AU5409794A - Antimicrobial 5-hydrazino-quinolone derivatives - Google Patents

Description

WON %'10163 PCT/US93/10091 -1- Antimicrobial 5-hydrazino-quinolone derivatives BACKGROUND OF THE INVENTION fhis invention relates to novel antimicrobial compounds, compositions, and methods of treatment. In particular, the compounds of this invention comprise a quinolone or related heterocyclic moiety.

The chemical and medical literature describes a myriad of compounds that are said to be antimicrobial, capable of destroying or suppressing the growth or reproduction of microorganisms, such as bacteria. In particular, antibacterials include a large variety of naturally-occurring (antibiotic), synthetic, or semi-synthetic compounds. They may be classified (for example) as the aminog:ycosides, ansamacrolides, beta-lactams (including penicillins and cephalosporins), lincosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines, and sulfonamides. Such antibacterials and other antimicrobials are described in AntibiotisL ChemotheraDeutlcs. and Antibacterial Agents for Disease Conto Grayson, editor, 1982), and E. Gale et al., The Molecular Basis of Antibiotic Action 2d edition (1981), both incorporated by reference herein.

The mechanism of action of these antibacterials vary.

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

Not surprisingly, the pharmacological characteristics of antibacterials and other antimicrobials, and their suitability WO 94/10163 PCV~US93/1001 -2for any given clinical use, also vary considerably. For example, the classes of antimicrobials (and members within a class) may vary in their relative efficacy against different types of microorganisms, and their susceptibility to development of microbial resistance. These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability, and biodistribution. Accordingly, selection of an appropriate antibacterial (or other antimicrobial) in any given clinical situation can be a complicated analysis of many factors, including the type of organism involved, the desired method of administration, and the location of the infection to be treated.

The pharmaceutical literature is replete with attempts to develop improved antimicrobials compounds that have a broader scope of activity, greater potency, 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 the quinolones. These compounds include, for example, nalidixic acid, difloxacin, enoxacin, fleroxacin, norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin, and pefloxacin. See, C.

Marchbanks and M. Dudley, "New Fluoroquinolones", 7 Hospital Therapy 18 (1988); P. Shah, "Quinolones", 31 Prog. Drug Res. 243 (1987); Quinolones Their Future in Clinical Practice, (A.

Percival, 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 produce improved antimicrobials have produced equivocal results. Indeed, few antimicrobials are developed that are truly clinically-acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial resistance, and pharmacology. For example, the quinolones often show reduced effectiveness against certain clinically important pathogens (for example, gram positive bacteria and/or anaerobic bacteria). The quinolones also have limited water solubility limiting their bioavailability and suitability for parenteral dosing. They may also produce adverse WO 94/0163 PCUS93/10091 -3side effects, such as gastrointestinal disturbance and central nervous system effects (such as convulsions). See, M. Neuman and A. Esanu, "Gaps and Perspectives of New Fluoroquinolones", 24 Drugs Exotl. Clin. Res. 385 (1988); W. Christ et al., "Specific Toxicologic Aspects of the Quinolones", 10 Rev. Infectious Diseases S141 (1988); H. Neu, "Clinical Use of the Quinolones", Lancet 1319 (1987); and "Ciprofloxacin Panacea or Blunder Drug?", J. South Carolina Med. Assoc 131 (March 1989).

SUMMARY OF THE INVENTION The present invention provides compounds of the general structure: 0 0 H-N,, N

'NR

4 1 R 2 wherein

R

I is alkyl; alkenyl; a carbocyclic ring; a heterocyclic ring; or -N(R 6

)(R

7 where RC and R 7 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R 6 and

R

7 together comprise a beterocyclic ring that includes the nitrogen to which they are bonded; and

R

2 is hydrogen, halogen, lower alkyl, or lower alkoxy; or

R

1 and R 2 may together comprise a six-membered heterocyclic ring that includes N' and the carbon atom to which R 2 is bonded;

R

3 is a heterocyclic ring or a carbocyclic ring; and WO 94/10163 PCr/ US93/1 0091

R

4 and R 5 are, independently, hydrogen; lower alkyl; cycloalkyl; heteroalkyl; or -C(O)-X-R 8 where X is a covalent bond, N, 0, or S, and R 8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or

R

4 and 25 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.

It has been found that the compounds of this invention, and compositions containing these cmpounds, are effective antimicrobial agents against a broad range of pathogenic microorganisms. Applicants have also discovered that, surprisingly, compounds of this invention offer significantly increased water solubility at physiological pH in comparison to related antimicrobials known in the art. This surprising property may allow for, among other things, improved pharmacology, including increased serum levels upon administration, ease of formulation, and a more flexible dosing regimen.

PESCRIPTION OF THE INVENTION The present invention encompasses certain novel quinolones, methods for their manufacture, dosage forms, and methods of administering the quinolones to a human or other animal subject.

Specific compounds and compositions to be used in the invention must, accordingly, be pharmaceutically acceptable. As used herein, such a "pharmaceutically-acceptable" component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

5-(N-heterosubstituted amino) ouinolones The compounds of this invention, herein referred tv as amino) quinolones", encompass any of a variety of quinolones (and related heterocyclic moieties) having an N-heteroamino substituent at the 5-position of the quinolone moiety.

The 5-(N-heterosubstituted amino) quinolones of this invention include compounds of the general structure: WO 94/10163 PCT/US93/10091 ,NNR4 wherein

R

1 is alkyl; alkenyl, a carbocyclic ring; a heterocyclic ring; or -N(R 6

)(R

7 (preferably alkyl or a carbocyclic ring), where R 6 and R 7 are independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R 6 and p7 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; and

R

2 is hydrogen, halogen, lower alkyl, or lower alkoxy (preferably halogen); or (Preferably) RI and R 2 may together comprise a sixmembered heterocyclic ring that includes N' and the carbon atom to which R 2 is bonded;

R

3 is a heterocyclic ring or a carbocyclic ring (preferably a heterocyclic ring); and

R

4 and R 5 are, independently, hydrogen; lower alkyl; cycloalkyl; heteroalkyl; or (preferably hydrogen or lower alkyl), where X is a covalent bond, N, 0, or S, and R 8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or (Preferably) R 4 and R5 together comprise a heterocyclic ring that includes the nitrogen to which they are bonded; WO 94/10163 PC/US93/10091 -6and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof.

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

"Heteroatom" is a nitrogen, sulfur or oxygen atom. Groups containing one or more heteroatoms may contain different heteroatoms.

"Alkyl" is an unsubstituted or substituted saturated hydrocarbon chain radical having from 1 to 8 carbon-ai om- preferably from I to 4 carbon atoms. Preferred alkyl groups include (for example) methyl, ethyl, propyl, isopropyl, and butyl.

