Quinoline carboxylic acid

5-Amino-7-((3S,4S)-3-amino-4-methyl (or ethyl)-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoqu inoline-3-carboxylic acid or a pharmacologically acceptable salt thereof represented by the following formula wherein asymmetric carbon atoms marked with asterisks are in the S-configurations and R.sup.1 represents methyl group or ethyl group; and an antibacterial agent comprising said compound as an active ingredient. ##STR1##

FIELD OF THE INVENTION 
The present invention relates to 
5-amino-8-methyl-7-pyrrolidinylquinoline-3-carboxylic acid derivatives and 
pharmacologically acceptable salts thereof which are useful for active 
ingredients of antibacterial agents, as well as to antibacterial agents 
comprising the substances as active ingredients. 
BACKGROUND ART 
Ciprofloxacin (The Merck Index 11th Edition, No.2315) is known as one of 
quinolone-type synthetic antibacterial agents that have cyclopropyl group 
at the 1-position of quinoline structure. A number of compounds with 
modifications at 5, 7, and 8-positions of this compound have been 
synthesized in order to improve antibacterial activity, physicochemical 
properties, e.g., water solubility, and safety of ciprofloxacin. For 
example, the Japanese Patent Unexamined Publication (KOKAI) No. 
(Sho)62-215572/1987 discloses the compound as set out below in which a 
piperazinyl group is introduced at the 7-position of the quinoline 
structure that has amino group at the 5-position and methyl group at the 
8-position. However, a compound has not yet been known in which 
3-amino-4-methyl (or ethyl)-pyrrolidinyl group is introduced at the 
7-position of the quinoline structure having amino group at the 5-position 
and methyl group at the 8-position. 
##STR2## 
Although the quinolone-type synthetic antibacterial agents so far reported 
have potent antibacterial activities, they have problems from a viewpoint 
of safety, for example, phototoxicity, induction of chromosomal 
aberration, and induction of convulsion. These problems of the 
quinolone-type synthetic antibacterial agents are explained in each of the 
following literatures: Quinolone Antimicrobial Agents, 2nd edition, 
Chapter 26, Ed. By D. C. Hooper and J. S. Wolfson, American Society for 
Microbiology, Washington D.C., 1993, p.489 (phototoxicity, induction of 
chromosomal aberration, induction of convulsion and other); Mutagenicity 
Test (Henigen-sei Shiken) 2(3), p.154, 1993 (chromosomal aberration and 
other); and Environ. Mol. Mutagen., 13, p.238, 1989 (chromosomal 
aberration and other). 
An object of the present invention is to provide quinolone-type synthetic 
antibacterial agents having high antibacterial activity, and in addition, 
whose adverse reactions such as phototoxicity, induction of chromosomal 
aberration, and induction of convulsion are reduced. 
As for correlation between structures and adverse reactions of the 
quinolone-type synthetic antibacterial agents, the following general 
predictability has been noted in view of the state of the art: (A) as a 
substituent at the 8-position of a quinoline structure, a somewhat bulky 
substituent such as a chlorine atom or methyl group is preferred from a 
viewpoint of antibacterial activity; however, a compound having a chlorine 
atom at the 8-position has strong adverse reactions such as phototoxicity 
or induction of chromosomal aberration, and a compound having methyl group 
exhibits strong adverse reactions such as induction of chromosomal 
aberration; (B) amino group, halogen atoms, methyl group and the like have 
been used as a substituent at the 5-position of a quinoline structure; 
however, these substituents decrease antibacterial activity, or 
alternatively, increase adverse reactions such as phototoxicity or 
induction of chromosomal aberration; and (C) antibacterial activity is 
improved when one of 3-aminopyrrolidines is introduced as a substituent at 
the 7-position of a quinoline structure; however, adverse reactions such 
as induction of chromosomal aberration are increased. 
The inventors of the present invention conducted various researches to 
achieve the foregoing object. As a result, they found that, contrary to 
the aforementioned general predictability, 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 
derivatives, in which amino group at the 5-position, methyl group at the 
8-position, and 3-amino-4-methyl (or ethyl)-pyrrolidinyl group at the 
7-position are substituted together, have potent antibacterial activities, 
and that the compounds are highly safe with reduced adverse reactions such 
as phototoxicity, induction of chromosomal aberration, and induction of 
convulsion. The Japanese patent application No. (Hei) 6-215213/1994 was 
filed on the basis of this invention. 
The inventors of the present invention conducted further researches, and 
they consequently found that, among compounds that fall within the 
compounds of the aforementioned general formula, optically active 
compounds each having the substituent in a specific stereostructure have 
both excellent antibacterial activities and remarkably high safeties. The 
present invention was achieved on the basis of these findings. 
DISCLOSURE OF THE INVENTION 
According to the first aspect of the present invention, there are provided 
5-amino-7-((3S,4S)-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 
-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, and 
5-amino-7-((3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid represented by the 
following formula (1) wherein the asymmetric carbon atoms marked with 
asterisks are in the S-configurations, and R.sup.1 represents methyl group 
or ethyl group, and pharmacologically acceptable salts thereof. 
Medicaments and antibacterial agents comprising the aforementioned 
compounds as active ingredients are also provided. 
##STR3## 
As preferred embodiments according to the invention, there are provided 
5-amino-7-((3S,4S)-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 
-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid and a 
pharmacologically acceptable salt thereof, and a medicament and an 
antibacterial agent comprising said compound as an active ingredient. 
According to another aspect of the present invention, there are provided 
5-amino-7-((3S,4S)-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 
-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid derivatives and 
5-amino-7-((3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid derivatives 
represented by the following formula (II) wherein the asymmetric carbon 
atoms marked with asterisks are in the S-configurations, R.sup.1 
represents methyl group or ethyl group, R.sup.2 represents a hydrogen 
atom, a lower alkyl group, or BF.sub.2 group, and R.sup.3 and R.sup.4 
independently represent a hydrogen atom or an amino protective group, with 
the proviso that R.sup.2, R.sup.3, and R.sup.4 are not simultaneously 
hydrogen atoms. These compounds are useful as synthetic intermediates for 
the manufacture of the aforementioned compound (I). 
##STR4## 
BEST MODE FOR CARRYING OUT THE INVENTION 
The compounds (I) of the present invention can be converted into salts, if 
desired, preferably into pharmacologically acceptable salts. Further 
conversions into compounds in the free form may be carried out by 
generating bases or acids from the resulting salts. As the 
pharmacologically acceptable salts, acid addition salts or alkali addition 
salts may be used. In addition, the compounds (I) of the present invention 
and salts thereof that may exist in any crystalline forms, as well as any 
hydrates of the compound (I) of the present invention and salts thereof 
fall within the scope of the present invention. 
As the acid addition salts, for example, mineral acid salts such as 
hydrochlorides, hydrobromides, nitrates, sulfates, hydroiodides, or 
phosphates; and organic acid salts such as acetates, maleates, fumarates, 
citrates, oxalates, malates, methanesulfonates, p-toluenesulfonates, 
mandelates, 10-camphorsulfonates, tartrates, lactates, 
5-oxotetrahydrofuran-2-carboxylates, or 2-hydroxygultarates may be used. 
As the alkali addition salts, for example, inorganic alkali salts such as 
sodium salts, potassium salts, calcium salts, magnesium salts, or ammonium 
salts, or salts of organic bases such as ethanolamine or 
N,N-dialkylethanolamine may be used. 
In the compounds (II) of the present invention, R.sup.2 represents a 
hydrogen atom, a lower alkyl group, or BF.sub.2. As the lower alkyl group, 
straight- or branched-chain alkyl groups having 1 to 6 carbon atoms, 
preferably 1 to 4 carbon atoms. For example, methyl group, ethyl group, 
n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl 
group, or tert-butyl group may preferably be used. 
As each of the amino protective groups represented by R.sup.3 and R.sup.4, 
any groups may be used so far that they are substantially inert in a 
reaction system in which the amino group should not be involved in the 
reaction, and that they can be readily cleaved under conditions of a 
certain deblocking reaction to regenerate the amino group. For example, 
lower alkanoyl groups, halogenated lower alkanoyl groups, arylcarbonyl 
groups, aryloxycarbonyl groups, aralkyloxycarbonyl groups, lower 
alkyloxycarbonyl groups, alkylsilyl groups, or aralkyl groups may be used. 
Where these protective groups are used, an ordinary skilled artisan may 
appropriately decide, depending on the sort of the protective group used 
as R.sup.3, which of a protective group or a hydrogen atom should be 
applied as R.sup.4. For example, where a lower alkanoyl group is used as 
R.sup.3, a hydrogen atom is generally used as R.sup.4. Where benzyl group 
is used as R.sup.3, an alkylsilyl group or other benzyl group can be 
introduced as R.sup.4. Where both of R.sup.3 and R.sup.4 are protective 
groups, examples include phthalimide group or maleimide group. 
