Quino-benoxazine compounds having the formula: ##STR1## wherein R.sub.2 is one or more substituents, R.sub.1 is a hydrogen or a carboxy-protecting group and Z is an amine group or an aliphatic heterocyclic group. The compounds have antibacterial activity.

This invention relates to a new quino-benoxazine derivatives having 
antibacterial properties, compositions containing the new quino-benoxazine 
derivatives and methods of treating mammalian patients with the new 
quino-benoxazine derivatives. 
It is known that certain quinoline compounds exhibit antibacterial 
properties, notably certain 
7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives 
which are substituted in the 1 position with an alkyl, benzyl or acetyl 
substituent. U.S. Pat. No. 4,292,317 discloses derivatives of 
7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids wherein the 1 
position is substituted by an alkyl group or a vinyl group. In U.S. Pat. 
No. 4,284,629 there are disclosed various 
4-oxo-1,4-dihydroquinoline-3-carboxylic acids in which the 1 position is 
substituted with a cycloalkyl group. 
This invention relates to novel antibacterial agents and, more 
particularly, to 1-substituted 
amino-2-fluoro-4-oxo-4-H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic acid 
and derivatives thereof having the formula: 
##STR2## 
wherein R.sub.2 is one or more of hydrogen, halogen, C.sub.1 to C.sub.6 
alkyl including substituted derivatives thereof, nitro, carboxyl, cyano, 
methylenedioxy, a group having the formula --Y--R.sub.3 wherein --Y-- is 
--O-- or --S-- and R.sub.3 is hydrogen or C.sub.1 to C.sub.6 alkyl and an 
amine having the formula: 
##STR3## 
wherein R.sub.4 and R.sub.5 are each independently hydrogen or C.sub.1 to 
C.sub.6 alkyl. 
R.sub.1 is hydrogen or a carboxy-protecting group. 
Z is an amino group having the formula: 
##STR4## 
wherein R.sub.6 is hydrogen or C.sub.1 to C.sub.10 alkyl as well as the 
corresponding substituted derivatives thereof; and R.sub.7 is alkyl or 
substituted alkyl, as described above with reference to R.sub.6, or an 
amino group, a mono-(C.sub.1 to C.sub.6) alkylamino group or a di-(C.sub.1 
to C.sub.6)alkylamino group. 
Alternatively, Z can be an aliphatic heterocyclic ring containing 4 to 7 
atoms, and preferably 5 to 6 atoms as well as substituted derivatives 
thereof. 
As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo 
groups, while the term "C.sub.1 to C.sub.6 alkyl" refers to loweralkyl 
groups including methyl, ethyl, propyl, isopropyl and butyl. 
As indicated above, R.sub.2 can be C.sub.1 to C.sub.6 alkyl as well as 
hydroxy and halo-substituted derivatives thereof. Such groups include a 
chloromethyl group, a chloroethyl group, a chloropropyl group, a 
hydroxyethyl group, and a trifluoromethyl group. 
R.sub.2 can also be a group of the formula --Y--R.sub.3. Representative 
groups of this type include a hydroxy group, a mercapto group, a lower 
alkoxy group, such as methoxy, ethoxy, propoxy, as well as the thio 
analogs thereof, namely a methylmercapto group, and an ethylmercapto 
group. 
As used herein, the term "carboxy-protecting group" refers to and includes 
the residue of a carboxylic acid ester group. Such carboxy-protecting 
groups are well known to those skilled in the art, having been extensively 
used in the protection of carboxyl groups in the penicillin and 
cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 
3,719,667, the disclosures of which are incorporated herein by reference. 
In general, such carboxy-protecting groups can be relatively easily 
cleaved to yield the corresponding free carboxy group. Representative 
protecting groups include C.sub.1 --C.sub.8 alkyl (e.g., methyl, ethyl, 
tertiary butyl), substituted alkyl (e.g., dimethylaminoethyl), benzyl and 
substituted derivatives thereof such as alkoxy and nitrobenzyl groups; 
also suitable are acyl groups such as pivaloyloxymethyl groups. 
