SK54795A3 - Antimicrobial 5-hydrazino-quinoline derivatives - Google Patents

Abstract

Antimicrobial 5-(N-heterosubstituted amino) quinolone compounds of general formula (I), wherein (1) R<1>, R<2> and R<3> 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) 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, O, or S, and R<8> is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring, or a heterocyclic ring; or (b) R<4> and R<5> 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

Antimicrobial 5-hydrazino-quinolone derivatives

Area, techniques

The invention relates to novel antimicrobial compounds, compositions and methods of treatment. Particular compounds of the invention contain a quinolone or related heterocyclic moiety.

:with

BACKGROUND OF THE INVENTION

The chemical medical literature describes a very large number of compounds, antimicrobials. or reproducing said to be capable of destroying or inhibiting the growth of microorganisms such as bacteria.

Arritibacterial agents include a large amount of naturally occurring polysynthetic (antibiotic), synthetic, or compounds. These may be classified (for example) as aminoglycosides, anzamacrolides, beta-a-lactams (including penicillins and cephalosporins), 1 incosaminides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers quinolones, sulfonaraids. Such antibacterial and other agents are described in Antibioties,

Cheinotherapeutics and Antibieterial Agents for Disease Control (M. Grayson, 1982) and in E. Gale et al., The Molecural Basis of Antibiotic Action 2-eds. (1981). Both publications are incorporated herein by reference.

tetracyclines and antimicrobials

The mechanism of action of these antibacterial agents varies. However, they can generally be classified as acting in one or more of four ways: by inhibiting cell wall synthesis or repair; altering cell wall permeability; by inhibiting protein synthesis or by inhibiting nucleic acid synthesis. For example

9762 beta-lacquer-thymic antimicrobials act by inhibiting the essential penicillin binding proteins (PBPs) in bacteria that are responsible for cell wall synthesis. Quinones, on the other hand, act by inhibiting bacterial DNA synthesis and thereby preventing bacterial replication.

Not surprisingly, the pharmacological characteristics of antibacterials and other antimicrobials and their suitability for any given clinical use also vary. For example, classes of antimicrobials (and class members) may vary in their relative potency relative to different types of microorganisms and their susceptibility to developing microbial resistance. These antimicrobials may also differ in their pharmacological characteristics, such as their bioavailability and biodistribution. Accordingly, the antibacterial agent (or other agent) in a given clinical situation may be complicated by analyzing many factors, including the type of organism in question, the desired method of administration and the location of the infection to be treated.

selecting a suitable antimicrobial

The pharmaceutical literature is flooded with efforts to develop improved antimicrobials (i.e., compounds that have a broader range of pharmacology of resistance).

include, for example, enoxacin, fleroxacin.

activity, greater potency, improved and / or less susceptibility to development For example, one class of antimicrobials that has been developed essentially in recent years for clinical use is the class of quinolones. These compounds are nalidixic acid, difloxacin, norfloxacin, lomefloxacin, ofloxacin.

c iprofloxacin and pefloxacin. See C- Marchbanks and M. Dudley, "New Fluoroquinolones, 7 Hospital Therapy 18 (1988); P31 Prog. Drug. Res in Clinical

243 (1987).

Practice, (A. Medical Services, 1986) and M. Clinical Uses of Quinolone

Shah, Quinolones, The Quinolones - The i r Fut-ure

Pere ival, Royal Society of Parry, Pharniacology, and

9762

Antibiotics, 116 Medical Times 39 (1988).

which are really their antimicrobial resistance and pharmacology. often reduced effectiveness against

However, these many efforts to obtain improved antimicrobials have not yielded adequate results. In fact, few antimicrobials have been developed clinically acceptable in terms of activity spectrum, microbial excretion Quinolones, for example, exhibit certain clinically important pathogens (e.g. gram positive bacteria and anaerobic bacteria). Quinolones also have limited solubility in water, limiting their bioavailability and suitability for parenteral dosing. They can also produce unwanted gastrointestinal side effects and affect the system (such as convulsions). See M. Neuman and effects such as Ä.Esana central nerve, Gaps and

Perspectives of New Fluoroquinolones, 25 Drugs Exptl. Clin.

Res. 385 (1988); Aspects of the S141 (1988)

W. Christ Quinolones

Neu, Clinical

Lancet 1319 (1987) and Ciprofloxacin:

et al., Specific Toxicologic 10 Rev. Infectious Diseases Use Quinolones, Panacea or Blunder

Drug?

J. South Carolina Med. Assoc 131 (March 1989).

SUMMARY OF THE INVENTION

The present invention relates to compounds of the general formula

9762 wherein (A) (1) (a) R ¹ is an alkyl, alkenyl, carbocyclic ring. heterocyclic ring or -N (R ^{6 '} (R ⁷ ) wherein R ⁶ and R ⁷ alkenyl, carbocyclic or R ⁶ and R 6 together containing nitrogen.

(B) are independently hydrogen, alkyl, a ring, a heterocyclic ring to form a heterocyclic ring to which they are attached, and (b) R ² is hydrogen, halogen, lower alkyl, or lower alkoxy, or (2) R ¹ and R ² together form a six membered heterocyclic ring containing N 'and the carbon atom to which R ^{2 is} attached,

R ³ is a heterocyclic or carbocyclic ring and (C) (1) R ⁴ and R ⁵ are independently hydrogen, lower alkyl, cycloalkyl, heteroalkyl or -C (= O) -XR ⁸ wherein X is a covalent bond, N, O or S and R ⁸ is a lower alkenyl, arylalkyl, a carbocyclic heterocyclic ring, or (2) ^R4 and ^R5 together form a heterocyclic ring containing the nitrogen to which they are attached, a1ky1, add Grade ring, or is a pharmaceutically-acceptable salts and biohydrolyzable esters and solvates.

The compounds of the present invention and compositions containing them have been found to be potent antimicrobial agents against a broad spectrum of pathogenic microorganisms. Applicants have also discovered that, surprisingly, the compounds of the present invention provide a significantly increased solubility in water at physiological pH as compared to substances known in the art. may contribute, inter alia, to improved pharmacology, including elevated serum levels following administration, ease of formulation, and a more flexible lipid regimen.

for both the ant and mrobial in the field. This surprising

9762

The present invention relates to certain novel quinolones. a method for producing them, a dosage form, and a method of administering quinolones to humans or other animals. The specific compounds and preparations to be used according to the invention must accordingly. pharmaceutically acceptable. As used herein, a pharmaceutically acceptable ingredient is one that is suitable for use in humans and / or animals without causing undesirable side effects (such as toxicity, irritation and allergic response), and yields an appropriate benefit / risk ratio of 5- (N- heterosubstituted amino) quinones

The compounds of the present invention, here, as "5- (N-heterosubstituted amino) quinolones, any of the various quinolones (and referred to refer to derived heterocyclic groups) having a quinolone group at the 5-position.

