CN1064357C

CN1064357C - Novel antimicrobial 5-(N-heterosubstituted amino) quinolones

Info

Publication number: CN1064357C
Application number: CN93120224A
Authority: CN
Inventors: 小·T·P·迪穆思; R·E·怀特
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1992-10-30
Filing date: 1993-10-30
Publication date: 2001-04-11
Anticipated expiration: 2013-10-30
Also published as: AU687018B2; SG59979A1; MX9306814A; FI952049A; BR9307347A; CN1092773A; IL107323A0; PL308671A1; ZA938089B; NO951640L; NZ257470A; CZ282581B6; AU5409794A; WO1994010163A1; FI952049A0; SK54795A3; JPH08502750A; KR950704301A; RU95110762A; NO951640D0

Abstract

Antimicrobial 5-(N-heterosubstituted amino) quinolone compounds, and pharmaceutically-acceptable salts and biohydrolyzable esters thereof, and solvates thereof.

Description

Antimicrobial 5- (N-heterosubstituted amino) quinolones and pharmaceutical compositions

The present invention relates to novel antimicrobial compounds, compositions and methods of treatment. More particularly, the compounds of the present invention are comprised of a quinolone or related heterocyclic moiety.

In particular, Antibacterial Agents include a wide variety of natural (Antibiotics), synthetic or semi-synthetic compounds which may be classified, for example, as aminoglycosides, ansamacrolides, β -lactams (including penicillin and cephalosporins), lincosamides, macrolides, nitrofurans, nucleosides, oligosaccharides, peptides and polypeptides, phenazines, polyenes, polyethers, quinolones, tetracyclines and sulfamoyls.

The mechanism of action of these antibacterial agents is variable, however, each can be generally classified as acting in one of up to four ways, either by inhibiting cell wall synthesis or repair, by altering cell wall permeability, by inhibiting protein synthesis, or by inhibiting nucleic acid synthesis, for example β -lactam antibacterial agents act by inhibiting the essential penicillin-linked proteins (PBPs) in bacteria, a process responsible for cell wall synthesis.

Not surprisingly, the pharmaceutical properties of antibacterial and other antimicrobial agents and their suitability for any clinical use vary widely. For example, antimicrobial agents (and members of this class) vary in their relative effectiveness against different types of microorganisms, and also vary in their susceptibility to the development of microbial tolerance. These antimicrobial agents may also differ in their pharmacological properties, such as their bioavailability and biodistribution. The selection of a clinically appropriate antibacterial (or other antimicrobial) agent is therefore a complex analysis of many factors, including the type of organism involved, the method of administration required, and the site of infection to be treated.

The pharmaceutical literature is rich in attempts to develop improved anti-microbial drugs (i.e., compounds with broader spectrum of activity, higher potency, higher pharmacological properties, and/or lower susceptibility to development of tolerance). For example, a group of clinically used antimicrobial quinolones has recently been developed. These compounds include, for example, nalidixic acid, difloxacin, enoxacin, floxa-cin, norfloxacin, lomefloxacin, ofloxacin, ciprofloxacin and pefloxacin. References c.marchbanks and m.dudley, "New Fluoroqui-nolons", 7 Hospital Therapy 18 (1988); p.shah, "Quinolones", 31 prog.drug res.243 (1987); quinolones-the fire Future in clinical Practice, (A. Percifal, editor, Royal Society of medical Services, 1986); and M.Parry, "pharmaceutical and pharmaceutical Uses of quinone Antibiotics," 116 Medical Times39 (1988).

However, many such attempts to improve antimicrobial agents have produced variable results. Indeed, few antimicrobials are precisely clinically acceptable in terms of their spectrum of antimicrobial activity, avoidance of microbial tolerance, and in terms of their pharmacological properties. For example, quinolones are not effective against certain clinically important pathogenic agents (e.g., gram-positive and/or anaerobic bacteria). The limited solubility of quinolones limits their bioavailability and the applicability to gastrointestinal dosing. They may also produce adverse side effects such as gastrointestinal distress and central nervous system effects (e.g. convulsions). Reference m.neuman and a.esanu, "Gaps and persictives of New Fluoroquinolones", 24 Druqs exptl.clin.res.385 (1988); christ et al, "Specific clinical laboratory of the principles", 10 Rev. infection Diseases S141 (1988); neu, "Clinical Use of th Quinolones", Lancet 1319 (1987); and "Ciprofloxacin: panacea or Blunder Drug? ", J.SouthChorolina Med.Assoc 131(March 1989).

The invention provides compounds of the general structure and pharmaceutically acceptable salts thereof, and biohydrolyzable esters and solvates thereof:

wherein

(A)(1)(a)R¹Is an alkyl group; an alkenyl group; a carbocyclic ring; a heterocycle; or-N (R)⁶)

(R⁷) Wherein R is⁶And R⁷Independently hydrogen, alkyl, alkene

A radical, carbocyclic ring, heterocyclic ring, or R⁶And R⁷Together form a nitrogen-containing heterocycle

Ring, and R⁶、R⁷Attached to the nitrogen atom, and

(b)R²is hydrogen, halogen, lower alkyl or lower alkoxy; or

(2)R¹And R²Together form a group containing N¹And a six-membered heterocyclic ring of carbon atoms,

R²attached to the carbon atom.

(B)R³Is a heterocycle or carbocycle; and

(C)(1)R⁴and R⁵Independently hydrogen, lower alkyl, cycloalkyl, heteroalkyl;

or-C (= O) -X-R⁸Wherein X is a covalent bond, N, O, or S,

and R is⁸Is lower alkyl, lower alkenyl, aralkyl, carbocyclic or heterocyclic;

or

(2)R⁴And R⁵Together forming a nitrogen atomHeterocycle, R⁴、R⁵Is connected with

Attached to the nitrogen atom.

It has been found that the compounds of the present invention, as well as compositions containing these compounds, are effective antimicrobial agents against a wide range of pathogenic microorganisms. Applicants have also found that the compounds of the present invention surprisingly have significantly increased aqueous solubility at physiological PH as compared to related antimicrobial agents known in the art. This surprising property, among other things, first increases pharmacological properties, including increased plasma concentrations following administration, ease of formulation, and more flexible dosing regimens.

The present invention includes certain novel quinolones, processes for their preparation, dosage forms, and methods of administration to humans or other animals. Of course, the compounds and compositions used in the present invention must be pharmaceutically acceptable. As used herein, a component that is "pharmaceutically acceptable" means a component that is suitable for use in humans and/or animals without undue side effects (such as toxicity, irritation, allergic response) as compared to a reasonable benefit/benefit ratio.

The compounds of the present invention, referred to herein as "5- (N-hetero-substituted amino) quinolones", include various quinolones (and related heterocyclic moieties) having an N-hetero-amino substituent at the 5-position of the quinolone moiety.

