DK159778B - 6,7-DIHYDRO-5,8-DIMETHYL-9-FLUORO-1-OXO-1H, 5H-BENZOOEIJAA-QUINOLIZIN-2-CARBOXYLIC ACID OR A DERIVATE THEREOF, PHARMACEUTICAL PREPARATION CONTAINING SUCH SUBSTANCES AND SUCH SUBSEQUENTLY IN VITRO - Google Patents

Description

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The present invention relates to novel derivatives of the heterocyclic system known as benzo [ij] ~ quinolizine. More particularly, it relates to the 8-substituted 6,7-di-hydro-5-methyl-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid and derivatives thereof. The use of the present compounds as antimicrobial agents and pharmaceutical compositions containing the compounds are also encompassed by the present invention.

U.S. Patent No. 3,896,131 discloses a broad class 10 of 6,7-dihydro-5-methyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] -quinolizine-2-carboxylic acids for use as antimicrobial agents. Specifically, the patent discloses several compounds substituted with halogen and / or methyl in the benzor ring. The compound 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid (now known as flumequin) disclosed in said patent the subject of the greatest attention because of its antimicrobial activity. It has now been found that the corresponding novel 8-methyl-9-fluorine compound exhibits much greater antimicrobial activity.

U.S. Patent No. 4,301,289 discloses the compounds 6-fluoroquinaldine, 6-fluoro-1,2,3,4-tetrahydroquinaldine and dialkyl-2- [N- (6-fluoro-1,2,3,4-tetrahydroquinaldinyl] - methylenlmalonater.

The present invention relates to the compound 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] quinolysine-2-carboxylic acid and its carboxylate derivatives. The invention also relates to the pharmacological use of these compounds as antibiotics and pharmaceutical compositions comprising these compounds.

The invention specifically relates to the novel compound 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benz-2

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zo [ij] quinolizine-2-carboxylic acid of the formula

ISLAND ISLAND

IT J

or a derivative thereof in the form of the acid chloride, an alkyl ester having 1-4 carbon atoms in the alkyl group, a dialkylamino alkyl ester having 1-4 carbon atoms in each alkyl group, or a pharmaceutically acceptable carboxylate thereof. These compounds are useful antimicrobial agents.

The compounds of this invention have an optically active carbon atom in the 5-position. All such optical isomers are encompassed by the present invention.

It is well known in the art that pharmaceutically acceptable salts such as alkali metal, alkaline earth metal, aluminum, iron, silver and other metal salts and amine salts of pharmaceutically active acids are equivalent to the acids in terms of activity, and in in some cases they may even offer the benefits of absorption, formulation and the like. Pharmaceutically acceptable carboxylate salts of the free acid compounds of the invention are readily prepared by reacting the acid with a base and subsequent evaporation to dryness. The base may be organic, e.g., sodium methoxide or an amine, or inorganic, e.g., sodium hydroxide. Alternatively, the cation of a carboxylate salt, e.g., sodium, can be replaced by another cation, such as calcium or magnesium, when the salt of the second cation 25 is more insoluble in a selected solvent.

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Other useful derivatives of the compound of the invention include the acyl chloride, esters and alkylamino alkyl ester salts thereof. In the acyl chloride derivative, the hydroxyl moiety of the carboxylic acid group is removed and replaced with chlorine. In the ester derivatives, the hydrogen moiety in the carboxylic acid group is replaced by an optionally substituted alkyl group, preferably an alkylaminoalkyl group.

The esters and acyl chloride of the compound of the invention can be obtained as intermediates during the preparation of the acidic compound. In some cases, the esters can be prepared directly using standard synthesis methods. These esters and the acyl chloride exhibit antimicrobial activity, but they are primarily of interest as synthesis intermediates, although hydrolysable or salt-forming esters may be of interest as therapeutic agents in some cases. Particularly preferred are alkylamino alkyl esters such as dimethylaminoethyl esters which form salts, e.g. hydrochlorides.

Ester derivatives are readily prepared by reacting the free acid of formula I with thionyl chloride to provide the novel acyl chloride derivative. The acyl chloride is reacted with the appropriate alcohol to provide the desired ester.