N-heteroamides

The 5- (heterosubstituted amino) quinolones of the invention include compounds of the general formula

wherein (A) (1) (a) R ¹ is alkyl, alkenyl, carbocyclic ring, heterocyclic ring or -N (R ⁶ ) (R ⁷ ), (preferably

9762 alkyl or carbocyclic ring) wherein R ⁶ and R ⁷ are independently hydrogen, alkyl, alkenyl, carbocyclic ring, heterocyclic ring, or R ⁶ and R ⁷ together form a heterocyclic ring containing nitrogen to which they are attached and (b) R ² is hydrogen, halogen, lower alkyl, or lower alkoxy (preferably halogen), or (2) (preferably) R ¹ and R ² may together form a six membered heterocyclic ring containing N 1 and a carbon atom to to which R ^{2 is} attached, (B) R ³ is a heterocyclic or carbocyclic ring, preferably a heterocyclic ring, and (C) (1) R ⁴ and R ⁵ are independently hydrogen, lower alkyl, cycloalkyl, heteroalkyl or -C (= O) - XR ^8, preferably hydrogen or lower alkyl, wherein X is a covalent bond. N, 0 or S, and ^R8 is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic or heterocyclic ki'uh 1 i cally ring, or (2) (Preferably) ^R4 and ^R5 together form a heterocyclic ring containing nitrogen, to which they are attached, and pharmaceutically acceptable salts and biohydrolyzable esters and solvates thereof.

Definitions and terms used:

(Below is a list of definitions of terms used)

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

"C 1-4 alkyl" is an unsubstituted or substituted hydrocarbon chain of 1 to 4 carbon atoms having 1 to 8 carbon atoms. Preferred and 1 keel groups saturated include, for example, methyl, ethyl, propyl, isopropyl and butyl.

9762

Heteroalkyl is an unsubstituted or substituted saturated moiety. having 3 to 8 members, including carbon atoms and one or two heteroatoms.

phenyl is an unsubstituted or substituted carbon moiety having a chain length of 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms and having at least one double bond, including, for example, vinyl, alkyl and butenyl.

A carbocyclic ring is an unsubstituted or substituted saturated, unsaturated or aromatic hydrocarbon ring moiety. The carbocyclic rings are monocyclic or fused, bridged or spiropolycyclic ring systems. Monocyclic rings contain 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain 7 to 17, preferably 7 to 13 atoms.

Cycloalkyl is a saturated carbocyclic ring moiety. Preferred cycloalkyl groups include, for example, cyclopropyl, cyclobutyl and cyclohexyl.

A heterocyclic ring is an unsubstituted or substituted saturated, unsaturated or aromatic ring moiety containing carbon atoms and one or more ring heteroatoms. The heterocyclic rings are monocyclic or fused, bridged or spirocyclic ring systems. Monocyclic rings contain 3 to 9 atoms, preferably 3 to 6 atoms. Polycyclic rings contain 7 to 17, preferably 7 to 13 atoms.

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

Heteroaryl is an aromatic heterocyclic ring moiety. Preferred heteroaryl groups include, for example, thienyl.

9762 furyl 1, pyrrole 1, piperidin 1, pyrazinyl 1, thiazolyl, pirimidinyl, quinolinyl and tetrazolyl.

Alkoxy is an oxygen radical having a hydrocarbon chain substituent, wherein the hydrocarbon chain is alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl). Preferred alkoxy groups include, for example, methoxy, ethoxy, propoxy and alkyloxy.

Alkylamino is an amino radical having one or two alkyl substituents (i.e., -N-alkyl).

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

Arylamino is an amino moiety substituted with an aryl group (i.e., -NH-aryl).

Aryloxy is an oxygen radical having an aryl substituent C i. O-ary1).

Acyl or carbonyl is a residue formed by removal of a hydroxy group from a carboxylic acid (i.e., R-C-C = O) -). Preferred alkylacyl groups include, for example, acetyl, formyl and propionyl.

Acyloxy is an oxygen moiety having an acyl substituent (i.e., -O-acyl), for example, -O-C (= O) -alkyl.

Halo, halogen or halide is a chlorine, bromine, fluorine or iodine atom. Preferred halides are chlorine and fluorine.

a hydrocarbon group alkyl) is a hydrocarbon group as described herein (e.g., a chain containing 1 to 6,

9762 preferably 1 to 4 carbon atoms.

A pharmaceutically acceptable salt is a cationic salt formed with any acidic group (e.g., carboxyl) or an anionic salt formed with any basic (e.g., amino) group. Many such salts are known in the art, as described e.g. in International Patent Publication 87/05927 by Johnston et al., published Sep. 11, 1987, which is incorporated herein by reference. Preferred cationic salts include alkali metal salts (such as sodium and potassium) and alkaline earth salts (such as magnesium and calcium). Preferred anionic salts include halides such as chloride salts.

The biohydrolyzable ester is an N- (N-heterosubstituted amino) quinolone ester which does not substantially affect the antimicrobial activity of the compounds, or which is readily converted in vivo by an animal or human into an antimicrobially active 5- (N-heterosubstituted amino) quinolone. These esters include those that interfere with the biological activity of quinolone antimicrobials. Many such esters are disclosed in, for example, Johnston et al.

Such esters include acyloxyalkyl esters (as known in the art and publication 87/05297, published Sep. 11, 1987 (incorporated herein by reference).

lower alkyl esters, lower are acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthaldyl esters). lower alkoxyacyloxyalkyl esters (such as ethoxycarbonyloxyethyl and isopropomethoxycarbonyloxymethyl, xycarboroyloxyethyl esters), alkoxyalkyl esters, cholinesters and alkylacylaminoalkyl esters (such as acetamidomethyl esters).

A solvate is a complex formed by a combination of a solvent (e.g. water) and a solute (e.g. 5-CN-heterosubstituted amino) quinolone)). See J.-Honig et al., The Van Nostrand

9762

Chemist Dictionary, p. 650 (1953). Pharmaceutically acceptable solvents used in the present invention include those. which do not interfere with the biological activity of quinolone antimicrobials (e.g., water, ethanol, acetic acid, N, N-dimethylformamide).

As defined above and as used herein, substituent groups may themselves be substituted. This substitution may consist of one or more substrates. Such substitutes include those set forth in C. Hansch and A. Lea, entitled Substituent Const. And Correlation Engineering in Chemistry and Biology (1979), incorporated herein by reference. Preferred substituents include, for example, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halogen, carboxy, alkoxyacyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g. piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.

The groups R ¹ , R ² and quinolone groups have antimicrobial activity known as described in the references included FluoroquinolonesResistance, and

R ³ is any of the various known in the art having

Such groups are well within the art of the following articles, which are here

Wolfson and Mechanisraus of

Activity In

J.

Strúctures, Spectra of et al., The Action and

Vitro, 29

Antiinicrobial Agents and Chemotherapy 581 (1985) and T. Rosen et al., 31 J. Med. Chem. 1586 (1988), T. Rosen et al., 31 J. Med. Chem. 1598 (1988), G. Klopman et al., 31 Antimicrob.

Agents Chemother

1831 (1987) 31: 1831-1840, J.P. Sanchez et al., 31 J. Med. Chem. 983 (1988), J.M. Domagalia et al 3.1 J. Med. Chem. 991 (1988). M. P. Ventland et al., In 20 Ann

Rep. Med. Chem. 145 (D.M. in 21 Ann. Rep. Med. Chem. Fernandes et al., In 22

Baily (1986) 139 (D.M.

