US 4,774,246 AGrant
Quinoline Antibacterial Compounds
Issue Date:1988-09-27
•19 Claims
Abstract
Quinoline compounds having the formula: ##STR1## wherein R is a phenyl or substituted phenyl group or an aromatic heterocyclic group, 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.
Metadata
Assignee
- Abbott Laboratories
Inventor
- Daniel T. Chu
Application Information
Application Number:US 9067248
Filing Date:1986-09-12
Priority Date:1984-01-26
Art Unit:129
Classifications
IPC:
A61K 31495C07D40104
Field of Search:
544546514363;62;116156254;314;210;218;222;233;236
Patent Drawings
This patent does not have any drawings.
Description
This invention relates to new quinoline derivatives having antibacterial properties, compositions containing the new quinoline derivatives and methods of treating mammalian patients with the new quinoline derivatives.
It is known that certain quinoline compounds exhibit antibacterial properties, notably certain 7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids. In U.S. Pat. No. 4,017,622, there are disclosed certain 7-piperazinyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acids 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 acid 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 6,8-difluoro-7-substituted amino-4-oxo-1,4-dihydroquinoline-3-carboxylic acids and derivatives thereof having the formula: ##STR2## 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: ##STR3## 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, 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, methylenedioxy and an amine having the formula: ##STR4## 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: ##STR5## 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 "aromatic heterocyclic" ring 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, O or N and the remaining atoms all being carbon atoms. Representative heterocyclic groups include pyridyl, pyrazinyl, thiazoyl, furyl, thienyl and substituted derivatives thereof. Substituents which may be present on the heterocyclic ring include C.sub.1 to C.sub.6 alkyl groups, halogen groups or a group of the formula --Y--R.sub.3 wherein Y is as described above and R.sub.3 is hydrogen or C.sub.1 to C.sub.6 alkyl.
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 lower alkyl groups including methyl, ethyl, propyl, isopropyl and butyl.
As indicated above, R.sub.2 can be C.sub.1 to C.sub.6 straight or branched 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 disclosure 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), 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: ##STR6## 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, an amino group having the formula: ##STR7## 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, C.sub.1 to C.sub.6 hydroxyalkyl, hydroxy, alkanoyl containing 1 to 6 carbon atoms and alkanoylamido containing 1 to 6 carbon atoms.
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 structure: ##STR8## wherein Z is piperazinyl or substituted piperazinyl as described above, R.sub.1 is as described above and is preferably hydrogen and R is phenyl or substituted phenyl wherein the substituent on the phenyl group is one or more of alkyl, halogen, methylenedioxy or hydroxy.
Representative of such preferred compounds are 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carb oxylic acid, 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-4(methyl)piperazinyl)-quinoli ne-3-carboxylic acid, 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline -3-carboxylic acid, 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoli ne-3-carboxylic acid and 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1,4-acetylpiperazinyl)- quinoline-3-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 non-toxic 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 nd 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 therefor 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, Bacillus, 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: ##STR9## wherein X is a halogen and R and Z are the same as described above.
The reaction may be performed by heating a compound of the formula (III) with an amine of formula (IV) 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 (III). The amine (IV) can also be used as acid acceptor in which 2 or more molar excess of this reagent is used. The compounds of the formula (III) may be prepared in accordance with the following reaction scheme, in which X, R are as described above: ##STR10##
In accordance with the foregoing reaction scheme, the acetophenone (1) is reacted with a dialkoxycarbonate (2) in the presence of a strong base to obtain the corresponding betaketoester (3). In the dialkoxycarbonate (2), R.sub.1 may be an alkyl group of, for example, 1 to 10 carbon atoms, but is preferably loweralkyl, 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 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.degree. C. to about 120.degree. C., and preferably from about 30.degree. C. to about 90.degree. C. until completion of the reaction. The B-ketoester may then be separated from the reaction mixture in a conventional manner.