The aliphatic heterocyclic rings representing Z are, in accordance with the 
preferred practice of the invention, aliphatic heterocyclic rings 
containing 1 or 2 hetero atoms which are selected from the group 
consisting of S, O and N, with the remaining atoms in the aliphatic 
heterocyclic ring being carbon atoms, as well as substituted derivatives 
thereof. In accordance with the practice of the invention, the aliphatic 
heterocyclic ring has the formula: 
##STR5## 
wherein R.sub.8 is selected from the group consisting of dimethylene and a 
group of the formula --CH.sub.2 --R.sub.9 --CH.sub.2 wherein R.sub.9 is 
selected from the group consisting of --S--, --O--, --N-- and --CH.sub.2 
--. Also included are substituted derivatives of such heterocyclic rings 
wherein the substituent is one or more of a C.sub.1 to C.sub.6 alkyl 
group, C.sub.1 to C.sub.6 hydroxyalkyl, hydroxy, alkanoyl containing 1 to 
6 carbon atoms, alkanoylamido containing 1 to 6 carbon atoms and an amino 
group having the formula: 
##STR6## 
wherein R.sub.10 and R.sub.11 are each independently selected from the 
group consisting of hydrogen, C.sub.1 to C.sub.6 alkyl, halo-substituted 
C.sub.1 to C.sub.6 alkyl and hydroxy-substituted C.sub.1 to C.sub.6 alkyl. 
Illustrative of such heterocyclic groups are azetidinyl groups, piperazinyl 
groups, 4-acylpiperazinyl groups, piperidinyl groups, pyrrolidinyl groups, 
morpholino groups, thiomorpholino groups and homopiperazinyl groups (i.e., 
hexahydro-1-H-1,4-diazepinyl). 
The preferred compounds of the present invention are those having the 
formula: 
##STR7## 
wherein Z is piperazinyl or substituted piperazinyl or 1-(3-amino or 
substituted amino)pyrrolidinyl as described above, R.sub.1 is as described 
above and is preferably hydrogen, and R.sub.2 is hydrogen or one or more 
of alkyl, halogen, hydroxy or methylenedioxy. 
Representative of such preferred compounds are 
1-(1-piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid, 
1-[1(4-methyl)piperazinyl]-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazi 
ne-5-carboxylic acid, 
1-(3-aminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benzoxazine 
-5-carboxylic acid, 
1-(1-piperazinyl)-2,10-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benzoxazine-5- 
carboxylic acid, 
1-[1-(4-methyl)piperazinyl]-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benzoxa 
zine-5-carboxylic acid, 
1-(3-aminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benzoxazine 
-5-carboxylic acid. 
Also included within the scope of the present invention are 
pharmaceutically acceptable salts of the foregoing compounds. As used 
herein, the term "pharmaceutically acceptable salts" refers to nontoxic 
acid addition salts and alkaline earth metal salts of the compounds of 
Formula I. The salts can be prepared in situ during the final isolation 
and purification of the compounds of formula I, or separately by reacting 
the free base or acid functions with a suitable organic acid or base. 
Representative acid addition salts include the hydrochloride, 
hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, 
palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, 
tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, 
glucoheptonate, lactobionate, lauryl sulfate salts and the like. 
Representative alkali or alkaline earth metal salts include the sodium, 
calcium, potassium and magnesium salts. It has been found that the 
compounds of the present invention possess antibacterial activity against 
a wide spectrum of gram positive and gram negative bacteria, as well as 
enterobacteria. The compounds of the invention are therefore useful in the 
antibiotic treatment of susceptible bacterial infections in both humans 
and animals. In addition, the compounds, by reason of their in vitro 
activity, may be used in scrub solutions for surface inhibition of 
bacterial growth. 
Susceptible organisms generally include those gram positive and gram 
negative, aerobic and anaerobic organisms whose growth can be inhibited by 
the compounds of the invention such as Staphylococcus, Lactobacillus, 
Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, 
Pseudomonas, Acinetobacter, Proteus, Citrobacter, Nisseria, Baccillus, 
Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, 
Haemophilus, Brucella, and other organisms. In addition to exhibiting 
highly effective antibacterial activity, the compounds of the invention 
exhibit increased and improved solubility characteristics as compared with 
prior quinoline-3-carboxylic acid compounds in the art. 
The compounds of Formula I may also be formulated into compositions 
together with pharmaceutically acceptable carriers for parenteral 
injection, for oral administration in solid or liquid form, for rectal 
administration, and the like. 
Compositions according to the invention for parenteral injection may 
comprise pharmaceutically acceptable sterile aqueous or nonaqueous 
solutions, suspensions or emulsions. Examples of suitable nonaqueous 
carriers, diluents, solvents or vehicles include propylene glycol, 
polyethylene glycol, vegetable oils, such as olive oil, and injectable 
organic esters such as ethyl oleate. Such compositions may also contain 
adjuvants such as preserving, wetting, emulsifying and dispersing agents. 