J.B- Cornet et al., Bailey, 1986), F.B. Med. Chem. 117 (D.M

9762

Elailey (1987), R. Albrecht, 21 Prog. Drug Research 9 (1977) and P.B. Fernandes et al., At 23 flnn. Rep. Med. Chem. (R > C > Alien, 1987).

alkenyl, alkylamino.

aryl, cycloalkyl, more preferably R ¹

R ¹ is preferably an alkyl heterocyclic ring or ethyl, 2-fluoroethyl,

2,4-dif1uórfeny1.

propyl, bicyclot 1-1-11 pent-al. Particularly preferred R ^{1 is} 2-fluorocyclopropyl. tert-butyl baths of 5- (N-heterosubstituted)

2-hydroxyethyl, tert-butyl, 4-fluorophenyl. methylamino, 3-oxetanyl, 2-fluorocyclovinyl, or cyclopropyl. the groups are cyclopropyl, and 2,4-difluorophenyl. Preferred aminoquinolines also include those wherein R ¹ and R ² together form a 6-membered heterocyclic ring of the formula

X

wherein X is O, S or CH ² R ² is preferably chloro, fluoro, methoxy or methyl Fluoro and chloro are preferred R ² groups.

Preferred heterocyclic

R ³ groups include nitrogen rings. Particularly preferred containing heterocyclic rings having 5 to 8 are nitrogen members of 8 members.

The heterocyclic ring may contain other heteroatoms such as oxygen, heterocyclic Petersen et al.

Sulfur or groups are issued on May 8,.

nitrogen, preferably nitrogen. Also described in U.S. Patent 4,599,334, July 1986, and U.S. Patent 4,670,444,

9762

Grohe et al., Issued Jun. 2, 1987 (both incorporated herein by reference). Preferred R ³ groups include unsubstituted or substituted pyridine, piperidine, morpholine, diazab and cyclot 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, and particularly preferred R ³ groups which include piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminoethylpyrrolidine, NN-dimethylaminomethylpyrrolidine, N-ethylaminomethylpyrrolidine, 3,5-dimethylpyridine, N-methylpiperazine and 3,5-dimethylpiperazine.

Preferred R ⁴ and R ⁵ groups include those wherein R ⁴ and R ⁵ together form a heterocyclic ring containing the nitrogen atom to which they are attached and these R ⁴ and R ⁵ are both

n i žš i e alkyl groups, those. where one from R ⁴ and R ⁵ is hydrogen and the other is lower alkyl t ie, where both R ⁴ and R ⁵ are hydrogen. More preferred groups are 11 e, where One of R ⁴ or R ⁵ is hydrogen the other is alkyl and t ie, where both R ⁴ and R ⁵ are hydrogen. especially groups are preferred. where both R ⁴ , and R ⁵ They are hydrogen.

Preferred compounds of the present invention include those having a basic nitrogen atom as R ³ , including, for example, pyridine, piperidine, diazabicyclo [3.1.1] heptane, diazabicyclo [2.2.1] heptane, diazabicyclo [3.2.11 octane, diazabicyclol 2.2.2] octane and imidazolidine and R ⁴ and R ⁵ groups which allow the nitrogen atom to which they are attached to be basic (including, for example, compounds wherein R ⁴ and R ⁵ together form a nitrogen-containing heterocyclic ring to which they are attached , both R ⁴ and R ⁵ are lower alkyl, one of R ⁴ and R ⁵ are lower alkyl and the other is H, or both R ⁴ and R ^s are hydrogen). Particularly preferred compounds are those wherein R ³

When perazi n, 3-aminopyrrolidine,

N, N-dimethylaminopyrrolidine, N-ethylaminomethylpyrrolidine,

N-methylpiperazine or 3,5-dimethylpiperidine and both R ⁴ and R ⁵ are piperazine, 3-methylaminomethylpyrrolidine,

9762 are hydrogen.

As used herein, a basic nitrogen atom is such an atom. which has a free pair of electrons that can be involved in ionic bonding with any of a number of different cations. It will be appreciated in the art that the basicity of a nitrogen atom of a given group will depend on the nature of the covalent bond of the nitrogen atoms. See e.g. A. Steitwieser and C. Heatcock, Introduction to Organic Chemistry, 2nd edition, p. 734-40 ¢ 1981), the publication of which is incorporated herein by reference.

Preferred includes:

5- (N-heterosubstituted amino) ions

F

Ε! ΝΗ

EtNH

CO 2 H

H2N / I

Corh

9762

ABOUT

NH

EtNH

CO 2 H

The compounds of the invention are also useful as intermediates in the synthesis of novel lactam-quinolones. Such compounds are described in International application no. WO 91/16327, published Oct. 31, 1991, incorporated herein by reference. Lactam-quinolones include any of the many lactam groups linked by a linker group to the quinolone group at the 5-position of the quinolone.

Lactam quinolones include compounds of the general formula wherein q, L and B have the following meanings:

<I) 0 has the formula I

II

9762 wherein (R) (1) A ¹ is N or CC R ⁷ ), wherein (i) R ⁷ is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl or NCR ⁸ (CR ⁹ ), preferably hydrogen or halogen , and (ii) R ⁸ and R ⁹ are independently R ^8a , wherein R ^8a is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring or R ⁸ and R ⁹ together form a nitrogen-containing heterocyclic ring to which they are attached, (2) A ² is N or C (R ² ), preferably C (R ² ), wherein R ² is hydrogen or halogen, (3) A ³ is N or preferably C (R ⁵ ), wherein R ⁵ is hydrogen, (4) R ¹ is hydrogen, alkyl, carbocyclic ring, heterocyclic ring, alkoxy, hydroxy, alkenyl, arylalkyl or N (R ⁸ ) (R ⁹ ), preferably alkyl or carbocyclic ring, (5) R ³ is hydrogen, halogen, an alkyl, carbocyclic ring or heterocyclic ring, preferably a heterocyclic ring, (6) R ⁴ is hydroxy and (7) R ⁶ is R ¹⁵ or R ¹⁶ X, wherein R ¹⁵ is L is absent, or is alkyl, heteroalkyl or alkenyl, R ¹⁶ is L and is alkyl, alkenyl, carboxy a bocyclic ring or heterocyclic ring and X is alkyl, heteroalkyl, alkenyl, oxygen, sulfur or NH, (B) except that

(1) if is A ¹ C (R ⁷ ), R ¹ a R ' ⁷ they can together forms t heterocyclic ring. include accounts N 'and A ¹ (2) if is A ² C (R ² ). R ² a R ³ they can together tvor i t -tl- (CII ₂₎ n-0- where n is whole č í s 1 o from 1 to 4, (3) if is A ³ C (R ⁵ ), R ⁴ a R ⁵ they can s after 1 u forms t

a heterocyclic ring containing the carbon atom to which R ⁴ and R ^{5 are} attached and the carbon atom of the formula I to which said carbon atoms are attached, and

9762 (4) if A ^{3 is} CCR ⁵ ). R ¹ and R ⁵ can together form a heterocyclic ring containing N 'and the adjacent carbon atom to which R ^{5 is} attached, (II) B is a structure of formula II wherein L is bound to R ¹⁴ :

wherein (R) R ¹⁰ is hydrogen, halogen, heteroalkyl, carbocyclic ring, heterocyclic ring, R ^8a -O-, R ^8a CH = N, (R ⁸ ) (R ⁹ ) N-, R ¹⁷ -CC = CHR ²⁰ ) -CC = O) NH-, or preferably alkyl, alkenyl, R ¹⁷ -CC = NO-R ¹⁹ ) -C - (= O) NH- or R ¹⁸ -CCH 2) _m -C (= O) NH-, wherein (1) m is an integer from 0 to 9, preferably from 0 to 3,

C 2) R ¹⁷ is H, alkyl, alkenyl, heteroalkyl.

