FI66175B - EXAMINATION OF ANALYTICAL AGAINST ANTIBACTERIA AEMNE ANVAENDBAR 1-DIFLUORMETHYL-6,7-METHYLENDIOXY-1,4-DIHYDRO-4-OXO-3-QUINOLINCARBOXYL SYRASE OCH DESS ESTRAR - Google Patents

Description

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(* ®) Patent coddclat (51) KvJu / lRLa.3 C 07 D 215/56 // C 07 D 491/04 FINLAND — FINLAND (ii) 770567 / Bl \ W HtiMMhpa «t — 'AMMariagAg 22 02 77' ' 22.02.77 rifnffl I> NkbtirilitntM ^ ^ «· * Ν 24.08.77 hf» och rutHwitynlwi '* vm-i - * irtyViΠηΐιηΓττ ~ τ iTf 31.05.81 ((32X33X31) grtortM 23.02.76 14.01.77 USA , 758331 (71) EI du Pont de Nemours and Company, 1007 Market Street, Wilmington, Delaware 19898, USA (72) Kyu Tai Lee, Wilmington, Delaware, USA (74) Oy Kolster Ab (54) Process for the preparation of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its esters and their salts useful as bactericides - For the preparation of a diffuse antibacterial agent Methyl) -6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and esters of the same salt

The present invention relates to a process for the preparation of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its esters of formula I useful as a bactericide.

M Τ I (1)

CF 2 H

2,66175 wherein R is hydrogen or - (CH 2 -n-N <r 1 * 2 R and R independently represent C 1-6 alkyl; and 1 n is 2 or 3; and pharmaceutically acceptable salts thereof.

In U.S. Patent No. 3,287,458, Kaminsky discloses bactericidal 6,7-methylenedioxy-1,4-dihydro-4-oxo-quinolinecarboxylic acids substituted in the 1-position with lower alkyl or other various substituents. A compound in which this substituent is ethyl is commonly known as oxolinic acid.

Oxolinic acid is a very effective bactericide, but it has been found to be burdened with many unwanted side effects. Cox, Claire, E., Delaware Medical Journal, November 1970, p. 327. Kershaw and Leigh (Journal of Antimicrobial Therapy.

1 (1975) 311-315) have stated that, due to its toxicity, "it should not be used as the primary drug in the treatment of urinary tract infections".

Nalidixic acid is another acid currently on the market used in the treatment of urinary tract infections. It was initially shown to be effective in this use. However, further experience with the use of nalidixic acid has given reason to suspect that its usefulness may be limited by its tendency to rapidly induce bacterial resistance. Ronald, A.R. et al. New England Journal of Medicine, 275 (1966) 1081-1088. In addition, the drug use of nalidixic acid is associated with a relatively high side effect burden, Cox. pp. 327.

The compounds of this invention are highly potent bactericides, but unlike the compounds previously known in the art, they do not cause undesirable side effects.

In a general pharmacological study, oxolinic acid caused ataxia, anorexia, agitation, and irritability, and nalidixic acid caused little ataxia and anorexia, whereas the compounds of this invention did not cause any of these embarrassing side effects (Tables 3 and 4).

Preferred compounds of the invention are 1-difluoromethyl-6,7-methylenedioxy-1,4,4-dihydro-4-oxo-3-quinolinecarboxylic acid due to its high bactericidal efficacy and absence of undesirable side effects, and 3,661,75-1-difluoromethyl-6, 7-Methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, Ν, Ν-diethylaminoethyl ester.

The process according to the invention for the preparation of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids and their derivatives is characterized in that the compound of formula II

\ ^ COOR_, \ IT j (II)

CF 2 H

wherein -CH 2, -C 2 H 2, or -C 2 H 2, is hydrolyzed with a dilute acid, and then, if desired, it is first contacted with PCl 2 and the product obtained is further contacted with a compound of formula III in an inert solvent.

R 1 HO- (CH 2 - N <2 n (III) R 2 wherein R 1, R 2 and n are as defined above, and if desired the product obtained is converted into a pharmaceutically acceptable salt.

