Pyridonecarboxylic acid derivatives and intermediates for the synthesis thereof

This invention relates to pyridonecarboxylic acid derivatives of the following general formula, esters thereof and salts thereof, as well as pharmaceutical preparations containing them. ##STR1## wherein: R is cycloalkyl which may be substituted by halogen, or the like; PA1 X is hydrogen, lower alkyl, amino or the like; PA1 Y is hydrogen or halogen; PA1 A is nitrogen or a group of the formula C--Z in which Z is lower alkoxy that may be substituted by halogen, or the like; PA1 R.sub.1 and R.sub.2 may be the same or different and are each hydrogen or the like; PA1 R.sub.3 is hydrogen or lower alkyl; PA1 R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 may be the same or different and are each hydrogen, halogen or lower alkyl; PA1 m is 0 or 1; and PA1 n and p may be the same or different and are each 0 or 1. This invention also relates to bicyclic amine compounds useful as direct intermediates for the synthesis of the above-described pyridonecarboxylic acid derivatives.

TECHNICAL FIELD 
This invention relates to novel pyridonecarboxylic acid derivatives useful 
as antibacterial agents, and novel intermediates for the synthesis 
thereof. 
BACKGROUND ART 
A variety of antibacterial pyridonecarboxylic acid derivatives are known. 
For example, Japanese Patent Laid-Open No. 239857/'94 (corresponding to 
European Patent Application Laid-Open No. EP-A-603887) discloses compounds 
of the general formula (A) 
##STR2## 
wherein: X.sub.1 and X.sub.2 are each a halogen atom; 
R.sub.1 is an amino group which may have one or more substituents, or the 
like; 
R.sub.3 and R.sub.4 are each a hydrogen atom, an alkyl group or the like; 
Y is O, N, a methylene group or the like; 
Z is O, S, a methylene group or the like; 
m and n are each an integer of 0 to 2, the sum of them being 2 or 3; 
p, q and r are each an integer of 0 to 3, the sum of them being 0 to 3; 
A is N or C-X (in which X is a hydrogen atom, a halogen or the like); and 
R is a hydrogen atom or the like. 
In these compounds of the general formula (A), the bicyclic amino group 
constituting the substituent group at the 7-position is composed of a 
first ring containing a nitrogen atom and a second ring containing an 
oxygen atom or the like. However, as to the substituent group on the first 
ring, these compounds differ from the compounds of the present invention 
which are represented by the formula (I) that will be given later. 
Moreover, in the compounds of the above formula (A) which are specifically 
described in the aforementioned Japanese Patent Laid-Open No. 239857/'94, 
only the following three groups are disclosed as examples of the bicyclic 
amino groups at the 7-position. 
##STR3## 
Moreover, Japanese Patent Laid-Open No. 192262/'94 (corresponding to 
European Patent Application Laid-Open No. EP-A-589318) discloses compounds 
of the general formula (B) 
##STR4## 
wherein: X.sub.1 is halogen or nitro; 
X.sub.2 is hydrogen, amino or the like; 
R.sub.1 is alkyl, cycloalkyl or the like; 
R.sub.2 is hydrogen or the like; 
A is N or C-R.sub.5 in which R.sub.5 is hydrogen, halogen or the like; and 
Z is a group of the formula 
##STR5## 
in which R.sub.3 and R.sub.4 are each hydrogen, methyl or the like. 
However, the bicyclic amino group (Z) constituting the substituent group 
at the 7-position in these compounds differs from that present in the 
compounds of the present invention, as to the mode of fusion between the 
first ring containing a nitrogen atom and the second ring containing an 
oxygen atom. 
DISCLOSURE OF THE INVENTION 
According to the present invention, there are provided novel 
pyridonecarboxylic acid derivatives of the following general formula (I) 
[which may hereinafter referred to as the compounds (I) of the present 
invention], esters thereof and salts thereof. 
##STR6## 
wherein: R represents a lower alkyl group, a lower alkenyl group or a 
lower cycloalkyl group (all of which may optionally be substituted by one 
or more halogen atoms), or represents a phenyl group which may optionally 
be substituted by one or more halogen atoms and/or an amino group; 
X represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower 
alkyl group, a lower alkoxy group or an amino group which may be 
protected; 
Y represents a hydrogen atom or a halogen atom; 
A represents a nitrogen atom or a group of the formula C-Z in which Z 
represents a hydrogen atom, a halogen atom or a cyano group, represents a 
lower alkoxy group, a lower alkyl group, a lower alkylthio group, a lower 
alkenyl group or a lower alkynyl group (all of which may optionally be 
substituted by one or more halogen atoms), or combines with R to form a 
bridge represented by the formula --O--CH.sub.2 --CH(CH.sub.3)--; 
R.sub.1 and R.sub.2 may be the same or different and each represent a 
hydrogen atom, a lower alkyl group or an amino-protecting group; 
R.sub.3 represents a hydrogen atom or a lower alkyl group; 
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 may be the same or 
different and each represent a hydrogen atom, a halogen atom or a lower 
alkyl group; 
m is 0 or 1; and 
n and p may be the same or different and are each 0 or 1. 