As the lower alkanoyl group, straight- or branched-chain alkanoyl groups 
having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms may be used. 
For example, formyl group, acetyl group, propanoyl group, butyroyl group, 
or trimethylacetyl group may preferably be used. As the halogenated lower 
alkanoyl group, those may be used include the aforementioned alkanoyl 
group substituted with one or more halogen atoms which may be the same or 
different. As the halogen atom, any one of a fluorine atom, a chlorine 
atom, a bromine atom, or an iodine atom may be used. Preferred examples 
include fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, 
chloroacetyl group, dichloroacetyl group, and trichloroacetyl group. 
As aryl groups that constitute the arylcarbonyl group, aryloxycarbonyl 
group, aralkyloxycarbonyl group, or aralkyl group, substituted or 
non-substituted aryl groups having 6 to 10 carbon atoms, e.g., phenyl 
group, p-methoxyphenyl group, p-chlorophenyl group, or naphthyl group, may 
be used. Benzoyl group or the like is preferable as the arylcarbonyl 
group, and phenoxycarbonyl group or the like is preferred as the 
aryloxycarbonyl group. As the aralkyloxycarbonyl group, preferable 
examples include benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group 
or the like, and as the aralkyl group, preferable examples include benzyl 
group, p-methoxybenzyl group or the like. As the lower alkyloxycarbonyl 
group, preferable examples include methoxycarbonyl group, ethoxycarbonyl 
group, tert-butoxycarbonyl group or the like. Trimethylsilyl group or the 
like may be used as the alkylsilyl group. 
Among them, compounds wherein R.sup.3 is a lower alkyloxycarbonyl group and 
R.sup.4 is a hydrogen atom are preferred, and compounds wherein R.sup.3 is 
tert-butoxycarbonyl group and R.sup.4 is a hydrogen atom are particularly 
preferred. Where the groups represented by R.sup.2, R.sup.3, and R.sup.4 
have one or more asymmetric carbon atoms, the asymmetric carbon atom(s) 
may have any configuration(s). In addition, among the compounds of the 
present invention represented by formula (II), where R.sup.2 is a hydrogen 
atom, or the amino group exhibit basicity depending on the sorts of 
R.sup.3 and R.sup.4, the compounds (II) may form acid addition salts or 
base addition salts. As the acid addition salts or base addition salts 
mentioned above, the pharmacologicallyacceptable acid addition salts or 
alkali addition salts exemplified above may preferably be used. 
The compounds (I) and (II) of the present invention can be prepared, for 
example, according to the method disclosed in the specification of the 
Japanese Patent Application No. (Hei) 6-215213/1994. 
More specifically, according to the first embodiment of the method for 
preparation, the compounds represented by formula (I) can be prepared by 
reacting a 7-halogenoquinoline-3-carboxylic acid derivative represented by 
the following formula (III): 
##STR5## 
wherein R.sup.2 represents a hydrogen atom or a lower alkyl group, and X 
represents a halogen atom, preferably a fluorine atom or a chlorine atom, 
and most preferably a fluorine atom, with a pyrrolidine derivative 
represented by the following formula (IV): 
##STR6## 
wherein each of R.sup.1, R.sup.3, R.sup.4, and * has the same meaning as 
that defied above, in the presence or absence of a base in a solvent to 
obtain the compound (II), optionally followed by deblocking of R.sup.3 and 
R.sup.4 and ester hydrolysis of R.sup.2. 
As for the solvents used for the reaction of the compound represented by 
the general formula (III) with the compound represented by the general 
formula (IV), any solvents may be used so far that they, per se, are inert 
in the reaction, and do not inhibit the reaction. For example, alcoholic 
solvents such as methanol, ethanol, n-propanol, isopropanol, or n-butanol; 
aprotic polar solvents such as acetonitrile, N,N-dimethylformamide, 
N-methyl-2-pyrrolidone, dimethylsulfoxide, sulfolane, or 
hexamethylphosphoric triamide; aromatic hydrocarbonic solvents such as 
benzene or toluene; organic basic solvents such as pyridine, picoline, 
lutidine, or collidine; or mixed solvents thereof may be used. 
Examples of the bases that are optionally used include, for example, 
triethylamine, N,N-diisopropylethylamine, 
1,8-diazabicyclo5.4.0!-7-undecene, 1,2,2,6,6-pentamethylpiperidine, 
1,4-diazabicyclo 2.2.2!octane, sodium carbonate, potassium carbonate, 
sodium hydrogen carbonate, and potassium hydrogen carbonate. Where organic 
bases such as pyridine are used as solvents, addition of a base may 
sometimes be unnecessary since the solvents, per se, can work as bases. 
The reaction may be carried out at a temperature ranging from ice-cooling 
to refluxing temperature of a solvent. 
Where R.sup.2 is a lower alkyl group, the hydrolysis of the ester may be 
carried out according to a method that is known, per se, by using an acid 
or a base. Acids such as hydrochloric acid or sulfuric acid may be used 
for acidic hydrolysis, and alkalis such as sodium hydroxide or potassium 
hydroxide may be used for alkaline hydrolysis. These acids or alkalis may 
used as aqueous solutions, or alternatively, they may be used as solutions 
in organic solvents such as methanol, ethanol, n-butanol, sec-butanol, or 
tert-butanol; or as solutions in water-containing organic solvents. The 
reaction may be carried out at a temperature ranging from room temperature 
to refluxing temperature of a solvent. 
The amino-deblocking reaction of R.sup.3 and R.sup.4 may be carried out by 
appropriate methods depending on the type of the protective group. For 
example, where R.sup.3 is a lower alkanoyl group or a halogenated lower 
alkanoyl group, the compound (I) can be prepared by treating the compound 
(II) under a similar condition to that of the aforementioned hydrolysis 
reaction. Where ester-type groups such as tert-butoxycarbonyl group are 
used as R.sup.3, deblocking reactions may be easily carried out by a 
treatment using an acid such as hydrochloric acid, hydrobromic acid, 
trifluoroacetic acid or the like without a solvent or in a solvent such as 
acetic acid, ethyl acetate, dioxane, water, methanol, ethanol, or a 
mixture thereof, optionally in the presence of a cation scavenger such as 
anisole or thioanisole. The reaction may be carried out at a temperature 
ranging from ice-cooling to refluxing temperature of a solvent. 
According to the second embodiment of the method for preparation, the 
compound (I) can be prepared by reacting a boronic derivative represented 
by the following general formula (V): 
##STR7## 
wherein X is the same as that defined above, with the pyrrolidine 
derivative represented by the aforementioned general formula (IV) in a 
solvent in the presence or absence of a base to prepare the compound (II), 
optionally followed by de-chelation of R.sup.2 and deblocking of R.sup.3 
and R.sup.4. The aforementioned de-chelation reactions may generally be 
carried out by a treatment with a protic polar solvent in the presence or 
absence of a base. 
In the method for preparation according to the aforementioned second 
embodiment, as for the solvents used for the reaction of the compound 
represented by the general formula (V) with the compound represented by 
the general formula (IV), any solvents may be used so far that they, per 
se, are inert in the reaction, and do not inhibit the reaction. For 
example, alcoholic solvents such as methanol, ethanol, n-propanol, 
isopropanol, or n-butanol; aprotic polar solvents such as acetonitrile, 
N,N-dimethylformamide, N-methyl-2-pyrrolidone, dimethylsulfoxide, or 
hexamethylphosphoric triamide; aromatic hydrocarbonic solvents such as 
benzene or toluene; organic basic solvents such as pyridine, picoline, 
lutidine, or collidine; halogenated hydrocarbonic solvents such as 
dichloromethane, 1,2-dichloroethane, or chloroform: or mixed solvents 
thereof may be used. 
Examples of the bases that are optionally used include, for example, 
triethylamine, N,N-diisopropylethylamine, 
1,8-diazabicyclo5.4.0!-7-undecene, 1,2,2,6,6-pentamethylpiperidine, 
1,4-diazabicyclo 2.2.2!octane, sodium carbonate, potassium carbonate, 
sodium hydrogen carbonate, and potassium hydrogen carbonate. Where organic 
bases such as pyridine are used as solvents, addition of a base may 
sometimes be unnecessary since the solvents, per se, can work as bases. 
The reaction may be carried out at a temperature ranging from ice-cooling 
to refluxing temperature of a solvent. 
As the protic polar solvents used in the de-chelation reaction, for 
example, alcoholic solvents such as methanol, ethanol, n-propanol, 
isopropanol, or n-butanol; water: or mixed solvents thereof may be used. 