heteroalkenyl, carbocyclic ring or heterocyclic ring, preferably alkyl, carbocyclic ring or heterocyclic ring, (3) R ¹⁸ is R ¹⁷ . -Y ¹ or -CHCY ² ) CR ¹⁷ ), (4) R ¹⁹ is R ¹⁷ , arylalkyl, heteroarylalkyl,

-CCR ²² ) CR ²³ ) COOH, -CC = O) OR ¹⁷ or -C (= O) NH-R ¹⁷ wherein R ²² and R ²³ are independently R ¹⁷ or together form a heterocyclic ring containing a carbon atom to which are R ²² and R ²³ bonded, preferably R ¹⁷ or -C (R ²² ) CR ²³ ) COOH, (5) R ²⁰ is R ¹⁹ , halogen. -Y ¹ , preferably R ¹⁹ or halogen.

or -CH CY ² > CR ¹⁷ )

9762

CC)

(6) Y ¹ is -C (= O) OR ²¹ , -CC = O) R ²¹ , -N (R ²⁴ ) R ²¹ or is Y ¹ or -OH, -SH preferably O, alkyl, and 1kenyl; , heteroalkyl, carbocyclic ring, hetero-SO 3 H, -CC = O) R ²⁵ , or, if

R ²⁴

R ²¹

-SCO) _P R ²⁹ or -OR ²⁹ and Y ² or -SO ³ H,

Ca) p is an integer from 0 to 2 C b) R ²⁴ is hydrogen heteroalkenyl, a cyclic ring

R ¹⁸ -CHC (N) CR ²⁴ ) CR ²¹ ) CR ¹⁷ ), a group attached to the heterocyclic ring and (c) R ²⁵ is R ¹⁷ , NHCR ¹⁷ ), NCR ¹⁷ ) (R ²⁶ ), OCR ²⁶ ) or SCR ²⁶ ), preferably R ¹⁷ , NHCR ¹⁷ ) or NCR ¹⁷ ) (R ²⁶ ), wherein R ²⁶ is alkyl, alkenyl, carbocyclic ring, heterocyclic ring, or preferably when R ²⁵ is NCR ¹⁷ ) (R ²⁶ ), R ²⁶ may contain a group bonded to R ¹⁷ to form a heterocyclic ring; and

may contain to form where R ²⁹ is alkyl, alkenyl, heteroalkenyl, heteroarylalkyl, carbocyclic ring, heterocyclic ring, or, when Y ¹ is NCR ²⁴ ) R ²¹ and R ²¹ is R ²⁹ , R ²¹ and R ²⁴ together may form a heterocyclic ring containing a nitrogen atom to which R ^{24 is} attached, preferably hydrogen, alkyl, a carbocyclic ring or a heterocyclic ring.

C 7) R ²¹ is R ²⁹ or hydrogen, aryl and alkyl, heteroalkyl

R ¹¹ is hydrogen, halogen, alkoxy or R ²⁷ C (= O) NH-, preferably hydrogen or alkoxy, wherein R ²⁷ is hydrogen or alkyl, preferably hydrogen, bond a is a single bond or is absent, and bond b is monovalent a bond, a double bond, or is absent, provided that the bond a and b are not both absent,

R ^{12 is} -CCR ^8a ) -, or -CH 2 -R ²⁸ -, preferably -CCR ^8a ) -, wherein R ²⁸ is -CCR ^8a ), -Cl- or -N- and R ²⁸ is directly attached

9762 k N in formula II to form a 5-membered ring, provided that if a is absent then R ^{12 is}

Cl) preferably -C (R ^8a ) (X ¹ ) -, wherein

C) X ¹ is R ^21, -0R ³ °, -S (0) r ³ ° wherein r is an integer from 0 to 2, preferably 0, -0 (C = 0) R ³ ° and NCR ^{3 O)} R 3 ! and (ii) R ³ and R ³¹ are independently alkyl, alkenyl, carbocyclic ring or heterocyclic ring, or R ³⁰ and R ³¹ together form a heterocyclic ring containing the nitrogen atom to which R ³⁰ and R ³¹ bonded, or (2 -CH ² R ³² -, wherein R ³² is -C (R ^8a ) (R ²¹ ), -O- or -NR ^8a , and R ³² is directly attached to the N 'of formula II to form a 5-membered ring.

CE) (1) (2) (3) when b is a single bond, R ^{13 is} preferably -CHCR ³³ ) -, or -C (O) NHSO 2 - if not a bond and present, or -C (CR ³³ ) when R ¹⁴ contains hydrogen or COOH, preferably COOH to R ³⁶ to form a 3-membered ring when b is a double bond. R ¹³ is -CCR ³³ ) =, or when b is absent, R ^{13 is} hydrogen, -SO 3 H, -CO ₃ NHSO ₂ NCR ³⁴ ) CR ³⁵ ), -OSO 3 H, or -OCHCR ³⁴ ) COOH, preferably -SO 3 H, or -CCO) NHSO 2 NRCR ³⁴ ) CR ³⁵ ); wherein R ³⁴ is hydrogen, alkyl, alkenyl, carbocyclic ring or heterocyclic ring and R ³⁵ is hydrogen, alkyl, alkenyl or -NHR ^8a or preferably when R ^{13 is} -C (O) NHSO 2 NRCR ³⁴ ) (R ³⁵ ), R ³⁴ and R ³⁵ may form together. a nitrogen-containing heterocyclic ring to which R ³⁴ and R ^{35 are} attached a

R ³⁶ : wherein R ³³ is and C ~ is attached

-PO (OR ³⁴ ) OH, -CHCR ³⁵ ) COOH

CF) C1) where b and the bond is absent, then R ¹⁴ is absent, and L is bonded directly to R ¹² or R ^13,

C 2) if the bond and on the bond b are single bonds, ^R14 is -W-C "= C (R ⁸⁾ -R ³⁷ - or -VC 'R ³⁶⁾ -R ³⁷ -, or (3) preferably, a bond, and when single bond and bond b is a double bond, is R ¹⁴ -CCR ^8a ) (R ³⁸ ) -WC '-R ³⁷ ,

9762 or preferably ^CCR-W-8) CR ³⁸⁾ _C --_ _ 37_ or _R

V-C'-R ³⁷ - wherein (a) W is 0, S (O) s, wherein s is an integer from 0 to 2, preferably 0, or CCR ³⁸ ) when R ³⁸ is hydrogen, alkyl or alkoxy, (b) R ³⁶ is H, alkyl, alkenyl, COOH or where R ¹³ is -C CR ^33), R ³⁶ may be bonded to ^C to form a 3-membered carbocyclic ring, (c) R ³⁷ is present means alkyl. alkenyl, carbocyclic ring or heterocyclic ring and (d) C 'is directly attached to R ¹³ to form a 5- or 6-membered ring.