Alternatively, the beta-ketoester (3) (X=F) is prepared as follows: ##STR11## The known 2,3,4,5-tetrafluorobenzoic acid (A) is treated with thionyl chloride to produce the corresponding acid chloride (B). Displacement of the acid chloride (B) with malonic acid half ester (C) 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 amine (5) to obtain the enaminoketoester (6). In the trialkylorthoformate (4), R.sub.4 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 amine (5) is preferably conducted in an appropriate aprotic or non-aprotic 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 1,4-dihydro-4-oxoquinoline-3-carboxylic acid ester (7). 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 (7) is subjected to hydrolysis, such as by treatment with sodium hydroxide, or dilute mineral acid to form the free acid (III).
The 1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (I, R.sub.1 =H) can then be converted into the corresponding ester, if desired, by conventional esterification procedures, such as by treating the free acid (I, R.sub.1 =H) with the appropriate alcohol in the presence of an acid catalyst, by converting the free acid (I, R.sub.1 =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 =H) with a suitable reactive halide, such as chloro-methylpivalate in dimethoxyethane to obtain, for example, the pivaloyloxymethyl ester (I) wherein R.sub.1 is --CH.sub.2 OCOC(CH.sub.3).sub.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 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, II and III.
EXAMPLE 1
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carbo xylic acid
(a) To a cold solution of 30 g., 2,3,4,5-tetrafluoroacetophenone in 400 ml. diethylcarbonate is slowly added of 12.5 g. 60% sodium hydride-in-oil suspension. The mixture is heated at 80.degree. C. for 11/2 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 MgSO.sub.4, evaporated and the obtained liquid is distilled to give (3), wherein R.sub.1 =C.sub.2 H.sub.5, X=F.
(b) A solution of 20 g. of the above B-ketoester (3) in 18.5 ml. of triethylorthoformate and 45 ml. of acetic anhydride is heated 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 9.9 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 R.sub.1 =C.sub.2 H.sub.5, R=phenyl and X=F).
(c) To a cold solution of 15 g. of the preceding product (6), R.sub.1 =C.sub.2 H.sub.5, R=phenyl, X=F, in 150 ml. tetrahydrofuran (THF) is slowly added 1.63 g. of a 60% sodium hydride-in-oil suspension. The mixture is refluxed for 6 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 (7) wherein R.sub.1 =C.sub.2 H.sub.5, R=phenyl, X=F.
(d) To a suspension of 7 g. of (7) (R.sub.1 =C.sub.2 H.sub.5, R=phenyl, X=F) in 30 ml. THF is added a sodium hydroxide solution (0.88 g. in 20 ml. H.sub.2 O). 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. H.sub.2 O, 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-phenyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (III). (R=phenyl, X=F).
(e) To a solution of 2.5 g. of 1-phenyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 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 =H, R=phenyl, ##STR12## The resulting dried solid (I) is suspended in 30 ml. H.sub.2 O and 7.8 ml. 1N HCl is added to and warmed to dissolve. Removal of the solvent under reduced pressure gives hydrochloride salt of 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carbo xylic acid (R.sub.1 =H, R=phenyl, ##STR13##
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-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carb oxylic acid.
(f) Alternately, the title compound is prepared as follows: To a suspension of 5 g. of compound (III) (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-carboethoxy-piperazine. 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 =H, R=phenyl, ##STR14##
To a suspension of 5 g. of the preceding compound (I) (R.sub.1 =H, R=phenyl, ##STR15## 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-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(piperazinyl)-quinoline-3-carbox ylic acid (I). (R.sub.1 =H, R=phenyl, ##STR16##
(g) Alternatively, the beta-ketoester (3) (R.sub.1 =C.sub.2 H.sub.5, X=F) is prepared as follows: To a solution of 3.9 g. of 2,3,4,5-tetrafluorobenzoic acid in 20 ml. of methylene chloride are 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).
EXAMPLE 2
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-quinoli ne-3-carboxylic acid
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) with N-methylpiperazine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)piperazinyl)-quinol ine-3-carb oxylic acid (I). (R.sub.1 =H, R=phenyl, ##STR17## and its hydrochloride salt.