The 5- (N-hetero-substituted amino) quinolone comprises compounds with general structures andpharmaceutically acceptable salts thereof, biohydrolyzable esters thereof, and solvates thereof:wherein

(R⁷) (preferably alkyl or carbocyclic), wherein R⁶And R⁷Is divided into

Other than hydrogen, alkyl, alkenyl, carbocyclic, heterocyclic, or R⁶And

R⁷together form a nitrogen-containing heterocycle, R⁶And R⁷Is attached to the nitrogen

On the atom(s),

(b)R²is hydrogen, halogen, lower alkyl, or lower alkoxy (preferably

Halogen)

(2) (preferred) R¹And R²Together form a compound containing N¹And six of carbon atoms

Membered heterocyclic ring, R²Attached to the carbon atom;

(B)R³is a heterocyclic or carbocyclic ring (preferably heterocyclic); and

(C)(1)R⁴and R⁵Independently hydrogen, lower alkyl, cycloalkyl, heteroalkyl;

or-C (= O) -X-R⁸(preferably hydrogen or lower alkyl), wherein X

Is a covalent bond, N, O, or S, and R⁸Is lower alkyl, lower chain

Alkenyl, aralkyl, carbocyclic or heterocyclic; or

(2) (preferably) R⁴And R⁵Taken together to form a nitrogen-containing heterocycle, R⁴And R⁵

Attached to the nitrogen atom.

The following are definitions of terms used herein:

a "heteroatom" is a nitrogen, sulfur or oxygen atom, and groups containing one or more heteroatoms may

Containing different hetero atoms

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

"Heteroalkyl" is an unsubstituted or substituted 3-8 membered saturated chain radical consisting of carbon atoms and one or two heteroatoms.

An "alkenyl group" is an unsubstituted or substituted hydrocarbon chain having 2 to 8 carbon atoms, preferably 2 to 4 carbon atoms, and at least one olefinic double bond (including, for example, vinyl, allyl, and butenyl).

A "carbocycle" is an unsubstituted or substituted, saturated, unsaturated or aromatic hydrocarbon ring radical. Carbocycles are monocyclic or fused, bridged or spiro polycyclic ring systems, monocyclic containing 3 to 9 atoms, preferably 3 to 6 atoms, and polycyclic containing 7 to 17 atoms, preferably 7 to 13 atoms.

"cycloalkyl" is a saturated carbocyclic group. Preferred cycloalkyl groups include, for example, cyclopropyl, cyclobutyl and cyclohexyl.

A "heterocycle" is an unsubstituted or substituted, saturated, unsaturated, or aromatic cyclic group that includes carbon atoms and one or more heteroatoms in the ring. Heterocycles are monocyclic or fused, bridged or spiro polycyclic ring systems. Monocyclic rings have 3 to 9 atoms, preferably 3 to 6 atoms. The polycyclic ring has 7 to 17 atoms, preferably 7 to 13 atoms.

"aryl" is an aromatic carbocyclic group, preferred aryl groups include, for example, phenyl, tolyl, xylyl, cumyl, and naphthyl.

"heteroaryl" is an aromatic heterocyclic radical. Preferred heteroaryl groups include, for example, thienyl, furyl, pyrrolyl, pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, and tetrazolyl.

"alkoxy" is an oxy group 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 allyloxy.

"alkylamino" is an amino group having one to two alkyl substituents (i.e., -N-alkyl).

"aralkyl" refers to an alkyl group substituted with an aryl group. Preferred aralkyl groups include, for example, benzyl, and phenethyl.

"arylamino" refers to an amine group substituted with an aryl group (i.e., -NH-aryl).

An "aryloxy" group is an oxy group having an aryl substituent (i.e., -O-aryl).

An "acyl" or "carbonyl" group is a group formed by removing a hydroxyl group from a carboxyl group, (i.e., R-C (= O) -). Preferred alkanoyl groups include, for example, acetyl, formyl, and propionyl.

An "acyloxy" group is an oxy group having an acyl substituent, (i.e., -O-acyl) such as-O-C (= O) -alkyl.

An "amido" is an amino group having an acyl substituent (i.e., -N-acyl) such as, -NH-C (= O) -alkyl.

"halo", "halogen" or "halide" refers to a chlorine, bromine, fluorine or iodine atom. Chlorides and fluorides are the preferred halides.

Similarly, reference herein to a "lower" hydrocarbyl moiety (e.g., "lower" alkyl) is to a hydrocarbyl chain of 1 to 6, preferably 1 to 4, carbon atoms.

"pharmaceutically acceptable salt" refers to a cationic salt formed with any acidic group (e.g., carboxyl), or an anionic salt formed with any basic group (e.g., amino). Many such salts are known in the art and are described in world patent publication 87/05297, published by Johnston et al, 1987.9.11 (incorporated herein by reference). Preferred cationic salts include alkali metal salts (e.g., sodium and potassium salts), and alkaline earth metal salts (e.g., magnesium and calcium salts). Preferred anionic salts include halides (e.g., chloride salts).

"biohydrolyzable esters" are esters of 5- (N-heterosubstituted amino) quinolones which do not substantially affect the antimicrobial activity of the compound or are readily convertible in vivo by humans or lower animals to yield antimicrobially active 5- (N-heterosubstituted amino) quinolones. These esters include those that do not interfere with the biological activity of the quinolone antimicrobial agent. Many such esters are known in the art, as described in world patent publication 87/. 05297, Johnston et al, 1987.9.11, which is incorporated herein by reference. These esters include lower alkyl esters, lower acyloxyalkyl esters (e.g., acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl), lactonyl esters (2-benzo [ c]furanone esters, thio 2-benzo [ c]furanone esters), lower alkoxyoxyalkyl esters (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl, isopropoxycarbonyloxyethyl), alkoxyalkyl esters, choline esters, and alkylamidoalkyl esters (acetamidomethyl).

A "solvate" is a complex formed by combining a solute (e.g., a 5- (N-heterosubstituted amino) quinolone) and a solvent (e.g., water). See J.Honig et al, The VanNostrand chemistry's Dictionary, P.650 (1953). Pharmaceutically acceptable solvents useful in the present invention include those that do not interfere with the biological activity of the quinolone antimicrobial agent (e.g., water, ethanol, acetic acid, N-dimethylformamide).

As defined above and used herein, a substituent group may itself be substituted. Such a substitution may have one or more substituents. These substituents include those listed in C.Hansch and.A.Leo, subsystem Constant for Correlation Analysis and Biology (1979), which is included by reference. Preferred substituents include, for example, alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, and the like), cyano, halo, carboxy, alkoxyacetyl (e.g., carbethoxy, and the like), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, and the like), imino, thio, hydroxyalkyl, aryloxy, aralkyl, and combinations thereof.

Radical R¹、R²And R³Any one of the quinolone moieties known in the art is formed having antimicrobial activity. These sections are well known in the art and are described in the following articles, all of which are incorporated herein by reference: wolfson et al, "The Fluoro-quinones: structures, mechanics of Action and Resistance, and Spectra of Activity In Vitro, 28 antibiotic Agentsan Chemotherapy 581 (1985); and t.rosen et al, 31 j.med chem.1586 (1988); rosen et al, 31 j. med. chem.1598 (1988); klopman et al, 31 Antimicrob.Agents Chemother.1831 (1987); 31: 1831-; sanchez et al, 31 j.med.chem.983 (1988); j.m. domagalia et al, 31 j.med.chem.991 (1988); m.p.wentland et al in 20 ann.rep.med.chem.145 (D).Baily, editor, 1986); cornett et al, in 21 ann. rep.med.chem.139 (d.m.bailey, editor, 1986); fernandes et al, in 22 ann. rep.med.chem.117 (d.m.bailey, editor, 1987); r. albrecht, 21 prog. drug Research 9 (1977); and P.B.FernandesEt al, in 23 ann. rep. med. chem. (r.c. allen, editor, 1987).