"Heteroalkyl" is an unsubstituted or substituted saturated chain radical having from 3 to 8 members comprising carbon atoms and one or two heteroatoms.

"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 ,.rng radical.

Carbocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.

"Cycloalkyl" is a saturated carbocyclic ring radical.

Preferred cycloalkyl groups include (for example) cyclopropyl, cyclobutyl and cyclohexyl.

"Heterocyclic ring" is an unsubstituted or substituted, saturated, unsaturated or aromatic ring radical comprised of carbon atoms and one or more heteroatoms in the ring.

Heterocyclic rings are monocyclic or are fused, bridged or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 13 atoms.

"Aryl" is an aromatic carbocyclic ring radical. Preferred aryl groups include (for example) phenyl, tolyl, xylyl, cumenyl and naphthyl.

WO 94/10163 PCr/~US93/10091 -7- "Heteroaryl" is an aromatic heterocyclic ring radical.

Preferred heteroaryl groups include (for example) thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl.

"Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl -0-alkyl or -0-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.

"Alkylamino" is an amino radical having one or two alkyl substituents -N-alkyl).

"Arylalkyl" is an alkyl radical substituted with an aryl group. Preferred arylalkyl groups include benzyl and phenylethyl.

"Arylamino" is an amine radical substituted with an aryl group -NH-aryl).

"Aryloxy" is an oxygen radical having an aryl substituent -0-aryl).

"Acyl" or "carbonyl" is a radical formed by removal of the hydroxy from a carboxylic acid Preferred alkylacyl groups include (for example) acetyl, formyl, and propionyl.

"Acyloxy" is an oxygen radical having an acyl substituent -0-acyl); for example,-0-C(-0)-alkyl.

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

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

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

A "pharmaceutically-acceptable salt" is a cationic salt formed at any acidic carboxyl) group, or an anionic salt formed at any basic amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published September 11, 1987 (incorporated by reference herein). Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium).

WO 94/10163 PCT/US93/1 0091 -8- Preferred anionic salts include the halides (such as chloride salts).

A "biohydrolyzable aster" is an ester of a substituted amino) quir lone that does not essentially interfere with the antimicrobial activity of the compounds, or that are readily converted in vivo by a human or lower animal subject to yield an antimicrobialy-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, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (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 a 5-(M-heterosubstituted amino) quinolone) and a solvent water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the quinolone antimicrobials water, ethanol, acetic acid, N,N-dimethylformamide).

As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and. Bily (1979), incorporated by reference herein. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl aminomethyl, etc.), cyano, halo, carboxy, alkoxyaceyl carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl piperidinyl, morpholinyl, pyrrolidinyl, Wn OAJI ni 4 etc.), imino, thioxo, hydroxyal kyl aryl oxy, aryl al kyl and combinations thereof.

Groups RI, R 2 and R 3 form any of a variety of quinolone moieties known in the art to have antimicrobial activity. Such moieties are well known in the art, as described in the following articles, all incorporated by reference herein: J. Wolfson et al., "The Fluoroquinolones: Structures, Mechanisms of Action and Resistance, and Spectra of Activity In Vitro", 28 Anti-microbial Agents and Chemotherapy 581 (1985); and T. Rosen et al., 31 J. Med Chem. 1586 (1988); T. Risen et al., 31 J.Md Chem. 1598 (1988); G. Klopman et al., 31 Antimi'crob. Agents Cjhemother. 1831 (1987); 31:1831-1840; J. P. Sanchez et al., 31 J. Med. Chem. 983 (1988); J. M. Doniagalia et al., 31 J. Med. Chem. 991 (1988); M. P, Wentland et al., in 20 Ann. Rep. Med. Chem. 145 M. Baily, editor, 1986); J. B. Cornett et al., in 21 Ann. Rep. Med. Chem,.

139 M. Bailey, editor, 1986); P. 8. Fernandes et al., in 22 Ann. Rep. Med. Chem., 117 M. Bailey, editor, 1987); R. Albrecht, 21 Prdo. Drug Research 9 (1977); and P. B. Fernandes et al., in 23 Ann. Rep. Med. Chem. C. Allen, editor, 1987).

R

1 is preferably alkyl, alkenyl, aryl, cycloalkyl, a heterocyclic ring, or alkylamino. More preferably, R1 is ethyl, 2-fluoroethyl, 2-hydroxyethyl, t-butyl, 4-fluorophenyl, 2,4-difluorophenyl, rethylamino, 3-oxetanyl, 2-fluorocyclopropyl, bicyclo pentane, vinyl, or cyclopropyl. Cycloprupyl, 2-fluorocyclopropyl, t-butyl, 2-fluorocyclopropyl, and 2,4-difluorophenyl are particularly preferred RI groups.

Preferred 5-(N-heterosubstituted amino) quinolones also include those where RI and R 2 together comprise a 6-membered heterocyclic ring, accordin~g to the formula: R 0 0 H.N

R

H-C-

I

100U91 wnod94/10163 PCT/US93/10091 V T where X is 0, S, or CH 2

R

2 is preferably chlorine, fluorine, methoxy, or methyl.

Fluorine and chlorine are particularly preferred R 2 groups.

Preferred R 3 groups include nitrogen-containing heterocyclic rings. Particularly preferred are nitrogen-containing heterocyclic rings having from 5 to 8 members. The heterocyclic ring muy contain additional heteroatoms, such as oxygen, sulfur, or nitrogen, preferably nitrogen. Such heterocyclic groups are described in U.S. Patent 4,599,334, Petersen et al., issued July 8, 1986; and U.S. Patent 4,670,444, Grohe et al., issued June 2, 1987 (both incorporated by reference herein). Preferred

R

3 groups include unsubstituted or substituted pyridine, piperidine, morpholine, diazabicyclo[3.1.1]heptane, diazabicyclo[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 R 3 groups which include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dimethylaminomethylpyrrolidine, N-ethylaminomethylpyrrolidine, N-methylpiperazine and azine.

Preferred R 4 and R 5 groups include those where R 4 and R together comprise a heterocyclic ring containing the nitrogen atom to which they are bonded, those where both R 4 and R 5 are lower alkyl, those where one of R 4 or R 5 is hydrogen and the other is lower alkyl, and those where both R 4 and R 5 are hydrogen. More preferred groups are where one of R 4 or R 5 is hydrogen and the other is alkyl and those where both R 4 and R 5 are hydrogen.

Particularly preferred groups are where both R 4 and R 5 are hydrogen.