They may be sterilized, for example, by filtration through a 
bacteria-retaining filter, or by incorporating sterilizing agents into the 
compositions. They can also be manufactured in the form of sterile solid 
compositions which can be dissolved in sterile water, or some other 
sterile injectable medium immediately before use. 
Solid dosage forms for oral administration include capsules, tablets, 
pills, powders and granules. In such solid dosage forms, the active 
compound is admixed with at least one inert diluent such as sucrose, 
lactose or starch. Such dosage forms can also comprise, as is normal 
practice, additional substances other than diluents, e.g., lubricating 
agents such as magnesium stearate. In the case of capsules, tablets and 
pills, the dosage forms may also comprise buffering agents. Tablets and 
pills can additionally be prepared with enteric coatings. 
Liquid dosage forms for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups and elixers 
containing inert diluents commonly used in the art, such as water. Besides 
such inert diluents, compositions can also include adjuvants, such as 
wetting agents, emulsifying and suspending agents, and sweetening, 
flavoring and perfuming agents. 
Compositions for rectal administration are preferably suppositories which 
may contain, in addition to the active substance, excipients such as cocoa 
butter or a suppository wax. 
Actual dosage levels of active ingredient in the compositions of the 
invention may be varied so as to obtain an amount of active ingredient 
effective to achieve antibacterial activity in accordance with the desired 
method of administration. The selected dosage level therefore depends upon 
the nature of the active compound administered, the route of 
administration, the desired duration of treatment and other factors. 
Generally, daily dosage levels of the compounds of Formula I of about 0.1 
to about 750, more preferably about 0.25 to about 500 and most preferably 
about 0.5 to about 300 mg. of active ingredient per kg. of body weight are 
effective when administered orally to a mammalian patient suffering from 
an infection caused by a susceptible organism. If desired, the daily dose 
may be divided into multiple doses for administration, e.g., two to four 
times per day. 
Compounds according to this invention can be prepared by the reaction 
illustrated below: 
##STR8## 
wherein X is a halogen and R.sub.2 and Z are the same as described above. 
The reaction may be performed by heating a compound of the formula (II) 
with an amine of formula (III) at a temperature of from 20.degree. C. to 
200.degree. C., and preferably from 70.degree. C. to 150.degree. C., in 
the presence of a suitable organic polar solvent such as 
dimethylsulfoxide, sulfolane, dimethylformamide, dimethylacetamide, 
1-methyl-2-pyrrolidinone or water. It is desirable to carry out the 
reaction in the presence of an acid-acceptor such as triethylamine, 
potassium carbonate and the like at a molar ratio of 1.0 to 1.2 mole of 
the acid-acceptor per mole of the compound of the formula (II). The amine 
(III) can also be used as acid acceptor in which 2 or more molar excess of 
this reagent is used. The compounds of the formula (II) may be prepared in 
accordance with the following reaction scheme, in which R.sub.2 is as 
described above, and X can be independently identical or nonidentical 
halogen: 
##STR9## 
In accordance with the foregoing reaction scheme, the 
2,3,4-trihalo-5-fluorobenzoic acid (1) is treated with thionyl chloride to 
produce the corresponding acid chloride (2). Displacement of the acid 
chloride (2) with malonic acid half ester (2a) in the presence of n-butyl 
lithium yields the .beta.-ketoester (3). 
The .beta.-ketoester (3) is then treated with a trialkylorthoformate (4) in 
the presence of an acid anhydride, preferably acetic anhydride, followed 
by reaction with substituted or unsubstituted O-hydroxyaniline (5) to 
obtain the enaminoketoester (6). In the trialkylorthoformate (4), R.sub.1 
may be an alkyl group of, for example, from 1 to 10 carbon atoms, but is 
preferably loweralkyl, such as ethyl. Reaction with the 
trialkylorthoformate is preferably conducted at elevated temperatures, 
such as from about 50.degree. C. to about 150.degree. C., preferably from 
about 100.degree. C. to about 140.degree. C., to obtain an oily liquid, 
which may be isolated or unisolated, as desired (shown in brackets in the 
reaction scheme). Reaction of the latter with the substituted or 
unsubstituted O-hydroxyaniline (5) is preferably conducted in an 
appropriate aprotic or nonaprotic solvent, preferably methylene chloride 
or tetrahydrofuran, and may be conducted at room or suitable elevated 
temperature, as desired. 
The enaminoketoester (6) is then cyclized, such as by treatment with a 
strong base as defined above, preferably sodium hydride, to obtain the 
1-chloro-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic 
acid ester (II) (R.sub.1 =alkyl) through the intermediate (6a). 