(III) L connects Q to B and L is L, -X ²¹ R ³⁹ -I or

-X ³ -R ³⁹ -L, where L 1 is Q ', -X ² -Q, -X ³ -Q or

-X ⁴ t ~ ³ in CCY) ~ ZQ, preferably ^-X2-Q. -X ³ -Q

-X ⁴ t-CC = Y ³ U) -ZQ, wherein (1) L au are independently 0 or 1, (2) R ³⁹ is alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocyclic ring or heterocyclic ring, preferably alkyl or alkenyl , (3) X ² is oxygen or S (O) _v , wherein v is an integer from 0 to 2, preferably 0, (4) X ³ is nitrogen, NCR ⁴⁰ ), N ⁺ CR ³¹ ) (R ⁴² ) or R ⁴³ -N (R ⁴¹ ).

a is attached to R ^{14 by a} single or double bond or, if R ^{14 is} absent, X ^{3 is} attached to B by a single or double bond, preferably X ³ is nitrogen, NCR ⁴⁰ ) or N * CR ⁴¹ ) (R ⁴² ), wherein (a) R ⁴⁰ is R ⁸³ , -OR ^8a or -C (= O) R ^8a , preferably R ^8a , (b) R ⁴¹ and R ⁴² are independently hydrogen, alkyl, alkenyl, carbocyclic rings, heterocyclic rings, or when R ^{6 is} R ¹⁶ X, then R ⁴¹ and R ⁴² together with Q may form a heterocyclic ring such as R ¹⁶ , (c) R ⁴³ is NCR ⁴¹ ), oxygen or sulfur, (5) X ⁴ is oxygen, sulfur, NR ⁴⁰ or R ⁴³ -NR ⁴¹ , preferably oxygen, sulfur or NR ⁴⁰ ,

9762 (6) Y ³ is oxygen, sulfur, NR ⁴⁰ or NMR ⁴¹ ) ⁴² 8 ⁴² ), ¢ 7) Y ⁴ is oxygen or NR ⁴¹ , preferably oxygen, ¢ 8) Z is absent, means oxygen, sulfur, nitrogen,

NR ⁴⁰ or NCR ⁴¹ -R ⁴³ , preferably oxygen, sulfur, nitrogen or NR ⁴⁰ ,

C9) Q 'is said R ⁶ substituent. Q and <10) Q is Q ', or together with X ² , X ³ , Z or Z' is said R ⁶ substance Q, and pharmaceutically acceptable salts and biohydrolyzable esters and hydrates thereof.

Preferred lactam-containing groups include cephemes, isocephems, iso-oxacephems, carbacephenes, penicillins, penems, carbapenems, and monocyclic beta-lactams. Particularly preferred are cephemes, penemas, carbapenems and monocyclic beta-lactams.

R ¹⁰ , in formula II, is any moiety that can be substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl of the microbially active lactam. (As used herein, the term antimicrobially active lactam refers to lactam containing a compound without a quinolone substituent that has other antimicrobial activity). This active position is beta (ie 7-bet.a) for cephemes, oxacephems and carbacephems (for example).

for penémy. carbapenems, clavems

The active location is alpha and clave. Suitable R ¹⁰ groups will be apparent to those skilled in the art.

The ion ion and ion ion methods of the present invention are described in the following works, which are hereby incorporated by reference (including the articles cited therein).

Processes for preparing among the products useful in the invention (incorporated by reference); 21 Progress in Drug Research, 9-104 ¢ 1977), 3.1 J. Med. Chem., 503-506 (1988), 32 J. Med. Chem., 1313-1318 (1989) Exp11.

1987

Clin

Liebigs Änn. Chem.

871-879 ¢ 1987), 14 December:

Res

379-383 (1988), 31 J. Med> Chem.,

9762

983-991 (1988), 32 J. Med. Chem. , 537-542 (1989) 78 J. Pharm. Sc i. . 585-588 (1989) 26 J. Het. Chem (1989), 24 J. Het. Chem. 181-185 (1987) US patent 45 99334, 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 266576, European Patent Publication 251308, 36 Chem. Pharm. Bull., 1223-122E (1988), European Patent Publication 227039, European Patent Publication 228661, 31 J. Med. Chem., 1586-1590 (1988), 31. J. Med. Chem., 1598-1611 (1988) and J. Med. Chem., 1358-1363 (1980).

Generally they can be. 5- (N-heterosubstituted amino) quinolones prepared by the following procedure:

(5-halo-quinolone) -1 H N-N (R ⁴ ) (R ⁵ ) ->

(5- (R ⁴ ) (R ⁵ ) (N-NH) -quinolone) wherein R ⁴ and R ⁵ are as previously defined and (5-halo-quinolone) is suitably protected 5-halo-substituted quinolone, wherein the halogen is preferably chlorine or fluorine, more preferably fluorine. The reaction may be referred to as nucleophilic aromatic substitution of the quinolone 5-halogen by (R ⁴ ) (R ⁵ ) N-NH 2 to give 5- (N-heterosubstituted amino) quinone.

A1 tertiary 5 - (N-heterosubstituted amino) (hinone) may be prepared by the following procedure:

(5,7-dihalo-quinolone) + H 2 N-N ^{(R4) (R5)} ->

(5-CR ⁴ ) (R ⁵ ) (N-NH) -7-halo-quinolone)

9762 wherein R ⁴ and R ⁵ are as previously defined and (5,7-dihaloquinolone) is suitably protected 5- and 7-halo substituted chiriolone, wherein the halogen at the 5 and 7 positions is independently chloro or fluoro, preferably fluoro. The reaction sequence may be referred to as a selective nucleophilic aromatic substitution of the 5-halogen quinolone substituent with (R ⁴ ) (R ⁵ ) N-NH 2 to give N- (5-heterosubstituted araino) quinolones. The reaction may preferably be carried out in a non-polar aprotic solvent, preferably benzene, toluene, xylene, etc., at an elevated temperature, preferably 50 ° C to reflux.

preparations

The formulations of the present invention include:

(a) a safe and effective amount of 5-CN-heterosubstituted amino) quinolone; and

b) a pharmaceutically acceptable carrier.

A safe and effective amount of 5- (N-heterosubstituted amino-quinolone) quinolone is an amount effective to inhibit robotic growth at the site of infection to be treated in humans or lower animals, without causing undesirable side effects (such as toxicity). , irritation or allergic response) associated with an acceptable benefit / risk ratio when used according to the method of the invention. The specific safe and effective amount will vary with factors such as the condition that the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form used, the carrier used, the solubility of 5- (N-heterosubstituted amino) such as treated, quinolone physical state in burrow and dosage regimen required for the formulation.

The formulations of the invention are generally in unit dosage form. A unit dosage form as used herein is a composition of the invention comprising an amount

9762

5- (N-heterosubstituted amino) quinolone, which is suitable for administration to a human or lower animal in a single dose according to known medical practice. These compositions preferably contain from about 30 mg to about 20000 mg, more preferably from about 50 mg to about 7000 mg, even more preferably from about 500 mg to about 3500 mg, of 5-CN-heterosubstituted amino) quinolones.

of the invention may be oral, rectal, depending on

The formulations of the present invention in any of the forms suitable, for example, for topical or parenteral administration to the desired route of administration, can be used in many different pharmaceutically acceptable carriers known in the art. These include solid or liquid fillers, diluents, hydrotopes, surfactants and encapsulating components. Optionally, pharmaceutically active materials that do not substantially affect the antimicrobial activity of 5- (N-heterosubstituted amino) quinolones may be present. The amount of carrier used in conjunction with 5- (N-heterosubstituted amino) quinolone is sufficient to provide a practical amount of material per unit dose of 5- (N-heterosubstituted amino) quinolones. Techniques and compositions for making dosage forms useful in the methods of the present invention are described in the following references, all of which are incorporated herein by reference in their entirety. 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, eds., 1979), Lieberman et al.

Tablets (1981) and, Pharmaceutical Introduction to

Dosage Forms: Tablets (1981) and Änsel, Pharmaceutical Dosage Forms, 2nd Ed., (1976)

Pharmaceutically acceptable carriers for systemic administration may be sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, phosphate buffer, emulsifiers alginic acid, isotonic saline solutions and anhydrous pyrogen . Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidine, ethanol and ethanol.

