~es.~ Such antibacterials and~ other ~ antimicrob1~1~s ~are; de5cribed ~`in~ D~ Qiç~

(M.~Bràyson ed~t~r 1982)~ ~and~E. Ga1e~et ~al~ The Mol~l ~r Basls~of Antib:tot~ Aetion 2d~ edition (I981~) ~both incorpor-ted~
2S~ by refereni~ herein.;~
Tbe~ echanism ~of~ ~àction:~of these~:~qntjbacterials vary.;;~
Howewr, each: can be generail:y~ classlfied as ~unctionin~ in~;one~ s or more of four ways: by inhihiting cell :wall synthesis or ~ .
`rep~1rl; by altering tell wall penmeability; by inhibit~ng protsin~ t' ; ~30~;synthiesis; or by inhib~t~ng ~synthesis~of nucle1c aclds. ~For~
exampl`e ~beta~lacta~antibacterials act~through inhib~ting th~e~
essential penicillin;~ binding prot~ins (PBPs~ in bacteria whih~
are responsibl~e ~for~cell~wall ~synthesis.~ Dn~the other hand quinolon~s ~act ~by inhib1ting synthesls~of~ bacterial DNA thus~
35; prevent1~ng~the~bacterl~a from~repl~lcating.
N`nt ~surprislngly~ the ~phar~aco~Qgical ~characterlstics~of~
;antibacterials~and~ather~an~imi~crobi~als,: and~thelr su~tabillty~

WO 94~10163 ; P~/US93~1~
z `
for any ~iven clinical use, also vary considerably. For example, the classes of antimicrobials (and members within a class) may vary in their relative efficacy against different types of microorganisms, and their susceptibility to development of microbial resistance. These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability, and biodistribution. AcGordingly, selection of an appropriate antibacterial (or other antimicrobial) in any given clinical situation can be a complicated analysis of many faetors~ including the type of organism involved, the desired ~ethod of administration, and the location of the infection to be treated.
The Phanmaceutical literature is replete with attempts to develop improved antimicrobials (i.e., compounds that have a broader scbpe of activity, greater pot`ency, improved pharmacology, and/or less susceptibility to ~resistance development.) For example, one group of antimicrobials that has been developed relatively recently for clinical use is th~
quinolones. These ~compounds include,~ for example, nalidixic acid, difloxacin, enoxacin, fleroxacin~; norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin, and pefloxacin. See, C.
Marchbanks and M. Dudl~ey, '`New fluoroquinolones",~ 7 HosDital ~ ;a1y~18~ (1988j; P. Shah, i'Quinolones", 31~Proq. Druq Res. 243 ; (1987j; Quinolones - Their Future in _ÇlYnical Practice, (A.
?erci~val, ~editor, Royal Society of Medical Services, 1986)~; and M.~ Parry, "Pharmacology and Clinical Uses of ~ Quinolone Antibiotics", 116 Medical Times 39 (1988)~
~ However, many such `attempts to prcduce~ ~improved antimicrobials have produced equivocal results. Indeed, few ant~imi~robials are developed that are trulylclinlcal`ly ~acc~ptable in terms of their spectrum of antimicrobial activity, avoidance :~ of microbi~l resistance, and pharmacology~ For ;example,~ the quinolones often show reduced effectiveness;~ against certain clinically important pathogens (for exampl~ej~ gram positlve bacteria and/or a~naerobic bacteriaj. The quinolones~ also have ~: : limited water solubility limiting their bioava~lability and ; suitability for pa~renteral doslng. They may also~p~roduce adverse , : W 0 94/10163 ~ 3 PCT/US~3/1~091 1 ~ ~
3 ' ::
side effects~ such as gastrnintestinal disturbance and central nervous system e~fects (such as convulsions). See, M. Neuman and A. Esanu, "Gaps and Perspectives of New Fluoroquinolones , 24 Druqs Exstl~ Clin. Res. 385 (1988); W. Christ et al., ~Specific . ;
i Toxicologic Aspects of the Quinolones~, 10 Rev. Infectious Diseases 5141 (1988j; H. Neu, ~Clinical Use of the quinolone Lancet 1319 (1987); and ~Ciprofloxàcin: Panacea or Blunder Drug?~, J. South Carolina Me~. Ass_c:131 (March 1989).
SUMMARY OF THE INYENTIOH
loThe present inventibn provldes compounds of the general structure:

~ 5 : ~ n : ~:

o O H~'N`R4 H~ Xl~ F

Rl R2 :: wherein 20 :(~A)(l)ta) R1 is alkyl; alkenyl; a:carbocyclic ring; a ~ :~
heterocyclic ring, or -N~R6)(R7), where R6 and R7 :: ~ -:are, independently, hydrogen, alkyl, ~alkenyl, a :~
~ : carbocyclic ring, a heterocycl~ic ~ing, or R6 ~nd :
: R7 together comprise: a heterocy~lic ring that 5 i ~1 , . includes the nitrogen~to which~ they are bohded;
and~
(b) ~R2 15 hydrogen~, halogen, :lower:alkyl,~or 1ower :;~
alkoxy; or : ~ t ~: (2) Rl~ and R2: may together: compri:se a six-mombered ::
: 30 : heterocycl~1~c r1ng that ~1ncl~udes ~N' ~and the carbon : atom to which R2 1S booded~
B) :R3 is a heterocyclic ring or:a carbocyclic ring;~and , ~ . . ~ . .

;: :

~o w ~ a~ 3 ` 4 PCT/US93/1~
(C)(l) R4 and R5 are, independent~y, hydrogen; lower alky1; ;
cycloalkyli heteroalkyli or -C(-O)-X-R8, where X is a ooYalent bond, N, `O, or 5, and R~ is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or ~2J R4 and R5 to~ether comprise a heteroeyolic ring that ~-includes the nitrogen to which they are bonded; "~
and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof.
It has been found ~that the compounds of this invention, and i~compositions containing these ~ compounds, are effective antimicrobial agents against a broad ~ range of pathogenic ;;
microorganisms. Appl icants have also discovered that, surprisingly, compounds of~ this invention offer~ significantly increased water solubility at physiological pH in eomparisoni to related antimicrobials known in the art. ~This surprising property ~.``
may allow for, among other things, improved pharmacology, including increased serum levels upon administration, eàse of formulation, and a more flexible dosing regimen.

The present inYention encompasses certain novel quinolones, ,.
methods for their manufacture, dosage~ forms, and methods of i`
administering the quinolones to a human or other animal subject.
Speeific compounds and compositions to be~used i~n the invention must, accordingly, be pharmaceutically acceptable. As used ,, herein, such a "pharmaceutically-acceptable" component is one that is su~table for use with humans and/or anlmals without undue~
adverse side effects (such as toxicity, irrita~ion, and allergic response) eo~mensurate with a reasonable benefit~risk ratio. ~ ' I 5-(N-heterosubstituted amino) quinolones The compounds of this i~vention, herein referred to as "5-(N-heterosubstituted amino) ~uinolonesn~9 encompass any ~of a variety of quinolones (and related heterocyclic~moietles) havlng 1, ~ an N-heteroamino substituent at the 5-position of the quinolone moiety. ; ~ ,The 5-~N-heterosubstituted amino) quinolones of ~his '~
; invent~on~incl~de compounds of the general structure: 1`

~ . .

94/l0!63 2 ~ PCT/IJS93/1,0091 -O O H-N ` R
H{) / ~' ~ F :

` ~N~ \~\ R3;

2;

: ~ wherein (A)(l)(a) ~1 is alkyli alkenyl, a carDocyclic ri~ng; a ~ heterocyclic ring; or `-N(R6)(R7) ~preferably ~ `:
lo alkyl or a carbocyclic :ring), ~where R6 and R7 : : -~.
arBt independently, hydrogen, alkyl,:alkenyl, a carbocyclic ring,~a heterocycli~ ring, or R6 and R7 toge:ther comprise a: hetero~ycl~;ic ring that includes~the nitrogen to which~ they are bonded;

(Sb) R2 is hydrogen, halogen, lower~alkyl, or lQwer " .
~: : alkoxy~:(preferab:ly halog~n);~or (2) (Prefera~bly)` RI~:and R2 may~together comprise a six~
membered ~heterocyclic ring:: that includes N' and the 20~ carbon;atom~to~whlch`R2 ~lS bonded~
B) R3~is a heterocyclic ring or:~:carbocyclic ring : (preferably a~heterocyclic ring);~?nd (Cj(lj R4 and R~are, independently, hydrosen; lower alkyl:;:`
cy loaikyl~;~ heteroalkyl; or C(-O):-jX-R8 (prefera~ly : hydrogen or::lower alkyl), where X:is a:coval:ent:~bond,~
N, O~ or j S~, and ~R$~ is lower~ ~alkyl~,~ lower~ alkenyl~
arylalkyl, a carbocyclic: r1ng,:~ or:;a~:heterocy~llc;; ;~