The antimicrobial activity of the compounds of the invention can be demonstrated by the known standard plate dilution method for testing bacterial sensitivity to difficult microorganisms against antibiotics, sulfonamides and other chemotherapeutic agents. Tryptone soybean (oxoid) of the following composition is the culture medium: 4

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Oxoid tryptone 15 g

Oxoid soy peptone 2 g

Sodium chloride 5 g

Oxide Agar Agar No. 3 15 g

Water 1 liter

Using this sample, the compounds of the invention have been found to have a broad spectrum activity against Gram-positive and Gram-negative microorganisms.

The compounds of the invention are active against microorganisms either in the absence or in the presence of 10um horse serum.

The test procedure used to determine the activity as used in the present invention provides information on the amount of a compound which provides complete inhibition, partial inhibition or no inhibition of microbial growth on the agar plates. In the test, the selected compound is added to the agar medium to obtain concentrations of 0, 1, 10 and 15 100 mg / ml. liter. A number of plates with these concentrations are produced. 10¾ horse serum is added to a variety of such plates. Culture aliquots of any of 12 species of microorganisms are seeded onto the agar plates containing the compound at various concentrations. The plates are incubated at 37 ° C in a 10 µl carbon dioxide atmosphere for 18-24 hours. The microbial growth on each plate is read visually and the minimum inhibitory concentrations (for partial or complete inhibition) recorded.

Some of the microorganisms used in this experiment are:

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1. Staphylococcus aureus 2. Bacillus subtilis 3. Escherichia coli 4. Pseudomonas aeruginosa 3 5. Streptococcus sp. * 6. Aspergillus niger 7. Candida albicans 8. Acinetobacter lwoffi 9. Acinetobacter anitratum 10 10. Klebsiella pneumoniae 11. Streptococcus fecaelis 12. Serratia marcescens * Strains isolated from dental caries in rats or hamsters at the National Institute of Dental Health and 15 grown in PFV or APT agar.

The compounds of the invention have antimicrobial activity against one or more of the above microorganisms. Of particular importance is the high activity level of the compound of formula I and its salts above 20 for Pseudomonas aeruginosa, a particularly difficult species associated with many topical infections. This type of activity is very uncommon in benzoquinolizine-type antimicrobials.

It will be appreciated by those skilled in the art that the 25 species used are representative indicator species as it would be impractical to test against all bacteria.

It will be well known in the art that broad spectrum activity can be predicted on the basis of activity exhibited against selected representative bacterial species.

The compounds of the invention are active against microorganisms in vitro. In vitro activity is useful as such as antimicrobial agents can be used for 6

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disinfection and sterilization, eg of medical and dental equipment, as constituents of disinfectants.

The acute oral toxicity of the compounds of the invention is generally moderate to low compared to the effective oral dose, and they have an acceptable therapeutic ratio (LD 2 g / ED 2 g) of over 80.

The acidic compound of the invention is a white crystalline material when purified. It is substantially insoluble in water, lower alcohols 10 or hydrocarbons and is more soluble in halogenated solvents, N, N-dimethylformamide and the like.

The salts, especially the alkali metal salts, have appreciated solubility in water and lower alcohols.

The compounds of the invention may be formulated by incorporating them into conventional pharmaceutical carrier materials, either organic or inorganic, suitable for oral or intraperitoneal use. For in vitro use, simple aqueous solutions or suspensions may be most conveniently used. For this purpose, concentrations of the order of 100 parts per 1 000 000 up to approx. 5 parts per 1,000 suitable, and the formulation is used by immersing objects to be treated therein or by application to an area to be disinfected.

The amount of a compound to be used for treatment, e.g. of a microbial urinary tract infection by oral administration will be an effective amount below the toxic amount. The amount to be administered to control or fight an infection will depend on the species, gender, weight, physical condition and many other factors, but this assessment is within the skill of the art. Seed-

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Usually the amount will be less than 100 mg per day. kg per dosage. This is conveniently administered in the form of the usual pharmaceutical compositions such as capsules, tablets, emulsions, solutions and the like. Excipients, fillers, coatings, etc. are used in conjunction with tablets or capsules, as is well known in the art.

It is known in the art that antimicrobial agents are used as growth promoters for various animal and bird species. Although not yet verified, it is concluded from their unique antimicrobial activity that the compounds of the invention can also be used for this purpose.

The acidic compound of the invention can be prepared as described in the following reaction scheme: 8

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IV

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polyphosphoric acid ° Εγ ^ γ ^ γ € 00Η (6) ch3AA.hJ k / '^ CH3 wherein alk and each group R3 independently represent alkyl groups of 1-4 carbon atoms, preferably 1-2 carbon atoms.

