Claims
- 1. A compound having the formula: ##STR11## wherein A is CH or N; R.sub.1 is hydrogen or a carboxy protecting group; R is selected from o,p-difluorophenyl or p-fluorophenyl; and z is (2S, 4S-4-amino-2-methylpyrrolidin-1yl; and pharmaceutically acceptable salts thereof.
- 2. A compound as defined in claim 1 wherein R.sub.1 is hydrogen.
- 3. A compound as defined in claim 1 wherein R is o,p-difluorophenyl, Z is (2S,4S)-4-amino-2-methylpyrrolidin-1-yl and R.sub.1 is hydrogen.
- 4. A compound as defined in claim 3 wherein A is N.
- 5. A compound as defined in claim 1 wherein R is p-fluorophenyl, Z is (2S,4S)-4amino-2-methylpyrrolidin-1-yl and R.sub.1 is hydrogen.
- 6. The compound having the formula: ##STR12## or pharmaceutically acceptable salts thereof.
- 7. A composition having antibacterial activity and improved solubility and pharmacokinetic profile in pharmaceutical dosage form containing a diluent and the compound as defined in claim 6.
- 8. A method of treating a bacterial infection in a patient comprising administering to a patient in need a therapeutically effective amount of the compound as defined in claim 6.
- 9. The compound having the formula; ##STR13## or pharmaceutically acceptable salts thereof.
- 10. A composition having antibacterial activity and improved solubility and pharmacokinetic profile in pharmaceutical dosage form containing a diluent and the compound as defined in claim 9.
- 11. A method of treating a bacterial infection in a patient comprising administering to a patient in need a therapeutically effective amount of the compound as defined in claim 9.
- 12. A composition having antibacterial activity and improved solubility and pharmacokinetic profile in pharmaceutical dosage form containing a diluent and a compound as defined in claim 1.
- 13. 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.
Parent Case Info
This is a continuation of application Ser. No. 081,416, filed Aug. 4, 1987.
This is a continuation-in-part of copending U.S. patent application, Ser. No. 784,421, filed Oct. 4, 1985, which is a continuation of Ser. No. 597,854 filed Apr. 9, 1984, which is a continuation-in-part of Ser. No. 574,227, filed Jan. 26, 1984, which is a continuation-in-part of Ser. No. 514,716, filed July 18, 1983.
This invention relates to new naphthyridine and quinoline derivatives having antibacterial properties, compositions containing the new naphthyridine and quinoline derivatives and methods of treating mammalian patients with the new naphthyridine and quinoline derivatives.
It is known that certain naphthyridine and quinoline compounds exhibit antibacterial properties, notably certain 7-piperazinyl-4-oxo-1,8-naphthyridine-3-carboxylic acids. In European Patent No. 9,425, there are disclosed certain 7-piperazinyl-6-fluoro-1, 4-dihyro-4-oxo-l,8-naphthyridine-3-carboxylic acid derivatives which are substituted in the 1 position with an alkyl or vinyl substituent.
This invention relates to novel antibacterial agents and, more particularly, to 7-substituted 6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine and quinoline-3-carboxylic acids and derivatives thereof having the formula: ##STR3## wherein A is CH or N, R is p-fluorophenyl (1) or o,p-difluorophenyl, R is hydrogen or a carboxy-protecting group and Z is the structure having the formula: ##STR4## The compounds of this invention have substantially improved solubility properties relative to those lackinq the 2-substituent on the pyrrolidine ring (Table 3); however they still maintain extremely potent antibacterial activity (Tables 1 and 2). The improvement in solubility treatly reduces the probability of crystalluria that is associated with compounds possessing low solubility at physiological pH. The increased solubility also eases in the preparation of i.v. formulations of these drugs. The improved solubility properties of these agents have also resulted in greatly improved oral absorption and pharmacokinetic properties (Table 4).
As used herein, the term "carboxy-protecting group" refers to and includes the residue of a carboxylic acid ester group. Such carboxy-protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields, as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are incorporated herein by reference. In general, such carboxy-protecting groups can be relatively easily cleaved to yield the corresponding free carboxy group. Representative protecting groups include C to C8 alkyl (e.g., methyl, ethyl, tertiary butyl), benzyl and substituted derivatives thereof such as alkoxy and nitrotrobenzyl groups; also suitable are acyloxyalkyl groups such as a pivaloyloxymethyl group.
The preferred compounds of the invention are those having the formula: ##STR5## wherein R is as described above and is preferably o,p-difluorophenyl, R.sub.1 is as described above and is preferably hydrogen, A is as described above and Z is as described above preferably having the formula: ##STR6## wherein the absolute stereoconfiguration of the 2-methyl substituent is S and the absolute stereoconfiguration of the 4-amino substituent is S.