(2) (Preferab~ly~l ~; R4~ and ~ R5 ~ together compri se ~a~ hetero~
30~ :cycl~l~c`~:ring~ that l~ncludes thejnltrogen`~to:wh~ich~ they~
; are: bonded~

,i` `
~' W O 94/lOIfi ~ 3 -6- ~CT/USs3/lo and pharmaceutically-acceptable salts and biohydrolyzable esters "~
thereof, and solvates thereof.
Def;nitions and Usane of Terms:
The following is a list of definitions for terms used herein.
"Heteroatom~ is a nitrogen, sulfur or oxygen atom. &roups ;~
containing one or more heteroatoms may contain dif~erent heteroatoms. .
"Alkyl n is an unsubstituted or subs~ituted saturated hydrocarbon chain radical having from l to 8 carbon atoms, preferably from l to 4 carbon atoms. Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.
"~eteroalkyl" is an unsubstituted or substituted saturated chain radical having from ~ to 8 members comprising carbon atoms and one or two heteroatoms.
lS "Alkenyl" is an unsubstituted or substituted hydrocarbon chain radical having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond (including, for example, vinyl, allyl and butenyl).
"Carbocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic, hydrocarbon ring radical.
Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. P~lycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.
"Cycloalkyl" is a saturated carbocyclic ring radical.
Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.
"Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and cne or more heteroatoms in the rinig.
Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 i-atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms. s-"Aryl" is an aromatic carbocy~lic ring radical. Preferred aryl gro~ps include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.

, ~ 0 94/10163 2.~ D'~ PCT/US93/~10091 ~Heteroaryl" is an aromatic heterocyclic ring radical.
Preferred heteroaryl groups include (for example) thienyl, furyl, ~
pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, ! ;
quinolinyl, and tetrazolyl. j -~
~Alkoxy~ is an oxygen radical havi ng a hydrocarbQn chai n substituent, where the hydracarbon chain is an~alkyl or ~lkenyl ~ i (i.e., -~-alkyl or -0-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, prapoxy and allylaxy.
"Al~ylamino~ is an amino radical having one~ or~ two alkyl }o substituents (i.e., -N-alkyl). ~ ~
"Aryla1kyl" is an alkyl radical substituted ~with an aryl group. Preferred arylalkyl graups include benzyl and phenylethyl.
"Arylamina" is an amine radical substituted with an aryl ~`;
graup (i.e., -NH-aryl). ~ `
"Aryloxy" is an oxygen radical having an aryl substituent (i.e., -0-aryl).
"Acyl" or "carbonyl" is a radical formed~ by removal of the ` ~ ;hydroxy from a carboxylic acid (i.e., R-C(~0)-). Preferred al~kylacyl graups include (for example`) acetyl, farmyl, and `propionyl. ~ ~
;"Acyloxy" is` an oxygen radical having an acyl substituent ;`
(i.e., -O-acyl); for exàmple,-0-C(=0)-alkyl.
"Acylamino" is an amina radical having an acyl substituent ; (i.e., -N-acyl); for example, -NH-C(-0)-alkyl.
2~ ~` "Halon, "halogen", or "halide" is a ch10ro, bromo, fluoro or iodo atom radical. Chlora~and fluora are preferred halides.
Also, as referred~to herein, a "lower~" hydrocarbon moiety ~e.g., "lower" alkyl) is a hydrocarbon chaln comprlsed of from 1 to 6, preferably from 1 to 4, carbon atoms.
0 ~1 A "pharmace~tically-acceptable `salt~` is ~a~ cationic slalt i formed at any acidic (e.g., carboxyl ) group, or an anionic salt~
formed at any baslc (e.g., amino) group.~ Many such salts are~
`known in the art,~ as desoribed in World~ Patent Publ k ati~n 87/05297, Johnston et al.,~ published ~September 1`1, lg87 ¦~
`;~ 35(incorporated by reference~ herein~ Preferred~cat~ionic~sa~lts~
include the alkali: metal: salts (such:as~sodium and potassium),: and ~ ~ -alkaline earth meta~l ~salts (such as ~magnes`ium~ and calciumj.

W O 94tlO163 PCT/US93/l~O~
Preferred anionic salts include the halides (such as chloride salts).
A ~biohydroly~able ester~ is an ester of a S-~N-hetero-substituted amino) quinolone that does not essentially interfere with the antimicrobial activity of the compounds, or that are readily converted in ~ivo by a human or lower animal subject to yield an antimicrobially-active 5-(N-heterosubstituted amino) quinolone Such esters include those that do not interfere with the biological activity of quinolone~ antimicrobials. Many such esters are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987, (incorporated by reference herein). Such ~esters include lower alkyl esters, lower acyloxy-alkyl ~esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloylox-ymethyl and pivaloyloxyethyl esters), lactonyl esters (such ~as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl es~ters ~such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
A "solvate" is a complex formed by the combination of a solute~ le.g., a 5-(N-heterosubstituted amino) quinolone) and a `solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist's ~ictionarv, p. 650 (1953). Pharmaceutically-acceptable sol~vents used according to this invention include those that do~
not ~interfere with the biological activity o~f the quinolone antimicrobials ~e.g-., ;water, ethanol, ~ acetic aci~
N,N-dimethylformamide). ~
As defined abovè and as used herein, substituent groups may " 30 thémselves be/subst!ituted.~ Such substitution may~;be'with one ior more substituents. Such substituents include those listed in C.~Hansch and~ A. Leo,~Substituent Constants ~or ~ Correlation Analysis~ in ~Chemlstrv and Biolo~Y ~1979), incorporated by reference h~erein. ~Preferred substi~tuents include~ (~for example) ~ 35 al~kyl, alkenyl, alkoxy,~ hydroxy, oxo, nitro,~amlno, am~noalkyl~
`~ ~e.g., aminomçthyl,~ etc.), cyanQ, halo,~ carboxy, alkoxyaceyl (e.g., carboethoxy,~ etc.), thiol~, aryl~,; cycloalkyl,~ heteroaryl, heterocycloalkyl ~e.g~ piperidi~nyl, ~morpholinyl, ~pyrrolidinyl, , ~ 94/10163 9 2 ~ PCT/uS93/~!oo9l ` ~

etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
Groups Rl, R2, and R3 form any of a variety of quinolone moieties known in the art to haYe antimicrobial activity. Such moieties are well known in the art, as described in the following articles, all incorporated by reference herein: ` J. ~olfson et al., The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro~, 28 Antimicrobial Aqents and ChemotheraPY 581 ~1985); and T. Rosen et al., 31 J. Med lo Chem. 1~86 (1988); T. Rosen et al., 31 J. Med._Chem. 1598 (1988);
G. Klopman et al., ~1 Antimicrob Aqents Chemother. I831 (1987);
31:1831-1840; J. P. Sanchez et al., 31 ?. Med. Chem.;983 (1~88);
J. M. Domagalia et al., 31 J. Med. Chem. 991 (1988); M. P.
~entland et al., in 20 Ann. Rep. Med. Chem. 145~ (D. M. Baily, editor, 1986~; J. B. Cornett et al., in 21 Ann. ReP. Med._Ch~m.f 139 (D. M. Bailey, editor, 1986); P. B. Fernandes et al., in 22 Ann. Re~ ed. Chem. 117 (D. M. Bailey, editor, 1987);
R~. Albrecht, 21 Proq. Druq Research 9 (1977); and P. B. Fernandes et al., in 23 Ann. Rep. Med. Chem. (R. C. Allen~ editor, 1987).
~0 Rl is preferably alkyl, alkenyl, aryl, cycloalkyl, a heterocyclic ring, or alkylamino. More preferably, R~ is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, methylamino, 3-oxetanyl, 2-fluorocyclopropyl, bicyclo '~1.1.1] pentane, vinyl, cr cyclopropyl. Cyclopropyl, : ~25 2-fluorocyclopropyl, t-butyl, 2-fluorocyclopropyl, and 2,4-difluorophenyl are particularly preferred ~ Rl groups.
Preferred 5-(N~heterosubstituted a~ino) qfuinolones also include those where Rl and R~ together comprise a 6-membered heterocycltc ring, according to the formula~
`:30~ R5 ~ F