According to the present invention, there are also provided novel bicyclic 
amine compounds of the following general formula (II) and salts thereof 
which are useful as intermediates for the synthesis of pyridonecarboxylic 
acid derivatives of the above formula (I). 
##STR7## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, R.sub.9, m, n and p have the same meanings as described 
previously. 
The compounds (I) of the present invention are structurally characterized 
by the fact that a conventionally unknown bicyclic amino group of the 
following general formula is joined to the 7-position of a specific 
pyridonecarboxylic acid or a position equivalent to the 7-position 
thereof. 
##STR8## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, R.sub.9, m, n and p have the same meanings as described 
previously. 
The compounds (I) of the present invention, which have the above-described 
structural features, exhibit excellent antibacterial activity, especially 
against Gram-positive bacteria, and are hence useful as antibacterial 
agents. 
The compounds of the present invention will be more specifically explained 
hereinbelow. 
As used herein, the term "halogen atom" comprehends, for example, fluorine, 
chlorine and bromine. The term "lower" means that the group modified by 
this word contains 1 to 7 carbon atoms, unless otherwise specified. 
The term "lower alkyl" comprehends straight-chain and branched alkyl groups 
having 1 to 7 carbon atoms, and examples thereof include methyl, ethyl, 
propyl, isopropyl, butyl, tert-butyl and pentyl. The term "lower alkoxy" 
comprehends lower alkyloxy groups in which the lower alkyl portion has the 
above-described meaning, and examples thereof include methoxy, ethoxy, 
propoxy, isopropoxy and butoxy. The term "lower alkenyl" comprehends 
straight-chain and branched alkenyl groups having 2 to 7 carbon atoms, and 
examples thereof include vinyl, allyl, 1-propenyl and isopropenyl. The 
term "lower alkynyl" comprehends, for example, ethynyl and 1-propynyl. The 
term "lower cycloalkyl" comprehends cycloalkyl groups having 3 to 7 carbon 
atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl 
and cyclohexyl. The term "lower alkylthio" comprehends, for example, 
methylthio and ethylthio. 
The lower alkyl group, lower alkenyl group and lower cycloalkyl group which 
are used in the definition of R may optionally be substituted by one or 
more halogen atoms. Examples of the aforesaid groups substituted by one or 
more halogen atoms include fluoromethyl, difluoromethyl, trifluoromethyl, 
2-fluoroethyl, 2-chloroethyl, 2,2-difluoroethyl, 2-fluorovinyl, 
1-fluorovinyl, 2,2-difluorovinyl, 2-fluorocyclopropyl and 
2-chlorocyclopropyl. On the other hand, the lower alkoxy group, lower 
alkyl group, lower alkylthio group, lower alkenyl group and lower alkynyl 
group which are used in the definition of Z may optionally be substituted 
by one or more halogen atoms. Examples of the aforesaid groups substituted 
by one or more halogen atoms include, in addition to the 
halogen-substituted lower alkyl and lower alkenyl groups which have been 
described above for R, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 
difluoromethylthio, trifluoromethylthio, fluoroethynyl and 
trifluoropropynyl. 
Examples of the phenyl group which may optionally be substituted by one or 
more halogen atoms and/or an amino group include 2,4-difluorophenyl, 
3-amino-4,6-difluorophenyl, 4-chloro-2fluorophenyl, 
2-chloro-4-fluorophenyl and 3-amino-4-fluorophenyl. 
As the protecting group in the "amino-protecting group" or the "amino group 
which may be protected", there may be used any of various groups which can 
readily be eliminated by a common deprotection reaction such as hydrolysis 
or hydrogenolysis, without exerting no substantial influence on other 
structural parts. 
Examples of amino-protecting groups which can readily be eliminated by 
hydrolysis (i.e., easily hydrolyzable amino-protecting groups) include 
oxycarbonyl groups such as ethoxycarbonyl, tert-butoxycarbonyl (which may 
be abbreviated as Boc), benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 
vinyloxycarbonyl and .beta.-(p-toluenesulfonyl)ethoxycarbonyl; acyl groups 
such as formyl, acetyl and trifluoroacetyl; silyl groups such as 
trimethylsilyl and tert-butyldimethylsilyl; and tetrahydropyranyl, 
o-nitrophenylsulfenyl and diphenylphosphenyl. 