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In the first step of the reaction scheme, 5-amino-2-fluorobenzoic acid of formula II is reacted with the croton aldehyde of formula III or a precursor of crotonal aldehyde which forms corotnaldehyde under the acidic reaction conditions. Suitable precursors for crotonaldehyde that can be used in step (1) include acetaldehyde, acetal or paraldehyde. The product of step (1) is the novel compound 5-carboxy-6-fluoroquinaldine of formula (IV). The reaction is carried out in the presence of a dilute aqueous acid such as sulfuric acid or hydrochloric acid, with hydrochloric acid being preferred. The reaction is carried out at a temperature between ca. 50 ° C and the reflux temperature of the reaction mixture.

It is advantageous to carry out the reaction in the presence of a reagent pair consisting of a weak oxidizing agent and a weak reducing agent. Suitable oxidizing agents include alkali metal or alkaline earth metal salts of the organic acid meta-nitrobenzenesulfonic acid. The sodium and potassium salts are preferred. The free acids can also be used as oxidizing agents. Suitable reducing agents include ferrous sulfate, ferric sulfate, ferric chloride and the like. The currently preferred reagent pair is the sodium salt of m-nitrobenzenesulfonic acid as the oxidizing agent and ferrous sulfate as the reducing agent. Use of at least about theoretical amounts of the oxidizing and reducing agent (i.e.

at least 0.25 moles of each moles of the amino benzoic acid of formula II) are preferred. If catalytic amounts of the reducing agent are used, the reaction proceeds, but at a slower rate.

Steps (2) and (3) of the reaction scheme involve reduction of the carboxyl group of the intermediate of formula IV. The intermediate of formula IV is reduced in step (2) to provide the novel intermediate 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine of formula V. This reduction is carried out using 10

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diborane in a suitable solvent such as tetrahydrofuran. The mixture is heated at reflux for several hours.

In step (3), 1,2-dihydro-6-fluoro-5-hydroxymethyl-quinaldine of formula V is reduced to provide the novel intermediate 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine with formula VI. This reduction is carried out using hydrogen gas and a mixture of palladium on coal and platinum on coal. Alternatively, the reduction can be carried out in two successive steps, the first step involving the use of one catalyst and the second step another. In each case, the reduction in a solvent such as ethanol is performed using a Paar apparatus.

The 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine of formula VI is condensed with a dialkylalkoxymethylene malonate of formula VII in step (4). The preferred dialkylalkoxymethylene malonate is diethylethoxymethylene malonate as it is the most readily available. The condensation reaction requires heating the reactants until the reaction is complete as determined by chromatographic analysis. The reaction is carried out in the absence of solvent at a temperature of 100 - 200 ° C for several hours. It is preferred that the reaction is carried out at a temperature 25 of 140-150 ° C for 2 hours. Alternatively, the reaction may be carried out in the presence of an inert organic solvent which forms an azeotropic mixture with the alcohol formed after the condensation of dialkylalkoxymethylene malonate (e.g. ethanol, where diethylethoxymethylene malonate 30 is used in step (4)). The reaction mixture is heated at its reflux temperature and the azeotropic mixture comprising the alcohol and the organic solvent is collected, for example, in a Dean-Stark trap. Fresh organic solution 11

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solvent is usually added to the reaction mixture as the solvent is used during the distillation. Removal of the alcohol from the reaction mixture drives the condensation reaction to substantially completion and increases the yield. The product of step (4) is the novel intermediate of formula VIII. This intermediate can be isolated, for example, as an oil or solid, or the product of step (4) can be used directly in step (5) without isolation of the intermediate.

Alternatively, an N-cycloisopropylidenyl alkoxymalonate of formula <RTI ID = 0.0> ch3 alkOCH = </RTI> Ch3 wherein alk is an alkyl group of 1-4 carbon atoms can be used as the diester of alkoxymethylene malonic acid in step (4) in place of the dialkylalkoxymethylene malalo shown. - night of formula VII.

In step (5), the intermediate of formula VIII is cyclized to form the ester of formula IX. The cyclization step is performed by heating the intermediate of formula VIII in the presence of polyphosphoric acid. The reaction temperature is preferably 150-160 ° C. Alternatively, cyclization of the intermediate of formula VIII is carried out in the presence of phosphorus oxychloride at reflux for several hours, evaporation of excess phosphorus oxychloride and reflux in the presence of water.

