Derivatives of quinolinecarboxylic acid

Quinolinecarboxylic acid derivatives of the formula (I) ##STR1## and pharmaceutically acceptable salts thereof wherein R.sup.1 is hydrogen, straight or branch chain lower alkyl or phenyl unsubstituted or substituted by one or more halo moieties; R.sup.2 is hydrogen or straight or branch chain lower alkyl; and ##STR2## is a 5- or 6-membered ring wherein the nitrogen atom is the only heteroatom or where there is a second heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, said 5- or 6-membered ring being unsubstituted or substituted by lower alkyl, amino or mono- or di-lower alkyl amino are useful for treating bacterial infections in humans and animals.

The present invention is concerned with quinolinecarboxylic acid 
derivatives and pharmaceutically acceptable salts thereof which are useful 
for treating bacterial infections in humans and animals. 
Nalidixic acid, piromidic acid, pipemidic acid, enoxacin (AT-2266), 
ofloxacin (DL-8280), and the like are known in the art and have been 
widely used as synthetic antibacterial agents for the treatment of 
gram-negative bacteria infections. However, these substances are not 
satisfactory for the treatment of gram-positive bacterial infections nor 
are they satisfactory for the treatment of chronic infectious diseases 
caused by Pseudomonas aeruginosa. 
The present inventors have found quinolinecarboxylic acids to have 
antibacterial activity and have filed a Japanese Patent Application No. 
79993/1987 directed thereto. In that application, there is a disclosure 
that thiazetoquinolinecarboxylic acids in which there is a chlorine or 
bromine atom at the 8-position but there is no disclosure of 
thiazetoquinolinecarboxylic acids having a fluorine atom at the 8-position 
according to the instant invention. Although the 8-chloro and 8-bromo 
compounds exhibit good antibacterial activity, they have not proven to be 
fully satisfactory on administration to humans and animals. 
One of the objects of the present invention was to develop antibacterial 
agents having better antibacterial activity and lower toxicity than 
previously known antibacterial agents. 
More particularly, the present invention is concerned with 
quinolinecarboxylic acid derivatives of the formula (I) 
##STR3## 
and pharmaceutically acceptable salts thereof wherein R.sup.1 is hydrogen, 
straight or branch chain lower alkyl or phenyl unsubstituted or 
substituted by one or more halo moieties; R.sup.2 is hydrogen or straight 
or branch chain lower alkyl; and 
##STR4## 
is a 5- or 6- membered ring wherein the nitrogen atom is the only 
heteroatom or where there is a second heteroatom selected from the group 
consisting of nitrogen, oxygen and sulfur, said 5- or 6- ring being 
unsubstituted or substituted by lower alkyl, amino or mono- or di- lower 
alkyl amino. 
These novel compounds of the present invention are characterized by two 
novel aspects: 
1. A ring formed between the nitrogen atom and the sulphur atom in the 
2-mercaptoquinolone skeleton is thiazetidine; and 
2. The quinoline skeleton is substituted with fluoro and cyclic amine as 
above defined at the 8- and 7-positions, respectively. 
When R.sup.1 and/or R.sup.2 are alkyl moieties, they are preferably methyl, 
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl or tert-butyl. 
When the phenyl moiety of R.sup.1 is substituted by halogen, it may be 
substituted with one or more fluoro, chloro, bromo or iodo moieties. 
Fluoro substitution is particularly preferred. 
According to one embodiment of the present invention, R.sup.1 is hydrogen, 
straight or branch chain alkyl of 1 to 4 carbon atoms, phenyl or 
halophenyl. 
According to another embodiment of the present invention, R.sup.2 is 
hydrogen or straight or branch chain alkyl of 1 to 4 carbon atoms. 
According to a further embodiment of the present invention, 
##STR5## 
is pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino 
unsubstituted or substituted by straight or branch chain alkyl of 1 to 4 
carbon atoms, amino or mono- or di- alkyl amino wherein each alkyl moiety 
is straight or branch chain of 1 to 4 carbon atoms. 
According to a further embodiment of the present invention, R.sup.1 is 
hydrogen, straight or branch chain alkyl of 1 to 4 carbon atoms, phenyl or 
halophenyl; R.sup.2 is hydrogen or straight or branch chain alkyl of 1 to 
4 carbon atoms; and 
##STR6## 
is pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino 
unsubstituted or substituted by straight or branch chain alkyl of 1 to 4 
carbon atoms, amino or mono- or di- alkyl amino wherein each alkyl moiety 
is straight or branch chain of 1 to 4 carbon atoms. 