Examples of amino-protecting groups which can readily be eliminated by 
hydrogenolysis (i.e., easily hydrogenolyzable amino-protecting groups) 
include arylsulfonyl groups such as p-toluenesulfonyl; phenyl- or 
benzyloxy-substituted methyl groups such as benzyl, trityl and 
benzyloxymethyl; arylmethoxycarbonyl groups such as benzyloxycarbonyl and 
o-methoxybenzyloxycarbonyl; and halogenoethoxycarbonyl groups such as 
.beta.,.beta.,.beta.-trichloroethoxycarbonyl and 
.beta.-iodoethoxycarbonyl. 
As esters of the compounds (I) of the present invention, there may 
preferably be used esters which can be converted into the compounds (I) of 
the present invention by eliminating the alcohol group therefrom within or 
outside the living body by chemical or enzymological means. 
The esters which can be converted into the corresponding free carboxylic 
acids by chemical means such as hydrolysis include, for example, lower 
alkyl esters such as methyl esters and ethyl esters. Moreover, the esters 
which can be converted into the corresponding free carboxylic acids not 
only by chemical means but also by enzymological means include, for 
example, lower alkanoyloxy-lower alkyl esters such as acetoxymethyl 
esters, 1-acetoxyethyl esters and pivaloyloxymethyl esters; lower 
alkoxycarbonyloxy-lower alkyl esters such as 1-ethoxycarbonyloxyethyl 
esters; aminoethyl esters such as 2-dimethylaminoethyl esters and 
2-(1-piperidinyl)ethyl esters; and other esters such as 3-butyrolactonyl 
esters, choline esters, phthalidyl esters and 
(5-methyl-2-oxo-1,3-dioxol-4-yl) methyl esters. 
As salts of the compounds (I) of the present invention, physiologically 
acceptable salts thereof are especially preferred. Examples thereof 
include salts formed with organic acids such as trifluoroacetic acid, 
acetic acid, lactic acid, succinic acid, methanesulfonic acid, maleic 
acid, malonic acid, gluconic acid and amino acids (e.g., aspartic acid and 
glutamic acid); salts formed with inorganic acids such as hydrochloric 
acid and phosphoric acid; metal salts such as sodium, potassium, zinc and 
silver salts; ammonium salts; and salts formed with organic bases such as 
trimethylamine, triethylamine and N-methylmorpholine. 
Salts of the bicyclic amine compounds (II) of the present invention include 
acid addition salts formed with inorganic acids such as hydrochloric acid 
and sulfuric acid; and acid addition salts formed with organic acids such 
as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid 
and p-toluenesulfonic acid. 
The pyridonecarboxylic acid derivatives (I) and bicyclic amine compounds 
(II) of the present invention may sometimes exist in the form of hydrates 
and solvates. Moreover, these compounds of the present invention may exist 
in the form of optical isomers, stereoisomers (cis- and trans-forms) or 
mixtures thereof. These compounds are also within the scope of the present 
invention. 
Preferred examples of the compounds (I) of the present invention are the 
compounds of the above general formula (I) in which n is 1. Among them, 
the following compounds of the above general formula (I) are more 
preferred. 
(i) The compounds wherein R is a lower cycloalkyl group that may optionally 
be substituted by halogen, such as cyclopropyl or 2-fluorocyclopropyl, or 
a phenyl group that is substituted by one or more halogen atoms and/or an 
amino group, such as 2,4-difluorophenyl or 3-amino-4,6-difluorophenyl. 
(ii) The compounds wherein X is a hydrogen atom, a lower alkyl group such 
as methyl, or an amino group. 
(iii) The compounds wherein Y is a fluorine atom. 
(iv) The compounds wherein A is a nitrogen atom or C-Z in which Z is a 
hydrogen atom; a halogen atom such as a fluorine or chlorine atom; a cyano 
group; a lower alkoxy group that may optionally be substituted by halogen, 
such as methoxy or difluoromethoxy; a lower alkyl group such as methyl; a 
lower alkylthio group such as methylthio; a lower alkenyl group such as 
vinyl; or a lower alkynyl group such as ethynyl. 
(v) The compounds wherein R.sub.1 and R.sub.2 may be the same or different 
and are each a hydrogen atom or a lower alkyl group such as methyl. 
(vi) The compounds wherein R.sub.3 is a hydrogen atom. 