Pharmaceutically acceptable salts include acid salts obtained using certain metals such as sodium, potassium and calcium, and ammonium. The salts are prepared by adding an alcoholic or aqueous solution of MOH (M is a metal) to an acid solution or suspension in a solvent, e.g. dimethylformamide, dimethyl sulfoxide or ethanol. The salt is isolated by filtration.

Pharmaceutically acceptable salts of esters include acid addition salts prepared using physiologically acceptable acids known in the art; such salts include e.g. hydrochloride, sulphate, nitrate, phosphate, citrate, tartrate and maleate.

The starting materials of formula II used in the process are prepared as shown in Scheme 1 4 66175

Scheme 1 / ° 'V <Xil COORj \ I | l + r3o-ch = c ^' 0 Nh2 COOR3 (A) (B) R3 = C1-C3-alkyl heat N / 0

Il C00Ro a1 2 'COOR * \ 3 V 3 / O Tl COOR3 J ^ \ Cl i ^ 0 "" ^ nh -

B

(D) (C) • CP • 2

V

o o ~, coor3 2

CF «H

3 (E) * 3,4-methylenedioxyaniline (A) is reacted with dialkylalkoxymethylene malonate (B) at 70-100 ° C with or without a solvent (the solvent is usually ethanol) to form a compound of formula C. Compound C is converted to compound (D) by heating in Dowtherm A (mixture of diphenyl ether and diphenyl) at 250-255 ° C (see J. Med. Chem. 11 (1968) 160).

The difluoromethyl group (sCF 3) is added to compound (D) by reacting it with HCF 2 Cl in the presence of a base such as R 6 OM of the formula R 10 OM having alkyl such as methyl, ethyl or t-butyl and M is an alkali metal such as sodium, potassium or lithium. The solvent for this reaction may be R 4 OH, wherein R 4 is as defined above, or another aprotic solvent such as dimethylformamide, dimethyl sulfoxide or ethylene glycol dimethyl ether. The reaction temperature may be about 50-100 ° C.

The difluoromethyl group can also be added to compound (D) by dry distillation at high temperature of an alkali metal salt of chlorodifluoroacetic acid in an aprotic solvent such as diethylene glycol dimethyl ether or diethyl malonate.

The compound of formula I is obtained from the difluoromethyl compound of formula II (E) as shown in Scheme 2.

Diagram 2 O 0 • I «

COOR3 0 __ ^ COOH

<° T If f - £ -> <i \ 1

^ F2H (F, CF2H

(E) ρα5 0 \ L? (f YT / two .(TY i \ kk k HO- (CHj -N

1 »2 I

CF2H f.- CF_H

(H) (G)

The difluoromethyl compound (E) is hydrolyzed by heating at about 80-110 ° C in dilute hydrochloric acid for about 1-2 hours to obtain the acid (F). Compound (F) is optionally converted to its acid chloride (G) using PCl 2. Esters (H) are prepared by reacting the acid chloride (G) with a suitable amino alcohol in an inert solvent such as benzene or toluene.

The bactericides of this invention may be administered as medicaments for the purpose of utilizing their bactericidal effect by any means which brings the active ingredient into contact with a site of infection in a mammalian body. They may be administered by any of the conventional methods of administering pharmaceutical agents; either as individual therapeutic agents or as combinations of therapeutic agents. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the desired route of administration and normal pharmaceutical practice.

The dose to be administered will, of course, vary with known factors such as the pharmacodynamic properties of the particular substance and the mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the nature of concomitant treatment, the frequency of treatment and the desired effect. The daily dose of active ingredient may usually be about 5 to 100 mg / kg body weight; and preferably 5-10 mg / kg per day administered in 2-4 daily doses.

Dosage forms (mixtures) suitable for internal administration contain from about 5 mg to about 500 mg of active ingredient per unit. Generally, in these pharmaceutical compositions, the active ingredient is present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions; it can also be administered other than through the gastrointestinal tract in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to make tablets. The tablets may be coated with sugar or film to mask any unpleasant taste and protect the tablet from the effects of air, or they may be coated with a substance that is preselectable to disintegrate in the gastrointestinal tract.

66175

Liquid dosage forms for oral administration may contain coloring or flavoring agents to increase patient acceptance.