According to a further embodiment of the present invention, R.sup.1 is 
hydrogen, straight or branch chain alkyl of 1 to 4 carbon atoms, phenyl or 
fluorophenyl; R.sup.2 is hydrogen or straight or branch chain alkyl of 1 
to 4 carbon atoms; and 
##STR7## 
is pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino 
unsubstituted or substituted by straight or branch chain alkyl of 1 to 4 
carbon atoms, amino or mono- or di- alkyl amino wherein each alkyl moiety 
is straight or branch chain of 1 to 4 carbon atoms. 
According to a further embodiment of the present invention, the compound of 
formula (I) is in the form of a pharmaceutically acceptable salt. Suitable 
salts according to the present invention are salts with mineral acids such 
as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, 
hydrofluoric acid, hydrobromic acid and the like; salts with organic acids 
such as formic acid, acetic acid, tartaric acid, lactic acid, citric acid, 
fumaric acid, maleic acid, succinic acid, methanesulfonic acid, 
ethanesulfonic acid, benezenesulfonic acid, toluenesulfonic acid, 
naphthalenesulfonic acid, camphorsulfonic acid and the like; and salts 
with alkali metals or alkali earth metals such as sodium, potassium, 
calcium and the like. 
Preferred compounds, according to the present invention are those set forth 
in the examples below. 
##STR8## 
wherein R.sup.1 and 
##STR9## 
are as above defined; Y and Z are the same or different and each is halo; 
and R.sup.3 is alkyl, especially lower alkyl. 
##STR10## 
wherein R.sup.1, R.sup.3 and 
##STR11## 
Y and Z are as above defined in Method A. 
##STR12## 
in which R.sup.1, R.sup.3 and 
##STR13## 
are as above defined in Method A. 
##STR14## 
in which R.sup.1 and 
##STR15## 
are as above defined. 
As can be seen from the above procedures, the compounds of the present 
invention can be manufactured according to two techniques. 
One is that the quinolinecarboxylic acid in which the 7-position is 
substituted with a cyclic amino group is used as a starting material and 
the thiazetidine ring is produced therefrom (Methods A and B). The second 
is that after formation of the thiazetidine ring, the cyclic amino group 
is introduced into the 7-position (Methods C and D). Each method is 
further illustrated below. 
Method A: Compound (II) is reacted with a dihalide (e.g. methylene iodide, 
ethylidene bromide, benzylidene bromide, etc.) in an inert solvent in the 
presence of an acid removing agent (e.g. sodium carbonate, potassium 
carbonate, triethylamine, etc.) usually at 0.degree. to 120.degree. C. so 
that cyclization is carried out to give a compound (Ia). 
For solvents, aprotic ones such as N, N-dimethylformamide, 
N,N-dimethylacetamide, dimethyl sulfoxide, sulforan, etc.) are suitable. 
The amount of the dihalide and acid-removing agent is not less than 
equimolar to one mole of (II) and is preferably 1.1 to 2.5 moles. In order 
to accelerate the reaction, 0.01 to 3.0 molar equivalents of sodium iodide 
or potassium iodide may be added to the reaction system. 
Method B: Compound (II) is reacted with a halide (ZCH.sub.2 R.sup.1 wherein 
Z and R.sup.1 are as above defined) using the same solvent and 
acid-removing agent as in the method A usually at 0.degree. to 80.degree. 
C. to produce a compound (IV). 
Then compound (IV) is halogenated in an inert solvent (e.g. halogenated 
hydrocarbon type solvent such as chloroform, dichloromethane, carbon 
tetrachloride, etc.) using a halogenating agent (e.g. N-bromosuccinimide, 
N-chlorosuccinimide, etc.) to produce a compound (V). Compound (V) is then 
cyclized using the same solvent and acid removing agent as in method A 
usually at 0.degree. to 80.degree. C. to give (Ia). 
Method C: Condensation of compound (VI) with a cyclic amine gives a 
compound (Ia). This reaction is conducted in an inert solvent (e.g. 
aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, 
dimethyl sulfoxide, sulforan, acetonitrile, etc.) preferably in the 
presence of an acid removing agent (e.g. sodium carbonate, potassium 
carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, etc.) 
usually at 0.degree. to 80.degree. C., for example at 40.degree. to 
60.degree. C., using a cyclic amine as a reactant. The amount of the 
cyclic amine used is 1.5 to 2.5 moles to one mole of compound (VI). 
Method D: Compound (VI) is hydrolyzed with an acid (e.g. concentrated 
sulfuric acid, fuming sulfuric acid, polyphosphoric acid or a mixture 
thereof) to give a compound (VII). This reaction is conducted using an 
excess of acid as a solvent (one to 30 times as much by weight or, 
preferably, 5to 10 times as much) usually at 0.degree. to 60.degree. C. 
This hydrolyzing reaction may also be conducted in 20 to 30 times as much 
(preferably 5 to 10 times as much) 1% to 5% solution of potassium 
hydroxide or sodium hydroxide in aqueous alcohol (e.g. methanol, ethanol, 
propanol, butanol, etc.) usually at the temperature range of from room 
temperature to 60.degree. C. 