(vii) The compounds wherein R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and 
R.sub.9 may be the same or different and are each a hydrogen atom or a 
lower alkyl group such as methyl. 
Still more preferred examples of the compounds of the present invention are 
the compounds of the above general formula (I) wherein R is a cyclopropyl, 
2-fluorocyclopropyl, 2,4-difluorophenyl or 3-amino-4,6-difluorophenyl 
group; X is a hydrogen atom, a methyl group or an amino group; Y is a 
fluorine atom; A is a nitrogen atom or C-Z in which Z is a hydrogen atom, 
a fluorine atom, a chlorine atom, a methoxy group, a difluoromethoxy 
group, a methyl group, a methylthio group, a vinyl group, an ethynyl group 
or a cyano group; R.sub.1 and R.sub.2 may be the same or different and are 
each a hydrogen atom or a methyl group; R.sub.3 is a hydrogen atom; 
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 may be the same or 
different and are each a hydrogen atom or a methyl group; and n is 1. More 
specific examples thereof are the compounds described in the Examples 
which will be given later. 
Excepting the compounds described in the Examples which will be given 
later, typical examples of the compounds (I) of the present invention are 
given below. Although the stereostructures thereof are not specified in 
the following designations, the compounds designated by the respective 
chemical names comprehend various isomers having different 
stereostructures. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-tert-butyl-6-fluoro-1,4-dih 
ydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-tert-butyl-6-fluoro-1,4-dih 
ydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-6,8-difluoro-1-(2-fluoroethyl 
)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-6-fluoro-1,4-dihydro-8-methox 
y-4-oxo-1-vinylquinoline-3-carboxylic acid. 
7-(4-Amino-6-oxa-2-azabicyclo[3.2.0]hept-2-yl)-1-cyclopropyl-6-fluoro-1,4-d 
ihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-8-methyl-2-oxa-6-azabicylo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluor 
o-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-4-fluoro-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluo 
ro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-4,4-difluoro-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6- 
fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-4-methyl-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluo 
ro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-di 
hydro-8-methyl-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-di 
hydro-5-hydroxy-8-methyl-4-oxoquinoline-3-carboxylic acid. 
7-(8-Amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluoro-1,4-di 
hydro-5-hydroxy-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
1-(3-Amino-4,6-difluorophenyl)-7-(8-amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl 
)-8-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. 
1-(3-Amino-4,6-difluorophenyl)-7-(8-amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl 
)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 
1-(3-Amino-4,6-difluorophenyl)-7-(8-amino-2-oxa-6-azabicyclo[3.3.0]oct-6-yl 
)-6-fluoro-1,4-dihydro-5-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid. 
5-Amino-1-(3-amino-4,6-difluorophenyl)-7-(8-amino-2-oxa-6-azabicyclo[3.3.0] 
oct-6-yl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 
7-(9-Amino-4,4-difluoro-2-oxa-7-azabicyclo[4.3.0]non-7-yl)-1-cyclopropyl-6- 
fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
7-(8-Aminomethyl-2-oxa-6-azabicyclo[3.3.0]oct-6-yl)-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. 
Preferred examples of the bicyclic amine compounds (II) of the present 
invention are the compounds corresponding to the substituent groups 
located at the 7-position of the above-described pyridonecarboxylic acid 
derivatives. 
The compounds (I) of the present invention may be prepared, for example, by 
an amination reaction or a ring closure reaction. A typical process based 
on the amination reaction is explained below. 
The compounds (I) of the present invention, esters thereof and salts 
thereof may readily be prepared by reacting a compound of the general 
formula (III) 
##STR9## 
wherein L is a leaving group, R, X, Y and A have the same meanings as 
described previously, and the carboxyl and oxo groups present in the above 
formula may form a boron chelate bond therebetween, an ester thereof or a 
salt thereof with a bicyclic amine compound of the general formula (II) 
##STR10## 
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, 
R.sub.8, R.sub.9, m, n and p have the same meanings as described 
previously; and if a boron chelate part is present in the product, 
hydrolyzing it. 
Examples of the leaving group L in the general formula (III) include 
halogen atoms, lower alkoxy groups, lower alkylthio groups, lower 
alkylsulfonyl groups, lower alkylsulfinyl groups, lower alkylsulfonyloxy 
groups and arylsulfonyloxy groups. Among them, halogen atoms such as 
fluorine and chlorine are preferred. 