Mixed solvents may also be used in which these solvents are added with 
aprotic solvents such as acetonitrile, N,N-dimethylformamide, 
N-methyl-2-pyrrolidone, dimethylsulfoxide, hexamethylphosphoric triamide, 
benzene, toluene, pyridine, picoline, lutidine, collidine, 
dichloromethane, 1,2-dichloroethane, or chloroform. 
Examples of the bases that are optionally used in the de-chelation reaction 
include, for example, triethylamine, N,N-diisopropylethylamine, 
1,8-diazabicyclo-5.4.0!-7-undecene, 1,2,2,6,6-pentamethylpiperidine, 
1,4-diazabicyclo2.2.2!octane, sodium carbonate, potassium carbonate, 
sodium hydrogen carbonate, and potassium hydrogen carbonate. The reaction 
may be carried out at a temperature ranging from ice-cooling to refluxing 
temperature of a solvent. 
Among the compounds used as starting materials for these methods of 
preparation, the compounds (III) and (V) can be prepared, for example, 
according to the method shown in the scheme set out below. In the scheme, 
the compound (VII) is known, i.e., disclosed in the Japanese Patent 
Unexamined Publication (KOKAI) No.(Sho)62-215572/1987. The symbol "X" has 
the same meaning as that defined above, and the symbol "Y" represents a 
halogen atom. 
##STR8## 
The reactions in the scheme will be explained. In the step 1 wherein 
3-methyl-2,4,5-trihalogenobenzoic acid (VII) is subjected to nitration to 
obtain the compound (VIII), nitric acid, niter, ammonium nitrate or the 
like may be used as the agent for nitration. Sulfuric acid, acetic acid, 
acetic anhydride, trifluoroacetic anhydride, fuming nitric acid or the 
like may be used as a solvent. The resulting compound (VIII) is treated 
with a chlorinating agent such as thionyl chloride, oxalyl chloride or the 
like according to the step 2 to convert into the acid chloride (IX). Where 
a solvent is used, solvents such as chloroform, methylene chloride, 
1,2-dichloroethane or the like may be used. The reaction may optionally be 
carried out in the presence of N,N-dimethylformamide. 
The compound (X) is obtained by condensing diethyl 
ethoxy-magnesium-malonate, that is prepared from ethanol, diethyl 
malonate, and magnesium, with the above compound (IX) in a solvent such as 
benzene or toluene (step 3), and then the compound (X) is heated with 
water in the presence of an acid such as hydrochloric acid, sulfuric acid, 
p-toluenesulfonic acid or the like to obtain the compound (XI) by 
simultaneous hydrolysis and decarboxylation (step 4). After then, the 
compound (XI) is allowed to react with ethyl orthoformate in acetic 
anhydride to obtain the compound (XII) (step 5). This reaction may 
optionally be carried out in the presence of a Lewis acid such as zinc 
chloride. 
The resulting compound (XII) is allowed to react with cyclopropylamine in a 
solvent to convert into the compound (XIII) (step 6). As the solvents, any 
solvents may be used so far that they, per se, are inert in the reaction 
and do not inhibit the reaction. For example, alcoholic solvents such as 
methanol or ethanol; halogenated hydrocarbonic solvents such as chloroform 
or 1,2-dichloroethane; aromatic hydrocarbonic solvents such as benzene or 
toluene; or aprotic polar solvents such as acetonitrile or 
N,N-dimethylformamide. 
The compound (XIII) is then treated with a base in a solvent to obtain the 
compound (XIV) by a ring closure (step 7). Potassium carbonate, sodium 
hydride, potassium tert-butoxide or the like may be used as the base. As 
the solvents, ethereal solvents such as dioxane or tetrahydrofuran; or 
aprotic polar solvents such as acetonitrile, or N,N-dimethylformamide may 
be used. A catalyst may optionally be used in this reaction. For example, 
catalysts such as crown ethers, tetrabutylammonium bromide, 
benzyltriethylammonium bromide or the like may be employed. 
The compound (III-a) can be obtained by subjecting the resulting compound 
(XIV) to catalytic hydrogenation using a catalyst such as Raney nickel, 
palladium carbon, platinum oxide or the like, or alternatively, to 
reduction under an acidic condition by using a metal such as iron, tin, 
zinc or the like (step 9). Acetic acid, water, methanol, ethanol, 
N,N-dimethylformamide or the like may be used as a solvent. Acids such as 
hydrochloric acid, acetic acid, hydrobromic acid or the like may be used 
for the reduction using a metal. The compound (III-b) can be obtained by 
hydrolyzing the compound (III-a) in a solvent such as water, acetic acid, 
alcohols, water-containing alcohols or the like under an acidic condition 
such as with hydrochloric acid, acetic acid, hydrobromic acid or the like. 
Then, the compound (V) can be obtained by reacting the compound (III-b) 
with boron trifluoride diethyl ether complex in a solvent such as ether, 
acetone, methylisobutylketone or the like. Each of the reactions has been 
explained along with the scheme. Further specific methods for preparation 
will be explained in Examples. 
Among the pyrrolidine derivatives represented by the general formula (IV), 
compounds wherein R.sup.4 is a hydrogen atom can be prepared according to 
the method shown in the scheme set out below. In the scheme, the compound 
(XV) is a known compound, i.e., disclosed in the Japanese Patent 
Publication for International Application (KOHYO) No. (Hei) 6-508136/1994. 
R.sup.1 and R.sup.3 are the same as those defined above, and the symbol 
"Z" represents a leaving group such as a halogen atom, triflate or the 
like. 
##STR9## 
The reactions in the scheme will be explained. Step 1 comprises the step of 
treating the compound (XV) with an alkylating agent in a solvent in the 
presence of a base to obtain the compound (XVI). As the base, for example, 
lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide or the 
like may preferably be used. As the solvent, for example, ethereal 
solvents such as ether, diisopropyl ether, tetrahydrofuran, 
1,2-dimethoxyethane or the like may preferably be used. The reaction may 
be carried out at a temperature ranging from -75.degree. C. to room 
temperature. 
Step 2 comprises the step of treating the compound (XVI) with a reducing 
agent in a solvent to obtain the compound (XVII) whose amino group is 
protected. As the reducing agent, for example, lithium aluminum hydride, 
diisobutylaluminum hydride, bis(2-methoxyethoxy)aluminum hydride or the 
like may preferably be used. As the solvent, for example, ethereal 
solvents such as ether, diisopropyl ether, tetrahydrofuran or the like may 
preferably be used. The reaction may be carried out at a temperature 
ranging from -40.degree. C. to a refluxing temperature of a solvent. 
Step 3 comprises the step of hydrogenolyzing the compound (XVII) in a 
solvent in the presence of a catalyst to obtain the compound (XVIII) whose 
amino group is deblocked. As the catalyst, for example, catalysts for 
hydrogenation such as Raney nickel, palladium carbon, platinum oxide or 
the like may preferably be used. The sorts of the solvents are not 
particularly limited so far that they do not inhibit the reaction. For 
example, alcoholic solvents such as methanol, ethanol, propanol, or 
butanol; water-containing alcoholic solvents; aromatic hydrocarbonic 
solvents such as benzene, toluene, or xylene; aprotic polar solvents such 
as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide; ester-type 
solvents such as methyl acetate or ethyl acetate may be used. As the 
source of hydrogen, cyclohexadiene, formic acid, ammonium formate or the 
like as well as hydrogen gas may be used. 
Step 4 comprises the step of treating the compound (XVIII) with 
(R.sup.3).sub.2 O or R.sup.3 Z in a solvent in the presence of absence of 
a base to obtain the compound (XIX) whose amino group is protected. As the 
base, for example, organic bases such as triethylamine, 
N,N-diisopropylethylamine, 1,8-diazabicyclo5.4.0!-7-undecene, or 
pyridine; or inorganic bases such as sodium carbonate, potassium 
carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate may 
be used. As the solvent, for example, alcoholic solvents such as methanol, 
ethanol, propanol, or butanol; ethereal solvents such as ether, 
diisopropyl ether, tetrahydrofuran, or 1,2-dimethoxyethane; aprotic polar 
solvents such as acetonitrile, N,N-dimethylformamide, or 
dimethylsulfoxide; ester-type solvents such as methyl acetate or ethyl 
acetate; halogen-containing hydrocarbonic solvents such as methylene 
chloride, chloroform, or 1,2-dichloroethane may be used. The reaction may 
be carried out at a temperature ranging from ice-cooling to a refluxing 
temperature of a solvent. 