Cyclization is conducted in the presence of an aprotic solvent, such as 
dimethoxyethane, bis(2-methoxyethyl)ether, dimethylformamide, 
tetrahydrofuran or chlorobenzene, and is preferably conducted at 
temperatures of about 20.degree. C. to about 145.degree. C., more 
preferably at the reflux temperature of the solvent employed. 
The ester (II) is subjected to hydrolysis, such as by treatment with sodium 
hydroxide, or dilute mineral acid to form the free acid (II) (R.sub.1 
.dbd.H). 
The 4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic acid (I) (R.sub.1 
.dbd.H) can then be converted into the corresponding ester (I) (R.sub.1 
.dbd.H), if desired, by conventional esterification procedures, such as by 
treating the free acid (I) (R.sub.1 .dbd.H) with the appropriate alcohol 
in the presence of an acid catalyst, by converting the free acid (I) 
(R.sub.1 .dbd.H) into the corresponding acid chloride followed by 
displacement of the chloro radical with the appropriate alcohol, or by 
treating the sodium salt of the acid (I) (R.sub.1 .dbd.H) with a suitable 
reactive halide, such as chloromethylpivalate or dimethylaminoethyl 
chloride in dimethoxyethane to obtain, for example, the pivaloyloxymethyl 
ester (I) wherein R.sub.1 is --CH.sub.2 OCOC(CH.sub.3).sub.3 or 
dimethylaminoethyl ester (I) wherein R.sub.1 is CH.sub.2 CH.sub.2 
N(CH.sub.3).sub.2.

The foregoing may be better understood from the following examples, which 
are presented for purposes of illustration and are not intended to limit 
the scope of the inventive concepts. As used in the following examples, 
the references to compounds, such as (1), (2), (3), etc., and to 
substituents, such as R, R.sub.1, R.sub.2, etc., refer to the 
corresponding compounds and substituents in the foregoing reaction scheme 
and in formulae I and II. 
EXAMPLE 1 
1-(1-piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carbo 
xylic acid 
(a) To a solution of 3.9 g. of 2,3,4,5-tetrafluorobenzoic acid in 20 ml. of 
methylene chloride is added 4 ml. of thionyl chloride. After refluxing for 
30 minutes, the reaction mixture is evaporated to dryness to give 4.95 g. 
of the acid chloride. 
This is slowly added to a dry ice-cooled solution of 3.5 g. of malonic acid 
monoethyl ester in 35 ml. of tetrahydrofuran, 37.9 ml. of 1.4M. n-butyl 
lithium in THF, and the flask is warmed to -5.degree. C. for 5 minutes and 
then is cooled back to -70.degree. C. To the resulting solution there is 
added 4.95 g. of the acid chloride in 10 ml. of THF. The cooling bath is 
removed, and the solution allowed to warm to room temperature after an 
hour. The solution is then partitioned between 1N HCl and ether. The ether 
portion is washed with NaHCO.sub.3 and dried over MgSO.sub.4, and then 
evaporated to obtain the liquid .beta.-ketoester (3). 
(b) A solution of 20 g. of the above .beta.-ketoester (3) in 18.5 ml. of 
triethylorthoformate and 45 ml. of acetic anhydride is treated at 
135.degree. C. for 11/2 hours with the removal of the ethyl acetate formed 
during the reaction. The solution is evaporated under reduced pressure to 
a mobile oil. The oil is then dissolved in 200 ml. of methylene chloride 
and 9.5 g. of o-hydroxyaniline is added into the solution. After 1 hour, 
the solution is evaporated to dryness and crystallized from 200 ml. of 
hexane and 5 ml. of ether yielding (6), wherein R.sub.1 .dbd.C.sub.2 
H.sub.5, R.sub.2 .dbd.H, X.dbd.F). 
(c) To a cold solution of 15 g. of the preceding product (6), R.sub.1 
.dbd.C.sub.2 H.sub.5, X.dbd.F, R.sub.2 .dbd.H in 150 ml dimethoxyethane 
(DME) is slowly added 3.33 g. of a 60% sodium hydride-in-oil suspension. 
The mixture is refluxed for 24 hours and is cooled and diluted with water 
to a volume of 1.5 liters. The mixture is then filtered and the solid is 
washed with a 1:1 hexane/ether solution to obtain (II), (R.sub.1 
.dbd.C.sub.2 H.sub.5, X.dbd.F, R.sub.2 .dbd.H). 