EXAMPLE 3
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-quinoline-3-carb oxylic acid
In the described fashion as Example 1, replacing piperizine in Example 1(e) with pyrrolidine, one can obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7(1-pyrrolidinyl)quinoline-3-carbo xylic acid in good yield (I). (R.sub.1 =H, R=phenyl, ##STR18##
EXAMPLE 4
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidinyl)-quinol ine-3-carboxylic acid
The procedure of Example 1 can be repeated replacing piperazine in Example 1(e) with 3-hydroxypyrrolidine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7(3-hydroxy-1-pyrrolidinyl)-quinol ine-3-carboxylic acid (I). (R.sub.1 =H, R=phenyl, ##STR19##
EXAMPLE 5
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)-quinolin e-3-carboxylic acid
(a) In the described fashion as Example 1 replacing piperazine in Example 1(e) with 3-acetamidopyrroldine, one can obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-acetamido-1-pyrrolidinyl)-qui noline-3-carboxylic acid (I). (R.sub.1 =H, R=phenyl, ##STR20## in good yield.
(b) The product of above reaction can then be hydrolyzed with hydrochloric acid at 80.degree. C. to give 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)quinolin e-3-carboxylic acid hydrochloride salt (I). (R.sub.1 =H, R=phenyl, ##STR21##
EXAMPLE 6
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperidinyl)-quinoline-3-carbo xylic acid
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) with piperidine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperidinyl)quinoline-3-carbo xylic acid (I). (R.sub.1 =H, R=phenyl, ##STR22##
EXAMPLE 7
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-morpholinyl)-quinoline-3-carbo xylic acid
In the described fashion as Example 1, replacing piperazine in Example 1(e) with morpholine, one can obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-morpholinyl)quinoline-3-carbo xylic acid (I). (R.sub.1 =H, R=phenyl, ##STR23## in good yield.
EXAMPLE 8
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-quinoline-3-c arboxylic acid
The procedure of Example 1 can be repeated replacing piperazine in Example 1(e) with thiomorpholine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)quinoline-3-c arboxylic acid (I). (R.sub.1 =H, R=phenyl, ##STR24##
EXAMPLE 9
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-quin oline-3-carboxylic acid
In the described fashion as Example 1, replacing piperazinyl in Example 1(e) with 2,6-dimethylpiperazine, one obtains 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperazinyl)-qui noline-3-carboxylic acid and its hydrochloride salt (I). (R.sub.1 =H, R=phenyl, ##STR25##
EXAMPLE 10
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-homopiperazinyl)-quinoline-3-c arboxylic acid
The procedure of Example 1 is repeated replacing piperazine in Example 1(e) with homopiperazine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-homopiperazinyl)-quinoline-3- carboxylic acid and its hydrochloride salt (I). (R.sub.1 =H, R=phenyl, ##STR26##
EXAMPLE 11
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(dimethylamino)-quinoline-3-carbo xylic acid
In the described fashion as Example 1, replacing piperazine in Example 1(e) with dimethylamine, one can obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(dimethylamino)quinoline-3-carbo xylic acid (I). (R.sub.1 =H, R=phenyl, Z=--N(CH.sub.3).sub.2).
EXAMPLE 12
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(N-2-hydroxyethylamino)-quinoline -3-carboxylic acid
The procedure of Example 1 can be repeated replacing piperazine in Example 1(e) with N-2-hydroxyethylamine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(N-2-hydroxy-ethylamino)-quinoli ne-3-carboxylic acid (I). (R.sub.1 =H, R=phenyl, Z=--NHC.sub.2 H.sub.4 --OH).
EXAMPLE 13
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-hydrazyl-quinoline-3-carboxylic acid
In the described fashion as Example 1, replacing piperazine in Example 1(e) with hydrazine, one can obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(hydrazyl)quinoline-3-carboxylic acid and its hydrochloride salt (I). (R.sub.1 =H, R=phenyl, Z=-NHNH.sub.2).
EXAMPLE 14
1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,2-dimethylhydrazyl)-quinoline- 3-carboxylic acid
The procedure of Example 1 can be repeated, replacing piperazine in Example 1(e) with 1,1-dimethylhydrazine to obtain 1-phenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,2-dimethyl-hydrazyl)-quinolin e-3-carboxylic acid and its hydrochloride salt (I). (R.sub.1 =H, R=phenyl, Z=NHN(CH.sub.3).sub.2).