9762 sesame oil. Preferably, the pharmaceutically acceptable carrier in the compositions for parenteral administration comprises at least about 90% by weight of the total composition.

They may be solid forms.

various dosage forms used, including such as tablets, capsules, granules, and bulk powders. These oral forms contain a safe and effective amount, usually at least about 5% and preferably from about 25% to about 50% of 5- (N-heterosubstituted amino) quinolone. The tablets may be. composite, triturated, enteric coated, sugar-coated, film-coated or multiply pressed, contain. suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow indicating agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent formulations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, 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 the invention may also be administered topically, i. directly by applying or spreading the composition on the epidermal or epithelial tissue of the subject. Such formulations include, for example, lotions, creams, solutions, gels and solids. safe and

These topical preparations preferably contain at least about 0.1% of the 5-N-heterosubstituted effective amount, and preferably from about 1% to about 5% of the aminoquinolones. Suitable carriers for topical administration preferably remain on the skin as a continuous film and the residue by immersion in water. Generally organic in nature and is able to dissolve in itself. The 5-C N-heterosubstituted lipase is persistent to remove the carrier

9762 amine quinone. Carrier with acceptable plasticizers, and solvents.

to contain.

it may contain pharmaceutical emulsifiers, thickeners

Routes of administration.

The present invention for the prevention of infectious also provides methods of treatment or disease in a human or other animal subject by administering a safe and effective amount

The 5- (N-heterosubstituted) used is an infectious amino group. As any disease, there is a disease characterized by the presence of a microbial infection. Preferred methods of the present invention are treatment of bacterial infections. Such infectious diseases include, for example, central nervous system infections, inner ear infections, middle ear infections (such as acute otitis media). Cranial sinus infections, eye infections, oral cavity infections (such as tooth, gum and mucosa infections), upper respiratory tract infections, lower respiratory tract infections, genitourinal infections, gastrointestinal tract infections, gynecological infections, septicemia, bone and joint infections and cutaneous structures, bacterial endocardium itis, burns, antibacterial prophylaxis of surgery and antibacterial prophylaxis in immunocompromised patients (such as patients with anti-cancer therapy or organ transplant patients).

The 5- (N-heterosubstituted amino) quinolones and compositions of the present invention may be administered topically or systemically. Systemic administration includes any method of introducing 5- (N-heterosubstituted amino) quinolone into body tissues, e.g. intrahecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal and oral. The specific dose of antimicrobial administered as well as the duration of treatment

9762 are interdependent. The dose and treatment regimen also depends on such factors as the 5- (N-heterosubstituted amino) quinone ion specifically used, the resistance of the infectious organism to 5- (N-heterosubstituted amino) quinolones by resistance, the ability of 5- (N) -heterosubstituted anino) quinolones achieve a minimal inhibitory concentration at the site of infection, the nature and extent of other infections (if any), the individual's personal attributes (such as weight), the acceptability of the treatment regimen, and the presence and difficulty of any side effects of treatment.

Typically, an adult (about 70 kilograms) is administered from about 75 mg to about 30000 mg, more preferably from about 100 mg to about 20000 mg, even more preferably from about 500 mg to about 3500 mg of 5- (N-heterosubstituted amino) quinolone per day. Treatment regimens preferably last from about 1 day to about 56 days, more preferably from about 7 to about 28 days. Prophylactic regimens (such as the exclusion of opportunistic infections in immunocompromised patients) may last for 6 months or longer, in accordance with good medical practice.

A preferred method of parenteral administration is intramuscular injection. As is known in the art, all preparations for parenteral administration must be sterile. In mammals, particularly humans (with an approximate body weight of 70 kilograms), individual dosages of from about 100 mg to about 7000 mg, preferably from about 500 mg to about 3500 mg, are acceptable.

The 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.

topické podanie? can be used for delivery

5- (N-Heterosubstituted amino) quinolone systemically or for the treatment of local infection. Amount of 5- (N-heterosubstitute32)

The 9762 amino-quinone to be topically administered depends on many factors, such as the sensitivity of the skin and the location of the tissue to be treated, the formulation and the carrier (if any) to be administered, the particular 5- (N-heterosubstituted amino) and no to the ion to be. administered, as well as the particular disease being treated and the extent to which systemic (different from local) effects are required.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(S) -7- (3-Amino-pyrrolidinyl) -1-cyclopropyl-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid dihydrochloride

I

CH

CO 3 H 2 HCl

F

9762

A mixture of methyl propiolate (983 g, 11.7 mol) and 500 mL of tetrahydrofuran was cooled to 5 ° C and cyclopropylamine (667 g, 11.7 mol) dissolved in 1000 mL of tetrahydrofuran was added dropwise at a rate of funnel at about 1 hour at the temperature of which does not exceed 3 to 7 ° C. The mixture was stirred for an additional hour at 5 ° C and the ice bath was removed. The reaction is stirred for about one hour at 20-25 ° C, at room temperature for 3 hours and allowed to stand at room temperature for about 2.5 days. the solvent is removed under reduced pressure and the residue is distilled off in vacuo to give the compound of formula I.

I

A solution of approximately 207 g of pentafluorobenzyl chloride II

I (0.90 mol) and 250 ml of dioxane were cooled to 15-20 ° C

A solution of approximately 126 g of I and 90.9 g of triethylamine (0.90 mol) in 300 ml of dioxane is added dropwise over a period of 5.5 hours. The addition funnel was washed with an additional 50 mL of dioxane and the reaction was stirred at 20 ° C overnight. The mixture was then vacuum filtered and the precipitate was washed twice with 100 ml portions of dioxane. The filtrate was distilled off under vacuum at 25 ° C and 1000 ml of hexane was added to the residue. A further precipitate formed and added to the first crop. The combined products were then resuspended in 1500 mL hexane, stirred briefly, filtered and dried in vacuo to give III.

at a temperature ranging from 15 to 20 ° C and thereafter, approximately 14.9 g (0.621 mole) of NaH is placed in a 5 liter three-necked round-bottomed flask equipped with a thermometer, an argon inlet, a mechanical stirrer and an addition funnel. (hexane washed with NaH mineral oil) and 1000

1 ml of dimethyiformamide. The mixture is cooled to 15-20 ° C and approximately 181.5 g of III (0.542 mol) is added dropwise over 3.5 hours; dissolved in 2 T i d. 1 methyl forms while maintaining stirring for 1.5 hours while further cooling the mixture to -10 ° C and adding 500 mL ice and 11 water. The mixture was neutralized to pH 7 with about 5 mL of acetic acid and extracted three times

9762 chloroform. The dried chloroform extracts were evaporated to give a slurry which was triturated with 400 ml of boiling ethanol. The resulting solids were filtered at room temperature. Further washing with 100 ml of cold ethanol after vacuum drying yields

IJV.

A mixture of IV (2.2g, 0.070 mol) and 2N H 2 SO 4 (600 mL) was stirred at 1000 ° C for 20 h and allowed to cool to room temperature. Product V is collected by filtration, washing with water.

To a mixture of (3S) -tert-butoxycarbonyl-aminopyrrolidine (18 g, 0.060 mol) (12 g, 0 mL) at 54 ° C was added dropwise The mixture was stirred at 54 ° C

1.066 moles) and dimethylformamide (130: a triethylamine (17 ml, 0.12 moles). Four hours. Acetonitrile (120 ml) was added and the mixture was heated to 75 ° C and then allowed to stand.