(d) To a suspension of 7 g. of (II) (R.sub.1 .dbd.C.sub.2 H.sub.5, X.dbd.F, 
R.sub.2 .dbd.H) in 30 ml. THF is added a sodium hydroxide solution (0.91 
g) in 20 ml. water. The mixture is heated at 80.degree. C. for 1 hour 
resulting in a clear solution which is evaporated under reduced pressure 
to dryness. The solid is dissolved in 200 ml. water and 2.5 ml. acetic 
acid is added. The resulting precipitate is filtered and washed with cold 
water, crystallized from dimethylformamide (DMF) to produce 
1,2-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]-benoxazine-5-carboxylic acid 
(II) (R.sub.1 .dbd.H, X.dbd.F, R.sub.2 .dbd.H). 
(e) To a solution of 2.7 g. of 
1,2-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic acid 
(II), (R.sub.1 .dbd.H, X.dbd.F, R.sub.2 .dbd.H) in 15 ml. of 
1-methyl-2-pyrrolidinone at 115.degree. C. is added 3 ml. piperazine. 
After stirring at 100.degree. C. for 20 hours, the solvent is removed by 
reduced pressure to dryness. Ethanol is added to the residue and the 
resulting mixture is filtered and washed with ether and then washed with 
very small amounts of cold water to give (I) (R.sub.1 .dbd.H, R.sub.2 
.dbd.H, 
##STR10## 
The resulting dried solid (I) is suspended in 30 ml. water and 8.5 ml. 1N 
HCl is added to and warmed to dissolve. Removal of the solvent under 
reduced pressure gives hydrochloride salt of 
1-(1-piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.H, 
##STR11## 
To the hydrochloride salt is added one molar equivalent of an aqueous 
solution of sodium hydroxide, and the resulting precipitate is filtered to 
obtain 
1-(1-piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid (I). 
(f) Alternately, the title compound is prepared as follows: To a suspension 
of 5 g. of compound (II) (product of 1(d) in 40 ml. 
1-methyl-2-pyrrolidinone at 120.degree. C. under nitrogen atmosphere is 
added 9.5 ml. of N-carboethoxypiperazine. After 20 hours, the solvent is 
removed under reduced pressure and the residue is suspended in 150 ml. 
ethanol and refluxed for 1/2 hour. The reaction mixture is then cooled and 
filtered. The resulting solid is washed with cold ethanol and water to 
obtain compound (I). (R.sub.1 .dbd.H, R.sub.2 .dbd.H, 
##STR12## 
To a suspension of 5 g. of the preceding compound (I) (R.sub.1 .dbd.H, 
R.sub.2 .dbd.H, 
##STR13## 
in 25 ml of ethanol at 80.degree. C. is added 50 ml. of 10% NaOH solution. 
The solution is heated at 80.degree. C. for 6 hours. The solvent is 
removed and the solid is dissolved in 100 ml water. The pH of the solution 
is adjusted to pH 7 by the addition of 10% acetic acid. The precipitate is 
filtered and washed with cold water yielding 
1-(1-piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]-benoxazine-5-car 
boxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.H, 
##STR14## 
EXAMPLE 2 
1-(1-(4-methyl)piperazinyl)-2-fluoro-4-oxo-4-H-quino[2,3,4-i,j][1,4]benoxaz 
ine-5-carboxylic acid 
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) 
with N-methylpiperazine to obtain 
1-(1-(4-methyl)piperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxaz 
ine-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.H, 
##STR15## 
and its hydrochloride salt. 
EXAMPLE 3 
1-(1-pyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid 
In the described fashion as Example 1, replacing piperazine in Example 1(e) 
with pyrrolidine, one can obtain 
1-(1-pyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-car 
boxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.H, 
##STR16## 
EXAMPLE 4 
1-(1-3-hydroxypyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazi 
ne-5-carboxylic acid 
The procedure of Example 1 can be repeated replacing piperazine in Example 
1(e) with 3-hydroxypyrrolidine to obtain 
1-(1-3-hydroxypyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxaz 
ine-5-carboxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR17## 
EXAMPLE 5 
1-(1-3-aminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine 
-5-carboxylic acid 
(a) In the described fashion as Example 1 replacing piperazine in Example 
1(e) with 3-acetamidopyrrolidine, one can obtain 
1-(1-3-acetamidopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benox 
azine-5-carboxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR18## 
(b) The product of the above reaction can be hydrolyzed with hydrochloric 
acid at 80.degree. C. to give 
1-(1-3-aminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazin 
e-5-carboxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR19## 
and its hydrochloride salt. 