3 ?~ PCI/U593/1,00 where X is 0, S, or CH2 R2 is preferably chlorine, fluorine, methoxy, or methyl.
Fluorine and chlorine are particularly preferred R2 groups.
Preferred R3 groups~include nitrogen-containing heterocy~clic rings. Particularly preferred are nitrogen-containing heterocyclic rings haYing from 5 to 8 members. The heterocyclic ring may contain additional heteroatoms, such as oxygen,~sulfur, or ni~rogen, preferably nitrogen. Such heterocyclic groups are described in U.S. Patent 4,599,334, Petersen et al., issued July 8, 19~6i and U.S. Patent 4,670,444, Grohe et al.j issued June 2, 1987 (both incorporated by reference ~herein). Preferred R3 ~roups include unsubstituted or substituted pyridine, piperi-dine, morpholine, diazabicyclo[3.1.1~heptane,; diazabicy-clo[2.2.1]heptane, diazabicyclo~3.2.1]octane, diazabicyclo[2.2.2]
octane, imidazolidine, and 5-amino-3-azabicyclo[4;.2.0]heptane, as well as particularly preferred R3 groups which include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminomethylpyrrolidine, N-ethylaminomethylpyrrolidine, 3,5-dimethylpyridine, N-methylpiperazine and 3,5-dimethylpiper-azine.
Preferred R4 and R5 groups include those where R4 and R5 together comprise a heterocyclic ring containing the nitrogen atom to~which they are bonded, those where both R4 and RS are lower alkyl~,~ those where one of R4 or R5 is hydrogen and the other is lower alkyl, and those where both R4 and R5 are hydrogén. More ' preferred groups are where one of R4 or RS is; hydrogen and the Z~ other is alkyl and those where both R4 and RS~ are hydrogen.
PartScularly p~referred~ groups are where both' R4 ~and RS are hydrogen.
l Preferred compounds of the present inventi~n! include those having bath an R3 group that contains a basic nitrogen atom nc;luding, ~or example, pyridine,~ piperidine, ;diazabicyclo~
[3.~1.1]heptane, ~diazabicyclo[2.2.i~]heptane,~ diazablc~
yclo[3.2.1]octane, ~diazabiclyo~2.2.2]octane,~and im~dazolSdine)~
~and R4~ and RS groups that allow t~he nitrogen~ atom~to which they are~bonded to be basic (lncluding~ e~g.~, ~where R4 and~ RS together compris~e a heterocyclic rSng contaSning~the ni~troge~n to which ~hey 2 1 '~ ~ 3 ~ ` -O 94/10163 ~ PCT~US93/~0091 are bonded, both R4 and R5 are lower alkyl, one of R4 and R5 are lower alkyl and the other is hydrogen, or both R4 and R5 are hydrogen). Particularly preferred compounds are those where the R3 group is one of piperazine, 3-methylpiperazine, 3-am~no-pyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethy~amino- ~ ;
pyrrolidine, N-ethylaminomethylpyrrolidine, N-methylplperazine, or 3,5-dimethylpiperazine; and both R4 and R5 are hydrogen.
As used herein, a ~basic nitrogen atom~ is one where the ~ -nitrogen atom possesses a lone pair of electrons that can be - ~`
involved in ionic bonding with any of a variety of cations. It is understood in the art that the basicity of a nttrogen atom of a given moie~y will depend on the nature of that nitrogen atom's covalent bonding. See, e.g.~, A. Streitwieser and ~. Heathcock, 1ntroduction to Orqanic Chemist_Y, 2d edition,~ pp~ 734-40 ~1981), lS I incorporated by reference herein.
Preferred 5-(N-heterosubstituted amino) quinolones include:
:.

i~2N` NH : ` NH O
~0 5 ~ ~ ~ ~ CC~H

F

W094/i~ 12-PCI/U593/lOOQ'~

f ~ f ~
~NJ o~l ~ ~N~J~: ~S~,J .

- :' ~: ~ F

MeNtt~ ~ `NH ~ O
~: 15 NH O I I t j: `
r ~ f ~ ~ ~
a 1 ~ ~ ~NJ F ~

Z MI~zN~ NH 0~ ~ ~ NH o ~, ~; ` ~CO2H : ~COal1, f N~ N~ 2N_~I~ N
N J 1~ ~ ~: a )~

2~ 3 ,~
~
.~ ~`'094/lQ163 ` ~3 rCI/U693i/10091 NH 0 NH 0 ¦ .
CO2H ~CO~
G c ~ G ; F

. .
1.

~N~ R~N~

~ H2N_<~N N ' `
` ~ N~J CJ~ ~ F

15~ f N~N ~ ~ ~ f NJ~N

W0 94/10163 ~i~ PCi/US93/l'OOr NH E~H~
~,J~CO2H I H R
N~ N ~ ~C02H `

~ F )~ ~ N ` .``
tl2N ~\~ F: ~F
3`''`' F:: ...

~2N~ : H2 ` NH 0 : ~ `

~ ~ r F l ` H2 N

~ ~N~ ?~C02H

20 ' ' ~ 2N` NH ~ o ~

H2N 2N""~N

:.t:' Rt'~'~ ~'' '` '' C~ t~ t~ ' 7' r~ ~~ ~r~ t ~`-'O 94/10163 ~ 3 ` PCI`/lJS~3/1~091 f`` `:. ` `` - l 5-~N~ NH . ,~

:`

H2 N~ ~ ~ 2A

N~ N ~

= ~

WO94/1~ 16- PCT~US93/100~ ` t H2jN~ : ~2 NH o ¦ ;

-- N
a i ÇJ F ~

o> H2~J , ~

NH O NH O

~0 l kN~", a ~, F H~ F k-- ~ , ~ .

: : ` H2~ ' ~ NH O ' `: ;'"
NH O ! ~ : 11 : ~;~`

` ~NJ~N : : ~

~N~ NH ~ O ~ Nll ~ O
` ~ CO2~ t- "'i ~N~N~I HzN~ J~N~

G¦ 6 ~ ;r 2 1 4 ~ ~0 ~
~; '0 ~4~10`163 ; .. -17- PCr~US93~10091 `~ ~
, "`.

~ '. .'`

NH O

N~ N ` ~ .
S ~ EtNH \_¦ k ~ :~

The compounds o:f ::~thi. ~:i:nvention~ ~are ~also useful as : intermed~ates in the: synthesis: of novel~ actam-quinolones. S~uch:~
compounds are disclosed in `International `Publication No. ~0 1/16327, published: October:3:1, 1991, incorporated by referencè~
10: :h:erein. Lactam-quinolones~é`ncompass any:Qf a variety of lactam moletl;es~l~inked,~by:~a llnklng~ mol-ety, to~a qu~lnblone moiety at the -pos:ition~:`of the`qulnol~one.
Lactam-qulnolones~ include~; compounds:~having the general~
structure~

` ~; ;wherel:n q~; L~and~a are defined as~follows~
q ;s a~:structure ~according~to~ Fo~nula (I~

W O 94/10~63 PCT/US93/i -l8 (A) (l) Al is N or C(R7); where (i) R7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R8)(R9) (preferably hydrogen or halogen), and '~
(ii) R8 and R9 'are, independently, R8a, where R8a is ''` ~
hydrogen~ alkyl, alkenyl, carbocyclic ring, or ~:
heterocycli:c ring substituents; or R8 and R9 together '-comprise a heterocyclic ring including the nitrogen ' to which they are bonded; : ;.` `
(2j A2 is N or C(R2) (preferably C~R2)); where R2 lS hydrogen .
or halogen;
(3) A3 is N or (preferably)~C(R5); where R5 is hydrogen; : ~ :~'`'

(4) R1 is hYdrogen, alkyl,':a carbocyclic ring,` ~:heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R8)(R9) (preferabl`y alkyl or a carbocyclic ring);;

(5) R3 ls hydrogen, hal:ogen, alkyl~, a carbocyclic ring, or a ; heterocyclic ring'(preferably a heterocyclic rlng);

(6) R4 is hydroxy;~and` ~

(7)' R6 is Rl5 or~R16X;:where Rl5 is a substituent moiety of L: ~;
` 20 ~ and is nil, alkyl, heteroalkyl, or~alkenyl; R16 is a ~ ;
substituent moie:ty of~: L and is :alkyl, alkenyl, a :c~arbocyclic ring~ or a heterocyclic ring;~and~X is alkyl, heteroalkyl,~ alkenyl~, oxygen, sulfur, or NH;:
;(B~)~except that 25 ~ when~ A1 is C(R7), Rl and R7 may together comprise ~2 heterocyclic~rl;ng lncluding N' and A1;
(2) when A2 is~:~C(R2);,~:: R2 ~and: R3: may~ tagether comprise 0-(CH2~)n-0~ where:n is an integer~rom l~to 4; ~ J
'(3) when A3 is C(R5), R4 and R5 may together comprise a , ~`~''' 30 ~ heterqcyclic''ring;including the carbon atoms to ~hich IR4 ` ~ :"
and R5 are bonded and~the carbon atom of Formula (I) to which said:carbon~ato~s are~bond@d; and ~ : h (4) wh~en A3:~ s~C(R5), Rl ~and R5~ may :together comprise::~a~
heterocycli:c~ring~inc~udlng:N':and the~;adJacent c:arbon to~
wh~i:ch:R5 is~bonded;:~
B is a:structure acc;ording t:o Formul~a:~II),:where L i's: bonded 2 1 ~ 3 ~ `
94/10163 19 PCI`/US93f10091 ~ ~

