QUINOLINE ANTIBACTERIAL COMPOUNDS

Abstract: Quinoline compounds having the formula: wherein R is an phenyl group or an aromatic heterocyclic group, Z is an aliphatic heterocyclic group or an amine, and R₁ is hydrogen or a carboxy-protecting group. The compounds here disclosed have antibacterial properties.

Description: QUINOLINE ANTIRACTERIAL COMPOUNDS This application is a continuation-in-part of copending application Serial No. 574,227, filed January 26, 1984, which is a continuation-in-part of copending application Serial No. 514,716, filed July 18, 1983. This invention relates to new and useful quinoline derivatives having antibacterial properties, to compositions containing the new quinoline derivatives and to methods of treating mammalian patients with the new quinoline derivatives. It is known that certain 7-piperazinyl-4-oxo1,4-dihydroquinoline-3-carboxylic acids exhibit antibacterial properties. For example, U. S. Patent No. 4,017,622 discloses certain 7-piperazinyl-4-oxo-l,4- dihydroquinoline-3-carboxylic acid derivatives wherein the 1 position substituent is alkyl, benzyl or acetyl. U.S. Patent No. 4,292,317 discloses certain 7-piperazinyl-6-halo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivatives wherein the 1 position substituent is methyl, ethyl, vinyl or alkyl. In U.S. Patent No. 4,284,629, various 4-oxo-1,4-dihydroquinoline-3carboxylic acids are disclosed in which the 1 position substituent may be cycloalkyl, although corresponding derivatives containing a 7-piperazinyl substituent are not disclosed. While the compounds of the foregoing patents may be useful in certain respects, the search continues for new quinoline derivatives which have improved properties or are otherwise useful in the treatment of bacterial infections. The present invention relates to new 7-substituted 6-fluoro-1,4-dihydro-4-oxo-quinoline3-carboxylic acids or esters having a substituted or unsubstituted phenyl radical or an aromatic heterocyclic radical in the 1 position, to compositions of the new compounds together with pharmaceutically acceptable carriers, and to uses of the new compounds in the treatment of bacterial infections. The compounds of the invention can be represented by the following Formula I: EMI2.1 wherein R is selected from the group consisting of an aromatic heterocyclic ring containing 5 to 7 atoms therein, with the heterocyclic atom being at least one of S, o and N and the remaining atoms being carbon atoms; a phenyl group of the formula: EMI2.2 wherein R2 is one or more hydrogen, halogen, C1 to C4 alkyl including substituted derivatives thereof, a group having the formula -Y-R3 wherein -Y- is -O- or -S- and R3 is hydrogen or C1 to C4 alkyl, nitro, carboxyl, cyano, methylenedioxy and an amine having the formula: EMI2.3 wherein R4 and R5 are each independently hydrogen or C1 to C4 alkyl. R1 is hydrogen or a carboxy-protecting group. Z is an amino group having the formula: EMI2.4 wherein R6 is hydrogen or C1 to C10 alkyl as well as the corresponding substituted derivatives thereof, and R7 is alkyl or substituted alkyl as described above with reference to R6, or an amino group NH2, mono-(C1-C4) alkylamino or di(C1-C4) alkylamino. 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 "aromatic heterocyclic" refers to heterocyclic rings containing 5 to 7 atoms in the ring and containing 1 or 2 hetero atoms selected from the group consisting of S, 0 or N and the remaining atoms all being carbon atoms. Representative heterocyclic groups include pyridyl, pyrazinyl, thiazoyl, furyl, thienyl and sbustituted derivatives thereof. Substituents which may be present on the heterocyclic ring include C1 to C4 alkyl groups, halogen groups or a group of the formula -Y-R6 wherein Y is as described above and R3 is hydrogen or C1 to C4 alkyl. As used herein, the term "halogen" refers to chloro, bromo, fluoro and iodo groups, while the term "C1 to C4 alkyl" refers to lower alkyl groups including methyl, ethyl, propyl, isopropyl, butyl. As indicated above, R2 can be straight or branched chain C1 to C4 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. R2 can also be a group of the formula -Y-R3. Representative groups of this type include a hydroxy group, a mercapto group, a lower alkoxy group, such as methoxy, ethoxy, propoxy, etc., as well as the thio analogs thereof 1 namely a methylmercapto group, 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. Patent 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. The aliphatic heterocyclic rings representing 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, 0 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: EMI4.1 wherein R8 is selected from the group consisting of dimethylene and a group of the formula -CH2-R9-CH2- wherein Rg is selected from the group consisting of -S-, -0-, -N- and -CH2-. Also included are substituted derivatives of such heterocyclic rings wherein the substituent is one or more of a C1 to C4 alkyl group, an amine group having the formula: EMI4.2 wherein R10 and R11 are each independently selected from the group consisting of hydrogen, C1 to C4 alkyl, C1 to C4 hydroxyalkyl, hydroxy, alkanoyl containing 1 to 4 carbon atoms and alkanoylamido containing 1 to 4 carbon atoms. Illustrative of such heterocyclic groups are azetidinyl groups, piperazinyl groups, piperidinyl groups, piperazinyl groups, piperidinyl groups, pyrrolidinyl groups, morpholino groups, thiomorpholino groups, and homopiperazinyl groups (i.e., hexahydro-1-H-l, 4-diazepin). The preferred