R¹Preferably alkyl, alkenyl, aryl, cycloalkyl; heterocyclic, or alkylamino. Further preferred is R¹Is ethyl, 2-fluoroethyl, 2-hydroxyethyl, tert-butyl, 4-fluorophenyl, 2, 4-difluorophenyl, methylamino, 3-oxolanyl, 2-fluorocyclopropyl, bicyclo [ 1.1.1]Pentane, vinyl, or cyclopropyl. Particularly preferred R¹The radicals are cyclopropyl, 2-fluorocyclopropyl, tert-butyl, 2-fluorocyclopropyl, and 2, 4-difluorophenyl. Preferred 5- (N-hetero-substituted amino) quinolones also include those wherein R is¹And R²Those which together form a six-membered heterocyclic ring, of the formula:

wherein X is O, S or CH₂。

R²Preferably chlorine, fluorine, methoxy or methyl. Fluorine and chlorine are particularly preferred R²And (4) a base.

Preferred R³The group includes nitrogen-containing heterocycles. Particularly preferred are nitrogen-containing 5-to 8-membered heterocycles. The heterocyclic ring may contain further heteroatoms, such as oxygen, sulphur or nitrogen, preferably nitrogen. These heterocyclic groups are described in U.S. patent 4, 559, 334, Petersen et al, grant 1986.7.8 and U.S. patent 4, 670, 444, Grohe et al, grant 1987.6.2. (both of themIncluded by reference). Preferred R³The radicals including unsubstituted or substituted pyridines, piperidines, morpholines, diazabicyclo [ 3.1.1]Heptane, diazabicyclo [ 2.2.1]Heptane, diazabicyclo [ 3.2.1]Octane, diazabicyclo [ 2.2.2]Octane, imidazoline, and 5-amino-3-azabicyclo [ 4.2.0]Heptane, and particularly preferably R³The group includes piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N-dimethylAminomethyl pyrrolidine, N-ethylaminomethyl pyrrolidine, 3, 5-dimethylpyridine, N-methylpiperazine and 3, 5-dimethylpiperazine.

Preferred R⁴And R⁵The groups include: wherein R is⁴And R⁵Together form a heterocyclic ring containing nitrogen atoms, R⁴And R⁵Attached to the nitrogen atom, wherein R⁴And R⁵Are each lower alkyl, wherein R⁴And R⁵One of which is hydrogen and the other is lower alkyl and wherein R is⁴And R⁵All of which are hydrogen. More preferred groups are those wherein R⁴Or R⁵One of which is hydrogen and the other is alkyl, and wherein R is⁴And R⁵All of which are hydrogen, particularly preferred groups are those in which R is⁴And R⁵All of which are hydrogen.

Preferred compounds of the invention include, on the one hand, R containing a basic nitrogen-containing atom³Radicals (including, for example, pyridine, piperidine, diazabicyclo [ 3.1.1)]Heptane, diazabicyclo [ 2.2.1]Heptane, diazabicyclo [ 3.2.1]Octane, diazabicyclo [ 2.2.2]Octane, and imidazoline), and on the other hand contains a compound of formula (I) with R⁴And R⁵R in which the nitrogen atom to which it is attached is basic⁴And R⁵A group (including as R)⁴And R⁵Together forming a heterocyclic ring with the nitrogen atom to which they are attached, R⁴And R⁵Are each lower alkyl, R⁴And R⁵One is lower alkyl and the other is hydrogen, or R⁴And R⁵Both hydrogen). Particularly preferred compounds are those in which R³The group is one of the following: piperazine, 3-methylpiperazine, 3-aminopyrrolidine, 3-aminomethylpyrrolidine, N, N-dimethylaminopyrrolidine, N-ethylaminomethylpyrrolidine, N-methylpiperazine, or 3, 5-dimethylpiperazine; and R⁴And R⁵All are hydrogen compounds.

As used herein, a "basic nitrogen atom" is a nitrogen atom containing a single isolated electron pair capable of forming ionic bonds with a variety of cations. The basic nature of the nitrogen atom of a given moiety, which depends on the nature of the covalent bond of the nitrogen atom, is known in the art, see for example, the Introduction to Organic Chemistry, 2 nd edition, pp.734-40 (1981), by a.

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

the compounds of the present invention are also useful as intermediates in the synthesis of novel lactam-quinolones. Such compounds are disclosed in the publication of international publication No. wo 91/16327, 1991.10.31. Which is hereby incorporated by reference. Lactam quinolones include a plurality of lactam moieties linked to the 5-position of the quinolone moiety through a linking moiety.

Lactam-quinolones include compounds having the general structure:

Q-L-B wherein Q, L and B are as defined below

(I) Q is a structure having the following formula (I):

wherein

(A)(1)A¹Is N or C (R)⁷) (ii) a Here, the

(i)R⁷Is hydrogen, hydroxy, alkoxy, nitro, cyano, halogen, alkyl,

or N (R)⁸)(R⁹) (preferably hydrogen or halogen), and

(ii)R⁸and R⁹Independently is R^8aWherein R is^8aIs hydrogen, alkyl, alkene

A radical, carbocyclic, or heterocyclic substituent; or R⁸And R⁹Together form a

A heterocyclic ring including the nitrogen to which they are attached;

(2)A²is N or C (R)²) (preferably (C (R)²) Wherein R) is²Is hydrogen

Or halogen;

(3)A³is N or (preferably C (R)⁵) ); wherein R is⁵Is hydrogen;

(4)R¹is hydrogen, alkyl, carbocycle, heterocycle, alkoxy, hydroxy, alkenyl,

Aralkyl, or N (R)⁸)(R⁹) (preferably alkyl or carbocyclic);

(5)R³is hydrogen, halogen, alkyl, carbocyclic, or heterocyclic, (preferably heterocyclic);

(6)R⁴is a hydroxyl group; and

(7)R⁶is R¹⁵Or R¹⁶X; wherein R is¹⁵Is a substituent part of L, an

And may be absent, or an alkyl, heteroalkyl, or alkenyl group; r¹⁶Is L

And is alkyl, alkenyl, carbocyclic, or heterocyclic; and

x is alkyl, heteroalkyl, alkenyl, oxygen, sulfur, or NH;

(B) with the following exceptions:

(1) when A is¹Is C (R)⁷) When R is¹And R⁷May be taken together to form a compound containing N¹

And A¹The heterocyclic ring of (1);

(2) when A is²Is C (R)²) When R is²And R³Can form together into

-O-(CH₂)_n-O-, wherein n is an integer from 1 to 4;

(3) when A is³Is C (R)⁵) When R is⁴And R⁵Can be formed together into a compound ofR⁴And R⁵A heterocycle of the attached carbon atom, and said carbon atom and formula

(I) To the carbon atom(s) of (a);

(4) when A is³Is C (R)⁵) When R is¹And R⁵May be taken together to form a compound containing N¹

And R⁵A heterocyclic ring of adjacent carbon atoms to which they are attached;