In general, water, a suitable oil, saline, dextrose (glucose) aqueous solution, and closely related sugar solutions and glycols such as propylene glycol or polyethylene glycol are other than suitable carriers for parenteral administration. Solutions other than for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizers and, if necessary, buffers. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination. Citric acid and its salts and sodium EDTA (ethylenediaminetetraacetic acid) are also used. In addition, non-gastrointestinal solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are disclosed in Remington's Pharmaceutical Sciences. E.W.Martin, a standard reference work in this field.

Dosage forms useful in administering the compounds of this invention can be described as follows:

The capsules

A large number of normal capsules are prepared by filling a normal two-part hard gelatin capsule with 100 mg of powdered active ingredient, 200 mg of lactose, 30 mg of talc and 10 mg of magnesium stearate.

The capsules

A mixture of the active ingredient and soybean oil is prepared and injected into the gelatin with a forced displacement pump to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed with petroleum ether and dried.

tablets

A large number of tablets are prepared using conventional methods so that the dosage unit is 250 mg of active ingredient, 50 mg of ethylcellulose, 5 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 10 mg of fine crystalline cellulose, 40 mg of corn starch and 66 mg of lactose. Suitable coating agents may be used for the tablets to increase the pleasant taste or to delay absorption.

To be administered in the form of injections

A mixture for non-gastrointestinal administration is prepared by mixing 5% by weight of the active ingredient with 10% by volume of propylene glycol and water. The solution is sterilized by filtration.

Suspension

An aqueous suspension for oral administration is prepared so that 5 ml always contains 100 mg of finely divided active ingredient, 500 mg of acacia, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (US-Pharmacopoeia), 5 mg of sodium saccharin and 0.025 ml of vanilla tincture.

Use The use of the compounds of this invention as bactericidal agents in mammals is explained by the following microbiological data for 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.

A. In vitro (glass): minimum contraceptive concentration (MIC)

The MIC of the compound was tested in test tubes with a normal bacteriological dilution test for several different bacteria. The bacterial bases listed in Table 1 were grown in bacterial culture medium at 37 ° C overnight and then diluted in culture tubes to the concentration previously determined in the tubes. Compound was added to give final concentrations of 10, 2, 0.4 and 0.08 ug / ml. These were incubated for 18 hours at 37 ° C and then examined for possible bacterial growth. The MIC is the lowest concentration of a compound that inhibits bacterial growth. The results obtained are shown in Table 1.

66175

Table 1 In vitro activity of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (DFMQ), oxolinic acid and nalidixic acid (effect in living organisms)

Small pigs prevent test concentrations * pg / ml

Roeorganisms DFMQ Oxolinic acid Nalidixic acid

Gram-negative bacteria:

Sal, typhi (02A) ** 2 0.4 10

Sai, typhi (02B) 0.4 0.4 2

Sal, typhosa (02D) <0.08 0.4 2

Sal, typhimurium (03A) 0.4 0.4 2

Sal, typhimurium (03C) 0.4 0.4 2

Sai, typhimurium (03K) <0.08 <0.08 2

Sai, gallinaran (04C) 2 2> 10

Sal, gallinarum (04D) 0.4 0.4 10

Sal, choleraesuis (18F) <0.08 <0.08 2

SHIG. dysenteriae (27A) 0.4 0.4> 10 E. ol (06C) 2 2> 10 E. ol (061) 10 10> 10 E. ol (06J) 0.4 0.4 2 E. ol (06K) ) 0,4 0,4 10 E. ol (06L) 0,4 0,4 10 E. ol (06M) 0,4 0,4 10 E. ol (06S) 0,4 2 10 E. ol (06V) ) 0,4 0,4 2 E. ol (06X) 22 10 E. ol (06-2B) 2 2> 10 E. ol (06-2D) 22 10 E. ol (06-2F) 0,4 0 .4 2 E. ool (06-2L) 10 10> 10 E. ool (06-2M) <0.08 <0.08 2 (continued ...) *) Brain-heart infusion solution, 20 hours incubation at 37 ° C **) These figures represent the specific type and source of the organism 10 661 75

Table I (continued ...)