The reaction of the compound (II) with the compound (III) may usually be 
carried out by stirring a mixture thereof in an inert solvent at a 
temperature of about 10 to 180.degree. C. and preferably about 20 to 
130.degree. C., for a period of time ranging from about 10 minutes to 7 
days and preferably from about 30 minutes to 3 days. The inert solvents 
which can be used for this purpose include, for example, water, methanol, 
ethanol, acetonitrile, chloroform, pyridine, N,N-dimethylformamide, 
dimethyl sulfoxide and 1-methyl-2-pyrrolidone. These solvents may be used 
alone or in admixture. 
This reaction is generally carried out in the presence of an acid acceptor 
by using the compound (II) in an amount equivalent to or in slightly 
excess of that of the compound (III). However, the compound (II) may be 
used in excess so as to function additionally as an acid acceptor. 
Examples of the acid acceptor include organic bases such as 
1,8-diazabicyclo[5.4.0]-7-undecene (DBU), triethylamine, pyridine, 
quinoline and picoline; and inorganic bases such as sodium hydroxide, 
potassium hydroxide, sodium carbonate, potassium carbonate, sodium 
hydrogen carbonate and potassium hydrogen carbonate. These acid acceptor 
may usually be used in an amount of about 1 to 3 moles per mole of the 
compound (II). 
Compounds (III) are well known or may be prepared according to well-known 
processes. Bicyclic amine compounds (II) are all novel and the processes 
for the preparation thereof will be described later. 
When the compound (I) of the present invention which has been prepared by 
the above-described amination reaction has an amino-protecting group 
and/or the compound (I) of the present invention is obtained in the form 
of an ester, the amino-protecting group and/or ester may optionally be 
eliminated or converted. If a free acid is obtained thereby, it may be 
converted into a salt as required, or if a salt is obtained, it may be 
converted into a free acid as required. The conversion of an ester into a 
free acid may be carried out by a hydrolysis reaction. The elimination of 
an amino-protecting group may be carried out by subjecting the resulting 
compound (I) to a hydrolysis reaction or a hydrogenolysis reaction 
according to the type of the protecting group. Thus, there can be obtained 
a compound (I) of the present invention in which the amino-protecting 
group has been converted into a hydrogen atom. The hydrolysis reaction and 
hydrogenolysis reaction are described below. 
The hydrolysis reaction may be carried out by bringing an ester of a 
compound (I) of the present invention and/or a compound (I) of the present 
invention having an easily hydrolyzable amino-protecting group into 
contact with water in a suitable solvent. In order to accelerate this 
reaction, it is usually carried out in the presence of an acid or a base. 
Usable acids include inorganic acids such as hydrochloric acid, 
hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids 
such as acetic acid, trifluoroacetic acid, formic acid and 
p-toluenesulfonic acid. Usable bases include metal hydroxides such as 
sodium hydroxide and barium hydroxide; carbonates such as sodium carbonate 
and potassium carbonate; and sodium acetate. 
Usually, water is used as the solvent. However, according to the properties 
of the aforesaid compound(s), a water-miscible organic solvent such as 
ethanol, ethylene glycol dimethyl ether or dioxane may be used in 
combination with water. The reaction temperature may usually range from 
about 0 to 150.degree. C. and preferably from about 30 to 100.degree. C. 
This reaction may also be carried out by heating the aforesaid compound(s) 
directly in the presence of an acid as described above, and then adding 
water thereto. 
The elimination of an amino-protecting group by hydrogenolysis may 
advantageously be carried out by treating a compound (1) of the present 
invention having an easily hydrogenolyzable amino-protecting group with 
hydrogen gas in a solvent in the presence of a catalyst. The catalysts 
which can be used in this reaction include, for example, catalysts for 
hydrogenation, such as platinum, palladium and Raney nickel catalyst. 
Usable solvents include, for example, ethylene glycol, dioxane, 
N,N-dimethylformamide, ethanol, acetic acid and water. This reaction may 
be carried out at a temperature of about 60.degree. C. or below and is 
usually carried out at room temperature. 
When the easily hydrogenolyzable amino-protecting group is benzyl, trityl, 
benzyloxycarbonyl, p-toluenesulfonyl or the like, the protecting group may 
also be eliminated by metallic sodium treatment in liquid ammonia at a 
temperature of about -50 to -20.degree. C. 
The compounds (I) of the present invention, which have been prepared by the 
above-described amination reaction, may be isolated and purified according 
to any conventional procedure. These compounds are obtained in the form of 
salts, free acids or hydrates, depending on the conditions of isolation 
and purification. However, according to the intended purposes, these forms 
may be changed into each other to obtain the compounds of the present 
invention in desired forms. 
The stereoisomers of the compounds (I) of the present invention may be 
separated from each other by any conventional method such as fractional 
crystallization or chromatography. Moreover, their optical isomers may be 
isolated by the application of a known optical resolution method. 