EXAMPLE 6 
1-(1-3-methylaminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]beno 
xazine-5-carboxylic acid 
(a) In the described fashion as Example 1 replacing piperazine in Example 
1(e) with 3-N-formyl-N-methylpyrrolidinyl, one can obtain 
1-(1-3-N-formyl-N-methylaminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i 
,j][1,4]benoxazine-5-carboxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR20## 
(b) The product of the above reaction can then be hydrolyzed with 
hydrochloric acid at 80.degree. C. to give 
1-(1-3-methylaminopyrrolidinyl)-2-fluoro-4-oxo-quino[2,3,4-i,j][1,4]benoxa 
zine-5-carboxylic acid (I), (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR21## 
and its hydrochloride salt. 
EXAMPLE 7 
1-(1-3-dimethylaminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]be 
noxazine-5-carboxylic acid 
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) 
with 3-dimethylaminopyrrolidine to obtain 
1-(1-3-dimethylaminopyrrolidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]b 
enoxazine-5-carboxylic acid (I) and its hydrochloride salt (R.sub.1 
.dbd.R.sub.2 .dbd.H, 
##STR22## 
EXAMPLE 8 
1-(1-piperidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carbo 
xylic acid 
The procedure of Example 1 can be repeated replacing piperazine in Example 
1(e) with piperidine to obtain 
1-(1-piperidinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR23## 
EXAMPLE 9 
1-(4-morpholinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carbo 
xylic acid 
In the described fashion as Example 1, replacing piperazine in Example 1(e) 
with morpholine, one can obtain 
1-(4-morpholinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carb 
oxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR24## 
EXAMPLE 10 
1-(4-thiomorpholinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-c 
arboxylic acid 
The procedure of Example 1 can be repeated replacing piperazine in Example 
1(e) with thiomorpholine to obtain 
1-(4-thiomorpholinyl)-2-fluoro-4-oxo-quino[2,3,4-i,j][1,4]benoxazine-5-car 
boxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, 
##STR25## 
EXAMPLE 11 
1-(1-3,5-dimethylpiperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxa 
zine-5-carboxylic acid 
In the described fashion as Example 1, replacing piperazine in Examle 1(e) 
with 2,6-dimethylpiperazine, one obtains 
1-(1-3,5-dimethylpiperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benox 
azine-5-carboxylic acid (I) and its hydrochloride salt. (R.sub.1 
.dbd.R.sub.2 .dbd.H, 
##STR26## 
EXAMPLE 12 
1-(1-homopiperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-c 
arboxylic acid 
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) 
with homopiperazine to obtain 
1-(1-homopiperazinyl)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5- 
carboxylic acid (I) and its hydrochloride salt (R.sub.1 .dbd.R.sub.2 
.dbd.H, 
##STR27## 
EXAMPLE 13 
1-dimethylamino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxy 
lic acid 
In the described fashion as Example 1, replacing piperazine in Example 1(e) 
with dimethylamine, one can obtain 
1-dimethylamino-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carbox 
ylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, Z.dbd.N(CH.sub.3).sub.2). 
EXAMPLE 14 
1-(N-2-hydroxyethylamino)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine 
-5-carboxylic acid 
The procedure of Example 1 can be repeated replacing piperazine in Example 
1(e) with N-2-hydroxyethylamine to obtain 
1-(N-2-hydroxyethylamino)-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazin 
e-5-carboxylic acid (I) (R.sub.1 .dbd.R.sub.2 .dbd.H, X.dbd.NHC.sub.2 
H.sub.4 --OH). 
EXAMPLE 15 
1-hydrazyl-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic 
acid 
In the described fashion as Example 1, replacing piperazine in Example 1(e) 
with hydrazine, one can obtain 
1-hydrazyl-2-fluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benozazine-5-carboxylic 
acid (R.sub.1 .dbd.R.sub.2 .dbd.H, Z.dbd.NHNH.sub.2). 
EXAMPLE 16 
1-(1-piperazinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5- 
carboxylic acid 
(a) In the described fashion as Example 1(b), replacing 2-hydroxyaniline 
with 2-hydroxy-4-fluoroaniline, one can obtain the enaminoketoester (6) 
(R.sub.1 .dbd.C.sub.2 H.sub.5, R.dbd.10-fluoro, X.dbd.F). 
(b) By following the Example 1(c) and 1(d), the preceding compound (6) can 
yield 
1,2,10-trifluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic 
acid (II), (R.sub.1 .dbd.H, X.dbd.F, R.sub.2 .dbd.10-fluoro. 