Preferred compounds of the present invention include those having both an R 3 group that contains a basic nitrogen atom (including, for example, pyridine, piperidine, diazabicyclo- [3.1.1]heptane, diazabicyclo[2.2.1]heptane, diazabicyclo[3,2.1]octane, diazabiclyo[2.2.2]octane, and imidazolidine) and R 4 and R 5 groups that allow the nitrogen atom to which they are bonded to be basic (including, where R 4 and R 5 together comprise a heterocyclic ring containing the nitrogen to which they 94/10163 PCT/llS9/nnol -11are bonded, both R 4 and R 5 are lower alkyl, one of R 4 and R 5 are lower alkyl and the other is hydrogen, or both R 4 and R 5 are hydrogen). Particularly preferred compounds are those where the

R

3 group is one of piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N,N-dinethylaminopyrrolidine, N-ethylaminomethylpyrrolidine, N-methylpiperazine, or and both R 4 and R 5 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 nitrogen atom of a given moiety will depend on the nature of that nitrogen atom's covalent bonding. See, A. Streitwieser and C. Heathcock, Introduction to Organic Chemistry, 2d edition, pp. 734-40 (1981), incorporated by reference herein.

Preferred 5-(N-heterosubstituted amino) quinolones include:

A

Ha 2 N H 2

N,

,C

2

H

HN% rCC02H CN I Nl F N WO 94/10163 WO 9410163PCI?!/US93/1 0091 -12- NH0

C

2

H

NN

fi 2

N%.

X0 2

H

2 NI), 1 Cy

I

C02H .C0 2

H

NVO 94/10163 PCr/US93/10091 -13-

R

2

N%,N

K2*1"

R

2

N.,

WO 94/10163 -14- PCr/US93/10091 EtNH,

H

K2N., K2WJ, C 1-11 NH 0

H

2

N,

NH

H

2

N,

0

H+

2 NNH 0 4JFKF WO 94/10163 PCT/JS93'1009 1 0% H2N.,

H

'11

I

F

A

M0 2 N, H F. C0 2

H

ztJ

I

H

2

N,

NH 0 C0 2

H

N'N

WO 94/10163 PCT/US93/10091

H

2

N..

Fi 2 ND.j Cr'

H

2

N,

NH

I

F

H

2

N,

IC0 2

H

I

I")

1WO\ nA/1013 Prr/I'll 1 /100nn 1

'V

v' tviuj -17-

H

2 N N 0 HCNs NH O EtNH lj y The compounds of this invention are also useful as intermediates in the synthesis of novel lactam-quinolones. Such compounds are disclosed in International Publication No. WO 91/16327, published October 31, 1991, incorporated by reference herein. Lactam-quinolones encompass any of a variety of lactam moieties linked, by a linking moiety, to a quinolone moiety at the of the quinolone.

Lactam-quinolones include compounds having the general structure: Q L B wherein Q, L and B are defined as follows: Q is a structure according to Formula (1)

A

0 0 R 6 R4 C

A

2 A3

N

A R3 wherein O QAod/1I1n P~T/US93/10091 -18- Al is N or C(R 7 where

R

7 is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl, or N(R 8

)(R

9 (preferably hydrogen or halogen), and (ii) R 8 and R 9 are, independently, R 8a where R8a is hydrogen, alkyl, alkenyl, carbocyclic ring, or heterocyclic ring substituents; or R 8 and R 9 together comprise a heterocyclic ring including the nitrogen to which thi;Y are bonded;

A

2 is N or C(R 2 (preferably C(R 2 where R 2 is hydrogen or halogen;

A

3 is N or (preferably) C(R 5 where R 5 is hydrogen;

R

1 is hydrogen, alkyl, a carbocyclic ring, a heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl, or N(R 8

)(R

9 (preferably alkyl or a carbocyclic ring);

R

3 is hydrogen, halogen, alkyl, a carbocyclic ring, or a heterocyclic ring (preferably a heterocyclic ring);

R

4 is hydroxy; and

R

6 is R 15 or R 16 X; where R 15 is a substituent moiety of L and is nil, alkyl, heteroalkyl, or alkenyl; R 16 is a substituent moiety of L and is alkyl, alkenyl, a carbocyclic ring or a heterocyclic ring; and X is alkyl, heteroalkyl, alkenyl, oxygen, sulfur, or NH; except that when A 1 is C(R 7 RI and R 7 may together comprise a heterocyclic ring including N' and Al; when A 2 is C(R 2

R

2 and R 3 may together comprise where n is an integer from 1 to 4; when A 3 is C(RS), R 4 and R 5 may together comprise a heterocyclic ring including the carbon atoms to which R 4 and R 5 are bonded and the carbon atom of Formula to which said carbon atoms are bonded; and when A 3 is C(RS), R 1 and R 5 may together comprise a heterocyclic ring including N' and the adjacent carbon to which R 5 is bonded; (II) B is a structure according to Formula where L is bonded to R 14 Wn OA11 01 A PC/US93/1 0091 ir\ U~f OA1Ah~ PI'!US3/1009 19-

R'

(0IIR.12 R 14 0 NIR 3/ wherein

R

10 is hydrogen, halogen, heteroalkyl, a carbocyclic ring, a heterocyclic ring, R8a-O-, RBaCH-N-, (R 8

)(R

9

R

17 -C(=CHR2O)-C(-O)NH', or (preferably) alkyl, alkenyl, R17-C(-NO-R 19 or R' 8 -(CH2)m-C(w0)NH-; where m is an integer from 0 to 9 (preferably from 0 to 3);

R

17 is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl, a carbocyc*,ic ring, or a heterocyclic ring);

R

18 is R 17 -yl, or -CH(y 2

)(R

7

R

19 is R 17 arylalkyl, heteroarylalkyl, -C(R 22

)(R

23

)COOH

-C(-O)O-Rl 7 or -C(-O)NH-RI 7 where R 22 and R 23 are, independently, R 17 or together comprise a carbocyclic ring or a heterocyclic ring including the carbon atom to which

R

22 and R 23 are bonded (preferably R 17 or

-C(R

22

)(R

23 )C00H)

R

20 is R 19 halogen, -YI, or -CH(Y 2 )(Rl 7 (preferably R 19 or halogen); YI is -C(-O)OR 21 -C(-0)R 21

-N(R

24

)R

21 or -S(O)pR 2 9 or

-OR

29 and V 2 is YI or -OH, -SH, or -SO3H; p is an integer from 0 to 2 (preferably 0);

R

24 is hydrogen; alkyl; alkenyl; heteroalkyl; heteroalkenyl; a carbocyclic ring; a heterocyclic rrig; -S03H; C(-O)R 25 or, when R 18 is

-CH(N(R

24

)R

21

)(R

7

R

24 may comprise a moiety bonded to R 21 to form a heterocyclic ring; and

R

25 is R 17

NH(R

17

N(R

17

)(R

26 0(R 26 or S(R 26 (preferably R 17

NH(R

17 or N(R 17

)(R

26 where R 26 is alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring or (preferably) when R 25 is N(R7)(R 26

R

26 may WO 94/10163 PC/US93/10091 comprise a moiety bonded to R1 7 to form a hetero.