Small snow prevention test concentrations *

Kbeorgani smit yg / ml _DEMQ Oxolinic acid Nalidixic acid

Pseud, aeruginosa (11B) 10 2> 10

Pseud, aeruginosa (11C) 2 2> 10

Pseud, aeruginosa (11D) 10 10> 10

Pseud, aeruginosa (11G) 10 10> 10

Pseud, aeruginosa (111) 2 2> 10

Pseud, aeruginosa (1U) 10 2> 10

Proteus vulgaris (14P) 2 2> 10

Proteus sp. <0.08 <0.08 2

Kleb. aerobacter (20F) 2> 10> 10

Ser. marcescens (22) 0.4 0.4 2

Aero, cloacae (39A) <0.08 <0.08 2

Grayrin-positive bacteria;

Bac. subtilis (07A) <0.08 <0.08 0.4

Staph, aureus (08F) 0.4 0.4 2

Strep, pyogenes (10V) <0.08 <0.08 10 *) Brain-heart infusion solution, 20-hour burial at 37 ° C B. In vivo (in living organisms) 1. Escherichia coli (mouse infections)

Female mice weighing about 20 g were infected by injecting a sufficient number of E. coli cells through the peritoneum to cause 85-100% mortality within 3 days of infection. Groups of 12 mice thus infected were orally administered the compound suspended in water by intubation in amounts corresponding to 40, 20, 10 and 5 mg / kg at the time of infection and again 4 hours after infection. Mice were observed for 72 hours and the experiment was then terminated. The effective dosage for rescuing 50% of mice (ED5Q) was calculated by the Reed-Muench method (Reed, L.J., Muench, H., A. Single Method of Estimating 50% Endpoints, Am. J. Hygiene 27 (1939) 493-497). The results obtained are shown in Table 2.

11 66175 2. Staphylococcus aureus (mouse infections) The same methods were used as in the previous experiment except that the concentrations were 400, 200, 100 and 50 mg / kg. The ED- (effective dosage to save 50%) is shown in Table 2.

Table 2 Effects of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in Escherichia coli and Staphylococcus aureus infected mice.

ED 1 (mg / kg) 50

Escherichia coli Staphylococcus aureus 9.9 149 ^ Reed Muench C. General pharmacological testing

Method White female mice weighing approximately 16-20 g or rats weighing 70-90 g and fasted for 17-24 hours were each orally administered 0, 4, 12, 36, 108 or 324 mg of test drug (or standard). in kg doses. Mice were monitored every 0.5, 2, 5, and 24 hours after drug administration for survival and signs of ataxia, impaired vertical detection, hyperthermia or hyperthermia (abnormally low or high body temperature), irritability when treated and anorexia (loss of appetite). Rats were observed at 1, 2, 4, 6, and 24 hours after drug administration, respectively, except that they were not subjected to an anorexia test.

Ataxia - A mouse or rat was placed upright on a bench with its back to the observer. Exercise coordination in target movements expressed by abnormal gait or lack of punctuality was considered ataxia. Mice that did not spontaneously run or walk were gently pushed.

Vertical Direction Testing - Mice or rats were waved from the tail end down toward a 1.27 cm (30.5 cm) diameter, 30.5 cm long vertical sticky adhesive tape coated rod. If an animal could not grip the rod with its forepaw, if it slipped or could not move when pushed, its ability to detect its vertical direction was considered impaired.

Body temperature - Rectal temperature was measured in mice and rats using the KC-1 thermocouple probe. Body temperatures that deviated below the mean body temperature of the experimentally studied observation animals by more than twice the mean deviation calculated from it were considered hypothermia, while hyperthermia was defined as deviations of more than two of the above-mentioned units above the mean body temperature.

Arousal and irritability - Increased voluntary business, running, and jumping prior to treatment were recorded as arousal. Jumping, pounding, biting, and whining during treatment were recorded as irritability.

Anorexia - After a half hour test period, each mouse was transferred to a private, the Lucite * clear division (13.3 cm x 12.7 cm x 12.7 cm) with a 0.64 cm x 0.64 cm vanunkiverkkolat-acetate. Inside each compartment was a piece of black Lucite rod (13 cm x 1.2 cm x 1.2 cm) with 10 wells (0.8 cm in diameter), each containing 0.05 ml of 50% sweetened condensed milk. After 30 minutes, the number of milk points consumed was calculated. 5 mice per dose can drink up to 50 points (2.5 ml of milk). If the amount of milk consumed by five mice was 15 points or less, it was considered anorexia.