EXAMPLE 15
1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(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). (R.sub.1 =C.sub.2 H.sub.5, R=p-fluorophenyl, X=F).
(b) By following the Example 1(c) and 1(d), the preceding compound (6) can yield 7-fluoro-1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carbo xylic acid (III). (R=p-fluorophenyl, X=F).
(c) In the described fashion as Example 1(e), the above acid (III) can give the desired 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinolin e-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR27## and its hydrochloride salt.
EXAMPLE 16
In the desired fashion as Example 1(e), replacing the acid (III) (R=phenyl, X=F) with the acid (III) of the product of Example 15(b) (R=p-fluorophenyl, X=F) and also replacing piperazine with an appropriate amine such as n-methylpiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetaminompyrrolidine, piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, diethylamine and 2,2-dimethylhydrazine, one can obtain the following compounds:
(a) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl(piperazinyl )-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR28## (b) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-qui noline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR29## (c) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrroli dinyl)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR30## (d) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-acetamino-1-pyrro lidinyl)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR31## (e) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperdinyl)-quino line-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR32## (f) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-morpholinyl)-quin oline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR33## (g) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)- quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR34## (h) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-pipe razinyl)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR35## (i) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-homopiperazinyl)- quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR36## (j) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(diethylamino)-quino line-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, Z=--N(C.sub.2
(k) 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,2-dimethylhydrazyl)-q uinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, Z=--NH--N(CH.sub.3).sub.2).
EXAMPLE 17
1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl)- quinoline-3-carboxylic acid
In the described fashion of Example 5(b), the compound of Example 16(d) can give 1-p-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl) quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-fluorophenyl, ##STR37##
EXAMPLE 18
1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinolin e-3-carboxylic acid
(a) In the described fashion as Example 1(b), replacing aniline with hydroxyaniline, one can obtain the enaminoketoester (6). (R.sub.1 =C.sub.2 H.sub.5, R=p-hydroxyphenyl, X=F).
(b) By following the Example 1(c) and 1(d), the preceding compound (6) can yield 7-fluoro-1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carb oxylic acid (III). (R=p-hydroxyphenyl, X=F).
(c) In the described fashion as Example 1(e), the above acid (III) can give the desired 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinolin e-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR38## and its hydrochloride salt.
EXAMPLE 19
In the described fashion as Example 1(e), replacing the acid (III) (R=phenyl, X=F) with the acid (III) of the product of Example 18(b) (R=p-hydroxyphenyl, X=F) and also replacing piperazine with an appropriate amine such as N-methylpiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, dimethylamine and 2,2-dimethylhydrazine, one can obtain the following compounds:
(a) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-(4-methyl)piperaziny l)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR39## and its hydrochloride salt.
(b) 1-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-quinolin e-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR40##
(c) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-hydroxy-1-pyrrolidin yl)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR41##
(d) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-acetamino-1-pyrrolid inyl)-quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR42##
(e) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperidinyl)-quinoli ne-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl), ##STR43##
(f) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-morpholinyl)-quinoli ne-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR44##
(g) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-qui noline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR45##
(h) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3,5-dimethyl-1-piperaz inyl)quinoline-3-carboxylic acid (I). (R.sub.1 =p-hydroxyphenyl, ##STR46##
(i) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-homopiperazinyl)-qui noline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR47##
(j) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(diethylamino)quinoline -3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, Z=--N(C.sub.2 H.sub.5).sub.2).
(k) 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(2,2-dimethyl-hydrazyl) -quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=hydroxyphenyl, Z=--NH--N(CH.sub.3).sub.2).
EXAMPLE 20
1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl) quinoline-3-carboxylic acid
In the described fashion of Example 5(b), the compound of Example 18(d) can give 1-p-hydroxyphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7(3-amino-1-pyrrolidinyl) quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-hydroxyphenyl, ##STR48##
EXAMPLE 21
In the described fashion as Example 1(a-d), replacing aniline with an appropriate amine (R--NH.sub.2), one can obtain the additional 1-substituted, 6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid III as listed in Table I.