cyclic ring; and

R

21 is R 29 or hydrogen; where R 29 is alkyl; alkenyl; arylalkyl; heteroalkyl; heteroalkenyl; heteroarylalkyl; a carbocyclic ring; a heterocyclic ring; or, when Yl is

N(R

24

)R

21 and R 21 is R 29

R

21 and R 24 may together comprise a heterocyclic ring including the nitrogen atom to which R 24 is bonded (preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring);

R

11 is hydrogen, halogen, alkoxy, or R 27 C(=O)NH- (preferably hydrogen or alkoxy), where R 27 is hydrogen or alkyl (preferably hydrogen); bond is a single bond or is nil; and bond is a single bond, a double bond, or is nil; except bond and bond "b" are not both nil;

R

12 is -C(R 8 or -CH2-R 28 (preferably -C(R 8 where R 28 is -C(R 8 or and R 28 is directly bonded to N" in Formula (II) to form a 5-membered ring; except, if bond is nil, then R 12 is (preferably) where

X

1 is -R 21

-OR

30 -S(O)rR 30 where r is an integer from 0 to 2 (preferably -O(C=O)R 30 or N(R 30

)R

31 and (ii) R 30 and R 31 are, independently, alkyl, alkenyl, carbocyclic ring or heterocyclic ring substituents; or R 30 and R 31 together comprise a heterocyclic ring including the nitrogen atom to which

R

30 and R 31 are bonded; or -CH2-R 32 where R 32 is -C(RBa)(R21), or -NRBa, and R 32 is directly bonded to N" in Formula (II) to form a 5-membered ring; if bond is a single bond, R 13 is preferably

-CH(R

33 or, -C(O)NHS02-, if bond is nil; or

-C*(R

33 if R 14 contains a R 36 moiety; where R 33 is hydrogen or COOH (preferably COOH), and C* is linked to R36 to form a 3-membered ring; if bond is a double bond, R 13 is -C(R 33 or WO 94/10163 PCT/US93/10091 -21i f bond i s nil, R 13 i s hydrogen, -S03H, -PO(0R 34 )OH, -C(0)NHSO2N(R 34

)(R

35 -OSO3H,

-CH(R

35 )COOI, or -OCH(R 34 )COOH (preferably -SO3H, or -C(O)NHSO2N(R 34

)(R

35 where R 34 is hydrogen, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and R 35 is hydrogen, alkyl, alkenyl, or -NHR~a; or (preferably), if R1 3 is -C(0)NHSO2N(R 34

)(R

35

R

34 and

R

35 may together comprise a heterocyclic ring inclu~ding the nitrogen to which R 34 and R 35 are bonded; and if bond or bond is nil, then R 14 is nil and L is bonded directly to R 12 or R1 3 if bond and are single bonds, R 14 is 37 or 36

)-R

37 or (preferably) if bond is a single bond and bond "b" is is a double bond, R1 4 is or (preferably) -WCRa R3)C-3- or where W isO0; S(0)S, where s is an integer from 0 to 2 (preferably or C(R 38 where R 38 is hydrogen, alkyl or alkoxy;

R

36 hydrogen; alkyl; alkenyl; -COGH; or, if R 13 is -C*(R 33

R

36 may be linked to C* to form a 3-membered carbocyclic ring;

R

37 is nil, alkyl, alkenyl, a carbocyclic ring, or a heterocyclic ring; and is directly bonded to R 13 to form a 5- or 6-membered ring, and (III) L links Q to B; and L is -X 2 t-R 39 or -y 3 t-R 39 where L' is -X 2

-X

3 or -X 4 t-C(.y 3 (preferably -X 2

-X

3 .qot, -X 4 t and u are, independently, 0 or 1;

R

39 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, a carbocyclic ring, or a heterocyclic ring (preferably alkyl or alkenyl);

X

2 is oxygen, or S(0)v, where v is an integer from 0 to 2 (preferably 0); WO 94/10163 PCTUS93/10091 -22-

X

3 is nitrogen; N(R 40

N+(R

4 1

)(R

42 or R43-N(R41); and is linked to R 14 by a single or double bond; or, if

R

14 is nil, X 3 is linked to B by a single or double bond (preferably X 3 is nitrogen, N(R 40 or

N+(R

41

)(R

42 where

R

40 is R8a; -OR 8 a; or -C(O=)R8a; (preferably R8a);

R

41 and R 42 are, independently, hydrogen; alkyl; alkenyl; carbocyclic rings; heterocyclic rings; or, if R 6 is R 16 X, then R 41 and R 42 together with may comprise a heterocyclic ring as R 16

R

43 is N(R 41 oxygen or sulfur;

X

4 is oxygen, sulfur, NR 40 or R 43

-NR

41 (preferably oxygen, sulfur or NR 4 0);

Y

3 is oxygen, sulfur, NR 40 or N+(R41)(R42); y4 is oxygen or NR 41 (preferably oxygen); Z is nil, oxygen, sulfur, nitrogen, NR 40 or N(R 4 1)-R 43 (preferably oxygen, sulfur, nitrogen or NR 40 Q' is said R 6 substituent of Q; and (10) Q" is or together with X 2

X

3 Z or is said R 6 substituent of Q; and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and hydrates thereof.

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

R

10 in formula is any radical that may be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of an antimicrobially-active lactam. (As used herein, the term "antimicrobially-active lactam" refers to a lactam-containing compound, without a quinolonyl substituent moiety, which has antimicrobial activity.) This "active" position is beta 7-beta) for cephems, oxacephems and carbacephems (for example). The active position is alpha for penems, carbapenems, clavems and clavams. Appropriate R10 groups will be apparent to one of ordinary skill in the art.

WO 94/10163 PCr/US3/10091 -23- Procedures for preparing quinolones and quinolone intermediates useful in the methods of this invention are described in the following references, all incorporated by reference herein (including articles listed within these references); 21 Progress in Drug Research, 9-104 (1977); 31 J. Med. Chem., 503-506 (1988); 32 J. Med. Chem., 1313-1318 (1989); 1987 Liebigs Ann. Chem., 871-879 (1987); 14 Drugs Exptl. Clin. Res., 379-383 (1988); 31 J. Med. Chem., 983-991 (1988); 32 J. Med, Chem., 537-542 (1989); 78 J. Pharm. Sci., 585-588 (1989); 26 J. Het. Chem., (1989); 24 J.

Het. Chem., 181-185 (1987); U.S. Patent 4,599,334, 35 Chem. Pharm.

Bull., 2281-2285 (1987); 29 J. Med. Chem., 2363-2369 (1986); 31 J.