Then compound (VII) is reacted with a cyclic amine in the same solvent as 
in method C to give a compound (Ib). The reaction is usually conducted at 
0.degree. to 60.degree. C. though 0.degree. C. to room temperature is 
preferred. 
Other methods described below can be used. For example, a compound of the 
formula (VIII) can be used as a starting material: 
##STR16## 
wherein R.sup.1, R.sup.3 and 
##STR17## 
are as above defined in the Method A. 
Thus compound (VIII) is reacted with a dihalide in the presence of an acid 
removing agent (e.g. potassium carbonate) in an inert solvent (e.g. 
N,N-dimethylformamide, etc.). Then compound (IX) is subjected to a ring 
closure to give a compound (Ia). This ring closure reaction may be carried 
out by a method known per se such as, for example, by a method with 
heating or by a method using acidic substance such as phosphorus 
oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl 
chloride, fuming sulfuric acid, concentrated sulfuric acid, polyphosphoric 
acid, polyphosphate, etc. When an acid substance is used for example, one 
mole to great excess (preferably 20 to 30 moles) of acidic substance per 
mole of compound (IX) is used and the reaction temperature is usually 
0.degree. to 100.degree. C. or, preferably, from 0.degree. to 60.degree. 
C. 
Another method is that the thiazetidine ring is produced using 
6,7,8-trifluoro compounds as a starting material, subjecting them to ring 
closure and condensation with an amine in the same manner as in method C 
to give a compound (Ia). 
When a diamine such as piperazine is reacted in the above method, one 
nitrogen atom thereof may, if necessary, be protected by a method known 
per se and made to react with compound (VI) followed by removal of the 
protective group to give a desired compound having no substituent at the 
nitrogen. 
Moreover, a substituent may be introduced onto a nitrogen atom to the 
N-unsubstituted one by a known method per se to afford an N-substituted 
diamino compound. 
When the compounds prepared in accordance with the above method is an ester 
(R.sup.2 is alkyl), it may, if and when desired, be hydrolyzed to give the 
corresponding carboxylic acid (R.sup.2 is hydrogen). The hydrolysis can be 
conducted by the use of a great excess of acid (e.g. sulfuric acid, fuming 
sulfuric acid, hydrochloric acid, hydrobromic acid, hydrobromic 
acid/acetic acid, chlorosulfonic acid, polyphosphoric acid, etc.), 
preferably 10 to 20 times as much acid, as a solvent at the temperature of 
from room temperature to 110.degree. C. Alternatively, the hydrolysis may 
be conducted by stirring at the temperature of from room temperature to 
60.degree. C. in 2 to 30 times as much volume (preferably 5 to 10 times a 
much volume) of 1 to 5% solution of potassium hydroxide or sodium 
hydroxide in aqueous alcohol such as methanol, ethanol, propanol or 
butanol (preferably, tert-butanol). 
Further, the ester may be heated at 60.degree.-150.degree. C., preferably 
at 100.degree.-110.degree. C., with stirring in 10 to 100 times as much 
amount of alcohol corresponding to the desired ester in the presence of a 
catalytic amount of concentrated sulfuric acid so that the ester can be 
converted to desired another ester. 
In the case of a carboxylic acid (i.e. R.sup.2 is hydrogen), it can, if and 
when desired, be esterified to give desired ester (i.e. R.sup.2 is alkyl). 
This esterification reaction can be conducted by a method known per se 
such as, for example, by the use of thionyl chloride with alcohol, 
condensing agent (e.g. dicyclocarbodiimide) with alcohol, or alkyl halide 
with alcoholate. Furthermore, in the case of a carboxylic acid, it can be 
used in a form of pharmacologically-acceptable salt such as sodium or 
potassium salt. 
Both starting materials (II) and (VIII) are novel and such novel compounds 
can be manufactured by a known method (e.g. by a method disclosed in 
Japanese Laid Open 57/136588). 
Novel starting material (VI) will be described below in reference examples 
and may be manufactured in accordance with the above methods A and B. 
Cyclic amines are known substances and can be manufactured by a known 
method. 
Compound (I) as such can be isolated and purified by a method known per se 
such as, for example, concentration, pH conversion, transfer to another 
solvent, extraction with a solvent, crystallization, recrystallization, 
fractional distillation, chromatography, etc. 
When the compounds of the present invention are administered as 
pharmaceuticals, to humans and animals, they are given per se or as a 
pharmaceutical composition containing, for example, 0.1 to 99.5% (more 
preferably, 0.5 to 90%) of active ingredient in combination with a 
pharmaceutically acceptable carrier. 
