DE2706781A1 - CHINOLINE DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to quinoline derivatives with antibacterial properties.

US Pat. No. 3,287,458 describes antibacterially effective 6,7-Methylenedioxy-1,4-dihydro-4-oxo-quinolinecarboxylic acids, which are in the 1-position with a lower alkyl radical are substituted or various other substituents contain. The compound in which this substituent is ethyl is commonly known as oxolinic acid.

Oxolinic acid is a potent antibacterial agent, but undesirable side effects are reported to be profound. Claire E. Cox (Delaware ^M edical Journal, Nov. 1970, p 327) and Kershaw and Leigh (Journal of Antimicrobial Therapy JL (1975) 311-315) pointed out that due to their Toxlzität "not as the main drug should be used for the therapy of urinary tract infections ".

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Another quinoline derivative currently on the market for the treatment of urinary tract infections is nalidixic acid. It was initially shown to be effective for this purpose, but further experience has been gained with nalidixic acid show that their benefit is due to their tendency to quickly provoke resistance in bacteria, is limited. (A.R. Ronald et al., New England Journal of Medicine 275 (1966) 1081-1088). Furthermore, also occur in proportion with nalidixic acid severe side effects (see Cox, loc.cit., p. 327).

The compounds according to the invention are also highly effective antibacterial agents, but they are effective In contrast to the known compounds, no undesirable side effects arise. With the general selection pharmacological studies, oxolinic acid induced ataxia, anorexia, arousal, and irritability, while Nalidixic acid caused some ataxia and anorexia. In contrast, the connections called according to the invention, none of these harmful side effects was found (Tables 3 and 4).

The invention relates to compounds of the formula

C-O-R

(I)

where R = hydrogen or - (CH_) -N

2 η

R, and R ₂ independently stand for C.-C.-alkyl radicals and η = 2 or 3, and their pharmaceutically acceptable salts, processes for their preparation and they contain

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Trendy pharmaceutical preparations for the treatment of bacterial infections in warm blooded animals.

Particularly preferred of the compounds according to the invention is due to their strong antibacterial properties Effect and the absence of undesirable side effects, the l-difluoromethyl-ejV- -. 3-quinolinecarboxylic acid.

The N, N-diethylaminoethyl ester of l-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-S-quinolinecarboxylic acid is also preferred.

The pharmaceutically harmless salts of the acid include those with certain metals such as sodium and potassium and calcium and also the salts made with ammonium. The salts are prepared by adding an alcoholic or aqueous solution of MOH (where M is the metal is) to a solution or suspension of the acid in a solvent, e.g. dimethylformamide, dimethyl sulfoxide or ethanol, and the salt formed is filtered off.

As pharmaceutically suitable acid addition salts of

Esters are the salts prepared with known physiologically harmless acids. Examples are the hydrochlorides, sulfates, nitrates, phosphates, citrates, tartrates and maleates.

The esters used as starting materials for the process are prepared in the following manner, which can be represented by Reaction Scheme 1 below: (J.Med.Chem. Λλ_, 16ο, 1968). 3,4-methylenedioxyaniline (A), which is commercially available, is reacted with dialkyl alkoxymethylenemalonate (B) at 70 ° to 100 ⁰ C with or without solvent (usually ethanol) to give a compound of formula C. Compound C is obtained by heating in Dowtherm A

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-A-

(Mixture of diphenyl ether and diphenyl) at 250 ° to j 255 ° C in the desired starting material ester (C) '■ converted.

Reaction scheme 1

+ RaO-CH = C:

, COOB ₃

NH2

"COOBa (B) Ra

Heat

COORs

00R ₃

The compounds according to the invention are prepared in the following manner according to Reaction Scheme 2 below manufactured: I.

The difluoromethyl radical 6CFp) is attached to the starting | material serving ester (D) attached by reacting with HCF ₂ Cl in the presence of a base, e.g. R ₄ OM, where R. is an 'alkyl radical, e.g. methyl, ethyl or t-butyl, and M is an alkali metal, e.g. sodium, potassium or lithium is reacted. Suitable solvents for this reaction I, can R 4 OH wherein R ₄ has the abovementioned meaning, or other aprotic solvents such as dimethylformamide, dimethyl sulfoxide or ethylene glycol- 'dimethyl ether can be used. The reaction temperature

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may be about 50 to 100 ⁰ C.

The difluoromethyl radical can be attached to the ester used also by pyrolysis of an alkali salt of chlorodifluoroacetic acid in an aprotic solvent, e.g. Diethylene glycol dimethyl ether or diethyl malonate, are added at elevated temperature.