(II) B is a structure of formula (II) wherein L and R¹⁴Connecting:wherein

(A)R¹⁰Is hydrogen, halogen, heteroalkyl, carbocyclic, heterocyclic, R^8a-O-，R^3a-CH=N-，

(R⁸)(R⁹)N-，R¹⁷-C(=CHR²⁰) -C (= O) -NH-, or (preferably) alkyl,

alkenyl radical, R¹⁷-C(=NO-R¹⁹) -C (= O) NH-or R¹⁸-(CH₂)_m-C (= O) NH-; wherein

(1) m is an integer of 0 to 9 (preferably 0 to 3);

(2)R¹⁷is hydrogen, alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocycle or heterocycle (preferably alkyl, carbocycle or heterocycle);

(3)R¹⁸is R¹⁷，-Y¹or-CH (Y)₂)(R¹⁷)；

(4)R¹⁹Is R¹⁷Aralkyl, heteroaralkyl, -C (R)²²)(R²³)COOH，-C(=O)O-R¹⁷or-C (= O) NH-R¹⁷Wherein R is²²And R²³Each is R¹⁷Or together with R²²And R²³Carbocyclicor heterocyclic ring of linked carbon atoms (preferably R)¹⁷or-C (R)²²)(R²³)COOH)；

(5)R²⁰Is R¹⁹Halogen, -Y¹or-CH (Y)²)(R¹⁷) (preferably R)¹⁹OrHalogen);

(6)Y¹-C(=O)OR²¹，-C(=O)R²¹，-N(R²⁴)R²¹or-S (O) pR²⁹OR-OR²⁹(ii) a And Y is²Is Y¹or-OH, -SH or-SO₃H；

(a) P is an integer of 0 to 2 (preferably 0);

(b)R²⁴is hydrogen; an alkyl group; an alkenyl group; a heteroalkyl group; a heteroalkenyl group; a carbocyclic ring; a heterocycle; -SO₃H；-C(=O)R²⁵(ii) a Or when R is¹⁸is-CH (N (R)²⁴)R²¹)(R²¹) When R is²⁴May contain R and²¹a linked heterocycle; and is

(c)R²⁵Is R¹⁷，NH(R¹⁷)，N(R¹⁷)(R²⁶)，O(R²⁶) Or S (R)²⁶) (preferably R)¹⁷，NH(R¹⁷) Or N (R)¹⁷)(R²⁶) ); wherein R is²⁶Alkyl, alkenyl, carbocyclic, heterocyclic or (preferably) when R is²⁵Is N (R)¹⁷)(R²⁶) When R is²⁶May contain R¹⁷A linked heterocycle; and is

(7)R²¹Is R²⁹Or hydrogen; wherein R is²⁹Is an alkyl group; an alkenyl group; aralkyl group; a heteroalkyl group; a heteroalkenyl group; a heteroaralkyl group; a carbocyclic ring; a heterocycle; or when Y is¹Is N (R)²⁴)R²¹And R is²¹Is R²⁹When R is²¹And R²⁴May together be a compound containing with R²⁴A heterocyclic ring (preferably hydrogen, alkyl, carbocyclic or heterocyclic) of the nitrogen atom to which it is attached;

(B)R¹¹is hydrogen, halogen, alkoxy or R²⁷C (= O) NH- (preferably hydrogen or alkoxy), wherein R²⁷Is hydrogen or alkyl (preferably hydrogen);

(C) the bond "a" is a single bond or absent; and bond "b" is a single bond, a double bond or absent; but the bond "a" is not both present at the same time as the bond "b";

(D)R¹²is-C (R)^8a) -, or-CH₂-R²⁸- (preferably-C (R)^8a) -) according to the formula (I); wherein R is²⁸is-C (R)^8a) -O-, or-N-, and R²⁸Directly with N in formula (II)¹¹Are linked to form a 5-membered ring; the following are removed: if the bond "a" is absent, then R¹²Is that

(1) (preferably) -C (R)^8a)(X¹) -, wherein

(i)X¹is-R²¹；-OR³⁰；-S(O)rR³⁰Wherein r is from 0 to 2

An integer of (2) (preferably 0); -O (C = O) R³⁰(ii) a Or N (R)³⁰)R³¹(ii) a And is

(ii)R³⁰And R³¹Each is an alkyl, alkenyl, carbocyclic or heterocyclic substituent;

or R³⁰And R³¹Together are containing with R³⁰And R³¹Of linked nitrogen atoms

A heterocycle; or

(2)-CH₂-R³²(ii) a Wherein R is³²is-C (R)^8a)(R²¹) -O-or-NR^8aAnd is and

R³²directly with N in formula (II)¹¹Are linked to form a 5-membered ring; (E) (1) if the bond "b" is a single bond, R¹³preferably-CH(R)³³) -; or

-C(O)NHSO₂-, if the bond "a" is absent; or-C (R)³³) -, wherein

R¹⁴Containing R³⁶(ii) a Wherein R is³³Is hydrogen or COOH (preferably COOH), and C^*And

R³⁶are linked to form a 3-membered ring;

(2) if the bond "b" is a double bond, R¹³is-C (R)¹³) =; or

(3) If the bond "b" is absent, R¹³Is hydrogen, -SO₃H，-PO(OR³⁴)OH，

-C(O)NHSO₂N(R³⁴)(R³⁵)，-OSO₃H，-CH(R³⁵) COOH or

-OCH(R³⁴) COOH (preferably-SO)₃H, or-C (O) NHSO₂N(R³⁴)(R³⁵)；

Wherein R is³⁴Is hydrogen, alkyl, alkenyl, carbocyclic, or heterocyclic; and R is¹³Is a hydrogen atom, and is,

alkyl, alkenyl or-NHR^8a(ii) a Or (preferably) if R is¹³Is that

-C(O)NHSO₂N(R³⁴)(R³⁵)，R³⁴And R³⁵Together are containing with R³⁴And

R³⁵a heterocyclic ring of the attached nitrogen; and (F) (1) if bond "a" or bond "b" is absent, then R is¹⁴Is absent and L is directly linked to

R¹²Or R¹³Connecting; (2) if the bond "a" or the bond "b" is a single bond, R¹⁴Is that

-W-C_=C(R^8a)-R³⁷-, or-W-C- (R)³⁶)-R³⁷-; or

(3) (preferably) if bond "a" is a single bond andbond "b" is a double bond,

then R is¹⁴is-C (R)^8a)(R³⁸)-W-C_-R³⁷-; or (preferably)

-W-C(R^8a)(R³⁸)-C_-R³⁷-, or-W-C-R³⁷-; wherein

(a) W is 0; s (O) S, wherein S is an integer of 0 to 2 (preferably 0);

or C (R)³⁸) Wherein R is³⁸Is hydrogen, alkyl or alkoxy;

(b)R³⁶is hydrogen; an alkyl group; an alkenyl group; -COOH; or, if R is¹³Is that

-C^*(R³³) Then R is³⁶Can be reacted with C^*Are linked to form a 3-membered carbocyclic ring;

(c)R³⁷absent, or alkyl, alkenyl, carbonA ring or a heterocycle; and is

(d) C _ direct and R¹³Are linked to form a 5-or 6-membered ring, and (III) L is linked to B through Q; and L is L', -X²t-R³⁹-L' or