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 1. The salts can be prepared in situ during the final isolation and purification of the compounds of formula 1, 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, etc.
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 and anaerobes. The compounds of the invention are therefore useful in the antibiotic treatment of susceptible bacterial infections in both humans and animals. In addition, the compounds, by reason of their in vitro activity, may be used in scrub solutions for surface inhibition of bacterial growth.
Susceptible organisms generally include those gram positive and gram negative, aerobic and anaerobic organisms whose growth can be inhibited by the compounds of the invention such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina, Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter, Proteus, . Campylobacter, Citrobacter, Nisseria, Baccillus, Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia, Haemophilus, Brucella and other organisms. In addition to exhibiting highly effective antibacterial activity, the compounds of the invention exhibit increased and improved solubility characteristics and oral absorption properties as compared with prior art naphthyridine-3-carboxylic acid compounds.
The compounds of formula 1 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 qlycol, polyethylene glycol, veqetable 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 coco 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 1 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 pr 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 or four times per day.
The naphthyridine compounds according to this invention can be prepared by the reaction sequence illustrated below: ##STR7## wherein X is a halogen, mesylate or methoxy group and R and R.sub.1 are the same as described above.
Heating a compound of the formula (2) with an amine of formula (3) at a temperature of from 20.degree. C. to 150.degree. C., in the presence of a suitable organic polar or non-polar solvent such as dimethylsulfoxide, sulfolane, dimethylformamide (DMF), dimethylacetamide, 1-methy-2-pyrrolidinone, pyridine, water, tetrahydrofuran (THF) or methylene chloride provides compound (4). It is desirable to carry out the reaction in the presence of an acid acceptor such as triethylamine, potassium carbonate or the like at a molar ratio of 1.0 to 2.0 moles of the acid-acceptor per mole of the compound of the formula (2). The amine (3) can also be used as acid acceptor in which 2 or more molar excess of this reagent is used. The ester in (4) is hydrolyzed by treatment with dilute sodium hydroxide in aqueous THF. Subsequent hydrolysis of the N-acetyl group with hydrochloric acid furnishes the naphthyridine (5) (R.sub.1 .dbd.H). The compounds of the formula (2) may be prepared in accordance with the prior art (U.S. Pat. No. 4,616,019).
Amines of the formula (3) may be prepared in accordance with the following reaction scheme. ##STR8## The known hydroxyproline (6) (R.sub.2 .dbd.R.sub.3 .dbd.H) is first converted to its corresponding alkyl, aryl or arylalkyl ester, preferably its methylester, upon refluxing in methanol containing HCL. The ester (6) (R.sub.2.dbd.CH.sub.3,R.sub.3 .dbd.H) may be isolated as its hydrochloride salt. Protection of the amine function by conversion to a suitable carbamate or amide derivative, preferably using the tert-butoxycarbonyl group by treatment of (6) (R.sub.2 .dbd.CH.sub.3,R.sub.3 .dbd.H) with di tert-butyl dicarbonate in the presence of a base such a triethylamine in a solvent such as dichloromethane or THF provides at a temperature of about -10.degree. C. to 25.degree. C. (6) (R.sub.2 .dbd.CH.sub.3,R.sub.3 .dbd.-COO.sup.t Bu). Protection of the secondary hydroxyl group with a suitable alkyl, alkoxyalkyl or silyl ether, preferably the tert-butyldimethylsilyl group by treatment of (6) (R.sub.2 .dbd.CH.sub.3,-COO.sup.t Bu) with tert-butylchlorodimethylsilane in the presence of a base such as imidazole, triethylamine or pyridine in a suitable solvent such as dichloromethane, THF or N,N-dimethylformamide (DMF) at a temperature of about 0.degree. C. to 60.degree. C. furnishes compound (7) (R.sub.2 .dbd.CH.sub.3,-COO.sup.t Bu, .sup.t BuSi(CH.sub.3).sub.2). The ester group in (7) is reduced with an appropriate hydride reagent such as lithium borohydride in a solvent such as THF or dimethoxyethane at a temperature of about -20.degree. C. to 25.degree. C. to afford the corresponding primary alcohol (8). The primary alcohol in (8) is converted to a good leaving group such as p-toluenesulfonyloxy, trifluoromethanesulfonyloxy or preferably methanesulfonyloxy upon treatment with methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as THF or preferably dichloromethane at a temperature of about -10 .degree. C. to 30.degree. C. to obtain (9) (R.sub.5 .dbd.SO.sub.2 CH.sub.3). Deoxygenation of (9) is accomplished by treatment with a good source of nucleophilic hydride, preferably lithium triethylborohydride, in a solvent such as