compounds of the present invention are those having the formula: EMI5.1 wherein R is phenyl or substituted phenyl wherein the substituent on the phenyl group is one or more of alkyl, halogen, methylenedioxy, or hydroxy, R1 is as described above1 preferably hydrogen, and Z is piperazinyl, substituted piperazinyl or substituted pyrrolidinyl as described above. Representative of such preferred compounds include l-phenyl-6-fluoro-1, 4-dihydro-4-oxo-7- (l-piperazinyl)-quinoline-3-carboxylic acid, 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl) piperazinyl)-quinoline-3-carboxylic acid, l-p-fluoro- phenyl-6-fluoro-1,4-dihydro-4-oxo-7" piperazinyl)- quinoline-3-carboxylic acid, l-p-fluorophenyl-6-fluoro- 1,4-dihydro-4-oxo-7-(1(4-methyl)-piperazinyl)-quinoline-3- carboxylic acid, l-p-bromophenyl-6-fluoro-l, 4-dihydro- 4-oxo-7-(l-piperazinyl)-quinoline-3-carboxylic acid, l-p-hydroxyphenyl-6-fluoro-l, 4-dihydro-4-oxo-7- (1- piperazinyl)-quinoline-3-carboxylic acid, 1-(2,4- difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1piperazinyl)-quinoline-3-carboxylic acid, l-p-fluoro phenyl-6-fluoro-l,4-dihydro-4-oxo-7-( l-(4-acetyl)- piperazinyl)-quinoline-3-carboxylic acid, l-p-fluoro phenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrroli- dinyl)-quinoline-3-carboxylic acid, l-p-fluorophenyl-6 fluoro-1,4-dihydro-4-oxo-7-(3-methylamino-1-pyrrolidinyl)- quinoline-3-carboxylic acid, l-p-fluorophenyl-6-fluoro1,4-dihydro-4-oxo-7-(3-dimethylamino-1-pyrrolidinyl)quinoline-3-carboxylic acid and l-(2,4-difluorophenyl)- 6-fluoro-1,4-dihydro-4-oxo-7-(3-dimethylamino-1-pyrro- lidinyl)-quinoline-3-carboxylic acid. As used herein, the term "pharmaceutically acceptabe salts" means the nontoxic acid addition or alkaline earth metal salts of the compounds of Formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, or by separately reacting the base or acid functions with a suitable organic or inorganic acid or base, respectively. Representative acid addition salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napsylate, glucoheptonate, lactobionate, lauryl sulfate salts and the like. Representative alkali metal or alkaline earth metal salts include the sodium, calcium, potassium, and magnesium salts, and the like. It has been found that the preferred compounds of the invention possess antibacterial activity against a wide spectrum of gram positive and gram negative bacteria. 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 may be used in scrub solutions, for surface inhibition of bacterial growth, e.g., on counter surfaces, and the like. Susceptible organisms generally include those gram positive and gram negative, aerobic and anazerobic 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, Baccullus, 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 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 in normal practice, additional substances other than inert 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 elixirs 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 desired1 the daily dose may be divided into multiple doses for administration, e.g., two to four times per day. The compounds of Formula I may be prepared in accordance with the following reaction scheme: EMI9.1 In accordance with the foregoing reaction scheme, 2,4-dichloro-5-fluoro-acetophenone (1) is reacted with a dialkoxycarbonate (2) in the presence of a strong base ot obtain the corresponding B-ketoester (3). In the dialkyoxcarbonate (2), R6 may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably lower alkyl, such as ethyl. Suitable bases include the metal hydrides, such as sodium hydride, potassium hydride and the like, as well as metal alkoxides in alcohol, such as sodium ethoxide in ethanol. The presently preferred base for this purpose is sodium hydride. Formation of the B-ketoester (3) is facilitated by reacting the acetophenone (1) with the dialkoxycarbonate (2) at elevated temperatures, such as from about 20 0C to about 120 0C, and preferably from about 30 0C to about 90 0C until completion of the reaction. The B-ketoester may then be separated from the reaction mixture in a conventional manner. The B-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 aniline or other aromatic heterocyclic amine (5) to obtain the enaminoketoester (6). In the trialkylorthoformate (4), R7 may be an alkyl group of, for example, from 1 to 10 carbon atoms, but is preferably lower alkyl, such as ethyl. Reaction with the trialkylorthoformate is preferably conducted at elevated temperatures, such as from about 500C to about 150 0C, preferably from about 1000C to about 140 0C, to obtain an oily liquid as an unisolated intermediate (shown in brackets in the reaction scheme). Reaction of the latter with the substituted or unsubstituted aniline or aromatic heterocyclic amine (5) is preferably conducted in an appropriate aprotic on 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 l-aryl-1,4dihydro-4-oxo-quinoline-3-carboxylic acid ester (7). Cyclization is conducted in the presence of an aprotic solvent, such as dimethoxyethane, dimethylformamide, tetrahydrofuran or chlorobenzene, and is preferably conducted at temperatures of about 200C to about 1450C, more preferably at the reflux temperature of the solvent employed. The ester (7) is subjected to hydrolysis, such as by treatment with sodium hydroxide, to form the free acid, followed by displacement of the 7-chloro radical with substituted or unsubstituted piperazine or other heterocyclic amines (8) as described above by techniques known in the art to obtain the desired l-aryl-6-fluoro-7-substituted amino-1,4-dihydroxy-4-oxo-quinoline-3-carboxylic acid (9). The l-aryl-6-fluoro-7-substituted amino-l, 4- dihydro-4-oxo-quinoline-3-carboxylic acid (9) can then be converted into the corresponding ester (10), if desired, by conventional esterification procedures, such as by treating the free acid (9) with the appropriate alcohol in the presence of an acid catalyst, by converting the free acid (9) into the corresponding acid chloride followed by displacement of the chloro radical with the appropriate alcohol, or by treating thed sodium salt of the acid (9) with a suitable reactive halide, such as chloro-methylpivalate in dimethoxyethane to obtain, for example, the pivaloyloxymethyl ester (1) wherein R2 is -CH20COC(CH3)3. 