-X³ _t-R³⁹-L ', wherein L ' is Q ', -X²-Q″，-X³-Q' or

-X⁴ _t-C(=Y³u) -Z-Q' (preferably-X)²-Q″，-X³-Q″，

-X⁴ _t-C(=Y³u)-Z-Q″)；

(1) t and u are each 0 or 1;

(2)R³⁹is alkyl, alkenyl, heteroalkyl, heteroalkenyl, carbocycle, or heterocycle

(preferably alkyl or alkenyl);

(3)X²is oxygen or S (O) v, wherein v is an integer from 0 to 2 (preferably 0);

(4)X³is nitrogen; n (R)⁴⁰)；N⁺(R⁴¹)(R⁴²) (ii) a Or R⁴³-N(R⁴¹) (ii) a Combined pipe

Through a single or double bond with R¹⁴Connecting; or, if R is¹⁴Is absent, then

X³Linked to B by a single or double bond (preferably X)¹³Is nitrogen, N (R)⁴⁰)

Or N⁺(R⁴¹)(R⁴²) ); wherein

(a)R⁴⁰Is R^8a，-OR^8a(ii) a or-C (= O) R^8a(ii) a (preferably R)^8a)；

(b)R⁴¹And R⁴²Are hydrogen, alkyl, respectively; an alkenyl group; a carbocyclic ring; a heterocycle; or

If R is⁶Is R¹⁶X, then R⁴¹And R⁴²Together with Q' may be

Is as in R¹⁶The heterocyclic ring of (1);

(c)R⁴³is N (R)⁴¹) Oxygen or sulfur;

(5)X⁴is oxygen, sulfur, NR⁴⁰Or R⁴³-NR⁴¹(preferably oxygen, sulfur or NR)⁴⁰)；

(6)Y³Is oxygen, sulfur, NR⁴⁰Or N⁺(R⁴¹)(R⁴²)；

(7)Y⁴Is oxygen or NR⁴¹(preferably oxygen);

(8) z is absent, or is oxygen, sulfur, nitrogen, NR⁴⁰Or N (R)⁴¹)-R⁴³(Excellent)

From oxygen, sulfur or NR⁴⁰)；

(9) Q' is R of said Q⁶A substituent group; and is

(10) Q 'is Q'; or with X²，X³Z or Z' together being said Q

R of (A) to (B)⁶And (4)a substituent.

Preferred lactam-containing moieties include cephem, isocephem, isooxocephem, oxocephem, carbacephem, penicillin, penem, carbapenem and monobactam β -particularly preferred are cephem, penem, carbapenem and monobactam β.

R in the formula (II)¹⁰Is any group substituted at the active stereoisomeric position of the carbon adjacent to the lactam carbonyl group of the antimicrobially active lactam (the term "antimicrobially active lactam" as used herein refers to lactam-containing compounds which have no quinolone substituent and possess antimicrobial activity.) the "active" position is position β (i.e., positions 7- β) for cephem, oxocephem, and carbacephem, the active position is position α for penems, carbapenems, clavulanes (clavams), and clavulans (clavams)¹⁰As will be apparent to one of ordinary skill in the art.

The processes for preparing quinolones and quinolone intermediates in the process of the present invention are described in the following references, all of which are incorporated herein by reference (including the articles listed in these references);

21 progress Drug Research, 9-104 (1977); med, chem, 503-506 (1988); med, chem, 1313-1318 (1989); 1987 Liebigs an. chem., 871-; 14 Druqs exptl. clin. res., 379-383 (1988); med, chem, 983-; med, chem., 537-542 (1989); 78 J.pharm.Sci., 585-; 26 j.het.chem., (1989); 24 j.het.chem., 181-; U.S. patent 4, 599, 334, 35 chem. pharm. bull, 2281-2285 (1987); med, chem, 2363-2369 (1986); med, chem, 991-1001 (1988); 25 j.het.chem., 479-485 (1988); european patent publications 266, 576; european patent publication 251, 308, 36 chem. pharm. bull, 1223-1228 (1988); european patent publication 227, 088; european patent publications 227, 039;

european patent publications 228, 661; med, chem., 1586-1590(1988); med, chem., 1598-1611 (1988); and 23 j. med. chem., 1358-.

In general, 5- (N-heterosubstituted amino) quinolones can be prepared by the following method:

wherein R is⁴And R⁵As previously defined [ 5-halo-quinolones]Is a suitably protected 5-halo quinolone wherein the halogen is preferably chloro or fluoro (preferably fluoro). This reaction can be thought of as a 5-halo quinolone substituted by (R)⁴)(R⁵)N-NH₂Nucleophilic aromatic displacement is performed to form a 5- (N-heterosubstituted amino) quinolone.

Furthermore, the 5- (N-hetero-substituted amino) quinolone can be prepared by the following method:

wherein R is⁴And R⁵As previously defined and [5, 7-dihaloquinolone]Is a suitably protected 5-and 7-halogenated quinolone]Wherein the halogen in the 5-and 7-positions is chlorine or fluorine (preferably fluorine), respectively. This reaction can be thought of as a quinolone 5-halogen substituent group (R)⁴)(R⁵)N-NH₂Selective nucleophilic aromatic displacement is performed to form a 5- (N-heterosubstituted amino) quinolone. The reaction is preferably carried out in a non-polar aprotic solvent, preferably benzene, toluene, xylene and the like, at elevated temperatures, preferably from 50 ℃ to reflux temperature.

The composition of the present invention comprises:

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

(b) a pharmaceutically acceptable carrier. A "safe and effective amount" of a 5- (N-heterosubstituted amino) quinolone is an amount effective to inhibit the growth of microorganisms at the site of infection to treat a human or lower animal patient without undue adverse side effects such as toxicity, irritation, or allergic response) and, when used in the present invention, is commensurate with a reasonable benefit/risk ratio. 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 time of treatment, the nature of concurrent therapy (if any), the specific dosage form employed, the carrier employed, the solubility of the 5- (N-heterosubstituted amino) quinolone, and the mode of administration desired for the composition.

The compositions of the present invention are preferably used in unit dosage form. As used herein, in accordance with the best medical practice, a "unit dosage form" is a composition of the present invention containing in unit dosage an amount of a 5- (N-heterosubstituted amino) quinolone suitable for administration to a human or lower animal patient. These compositions preferably contain from about 30mg to about 20000mg, more preferably from about 50mg (mg) to about 7000mg, most preferably from about 500mg to about 3500mg of 5- (N-heterosubstituted amino) quinolone.

The compositions of the invention may be presented in a number of forms suitable for (e.g.) oral, rectal, topical or parenteral administration. Many pharmaceutically acceptable carriers known in the art may be used depending on the particular route of administration desired. They include solid or liquid fillers, diluents, hydrotropes, surfactants and encapsulating substances. Any pharmaceutically active substance which does not substantially interfere with the antimicrobial activity of the 5- (N-heterosubstituted amino) quinolone may be included. The amount of carrier employed in combination with the 5- (N-heterosubstituted amino) quinolone should be sufficientto provide a practical amount of the substance to be administered per unit dose of the 5- (N-heterosubstituted amino) quinolone. The techniques and compositions for preparing dosage forms used in the methods of the present invention are described in the following references, all of which are incorporated herein by reference: 7 Modern pharmaceuticals, Chapters 9 and 10(Bank&Rhodes, editors, 1979); lieberman et al, pharmaceutical Dosage Forms: tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Editon (1976).