Med. Chem., 991-1001 (1988); 25 J. Het. Chem., 479-485 (1988); European Patent Publication 266,576; European Patent Publication 251,308, 36 Chem. Pharm. Bull., 1223-1228 (1988); European Patent Publication 227,088; European Patent Publication 227,039; European Patent Publication 228,661; 31 J. Med. Chem., 1586-1590 (1988); 31 J. Med. Chem., 1598-1611 (1988); and 23 J. Med. Chem., 1358-1363 (1980).

In general, 5-(N-heterosubstituted amino) quinolones can be prepared by the following procedure: H2N-N(R 4

)(R

5 4 where R 4 and R- sre previously defined and [5-Halo-Quinolone] is an appropriately protected 5-halogen substituted quinolone where the halogen is preferably chloro or fluoro (preferably fluoro).

The reaction sequence can be envisioned as a nucleophilic aromatic displacement of the quinolone 5-halogen substituted by

(R

4

)(R

5 )N-NH2 to form the 5-(N-heterosbxbtituted amino)quinolones.

Alternatively, 5-(N-heterosubstituted amino)quinolones can be prepared by the following procedure: [5,7-Dihalo-Quinolone] H2N-N(R 4

)(R

5 4

)(R

5 )N-NH)-7-Halo-Quinolone] where R 4 and R 5 are previously defined and [3,7-Dihalo-Quinolone] is an appropriately protected 5- and 7- halogen substituted WO41 aAIIA.1 PC/us93/10091 TTrVJ ,71 V~IAVJ -24quinolone 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 (R 4

)(R

5 )N-NH2 to form the 5-(N-heterosubstituted amino)quinolones. The reaction can preferably be carried out in a nonpolar aprotic solvent, preferably benzene, toluene, xylene, etc., at an elevated temperature, preferably 50oC to reflux.

Compositions The compositions of this invention comprise: a safe and effective amount of a amino) quinolone; and a pharmaceutically:acceptable carrier.

A "safe and effective amount" of a 5-(N-heterosubstituted amino) quinolone is an amount that is effective, to inhibit m'crobial growth at the site of an infection to be treated in a human or lower animal subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific "safe and effective amount" will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the 5-(N-heterosubstituted amino) quinolone therein, and the dosage regimen desired for the composition.

The compositions of this invention are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition of this invention containing an amount of a 5-(N-heterosubstituted amino) quinolone that is suitable for administration to a human or lower animal subject, in a single dose, according to good medical practice. These compositions preferably contain from about 30 mg to about 20,000 mg, more preferably from about 50 mg (milligrams) to about 7000 mg, more preferably from about 500 mg to about 3500 mg, of a substituted amino) quinolonn.

The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical or WO 94/10163 PCT/US93/10091 parenteral administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the antimicrobial activity of the amino) quinolnne. 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 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 herein4 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker Rhodes, editors, 3979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

In particular, pharmaceutically-acceptable carriers for systemic administration include sugars, starch)s, 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.

Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight by the total composition.

Various ori d- agI forms can be used, including such solid forms as tablets, capsules, granules and Bulk pszg"rs. These oral forms comprise a safe and effective amount, usually at least about and preferably from about 25% to about 50%, of the amino) quiolone. Tablets can be Compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.

Liquid oral dosage forms include aqueous solutions, emulsions, 1WO11 A tI nl Dr'T/ni mni/1nni1 T vJ IvU4J .26-& suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents. Preferred carriers for oral administration include gelatin, propylene glycol, cottonseed oil and sesame oil.

The compositions of this invention can also be administered topically to a subject, by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject. Such compositions include, for example, lotions, creams, solutions, gels and solids, These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1%, and preferably from about 1% to about of the 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) quinolone. The carrier may include pharmaceutically-acceptable emolients, emulsifiers, thickening agents, and solvents, Methods ofAdministration This invention also provides methods of treating or preventing an infectious disorder in a human or other animal subject, by administering a safe and effective amount of a substituted amino) quinolone to said subject, As used herein, an "infectious disorder" is any disorder characterized by the presence of a microbial infection. Preferred methods of this invention are for the treatment of bacterial infections. Such infectious disorders include (for example) central nervous system infections, external ear infections, infections of the middle ear (such as acute otitis media), infections of the cranial sinuses, eye infections, infections of the oral cavity (such as infections of the teeth, gums and mucosa), upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure WO 94/10163 PCUS93/1 0091 v -27infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients (such as patients receiving 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 introducing the amino) quinolone into the tissues of the body, intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublinguai, 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 amino) quinolone used, the resistance pattern of the infecting organism to the 5-(N-heterosubstituted amino) quinolone used, the ability of the r-(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 (stch as weight), compliance with the treatment reqimen, and the presence and severity of any side effects of the treatment, Typically, for a human adult (weighing approximately kilograms), from about 75 mg to about 30,000 mg, more preferably from about 100 mg to about 20,000 mg, more preferably from about 500 mg to about 3500 mg, of 5-(N-heterosubstituted amino) quinolone are administered per day. Treatment regimens preferably extend from about 1 to about 56 days, preferably from about 7 to about 28 days, in duration. Prophylactic regimens (such as avoidance of opportunistic infections in immunocompromised patients) may extend 6 months, or longer, according to good medical practice.

A preferred method of parenteral administration is through intramuscular injection, As is known and practiced in the art, all formulations for parenteral administration must be sterile.

For mammals, especially humans, (assuming an approximate body weight of 70 kilograms) individual doses of from about 100 mg to WO94/1n163 PCT/US93/10091 -28about 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 100 mg to about 2500 mg, preferably from about 250 mg to about 1000 mg are preferred.

Topical administration can be used to deliver the 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 sensitivity, type and location of the tissue to be treated, the composition and carrier (if any) to be administered, the particular 5-(N-heterosubstituted amino) quinolone to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) effects are desired.

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

EXAMPLE 1 (S)-7-(3-Aminopyrrolidinyl)-l-cyclopropy1-6,8-difluoro-5hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic Acid Dihydrochloride 0 F 0 0 F CH F F

F

III

WO 94/10163 WO 9419163PCT/US93/10091 -29tin ItF 14 2

N,

2 O.4*th~.

KZNH' 0 H2WIII N WO 94/10163 PCr/US93/10091 A mixture of methyl propiolate (983 g, 11.7 mole) and 500 ml of tetrahydrofuran is cooled to 50o and cyclopropylamine (667 g, 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 3-70C. The mixture is stirred for an additional hour at 500C and the ice bath is removed. The reaction is stirred for approximately one hour at 20-250C 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 give I.

A solution of approximately 207 g of pentafluorobenzoyl chloride II (0.90 mole) and 250 ml of dioxane is cooled to 15-2000 with an ice water bath and a solution of approximately 126 g of I and 90.9 g of triethylamine (0.90 mole) in 300 ml of dioxane is added dropwise over 5.5 hours. The addition funnel is rinsed with an additional 50 ml of dioxane and the reaction is stirred at 2000C 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 250C 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 in 1500 ml of hexane, stirred briefly, filtered and vacuum dried to give III.