Step 5 comprises the step of condensing the compound (XIX) with 
methanesulfonyl chloride in a solvent in the presence or absence of a base 
to obtain the compound (XX) in which each of the two hydroxyl groups is 
sulfonylated. As the base, for example, organic bases such as 
triethylamine, N,N-diisopropylethylamine, 
1,8-diazabicyclo5.4.0!-7-undecene, or pyridine; or inorganic bases such 
as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or 
potassium hydrogen carbonate may be used. The sorts of the solvents are 
not particularly limited so far that they do not inhibit the reaction. For 
example, aprotic polar solvents such as acetonitrile, 
N,N-dimethylformamide, or dimethylsulfoxide; ester-type solvents such as 
methyl acetate or ethyl acetate; halogen-containing hydrocarbonic solvents 
such as methylene chloride, chloroform, or 1,2-dichloroethane; aromatic 
hydrocarbonic solvents such as benzene, toluene, or xylene; ethereal 
solvents such as ether, diisopropyl ether, tetrahydrofuran, or 1,4-dioxane 
may be used. The reaction may be carried out at a temperature ranging from 
ice-cooling to a refluxing temperature of a solvent. 
Step 6 comprises the step of reacting the compound (XX) with benzylamine in 
the presence or absence of a base in a solvent or without a solvent to 
prepare a (3S,4S)-3-amino-4-methyl (or ethyl)-pyrrolidine derivative (XXI) 
which is protected at the 1-position. As the base, for example, organic 
bases such as triethylamine, N,N-diisopropylethylamine, 
1,8-diazabicyclo5.4.0!-7-undecene, or pyridine; or inorganic bases such 
as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or 
potassium hydrogen carbonate may be used. The sorts of the solvents are 
not particularly limited so far that they do not inhibit the reaction. For 
example, aromatic hydrocarbonic solvents such as benzene, toluene, or 
xylene; aprotic polar solvents such as acetonitrile, 
N,N-dimethylformamide, or dimethylsulfoxide; ester-type solvents such as 
methyl acetate or ethyl acetate; halogen-containing hydrocarbonic solvents 
such as methylene chloride, chloroform, or 1,2-dichloroethane; ethereal 
solvents such as ether, tetrahydrofuran, 1,4-dioxane, or diisopropyl ether 
may be used. The reaction may be carried out at a temperature ranging from 
ice-cooling to 200.degree. C. 
Step 7 comprises the step of hydrogenolyzing the (3S,4S)-3-amino-4-methyl 
(or ethyl)-pyrrolidine derivative (XXI) which is protected at the 
1-position in a solvent in the presence of a catalyst to prepare a 
(3S,4S)-3-amino-4-methyl (or ethyl)-pyrrolidine derivative (IV) whose 
1-position is deblocked. As the catalyst, for example, catalysts for 
hydrogenation such as Raney nickel, palladium carbon, platinum oxide or 
the like may preferably be used. The sorts of the solvents are not 
particularly limited so far that they do not inhibit the reaction. For 
example, alcoholic solvents such as methanol, ethanol, propanol, or 
butanol; water-containing alcoholic solvents; aromatic hydrocarbonic 
solvents such as benzene, toluene, or xylene; aprotic polar solvents such 
as acetonitrile, N,N-dimethylformamide, or dimethylsulfoxide; ester-type 
solvents such as methyl acetate or ethyl acetate may be used. As the 
source of hydrogen, cyclohexadiene, formic acid, ammonium formate or the 
like as well as hydrogen gas may be used. 
Each of the reactions has been explained along with the scheme. Further 
specific methods for preparation will be explained in Examples. 
The medicament, which comprises, as an active ingredient, at least one 
substance selected from the group consisting of the aforementioned 
compound (I): 
5-amino-7-((3S,4S)-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 
-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 
5-amino-7-((3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, and 
pharmacologically acceptable salts thereof, is useful as an antibacterial 
agent. The antibacterial agents mentioned above may generally be 
administered for therapeutic and/or preventive treatments of infectious 
diseases of human or mammals as orally available preparations such as 
capsules, tablets, fine granules, granules, powders, syrups or the like, 
or alternatively, as injections, suppositories, eye drops, ophthalmic 
ointments, ear solutions, or topical preparations. 
These preparations may be manufactured according to ordinary methods by 
using pharmacologically and pharmaceutically acceptable additives. For the 
manufactures of oral preparations and suppositories, pharmaceutical 
additives such as, for example, excipients such as lactose, D-mannitol, 
corn starch, or crystalline cellulose; disintegrators such as 
carboxymethylcellulose or carboxymethylcellulose calcium; binders such as 
hydroxypropylcellulose, hydroxypropylmethylcellulose, or 
polyvinylpyrrolidone; lubricants such as magnesium stearate or talc; 
coating materials such as hydroxypropylmethylcellulose, sucrose, or 
titanium oxide; plasticizer such as polyethyleneglycol; base materials 
such as polyethyleneglycol or hard fat may be used. 
For the manufactures of injections, eye drops, or ear solutions, 
pharmaceutical additives such as solubilizers or solubilizing agents, 
which are ingredients for aqueous formulations or formulations to be 
dissolved before use, such as water for injection, physiological saline, 
or propyleneglycol; pH modifier such as inorganic or organic acids or 
bases; isotonicities such as sodium chloride, glucose, or glycerin; or 
stabilizers may be used. In addition, for the manufactures of ophthalmic 
ointments or topical preparations, pharmaceutical additives suitable as 
base materials for ointments, creams, or patches such as white soft 
paraffin, macrogol, glycerol, liquid paraffin, cotton sheet may be used. 
Where the aforementioned antibacterial agent is administered for 
therapeutic or preventive treatment of a human infectious disease, an oral 
dose of about 10 to 1,000 mg, or parenteral dose of 1 to 500 mg per day 
for an adult may be administered once a day or several times as divided 
dosages. However, it is desirable that the dosage should be appropriately 
increased or decreased depending on the purpose of therapeutic or 
preventive treatment, focus of infection or the sort of pathogenic 
bacteria, the age of a patient, symptoms and the like.

EXAMPLE 
The present invention will be explained more specifically by Examples. 
However, the scope of the present invention is not limited to these 
examples. 
Example 1 
Manufacture of the compound (I) of the present invention 
2,4,5-Trifluoro-3-methyl-6-nitrobenzoic acid 
To a mixture of acids containing 370 ml of conc. sulfuric acid and 61.2 ml 
of 70% nitric acid, 36.6 g of 2,4,5-trifluoro-3-methylbenzoic acid was 
added portionwise at the inner temperature of 55.degree.-70.degree. C. 
with stirring, and then stirring was continued for 2 hours at room 
temperature. The reaction mixture was poured into ice and extracted with 
isopropyl ether. The extract was washed with brine, and then dried and 
concentrated to give 30.6 g of yellow crystals. 
NMR spectrum .delta.(CD.sub.3 OD) ppm: 2.29 (3H, t, J=2 Hz) 
Diethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate 
A suspension containing 27.0 g of 2,4,5-trifluoro-3-methyl-6-nitrobenzoic 
acid, 19.5 ml of oxalyl chloride, 270 ml of methylene chloride, and a few 
drops of N,N-dimethylformamide was stirred at room temperature for 2 
hours. The reaction mixture was concentrated under reduced pressure to 
give 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride. Separately, a few 
drops of carbon tetrachloride was added to a suspension of 3.08 g of 
magnesium in 6.4 ml of absolute ethanol, and then a solution of 19.2 ml of 
diethyl malonate in 12 ml of absolute ethanol was added dropwise to the 
suspension under heating at 50.degree. C., and the mixture was stirred at 
the same temperature for 1.5 hours. The reaction mixture was concentrated 
under reduced pressure, and then, toluene was added to dissolve the 
residue and the solution was again concentrated. To a solution of the 
residue in 30 ml of toluene, a solution of 
2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride in 30 ml of toluene was 
added dropwise with stirring under ice cooling, and then stirring was 
continued for 2 hours at room temperature. The reaction mixture was added 
with 100 ml of 5% sulfuric acid, and was then extracted with diethyl 
ether. The extract was washed with brine, and then dried and concentrated 
to give 47.3 of brown oil. 
NMR spectrum .delta.(CDCl.sub.3) ppm: 1.12 (3H, t, J=7.5 Hz), 1.38 (3H, t, 
J=7.5 Hz), 2.33 (3H, t, J=2 Hz), 3.36, 14.18 (total 1H, each s), 4.07 (2H, 
q, J=7.5 Hz), 4.38 (2H, q, J=7.5 Hz) 
Ethyl (2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acetate 
A mixture of 45.3 g of diethyl 
(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)malonate, 30 mg of 
p-toluenesulfonic acid, and 120 ml of water was heated under reflux for 50 
minutes. After cooling, the reaction mixture was extracted with diethyl 
ether, and the extract was washed with brine, and then dried and 
concentrated to give 34.2 g of brown oil. 