The ester of formula IX is saponified in step (6) in conventional manner to provide 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] quinolizine-2 carboxyl-12

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acid of formula I.

When the above N-cycloisopropylidenyl alkoxymalonate is used in step (4), step (5) generally results directly in the formation of 6,7-dihydro-5,8-dimethyl-9-fluoro-1-5 oxo-H, 5H-benzo [ quinolizine-2-carboxylic acid, and no separate hydrolysis step is required.

The invention is explained by the following examples.

EXAMPLE 1 Preparation of 5-carboxyl-6-fluoroquinaldine

A mixture of 95.2 g of 5-amino-2-fluorobenzoic acid (0.60 mole), 74.3 g (0.33 mole) of sodium meta-nitrobenzenesulfonate, 46.2 g (0.17 mole) of ferrous sulfate heptahydrate and 660 ml of 9 N hydrochloric acid were heated to 90 - 95 ° C. Crotonal aldehyde (96%), 77 g (1.0 mol), was added dropwise over 2.5 hours with vigorous stirring, keeping the temperature just below the reflux temperature. After stirring for another 1/2 hour, the hot solution was filtered through a glass wool plug. The filtrate was cooled to 30 ° C, decolorized and filtered.

The clear filtrate was cooled on ice with stirring to give a yellow solid. The solid was separated by filtration, washed with acetone and dried. The solid was then dissolved in 400 ml of warm water and a solution of 50 g of sodium acetate in 100 ml of water was added thereto. The product was 58.2 g of cream colored crystals of 5-carboxyl-6-fluoroquinaldine. The structure was confirmed by infrared analysis and nuclear magnetic resonance spectral analysis.

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EXAMPLE 2

Preparation of the novel intermediate 1,2-di-hydro-6-fluoro-5-hydroxymethylquinaldine

To a stirred slurry of 20.0 g (97.6 mol) of 5-carbo-5-xyl-6-fluoroquinaldine in 400 ml of tetrahydrofuran was added dropwise 300 ml of 1 M diborane in tetrahydrofuran (0.3 mol). The solution was stirred at 20 ° C for one hour, heated at reflux temperature for 2 hours and then allowed to cool. A mixture of 150 ml of water and 100 ml of tetrahydrofurfuran was added and the mixture was stirred for 30 minutes on a steam bath and cooled. The aqueous layer was saturated with sodium carbonate by stepwise addition of the salt. The organic layer was separated and the aqueous layer was extracted with 200 ml of diethyl ether. The extracts were combined with the organic layer and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was dissolved in a solution of 400 ml of ethanol and 15 ml of concentrated hydrochloric acid. After heating this mixture at reflux for one hour, the solvent was evaporated to provide a solid. The solid was dissolved in 200 ml of water and the solution was basified with aqueous sodium hydroxide to give a solid which was mainly 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine as determined by nuclear magnetic spectral analysis. Other isomers were also present.

EXAMPLE 3

Preparation of the New Intermediate 6-Fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine A solid which was mainly 1,2-dihydro-6-fluoro-14

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5- Hydroxymethylquinaldine (13.2 g), prepared according to Example 2, was dissolved in 300 ml of ethanol and 10 ml of concentrated hydrochloric acid. To this solution was added 1 g of 5% platinum on coal and 3 g of 5% palladium on coal.

The solution was hydrogenated at 50 psi at approx. 20 ° C on a Paar apparatus. After absorption of ca. 12 psi of hydrogen (the theoretically required amount), the solution was filtered and the solvent was removed by evaporation to give a solid. Nuclear Magnetic Resonance Spectral Analysis showed a slightly incomplete reduction. Therefore, the solid was dissolved in 300 ml of aqueous (90? 1 s) ethanol, to which 2 g of platinum was added to charcoal and the solution was hydrogenated at 50 psi on the Paar apparatus for approx. 16 hours. The solution was then filtered and the solvent was evaporated.

The recovered solid was dissolved in 50 ml of water. This solution was basified with aqueous sodium hydroxide and then extracted with diethyl ether. Evaporation of the ether gave 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinal-20dine as an oil.