It (Il) R ~ I ~RI4 ~ N R ~ `0 ` ;.. i '....
wherein ` :`
(A) RIO is hydrogen, ha)ogen, heteroalkyl, a car~ocyclic ring, a heterocyclic ring, R8a-O-, R~aCH~N-, (R8)(R9)N-, R17-C(=CHR20)-c(~o)NH-~ or ~preferably): alky7, alkenyl9 R17-C(~No-Rl9)-C(~o)NH-, or R18-(CH2)m-C(~O)NH-; where .:
(I) ~ is an integer from 0 to 9 (preferably from 0 to 3?; .`
(2) R17 is hydrogen, alkyl, alkenyl, heteroalkyl, hetero-alkenyl, a carbocyclic ring, or a heterocycl k ring (preferably alkyl, a carbocyclic ring~ or a heterocyolio ring)i lB is R17, yl, or -CH(Y2)(R17)~
(4) Rl9 is R17, arylalkyl, heteroarylalkyl, -C(R22)(R23)CooH, -C(-o)o-R17, or -C(~o)NH-RI7, where R22 and R~3 are, independently, R17 or together comprise a oarbocyclic rins ~1 2a or a heterocyclic ring including the carbon atom to which R22 and R23 are bonded (preferably R17 or -C(R22)~R23)CooH) (5) R20 is RI9, halogen, yl, or -CH(Y2)(R~7) (preferably Rl9 . or halogen);
(6) yl is -C(~O)OR21, -C(~O)R2I, -N(R24)R21, or -s(O)pR29 or oR29; and y2 is YI or~-OH, -SH, or -SO3H;:~
(a) p is an integer from O to 2 (pref~ably 0); :
.l . . (b) jR24 is hydrogeni alkyl; alkenyl; heteroalkyl; hetéro~ talkenyl; a carbocyclic ring;~a he$ero~yclic ring; : :~
-S~3~; -C~no)R25; or,: when Ri~ i5 : C~(N(~24~R2l~(Rl7)~ RZ4:may comprise a moiety bsnded to R21 to ~orm a heterocyc1io ~ing; and :
(c) R25 is ~17, N~Rl7)9 N(Ri7j(R26j~ o~R26), or S:(R26) :~
(preferably~R17, N~(RI7) or~ N(Rl7)(R26)j; wh~re: R26 :~
3S is alkyl9 alkenyl, a carbocyclic rin~,~a heterocyclic ring or (preferably~ when R25 i~s N(RI7)(~6)~ ~26 may , .
., .

i, ~

W 0 94/10163~ 20- pcT/us93 comprise a moiety bonded to R17 to form a hetero-cyclic ring, and (7) R21 is R29 or hydrogen; where R29 is alkyl; alkenyl;
arylalkyl; heteroalkyli he~eroalkenyli heteroarylalkyl; a S carbocyclic ring; a heterocyclic ring; or, when yl is N(R24)R71 and R21 is R29, R21 ahd R~4 may together comprise a heterocyclic ring including~the nitrogen atom : to which R24 is bonded (preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring);
(B) Rll is hydrogen, halogen,~ alkoxy, or R27C(=O)NH- Ipreferably hydrogen or alkoxy), where R27 is hydrogen or al kyl ~: : (preferably hydrogen);
(C) bond "a" is a single bond or :is nil; and bond "b" is a single bond, a double bond, or is nil; except bond "a" and bond "b"
are not both nil;
(D) R12 is -C(R8a)-, or -CH2-R28- (preferably -CtR8a)-); where R28 is -C(R8a), -O-, or -N-, and R28 is directly bonded to N" in Formula tII) to form a S-membered ring; except, i~ bond "a" is nil, then R12 is `:
(1) (preferably) -C(R~aj(Xl)-, where (j) xl is R21; -oR30; -S(o)rR30, where r is an integer fr~m O to 2 (preferab1y 0); -o(cso)R3o;
: `or N(R30)R31; and : (ii) R30 and R3l are,:~independently, alkyl,: alkenyl,~
~ carbocycl ic ring or heterocyclic ring substitu-ents;~or:R30 and R31 together comprise a hetero-: cyclic r-ng including the nitrogen~atom to which R30 and~R31:~are~bonded; or ~ ` (2) -CH2-R32-; where R32 is -c(R8a)(R2l)~ -O-, or NR8a, ;:/ 30 ,~ . ind R32 js~ direct1y bonded to N" in Form,ula (III) tO
form, a 5-membered ring;
(E)~(I) ::if bond nbn~is a~ single bond, :~R13 :is preferably CH(R33):-;~ or,~ -C~O)NYS02-, if bond "a'i: is nil; or -C*lR33)~ if; R14 ~cont:ains~ a R36 moiety, where R33 :is 35~ hydrogen:or COOH~(prefe~rably CO~H):, and C~ is:linked to R36 to form~a~3-mèmbered ri~n~
;if~b:ond ~"b" is a~double~:bond,~R13~1s - C~R33)=; or , ''~' . '`,' 2 1 ~ . 3 ~
. .~'0 9~/10~63 ; 21 P~r/US93/toO91 .
(3) if bond "b" is nil, R13 is hydrogen, -S03H, -Po(oR34)oH, -C(o)NHSo2N(R34)(R35), -OS03H, --CH(R35)CooH, or -~CH(R34)CooH ~preferabl~ -S03H, or ..
-C(o)NHSo2N(R34)~R35); where R34 is; hydrogen, a~kyl alkenyl, a carbocyclic rin~, or a:heterocyclic ring; ~ ;
and R35 is hydrogen, alkyl, alkeny!, or -NHR8a; or :,`
~ (preferably), if R~13 is -C(o)NHso2N(R34)(R3s)~ R34 and ~ :
: : R35 may together comprise a heterocyclic ring incl~ding the nitrogen to whi:ch R34 and R~5 are bon:ded; and : :
(F) (1): lf:bond~-a" or bond~b" is nil, then~R14 1S nil and~ L ,.,',A,-~
: is bonded directly to:R12 or R13i ; : ~
(2) if bond :"a"~ and~ "b" aré; ~single:~ bonds, R14 is W-C"'=C(R8a)-R3;7~ or: -w-cn/(R36)~-R37- or (3) (preferably) if bond l'al' is a single bond and bond "b" :
is a double bond, R14 is -C(R8a)(R38)-W-C"'-R37-; or (preferabl`y)`-W-C(R8a):(R38) C"'-R37-,~ or -W-C"'-R37 where~ L~
(a)` W~ts~O; 5(0)~5,~ where s;is an integer~from O to 2 ~ (pre:fer:abl~y:~`O)~;;or C(R3a)~, where R38~is hydrogen, ;~
-~ 20:~ : alkyl~or~alkoxy;
(b) R36~ hydrogen; al~ky1; alkenyl; -COOH; or, if Rl3 `:
is~-C*(~R33);~ R36 may be linked to C* to form a 3-~membered:carbocyclic ring;
:: (c) R37 is~ni~l, al~kyl, alkenyl~ a:carbocyclic ring, ` 25 ~ or~a~heterocyclic r1ng and; ~
:: (d:) :~C '~ s:~d~i~re:ctly~bonded to RI3 to form~a 5- or 6-~membered rlng,~

L llnks Q to Bj~ and L is L', -X2t-R~9-L', or -X3t-R39-L', ~v~ ` 30~ where~lL~ i's~`Q~ X2-~Qn~` X3~ or'-~X4t-c(~y3u)~ t (preferably~:-X2-~Q~ :-X3~-Q"~ -X~4t-C(~Y3:u)-Z-;Q")~
t and;~ ar ,:~independently,~O or~
2~ R39 i ~ a~l~yl~ alkeny: ,::heterQalkylt heteroalkenyl,~::a~
~ carb llc~ rlng~ or a~ heterocycl~l~c~; r~l~ng~(preferably `~ ~35~ alk :l o alkq 1 (3)~ ;X2~i:s~o gen,~or~:5(0)v,:~:whe~re~:v:i:s~an i:nteger from~;O to ;~
2~(pre~e~rab1y~0)~