(c) In the described fashion as Example 1(e), the above acid (II) can give 
the desired 
1-(1-piperazinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5 
-carboxylic acid (I) and its hydrochloride salt (R.sub.1 .dbd.H, R.sub.2 
.dbd.10-fluoro, 
##STR28## 
EXAMPLE 17 
In the described fashion as Example 1(e), replacing the acid (II) (R.sub.1 
.dbd.R.sub.2 .dbd.H, X.dbd.F) with the acid (II) of the product of Example 
16(b) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, X.dbd.F) and also replacing 
piperazine with an appropriate amine such as N-methylpiperazine, 
pyrrolidine, 3-hydroxypyrrolidine, 3-acetaminopyrrolidine, 
3-N-formyl-N-methylaminopyrrolidine, 3-dimethylaminopyrrolidine, 
piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, 
homopiperazine, diethylamine and 2,2-dimethylhydrazine, one can obtain the 
following compounds: 
(a) 
1-(1-4-methylpiperazinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]beno 
xazine-5-carboxylic acid (I) and its hydrochloride salt (R.sub.1 .dbd.H, 
R.sub.2 .dbd.10-fluoro, 
##STR29## 
(b) 
1-(1-pyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine- 
5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR30## 
(c) 
1-(1-3-hydroxypyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]be 
noxazine-5-carboxylic acid (I) (R.sub.1 H, R.sub.2 .dbd.10-fluoro, 
##STR31## 
(d) 
1-(1-3-acetamidopyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4] 
benoxazine-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR32## 
(e) 
1-(1-3-N-formyl-N-methylaminopyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino[2, 
3,4-i,j][1,4]benoxazine-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 
.dbd.10-fluoro, 
##STR33## 
(f) 
1-(1-3-dimethylaminopyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino-[2,3,4-i,j] 
[1,4]benoxazine-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 
.dbd.10-fluoro, 
##STR34## 
and its hydrochloride salt. 
(g) 
1-(1-piperidinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5 
-carboxylic acid (I) (R.sub.1 H, R.sub.2 .dbd.10-fluoro, 
##STR35## 
(h) 
1-(4-morpholinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5 
-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR36## 
(i) 
1-(4-thiomorpholinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazi 
ne-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR37## 
(j) 
1-(1-3,5-dimethylpiperazinyl)-2,10-difluoro-4-oxo-4H-quino-[2,3,4-i,j][1,4 
]benoxazine-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR38## 
and its hydrochloride salt. 
(k) 
1-(1-homopiperazinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazi 
ne-5-carboxylic acid (I) (R.sub.1 H, R.sub.2 .dbd.10-fluoro, 
##STR39## 
and its hydrochloride salt. 
(l) 
1-diethylamino-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-ca 
rboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
Z.dbd.N(CH.sub.3).sub.2). 
(m) 
1N,N-dimethylhydrazyl-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazi 
ne-5-carboxylic acid (I) (R.sub.1 .dbd.H, R.sub.2 .dbd.10-fluoro, 
Z.dbd.NHN(CH.sub.3).sub.2). 
EXAMPLE 18 
In the described fashion of Example 5(b), the compounds of Examples 17(d) 
and 17(e) can give the following 2 compounds. 
(a) 
1-(1-3-aminopyrrolidinyl)-2,10-difluoro-4-oxo-quino[2,3,4-i,j][1,4]benoxaz 
ine-5-carboxylic acid (I) and its hydrochloride salt (R.sub.1 .dbd.H, 
R.sub.2 .dbd.1-fluoro, 
##STR40## 
(b) 
1-(1-3-methylaminopyrrolidinyl)-2,10-difluoro-4-oxo-4H-quino[2,3,4-i,j][1, 
4]benoxazine-5-carboxylic acid (I) and its hydrochloride salt (R.sub.1 
.dbd.H, R.sub.2 .dbd.10-fluoro, 
##STR41## 
EXAMPLE 19 
In the described fashion as Example 1(a-d), replacing o-hydroxyaniline with 
an appropriate substituted 
##STR42## 
one can obtain the additional substituted 
1,2-difluoro-4-oxo-4H-quino[2,3,4-i,j][1,4]benoxazine-5-carboxylic acid 
(II) as listed in Table I. 