NMR spectrum .delta.(CDCl.sub.3) ppm: 1.26, 1.34 (total 3H, each t, J=7 
Hz), 2.33, 2.35 (total 3H, each t, J=2.5 Hz), 3.91, 5.48, 12.34 (total 2H, 
each s), 4.20, 4.28 (total 2H, each q, J=7 Hz). 
Ethyl 
3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate 
A mixture of 31.9 g of ethyl 
(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acetate, 26.2 ml of ethyl 
orthoformate and 23.8 ml of acetic anhydride was heated under reflux for 1 
hour. The reaction mixture was concentrated under reduced pressure to give 
46.2 g of ethyl 3-ethoxy-2-(2,4,5-trifluoro-3 
-methyl-6-nitrobenzoyl)acrylate as brown oil. To a solution of 45.4 g of 
the above compound in 328 ml of ethanol, 9.6 ml of cyclopropylamine was 
added dropwise with stirring under ice cooling, and then stirring was 
continued for 30 minutes at room temperature. The reaction mixture was 
concentrated under reduced pressure, and the residue was purified by 
column chromatography (silica gel, n-hexane-methylene chloride (1:1)) to 
give 28.8 g of yellow crystals. The crystals were recrystallized from 
isopropyl ether to give yellow needles, m.p. 115.degree.-115.5.degree. C. 
______________________________________ 
Analysis for C.sub.16 H.sub.15 F.sub.3 N.sub.2 O.sub.5 
______________________________________ 
Calculated % 
C, 51.62 H, 4.06 N, 7.52 
Found % C, 51.57 H, 3.92 N, 7.53 
______________________________________ 
Ethyl 
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-c 
arboxylate 
To a solution of 27.1 g of ethyl 
3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate in 
270 ml of dioxane, 3.2 g of 60% sodium hydride was added, and then 
stirring was continued for 1 hour at room temperature. Water (300 ml) was 
added to the reaction mixture, and then the crystals precipitated were 
collected by filtration to obtain 19.5 g of colorless crystals. The 
crystals were. recrystallized from N,N-dimethylformamide to colorless 
needles, m.p. 260.degree.-263.degree. C. 
______________________________________ 
Analysis for C.sub.16 H.sub.14 F.sub.2 N.sub.2 O.sub.5 
______________________________________ 
Calculated % 
C, 54.55 H, 4.01 N, 7.95 
Found % C, 54.51 H, 4.00 N, 7.90 
______________________________________ 
Ethyl 
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-c 
arboxylate 
A suspension containing 18.5 g of ethyl 
1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-5-nitro-4-oxoquinoline-3-c 
arboxylate, 10 ml of Raney nickel, and 300 ml of acetic acid was 
hydrogenated at room temperature for 1.5 hours under atmospheric pressure. 
The catalyst was filtered off and the filtrate was concentrated. The 
resulting residue was added with 150 ml of 10% aqueous potassium 
carbonate, and then the mixture was extracted with methylene chloride. The 
organic layer was dried and concentrated to give 14.8 g of pale yellow 
crystals. The crystals were recrystallized from acetonitrile to give pale 
yellow needles, m.p. 182.5.degree.-185.5.degree. C. 
______________________________________ 
Analysis for C.sub.16 H.sub.16 F.sub.2 N.sub.2 O.sub.3 
______________________________________ 
Calculated % 
C, 59.62 H, 5.00 N, 8.69 
Found % C, 59.74 H, 5.08 N, 8.60 
______________________________________ 
5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-ca 
rboxlic acid 
A mixture of 14.8 g of ethyl 
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-c 
arboxylate, 150 ml of 90% acetic acid, and 37.2 ml of conc. hydrochloric 
acid was heated under reflux for 2 hours. The crystals precipitated were 
collected by filtration and washed with water to give 11.8 g of yellow 
crystals. The crystals were recrystallized from N,N-dimethylformamide to 
give yellow crystals, m.p. 290.5.degree. C. (decomp.). 
______________________________________ 
Analysis for C.sub.14 H.sub.12 F.sub.2 N.sub.2 O.sub.3 
______________________________________ 
Calculated % 
C, 57.15 H, 4.11 N, 9.52 
Found % C, 57.10 H, 4.03 N, 9.53 
______________________________________ 
5-Amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-c 
arboxylate-O.sup.3,O.sup.4 !difluoroboron 
(5-Amino-1-cycloprolpyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3 
-carboxylic acid Bf.sub.2 chelate) 
A mixture of 5.00 g of 
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-c 
arboxylic acid, 3.13 ml of boron trifluoride diethyletherate, and 75 ml of 
methyl isobutyl ketone was heated under reflux for 1 hour. After cooling, 
the crystals precipitated were collected by filtration and washed with 
diethyl ether to give 5.38 g of yellow crystals. 
NMR spectrum .delta.(DMSO-d.sub.6) ppm: 1.08-1.15 (2H, m), 1.21-1.30 (2H, 
m), 2.67 (3H, d, J=2.5 Hz), 4.52-4.59 (1H, m), 7.28 (2H, br-s), 9.10 (1H, 
s) 
Dimethyl (2S,3R)-N-benzyl-3-methyl-N-(9-phenylfluoren-9-yl)aspartate 
A solution of 1.66M of n-butyl lithium in 1966 ml of n-hexane was added 
dropwise with stirring to a solution of 608 ml of hexamethyldisilazane in 
3.2 L of tetrahydrofuran at -10.degree. C. under nitrogen atmosphere, and 
then stirring was continued at from -8.degree. to 4.degree. C. for 30 
minutes. A solution of 942 g of dimethyl 
(2S)-N-benzyl-N-(9-phenylfluoren-9-yl)aspartate in 3.2 L of 
tetrahydrofuran was added dropwise to the above reaction solution while 
the temperature was kept in the range of from -28.degree. to -23.degree. 
C., and then the stirring was continued at from -26.degree. to 24.degree. 
C. for 30 minutes. After the mixture was cooled at from -65.degree. to 
-64.degree. C., the mixture was added dropwise with 143 ml of methyl 
iodide and then stirred at from -73.degree. to -65.degree. C. for 1.5 
hours, and stirring was further continued for 1 hour at from -30.degree. 
to -21.degree. C. Saturated aqueous ammonium chloride (3.8 L) was added to 
the reaction mixture, and the mixture was stirred for 15 minutes under ice 
cooling and then layers were separated. The aqueous layer was extracted 
with ethyl acetate, and the extract was combined with the organic layer 
previously obtained and washed with brine. The extract was dried over 
sodium sulfate, and the solvent was evaporated under reduced pressure. The 
residue was washed with methanol to obtain 880 g of colorless crystals. 
The crystals were recrystallized from methanol to give the colorless 
plates, m.p. 153.degree.-155.degree. C. 
______________________________________ 
Analysis for C.sub.33 H.sub.31 NO.sub.4 
______________________________________ 
Calculated % 
C, 78.39 H, 6.18 N, 2.77 
Found % C, 78.41 H, 6.15 N, 2.75 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 -344.5.degree. (c=1, CHCl.sub.3) 
The following compound was obtained in a similar manner. 
Dimethyl (2S,3R)-N-benzyl-3-ethyl-N-(9-phenylfluoren-9-yl)aspartate 
Appearance: colorless plates (MeOH) 
m.p.: 162.5.degree.-163.5.degree. C. 
______________________________________ 
Analysis for C.sub.34 H.sub.33 NO.sub.4 
______________________________________ 
Calculated % 
C, 78.59 H, 6.40 N, 2.70 
Found % C, 78.50 H, 6.48 N, 2.57 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 -331.8.degree. (c=1, CHCl.sub.3) 
(2S,3R-)-2-N-Benzyl-N-(9-phenylfluoren-9-yl)!amino-3-methylbutane-1,4-diol 
A suspension of 63 g of lithium aluminum hydride in 3.0 L of anhydrous 
tetrahydrofuran was ice cooled, and a solution of 560 g of dimethyl 
(2S,3R)-N-benzyl-3-methyl-N-(9-phenylfluoren-9-yl)aspartate in 1.8 L of 
anhydrous tetrahydrofuran was added dropwise to the above suspension under 
nitrogen atmosphere. After the mixture was stirred at room temperature for 
30 minutes, 300 ml of water and 110 ml of 15% aqueous sodium hydroxide 
were added successively to the mixture under ice cooling. Stirring was 
continued for 2 hours at room temperature, and then the insoluble 
substances were removed by filtration. The insoluble substances were 
washed with 1 L of tetrahydrofuran, and the filtrate and washings were 
combined and then concentrated under reduced pressure. The residue was 
dissolved in ethyl acetate, and the solution was dried over sodium 
sulfate, and then, the solvent was evaporated under reduced pressure to 
obtain 544 g of colorless viscous oil. This product was suitable for use 
in the next step without further purification. A part of the product was 
purified by column chromatography (silica gel, ethyl acetate:n-hexane=1:2) 
to give colorless viscous oil. 