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 subiturnts, such as R, R1, R2, etc., refer to the correspondings and substituents in the foregoing scheme. Example 1 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-piperazinyl) quinoline-3-carboxylic acid a) To a cold solution of 20.5 g. 2,4-dichloro 5-fluoroacetophenone in 300 ml. diethylcarbonate is slowly added 8.2 9.608 sodium hydride-in-oil suspension. The mixture is heated at 800C for 1-1/2 hours, then poured into 700 ml. ice cold water solution containing 25 ml. acetic acid. The mixture is extracted with three 400 ml. portions of ether. The organic phase is dried over MgSO4, evaporated and the obtained liquid is distilled at 111 C at 0.7 mm. of Hg. pressure to give 22.2 g. of (3) wherein R6=C2H5. b) A solution of 15.18 g. of B-ketoester (3) (R6-C2H5) in 14 ml. of triethylorthoformate and 35 ml. of acetic anhydride is heated at 1350C for 1-1/2 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 150 ml. of methylene chloride and 7.5 ml. of aniline 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 R6"C2H5 and R"phenyl in 898 yield, m.p. 96-970C. c) To a cold solution of 13.9 g. of the preceding product (6), R6-CR5, R=phenyl in 140 ml. dimethoxymethane (DME) is slowly added 1.49 g. of a 60% sodium hydride-in-oil suspension. The mixture is refluxed for 4-1/2 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 10.4 g. of (7) wherein R6sC2H5 and R"phenyl in 811 yield. d) To a suspension of 5.4 9. of (7) (R6-C2R5, R"phenyl) in 30 ml. THF is added a sodium hydroxide solution (0.73 g. in 20 ml. H20). The mixture is heated at 800C for 1 hour resulting in a clear solution which is evaporated under reduced pressure to dryness. The solid is dissolved in 200 ml. H2O, and 2 ml. acetic acid is added. The resulting precipitate is filtered and washed with cold water, crystallized from dimethylformamide (DMF) to produce 4.6 g. of 7-chloro-l- phenyl-6-fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid (7) (R6-hydrogen, R-phenyl), m.p. 271-273 C. e) To a solution of 1.25 g. of 7-chloro-l phenyl-6-fluoro-l, 4-dihydro-4-oxo-quinol ine-3-carboxylic acid in 15 ml. of l-methyl-2-pyrrolidinone at 115 C is added 2 ml. piperazine. After stirring at 1000C 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. The resulting dried solid is suspended in 30 ml. H20 and 2.35 ml. 1N HCl is added to and warmed to dissolve. Removal of the solvent under reduced pressure gives 835 mg. hydrochloride salt of l-phenyl-6-fluoro-l, 4-dihydro-4-oxo-7- (1-pi quinoline-3-carboxylic acid (9) (R-phenyl, EMI13.1 To the hydrochloride salt is added one molar equivalent of an aqueous solution of sodium hydroxide, and the resulting precipitate is filtered to obtain l-phenyl-6fluoro-l,4-dihydro-4-oxo-7-(l-piperazinyl)quinoline-3carboxylic acid. f) Alternately, the title compound is prepared as follows: To a suspension of 5.87 g. of compound (7) (R6sH,Rsphenyl; product of 1(d)) in 40 ml. l-methyl-2pyrrolidinone at 1200C under nitrogen atmosphere i'8 added 9.5 ml. of N-carboethoxy-p-perazine. 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 6.15 g. of compound (9) (R=phenyl, Z=-N N-COC2H5) in 87% yield. ethanol at 80 C is added 50 ml. of 10% NaOH solution. The solution is heated at 80 0C 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 4.26 of l-phenyl-6-fluoro-l,4 dihYdro-4-oxo-7-(1-PiPerazinYl)quinoline-3-carboxylic acid (9) (R-phenyl, EMI14.1 Example 2 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid The procedure of Example 1 can be repeated, replacing piperazine in Example l(e) with N-methylpiperazine to obtain l-phenyl-6-fluoro-l,4-dihydro-4-oxo- 7(1-(4-meth EMI14.2 ,inyl)-quinoline-3-carboxylic acid (9) (R=pbenyl, and its hydrochloride salt. To a suspension of 5.5 g, of the preceding compound (9) (R=phenyl, EMI14.3 in 25 ml. of ExamPle 3 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-ethyl)-piperazinyl)quinoline-3-carboxylic acid The procedure of Example 1 can be repeated, replacing piperazine in Example 1 (e) with N-ethylpiperazine to obtain the 1-phenyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-(4-ethyl EMI15.1 -quinoline-3-carboxylic acid (9) (R-phenyl, and its hydrochloride salt. Example 4 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4 oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with p-fluoroaniline, one can obtain the enaminoketoester (6) (R6-C2H5, R=p-fluorophenyl) in 78% yield, m.p. 108 C. b) By following the Example 1(c) and l(d), the preceding compound (6) (R6=C2E5, R-p-Eluorophenyl) can yield 7-chloro-1-p-fluorophenyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid (7) (R6=H, R=p-fluoro- phenyl). c) In the described fashion