In particular, pharmaceutically acceptable carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidones, ethanol and castor oil. Preferably, the pharmaceutically acceptable carrier in the parenterally administrable composition constitutes at least 90% of the total weight of the composition.

Various oral dosage forms may be used, including solid dosage forms such as tablets, capsules, granules and loose powders. These oral dosage forms contain a safe and effective amount, typically at least 5%, preferably from about 25% to about 50%, of a 5- (N-heterosubstituted amino) quinolone. Tablets may be compressed, milled, enteric coated, sugar coated, film coated or multiple compressed and contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, draining 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, which contain suitable solvents, preservatives,emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and flavoring agents. Preferred carriers for oral administration include gelatin, propylene glycol, cottonseed oil and castor oil.

The compositions of the present invention may also be administered to a patient topically, i.e., by placing or dispensing the composition directly onto the epidermis or epithelial tissue of the patient. Such compositions include, for example, lotions, ointments, solutions, gels, and solids. These topical compositions preferably contain the most safe and effective 5- (N-heterosubstituted amino) quinolones, usually at least about 0.1%, preferably from about 1% to about 5%. For topical administration, a suitable carrier should preferably remain as a continuous film on the skin at the site of administration and resist loss due to perspiration or immersion in water. Typically, the carrier is organic in nature and is capable of dispersing or dissolving the 5- (N-heterosubstituted amino) quinolone therein. The carrier may include pharmaceutically acceptable emollients, emulsifiers, thickeners and solvents.

The present invention also provides a method for treating or preventing infectious diseases in humans or other animals comprising administering to said patient a safe and effective amount of a 5- (N-heterosubstituted amino) quinolone. As used herein, an "infectious disease" is any disease characterized by a microbial infection. Preferred methods of the invention are used to treat bacterial infections. These infectious diseases include, for example, central nervous system infections, external ear infections, middle ear infections (e.g., acute otitis), sinus duralis infections, eye infections, oral infections (e.g., tooth, gum and mucosal infections), upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skinand skin structure infections, bacterial endocarditis, burns, surgical antibacterial prophylaxis and antibacterial prophylaxis in immunosuppressed patients (e.g., patients receiving cancer chemotherapy, or patients undergoing organ transplantation).

The 5- (N-heterosubstituted amino) quinolones and compositions of the present invention can be administered locally or systemically. Systemic use includes any method of introducing the 5- (N-heterosubstituted amino) quinolone into the tissues of the body, such as intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The particular antimicrobial dose administered is correlated with the duration of treatment. The dosage and treatment regimen will also depend on such factors as the particular 5- (N-heterosubstituted amino) quinolone used, the mode of resistance of the infected organism to the 5- (N-heterosubstituted amino) quinolone used, the ability of the 5- (N-heterosubstituted amino) quinolone to reach a minimum inhibitory concentration at the site of infection, the nature and extent of other infections, if any, the patient's own characteristics (e.g., body weight), the coordination with the treatment regimen, the occurrence and severity of any side effects in the treatment.

Generally, for an adult (weighing about 70 kg), about 75mg to about 30000mg, more preferably about 100mg to about 20000mg, and even more preferably about 500mg to about 3500mg of 5- (N-heterosubstituted amino) quinolone is administered daily. The treatment regimen is continued for about 1 to 56 days, preferably about 7 to 28 days. Prophylactic regimens (e.g., to avoid opportunistic infections in immunocompromised patients) can last 6 months or more, depending on good medical practice.

A preferred method of parenteral administration is by intramuscular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans (assuming a body weight of about 70 kg), individual doses of from about 100mg to about 7000mg, preferably from about 500mg to about 3500mg, are acceptable.

A preferred method of systemic administration is oral. An individual dose of about 100mg to about 2500mg, preferably about 250mg to about 1000mg, is preferred.

Local administration can be used to systemically release 5- (N-heterosubstituted amino) quinolones or to treat local infections. The amount of 5- (N-heterosubstituted amino) quinolone to be topically applied depends on such factors as the sensitivity of the skin, the type and location of the tissue being treated, the composition and carrier (if any) used for administration, the particular 5- (N-heterosubstituted amino) quinolone used for administration, and the degree of systemic action (as distinguished from local) required for the particular disorder being treated.

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

Example 1

(S) -7- (3-Aminopyrrolidinyl) -1-cyclopropyl-6, 8-difluoro-5-1, 2-hydrazono-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid dihydrochloride

A mixture of methyl propionate (983g, 11.7 mole) and 500ml of tetrahydrofuran was cooled to 5 ℃ and cyclopropylamine (667g, 11.7 mole) dissolved in 1000ml of tetrahydrofuran was added from the attached funnel over about 1 hour at a rate that maintained the temperature at 3-7 ℃. The mixture was stirred at 5 ℃ for a further 1 hour and the ice bath was removed. The reaction was stirred at 20-25 ℃ for 1 hour, at room temperature for 3 hours, and allowed to stand at room temperature for about 2.5 days. The solvent was removed under reduced pressure and the residue was distilled under vacuum to give I.

A solution of about 207g of pentafluorobenzoyl chloride II (0.90 mole) and 250ml of dioxane was cooled to 15-20 ℃ with an ice water bath and a solution of about 126g I and 90.9 g of triethylamine (0.90 mole) in 300ml of dioxane was added dropwise over 5.5 hours, the attached funnel was washed with an additional 500ml of dioxane and the reaction was stirred at 20 ℃ overnight. The mixture was then filtered under vacuum and the precipitate was washed twice with 100ml dioxane. The filtrate was vacuum stripped at 25 ℃ and 1000ml hexane was added to the residue. More precipitate was collected and added to the first batch. The combined products were then resuspended in 1500ml of hexane, stirred briefly, filtered and dried in vacuo to give III.

In a 5L three neck round bottom flask equipped with a thermometer, argon inlet, mechanical stirring and an additional funnel were placed about 14.9 g (0.621 mole) NaH (from hexane washed NaH/mineral oil) and 1000mL dimethylformamide. The mixture was cooled to 15-20 ℃. And about 181.5 g of III (0.542 mole) dissolved in 2L of aqueous dimethylformamide was added dropwise over 3.5 hours while maintaining the temperature at 15-20 ℃. Stirring was continued at this temperature for 1.5 hours, after which the mixture was further cooled to 10 ℃ and 500ml of ice and 1L of water were added. The mixture was neutralized to pH7 with about 5ml of acetic acid and extracted three times with chloroform. The dried chloroform extract was evaporated to give a slurry which was triturated with 400ml of boiling ethanol. The resulting solid was filtered at room temperature. Washed once more with100ml cold ethanol and then dried under vacuum to give IV.

Mixing IV (22g, 0.070 mole) and 2N H₂SO₄(600ml) mixture at 100Stir 20 h and cool to room temperature. The product V was collected by filtration and washed with water.