IR spectrum .nu.(liq) cm.sup.-1 : 3324 NMR spectrum .delta.(CDCl.sub.3) 
ppm: 0.54 (3H, d, J=7 Hz), 1.50-1.60 (1H, m), 2.58-2.64 (1H, m), 2.84-2.93 
(1H, m), 3.02-3.10 (1H, m), 3.12-3.19 (1H, m), 3.22-3.29 (1H, m), 4.18 
(1H, d, J=15.5 Hz), 4.29 (1H, d, J=15.5 Hz), 7.17-7.75 (18H, m) Specific 
rotation .alpha.!.sub.D.sup.20 +106.7.degree. (c=1, CHCl.sub.3) 
The following compound was obtained in a similar manner. 
(2S,3R)-2-N-Benzyl-N-(9-phenylfluoren-9-yl)!amino-3-ethylbutane-1,4-diol 
Appearance: colorless oil 
IR spectrum .nu.(liq) cm.sup.-1 : 3292 NMR spectrum .delta.(CDCl.sub.3) 
ppm: 0.64 (3H, t, J=7.5 Hz), 0.81-1.02 (2H, m), 1.29-1.38 (1H, m), 1.81 
(2H, br-s), 2.76-2.87 (2H, m), 3.08-3.17 (1H, m), 3.24-3.35 (2H, m), 4.09 
(1H, d, J=15 Hz), 4.26 (1H, d, J=15 Hz), 7.16-7.77(18H, m) Specific 
rotation .alpha.!.sub.D.sup.20 +158.90 (c=1, CHCl.sub.3) 
(2S,3R)-2-Amino-3-methylbutane-1,4-diol 
A mixture of 60 g of 
(2S,3R)-2-N-benzyl-N-(9-phenylfluoren-9-yl)!amino-3-methylbutane-1,4-diol 
, 6.0 g of 20% palladium hydroxide on charcoal, and 500 ml of methanol was 
hydrogenated in an autoclave under 5 kgf/cm.sup.2 hydrogen pressure at 
40.degree. C. for 2 hours. The catalyst was removed by filtration and the 
filtrate was concentrated under reduced pressure. The residue was added 
with isopropylalcohol and insoluble substances were removed by filtration. 
The filtrate was concentrated under reduced pressure to give 16.7 g of 
colorless viscous oil. 
IR spectrum .nu.(liq) cm.sup.-1 : 3360 NMR spectrum .delta.(CDCl.sub.3) 
ppm: 0.90 (3H, d, J=7.5 Hz), 1.65-1.76 (1H, m), 2.60-3.00 (5H, m), 
3.50-3.61 (2H, m), 3.64-3.70 (2H, m) 
The following compound was obtained in a similar manner. 
(2S,3R)-2-Amino-3-ethylbutane-1,4-diol 
Appearance: yellow oil 
IR spectrum .nu.(liq) cm.sup.-1 : 3360 NMR spectrum .delta.(CDCl.sub.3) 
ppm: 0.95 (3H, t, J=7.5 Hz), 1.29-1.49 (3H, m), 2.41 (4H, br-s), 2.95-3.05 
(1H, m), 3.57-3.83 (4H, m) 
(2S,3R)-2-(tert-Butoxycarbonyl)amino-3-methylbutane-1,4-diol 
A solution of 234 g of di-tert-butyldicarbonate in 140 ml of 
isopropylalcohol was added dropwise to a solution of 146 g of 
(2S,3R)-2-amino-3-methylbutane-1,4-diol in 500 ml of isopropylalcohol at 
room temperature with stirring. After stirring was continued at room 
temperature for 30 minutes, the solvent was evaporated under reduced 
pressure to give 260 g of pale yellow viscous oil. This product was 
suitable for use in the next step without further purification. A part of 
the product was purified by column chromatography (silica gel, methylene 
chloride:ethyl acetate=1:1) to give colorless viscous oil. 
IR spectrum .nu.(liq) cm.sup.-1 : 3352, 1690 NMR spectrum 
.delta.(CDCl.sub.3) ppm: 1.03 (3H, d, J=7 Hz), 1.45 (9H, s), 1.75-1.90 
(1H, m), 2.72 (1H, br-s), 3.17 (1H, br-s), 3.42-3.80 (5H, m), 5.23 (1H, 
br-s) Specific rotation .alpha.!.sub.D.sup.20 -10.4.degree. (c=1, 
CHCl.sub.3) 
The following compound was obtained in a similar manner. 
(2S,3R)-2-(tert-Butoxycarbonyl)amino-3-ethylbutane-1,4-diol 
Appearance: colorless oil. 
IR spectrum .nu.(liq) cm.sup.-1 : 3384, 1692 NMR spectrum 
.delta.(CDCl.sub.3) ppm: 0.98 (3H, t, J=7.5 Hz), 1.38-1.60 (3H, m), 1.45 
(9H, s), 2.77 (1H, br-s), 2.84 (1H, br-s), 3.60-3.80 (5H, m), 5.28-5.35 
(1H, m) Specific rotation .alpha.!.sub.D.sup.20 -0.4.degree. (c=1, 
CHCl.sub.3) 
(2S,3R)-2-(tert-Butoxycarbonyl)amino-1,4-bis(methanesulfonyloxyy-3-methylbu 
tane 
A solution of 249 g of 
(2S,3R)-2-(tert-butoxycarbonyl)amino-3-methylbutane-1,4-diol and 34 ml of 
triethylamine in 1,600 ml of methylene chloride was ice cooled, and the 
solution was added dropwise with methanesulfonyl chloride (174 ml) with 
stirring. After stirring was continued for 30 minutes at room temperature, 
the mixture was washed twice with water. The organic layer was dried over 
sodium sulfate and the solvent was evaporated under reduced pressure. The 
residue was washed with isopropyl ether to give 341 g of pale brown 
crystals. 
IR spectrum .nu.(KBr) cm.sup.-1 : 3336, 1676 NMR spectrum 
.delta.(CDCl.sub.3) ppm: 1.13 (3H, d, J=7 Hz), 1.45 (9H, s), 2.10-2.22 
(1H, m), 3.04 (3H, s), 3.06 (3H, s), 3.81-3.93 (1H, m), 4.15-4.26 (2H, m), 
4.26-4.40 (2H, m), 4.85 (1H, br-s) Specific rotation 
.alpha.!.sub.D.sup.20 -26.0.degree. (c=1, CHCl.sub.3) 
The following compound was obtained in a similar manner. 
(2S,3R)-2-(tert-Butoxycarbonyl)amino-1,4-bis(methanesulfonyloxy)-3-ethylbut 
ane 
Appearance: pale brown crystals 
m.p.: 75.5.degree.-76.5.degree. C. (decomp.) IR spectrum .nu.(KBr) 
cm.sup.-1 : 3380, 1692 NMR spectrum .delta.(CHCl.sub.3) ppm: 1.01 (3H, t, 
J=7.5 Hz), 1.38-1.68 (2H, m), 1.45 (9H,s), 1.90-2.00 (1H, m), 3.047 (3H, 
s), 3.053 (3H, s), 4.00-4.09 (1H, m), 4.28-4.38 (4H, m), 4.80-4.91 (1H, m) 
Specific rotation .alpha.!.sub.D.sup.20 -11.1.degree. (c=1, CHCl.sub.3) 
(3S,4S)-1-Benzyl-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine 
Benzylamine (290 ml) was stirred at room temperature and then added 
portionwise with 
(2S,3R)-2-(tert-butoxycarbonyl)amino-1,4-bis(methanesulfonyloxy)-3-methylb 
utane (100 g). The mixture was stirred at room temperature for 24 hours, 
and then poured into 600 ml of ice-water and stirring was continued for 30 
minutes. The crystals precipitated were collected by suction filtration to 
give 45.1 g of pale brown crystals. The crystals were recrystallized from 
isopropyl ether to give colorless needles, m.p. 100.degree.-102.degree. C. 
Specific rotation .alpha.!.sub.D.sup.20 +31.10 (c=1, CHCl.sub.3) 
The following compound was obtained in a similar manner. 
(3S,4S)-1-Benzyl-3-(tert-butoxycarbonyl)amino-4-ethylpyrrolidine 
Appearance: colorless needles (n-Hexane) 
m.p. :97.degree.-98.5.degree. C. 