as Example l(e), the above acid (7) (R6-H, R=p-fluorophenyl) can give the desired 1-p-fluoro-phenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-piperazinyl)quinoline-3-carboxylic acid (9) EMI15.2 R=p-fluorophenyl) and its hydrochloride salt. ExamPle 5 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4oxo-7(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example 1(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, Rsp-fluorophenyl in Example 4(b) can yield the described l-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI16.1 R=p-fluorophenyl and its hydrochloride salt. Example 6 1-p-chlorophenyl-6-fluoro-1,4-dihydro 4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with p-chloroaniline, one can obtain the enaminoketoester (6) (R6wC2H5, R-p-chlorophenyl) in 64% yield. b) By following Example 1(c) and l(d), the preceding compound (6) (R6-C2H5, R=p-chlorophenyl) can yield 7-chloro-1-p-chlorophenyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid (7) (R6=H, R-p-chlorophenyl). c) In the described fashion as Example l(e), the above acid (7) (R6=H, R-p-chlorophenyl) can give the described 1-p-chloro-phenyl-6-fluoro-1,4-dihydro-4-oxo-7 (piperazinyl) quinoline-3-carboxylic acid (9) EMI16.2 R-p-chlorophenyl) and its hydrochloride salt. Example 7 1-p-chlorophenyl-6-fluoro-1,4-dihydro-4-oxo7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example 1(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, R-p-chlorophenyl) in Example 6(b) can yield the desired l-p-chlorophenyl-6-fluoro-l,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI17.1 Rap-chlorophenyl) and its hydrochloride salt. Example 8 1-p-methoxyphenyl-6-fluoro-1,4-dihydro 4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example l(b), replacing aniline with p-methoxyaniline, one can obtain the enaminoketoester (6) (R6XC2H5, R=p-OCH3-phenyl) in 77% yield (m.p. 1050C). b) By following the Example l(c) and l(d), the preceding compound (6) (R6wC2H5, R-p-methoxyphenyl) can yield 7-chloro-l-p-methoxyphenyl-6-fluoro-l,4-dibydro- 4-oxo-quinoline-3-carboxylic acid (7) (R6=H, R=p-methoxyphenyl). c) In the described fashion as Example 1(e), the above acid (7) (R6-H, R=p-methoxyphenyl) can give the desired l-p-methoxyphenyl-6-fluoro-l,4-dihydro-4-oxo7-(1-piperazinyl)-quinoline-3-carboxylic acid (9) EMI17.2 R-p-methoxyphenyl) and its hydrochloride salt. Example 9 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example l(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, R=p-methoxyphenyl) in Example 8(b) can yield the described 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(melthYl)-Piperazinyl)quino line-3-carboxylic acid (9) EMI18.1 R=p-methoxyphenyl and its hydrochloride salt. Example 10 1-p-methylphenyl-6-fluoro-1,4-dihydro-4-oxo 7-(piperazinyl)quinoline-3-carboxylic acid a) In 'the described fashion as Example l(b), replacing aniline with p-methylaniline, one can obtain the enaminoketoester (6) (R6=C2H5, R=p-methylphenyl) in 80% yield (m.p. 115.50C). b) By following the Example l(c) and l(d), the preceding compound (6) (R6=C2H5, R=p-methylphenyl) can yield 7-chloro-1-p-methylphenyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid (7) (R6=H, R=p-methylphenyl). c) In the described fashion as Example l(e), the above acid (7) (R6H, R=p-methylphenyl) can give the desired 1-p-methylphenyl-6-fluoro-1,4-dihydro-4-oxy-7 (l-piperazinyl)-quinoline-3-carboxylic acid (9) EMI18.2 R=p-methylphenyl) and its hydrochloride salt. Example 11 1-p-methylphenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example 1(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, R-p-methylphenyl) in Example 10(b) can yield the desired l-p-methylphenyl-6-fluoro-l,4-dihydro-4-oxo 7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxyulic acid (9) EMI19.1 R=p-methylphenyl) and its hydrochloride salt. Example 12 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro 4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with p-hydroxyaniline, one can obtain the enaminoketoester (6) (R6-C2H5, R-p-hydroxyphenyl) in 84% yield, b) By following the Example 1(c) and 1(d), the preceding compound (6) (R6aC2H5, Rnp-hydroxyphenyl) can yield 7-chloro-1-p-hydroxyphenyl-6-fluoro-1,4-dihydro4-oxo-quinoline-3-carboxylic acid (7) (R6MH, R=p-hydroxy- phenyl) in good yield. c) In the described fashion as Example ilex, the above acid (7) (R6-H, R-p-hydroxyphenyl) can give the desired 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7 (l-piperazinyl)-quinoline-3-carboxylic acid (9) EMI19.2 R-p-hydroxyphenyl) and its hydrochloride salt. Example 13 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo7(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example l(e), replacing piperazine with N-methylpiperazine, the acid (7)(R6=, R=p-hydroxyphenyl) in Example 12(b) can yield the desired l-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI20.1 R=P-hydroxyphenyl) and its hydrochloride salt. Example 14 1-o-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo (1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with o-fluoroaniline, one can obtain the enaminoketoester (7) (Rg=C2H5, R=o-fluorophenyl) in 78.8% yield (m.p. 90-92 C). b) By following the Example l(c) and l(d), the preceding compound (6) (R6=C2H5, R=o-fluorophenyl) can yield 7-chloro-1-o-fluorophenyl-6-fluoro-1,4-dihydro4-oxo-quinoline- 3-carboxylic acid (7) (R6=H, R=o-fluorophenyl). c) In the described fashion as Example l(e), the above acid (7) (R6=H, R=o-fluorophenyl) can give the desired 