The compounds (I) of the present invention and salts thereof, which can be 
obtained in the above-described manner, are all novel compounds and are 
valuable as antibacterial agents because of their high antibacterial 
activities. The compounds (I) of the present invention and salts thereof 
can be used not only as drugs for human beings and other animals, but also 
as agricultural chemicals, food preservatives and the like. 
Esters of the compounds (I) of the present invention are valuable as 
starting materials for the synthesis of the compounds (I) of the present 
invention. However, if these esters themselves are readily converted into 
the compounds (I) of the present invention within the living body, they 
are useful as prodrugs. Accordingly, they may be used as antibacterial 
agents similarly to the compounds (I) of the present invention. 
The compounds (II) used as starting materials in the above-described 
amination reaction process may be prepared, for example, by eliminating 
the amino-protecting group R.sub.10 from a compound of the general formula 
(IV) 
##STR11## 
wherein R.sub.10 is an amino-protecting group, and R.sub.1, R.sub.2, 
R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, m, n and p 
have the same meanings as described previously, and thereby converting it 
into a hydrogen atom. 
In this case, examples of the amino-protecting group R.sub.10 include the 
above-described easily hydrogenolyzable amino-protecting groups and easily 
hydrolyzable amino-protecting groups. 
When R.sub.1 and/or R.sub.2 in the compound (IV) are amino-protecting 
groups, it is desirable for subsequent reactions to employ, for R.sub.10, 
an amino-protecting group differing in character from the amino-protecting 
groups represented by R.sub.1 and/or R.sub.2. For example, when the 
amino-protecting groups represented by R.sub.1 and/or R.sub.2 are easily 
hydrolyzable amino-protecting groups such as tert-butoxycarbonyl, an 
easily hydrogenolyzable amino-protecting group such as benzyl or trityl is 
preferably chosen for R.sub.10. 
The elimination reaction for the amino-protecting group R.sub.10 may be 
carried out by subjecting the compound (IV) to a hydrogenolysis or 
hydrolysis reaction which has previously been explained. 
When R.sub.1 and/or R.sub.2 in the compound obtained as a result of this 
elimination reaction are amino-protecting groups, they may optionally be 
eliminated and converted into hydrogen atoms in the same manner. If a free 
base is obtained thereby, it may be converted into a salt in the usual 
manner as required, or if a salt is obtained, it may be converted into a 
free base as required. 
The stereoisomers of the compounds (II) of the present invention which are 
prepared in the above-described manner may be separated from each other by 
any conventional method such as fractional crystallization or 
chromatography. Moreover, their optical isomers may be isolated by the 
application of a known optical resolution method. 
The compounds (IV) are also novel, and they may be prepared according to 
the processes shown in the following reaction schemes 1-9 or processes 
equivalent thereto. 
##STR12## 
wherein: 
R.sub.10 has the same meaning as described previously; 
R.sub.11 represents an alcohol-protecting group such as 
tert-butyidimethylsilyl, acetyl or tetrahydroyranyl; 
R.sub.12 represents a (lower alkyl)sulfonyl, a (halogeno lower 
alkyl)sulfonyl group or an arylsulfonyl group; 
R.sub.13 represents a hydrogen atom or a lower alkyl group; 
R.sub.1 ' represents an amino-protecting group; 
R.sub.2 ' and R.sub.3 ' each represent a lower alkyl group; 
X.sub.1, X.sub.2 and X.sub.3 each represent a halogen atom; 
q represents an integer of 1 to 3; and 
r is 0 or 1. 
Now, the foregoing reaction schemes will be briefly explained herein below. 
Reaction Scheme 1 
A compound 3 (q=1 or 2) is obtained by oxidizing a known compound 1 or 2 
with ozone and then reducing the resulting product. Moreover, the compound 
3 (q=3) may be obtained by the hydroboration of the compound 1. The 
terminal alcohol group of the compound 3 is sulfonylated to yield a 
compound 4, the alcohol-protecting groups R.sub.11 thereof are eliminated 
to yield a compound 5, and this is converted into a compound 7 by ring 
closure. Alternatively, the compound 7 may also be obtained by eliminating 
the alcohol-protecting groups R.sub.11 of the compound 3 to yield a 
compound 6, and reacting this compound 6 with a sulfonylation reagent in 
the presence of a base. Subsequently, the hydroxyl group of the compound 7 
is inverted via a compound 8 to yield a compound 9. 