Cool to room temperature. The mixture was cooled to 15 ° C and the solid was filtered off, washed with acetonitrile (2 x 60 mL). The solid was stirred in acetonitrile (180 mL) for 10 minutes and the product VI was collected by filtration and washed with acetonitrile (2 x 60 mL).

A mixture of VI (4.0 g, 0.0086 mol) of acetonitrile (120 ml) and hydrazine monohydrate (4.0 ml, 0.082 mol) was refluxed for 2.5 hours to form a solution. The solution was diluted with acetonitrile (100 mL) and stirred at room temperature for 2 hours. The precipitate was collected by filtration and heated in acetonitrile (150 mL). The undissolved material was removed by filtration and the filtrate was stored at room temperature overnight. Product VII is collected by filtration and washed with acetonitrile.

To a mixture of VII (4.0 g, 0.0083 mol) and methylene chloride (85 mL) at room temperature was added saturated ethanol (HCl) (55 mL) with slow stirring of the room for 4.5 hours and solid.

The mixture is stirred at temperature and the substance is separated by filtration.

CHCl 3 (100 mL) and methanol (10 mL) was added. The mixture was cooled to room temperature

9762 and the final product VIII are collected by filtration and washed with CHCl 3. Example 2 t

(3S) -7-C3-Amino-1-pyrrolidinyl) -1 (2,4-difluorophenyl) -6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid dihydrochloride of

H ₂ NNH ₂ ch ₃ cn

9762

Monoethyl hydrogen malonate (13.2 g, 0.10 mol) was dissolved in tetrahydrofuran (260 mL) and cooled to -65 ° C. Then, 2M n-butyl 1.1 liters (100 mL, 0.20 mol) was added dropwise while maintaining the temperature below -50 ^{θ Ε.} The reaction is warmed to -5 ° C and recooled to -65 ° C. Pentafluorobenzoyl chlorid I (7.20 mL, 0.05 mol) was dissolved in tetrahydrofuran (32 mL) and added dropwise while maintaining the temperature below -50 ° C. After addition, the reaction was maintained at -35 ° C and stirred for 1 hour. Aqueous HCl 13% (316 mL) was added to the solution and stirred for 30 min. The mixture was extracted with CH 2 Cl 2 and washed with aqueous sodium bicarbonate and concentrated to give product 2, which exists as a mixture of keto-enol tautomers in solution.

Pentafluorobenzoic acid ethyl ester 2 (10 g, 0.035 mol) was added to acetic anhydride (8.5 mL, 0.09 mol) and triethyl orthoformate (10 mL, 0.06 mol). The reaction was heated to 110 ° C for 2.25 h. The reaction is concentrated. The product was dissolved in ethanol (250 mL) and cooled to 0 ° C. Then add slowly

2,4-Difluoroaniline (4.7 mL, 0.046 mol) and ice bath removed. The reaction was stirred overnight and concentrated to dryness under reduced pressure to give a residue. This was triturated in petroleum ether and the product collected by filtration to give 3 as a mixture of the cis-trans isomers.

in dimethyl (9.46 g, concentrated).

Organic drying in

Vinylamide 3 (9.43 g, 0.022 mol) was dissolved in formamide (57.0 mL) and potassium carbonate (0.068 mol) was added. The reaction is stirred overnight and then methylene chloride is added and the solution is washed with water, the phase is dried over sodium sulphate, concentrated and concentrated in vacuo to give quinolone 4.

Ester 4 (8.49 g, 0.02.1 mol) was placed in 8: 6: 1 acetic acid / water / sulfuric acid solution (309 mL) and heated at 100 ° C until the reaction was complete. The solution was poured into ice water and the precipitate was filtered off. The product is recrystallized by dissolving in CH 2 Cl 2 and precipitating

9762 hexane. Filtrate. It is concentrated and the residue is purified as mentioned from CH 2 Cl 2 to give a second crop.

Chi noIón

CIO

(0.027 mol) was dissolved in dimethylformamide (60 ml) and C3 S-tert-butoxycarbonylaminopyrrolidine (6.0 g, 0.032 mol) was added. The reaction was heated to 55 ° C and triethylamine (7.5 ml, 0.054 mol) was added over 20 minutes. The reaction is complete in 45 min. by TLC and the heater is removed. The product precipitated from solution is filtered off. The solid was washed with ether. The product was dissolved in hot EtOAc and precipitated by the addition of hexanes. The solid is filtered off and dried under vacuum to give 6.

A mixture of quinolone 6 (2.0 g (0.0037 mol) acetonitrile (60 ml) and hydrazine CO (46 ml, 0.0095 mol) was refluxed for 1.6 hours. Cool to room temperature. The product was collected by filtration and recrystallized from acetonitrile to give 7.

A mixture of 7 (0.20 g, 0.00036 mol) and saturated HCl / EtOH (4 mL) was stirred at room temperature for 1 hour and an additional 4 mL of HCl / EtOH was added. The reaction was stirred for an additional 3 hours and the solid was collected by filtration. The solid was triturated in CH 2 Cl 2 and filtered. The product was recrystallized from acetonitrile / water to give the final product.

9762

Example 3

1-Cyclopropyl-6,8-difluoro-5-hydrazino-1,4-dihydro-4-oxo-7-piperazinyl-3-quinolinecarboxylic acid dihydrochloride

O ^H 2 ^N - <] HD (Z ^{CH 3}

CO & u

T

CO2 COISIS,.

I,

41st

9762

A mixture of methyl propiolate (983 g, 11.7 mol) and 500 ml of tetrahydrofuran was cooled to 5 ° C and cyclopropylamine (667 g, 11 ml) was added via addition funnel at a rate such that the temperature did not exceed 3-7 ° C. , 7 mol) dissolved in 1000 ml of tetrahydrofuran. The mixture was stirred for an additional hour at 5 ° C and the ice bath was removed. The reaction is stirred for about one hour at 20-25 ° C at room temperature for 3 hours and allowed to stand for about 2.5 days at room temperature. The solvent is removed under reduced pressure and the residue is distilled under vacuum to give I.

A solution of approximately 207 pentafluorobenzylchloride II (0.90 mol) and 250 ml of dioxane is cooled to 15-20 ° C with an ice-water bath and a solution of approximately 126 g I and 90.9 g triethylamine (0.1 g) is added dropwise over 5.5 hours. 90 mol) in 300 ml dioxane. Wash the addition funnel with an additional 50 mL of dioxane and stir the reaction at 20 ° C overnight. The mixture is then vacuum filtered and the precipitate is washed twice with 100 ml portions of dioxane. The filtrate was distilled off under vacuum at 25 ° C and 1000 ml of hexane were added to the residue. Another precipitate was collected and added to the first crop. The combined product was then resuspended in 1500 mL of hexane, stirred briefly, filtered and dried in vacuo to give III.

Approximately 14.9 g (0.621 mol) of NaH (from hexane washed with NaH (mineral oil)) and 1000 ml of dimethylformamide are placed in a 5-liter three-necked round bottom flask equipped with a thermometer, argon inlet, mechanical stirrer and dropping funnel. It is cooled to 15-20 ° C and approximately 181.5 g of III (0.542 mol) dissolved in 2 L of dimethylformamide is added dropwise over 3.5 hours while maintaining the temperature at 15-20 ° C. Stirring is continued for 1.5 hours at this temperature and then at 10 ° C and 500 ml of ice are added and neutralized to pH 7 with about 5 ml of the mixture further cooled with 1 l of water. The mixture is acidified with acetic acid and extracted three times with chloroform.