DMF or preferably THF at a temperature of about 25.degree. C. to obtain (10). Cleavage of the hydroxyl protecting group in (10) using an acid such as hydrofluoric acid, hydrobromic acid or hydrochloric acid or a base such as sodium hydroxide in aqueous THF or a source of fluoride ion such as cesium fluoride, potassium fluoride or preferably tetra-n-butylammonium fluoride in the preferential case where R.sub.5 .dbd..sup.t BuSi(CH.sub.3).sub.2 -in a solvent such as THF, methanol or acetonitrile gives the alcohol (11) (R.sub.5 .dbd.H). Activation of the hydroxyl group in (11) by conversion to a leaving group such as p-toluenesulfonyloxy, trifluoromethanesulfonyloxy or preferably methanesulfonyloxy by treatment with methanesulfonyl chloride in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane or THF at a temperature of about 0.degree. C. to 40.degree. C. furnishes (11) (R.dbd.SO.sub.2 CH.sub.3). Displacement of the leaving group in (11) with a source of azide such as lithium azide, sodium azide or preferably tetra-n-butylammonium azide in a solvent such as acetonitrile at a temperature of about 30.degree. C. to 80.degree. C. gives (12). Reduction of the azide group with a hydride reagent such as lithium borohydride or sodium borohydride or preferably with hydrogen in the presence of a suitable catalyst in a solvent such as methanol at a temperature of about 25.degree. C. affords the corresponding amine (13) (R.sub.6 .dbd.H) which is acetylated with acetic anhydride in the presence of a base such as triethylamine in a solvent such as pyridine or dichloromethane at a temperature of about -15.degree. C. to 40.degree. C. to afford the N-acetylderivative (13) (R.sub.6 .dbd.--COCH.sub.3). Alternatively, (12) can be converted directly to (13) (R.sub.6 .dbd.--COCH.sub.3) upon treatment with thiolacetic acid. The nitrogen-protecting group R.sub.3 is removed to give (13). In the preferable case where R.sub.3 .dbd.COO.sup.t Bu, this transformation is accomplished by treatment of (13) with an acid, preferably trifluoroacetic acid at temperature of about --20.degree. C. to 40.degree. C. Compound (13) may be isolated as its trifluoroacetic acid salt, or alternatively the salt may be dissolved in a solvent such as methanol or dichloromethane and treated with a basic exchange resin. Filtration of the resin followed by concentration of the filtrate affords the base (13). Alternatively, compound (11) (R.sub.5 .dbd.H) may be transformed to (13) (R.sub.6 .dbd.H) by the method shown below. ##STR9## Oxidation of (11) (R.sub.5 .dbd.H), preferably employing the Swern protocol (DMSO,(C1CO).sub.2,CH.sub.2 Cl.sub.2 ;Et.sub.3 N) provides the ketone (14). Treatment of (14) with hydroxylamine provides the corresponding oxime (15) which is reduced by hydrogen in the presence of a suitable catalyst such as Raney Nickel in a solvent such as methanol to afford the amine (13) (R.sub.6 .dbd.H).
The quinoline compounds according to this invention can be prepared by the reaction sequence illustrated below: ##STR10## wherein B is hydrogen or fluoro and L is Cl or F.
Heating a compound (16) with an amine of compound (3) at a temperature of from 20.degree. C. to 150.degree. C., in the presence of a suitable organic polar or non-polar solvent such as dimethylsulfoxide, sulfolane, dimethylformamide (DMF), dimethylacetamide, 1-methy-2-pyrrolidinone, pyridine, water, tetrahydrofuran (THF) or methylene chloride provides compound (17). It is desirable to carry out the reaction in the presence of an acid-acceptor such as triethylamine, potassium carbonate or the like at a molar ratio of 1.0 to 2.0 moles of the acid-acceptor per mole of the compound (16). The amine (3) can also be used as acid acceptor in which 2 or more molar excess of this reagent is used. The ester in (17) is hydrolyzed by treatment with dilute sodium hydroxide in aqueous THF. Subsequent hydrolysis of the N-acetyl- group with hydrochloric acid furnishes the quinoline (18) (R.sub.1 .dbd.H). The compounds (16) may be prepared in accordance with the prior art (D. Chu et al., Journal of Medicinal Chemistry, 1985, Vol. 28, 1558; D. Chu et al. 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, Sept. 28-Octobrt 1, 1986; New Orleans, LA, Abstract #428).
US Referenced Citations (2)
Foreign Referenced Citations (1)
| Number |
Date |
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| EP0131839 |
Jan 1985 |
EPX |
Continuations (2)
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Number |
Date |
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| Parent |
81416 |
Aug 1987 |
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| Parent |
597854 |
Apr 1984 |
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Continuation in Parts (3)
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| Parent |
784421 |
Oct 1985 |
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| Parent |
574227 |
Jan 1984 |
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| Parent |
514716 |
Jul 1983 |
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Patent Grant
4962112