The Difluormethylverblndung (E) is hydrolyzed by being heated for about 1-110 ⁰ C to 2 hours in dilute hydrochloric acid to about 80 °, wherein the acid (F) is obtained. This acid is converted to its acid chloride _{using PCl 5.} The esters (H) are prepared by reacting the acid chloride (G) with the suitable amino alcohol in an inert solvent, for example benzene or toluene.

In addition to the compounds of the formula I, there are also the alkyl esters (E) and that formed as intermediates Acid chloride (G) new compounds.

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Reaction scheme 2

COOR ₃

R ₃ = C ₁ -C ₃ alkYl

1O ^ ζ

COOR ₃

CPaH

(E)

H +

COCl

<Γ

PCIs

CFaH COOH

CPaH

(P)

RAW

COOR

CF ₂ H

(H)

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example 1

1-Difluoromethyl-e ^ -methylenedioxy-l ^ -dihydro ^ -oxo-S- quinolinecarboxylic acid thyester

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 NaOC ₂ H ₁ . in 150 ml of ethanol is placed in a bomb, whereupon 13.2 g of HCF_C1 are added. The bomb is sealed and the temperature to 80 ° C and held for 8 hours at 80 ⁰ C. The cooled mixture is poured into water. The solid precipitate is filtered off, dissolved in hot CH-CN and filtered hot in order to remove unreacted starting material. After the filtrate has been cooled, the solid product with a melting point of 218-219 ° C. is isolated by filtration.

Method B; A solution of 13 g of sodium chlorodifluoroacetate in 50 ml of diglyme is added to a mixture of 10 g of 6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolincarboxylic acid ethyl ester in 50 ml of ethylene glycol dimethyl ether (diglyme), while the temperature is 16O -165 ° C is maintained. After the addition is complete, the mixture is heated to 163 ° C. for a further 30 minutes, cooled and poured into water. The solid precipitate is filtered off and purified as in method A. Melting point 219-220 ° C. The infrared spectrum and NMR spectrum of the compound are identical to the spectra of the compound prepared according to method A.

Educational analysis;

Calculated for 30 found:

C. 3 H 4th N 54, 03 3 , 56 4th , 50 54, 03 , 50 , 64

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Example 2

1-difluoromethyl-e ^ -methylenedioxy-l ^ -dihydro ^ -oxo-S- quinolinecarboxylic acid

A mixture of 27.5 g of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ester and 600 mg of 6N hydrochloric acid is refluxed for 1.5 hours. The mixture is mixed with 1 l of water diluted, chilled and filtered. The solid product is triturated with cold ethanol and filtered, whereby 24.5 g of the desired product from melting point to 328 "C (dec.) Can be obtained.

Elemental analysis:

Calculated Found:

Calculated for ^c i2 ^H 7 ^F 2 ° 5 ^:

C. 2, H 4th N 50, 89 2, 49 4th , 95 50, 95 54 , 84

Example 3

1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3- quinolinecarboxylic acid -Ν, Ν-dlethylaminoethyl ester

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 j ^pc * 5 ⁱⁿ 17 ° ml dry benzene is 17 hours on Heated reflux condenser. The mixture is cooled and filtered to give the desired acid chloride will.

The acid chloride is suspended in 100 ml of dry benzene. 20 g of 2- (N, N-diethylamino) ethanol are added to the suspension. The resulting mixture is refluxed for 5 hours and concentrated under reduced pressure. Ice water is added to the residue and the mixture is then made basic by adding aqueous NaOH. The solid precipitate is filtered off and _{recrystallized from CH 3} CN. Melting point 164-165 ⁰ C. Elemental analysis: CHN

Calculated for ^{c i} 8 ^{H 20 F} 2 ^N 2 ° 5 i 56.54 5.27 7.33 Found: 56.54 5.30 7.37

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Example 4

1-difluoromethyl-6, T-yy ^ quinolinecarboxylic acid - 3- (N, N-dimethylamino) -n-propyl ester

The product can be prepared in the manner described in Example 3, but using 3- (N, N-dimethylamino) -n-propanol instead of 2- (N, N-dimethylamino) ethanol.

Dosage forms

The antibacterial agents according to the invention can be used to exert their antibacterial activity on any any way in which the active ingredient comes into contact with the focus of infection in the body of warm-blooded animals is brought to be administered. Administration can be by any conventional means applicable to drugs are available, either as a single drug or in combination with drugs. The antibacterial agents can be administered alone, but they are generally administered with one pharmaceutically acceptable carrier, which is chosen according to the chosen route of administration, according to the usual administered in pharmaceutical practice.