In. a 5 L three-necked round-bottom flask equipped with thermometer, argon inlet, mechanical stirrer, and an addition funnel is placed approximately 14.9 g (0.621 mole) NaH (from hexane-washed NaH/mineral oil) and 1000 ml of dimethylformamide.

This mixture is cooled to 15-2000 and approximately 181.5 g of III (0.542 mole) dissolved in 2 L of dimethylformamide is added dropwise over 3.5 hours while keeping the temperature at 15-200C.

Stirring is continued for 1.5 hours at this temperature and then the mixture is further cooled to 100 and 500 ml of ice and 1 L of water is added. The mixture is neutralized to pH 7 with approximately 5 ml of acetic acid and is extracted three times with chloroform. The dried chloroform extracts are evaporated to give a slurry which is triturated with 400 ml of boiling ethanol.

The resulting solids are filtered at room temperature. An additional wash with 100 ml of cold ethanol followed by vacuum drying gives IV.

WO 94/10163 PCr/US93/10091 -31- A mixture of IV (22g. 0.070 mole) and 2N H2S04 (600 ml) is stirred at 100oC for 20 hours and allowed to cool to room temperature. The product V is collected by filtration, washing with water.

To a mixture of V (18g, 0.060 mole) (3S)-t-butoxy- carbonylaminopyrrolidine (12g, 0.066 mole) and dimethylformamide (130 ml) at 54 0 C is added dropwise triethylamine'(17 ml, 0.12 mole). The mixture is stirred at 54 0 C for four hours. Acetonitrile (120 ml) is added and the mixture is heated to 7500 and then allowed to cool to room temperature. The mixture is cooled to 15 0 C and the solid is collected by filtration, washing with acetonitrile (2 x ml). The solid is stirred in acetonitrile (180 ml) for minutes and the product VI is collected by filtration, washing with acetonitrile (2 x 60 ml).

A mixture of VI (4.0g, 0.0086 mole), acetonitrile (120 ml) and hydrazine monohydrate (4.0 ml, 0.082 mole) is refluxed for hours with a solution forming. The solution is diluted with acetonitrile (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 room temperature overnight. The product VII is collected by filtration washing with acetonitrile.

To a mixture of VII (4.0g, 0.0083 mole) and methylene chloride (85 ml)'at room temperature is added saturated ethanol/HC1 (55 ml) slowly with stirring. The mixture is stirred at room temperature for 4.5 hours and the solid is collected by filtration. This material is heated in CHC13 (100 ml) and methanol (10 ml) is added. The mixture is cooled to room temperature and the final product (VIII) is collected by filtration, washing with CHC13.

WO 94/10163 WO 9410163PCT/US93/10091 -32- EXAMPLE-2 (3S) (3-ai no- 1 -pyrrol idi nl1) di f1 uoropheny 8difluoro-5-hydrazino-1,4-dihydro-4-xo-3-quiliflecarboxylic acid di hydrochi oride F F0 F F

I

HOOCCH

2 COOCH .,CHI n-EBul F F o 0 F CCH 2 COCH 2

CH

3 F F F 0

OCH

2

CH

3

K

2 C0 3

F

DMF

F F CCHCO0CH 2

CH-

3

I~F

F F CHM-NI{t& 4., F 0

DMF

BocNH

H

2

NNH

2

ICH

3

CN

f N \H0

HCI

EtCH 2HCI VO 94/10163 PCT/US93/10091 -33- Monoethyl hydrogenmalonate (13.2g, 0.10 mol) is dissolved in tetrahydrofuran (260 ml) and cooled to -650C. Then 2M n-butyl lithium (100 ml, 0.20 mol) is added dropwise to maintain a temperature below -500C. The reaction is warmed to -50C and recooed to -65oC. Pentafluorobenzoyl chloride 1 (7.20 ml, 0.05 mol) is dissolved in tetrahydrofuran (32 ml) and is added dropwise to keep the temperature below -5000C. After the addition, the reaction was warmed to -350C and stirred for 1 hr. Aqueous HC1 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 is dried with Na2S04 and concentrated to give the product 2, which exists as a mixture of keto-enol tautomers in solution.

Pentafluorobenzoyl acetic acid ethyl ester 2 (lOg, 0.035 mol) is added to acetic anhydride (8.5 ml, 0.09 mol) and triethylorthoformate (10 ml, 0.06 mol). The reaction is heated to 110 0 C for 2.25 hrs. The reaction is concentrated. The product is dissolved in ethanol (250 ml) and cooled to OoC. Then 2,4-difluoroaniline (4.7 ml, 0.046 mol) is slowly added and the ice bath is removed.

The reaction is stirred overnight and concentrated to dryness under reduced pressure. The residue is triturated in petroleum ether and the product is collected by filtration to give 3 as a mixture of cis-trans isomers.

The vinylogous amide 3 (9.43g, 0.022 mol) is dissolved in dimethylformamide (57.0 ml) and K2C03 (9.46g, 0.068 mol) is added.

The reaction is stirred overnight and then concentrated.

Methylene chloride is added and the solution is washed with water.

The organic phase is dried over Na2S04, concentrated, and vacuum dried to give the quinolone 4.

The ester 4 (8.49g, 0.021 mol) is placed in a solution of 8:6:1 acetic acid/water/H2S04 (309 ml) and is heated to 100OC until the reaction is complete. The solution is poured into ice .,water, and the precipitate is filtered. The product is recrystallized by dissolving in CH2C12 and precipitating out with hexane. The solid is collected to afford the acid 5. The filtrate is concentrated and the residue is purified as previously from CH2C12 to give a second crop.

v' 4/'n 1/1n3 PC/US93/10091

T

-34- The quinolone 5 (10g, 0.027 mol) is dissolved in dimethylformamide (60 ml) and (3S)-t-butoxycarbonylamino pyrrolidine (6.0g, 0.032 mol) was added. The reaction is heated to 55 0 C and triethylamine (7.5 ml, 0.054 mol) is added over min. The reaction is complete in 45 min. as determined by TLC and the heat is removed. The product precipitates out of solution and is filtered. The solid is rinsed with ether. The product is dissolved in hot EtOAc and is precipitated out by the addition of hexanes. The solid is filtered and vacuum dried to afford 6.

A mixture of quinolone 6 (2.0g, 0.0037 mol), acetonitrile 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 filtration and is recrystallized from acetonitrile to give 7.

A mixture of 7 (0.20g, 0.00036 mol) and saturated HCI/EtOH (4 ml) is stirred at room temperature for one hr. and another 4 ml of HC1/EtOH is added. The reaction is stirred for an additional 3 hrs. and the solid is collected by filtration. The solid is triturated in CH 2 C12 and is collected by filtration. The product is recrystallized from acetonitrile/H20 to give final product.