~ ~3 PCT/US93/lD0 : -~2-(4) X3 is nitrogen; N(R40); N+(R4l)(R42); or R43 N(R41);
and is linked to R14 by a single or double bond; or, if R14.is nil, X3 is linked to B by a single or double bond (preferably X3 is nitrogen, N(R40) or N~(R41)(R42)); where a) R40 is R8a; 0R8a; or ^C(=O)R8a; (preferably R8a); ' (b) R4l and R42 aret independently, hydrogen; alkyl;
alkenyl; carbocyclic rings; heterocyclic rings;
or, if R6 is R16X, then R4l and R42 together with Q", may comprise a heterocyclic ring as R16;
~ (c) R43 is N(R41), oxygen or sulfur; ~
: (5) X4 is oxygen, sulfur, NR40, or R43-NR41 (preferably oxygen, sulfur or NR40);
(6) Y3 is oxygen, sulfur, NR40 or N+(R41)(R42j;
(7) Y4 is oxygen or NR41 (preferably oxygen);~
~8) Z is nil, oxygen, sulfur, nitrogen, NR40, or N(R41)-R43 : (preferably oxygen,~sulfur, nitrogen or NR40);
(9): q' is said R6~ subs~tituent of Q; and `': Z0 ~;;(10) Q" is Q'; or together with X2, ~3,~ Z~or Z', ls said R6 : : substituent ~of Q;~
and;:pharmaceutically-acceptable salts and biohydrolyz~ble esters : thereof, and hydrates th~ereof.
Preferred lactam-c:ontaining moieties include cephems, .25~socephems,: iso-oxacephems,: oxacephems, carbacephems, penicillins, p`eaems, carbapenems,~';and~monocyclic :beta-lactams. Particularly preferred ~ are cephems,:~ penems, carbapenems ~ and ~monocyclic beta- l actams .
R~10, in formula (lI)~, is any :radi~al that may be substituted 0 ~; ~at the active sbereolsomeric position: of ~the darbon adJacent! to'~
:the~lactam carbonyl of an:ant~imicrobially-act~ive lactam. (As~used :herein, the.~term~ "ant~imi~crobia~l:ly:a~tive; lactam" refers:~:to a actam-:contalning::~:compound:,~without :a ~ quinolonyl~ substituent:
moi~ety,~whlch~has,~antimlcrobial actlvl~ty~.); This "actlve" position 3~5 ~ is~beta~:~(i,e~ 7-~b~t:a~ 'for:~cephems,~: oxac~phems~ and~carbacephems~
or~examplè).~ :'The ~active~: position is alpha ~ for penems, carb~ap~enems,:~clavems:and:clavams~ Approprlate R1O~groups wlll be appar~nt to~ona~of~.~ordin~ary~skill~in~the:art.~

214~
`'0 94/10163 PCTJUS93/110091 i~`
-23- , ;
Procedures for preparing quinolones and quinolone intermedi- j ' ``ates use~ul in the methods of this invention are described in the following references, all incorporated by reference herein I ~
(including articles listed within these references); 21 Proqress ~ ~`
in Druq Research, 9-104 (1977); 31 J. Med. Chem., 503-5Q6 (1988); ~ ``
32 J. Med. Chem., 1313-1318 (1989~; 1987 Liebiqs Ann. rhem., i-871-879 (1987); 14 Druqs ExDtl. Clin. Res., 379-383 (1988); 31 J. Med._ Chem., 983-991 (1988); 32 J. ~ed. Chem., 537-542 (1989);
78 J. Pharm. 5cl., 585-588 (1989); 26 J. Het. Chem., (1989~; 24 J.
lQ Het. Chem., 181-185 (1987); U.S. Patent 4,599,334, 35 Chem. Pharm.
Bull., 2281-2285 (1987); 2g J. Med. Chem., 2363-2369 (1986); 31 _ Med. Chem., 991-1001 (1988); 25 J. Het. Chem.j 479-485 (1988);
European Patent Publicatton 266,576i European Patent Publication ~`-251,308, 36 Chem. Pharm. Bull , 1223-1228 (1988); European Patent Publication 227,088; European Patent Publication 227,039; European Patent Publication 228,661; 31 J. Med. Chem., I586-1590 (1988); 31 ~i-J. Med. Chem., 1598-1611 (198~); and 23 J. Med. Chem., 1358-1363 (1980).
In general, 5-(N-heterosubstituted amino) quinolones can be "
~o prepared by the following procedure~
.`. .
[5-Halo-Quinulone~ + H2N-N(R4)(R~
~5-((R4)(R5)N-NH)-Quinolone~
-;
where R4 and R5 are previously defined and [~-Halo-Quinolone] is an appropriately protected 5-halogen substituted quinolone where 5 the halogen is preferably chloro or ~luoro~ (preferably fluoro).
The reaction sequence can be envisioned as a nucleophilic aromatic displacement of the quinolone 5-halogen substituted by ;~, R4)tR5)N-NH2 to ~orm the 5-(N-heterosubstituted amino)quinoldnes.
Alternatively, 5-(N-heterosubstitut~d amino)quinolones can be `~
~; 3~0 prepared by the follow1ng procedure:

[5,7-Dihalo-Quinolone~] + H2N-N~R4)(RS) --> ;~`~
; [5-((R4)(R5)N-NH)-7-Halo-Quinolone]

..
w~ere R4 and R5 are previously defined and ~5,7-Dihalo-Quinolone~
is an appropriately protected ~5- and ~'- halogen substituted ;~
. ..

W 0 94/101~ ~r` ~ ~ -24- pcT/us93/lpos~

quinolone where the halogen at positions 5 and 7 is independently a chloro or fluoro (preferably fluoro). The reaction sequence can be envisioned as a selective nucleophilic aromatic displacement of the quinolone 5-halogen substitutent by (R4)(R5)N-NH2 to form the S-(N-heterosubstituted amino)quinolones. The reaction can ' ~ `
preferably be carried out in a nonpolar aprotie sol~ent, preferably ben~ene, toluene, xylene, etc., at an elevated temperature, preferably ~0C to reflux.
Oompositions ~ ;
The compositions of this inYention comprise:
(a) a safe and ef:fective amount of a 5-~H-heterosubstituted amino) quinolone; and ~
(b) a pharmaceutically:ac eptable carrier. `;
A "safe and effective amount" of a 5-(N-heterosubstituted amino) quinolone is an amount that is effective, to inhibit microbial growth at the site of an infection to be treated in a human or lower animal subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific 'isafe and effective amount" ~ will, ;~
obviously, vary with such factors as the particular condition beiny treated, the physical condition of the patient, the duration ~;
; ~ of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the 2S solubility of the 5-(N-heterosubstituted àmlnoj quinolone therein, ; and the dosage regimen desired for the composition.
The campositions of this invention are preferably provided in ; unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a i j 5l(N heterosubstituted amino) quinolone~l that is suitable ifor ad~inistratian to a human or lower animal subject, in a single ~ ~ .
dose, according to good medical practice. These compositions ~`
preferably contain ~from about~ 30 mg to about 201000 mg, more t, ` preferably from àbout S0 mg (milligrams) to about 7000 mg, more preferably from about S00 mg to about 3500 mg, of a 5-(N-hetero-` substituted amino)~quinolone.
The compositions of this invention may be in~any of a variety of farms, suitable ~for~ exam~le;j for oral, rectal, topical or :
, .

2 1 ~ 3 ~ ~`
/10163 2~ PCT/~S93/10091 parenteral administration. Depending upon the particular route of ~ `~administration desired, a variety of pharmaceutically-acceptable I .i~ -carriers well-known in the art may be used. These include solid nr liquld fil~ers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfère with the antimicrobial activity of the S-(N-heterosubstituted amino) quinolone. The amount of carrier employed in conjunction with the 5-(N-heterosubstituted amino) quinolone is sufficient to provide a practical quantity of material for administration per !``j'~`:``' unit dose of the 5-~N-heterosubstituted amino) quinolones. `
Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: 7 Modern Pharmaceutics, Chapters 9 and IO (Banker & Rhodes, editors, 1979); ~
Lieberman et al., Pharmaceutical Dosaqe Forms: Tablets (1981)i and !r;
Ansel, Introduction to Pharmaceutlcal Dosaq~ Forms 2d Edition ;`~1976). ;`
In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starches, cellulose and ,~its derivatives, malt, gelatin, talc, calcium sulfate, vegetable ;
oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water.
Preferred carriers for parenteral administration include propylene ' glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. i `
Preferably, the pharmaceutically-acceptable carrier, in I;
compositions for parenteral administration, comprises at least about 90% by weight by the total composition. ~ .
Various oral dosage forms can be used, inciuding such solid ~ `
Ifolrms as tablets,~ca~psules, granule~s and bulk powders. These oral~
forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the 5-(N-heterosubstituted amino) quinolone. Tablets can be i~
compressed, tablet triturates, enteric-coated, sugar-coated, ~ j film-coated, or multiple-comprcssed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and me~tiflg agents.
Liquid oral dosage ~orms; include aqueous solutions, emulsions, W O 94/lOl~ ~ ' 26 PCT/US93/l~Q

suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifyin9 agents, suspending ~ents, diluents, sweeteners, melting agents, coloring agents and ~lavoring agents. Preferred carriers for oral administration include gelatin, propyl~ne glycol, cottonseed oil and sesame oil.
The compositions of this invention can also be administered topically to a subject, i.e., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject. Such compositions include, for example? lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usual~ly at least about 0.1 and preferably from about lX to about 5%9 of the 5-(N-hetero-substituted amino) quinolone. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature ~and capable of having dispersed or dissolved therein the 5-(N-heterosubstituted amino) qulnolone. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, and solvents.
Methods of Administration ~
This invention also provides methods~of treating or preYenting ~an infectious disorder in~a human or other animal subject, by administering a safe~ and effective amount of a 5-~N-hetero-substituted amino) quinolone to said subject. As used herein, an "infectious disorder"~ is any disorder characterized by the presence of a mi`crobial infection. Preferred methods of this linlvention are fo~ the treatment of bacterial infections. I Su~ch infectious disorders include (for example) central nervous system infeetions, external ear 1nfections, infections of~the mlddle ear~
(such~;as acute OtltiS media~, infect~ons of the cranial sinu~ses, eye lnfections, infe~tions of the oral cavity;(such as infections ~ g o~ the teeth, ~ gums~ and mucosa), upper ~respiratory tract ;;; ~ infections, lowe~r ~rcspiratory tract ;infections, genitourinary infectlons, gastrointesti;nal infections, gynecological infecti~ns, septicemia, bone~ and Joint infections, sk1n and skin structure D ~ 3 ~`
O 94/10163 -27- PCT~US93~1009t infections, bacterial endocarditis, burns, antibacterial prophylaxis o~ surgery, and antibacterial prophylaxis in immuno-suppressed patients (such as patients recei~ting cancer chemotherapy, or organ transplant patients)~
The 5-(N-heterosubstituted amino) quinolones and compositions of this invention can be administered topically or systemically.
Systemic application includes any method of lntroducing the ~-(N-heterosubstituted amino) quinolone into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intraveno~s, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The specific dosage of antimicrobial to be administered, as well as the duration of treatment, are mutually dependent. The dosage and treatment regimen will also depend upon such factors as the specific 5-(N-heterosubstituted ` amino) quinolone used, the resistance pattern of the infe'cting organism to the S-(N-heterosubstituted amino) quinolone used, the , ..
ability of the 5-~N-heterosubstituted amino) quinolone to reach minimum inhibitory concentrations at the site of the infection, the nature and extent of other infections (if any), the personal attributes of the subject (such as weight~, compliance with the treatment regimen, and the presence and severity of any side effects of the treatment. ~
Typically, for a human adult (weighin~ approximately 70 kilograms), from about 75 mg to about 30,Q00 mg, more preferably from about lO0 mg to about 20,000 mg, more preferably from about 500~mg to about 3500 mg, of 5-(N-heterosubstituted amino) quinolone are administered per day. Treatment regimens preferabty extend from aboùt l to about S6 days, preferably from about 7 to about 28 days, in duration. Prophylactic regimens (such as ; ! ! 3~ avoidance of opportunistic infections in~ immunoclompro~ised patients) may extend 6 months, or longer, according ts good medical practice.~
A pre~erred~ method of~parenteral administration is through intramuscular inJection. As is known and practiced in the art, a~ll fqrmulations~for parenteral administratiDn must be sterile.
For mammalst~ especially ~humans, (assuming an approxima~e body weight of 70 kilograms) individual doses ;of from;about lO0 mg to WO 94/10~63 ~8 PCI'/VS93/1~0~--,,~
about 7000 mg, preferably from about 500 mg to about 3500 mg, are acceptable.
A preferred method of systemic administration is oral.
Individual doses of from about I00 mg to about 2500 mg, preferably ~ `
from about 250 mg to about 1000 mg are preferred.
Topical administration can be used to deliver the 5-(N-h~ters-substituted amino) quinolone systemically, or to treat a local ;
infection. The amounts of 5-(N-heterosubstituted amino) quinolone to be topically administered depends upon such factors as skin lo sensitivity, type and location of the tissue to be treated, the compos1ti`on and carrier (if any) to be administered, the particular 5-(N-heterosubstituted amino) quinolone to be adminlstered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) effects are desired.
The following non-limiting examples illustrate the compounds, `
compositions, processes, and uses of the present inventlon.
EXAMP~E I
(S)-7-(3-Aminopyrrolidinyl)-l-cyclopropyl-6,8-difluoro-5-20~ ~ hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic ~ Acid Dihydro-chloride o H2N ~ + ; ~ ~ o/C~3 F 0 ~ ~` o ~a ~CH3 ~.: ~`, ',.' 4 ~
i ~'O 94~10163 2g PCI/US93/10091 .'.,:
F CH3 ~`
F ~ ~ !;
~ o . ~.,:'.,`
F~--F N~ ~ ~ `` ```
m ; .~ :.
~ .. i; .
. fr . ~

. ~
F: O

o ~ ~ F /~
. , . . j ~N~ H O ~ F ~ o N ~ a2C;NHlj"~l~ N

H2N~. ~ ' t `i~
CS~
` ~20~ : IJ 2 HCI

~ .
W O 94/10163 ~ , PCT/US93/lOOa?-7~
A mixture o~ methyl propiolate (983 9, 11.7 mole) and 500 ml of tetrahydrofuran is cooled to 5C and cyclopropylamine ~667 9, 11.7 mole) dissolved in 1000 ml of tetrahydrofuran is added over approximately one hour from an addition funnel at a rate to keep the temperature at 3-7C. The mixture is stirred for an additional hour at 5C and the ice ~ath is removed. The reacticn is stirred for approximately ~one hour at~ 20-25C at room temperature for 3 hours and is allowed to stand for about 2.5 days at room temperature. The solvent is removed under reduced pressure and the residue is vacuum distilled to giYe I.
A solution of approximatel~y 207 9 of ~pentafluorobenzoyl chloride II (0.90 mole) and 250 ml of dioxane is cooled to 15-20C
with an ice water bath and a solution of approximately~126 9 of I
and 90.9 g of triethylamine (0.90 mole) in 300~ml of dloxane is 1'5 added dropwise over 5.~ hours. The addition `funnel is rinsed with an additional 50 ml of dioxane and~ the reaction is~stirred;at 20C
overnlght. ~The mixture ~is,~then vacuum filtered `and the precipitate is washed twice with 100 ml portions;of dioxane. The fi~ltrate is vacuum stripped at 25C and 1000 ml of hexane is added ~ to,t,he residue. More preclpitate is collected and added to the first batch. The combined product is then~resuspended in 150~ mt of h~exane,~stirred brlefly,~fil~tered and vacuum dried to give III.
Ini~a' S L three-necked ~ro~und-bottom flask equipped with ther~ometer, argon Inlet,~ mechanical stirrer, ~and~ an~ addition ~ 25~ ~``funnel~ s ~placed approx~lmateiy~ 4.9 9~(0.621 mole) NaH ~from "~5 ~ hexane-washed NaH/mine'ral,~oi~ and 1000 ml~ of dimethylformamide.
` ';;`This~,mi~xture~i~s cooled~;~;to~IS-2~C~and approximately ~181.5 ~ of III
,(0.~542 mole);~dis,solved~ n~2; L ~of dimethylformamide ls added dropwise over 3.5 hours~while keeping 'the temperature at 15-20C.
o~, Stilrrjng lS eontl~nuqd!~for~ 5~ hours~at this `temperature andl~then! '~
thè~ mixture is further coo1ed to 10 and~500 ml of ice and 1 L of ;` water`~ is~added.~ The ~ml~xture; ~l~s~ neutralized to pH~ 7 with approximately ~5~ml~of~ace~tic~'~acid~ and~ is;~extrac~ed three times with`~chlorofo`~;,~ The,~;drled~chl~orofo ~ extracts~are evaporated- to 3'~ g~' e a~-sl~ ry~whl~ch~ls~triturated 1th~400 ml~of~boil~lng~ethanol.
Thè~ re~sulting~ soiid~s~ ar~'e;~ltered~ at~ room~ temperature. ~An ddit~o al~ wash~ 1th 0~ of~ cold~ethanol followed~by vacuum d ng~gi~ves~IV.~

;'"O 94/10163 P ~ /VSs3~100~1 1 ;