1-o-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7 (l-piperazinyl)-quinoline-3-carboxylic acid (9) EMI20.2 R=o-fluorophenyl) and its hydrochloride salt. Example 15 1-o-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo 7(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example 1(e), replacing piperazine with N-mothylpiperazine, the acid (7) tac-R, R-o-fluorophenyl) in Example 14(b) can yield the desired 1-o-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI21.1 R.o-fluorophenyl) and its hydrochloride salt. Example 16 1-m-fluorophenyl-6-fluoro-1,4-dihydro 4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with m-fluoroaniline, one can obtain the enaminoketoester (6) (R6iC2M5, R=m-fluorophenyl) in 68.5% yield (m.p. 103-104 C). b) By following the Example 1(c) and 1(d), the preceding compound (6) (R6=C2H5, R=m-fluorophenyl) can yield 7-chloro-l-m-fluorophenyl-6-fluoro-l,4-dihydro-4oxo-quinoline-3-carboxylic acid (7) (R6IH, R=m-fluoro- phenyl). c) In the described fashion as Example 1(e), the above acid (7) tR6"H, R=m-fluorophenyl) can give the described 1-m-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo7-(1-piperazinyl)-quinoline-3-carboxylic acid (9) EMI21.2 R-m-fluorophenyl) and its hydrochloride salt. Example 17 1-p-cyanophenyl-6-fluoro-1,4-dihydro 4-oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with p-cyanoaniline, one can obtain the enaminoketoester (6) (R6"C2H5, R-p-cyanophenyl) in 91.2% yield. b) By following the Example l(c) and l(d), the preceding compound (6) (R6=C2H5, R=p-cyanophenyl) can yield 7-chloro-1-p-cyanophenyl-6-fluoro-1,4-dihydro-4-oXo- quinoline-3-carboxylic acid (7) (R6=H, R=p-cyanophenyl). c) In the described fashion as Example l(e), the above acid (7) (R6=C2H5, R=p-cyanophenyl) can give the desired 1-p-cyanophenyl-6-fluoro-l, 4-dihydro-4-oxo-7- (l-piperazinyl)-quinoline-3-carboxylic acid (9) EMI22.1 R=p-cyanophenyl) and its hydrochloride salt. Example 18 1-p-cyanophenyl-6-fluoro-l, 4-dihydro-4-oxo- 7-(1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example l(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, R=p-cyanophenyl) in example 17(b) can yield the describedl-p-cyanophenyl-6-fluoro-1,4-aihydro-4-oXo-7- (l-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI22.2 R=p-cyanophenyl) and its hydrochloride salt. Example 19 1-4-pyridyl-6-fluoro-1,4-dihydro-4-oxo (1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example l(b), replacing aniline with 4-aminopyridine, one can obtain the enaminoketoester (6) (R6=C2H5), R-4-pyridyl) in 70% yield as oil. b) By following the Example l(c) and l(d), the preceding compound (6) (R63C2H5, R=4-pyridyl) can yield 7-chloro-l-(4-pyridyl) -6-fluoro-l,4-dihydro-4-oxo-quinoline- 3-carboxylic acid (7) (R6=H, R=4-pyridyl). c) In the described fashion as Example 1(e), the above acid (7) (R6=H, R=4-pyridyl) can give the desired 1-4-pyridyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)- quinoline-3-carboxylic acid (9) (R=4-pyridyl, EMI23.1 and its hydrochloride salt. Example 20 1-4-pyridyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example l(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6xH, R=4-pyridyl) in Example 19(b) can yield the desired 1-4-pyridyl-6-fluoro-1,4-dihydro-4-oxo-4-(1 (4-methyl)-piperazinyl)quinoline-3-carboxylic acid (9) EMI23.2 R=4-pyridyl). Example 21 1-3-pyridyl-6-fluoro-1,4-dihydro-4 oxo-(1-piperazinyl)quinoline-3-carboxylic acid a) In the described fashion as Example 1(b), replacing aniline with 3-aminopyridine, one can obtain the enaminoketoester (6) (R6=C2H5, R-3-pyridyl) in 80% yield. b) By following the Example 1(c) and 1(d), the preceding compound (6) (R6sC2H5, R-3-pyridyl) can yield 7-chloro-1-(3-pyridyl)-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (7) (R6aH, R-3-pyridyl). c) In the described fashion as Example 1(e), the above acid (7) (R6=H, R=3-pyridyl) can give the desired 1-(3-pyridyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid (9) (R-3-pyridyl, EMI24.1 and its hydrochloride salt. Example 22 1-3-pyridyl-6-fluoro-1,4-dihydro-4-oxo-7 (1-(4-methyl)-piperazinyl)quinoline-3-carboxylic acid In the described fashion as Example 1(e), replacing piperazine with N-methylpiperazine, the acid (7) (R6-H, R=3-pyridyl) in Example 21(b) can yield the desired 1-3-pyridyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-(4methyl)-piperazinyl)quinoline-3-carboxylic acid in good yield (9) EMI24.2 R-3-pyridyl). Example 23 In similar fashion as Example 1, the use of various substituted anilines and other amino aromatic compounds in place of aniline and the use of appropriate N-substituted piperazine, the following additional compounds and their hydrochloride salts can be made as summarized in Table I. Table I Aniline Piperazine Compound (9) Obtained Replacement Substituent 1. p-nitroaniline CH3 N-methyl- p-nitrophenyl piperazinyl 2. p-nitroaniline H piperazinyl p-nitrophenyl 3. p-dimethylamino- H piperazinyl p-dimethyl aniline aminophenyl 4. p-aminobenzoic acid H piperazinyl p-carboxylphenyl 5. p-trifluoro methylaniline H piperazinyl p-trifluoro methylphenyl 6. 2,4-difluoro aniline H piperazinyl 2,4-difluorophenyl 7. 2,4-difluoro- N-methyl aniline CH3 piperazinyl 2,4-difluoro phenyl 8. 2-chloro-4- 2-chloro fluoroaniline H piperazinyl 4-fluorophenyl 9. 2-fluoro-4- 2-fluoro hydroxyaniline H piperazinyl 4-hydroxyphenyl 10. 3 ,4-methylene- dioxyaniline H piperazinyl p-fluorophenyl 11. 2,4-dihydroxy aniline H piperazinyl 2,4-hydroxyphenyl 12. p-methylmercapto- N-methyl- p-methyl aniline CH3 piperazinyl mercapto 13. p-methylmercapto- p-methyl aniline H piperazinyl mercapto 14. 