Triethylamine (17ml, 0.12 mole) was added dropwise to a mixture of V (18g, 0.060 mole), (3S) -tert-butoxycarbonylaminopyrrolidine (12g, 0.066 mole) and dimethylformamide (130ml) at 54 ℃. The mixture was stirred at 54 ℃ for 4 hours. Acetonitrile (120ml) was added and the mixture was heated to 75 ℃ and then cooled to room temperature. The mixture was cooled to 15 ℃ and the solid collected by filtration, washed with acetonitrile (2X 60 ml). The solid was stirred in acetonitrile (180ml) for 10 minutes and product VI was collected by filtration, washed with acetonitrile (2 × 60 ml).

VI (4.0 g, 0.0086 mole), acetonitrile (120ml) and hydrazine monohydrate (4.0 ml, 0.082 mole) were refluxed for 2.5 hours until a solution formed. The solution was diluted with acetonitrile (100ml) and stirred at room temperature for 2 hours. The precipitate was collected by filtration and heated in acetonitrile (150 ml). Insoluble material was removed by filtration and the filtrate was stored at room temperature overnight. The product VII was collected by filtration and washed with acetonitrile.

To a mixture of VII (4.0 g, 0.0083 mole) and dichloromethane (85ml) was slowly added saturated ethanol/HCl (55ml) at room temperature with stirring. The mixture was stirred at room temperature for 4.5 hours and the solid was collected by filtration. The material was placed in CHCl₃(100ml) was heated and methanol (10ml) was added. The mixture was cooled to room temperature and the final product (VIII) was collected by filtration and washed with CHCl₃And (6) washing.

Example 2

(3S) -7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6, 8-difluoro-5-1, 2-hydrazono-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid dihydrochloride

Hydrogen monoethyl malonate (13.2 g, 0.10 mol) was dissolved in tetra-ethyl hydrogenTetrahydrofuran (260ml) and cooled to-65 ℃. 2M n-butyllithium (100ml, 0.20 mol) was then added dropwise to maintain the temperature below-50 ℃, the solution was heated to-5 ℃ and cooled to-65 ℃ again. Pentafluorobenzoyl chloride 1 (7.20 ml, 0.05 mol) was dissolved in tetrahydrofuran (32ml) and added dropwise to keep the temperature below-50 ℃. After the addition was complete, the reaction was brought to-35 ℃ and stirred for 1 hour. Aqueous HCl (l 3%, 316ml) was added to the solution and stirred for 30 min. Subjecting the mixture to CH₂Cl₂Taking benzene and using NaHCO₃Aqueous solution and water washing. The organic layer was washed with Na₂SO₄Drying and concentration gave product 2, which was present as a mixture of keto-enol tautomers in solution.

Ethyl pentafluorobenzoylacetate 2(10g, 0.035 mol) was added to acetic anhydride (8.5 ml, 0.09 mol) and triethyl orthoformate (10ml, 0.06 mol). The reaction was heated to 110 ℃ for a total of 2.25 hours. The reaction was concentrated. The product was dissolved in ethanol (250ml) and cooled to 0 ℃. 2, 4-difluoroaniline (4.7 ml, 0.046 mol) was then added slowly and the ice bath removed. The reaction was stirred overnight and concentrated to dryness under reduced pressure. The residue was triturated in petroleum ether and the product was collected by filtration to give cis-trans isomer mixture 3.

Vinylogous amide 3 (9.43 g, 0.022 mol) was dissolved in dimethylformamide (57.0 ml) and K was added₂CO₃(9.46 g, 0.068 mol). The reaction was stirred overnight and then concentrated. Dichloromethane was added and the solution was washed with water. The organic phase is treated with Na₂SO₄Drying, concentration and vacuum drying to obtain quinolone 4.

The ester 4 (8.49 g, 0.21 mol) was placed in an acetic acid/water/H ratio of 8: 6: 1₂SO₄(309ml) and heated to 100 ℃ until the reaction is complete. The solution was poured into ice water and the precipitate was filtered. Dissolving the product in CH₂Cl₂Recrystallized and precipitated with hexane. The solid was collected to give acid 5. The filtrate was concentrated and removed from CH as before₂Cl₂The residue was purified to give a second crop of product.

Quinolone 5(10g, 0.027 mol) was dissolved in dimethylformamide (60ml) and (3S) -tert-butoxycarbonylaminopyrrolidine (6.0 g, 0.032 mol) was added. The reaction was heated to 55 ℃ and triethylamine (7.5 ml, 0.054 mol) was added over 20 minutes. The reaction was completed in 45 minutes, checked by TLC, and the heat source was removed. The product was precipitated from solution and filtered. The solid was washed with diethyl ether. The product was dissolved in hot EtOAc and precipitated by addition of hexanes. The solid was filtered off and dried in vacuo to give 6.

A mixture of quinolone 6 (2.0 g, 0.0037 mol), acetonitrile (60ml) and hydrazine (0.46 ml, 0.0095 mole) was refluxed for 1.6 hours and cooled 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 (4ml) was stirred at room temperature for 1 hour, followed by addition of 4ml HCl/EtOH. The reaction was stirred for an additional 3 hours and the solid was collected by filtration. Placing the solid in CH₂Cl₂Triturating and collecting by filtration. The product is separated from acetonitrile/H₂And recrystallizing in O to obtain the final product.

Example 3

1-cyclopropyl-6, 8-difluoro-5-1, 2-hydrazono-1, 4-dihydro-4-oxo-7-piperazinyl-3-quinolinecarboxylic acid dihydrochloride

A mixture of methyl propionate (983g, 11.7 mole) and 500ml of tetrahydrofuran was cooled to 5 ℃ and cyclopropylamine (667g, 11.7 mole) dissolved in 1000ml of tetrahydrofuran was added from an attached funnel over about 1 hour at a rate to maintain the temperature at 3-7 ℃. The mixture was stirred at 5 ℃ for a further 1 hour and the ice bath was removed. The reaction was stirred at 20-25 ℃ for about 1 hour, at room temperature for about 3 hours, and then allowed to stand at room temperature for about 2.5 days. The solvent was removed under reduced pressure and the residue was distilled under vacuum to give I.

A solution of about 207g of pentafluorobenzoyl chloride II (0.90 mole) and 250ml of dioxane was cooled to 15-20 ℃ with an ice water bath and a solution of about 126g I and 90.9 g of triethylamine (0.90 mole) in 300ml of dioxane was added dropwise over 5.5 hours. The attached funnel was washed with 50ml dioxane and the reaction was stirred at 20 ℃ overnight. The mixture was then filtered under vacuum and the precipitate was washed twice with 100ml dioxane. The filtrate was vacuum stripped at 25 ℃ and 1000ml hexane was added to the residue. More precipitate was collected and added to the first batch. The combined products werethen resuspended in 1500ml of hexane, stirred briefly, filtered and dried in vacuo to give III.

In a 5L three neck round bottom flask equipped with a thermometer, argon inlet, mechanical stirring and an attached funnel were placed about 14.9 g (0.621 mole) NaH (from hexane washed NaH/mineral oil) and 1000mL dimethylformamide. The mixture was cooled to 15-20 ℃ and about 181.5 g of III (0.542 mole) dissolved in 2L of dimethylformamide was added dropwise over 3.5 hours while maintaining the temperature at 15-20 ℃ and stirring was continued at this temperature for 1.5 hours, after which the mixture was further cooled to 10 ℃ and 500ml of ice and 1L of water were added. The mixture was neutralized to pH7 with about 5ml of acetic acid and extracted three times with chloroform. The dried chloroform extract was evaporated to give a slurry which was triturated with 400ml of boiling ethanol. The resulting solid was filtered at room temperature. Washed once more with 100ml cold ethanol and then dried under vacuum to give IV.