Results - EDcn, calculated dosage amount, after which 50%

- bO

of the experimental animals would have reacted, were calculated for each of the described parameters of the compound of the invention and the standard drugs; the results obtained are shown in Tables 3 and 4.

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is 66175

Example 1 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester

Method A:

A mixture of 13 g of 6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and 10.3 g of NaCl 2 H 2 in 150 ml of ethanol is placed in a vessel and 13.2 g of HCF2Cl: a. The vessel is tightly closed, the temperature is raised to 80 ° C and kept for 8 hours. The cooled mixture is poured into CH 2 Cl 2 and the solid precipitate is collected by filtration, dissolved in hot CH 2 Cl 2 and filtered hot to remove unreacted starting material. After cooling, the solid product is isolated by filtration, mp 218-219 ° C.

Method B:

To a mixture of 10 g of 6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester in 50 ml of diethylene glycol dimethyl ether (diglyme) is added, maintaining the temperature at 160-165 ° C, to 50 ml. diglyme solution containing 13 g of sodium chlorodifluoroacetate. When the addition is complete, the mixture is heated at 163 ° C for an additional 0.5 h, cooled and poured into water. The solid precipitate is isolated by filtration and purified according to Method A, melting point 219-220 ° C.

Its IR (infrared) and NMR (nuclear magnetic resonance) spectra are similar to those obtained by Method A.

Analysis: Calculated: (C 14 H 11 F 2 NC) δ · C: 54.03, H: 3.56, N: 4.50 Found: C: 54.03, H: 3.50, N: 4.64.

Example 2 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 27.5 g of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3 A mixture of quinolinecarboxylic acid ethyl ester and 600 ml of 6N-hydrochloric acid is refluxed for 1.5 hours. The mixture is diluted with 1 liter of water, cooled and filtered. The solid product is triturated to dryness with cold ethanol and filtered to give 24.5 g of the desired product, mp 327-8 ° (decomposes).

66175 BC

Analysis: Calculated: C 12 H 7 F 2 O 5 * C: H: 2 * 49, N: 4.95 Found: C: 50.95, H: 2.54, N: 4.84.

Example 3 N, N-Diethylaminoethyl ester of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxy-3-quinolinecarboxylic acid

A mixture of 5.0 g of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 4.2 g of PClg in 170 ml of dry benzene is boiled under reflux. 7 hours. The mixture is cooled and filtered to give the desired acid chloride.

The acid chloride is suspended in 100 ml of dry benzene and 20 g of 2- (N, N-dimethylamino) ethanol are added. The resulting mixture is refluxed for 5 hours and concentrated under reduced pressure. Ice water is added to the residue, which is then basified by adding aqueous NaOH. The solid precipitate is collected by filtration and recrystallized from CH 2 CN, m.p. 164-165 ° C.

Analysis: Calculated: C 18 H 20 F 2 N 2 O 5; C: 56-54'H: 5 · 2Ί · N: 7'33 found: C: 56.54, H: 5.30, N: 7.37.

Example 4 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 3- (N, N-dimethylamino) -n-propyl ester

The product can be obtained by replacing the 2- (N, N-dimethylamino) ethanol of Example 3 with 3- (N, N-dimethylamino) -N-propanol.

Claims (1)

A process for the preparation of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and its esters of the formula I and R 2 H 'p wherein R is hydrogen or / 1 - (CH 2> n - <* R 2 R 1 and R 2 independently represent C 1 -C 4 alkyl; and n is 2 or 3; and for the preparation of their pharmaceutically acceptable salts, characterized in that the compound of formula II CF 2 H wherein R 2 is -CH 2, -C 2 H 2 - or -C 1 H 2 O is hydrolyzed with dilute acid and then, if desired, first contacted with PCI, and the resulting product is further contacted in an inert solvent with a compound having Formula III / * 1 H ° - (CH 2) n N (III) 1 wherein R 2 and n are as defined above, and if desired the product obtained is converted into a pharmaceutically acceptable salt.