3-fluoro-4- 3-fluoro-4 hydroxyaniline H piperazinyl hydroxyphenyl 15. 3-chloro-4- 3-chloro-4 hydroxyaniline H piperazinyl hydroxyphenyl 16. 3,4-methylene- 3, 4-methylene- dioxyaniline H piperazinyl dioxyphenyl 17. 3,4-methylene- N-methyl- 3,4-methylene dioxyaniline H piperazinyl dioxyphenyl Example 24 In similar fashion to that described in Example 1, the use of various heterocyclic amines in place of aniline and the use of appropriate N-substituted piperazines can result in the following additional compounds and their hydrochloride salts as summarized in Table II. Table II Aniline Piperazine Compound (9), Obtained Replacement Substituent Z R 1. 4-aminopyridine- 4-N-oxide N-oxide H piperazinyl pyridinyl 2. 3-pyrazine H piperazinyl 3-pyrazinyl 3. 3-pyrazine CH3 N-methyl- 3-pyrazinyl piperazinyl 4. 2-aminothiazole H piperazinyl 2-thiazolyl 5. 1,2,4-triazole H piperazinyl triazolyl 6. 3-aminofuran H piperazinyl 3-furyl 7. 3-aminothiophene H piperazinyl 3-thienyl Example 25 1-p-fluorophenyl-6-fluoro-1,4-dihydro 4-oxo-7-thiomorpholino-quinoline-3-carboxylic acid To a solution of 3.36 g. of 7-chloro-l-p-fluoro phenyl-6-fluoro-l, 4-dihydro-4-oxo-quinol ine-3-carboxylic acid (the product of Example 4(b)) in 35 ml. of l-methyl2-pyrrolidinone at 1150C is added 4.13 g. of thiomorpholine. After stirring at 1150C for 20 hours, the solvent is removed by reduced pressure to dryness. Methanol is added to the residue and the resulting mixture is filtered and washed with ethylacetate and then washed with water. The solid is dried, yielding 2.51 g. l-p- fluorophenyl-6-fluoro-l, 4-dihydro-4-oxo-7-thiomorpholino- quinoline-3-carboxylic acid (9) EMI29.1 R=p-fluorophenyl) in 62% yield. Example 26 1-phenyl-6-fluoro-1,4-dihydro-4-oxo 7-thiomorpholino-quinoline-3-carboxylic acid The procedure of Example 25 can be repeated, replacing the 7-chloro-l-p-fluorophenyl-6-fluoro-1,4- dihydro-4-oxo-quinoline-3-carboxylic acid with 7chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline3-carboxylic acid to obtain l-phenyl-6-fluoro-l,4 dihydro-4-oxo-7-thiomorpholino-cruinoline-3-carboxvlic acid (9) EMI29.2 R=phenyl). Example 27 1-p-methoxyphenyl-6-fluoro-1,4-dihydro-4-oxo 7-thiomorpholino-quinoline-3-carboxylic acid In the described fashion as Example 25, replacing the 7-chloro-1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oXo- quinoline-3-carboxylic acid with 7-chloro-1-p-methoxy- phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, one can obtain the l-p-methoxyphenyl-6-fluoro-l,4-di- hydro-4-oxo-7-thiomorphol ino-quinoline-3-carboxylic acid (9) EMI30.1 R"p-methoxyphenyl). Example 28 1-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo 7-thiomorpholino-quinoline-3-carboxylic acid The procedure of Example 25 can be repeated, replacing the 7-chloro-1-p-fluorophenyl-6-fluoro-1,4dihydro-4-oxo-quinoline-3-carboxylic acid with 7-chloro l-p-hydroxy-phenyl-6-fluoro-l, 4-dihydro-4-oxo-quinoline- 3-carboxylic acid to obtain l-p-kydroxyphenyl-6-fluoro- 1,4-dihvdro-4-oxo-7-thiomorDholino-auinoline-3-carboXvlic acid (9) EMI30.2 R-p-hydroxyphenyl). Example 29 1-phenyl-6-fluoro-1,4-dihydro-4-oxo 7-morpholino-suinoline-3-carboxvlic acid To a solution of 2.5 g. of 7-chloro-l-phenyl-6 fluoro-l,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 30 ml. of l-methyl-2-pyrrolidinone at 1150C is added in 4 ml. of morpholine. After stirring at 1150C for 20 horse the solvent is removed by reduced pressure to dryness. Ethanol is added to the residue and the resulting mixture is filtered and washed with ethanol and then water. The solid is dried, yielding 1.98 g. l-phenyl-6-fluoro-l,4-dihydro-4- oxo-7-morpholino-quinoline-3-carboxylic acid (9) EMI31.1 R-phenyl). Example 30 l-p-fluorophenyl-6-fluoro-l, 4-dihydro-4-oxo- 7-morpholino-quinoline-3-carboxylic acid The procedure of Example 29 can be repeated, replacing the 7-chloro-l-phenyl-6-fluoro-1,4-dihydro-4 oxo-quinoline-3-carboxylic acid with 7-chloro-l-p-fluoro- phenyl-6-fluoro-l, 4-dihydro-4-oxo-quinol ine-3-carboxylic acid to obtain l-p-fluorophenyl-6-fluoro-1,4-dihydro-4oxo-7-morpholino-quinoline-3-carboxylic acid (9) EMI31.2 R=p-fluorophenyl). Example 31 l-p-hydroxyphenyl-6-fluoro-l, 4-dihydro-4-oxo- 7-morpholino-suinoline-3-carboxylic acid In the described fashion as Example 29, replacing the 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxo-quinoline- 3-carboxylic acid with 7-chloro-l-p-hydroxyphenyl-6-fluoro- 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, one can obtain the l-p-hydroxyphenyl-6-fluoro-l, 4-dihydro-4-oxo- 7-morpholino-quinoline-3-carboxylic acid (9) EMI31.3 R=p-hydroxyphenyl). Example 32 l-phenyl-6-fluoro-l,4-dihydco-4-oxo- 0-4-5xo- 7-(3-amino-l-evrrolidinyl)suinolne-3-ca acid (a) To a solution of 1.5 g. of 7-chloro-l-phenyl6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid in 20 ml. of l-methyl-2-pyrrolidinone at 1150C is added 3 g. of 3-acetamido-pyrrolidine. After stirring at 1000C. for 20 hours, the solvent is removed by reduced pressure to dryness. Ethanol is added to the residue and washed with ether and then diluted cold hydrochloric acid and then water. The solid is dried, yielding 1.60 g. l-phenyl-6fluoro-1,4-dihydro-4-oxo-7-(3-acetamido-1-pyrrolidinyl)quinoline-3-carboxylic acid (9) EMI32.1 R-phenyl). (b) The above product is then hydrolysed with hydrochloric acid at 80 0C to give l-phenyl-6-fluoro 1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinoline- 3-carboxylic acid (9) hydrochloride salt. EMI32.2 R=phenyl) Example 33 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo 7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid In the described fashion as Example 32, replacing the 7-chloro-l-phenyl-6-fluor o-l, 4-dihydro-4-oxo-quinol ine- 3-carboxylic acid with 7-chloro-l-p-fluorophenyl-6-fluoro1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, one can obtain the 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7 (3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid hydrochloride salt (9) EMI32.3 R=p-fluorophenyl) in good yield. Example 34 l-p-hydroxyphenyl-6-fluoro-1,4-dihydro-4-oxo- 7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid In the described fashion as Example 32, replacing the 7-chloro-l-phenyl-6-fluoro-l,4-dihydro-4-oxo-quinoline3-carboxylic acid with 7-chloro-l-p-hydroxyphenyl-6-fluoro1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, one can obtain the l-p-hydroxyphenyl-6-fluoro-l,4-dihydro-4-oxo-7- (3-amino-l-pyrrolidinyl)quinoline-3-carboxylic acid hydrochloride salt (9) EMI33.1 R=p-hydroxyphenyl) in good yield. Example 35 l-o,p-difluorophenyl-6-fluoro-1,4-dihydro-4-oXo- 7- (3-amino-l-pyrrolidinyl)quinoline-3-carboxylic acid In the described fashion as Example 32, replacing the 7-chloro-l-phenyl-6-fluoro-l , 4-dihydro-4-oxo-quinoline3-carboxylic acid with 7-chloro-1-o, p-dihydrophenyl-6-fluoro1,4-dihydro-4-oxo-quinoline-3-carboxylic acid, one can obtain the l-o, p-difluorophenyl-6-fluoro-l , 4-dihydro-4-oxo- 7-(3-amino-1-pyrrolidinyl)quinoline-3-carboxylic acid and its hydrochloride salt (9) EMI33.2 R=2, 4-difluorophenyl). Example 36 l-p-fluorophenyl-6-fluoro-l , 4-dihydro-4-oxo- 7-(3-dimethylamino-1-pyrrolidinyl)quinoline-3-carboxylic acid The procedure of Example 25 can be repeated, replacing thiomorpholine with 3-dimethylamino pyrrolidine to obtain 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7-(3-dimethylaminol-pyrrolidinyl)quinoline-3-carboxylic acid and its hydrochloride salt (9) EMI33.3 R=4-fluorophenyl). Example 37 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4-oxo-7 (3-methylamlno-l-pyrrolidinyl)quinoline-3-carboxZllc acid a) The procedure of Example 36 can be repeated, replacing 3-dimethylamino pyrrolidine with 3-N-methylacetamidopyrrolidine to obtain 1-p-fluorophenyl-6-fluoro-1,4-dihydro-4- oxo-7- (3-N-methylacetamidopyrrolidinyl) quinoline-3-carboxylic acid (9) EMI34.1 R-4-fluorophenyl). b) The above product is then hydrolyzed with hydrochloric acid at 800C to give 1-p-f luorophenyl-6-fluoro-l,4- dihydro-4-oxo-7-(3-methylaminopyrrolidinyl)quinoline-3carboxylic acid. Example 38 In similar fashion as Example 29, the use of various l-aryl-7-chloro-6-fluoro-l, 4-dihydro-4-oxo-quino- line-3-carboxylic acids (7), wherein aryl represents R, in place of 7-chloro-1-phenyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (7) (R=phenyl) and the use of appropriate substituted amines in place of morpholine, the following additional compounds (9) can be made as summarized in Table III. Table III EMI35.1 <SEP> Morpholine <SEP> Acid <SEP> (7) <SEP> R6=H <SEP> Compound <SEP> (9) <SEP> Obtained <tb> <SEP> Replacement <SEP> R <SEP> Z <SEP> R <tb> 1. <SEP> ethylamine <SEP> phenyl <SEP> -NHC2H5 <SEP> phenyl <tb> 2. <SEP> ethylamine <SEP> p-fluorophenyl <SEP> -NHC2H5 <SEP> p-fluorophenyl <tb> 3. <SEP> methylamine <SEP> p-fluorophenyl <SEP> -NHCH3 <SEP> p-fluorophenyl <tb> 4. <SEP> methylamine <SEP> p-hydroxyphenyl <SEP> -NHCH3 <SEP> hydroxyphenyl <tb> 5. <SEP> dimethylamine <SEP> p-fluorophenyl <SEP> -N(CH3)2 <SEP> p-fluorophenyl <tb> 6. <SEP> diethylamine <SEP> p-hydroxyphenyl <SEP> -N(C2H5) <SEP> p-hydroxyphenyl <tb> 7. <SEP> hydrazine <SEP> phenyl <SEP> -NHNH2 <SEP> phenyl <tb> 8. <SEP> N-methyl <SEP> hydrazine <SEP> p-fluorophenyl <SEP> -NCH3NH2 <SEP> p-fluorophenyl <tb> 9. <SEP> 3-hydroxy <SEP> pyrrolidine <SEP> phenyl <SEP> -N#-OH <SEP> phenyl <tb> 10. <SEP> 3-hydroxy <SEP> pyrrolidine <SEP> p-fluorophenyl <SEP> -N#-OH <SEP> p-fluorophenyl <tb> 11. <SEP> 3-hydroxy <SEP> pyrrolidine <SEP> p-hydroxyphenyl <SEP> -N#-OH <SEP> p-hydroxyphenyl <tb> 12. <SEP> 3-hydroxy <SEP> pyrrolidine <SEP> p-methylphenyl <SEP> -N#-OH <SEP> p-methylphenyl <tb> EMI36.1 13. <SEP> pyrrolidine <SEP> phenyl <SEP> -N# <SEP> phenyl <tb> 14. <SEP> pyrrolidine <SEP> p-fluorophenyl <SEP> -N# <SEP> p-fluorophenyl <tb> 15. <SEP> pyrrolidine <SEP> p-hydroxyphenyl <SEP> -N# <SEP> p-hydroxyphenyl <tb> 16. <SEP> azetidine <SEP> p-fluorophenyl <SEP> -N# <SEP> p-fluorophenyl <tb> 17. <SEP> piperidine <SEP> phenyl <SEP> -N# <SEP> phenyl <tb> 18. <SEP> piperidine <SEP> p-fluorophenyl <SEP> -N# <SEP> p-fluorophenyl <tb> 19. <SEP> piperidine <SEP> p-hydroxyphenyl <SEP> -N# <SEP> p-hydroxyphenyl <tb> 20. <SEP> piperidine <SEP> 4-pyridinyl <SEP> -N# <SEP> 4-pyridinyl <tb> 21. <SEP> piperidine <SEP> 3-furyl <SEP> -N# <SEP> 3-furly <tb> 22. <SEP> N-(2-hydroxy <SEP> ethylamine <SEP> p-fluorophenyl <SEP> -N-CH2CH2OH <SEP> p-fluorophenyl <tb> 23. <SEP> pyrrolidine <SEP> 2,4-difluorophenyl <SEP> -N# <SEP> 2,4-difluoro <SEP> phenyl <tb> 24. <SEP> pyrrolidine <SEP> 2-hydroxy-4- <SEP> 2-hydroxy-4 <SEP> fluorophenyl <SEP> -N# <SEP> fluorophenyl <tb> 25. <SEP> pyrrolidine <SEP> 4-hydroxy-2- <SEP> 4-hydroxy-2 <SEP> fluorophenyl <SEP> -N# <SEP> fluorophenyl <tb> 26. <SEP> 4-acetylpiperazine <SEP> p-fluorophenyl <SEP> -N#N-COCH3 <SEP> p-fluorophenyl <tb> 27. <SEP> 4-propionyl- <SEP> p-fluorophenyl <SEP> -N#N-COC2H5 <SEP> p-fluorophenyl <tb> 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