VO 94/10163 PCr/US93/10091 EXAMPLE 3 1-cyclopropyl-6,8-difluoro-5-hydrazino-I,4-dihydro-4-oxo-7piperazinyl-3-quinolinecarboxylic acid dihydrochioride

H

2 iCH, F 00 F 1-CH 3 F F 0 06 F FIN WO 94/10163 'US93/10091 -36- F 0 v

F

HN%%

tSU0 2 C' NNr Fi -2 1tCI WO 94/10163 PC/US9310091 -37- A mixture of methyl propiolate (983 g, 11.7 mole) and 500 ml of tetrahydrofuran is cooled to 5oc and cyclopropylamine (667 g, 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 3-70C. The mixture is stirred for an additional hour at 5 0 C and the ice bath is removed. The reaction is stirred for approximately one hour at 20-25oC 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 give I.

A solution of approximately 207 g of pentafluorobenzoyl chloride II (0.90 mole) and 250 ml of dioxane is cooled to 15-200C with an ice water bath and a solution of approximately 126 g of I and 90.9 g of triethylamine (0.90 mole) in 300 ml of dioxane is added dropwise over 5.5 hours. The addition funnel is rinsed with an additional 50 :1l of dioxane and the reaction is stirred at 200o overnight. The mixture is then vacuum filtered and the precipitate is washed twice with 100 ml portions of dioxane.

filtrate is vacuum stripped at 25 0 o and 1000 ml of hexane is added to thte residue. More precipitate is collected and added to the first batch. The combined product is then resuspended in 1500 ml of hexane, stirred briefly, filtered and vacuum dried to give III.

In a 5 L three-necked round-bottom flask equipped with thermometer, argon inlet, mechanical stirrer, and an addition funnel is placed approximately 14.9 g (0.621 mole) NaH (from hexane-washed NaH/mineral oil) and 1000 ml of dimethylformamide.

This mixture is cooled to 15-200C and approximately 181.5 g of III (0.542 mole) dissolved in 2 L of dimethylformamide is added dropwise over 3.5 hours while keeping the temperature at 15-200C.

Stirring is continued for 1.5 hours at this temperature and then the mixture is further cooled to 10o and 500 ml of ice and 1 L of water is added. The mixture is neutralized to pH 7 with approximately 5 ml of acetic acid and is extracted three times with chloroform. The dried chloroform extracts are evaporated to give a slurry which is triturated with 400 ml of boiling ethanol.

The resulting solids are filtered at room temperature. Ai additional wash with 100 ml of cold ethanol followed by vacuum drying gives IV.

VO 94/10163 PCF/US93/10091 -38- A stirred mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo- 3-carboxylic acid, methyl ester (compound IV) (8.2g), triethylamine (4 ml), t-butyl carbazate and toluene is refluxed for approximately one hour and concentrated to dryness under reduced pressure. The residue is dissolved in CH2C12 (200 ml) and washed with water (200 ml) and brine (200 ml). The 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 gel) with 5% MeOH/CH2C12 to give the desired C-5 substituted product V.

A mixture of approximately 3.5 g of V, tetrahydrofuran (THF) ml) and 17 ml of I N NaOH is heated at 8000 for approximately hours. The reaction is cooled in an ice bath and water (200 ml) is added, followed by the addition of glacial acetic acid (2.3 ml). The precipitate is filtered, washing with water and ether to give compound VI.

A mixture of approximately 2.6 g of VI, 1.3 g of 1-(t-butoxycarbony1)piperazine, and pyridine (20 ml) is heated at for approximately one hour and the reaction mixture is concentrated to dryness under reduced pressure. The residue is dissolved in CH2C12 (100 ml) and washed with water, 5% citric acid, water, and brine. The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated to dryness. The residue is purified by flash chromatography (silica gel) with MeOH/CH2C12 to afford compound of VII.

To a mixture of VII (2.3 g) and CH2CI2 (40 ml) at room temperature is added slowly approximately 28 ml of saturated ethanol/HC1. The mixture is stirred at room temperature for approximately 4.5 hours and the product is collected by filtration. The solid is heated in CHC13 (50 ml) and methanol ml) is added. The mixture is cooled to room temperature and the product is collected by filtration to give compound VIII.

EXAMPLE 4 An antimicrobial composition for parenteral idrwinistration, according to this invention, is made comprising: VO 94/10163 -39- Comnonent (S)-7-(3-Asninopyrrolidine) -1cyclopropyl 5,8-difluoro-5-hydrazino-1 ,4-dihydro-4-oxo-3-quinolime carboxylic acid 1 Carrier: sodium citrate buffer with (percent by weight of carrier): lecithin carboxymethyl cellulose povi done methyl paraben propyl parabei 1: a 5-(N-heterosubstituted amino) to Example I PCI'/US93/10091 100 mg/mi carrier 0.*48% 0.53 0.50 0.11 0.011 quinolone made according The above ingredients are mixed, forming a suspension.

Apprc.ximately 2.0 ml of the suspension is systemically administered, via intramuscular injection, to a human subject sufferling from a lower respiratory tract infection, with pneumonia present. This dosage is repeated twice daily, for approximately 14 days. After 4 days, symptoms of the disease subside, indicating that the pathogen has been substantially eradicated.

An enteric coated administration, according the following core tablet: (S)-7-(3-Aminopyrrol idine).

cyclopropyl -(,,-difluoro-5S.

zino-1 ,4-dihydro-4-oXo-3-qL carboxylic acidl starch magnfrsium ste&zrate microcrystalline cellulose antimicrobial composition for oral to this invention, -is made comprising *hydraiinoline 350.0 30.0 100.0 Vn QAII (1161 VA OA/1I~i~PCTr/1S93/10091 coll~oidal silica~n dioxide povi'done 12.5 1: a 5-(N-heterosubstituted amino) quiriolone made according to Example I The componenrts are admixed into a bulk mixture. Compressed tablets are forwed, using tabletting methods known in the art.

The tablet is then coated with a suspension of methacrylic acid/methacrylic acid ester polymet in i sopropanol /acetone. A human subject, Wiving a urinary tract infection with Escherichia coij present, is orally administered two of the tablets, every 8 hours, for 14 days. Symptoms of the disease then subside, indicating substaritial eradication of the pathogen.