A mixture of IV (229. 0.070 mole) and 2N H2S04 (600 ml) is stirred at 100C for 20 hours and allowed to cool to room ¦' ' ~
temperature. The product V is collected by filtration.~ washing with water. i: ``~';`'' To a mixture of V (189, 0.060 mole) (~S)-t-butoxy- carbonyl- ` i`
aminopyrrolidine ~12g, O.Q66 mole) and dimethylformamide (130 ml) ~'' at 54~C is added dropwise triethylamine (17 ml, 0.12 mole). The `'mixture is stirred at 54C for four hours. Acetonitrile (120 ml) is~added and the mixture is heated to 75C~ and then allowed to '`
cool to room temperature. The mixture is cooled to 15C and the~
solid is collected by filtration, washing with acetonitrile (2 x 60 mlj. The s~olid is stirred in acetonitrile (180 ml) for 10 ~ '`.
minutes and the product VI ls collected by~ filtration, washing~
with acetonitr~le (2 x 60 ml). ~ `
' A mixture of VI ~4.0g, 0.0086 mole), acetoni~rile (120 ml) and ~ '.
hydrazine monohydrate ~(4.0 ml, 0.082 mole) is~ refluxed ~or 2.5 hours with a solution forming. The solution is diluted with a'cetonitrile (100 ml)~ and stirred for 2 hours at room temperature. ` ' ;"
` The precipitate is collected by filtration and heated~ in ~ ~' acetonitrile (150 ml). Some undissolved material is removed by `'' filtration and the filtrate is stored ~ at roam temperature overnight. The product VlI is collected by filtration washing with~acetonitrile. ~
To a mixture~of VI1 (4.09, O.Q083 mole) and methylene chloride 25 ~ (8$ ml) at room tempe~rature is added saturated ethanol~HCl (55 ml) ;slowly with sti;rring. ; The~ mixture is stirred~at~room temperature for~4.5~ hours~`~and~ the~solid is collected by ~filtration. This aterial~ is ::heated in~ `CHC13 (100 ml) and methanol (1~0 ml) is' added. The mixture is~cooled to room temperature and thèlfinal ! '~iprbduct (YIII~)~`i's`collected by f'iltration, washing with CHCl3.

3 ~ ``

Pcr/~ss3/1joo~
W O 94l10163 i -32-(~S)-7-(3-amino-l-pyrrolidinyl)-l-(2,4.difluorophenyl)-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oXO-3-qUinOlineCarboXyliC acid : :
dihydrochloride ~

F F o : ~ : ~ F: F o O '. :
F ~ Il-CI ~ HCX~CCH Coc~:H`~cH~F ~ CCH2COCH2CHJ . `"``
~ F } : ~n-Eu~ : :F : F

: 10 F O ~ F` :F o 1 ,.
~ , " ~
F ~ COOCH~CH~ ~ F: ~ r-CcHCOocH~tcH~

COOH ~ DMF ~ ~ C~O~H

H ~ HCI ~ H; , ~ e ~L ~ ~

, ~ro 94/lql63 33 P ~ /US93/10091 Monoethyl hydrogenmalonate (13.29, 0.10 mol) is dissolved in tetrahydrofuran (760 ml) and cooled to -65C. Then 2M n-butyl lithium (100 ml, 0.20 mol) is added dropwise to maintain a temperature below -50C. The reaction is warmed to -5C and recooled to -65C. Pentafluorobenzoyl chloride 1 (~.20 ml, 0.05 mol~ is di~solved ln tetrahydrofuran (32 ml) and is added dropwise to keep the temperature below -50C. After the addition, the reaction was warmed to -35C and stirred for 1 hr. Aqueous HCl (13~, 316 ml) is added to the solution and stirred for 30 min.
The mixture is extracted with CH2C12 and washed with aqueous NaHC03 followed by water.~ The organic layer ls dried with Na2S04 and concentrated to give the product 2, which ex1sts as a mixture of keto-enol tautomers in solut'ion.
Pentafluorobenzoyl acetic acid ethyl ester 2 (109, 0.035 mol) is added to acetic anhydride (8.5 ml, 0.09 mol) and triethylortho~
formate (10 ml, 0.06 mol). The reaction is heated to 110C for 2.25 hrs. The reaction is concentrated. The product is dissolved in ethanol '(250 ml) and cooled to 0C. Then 2,4-difluoroaniline ; (4.7 ml, 0.046 mol) is slowly added and the ice bath is removed.
; 20 The reaction is stirred overnight and concentrated to dryness under reduced pressure. ~The residue is triturated in petroleu~
ether and the product is collected by filtration to give 3 as a miXture of cis-tr'ans isomers.
` The Yinylogous ~amide ~ (9.439, 0.022 mol) is dissolved in ~ .
;; ~' 25' ~d~imethylformamide (57.0 ml) and K2C03 (9.469, 0.068 mol) is added.
The rèaction is stirred overnight and then concentrated.
Methylene chloride is~ added and the so~ut1on is washed with water.
The organic phase is~dried over Na2S04,~concentrated, and 'vacuum ~ dri`ed to give the quinolone 4.
;~ l '30 , l The ester 4 (8.499, 0.021 mol) is placed in `a solutioni of i '` 8:6:1 acetic acid/water/~2504 (309 ml) and is heated~ to 100C
until the reaction is complete. The solu~ion is poured into ice water, and; the precipitate is filtered. The pr~doot is recrystallized by dlssolviag in CH2C12 and precip~itating out with 3~' ~ hexane. ~ The solid is collected to ~a~or~ the acid 5. The filtrate~is concentrated and the~res1due is purified ~as previously ~ '~
from:~CH~C12:to~give a~sec~ond crop.

PCl'lUS93~100F ~, .

The quinolone 5 (109 0.027 mol) is dissolved in ¦ I
dimethylformamide (60 ml) and (3S)-t-butoxycarbonylamino pyrrolidine (6.0g Q.032 mol) was added. The reaction is heated to 55C and triethylamine ~7.5 ml 0.~54 mol) is added over 20 min. The reaction is completè in 45 min. as determined by TLC and ~``~ ` `
the heat is removed. The product precipitates nut of solution and ``
is filtered. The solid is rinsed with ether. The product is j `
dissolved in hot EtOAc and is`precipitated out by the addition of hexanes. The solid is ~iltered and vacuum ~sried to afford 6.
A mixture of quinolone 6 (2.0g 0.0037 mol) acetonitrile (60 `~
ml) and hydrazine (0.46 ml 0~.0095 mole) is refluxed for 1.6 hrs.
and cooled to room temperature. The product is collected by `;;~
filtràtion and is recrystallized from acetonitril~e to give 7. ~`
A mixture of 7 (0.209 0.00036 mol) and saturated HCl~EtOH (4 ~ :
ml) is stirred at room temperature for one hr. and another 4 ml of ;~;`;`
HCl/EtOH is added. The rea-tion is stirred for an additional 3 hrs. and the solid is colle~ted by filtration. The solid is triturated in CH2C12 and is collected by filtrat;ion.~ The product is~recrystal~lized from acetoni~trilejH20 to give final product.
O

25 ,~

'Z :

2 1 ~ 3 ~` ~
,0 94/10163 PC~r/~USg3/10091 ~ :
, .
EXAMPLE~

l-cyclopropyl-6,8-difluoro~S-hydrazino-1,4-dihydro-4-oxo-7-piperazinyl-3-quinolinecarboxyllc acid dihydrochloride ~

.` .',~:

o .
:5 H2N ~ ~ ~ CH3 ~
,:

\~ .:

F~ ~o/cH3 F F
o F : : :~
/ ~ II I

`15 ~ ~ F`

~ '`,~`'`,''`.

PCIIUS93/li,~O~.- ~`' ",`.`' W0 94/10~ 36~

~.
t"

F O ~ NH O
F~

F 1 : ~ V ;~ `

N~N ~ ~N~

21~Q~ ~ ~
` ~ 94/l0l63 PCT/US93/bOo91 -~7~
A mixture of methyl propiolate (983 9, 11.7 mole) and 500 ml of tetrahydrofuran is cooled to ~C and cyctopropylamine (667 9, 11.7 mole) dissolved in 1000 ml of tetrahydrofuran is added over approximately one hour from an addttion funnel at a rate to keep the temperature at 3-70C. The mixture is stirred for an addit10nal hour at 5C and the ice bath is removed. ~he reaction is sttrred for approximately one hour at 20-25C at room temperature for 3 hours and is allowed to stand for about 2.5 days at room temperature. The solvent is removed under reduced pressure and the residue is vacuum dlst~lled to gî~e I.
A solution of approximately 207 9 o~ pentafluorobenzoyl chloride II ~0.90 mole3 and 250 ml of d~oxane is cooled to 15-20C
with an ioe water bath and a solution of appro%imately 126 9 of I
and 90.9 9 of triethylamine (0.90 mole) in 300 ml of dioxane is added dropwise over 5.5 hours. The addition funnel is rinse~ with an add1tional S0 ml of dioxane and the reaotion ~is stirred at 20~
overnight. The mixture is then vacuum filtered and the precipitate is washed twice with 100 ml portions of dioxane. The ~; filtrate is vacuum stripped~at 25C and 1000 ml of hexane is added to~the residue. More precipitate is collected and added to the first batch. The combined product is then resuspended i~n 15~0 ml of hexane, st1rred brie~ly, f~ltered and YaCUUm dried to give III.
:ln: a S L three-necked round-bottom flask equipped with thermometer, argon inlet, mechanical sttrrer, and an addition 25 ~ ~funnel;~ ~;s placed approximately~ 14.g g (0.621 mole) NaH ~from hex-ne-w~shed NaH/mineral oi~ and 1000 ml of dimethylformamide.
This~mtxture is cooled~to l5-20C and approxim~tely 181.5 9 of III
(0.542 mo1e) dissolved:; in ~2 L of dimethy1formamide is added dropwise over 3.5 hours while keeping the temperature at 15-20C.~; ~0~ i Sttrring ts cont~nued,for 1-5~hours at this'itemperatur2 and then the mixture is further~cooled to~10 and 500~ml of ice and l L of ; water~ ~s added. -~The mixture ~is neutraltzed to pH 7 with approximately 5~ml o~àcet~lc acid~nd is extracted three times with ~hlorofonm. The~dried chloroform extracts are evaporated to35~ ~ gtve a slurry which i~s~tri~turated~with 400 ml~of boi~iog ethanol.
The resulting s~olids are ~iltered at room ~temperature~ An additional~w-sh with IOO~ml of cold ~ethanol` followed by vacuum drying gtves ~IV.