The 9762 extract was evaporated to give a slurry which was triturated with 400 ml of boiling ethanol. The resulting solids were filtered at room temperature. After further washing with 1.00 ml of cold ethanol and drying under vacuum, IV is obtained.

A stirred mixture of 1-cyclopropyl-15,6,7,8-tetrafluoro-4-oxo-3-carboxylic acid methyl ester (compound IV) (8.2 g), triethylamine (4 mL), tert-butyl carbazate (3.8 g) and of toluene was refluxed for about one hour and concentrated to dryness to give a residue under reduced pressure. The residue was dissolved in CH 2 Cl 2 (200 mL) and washed with water (200 mL) and brine (200 mL). The organic phase is dried over sodium sulphate, filtered and the filtrate is concentrated to dryness to give a residue under reduced pressure. This residue is purified by flash chromatography (silica gel) of 5% MeOH / CH 2 Cl 2 to give the desired C-5 substituted product V.

A mixture of about 3.5 g of V, tetrahydrofuran (THF) (30 ml) and 17 ml of 1N NaOH was heated at 80 ° C for about 1.5 hours. The reaction mixture was cooled in an ice bath and water (200 mL) was added followed by glacial acetic acid (2.3 mL). The precipitate was filtered off, washed with water and ether to give compound IV.

A mixture of approximately 2.6 g of VI piperazine and pyridine (20 ml) for one hour and the reaction mixture, 1.3 g of 1- (tert-butoxycarbonyl), is heated to 80 ° C and approximately concentrated to dryness under reduced pressure. The residue was dissolved in CH 2 Cl 2 (100 mL) and washed with water, 5'-citric acid, water and brine. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel) with 5% MeOH / CH 2 Cl 2 to give compound VII.

To a mixture of VII (2.3 g) and CH 2 Cl 2 (40 mL) at room temperature was slowly added approximately 28 mL of saturated ethanol / HCl. The mixture was stirred at room temperature for approximately

9762

After heating for 4.5 hours, cool to obtain and collect the product by filtration. The solid was CHCl 3 (50 mL) and methanol (10 mL) was added. The mixture was stirred at room temperature and the product was collected by filtration of compound VIII.

Example 4

The antimicrobial preparation for parenteral administration according to the invention content is ^: component: amount:

(S) -7- (3-Amino-pyrrolidine) -1-cyclopropyl-6,8-fluoro-5-hydrazino-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ¹ 100 mg / ml

carrier: puf or sodium citrate lecithin karboxymety1ce1u1óza povidone mety1parabén propy1parabén (percent carrier weight) 0,48% 0.53% 0.50% 0.11% 0.011%

^1: 5- (N-heterosubstituted amino) quinolone produced according to Example 1

The ingredients are mixed to form a suspension. Approximately 2.0 ml of the suspension is systemically administered by intramuscular injection to a human subject suffering from lower respiratory tract infection in the presence of Streptococus pneumonia. This dose is repeated twice a day for approximately 14 days. After 4 days the symptoms of the disease disappear, which means that the pathogen has been essentially exterminated.

9762

Example 5

The enteric-coated antimicrobial composition for oral administration of the present invention is prepared comprising the following tablet core. hydrazino-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid ¹ 350.0 starch 30.0 magnesium stearate 5.0 microcrystalline cellulose 100.0 colloidal silica 2.5 povidone 12.5 ¹ : 5- (N- heterosubstituted amino) quinolone produced according to Example 1.

The ingredients are mixed to give a free-flowing mixture. Compressed tablets are made using t-abletting methods known in the art. The tablet is coated with a suspension of a methacrylic acid / methacrylic acid polymer in isopropanol / acetone. A human with urinary tract infection of Escherichia Coli is orally administered two tablets every 8 hours for 14 days. The symptoms of the disease then disappear, which means that the pathogen has been essentially exterminated.

Claims (2)

PATENT CLAIMS A 5-hydrazinoquinolone derivative according to the general formula wherein CA) (1) (a) R ¹ is alkyl, alkenyl, carbocyclic ring, heterocyclic ring or -NCR ⁶ (CR ⁷ ) wherein R ⁶ and R ⁷ are independently hydrogen, alkyl, alkenyl, carbocyclic ring, heterocyclic ring, or R ⁶ and R ⁷ together form a heterocyclic ring that contains the nitrogen to which they are attached and a C b) R ² is hydrogen, halogen, lower alkyl, or lower alkoxy, or C 2) R ¹ and R ² together form a six-membered heterocyclic ring which contains the N atom and the carbon to which ^R2 is attached, CB) R ³ is a heterocyclic or carbocyclic ring and CC (Cl) R ⁴ and R ⁵ are independently hydrogen, lower alkyl, cycloalkyl, heteroalkyl or -CC = O) -XR ⁸ wherein X is covalent 9762 binding. N, O or S and R ⁸ is lower alkyl, lower alkenyl, arylalkyl, a carbocyclic ring or a heterocyclic ring, or (2) R ⁴ and R ⁵ together form a heterocyclic ring containing the nitrogen to which they are attached and their pharmaceutically acceptable salts and biohydrolyzable esters and solvates. A quinolone derivative according to claim 1, wherein R ¹ is ethyl, 2-fluoroethyl, 2-hydroxyethyl, tert-butyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluórcyklopropy1. mety 1 am i no, cyclopropyl or Third Quinolone derivative by Claim 1 wherein R ² is chlorine or f 1uór. 4th Quinolone derivative by Claim 1 wherein R ⁴ is hydrogen and R ⁵ is hydrogen or lower alkyl. A quinolone derivative according to claim 4, wherein R ⁴ and R ⁵ are both hydrogen. The quinolone derivative according to claim 5, wherein R ³ is a heterocyclic ring. The quinolone derivative according to claim 6, wherein said heterocyclic ring is 3-aminopyrrolidine The quinolone derivative according to claim 7, wherein R ¹ is cyclopropyl and R ² is fluoro. The quinolone derivative according to claim 7, wherein R ¹ is 2,4-difluorophenyl and R ² is fluoro. The quinolone derivative according to claim 6, wherein said heterocyclic ring is piperazine. 9762 11. ChinoIónový cyk1opropy1 and the compound of R ² is fluoro. claim 10, wherein R ¹ is a 12th Chi noIónový and 1ky1. derivative by Claim 4 wherein R ⁵ is lower 13th ChinoIónový derivative by claim 12, wherein R ³ is a heterocyclic ring. 14th A quinone derivative heterocyclic ring by is 3. Claim 13 and i nopyrrolidine. where said 15th ChinoIónový cyk1opropy1 and the compound of R ² is fluoro. claim 14 where R ¹ is 16th Chi noIónový derivative by claim 13 where said the heterocyclic ring is piperazine. 17. ChinoIónový cyklopropy1 and R ² is fluoro. where R ¹ is 18th Ch i noon a derivative selected from the group, involving (3S) -7- (3-Amino-1-pyrrolidinyl) -1-C2,4-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 their pharmaceutically acceptable salts, biohydrolyzable esters and salts. 19. p r a n i n i e n e r: i e i n e n e n i n e n e n e n e n e n e n e n o n e n e n e n e n o n e n e n e n e n e n e n e 2 i i n: i n c: i, contains: í j. ) is from the transversal and practical part of the article. 1. and (2) a pharmaceutically acceptable carrier " The method of claim 1 for use in preventing or treating infectious cernobas in a human or other animal subject.