Reaction Scheme 2 
The hydroxyl group of the compound 9 obtained in the above-described manner 
is sulfonylated and then substituted by an azide to yield a compound 10, 
and this is reduced to yield a compound 11. Thereafter, a desired compound 
12 falling under the category of the compounds (IV) may be obtained by 
protecting the amino group of the compound 11. Furthermore, a desired 
compound 13 falling under the category of the compounds (IV) may be 
obtained by alkylating the compound 12 or by reducing the amino-protecting 
group R.sub.1 ' to form a lower alkyl group R.sub.2 ' and then introducing 
an amino-protecting group R.sub.1 '. 
Reaction Scheme 3 
Desired compounds 16 and 17 falling under the category of the compounds 
(IV) may be obtained from the compound 7 in exactly the same manner as in 
the reaction scheme 2. 
Reaction Scheme 4 
The alcohol-protecting group R.sub.11 of a compound 18 is eliminated to 
yield a compound 19, and this is treated with a halogenation reagent to 
yield a compound 20. The compound 20 is dehalogenated to yield a compound 
21, and the hydroxyl group of the compound 21 is inverted via a compound 
22 to yield a compound 23. 
Reaction Scheme 5 
A desired compound 26 falling under the category of the compounds (IV) may 
be obtained from the compound 23 in exactly the same manner as in the 
reaction scheme 2. 
Reaction Scheme 6 
A desired compound 29 falling under the category of the compounds (IV) may 
be obtained from the compound 21 in exactly the same manner as in the 
reaction scheme 2. 
Reaction Scheme 7 
The hydroxyl group of the compound 7 obtained in the reaction scheme 1 is 
sulfonylated and then substituted by a cyanide to yield a compound 30, and 
this is reduced to yield a compound 31. Thereafter, a desired compound 32 
falling under the category of the compounds (IV) may be obtained by 
protecting the amino group of the compound 31. 
Reaction Scheme 8 
The compound 7 obtained in the reaction scheme 1 is oxidized to yield a 
compound 33, and this is reacted with a lower alkyl metal reagent to yield 
a compound 34. The compound 34 is reduced to a compound 35. Thereafter, a 
desired compound 36 falling under the category of the compounds (IV) may 
be obtained by the Ritter reaction. 
Reaction Scheme 9 
The compound 3 (q=2) obtained in the reaction scheme 1 is dehydrated to 
yield a compound 37, and this compound 37 is oxidized and halogenated to 
yield a compound 38 (r=0). A compound 38 (r=1) may be obtained by 
oxidizing and halogenating the compound 1. The alcohol-protecting group 
R.sub.11 of the compound 38 is eliminated to yield a compound 39, and this 
is converted into a compound 40 by ring closure. The compound 40 is 
halogenated to yield a compound 41. Thereafter, a desired compound 44 
falling under the category of the compounds (IV) may be obtained from the 
compound 41 in exactly the same manner as in the reaction scheme 2. 
The foregoing various reactions are more specifically described in Examples 
A to M which will be given later. 
Now, the in vitro antibacterial activities and in vivo effects of various 
compounds (I) in accordance with the present invention are described with 
reference to the following experimental data. 
Table 1 shows their minimum inhibitory concentrations (MIC; .mu.g/ml) as 
measured according to the procedure described in Chemotherapy, 29(1), 76 
(1981), and Table 2 shows their effects (ED.sub.50 ; mg/kg) on systemic 
infection in mice. The effects (ED.sub.50 ; mg/kg) on systemic infection 
in mice were determined as follows: Male Std-ddy strain mice (weighing 
about 20 g) were infected with each of the pathogenic bacteria shown in 
Table 2 by administering 5.times.10.sup.3 viable cells intraperitoneally 
to each mouse. Then, a suspension of each test compound in 0.4% 
carboxymethylcellulose was orally administered twice, i.e., immediately 
after infection and 6 hours after infection. Seven days after infection, 
the ED.sub.50 value was calculated from the survival rate of each mouse 
group by probit analysis. 
As a reference compound, there was used enoxacin 
[1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl-1,8-naphthyridine-3-c 
arboxylic acid; hereinafter abbreviated as ENX] that is an excellent 
antibacterial agent currently on the market. 
The test compounds shown in the following Tables 1 and 2 are identified by 
the respective numbers of the Examples which will be given later. 