______________________________________ 
Analysis for C.sub.18 H.sub.28 N.sub.2 O.sub.2 
______________________________________ 
Calculated % 
C, 71.02 H, 9.27 N, 9.20 
Found % C, 71.02 H, 9.55 N, 8.93 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 +31.9.degree. (c=1, CHCl.sub.3) 
(3S,4S)-3-(tert-Butoxycarbonyl)amino-4-methylpyrrolidine 
A mixture of 60.0 g of 
(3S,4S)-1-benzyl-3-(tert-butoxycarbonyl)amino-4-methylpyrrolidine, 6.00 g 
of 5% palladium on charcoal, and 500 ml of methanol was hydrogenated in an 
autoclave under 5 kgf/cm.sup.2 hydrogen pressure at 40.degree. C. for 3 
hours. The catalyst was removed by filtration, and then the filtrate was 
concentrated under reduced pressure. The product was recrystallized from 
n-hexane to give 38.0 g of colorless needles, m.p. 83.degree.-85.degree. 
C. 
NMR spectrum .delta.(CDCl.sub.3) ppm: 0.97 (3H, d, J=7 Hz), 1.45 (9H, s), 
2.20-2.30 (1H, m), 2.44-2.53 (1H, m), 2.70 (1H, dd, J=11.5, 4.5 Hz), 3.15 
(1H, dd, J=11, 7.5 Hz), 3.20-3.30 (1H, m), 4.05-4.20 (1H, m), 4.62 (1H, 
br-s) 
______________________________________ 
High resolution mass spectrum for C.sub.10 H.sub.21 N.sub.2 O.sub.2 
______________________________________ 
Calculated m/z: 
201.1603 
Found m/z: 201.1601 
______________________________________ 
Specific rotation .alpha.!D.sup.20 +19.6.degree. (c=1, CHCl.sub.3) 
The following compound was obtained in a similar manner. 
(3S,4S)-3-(tert-Butoxycarbonyl)amino-4-ethylpyrrolidine 
Appearance: pale yellow crystals 
m.p.: 63.5.degree.-65.5.degree. C. IR spectrum .nu.(KBr) cm.sup.-1 : 1712 
NMR spectrum .delta.(CDCl.sub.3) ppm: 0.94 (3H, t, J=7.5 Hz), 1.20-1.33 
(1H, m), 1.39-1.51 (1H, m), 1.44 (9H, s), 1.98-2.08 (1H, m), 2.49-2.57 
(1H, m), 2.75-2.81 (1H, m), 3.10-3.24 (2H, m), 4.09-4.20 (1H, m), 
4.68-4.79 (1H, m) Specific rotation: .alpha.!.sub.D.sup.20 +2.30 (c=1, 
CHCl.sub.3) 
5-Amino-7-(3S,4S)-3-tert-butoxycarbonylamino-4-methyl-1-pyrrolidinyl!-1-cy 
clopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 
A mixture of 1.01 g of 
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3- 
carboxylic acid-O.sup.3,O.sup.4 !difluoroborate, 0.71 g of 
(3S,4S)-3-tert-butoxycarbonylamino-4-methylpyrrolidine, 0.51 ml of 
N,N-diisopropylethylamine, and 4.04 ml of dimethylsulfoxide was stirred at 
outer temperature of 30.degree. C. for 64 hours. Water was added to the 
reaction mixture under ice cooling, and the mixture was extracted with 
methylene chloride. The methylene chloride layer was washed successively 
with water and brine, and then dried and concentrated under reduced 
pressure. The resulting residue was purified by column chromatography 
(silica gel, methylene chloride: methanol=100:1), and crystals obtained 
were washed with diethyl ether to give 0.58 g of yellowish orange 
crystals. A mixture of 0.58 g of the crystals obtained, 0.58 ml of 
triethylamine, 11.6 ml of methanol, and 5.8 ml of 1,2-dichloroethane was 
heated under reflux for 3 hours. The reaction mixture was concentrated 
under reduced pressure, and then, the residue was added with water and 
crystals precipitated were collected by filtration. The crystals were 
washed with water to give 0.52 g of yellow crystals. The crystals were 
recrystallized from acetone-diisopropyl ether to give yellow crystals, 
m.p. 178.5.degree.-180.degree. C. 
______________________________________ 
Analysis for C.sub.24 H.sub.31 FN.sub.4 O.sub.5 
______________________________________ 
Calculated % 
C, 60.75 H, 6.58 N, 11.81 
Found % C, 60.59 H, 6.55 N, 11.73 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 -141.9.degree. (c=0.1, CHCl.sub.3) 
5-Amino-7-(3S,4S)-3-amino-4-methyl-1-pyrrolidinyl!-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 
5-Amino-7-(3S,4S)-3-tert-butoxycarbonylamino-4-methyl-1-pyrrolidinyl!-1-cy 
clopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 
(0.45 g) was added with stirring to 0.77 ml of conc. hydrochloric acid 
under ice cooling, and after stirring was continued for 3 minutes at room 
temperature, 0.77 ml of water was added to the mixture and stirring was 
further continued at room temperature for 10 minutes. The mixture was 
adjusted to pH 11 with 10% aqueous sodium hydroxide, and then to pH 8 with 
10% hydrochloric acid and extracted with methylene chloride-methanol 
(9:1). The organic layer was washed with water and then dried, and 
concentrated under reduced pressure to obtain yellow crystals. The 
crystals were recrystallized from methylene chloride-diethyl ether to give 
0.24 g of yellow crystals. The crystals were recrystallized from 
ethanol-diethyl ether to give yellow crystals, m.p. 
212.5.degree.-213.5.degree. C. 
______________________________________ 
Analysis for C.sub.19 H.sub.23 FN.sub.4 O.sub.3.1/4H.sub.2 O 
______________________________________ 
Calculated % 
C, 60.23 H, 6.25 N, 14.79 
Found % C, 60.32 H, 6.32 N, 14.47 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 -159.8.degree. (c=0.1, DMF) 
5-Amino-7-(3S,4S-3-tert-butoxycarbonylamino-4-ethyl-1-pyrrolidinyl!-1-cycl 
opropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 
A mixture of 2.00 g of 
5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-c 
arboxylic acid, 2.19 g of 
(3S,4S)-3-tert-butoxycarbonylamino-4-ethylpyrrolidine, 0.95 ml of 
triethylamine, and 8 ml of dimethylsulfoxide was heated with stirring at 
inner temperature of 94.degree.-102.degree. C. for 87 hours. The reaction 
mixture was poured into 40 ml of ice-water, and then the crystals 
precipitated were collected by filtration and washed with water to obtain 
3.41 g of yellowish brown crystals. The product was purified by column 
chromatography (silica gel, methylene chloride:methanol=50:1) to give 2.01 
g of yellow foamy product. 
NMR spectrum .delta.(DMSO-d.sub.6) ppm: 0.66-0.75 (1H, m), 0.80-0.85 (1H, 
m), 0.92 (3H, t, J=7.5 Hz), 1.03-1.19 (2H, m), 1.30-1.55 (2H, m), 1.41 
(9H, s), 2.16-2.25 (1H, m), 2.32 (3H, s), 3.13-3.29 (1H, m), 3.41-3.52 
(2H, m), 3.83-3.93 (1H, m), 4.10-4.29 (2H, m), 6.93-7.10 (3H, m), 8.60 
(1H, s) Specific rotation .alpha.!.sub.D.sup.20 -213.1.degree. (c=0.1, 
CHCl.sub.3) 
5-Amino-7-(3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl!-1-cyclopropyl-6-fluoro-1 
,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid 
Concentrated hydrochloric acid (2.9 ml) was stirred under ice cooling, and 
then added portionwise with 1.70 g of 
5-amino-7-(3S,4S)-3-tert-butoxycarbonylamino-4-ethyl-1-pyrrolidinyl!-1-cy 
clopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid. 
The mixture was stirred at room temperature for 5 minutes, and then added 
with 2.9 ml of water and stirring was further continued for 10 minutes. 
The reaction mixture was added with 5 ml of methylene chloride and 
stirred, and then layers were separated and aqueous layer was washed twice 
with methylene chloride. The aqueous layer was added with 10% aqueous 
sodium hydroxide to adjust its pH to above 11. After stirring was 
continued for 20 minutes, the mixture was adjusted to pH 8 with 10% 
hydrochloric acid, and then crystals precipitated were collected by 
filtration and washed with water to obtain 1.09 g of yellow crystals. The 
crystals were recrystallized from methanol:water=4:1 to give 0.84 g of 
yellow crystals, m.p. 222.5.degree.-224.5.degree. C. 
______________________________________ 
Analaysis for C.sub.20 H.sub.25 FN.sub.4 O.sub.3 .multidot.5/4H.sub.2 O 
Calculated % C, 58.45 H, 6.74 N, 13.63 
Found % C, 58.22 H, 6.52 N, 13.68 
______________________________________ 
Specific rotation .alpha.!.sub.D.sup.20 -244.8.degree. (c=0.1, 0.1N HCl) 
Example 2 
Test example 
In the following test examples, 
5-amino-7-((3S,4S)-3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro 
-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid was used as the 
compound 1 of the present invention, and 
5-amino-7-((3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro- 
1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid as the compound 2 of 
the present invention. Ciprofloxacin (The Merck Index 11th Edition, 
No.2315) was used as the reference compound A, and 
5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxo-7-piperazinylqui 
noline-3-carboxylic acid (the Japanese Patent Unexamined Publication 
(KOKAI) No.(Sho) 62-215572/1987) as the reference compound B. 