The quinolinecarboxylic acid derivatives of the present invention may be 
given orally, parenterally, topically, or rectally. They are, of course, 
given by forms suitable for each administration route. For example, they 
are administered in tablet or capsule form, by injection, infusion, 
inhalation, eye lotion, ointment, suppository, etc. Administration may 
also be topical by lotion or ointment; and rectal by suppositories. Oral 
administration is preferred. 
As to carriers, one or more liquid, solid or semisolid diluent, filler and 
other auxillary agents for pharmaceutical preparations may be used. It is 
desired that the pharmaceutical compositions are administered in unit 
dosage form. 
Oral administration can be effected utilizing solid and liquid dosage unit 
forms such as powders, tablets, capsules, granules and the like. 
Powders are prepared by comminuting the compound to a suitable fine size 
and mixing with a similarly comminuted pharmaceutical carrier such as an 
edible carbohydrate as, for example, starch or mannitol. Flavoring, 
preservative, dispersing and coloring agents can also be present. 
Capsules are made by preparing a powder mixture as described above and 
filling formed gelatin sheaths. Glidants and lubricants such as colloidal 
silica, talc, magnesium stearate, calcium stearate or solid polyethylene 
glycol can be added to the powder mixture before the filling operation. A 
disintegrating or solubilizing agent such as agar-agar, calcium carbonate 
or sodium carbonate can also be added to improve the availability of the 
medicament when the capsule is ingested. 
Tablets are formulated, for example, by preparing a powder mixture, 
granulating or slugging, adding a lubricant and disintegrant and pressing 
into tablets. A powder mixture is prepared by mixing the compound, 
suitably comminuted, with a diluent or base as described above, and 
optionally, with a binder as carboxymethyl cellulose, an alginate, 
gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, 
a resorption accelerator such as a quarternary salt and/or an absorption 
agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture 
can be granulated by wetting with a binder such as syrup, starch paste, 
acadia mucilage or solutions of cellulosic or polymeric materials and 
forcing through a screen. As an alternative to granulating, the powder 
mixture can be run through the tablet machine and the resulting 
imperfectly formed slugs broken into granules. The granules can be 
lubricated to prevent sticking to the tablet forming dies by means of the 
addition of stearic acid, a stearate salt, talc or mineral oil. The 
lubricated mixture is then compressed into tablets. The compounds and 
pharmaceutically accetable acid addition salts of the present invention 
can also be combined with free flowing inert carriers and compressed into 
tablets directly without going through the granulating or slugging steps. 
A clear or opaque protective coating consisting of a sealing coat of 
shellac, a coating of sugar or polymeric material and a polish coating of 
wax can be provided. Dyestuffs can be added to these coatings to 
distinguish different unit dosages. 
Oral fluids such as solutions, syrups and elixirs can be prepared in dosage 
unit form so that a given quantity contains a predetermined amount of the 
compound. Syrups can be prepared by dissolving the compound in a suitably 
flavored aqueous solution, while elixirs are prepared through the use of a 
nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing 
the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as 
ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, 
preservatives, flavor additives such as peppermint oil or saccharin, and 
the like can also be added. 
Where appropriate, dosage unit formulations or oral administration can be 
microencapsulated. The formulation can also be prepared to prolong or 
sustain the release as for example by coating or embedding particulate 
material in polymers, wax or the like. 
Parenteral administration can be effected utilizing liquid dosage unit 
forms such as sterile solutions and suspensions intended for subcutaneous, 
intramuscular or intravenous injection. These are prepared by suspending 
or dissolving a measured amount of the compound in a nontoxic liquid 
vehicle suitable for injection such as aqueous or oleaginous medium and 
sterilizing the suspension or solution. Alternatively, a measured amount 
of the compound is placed in a vial and the vial and its contents are 
sterilized and sealed. An accompanying vial or vehicle can be provided for 
mixing prior to administration. Nontoxic salts and salt solutions can be 
added to render the injection isotonic. Stabilizers, preservatives and 
emulsifiers can also be added. 
Rectal administration can be effected utilizing suppositories in which the 
compound is admixed with low-melting, water-soluble or insoluble solids 
such as polyethylene glycol, cocoa butter, higher esters as for example 
flavored aqueous solution, while elixirs are prepared through myristyl 
palmitate or mixtures thereof. 
In determining the dosage for treating bacterial infections a number of 
factors such as the age of the patient, body weight, severity of 
condition, administration route, and the like must be considered. 
Generally, 50 to 1000 mg is administered per day for a human adult 
preferably 100 to 300 mg per day for a human adult orally. In some cases, 
a lower dose is sufficient and, in some other cases, a higher dose or more 
doses may be necessary. The administration may be once a day or divided 
among administration several times a day. 
It is preferred that the administration be divided so that it takes place 2 
or 3 times per day. 
The present invention will be more fully appreciated by