Claims: CLAIMS 1. 9 compound having the formula EMI38.1 wherein R1 is hydrogen or a carboxy protecting group; R is selected from the group consisting of an aromatic heterocyclic ring containing 5 to 7 atoms therein, with the hetero atom being at least one of S, O and N and the remaining atoms in the ring being carbon atoms, and a phenyl group having the formula: EMI38.2 wherein R2 is one or more groups selected from the group consisting of hydrogen, halogen, nitro, carboxyl, cyano, methylenedioxy, C1 to C6 alkyl and substituted derivatives thereof, a group having the formula: -Y-R3 wherein -Y- is -0- or -S- and R3 is hydrogen or C1 to C6 alkyl, and an amine group having the formula: EMI38.3 wherein R4 and R5 are independently hydrogen or C1 to C6 alkyl; and Z is selected from the group consisting of an aliphatic heterocyclic ring containing 4 to 7 atoms and substituted derivatives thereof, an amino group of the formula: EMI39.1 wherein R6 is hydrogen or C1 to C10 alkyl and substituted derivatives thereof; and R7 is selected from the group consisting of C1 to C10 alkyl and substituted derivatives thereof, an amine group, a mono-(C1 to C6) alkylamino group and a di-(C1 to C6) ) alkylamino group, and pharmaceutically acceptable salts thereof. 2. A compound having the formula: EMI39.2 wherein Z is piperazinyl, substituted piperazinyl, or aminosubstituted pyrrolidinyl, R is phenyl or substituted phenyl wherein the substituent on the phenyl group is one or more of an alkyl group, a halogen group, a methylenedioxy group and a hydroxy group and R1 is hydrogen or a carboxy protecting group. 3. A compound as defined in Claim 2 wherein R is phenyl, Z is piperazinyl and R1 is hydrogen. 4. A compound as defined in Claim 2 wherein R is phenyl, Z is 4-methylpiperazinyl and R1 is hydrogen. 5. A compound as defined in Claim 2 wherein R is p-fluorophenyl, Z is piperazinyl and R1 is hydrogen. 6. A compound as defined in Claim 2 wherein R2 is p-fluorophenyl, Z is 4-methylpiperazinyl and R1 is hydrogen. 7. A compound as defined in Claim 2 wherein Z is piperazinyl, R is 2,4-difluorophenyl and R1 is hydrogen. 8. A compound as defined in Claim 2 wherein Z is methylpiperazinyl, R is 2,4-difluorophenyl and R1 is hydrogen. 9. A composition having antibacterial activity in pharmaceutical dosage form containing a diluent and a compound as defined in Claim 1. 10. A composition having antibacterial activity in pharmaceutical dosage form containing a diluent and acompdundhaving the formula: EMI40.1 wherein Z is piperazinyl, substituted piperazinyl or amino substituted pyrrolidinyl, and R is phenyl or substituted phenyl wherein the substituent on the phenyl group is one or more of an alkyl group, a halogen group, a methylenedioxy group and a hydroxy group. 11. A composition as defined in Claim 10 wherein Z is piperazinyl, R is p-fluorophenyl and R1 is hydrogen. 12. A composition as defined in Claim 10 wherein Z is methylpiperazinylt R is p-fluorophenyl and R1 is hydrogen. 13. A composition as defined in Claim 10 wherein Z is piperazinyl, R is phenyl and R1 is hydrogen. 14. A method of treating a bacterial infection in a patient comprising administering to a patient in need a therapeutically effective amount of a compound as defined in Claim 1. 15. A method of treating a bacterial infection in a patient comprising administering to a patient in need a therapeutically effective amount of a compound having the formula: EMI41.1 wherein Z is piperazinyl, substituted piperazinyl or amino substituted pyrrolidinyl and R is phenyl or substituted phenyl wherein the substituent on the phenyl group is one or more of an alkyl group, a halogen group, a methylenedioxy group and a hydroxy group. 16. A method as defined in Claim 15 wherein Z is piperazinyl, R is p-fluorophenyl and R1 is hydrogen. 17. A method as defined in Claim 15 wherein Z is methylpiperazinyl, R is p-fluorophenyl and R1 is hydrogen. 18. A method as defined in Claim 15 wherein Z is piperazinyl, R and R1 are hydrogen. 19. A method of producing 1,4-dihAdro-4-oxo- quinoline-3-carboxylic acids, comprising reacting the compound of the formul EMI42.1 wherein R6 is an alkyl group of 1 to 10 carbon atoms, Re is a leaving group and R is selected from the group consisting of an aromatic heterocyclic ring containing 5 to 7 atoms therein, with the hetero atom being at least one of S, 0 and N and the remaining atoms in the ring being carbon atoms, and a phenyl group having the formula: : EMI42.2 wherein R2 is one or more groups selected from the group consisting of hydrogen, halogen, nitro, carboxyl, cyano1 methylenedioxy, C1 to C6 alkyl and substituted derivatives thereof, a group having the formula -Y-R3 wherein -Y- is -0- or -S- and R3 is hydrogen or C1 to C6 alkyl, and an amine group having the formula: EMI42.3 wherein R4 and R5 are independently hydrogen or C1 to C6 alkyl; with a compound of the formula ZH wherein Z is selected from the group consisting of an aliphatic heterocyclic ring containing 4 to 7 atoms and substituted derivatives thereof, an amino group of the formula: EMI43.1 wherein R6 is hydrogen or C1 to C10 alkyl and substituted derivatives thereof; and R7 is selected from the group consisting of C1 to C10 alkyl and substituted derivatives thereof, an amine group, a mono-(Cl to C6) alkylamino group and a di-(C1 to C6) alkylamino group.

Inventors: CHU, DANIEL TIM-WO
Applicants: ABBOTT LABORATORIES
Application year: 1984
Main classification: C07D215
IPC codes: C07D409, C07D405, C07D521, C07D401, C07D417, C07D215