1. Antibacterial spectrum against standard strains and clinically isolated 
strains 
Antibacterial activities (minimum inhibitory concentration: MIC) were 
determined according to the standard method of the Japan Society of 
Chemotherapy (Chemotherapy (Tokyo), 29 (1), 76, 1981) by using standard 
strains and strains isolated from patients of infectious disease 
(clinically isolated strains) and applying 10.sup.6 viable cells per ml. 
Results are shown in Table 1-A and Table 1-B. The compound (I) of the 
present invention exhibited excellent antibacterial activities compared to 
the reference compound A and B, especially against clinically isolated 
strains. Names of the bacteria are as follows: 
Staphylococcus aureus (S. aureus) 
Enterococcus faecalis (E. faecalis) 
Escherichia coli (E. coli) 
Klebsiella pneumoniae (K. pneumoniae) 
Serratia marcescens (S. marcescens) 
Enterobacter cloacae (E. cloacae) 
Acinetobacter calcoaceticus (A. calcoaceticus) 
TABLE 1-A 
__________________________________________________________________________ 
Antibacterial activities (standard strains, minimum inhibitory 
concentrations, .mu. g/ml) 
Bacteria Compound 
Compound 
Reference 
Reference 
tested Gram 
1 2 Compound A 
Compound B 
__________________________________________________________________________ 
S. aureus 
+ 0.006 0.006 0.20 0.10 
FDA 209P JC-1 
E. coli -- 0.006 0.012 0.025 0.05 
NIHJ JC-2 
K. pneumoniae 
- 0.0008 
.ltoreq.0.0015 
0.012 0.006 
PCI-602 
S. marcescens 
- 0.05 0.10 0.10 0.20 
IAM 1184 
E. colacae 963 
- 0.012 0.025 0.05 0.10 
__________________________________________________________________________ 
TABLE 1-B 
__________________________________________________________________________ 
Antibacterial activities (clinically isolated strains, minimum 
inhibitory 
concentrations, .mu.g/ml) 
Compound 
Compound 
Reference 
Reference 
Bacteria tested 
Gram 
1 2 Compound A 
Compound B 
__________________________________________________________________________ 
S. aureus HPC527 
+ 0.006 0.006 0.39 0.10 
S. aureus HPC308 
+ 0.20 0.10 25 6.25 
S. aureusHPC292 
+ 0.78 0.78 50 25 
E. faecalis HPC984 
+ 0.05 0.05 0.39 0.39 
E. faecalis HPC948 
+ 0.10 0.20 3.13 6.25 
E. faecalis HPC975 
+ 0.78 0.78 50 12.5 
E. cloacae HNR1939 
- 0.10 0.20 0.78 0.78 
E. cloacae HNR1946 
- 0.10 0.20 0.78 0.78 
E. cloacae HNR1941 
- 3.13 6.25 25 25 
A. calcoaceticus HNR916 
- 0.006 0.012 0.39 0.10 
A. calcoaceticus HNR939 
- 0.20 0.20 6.25 3.13 
A. calcoaceticus HNR904 
- 1.56 3.13 100 50 
K. pneumoniae HNR858 
- 0.10 0.20 0.78 0.78 
K. pneumoniae HNR869 
- 0.78 1.56 3.13 6.25 
K. pneumoniae HNR828 
- 3.13 3.13 12.5 12.5 
S. marcescens HNR1544 
- 0.025 0.05 0.10 0.10 
S. marcescens HNR1792 
- 1.56 1.56 6.25 6.25 
S. marcescens HNR1767 
- 6.25 12.5 50 50 
__________________________________________________________________________ 
2. Chromosomal aberration test 
The experiments were carried out using a Chinese hamster lung cell line 
(CHL cell). The test compounds prepared were added to cultured cells, and 
cultivation was continued for 6 hours at 37.degree. C. in 5% CO.sub.2. 
2-(2-furyl)-3-(5-nitro-2-furyl) acrylamide was used as a positive control. 
After the cultivation for 6 hours, the cells were washed and added with 
fresh medium, and then cultivation was further continued for 18 hours. 
Colcemide solution was added to the culture 2 hours before the completion 
of the cultivation, and the chromosomal specimens were prepared after the 
cultivation was completed. Incidence rates of aberration cells were 
measured at the treatments with 100 .mu.g/ml of the test compounds. As a 
result, the incidence rate of the aberration cells was less than 10% for 
each of the compound 1 of the present invention, the reference compound A, 
and the reference compound B. 
3. Phototoxicity 
Male Hartley guinea pigs were intravenously administered with test 
compounds at a dose of 10 mg/kg, and then immediately exposed to WVA on 
their backs for 90 minutes. Erythemas on the UV irradiated skin were 
observed 24 hours after the irradiation. The number of guinea pigs with 
erythemas was shown in Table 2. The compound 1 of the present invention 
induced no phototoxicity, whereas phototoxicities were observed in more 
than the half (three of five animals) as for the reference compound A. 
4. The induction of convulsions 
1) Intraperitoneal (i.p.) administration 
Fasted five-week-old male ICR mice were orally administered with fenbufen 
at a dose of 100 mg/kg. After 30 minutes, the animals were 
intraperitoneally administered with the test compound at a dose of 100 
mg/kg, and the absence or presence of induction of convulsions was 
observed. The number of mice with convulsions was shown in Table 2. The 
compound 1 of the present invention did not induce convulsions, whereas 
convulsions were observed in the half of the animals as for the reference 
compound A. In addition, although inducing actions of convulsions were not 
noticeable as for the reference compound B, all of the animals exhibited 
sedative symptoms that were considered as precursory symptoms of 
convulsions. 
2) Intracerebroventricular (i.c.v.) administration 
Male Wistar rats (weighing 180-220 g) were anesthetized with sodium 
pentobarbital at 45 mg/kg, i.p., and then the head of the rat was fixed in 
a stereotaxic apparatus. A stainless steel guide cannula for 
intracerebroventricular injectionin in 0.6 mm diameter was implanted as a 
guide cannula so as to be positioned at 1.5 mm above the left lateral 
cerebroventricle (A:6.2,R:1.0,H:+1.0) according to the brain atlas of De 
Groot (1959). The guide cannula was fixed by using a dental cement, and 
then closed with a stainless steel stylet in 0.3 mm diameter. Potassium 
penicillin G (10,000 units) were subcutaneously administered to prevent an 
infection. The rats were subjected to the experiments after recovery time 
for several days from the surgery. 
For the measurement of the induction of convulsions, 50 mg/kg of fenbufen 
was intraperitoneally administered, and then the test compound was 
intracerebroventricularly administered after 30 minutes from the 
administration of fenbufen by means of a stainless steel cannula in 0.3 mm 
diameter that was connected with a polyethylene catheter and adjusted so 
as to be 1.5 mm longer than the guide cannula for an administration at an 
accurate position of cerebroventricle (H:+1.0). Absence or presence of 
appearance of convulsions was observed for at least 4 hours. After the 
completion of the above experiment, the administered positions were 
confirmed by intraventricularly injecting 10 .mu.l of 1% Evans blue to 
each of the rats, and followed by sectioning the brains. The numbers of 
rats with induction of convulsions were shown in Table 2. The compound 1 
of the present invention induced no convulsions, whereas convulsions were 
observed in all of the animals (each three animals) as for the reference 
compound A and B. 
(Reference) 
De Groot, J. (1959). The rat forebrain in stereotaxic coordinates. Ver. 
Kon. Ned. Acad. Wet., Natuurkunde 52: 1-40 
TABLE 2 
______________________________________ 
Photoxicity and induction of convulsions 
Induction of convulsion 
Compound tested 
Photoxicity i.p. i.c.v. 
______________________________________ 
Compound 1 0/5 0/6 0/6 
Reference Compound A 
3/5 3/6 3/3 
Reference Compound B 
0/5 0/6.sup.1) 
3/3 
______________________________________ 
.sup.1) All of the animals exhibited sedative symptoms that were 
considered as precursory symptoms of convulsions 
INDUSTRIAL APPLICABILITY 
The compounds (I) of the present invention have excellent antibacterial 
activities, and induce no phototoxicity, chromosomal aberration, and 
induction of convulsion, and thus they are useful as antibacterial agents. 
The compounds (II) of the present invention are useful for efficient 
preparations of the aforementioned compounds (I).