TABLE I 
______________________________________ 
Substituted 2- Compound (II) 
hydroxyaniline (R.sub.1 = H, X = F) obtained 
______________________________________ 
##STR43## R.sub.2 
(a) 4-methoxy 10-methoxy 
(b) 4-methyl 10-methyl 
(c) 4-chloro 10-chloro 
(d) 4,6-difluoro 8,10-difluoro 
(e) 4,6-methylenedioxy 
9,10-methylenedioxy 
(f) 4-hydroxy 10-hydroxy 
(g) 4-dimethylamino 
10-dimethylamino 
(h) 5-fluoro 9-fluoro 
______________________________________ 
EXAMPLE 20 
In the described fashion of Example 1(e), replacing the acid (II) (R.sub.1 
.dbd.H, R.sub.2 .dbd.H, X.dbd.F) with the acid (II) of the compounds 
listed in Table I of Example 19 and also replacing piperazine with an 
appropriate amine such as N-methylpiperazine, pyrrolidine, 
3-hydroxypyrrolidine, 3-acetamidopyrrolidine, 
3-N-formyl-N-methylaminopyrrolidine, 3-dimethylaminopyrrolidine, 
piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, 
homopiperazine, dimethylamine and 2,2-dimethylhydrazine, and extra 
hydrolysis step if required as in Example 5(b), one can obtain the 
following additional compounds (I) as summarized in Table II. 
TABLE II 
__________________________________________________________________________ 
Compound II used 
Compound I obtained 
Piperazine replacement 
(R.sub.1 = H, X = F) 
(R.sub.1 = H) 
ZH R.sub.2 R.sub.2 Z 
__________________________________________________________________________ 
piperazine 8,10-difluoro 
8,10-difluoro 
piperazinyl 
piperazine 9,10-methylenedioxy 
9,10-methylenedioxy 
piperazinyl 
piperazine 10-hydroxy 
10-hydroxy piperazinyl 
piperazine 10-methyl 10-methyl piperazinyl 
4-methylpiperazine 
8,10-difluoro 
8,10-difluoro 
4-methylpiperazinyl 
4-methylpiperazine 
9,10-methylenedioxy 
9,10-methylenedioxy 
4-methylpiperazinyl 
4-methylpiperazine 
10-hydroxy 
10-hydroxy 4-methylpiperazinyl 
4-methylpiperazine 
10-chloro 10-chloro 4-methylpiperazinyl 
3-acetamidopyrrolidine 
8,10-difluoro 
8,10-difluoro 
3-aminopyrrolidinyl 
10. 
3-acetamidopyrrolidine 
9,10-methylenedioxy 
9,10-methylenedioxy 
3-aminopyrrolidinyl 
3-acetamidopyrrolidine 
10-hydroxy 
10-hydroxy 3-aminopyrrolidinyl 
3-acetamidopyrrolidine 
9-fluoro 9-fluoro 3-aminopyrrolidinyl 
3-methylacetamido- 
8,10-difluoro 
8,10-difluoro 
3-methylaminopyrrolidinyl 
pyrrolidine 
3-methylacetamido- 
9,10-methylenedioxy 
9,10-methylenedioxy 
3-methylaminopyrrolidinyl 
pyrrolidine 
3-methylacetamido- 
10-hydroxy 
10-hydroxy 3-methylaminopyrrolidinyl 
pyrrolidine 
3-methylacetamido- 
10-dimethylamino 
10-dimethylamino 
3-methylaminopyrrolidinyl 
pyrrolidine 
pyrrolidine 10-methoxy 
10-methoxy pyrrolidinyl 
3-dimethylamino- 
9,10-methylenedioxy 
9,10-methylenedioxy 
3-dimethylaminopyrrolidinyl 
pyrrolidine 
3-dimethylamino- 
8,10-difluoro 
8,10-difluoro 
3-dimethylaminopyrrolidinyl 
pyrrolidine 
20. 
3-hydroxypyrrolidine 
9-fluoro 9-fluoro 3-hydroxypyrrolidinyl 
piperidine 10-hydroxy 
10-hydroxy piperidinyl 
morpholine 10-chloro 10-chloro morpholinyl 
thiomorpholine 
10-methyl 10-methyl thiomorpholinyl 
N,N--dimethylhydrazine 
10-methoxy 
10-methoxy N,N--dimethylhydrazyl 
dimethylamine 
10-chloro 10-chloro dimethylamino 
homopiperazine 
8,10-difluoro 
8,10-difluoro 
homopiperazinyl 
2,6-dimethylpiperazine 
9,10-methylenedioxy 
9,10-methylenedioxy 
3,5-dimethylpiperazinyl 
__________________________________________________________________________ 
It will be understood that various changes and modifications can be made in 
the details of procedure, formulation and use without departing from the 
spirit of the invention, especially as defined in the following claims.