EXAMPLE 22
In the described fashion as Example 1(e), replacing the acid (III) (R=phenyl, X=F) with the acid (III) of the compounds listed in Table 1 of Example 21 and also replacing piperazine with an appropriate amine such as N-methylpiperazine, pyrrolidine, 3-hydroxypyrrolidine, 3-acetamidopyrrolidine, 3-dimethylaminopyrrolidine, piperidine, morpholine, thiomorpholine, 2,6-dimethylpiperazine, homopiperazine, dimethylamine and 2,2-dimethylhydrazine, one can obtain the following additional compounds as summarized in Table II.
EXAMPLE 23
In the described fashion of Example 5(b), the compounds 11 and 12 in Example 22 can be converted to:
(a) 1-o-fluorophenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(3-amino-1-pyrrolidinyl) quinoline-3-carboxylic acid (I). (R.sub.1 =H, R=o-fluorophenyl, ##STR51##
(b) 1-p-methylphenyl-6,8-difluoro-1,4-dihydro-4-oxo-7-3-amino-1-pyrrolidinyl)q uinoline-3-carboxylic acid (I). (R.sub.1 =H, R=p-methylphenyl, ##STR52##
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
I claim:
1. A compound having the formula: ##STR53## wherein R.sub.1 is hydrogen or a carboxy protecting group; R is phenyl having the formula: ##STR54## wherein R.sub.2 is methylenedioxy or one or two substituents independently selected from hydrogen, halogen, nitro, carboxyl, cyano, C.sub.1 to C.sub.6 alkyl, hydroxy-substituted C.sub.1 to C.sub.6 alkyl, halo substituted C.sub.1 to C.sub.6 alkyl, a substituent having the formula: wherein --Y-- is --O-- or --S-- and R.sub.3 is hydrogen or C.sub.1 to C.sub.6 alkyl, and a substituent of the formula: ##STR55## wherein R.sub.4 and R.sub.5 are independently hydrogen or C.sub.1 or C.sub.6 alkyl; and, Z is selected from (1) an aliphatic heterocyclic ring having the structure: ##STR56## wherein R.sub.8 is CH.sub.2, (CH.sub.2).sub.2, or -CH.sub.2 R.sub.9 (CH.sub.2).sub.n - wherein R.sub.9 is selected from the group consisting of --S, --O-- and --N-- and n is O or 1; (2) substituted derivatives of said aliphatic heterocyclic ring having one or two substitutents independently selected from C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 hydroxyalkyl, hydroxy, alkanoyl having 1 to 6 carbon atoms, alkanoylamino having 1 to 6 carbon atoms and a substituent of the formula: ##STR57## wherein R.sub.10 and R.sub.11 are each independently selected from 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; and (3) a substituent of the formula: ##STR58## wherein R.sub.6 is hydrogen, C.sub.1 to C.sub.10 alkyl, halo-substituted C.sub.1 to C.sub.10 alkyl or hydroxy-substituted C.sub.1 to C.sub.10 alkyl, and R.sub.7 is selected from C.sub.1 to C.sub.10 alkyl, halo-substituted C.sub.1 to C.sub.10 alkyl, hydroxy-substituted C.sub.1 to C.sub.10 alkyl, --NH.sub.2, a mono-(C.sub.1 to C.sub.6) alkylamino and a di-(C.sub.1 to C.sub.6) alkylamino; and pharmaceutically acceptable salts thereof.
2. A compound as defined in claim 1 wherein the aliphatic heterocyclic ring is selected from the group consisting of azetidinyl, piperazinyl piperidinyl, pyrrolidinyl, morpholino, thiomorpholino and homopiperazinyl.
3. A compound as defined in claim 1 wherein R.sub.1 is hydrogen.
4. A compound as defined in claim 1 wherein Z is an amino group having the formula: ##STR59## wherein R.sub.6 is hydrogen, C.sub.1 -C.sub.10 alkyl, halo-substituted C.sub.1 -C.sub.10 alkyl, hydroxy-substituted C.sub.1 -C.sub.10 alkyl and R.sub.7 is C.sub.1 -C.sub.10 alkyl, halo-substituted C.sub.1 -C.sub.10 alkyl, hydroxy-substituted C.sub.1 -C.sub.10 alkyl, amino, mono-(C.sub.1 -C.sub.4)alkylamino or di(C.sub.1 -C.sub.4)alkylamino.