Claims (16)

1. Compounds of the general structure: F R R wherein R 1 is alkyl; alkenyl; a carbocyclic ring; a heterocyclic ring; or 7 where R 6 and R 7 are, independently, hydrogen, alkyl, alkenyl, a carbocyclic ring, a heterocyclic ring, or R 6 and R7 together comprise a heterocyclic ring that includes the nitrogen to which they are bondedt and R2 is hydrogen, halogen, lower. alkyl# or lower alkoxy; or RI and R 2 may together comprise a six-membered heterocyclic ring that includes N1 and the carbon atom to which R 2 is bonded~; R 3 is a heterocyclic ring or a, carbocyclic ring; and R 4 and R 5 are, independently, hydrogen; lower alkyl; cycloalkyl; heteroalkyl;, or 8 where X is a covalent bond, N, 0, or St and R 8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or R 4 and R 5 togethe corny -se a heterocyclic ring that includes the nitrogen to wi~ch they are bonded; and pharniaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof. WO 94/10163 PCI'/US93/13091 -42-

2. A compound, according to Claim I, wherein RI is ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2,4-difluorophetyl, methylamino, cyclopropyl. t-butyl, cyclopropyl,

4-fluorophenyl, or 2-fluoro- 3. A compound, according to Claim 1, wherein or fluorine. 4. A compound, according to Claim 1, wherein and R 5 is hydrogen or lower alkyl. A compound, according to Claim 4, wherein are hydrogen. R 2 is chlorine R 4 is hydrogen both R 4 and R

6. A compound, according to Claim 5, wherein R 3 is a heterocyclic ring.

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

8. A compound, according to Claim 7, propyl and R2 is fluorine.

9. A compound, according to Claim 2,4-difluorophenyl and R 2 is fluorine. A compound, according to Claim 6, cyclic ring is piperazine.

11. A compound, according to Claim cyclopropyl and R 2 is fluorine. wherein said hetero- wherein RI is cyc'o- 7, wherein RI wherein said hetero- 10, wherein RI is

12. A compound, according to Claim 4, wherein R 5 is lower alkyl.

13. A compound, according to Claim 12, wherein R 3 is a heterocyclic ring. WO 94/10163 PTU9/09 PCT/US93/10091 -43-.

14. A compound, according to Claim 13, cyclic ring is 3-aminopyrrolidine. whe.rein said hetero- A compound, according cyclopropyl and R 2 is fluorine.

16. A compound, according heterocyclic ring is piparazine. to Claim 14, wherein RI is to Claim 13, wherein said

17. A compound, according to Claim cyclopropyl and R 2 is fluorine. 16, wherein R 1 is

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

19. A composition for treating or preventing an infectious disorder in a human or other animal subject, comprising: a safe and effective amount of a compound of Claim 1; and a pharnaceutically-acceptable carrier. 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. 11'* 1 R11AILIUNAL SEARCli REPORT Intemsti"pa Application No IPCT/US 93/10091 A. CLASSIFICATION OF SUEUECr' MATrER IPC 5 C070401/04 A61K31/47 C070215/56 According to International Patent Classification or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classifcaton system followed by classification symbols) IPC 5 C07D A61K Documnentation, searched other than, minimum documentation to the extent that such documents are includcd in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search trsused) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where apprvpnate, of the relevant passages Relevant to claim No. X WO,A,91 16327 (NORWICH EATON 1 PHARMACEUTICALS, INC.) 31 October 1991 *example 1, compound III* A US,A,4 668 680 (WARNER-LAMBERT COMPANY) 26 1,19 May 1987 see claims A WO,A,92 09596 (WARNER-LAMBERT COMPANY) 11 1,19 June 1992 e.g. examples 34,35,41,42,53 A EP,A,0 350 733 (BAYER AG) 17 January 1990 1,19 *page 95-96: example Further documents are listed in the continuation of box C, Patent family members Are listed in annex *Special categories of cited documents: I latw document published After the international Ciling date document defining the general stAte of the ar which isno orpunYdt not inconlict with the application but citedto tm aderte the principle or theory uneligthe considered to be of particular relevance inventon earlier document but piablished on or afbtr the international *X document of pr~ evno;the claimed invention fiin dtecannot be telor cannot be considered to L documet which may throw douti on priorty daim(s) or involve an ineo diep when the 6--cument; is taken alone Mich is cited to estAblub the publicaton date of Ame domcumnt of particular relevanee; dt claimed invention citation or other special reason (as speciied) cannot be considered to involve an inventive step when the 0' document referring to an oral disclotue, use, c~fibition or document is combined with one or moeother such docu. other measmeumsc combination bein obvious to a peson iskilled *P document published prior to the iinternational filing dame but inuthe ftesm aetfml later thnthe priorty date claimed documt memberoftesmpantail Date of the actual completion of the international search Date of mailing of the international search report 13 January 1994 3.0Li 9ff Name and mailing drs of the ISA Authorized officcr European Patent Office, P.O. Sil1 Patentian 2 NL. HY Rliswatk Tel. (3170) 340-MA oTiL 31651 epo nI,VA BI EN H Fain (+31-M0 U40.3016VA ILN H Potta P=#/SAMO1 (macnod s"0t (uly IM2) INTERNATIONAL SEARCH REPORT '1irnational appllcation No. PCT/US 93/ 10091 Box I Observations where certain claims were found unsearchable (Continuation of item I of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: Although claim 20 is directed to a method of treatment of (diagnostic method practised on) the human/animal body, the search has been carried out and based on the alleged effects of the compound/composition. 2. Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful internauonal search can be carried out, specifically: 3. C Claims Nos,: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box II Observations where unity of invention is lacking (Continuation of item 2 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: 1. O As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. 2. As all searchable claims could be searches without effort justifying an additional fee, this Authority did not invite payment of any additional fee. 3. D As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.: 4. No required additional search fees were timely paid by the applicant. Consequently, this International search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.: Remark on Protest D The additional search fees were accompanied by the applicant's protest. 7 No protest accompanied the payment of additional search fees. Form PCT/ISA/210 (continuation of first sheet (July 1992) INTERNATIONAL SEARCH- REPORT IntebisI App~ucaon No ormution on patcnt fmn*ily embcs I CIU 93/10091 Patent document Publication Patent family Publication cited in search report I date 7 member(s) I date WO-A-9116327 31-10-91 AU-B- AU-A- EP-A- 640481 7764391 0525057

26-08-93 11-11-9 1 03-02-93 US-A-4668680 26-05-87 AU-B- 591732 14-12-89 AU-A- 6587986 18-06-87 EP-AB 0226961 01-07-87 JP-A- 62187459 15-08-87 DA-A- 8561 30-09-88 US-A- 4977154 11-12-90 WO-A-9209596 11-06-92 AU-A- 9057491 25-06-92 EP-A- 0559774 15-09-93 US-A- 5258528 02-11-93 EP-A-0350733 17-01-90 DE-A- 3906365 18-01-90 AU-A- 2528692 26-11-92 JP-A- 2069474 08-03-90 US-A- 4990517 05-02-91 US-A- 50591 .,97 22-10-91 Form F=ASAMC (pdwt famgy aun) (JWY IM)