~ Q ~1~3 W O 94/lOt632 PC~/US93/~oo~

A stirred mixture of l-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo- ¦ `;
3-carboxylic acid, methyl ester (compound IV) (8.2 triethylamine (4 ml), t butyl carba~ate (3.89), and toluene is i~
refluxed for approximately one hour and concentrated to dryness 5under reduced pressure. The residue is dissolved in CH2Cl2 (200 ml) and washed with water t~OO ml) and brine (200 ~ he `~`
organic phase is dried over Na2S04, filtered and the filtrate is ~ `
concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (silica ge1) with 5X MeOH/CH~Cl2 10to give the destred C-5 substituted product V.
A mixture of approximately 3.5 9 of Y, tetrahydrofuran (TMF) (30 ml) and 17 ml of l N NaOH is heated at~80t for approximately 1.5 hours. The reaction i~s cooled in an ice bath and water (200 ~I3:
ml) is added, followed by the addition of glacial acetie acid (2.3 15ml~. The precipitate is filtered, washing with water and ether to give eompound YI.
A mixture of approximately 2.6 9 of VI, l~ g of -!~r t-butoxycarbonyl)piperazine, and pyridine (20 ml) is heated at ~r~
`80C for approximately one hour and the react1on mixture is 20concentrated to dryness under reduced pressure. The residue is dissolved in CH2Cl~ (lOO ml) and washed w1th water, 5% citric acid, water, and brine. The organic layer is dried oYer Na2S04, filtered and the filtrate is concentrated to dryness. The residue is purified by flash chromatography (silica; gel) with 5X
25MeOH/CH2Cl2 to afford sompound of VII.
; To a mixture of VI1~ (2.3 9) and CH2C12 (40 ml) at room temperature is added ~slowly approximately 28 ml of saturated ethanol/HCl. The mixture is stirred at room temperature for approximately 4.5 hours and the product is collected by 30~filltration. The;solid is heated in CHCl3 (50 ml) and methanol l~lO
ml~ is addad. The mixture is cooled to room temperature and the i ';
product is col1ected by filtration to give compound VIII.
XAMeLE_A
An antimicrobial composit1on for parenteral administration~
35according to this invention, is made comprising:

.

.

; 2 ~ 4 ~ ~ 0 ~i PcT/us93/,lo~s Component Amount (S)-7-(3-Aminopyrrolidine)-l-cyclopropyl-6,8-difluoro-5-hydra-zino-1,4-dihydro-4-oxo-3-quinoline carboxylic acidl 100 mg/ml carri er Carrier: " ;
sodium citrate buffer with (percent by weight of carrier):
lecithin 0.48X ~
carboxymethylcellulose : ` 0.53 ~
povidone 0.50 ~l methyl paraben : ; Q.ll ;
propyl p`araben ~ O.OlI
1 5 ` i .
1 a 5-(N-heterosubstituted amino) quinolone made according to Example I
.
: The above ingredients~ are mixed, forming a suspension.`
; 20 Approximately 2.0 ml of the suspènsion~ is systemically `; :: : administered, via intramuscular inject~on, to a human subject ::
suffering -from a lower respir~tory tract infection, with ~.
~trePtococ~us Dneum~ni~: present. This dosage: is repeated twice : ~:' dily, for approximately;l4;days. A~ter:4 days, symptoms of the :
25 dtsea5e subside, indicating that : the ~athogen has ~been substantially eradicated~
EXAMPLE 5 :
An ~:enteric~ ~coated~ antimicrobial composition for~ oral admtnistrat10n, accordtng to this invention, is made comprising ' t~he"following core tablet~

7-(3-Amtnopyrrolidine)~
cyclopropyl~6,8-d~tfluoro-5-hydra~ $ ' : :z~no~ dihydro-4-oxo-3-quinoli:ne 35 ~ :~carboxylic :acid`~ 50 0 starch~ ; 3~.0 :;`:: :`magnesium stearate : :: s.o microcrystalline cell~ulose; ~ 100.0 W O 94/1~163J ~0 colloidal silicon dioxide 2.5 povidone 12.5 1 a S-(N-heterosubstituted amino) quinolQne made acco~rding to Example I

The components are admixed into a :bulk mixture. Compressed tablets are formed, using.tablett~ng methods known in the art.
The tablet is then coated with a suspension of methacrylic acid/methacrylic acid ester polymer in isopropanol/acetone. A
human subject, having a urinary tract infection with Escherichia coli present, is orally admlnistered two of the tablets, every 8 u hours9 for 14 days. Symptoms of the disease then subside, indicating substantial eradication of the pathogen.
~.,,j,, ~ ~

~;, ' !~

~: ` `~' ''~''I'i`.
~ !.

~: l 30 . I . ....

- : ~

Claims (20)

WHAT IS CLAIMED IS:

1. Compounds of the general structure:

wherein (A)(1)(a) R1 is alkyl; alkenyl; a carbocyclic ring; a heterocyclic ring; or -N(R6)(R7), where R6 and R7 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R6 and R7 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded;
and (b) R2 is hydrogen, halogen, lower alkyl, or lower alkoxy; or (2) R1 and R2 may: together comprise a six-membered heterocyclic ring that includes N' and the carbon atom to which R2 is bonded;
(B) R3 is a heterocyclic ring or a carbocyclic ring; and (C)(1) R4 and R5 are, independently, hydrogen; lower alkyl;
cycloalkyl; heteroalkyl; or -C(=O)-X-R8, where X is a covalent bond, N, O, or S, and R8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocylic ring; or (2) R4 and R5 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded;
and pharmaceutically acceptable salts and biohydrolyzable esters thereof, and solvates thereof.

2. A compound, according to Claim 1, wherein R1 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, methylamino, cyclopropyl, or 2-fluoro-cyclopropyl.

3. A compound, according to Claim 1, wherein R2 is chlorine or fluorine.

4. A compound, according to Claim 1, wherein R4 is hydrogen and R5 is hydrogen or lower alkyl.

5. A compound, according to Claim 4, wherein both R4 and R5 are hydrogen.

6. A compound, according to Claim 5, wherein R3 is a heterocyclic ring.

7. A compound, according to Claim 6, wherein said hetero-cyclic ring is 3-aminopyrrolidine.

8. A compound, according to Claim 7, wherein R1 is cyclo-propyl and R2 is fluorine.

9. A compound, according to Claim 7, wherein R1 is 2,4-difluorophenyl and R2 is fluorine.

10. A compound, according to Claim 6, wherein said hetero-cyclic ring is piperazine.

11. A compound, according to Claim 10, wherein R1 is cyclopropyl and R2 is fluorine.

12. A compound, according to Claim 4, wherein R5 is lower alkyl.

13. A compound, according to Claim 12, wherein R3 is a heterocyclic ring.

14. A compound, according to Claim 13, wherein said hetero-cyclic ring is 3-aminopyrrolidine.

15. A compound, according to Claim 14, wherein R1 is cyclopropyl and R2 is fluorine.

16. A compound, according to Claim 13, wherein said heterocyclic ring is piperazine.

17. A compound, according to Claim 16, wherein R1 is cyclopropyl and R2 is fluorine.

18. A compound selected from the group consisting of (3S)-7-(3-amino-1-pyrrolidinyl)-1-(2,4,difluorophenyl)-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid;
(3S)-7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid; and 1-cyclopropyl-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-7-piperazinyl-3-quinolinecarboxylic acid; and pharmaceutically-acceptable salts, biohydrolyzable esters, and solvates thereof.

19. A composition for treating or preventing an infectious disorder in a human or other animal subject, comprising:
(1) a safe and effective amount of a compound of Claim 1;
and (2) a pharmaceutically-acceptable carrier.

20. A method for preventing or treating an infectious disorder in a human or other animal subject, by administering to said subject a safe and effective amount of a compound of Claim 1.