5. A compound having the formula: ##STR60## wherein Z is piperazinyl or C.sub.1 to C.sub.6 alkyl-substituted piperazinyl, or 4-acetylpiperazinyl, and R is phenyl or substituted phenyl wherein the substitutent on the phenyl group is methylenedioxy or one or two substituents independently selected from C.sub.1 to C.sub.6 alkyl, halo and hydroxy, and pharmaceutically acceptable salts thereof.
6. A compound as defined in claim 1 wherein R is O,p-difluorophenyl.
7. A compound as defined in claim 6 wherein Z is 4-methyl-1-piperazinyl.
8. A compound as defined in claim 1 wherein R is p-fluorophenyl.
9. A compound as defined in claim 1 wherein Z in 3-aminopyrrolidin-1-yl.
10. A compound as defined in claim 5 wherein R is phenyl, Z is piperazinyl and R.sub.1 is hydrogen.
11. A compound as defined in claim 5 wherein R is phenyl, Z is 4-methylpiperazinyl and R.sub.1 is hydrogen.
12. A compound as defined in claim 5 wherein R is fluorophenyl, Z is piperazinyl and R.sub.1 is hydrogen.
13. A compound as defined in claim 5 wherein R is fluorophenyl, Z is 4-methylpiperazinyl and R.sub.1 is hydrogen.
14. A compound as defined in claim 5 wherein R is hydroxyphenyl, Z is piperazinyl and R.sub.1 is hydrogen.
15. A compound as defined in claim 5 wherein R is fluorophenyl, Z is 4-acetylpiperazinyl and R.sub.1 is hydrogen.
16. A composition having antibacterial activity in pharmaceutical dosage form containing a diluent and a compound as defined in claim 1.
17. A composition having antibacterial activity in pharmaceutical dosage form containing a diluent and a compound as defined in claim 5.
18. 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.
19. 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 5.
Patent Citations (19)
| Patent | Date | Inventor | Cited By |
|---|---|---|---|
| US3149104 | 1964-09-01 | Lesher et al. | |
| US3887557 | 1975-06-01 | Minami et al. | |
| US3950338 | 1976-04-01 | Pesson | |
| US4017622 | 1977-04-01 | Minami et al. | |
| US4284629 | 1981-08-01 | Grohe et al. | |
| US4352803 | 1982-10-01 | Matsumato et al. | |
| US4382892 | 1983-05-01 | Hayakawa et al. | |
| US4415572 | 1983-11-01 | Tominaga et al. | |
| US4416719 | 1983-03-01 | Irikura | |
| US4429127 | 1984-01-01 | Irikura et al. | |
| US4439436 | 1984-03-01 | Wentland et al. | |
| US4443447 | 1984-04-01 | Gerster et al. | |
| US4473568 | 1984-09-01 | Hutt | |
| US4617308 | 1986-10-01 | Mitch et al. | |
| US4620007 | 1986-10-01 | Grohe et al. | |
| DEX2362553 | 1973-12-01 | ||
| JPX56-128764 | 1981-10-01 | ||
| GBX1147336 | 1965-06-01 | ||
| GBX2034698 | 1979-10-01 |
Non-Patent Literature (4)
- Passon, "Chemical Abstracts", vol. 91, 1979, col. 91:20344X.
- Minami, et al., "Chemical Abstracts", vol. 81, 1974, col. 105562k.
- Sato et al. "In Vitro and In Vivo Activity of DL-8280, a New Oxazine Derivative", Antimicrobial Agents and Chemotherapy vol. 22, No. 4, p. 548-553, Oct. 1982.
- Koga et al. "SAR" of Substituted Quinoline-3-Carboxylic Acids", Journal of Medicinal Chemistry, 1980, vol. 23, No. 12, p. 1358.