TABLE 1 
______________________________________ 
In vitro antibacterial activities (MIC: .mu.g/ml) 
Strain 
Staphylococcus 
Escherichia 
Pseudomonas 
aureus coli aeruginosa 
Example 50774 MS16405 NIHJ JC-2 
No 12 
______________________________________ 
1 .ltoreq.0.003 
0.39 0.013 0.39 
2 0.006 0.39 0.013 0.39 
3 0.013 1.56 0.006 0.2 
4 0.006 0.39 0.025 0.78 
5 .ltoreq.0.003 0.39 0.025 0.78 
6 0.025 1.56 0.025 1.56 
7 0.006 0.39 0.025 0.39 
8 0.013 3.13 0.2 1.56 
9 0.025 1.56 0.05 1.56 
10 0.013 0.39 0.1 3.13 
11 0.013 -- 0.25 0.39 
12 0.013 0.39 0.1 1.56 
13 0.013 1.56 0.05 0.78 
14 0.025 1.56 0.025 1.56 
15 0.025 0.78 0.013 0.78 
16 0.006 1.56 0.1 1.56 
17 0.05 -- 0.1 0.78 
18 0.025 1.56 0.006 0.39 
ENX 0.39 100 0.05 0.78 
19 0.013 0.78 0.1 1.56 
20 0.1 3.13 0.05 1.56 
21 .ltoreq.0.003 0.78 0.013 0.39 
22 0.05 -- .ltoreq.0.003 0.39 
23 .ltoreq.0.003 0.78 0.025 0.78 
24 0.013 1.56 0.025 0.78 
25 0.025 1.56 0.025 1.56 
26 0.05 -- 0.013 0.39 
27 0.025 1.56 0.025 1.56 
28 0.025 0.78 0.025 1.56 
29 0.025 -- 0.025 0.39 
30 0.013 3.13 0.05 0.78 
31 0.013 0.78 0.1 0.78 
32 0.013 0.78 0.1 1.56 
33 0.025 1.56 0.05 3.13 
34 0.05 6.25 0.05 1.56 
35 0.025 6.25 0.1 3.13 
56 0.013 0.78 0.2 3.13 
ENX 0.39 100 0.05 0.78 
37 0.05 6.25 0.1 3.13 
38 0.1 -- 0.05 3.13 
39 0.025 3.13 0.2 0.78 
40 0.025 1.56 0.1 3.13 
ENX 0.39 100 0.05 0.78 
______________________________________ 
TABLE 2 
______________________________________ 
Effects (ED.sub.50 ; mg/kg) on systemic infection in mice 
Strain 
Staphylococcus 
Example aureus 50774 
______________________________________ 
1 0.36 
2 0.383 
3 0.398 
4 0.246 
5 0.257 
6 0.292 
7 0.331 
8 0.345 
9 0.415 
10 0.465 
11 0.579 
12 0.715 
13 0.778 
14 .ltoreq.0.78 
15 1.12 
16 0.78 
17 0.78 
18 0.928 
19 0.928 
ENX 9.89 
______________________________________ 
As shown in Tables 1 and 2, the compounds (I) of the present invention 
exhibit an excellent in vitro antibacterial activity and in vivo effect. 
In particular, with respect to antibacterial activity against 
Gram-positive bacteria, the compounds (I) of the present invention are 
much more powerful than ENX (enoxacin). 
Thus, the compounds (I) of the present invention, esters thereof, and 
physiologically acceptable salts thereof can suitably be used as 
antibacterial agents for the treatment of bacterial diseases in human 
beings and other animals. 
When the compounds (I) of the present invention are used as antibacterial 
agents in human beings, their dosage may vary according to the age and 
body weight of the patient, the severity of symptoms, the route of 
administration, and the like. However, it is recommended to administer 
them in a daily dose of 5 mg to 5 g which may be given once or in several 
divided doses. Although the route of administration may be oral, 
parenteral or topical, oral administration is recommended. 
The compounds (I) of the present invention, may be directly administered in 
their bulk form to human beings and other animals. However, they are 
usually combined with one or more pharmaceutically acceptable additives 
and administered in the form of pharmaceutical preparations (or 
pharmaceutical compositions). Such pharmaceutical preparations include 
tablets, solutions, capsules, granules, fine subtilaes, powders, syrups, 
injections, suppositories, ointments, sprays, ophthalmic solutions and the 
like. These pharmaceutical preparations may be made in the usual manner by 
using common additives. For example, as additives for oral preparations, 
there may be used various solid and liquid carriers or diluents which are 
commonly used in the field of pharmaceutics and do not react with the 
compounds (I) of the present invention, such as starch, mannitol, 
crystalline cellulose, carboxymethylcellulose calcium, water and ethanol. 
Moreover, as additives for injections, there may be used various additives 
which are commonly used in the field of injections, such as water, 
physiological saline, glucose solutions and transfusions. 
The aforesaid sprays and ointments may also be used for purposes of therapy 
and treatment in the fields of otorhinolaryngology and ophthalmology.