EXAMPLE 4

Alternative preparation of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine

A solid which was mainly 1,2-dihydro-6-fluoro-5-hydroxymethylquinaldine (7.0 g) was dissolved in 200 ml of ethanol containing 1 ml of concentrated hydrochloric acid, 1.0 g of 5% palladium on coal and 1.0 g of platinum on coal and the mixture was hydrogenated at 50 psi at 20 ° C for 5 hours. The solution was filtered and the filtrate 30 was evaporated to give a white solid which, according to nuclear magnetic resonance spectral analysis, was 6-fluoro-5-hydroxymethyl-1,2,3,4-tetrahydroquinaldine.

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The solid was dissolved in 350 ml of ethanol containing 3 ml of concentrated hydrochloric acid and 3.0 g of palladium on charcoal and hydrogenated at 50 psi overnight. The mixture was filtered and the filtrate was evaporated to give 5 of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine hydrochloride as a white solid. The free base was separated by dissolving solid in water, then basified with 10% aqueous sodium hydroxide solution and extracted with diethyl ether followed by evaporation of the ether to provide a yellow solid.

EXAMPLE 5

A mixture of 9.3 g of 6-fluoro-5-methyl-1,2,3,4-tetrahydroquinaldine and 17 ml of diethylethoxymethylene malonate was heated at 150-160 ° C for 3.5 hours and then cooled to 100 ° C. ° C. To this solution was added 56 g of polyphosphoric acid and the mixture was stirred for 1 hour while heating on a steam bath. The mixture was then cooled to room temperature and allowed to stand for approx. 72 20 hours. To this mixture containing ethyl 1,2-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylate was added 250 ml of 20 Å aqueous sodium hydroxide. to make the solution basic. The solution was then heated at its reflux temperature for 2 hours, cooled and acidified with concentrated hydrochloric acid.

The solid was separated by filtration and recrystallized from aqueous N, N-dimethylformamide. washing with ethanol followed by drying gave 6,7-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] quinolizine-2-carboxylic acid as an off-white solid, m.p. 269 - 272 ° C.

Analysis calculated for: C ^H ^FNO ^

Calculated: C 65.4, H 5.1, N 5.1 Found: C 65.0, H 5.0, N 5.0.

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EXAMPLE 6

The antibacterial activity of the free acid compound of the invention and the activity of several 6,7-dihydro-5-methyl-1-oxo-1H, 5H-benzo [ij] quinolizine-2-5 carboxylic acids of the prior art were determined using the standard plate dilution method as described above. The experiments were performed both in the absence (column A) and in the presence (column B) of horse serum as described above, and the amounts of the antimicrobial agent were as indicated. The results (listed as the minimum concentrations in mg of the active antimicrobial agent per liter which gave partial or complete inhibition of the growth of the indicated microorganisms) are shown in the following table:

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It is seen that the compound of the invention exhibits significantly greater activity than the prior art compounds.

EXAMPLE 7 To a solution of 0.17 g (4.25 mmol) of sodium hydroxide in 75 ml of water was added 1.3 g (4.73 mmol) of 1,2-dihydro-5,8-dimethyl-9-fluoro -l-oxo-lH, 5H-benzo [ij] quinolizine-2-carboxylic acid. The mixture was stirred for approx. 30 minutes, and dissolved acid was removed by filtration. The solution 10 was lyophilized to give 1.1 g of white fluffy solid sodium 1,2-dihydro-5,8-dimethyl-9-fluoro-1-oxo-1H, 5H-benzo [ij] quinolizine-2 carboxylate.

Analysis calculated for C C ^^H ^^ FN FNONα.0.5 HgO Calculated: C 58.8, H 4.6, N 4.6.

Found: C, 58.9; H, 4.6; N, 4.4.

Claims (5)

1. Benzoquinolizine derivative of the formula O O An. J! h3c ch3 or a derivative thereof in the form of the acid chloride, an alkyl ester having 1-4 carbon atoms in the alkyl group, a dialkylaminoalkyl ester having 1-4 carbon atoms in each alkyl group or a pharmaceutically acceptable carboxylate. Compound according to claim 1, characterized in that the carboxylate is alkali metal or alkaline earth metal carboxylate. A pharmaceutical composition containing a compound according to claim 1 or 2 and a pharmaceutically acceptable carrier. Method for inhibiting the growth of microorganisms in vitro, characterized in that the microorganisms are contacted with a compound according to claim 1 or 2. A method according to claim 4 for inhibiting the growth of bacteria in vitro, characterized in that the bacteria are contacted with a compound according to claim 1 or 2.