A stirred mixture of 1-cyclopropyl-5, 6, 7, 8-tetrafluoro-4-oxo-3-carboxylic acid, methyl ester (compound IV) (8.2 g), triethylamine (4ml), tert-butyl carbazate (3.8 g) and toluene was refluxed for about 1 hour and concentrated to dryness under reduced pressure. Dissolving the residue in CH₂Cl₂(200ml) and washed with water (200ml) and brine (200 ml). The organic phase is treated with Na₂SO₄Dried, filtered and the filtrate concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (silica gel) with 5% MeOH/CH₂Cl₂Elution afforded the desired C-5 substituted product V.

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

A mixture of about 2.6 g of VI, 1.3 g of 1- (tert-butoxycarbonyl) piperazine and pyridine (20ml) was heated at 80 ℃ for about 1 hour and the reaction mixture was concentrated to dryness under reduced pressure. Dissolving the residue in CH₂Cl₂(100ml) and washed with water, 5% citric acid, water and brine. The organic layer was washed with Na₂SO₄Dry, filter and concentrate the filtrate to dryness. The residue was purified by flash chromatography (silica gel) with 5% MeOH/CH₂Cl₂Eluting to obtain VII compound.

VII (2.3 g) and HC at room temperature₂Cl₂(40ml) to the mixture was slowly added about 28ml of saturated ethanol/HCl. The mixture was stirred at room temperature for about 4.5 hours and the product was collected by filtration. Dissolving the solid in CHCl₃(50ml) was heated and methanol (10ml) was added. The mixture was cooled to room temperature and the product was collected by filtration to give compound VIII.

Example 4

The antibacterial composition for parenteral administration of the present invention comprises:

component amounts

(S) -7- (3-Aminopyrrolidine) -1-cyclopropyl-

6, 8-difluoro-5-1, 2-hydrazono-1, 4-dihydro

-4-oxo-3-quinolinecarboxylic acids¹100 mg/ml carrier

Carrier

Sodium citrate buffer containing (by weight of carrier)

Percent):

lecithin 0.48%

Carboxymethyl cellulose 0.53

Polyalkylpyrrolones 0.50

Methyl p-hydroxybenzoate 0.11

Para hydroxybenzoic acid ethyl ester 0.011

1: a5- (N-hetero-substituted amino) quinolone prepared as in example 1

The above components were mixed to form a suspension. Approximately 2.0 ml of the suspension was administered systemically by intramuscular injection to patients with lower respiratory tract infections accompanied by streptococcal pneumonia. This dose was repeated twice daily for about 14 days. After 4 days, disease symptoms subsided, indicating that the pathogen had essentially disappeared.

Example 5

The enteric-coated antibacterial composition for oral use of the present invention comprises the following core tablets:

component amounts

(S) -7- (3-Aminopyrrolidine) -1-cyclopropyl-

6, 8-difluoro-5-1, 2-hydrazono-1, 4-dihydro

-4-oxo-3-quinolinecarboxylic acids¹350．0

Starch 30.0

Magnesium stearate 5.0

Microcrystalline cellulose 100.0

Colloidal silica 2.5

Povidone 12.5

1: a5- (N-hetero-substituted amino) quinolone prepared as in example 1

The components are mixed into a loose mixture. The compressed tablets are formed by tableting methods known in the art. The tablets were then coated with a suspension of methacrylic acid/methacrylate polymer in isopropanol/acetone. Patients with urinary tract infections with simultaneous appearance of E.coli were orally administered two tablets every 8 hours for 14 days. The symptoms of the disease then subside, indicating that the pathogen has essentially disappeared.

Claims

1. A compound of the formula and pharmaceutically acceptable salts and biohydrolyzable esters thereof:wherein

(A)(1)(a)R¹Is an alkyl group; an alkenyl group; a carbocyclic ring; or-N (R)⁶)(R⁷) Wherein R is⁶

And R⁷Independently hydrogen, alkyl, alkenyl, and

(b)R²is hydrogen, halogen, alkyl or alkoxy; or

(2)R¹And R²Together form a group comprising N' and R²Six of the carbon atoms to which they are attached

A member of a heterocyclic ring is a member of the group,

(B)R³is a heterocycle or carbocycle; and

(C)R⁴and R⁵Independently hydrogen, alkyl;

wherein the alkyl group is C₁-C₄An alkyl group; said alkenyl group is C₂-C₄An alkenyl group;

the carbocyclic ring is a monocyclic group having 3 to 6 carbon atoms or a polycyclic group having 7 to 13 carbon atoms

A cyclic group; said heterocyclic ring being composed of carbon atoms and one or more substituents independently selected from nitrogen, sulfur and

monocyclic radicals containing 3-6 atoms or 7-13 atoms, consisting of hetero atoms of oxygen

The polycyclic group of (a); the alkoxy group is C₁-C₄An alkoxy group.

2. A compound according to claim 1, wherein R¹Is ethyl, 2-fluoroethyl, 2-hydroxyethyl, tert-butyl, 4-fluorophenyl, 2, 4-difluorophenyl, methylaminoA cyclopropyl group or a 2-fluorocyclopropyl group.

3. A compound according to claim 1, wherein R²Is chlorine or fluorine.

4. A compound according to claim 1, wherein R⁴Is hydrogen and R⁵Is hydrogen or alkyl.

5. A compound according to claim 4, wherein R⁴And R⁵Are all hydrogen.

6. A compound according to claim 5, wherein R³Is a heterocyclic ring.

7. A compound according to claim 6 wherein said heterocycle is 3-aminopyrrolidine.

8. A compound according to claim 7, wherein R¹Is cyclopropyl and R²Is fluorine.

9. A compound according to claim 7, wherein R¹Is 2, 4-difluorophenyl and R²Is fluorine.

10. A compound according to claim 6 wherein said heterocycle is piperazine.

11. A compound according to claim 10, wherein R¹Is cyclopropyl and R²Is fluorine.

12. A compound according to claim 4, wherein R⁵Is an alkyl group.

13. A compound according to claim 12, wherein R³Is a heterocyclic ring.

14. A compound according to claim 13, wherein said heterocycle is 3-aminopyrrolidine.

15. A compound according to claim 14, wherein R¹Is cyclopropyl and R²Is fluorine.

16. A compound according to claim 13, wherein said heterocycle is piperazine.

17. A compound according to claim 16, wherein R¹Is cyclopropyl and R²Is fluorine.

18. A compound selected from the group consisting of:

(3S) -7- (3-amino-1-pyrrolidinyl) -1- (2, 4-difluorophenyl) -6, 8-difluoro-5-hydrazino-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid;

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

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

19. A pharmaceutical composition for the treatment or prophylaxis of infectious diseases of the human or other animal body, comprising:

(1) a safe and effective amount of a compound of claim 1; and

(2) a pharmaceutically acceptable carrier.