The dose administered will of course vary depending on known factors such as pharmacodynamics Properties of the respective agent, the route of administration, the age, health status and weight of the recipient, the type and intensity of symptoms, the type of concurrent treatment, the frequency of treatment and the desired effect. In general the daily dose of the active ingredient can be about 5 to 100 mg / kg of body weight. Preferably 5 to 10 mg / kg are administered daily in divided doses two to four times daily.

The drug forms that are suitable for internal administration

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range, contain about 5 to 500 mg of active ingredient per unit. These pharmaceutical preparations generally contain the active ingredient in an amount of about 0.5 to 95% by weight based on the total weight of the preparation.

The active ingredient can be taken orally in solid drug forms, e.g. capsules, tablets and powders, or in liquid drug forms, e.g. elixirs, syrups and suspensions. It can also be used parenterally in drug forms that are a sterile liquid Contained as a carrier material, are administered.

Gelatine capsules contain the active ingredients and powdered carriers, e.g. lactose, sucrose, mannitol, Starch, cellulose derivatives, magnesium stearate and stearic acid. Similar diluents and extenders can used to make tablets. Tablets can be coated with sugar or a film, to hide any unpleasant taste and to protect the tablet from the atmosphere, or they can be provided with a stomach-resistant coating for selective disintegration in the gastrointestinal canal.

Liquid pharmaceutical preparations for oral administration may contain colorings and flavorings, to make it more comfortable for the patient to take it.

In general, are water, suitable oils, saline, aqueous dextrose (glucose) and the like Sugar solutions and glycols, e.g. propylene glycol and polyethylene glycols, as carriers for parenteral solutions suitable. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredients, suitable stabilizers and, if necessary, buffer substances. Antioxidants,

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e.g. sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination are suitable as stabilizers. Likewise, citric acid and its Salts and sodium EDTA used. Parenteral solutions can also contain preservatives, e.g. benzalkonium chloride, Methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E.W. Martin, a standard ΙΟ Manual in this field.

Suitable pharmaceutical forms for the administration of the compounds according to the invention are described below.

Capsules

A large number of unit capsules are manufactured by using conventional two-part hard gelatin capsules each with 100 mg of the powdered active ingredient, 200 mg of lactose, 30 mg of talc and 10 mg of magnesium stearate will.

20 capsules

A mixture of the active ingredient in soybean oil is prepared and placed in gelatin with a positive displacement pump injected to obtain soft gelatin capsules containing 100 mg of the active ingredient. the Capsules are washed in petroleum ether and dried.

Tablets

A large number of tablets are prepared by conventional methods so that one tablet is 250 mg of active Ingredients, 50 mg ethyl cellulose, 5 mg colloidal silicon dioxide, 5 mg magnesium stearate, 10 mg microcrystalline Contains cellulose, 40 mg corn starch and 150 mg lactose. Suitable covers and blankets can

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• / tsr-

can be applied to improve palatability or to delay absorption.

Injection solution

A parenteral suitable for administration by injection The preparation is made by stirring 5% by weight of the active ingredient in water, the 10% by volume of propylene glycol contains, and sterilization of the solution prepared by filtration.

suspension

An aqueous suspension for oral administration

she
is prepared so that / per 5 ml contains 100 mg of finely divided active ingredient, 500 mg of gum arabic, 5 mg of sodium benzoate, 1.0 g of sorbitol solution USP, 5 mg of sodium saccharin and 0.025 ml of vanilla tincture.

15 possible uses

The use of the compounds according to the invention as antibacterial agents in warm-blooded animals is illustrated by the following microbiological data for 1-difluoromethyl-ejT-methylenedioxy-l ^ -dihydro- ^ oxo-B-quinoline- ' carboxylic acid.

A. In vitro: Minimum Inhibitory Concentration (MIC)

The compound was determined using the standard bacteriological tube dilution test to determine the Minimum inhibitory concentration for various bacteria!

tested. Stock cultures of the ones listed in Table 1, Bacteria were grown in bacterial culture media at 37 ° C. overnight and placed in culture tubes on an i previously determined "concentration suitable for the test" diluted. The compound was drawn in such quantities:

assumes that final concentrations of 10, 2, 0.4 and 0.08 µg / ml were obtained. After incubation for 18 hours at 37 ° C it was determined whether growth of the bacteria:

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- ta- -

• 46.

had taken place. The smallest concentration of the compound at which the bacteria can grow completely is inhibited is the minimum inhibitory concentration. The results are given in Table 1.

Table 1

In vitro activity of 1-difluoromethyl-6,7-methylene-dioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (DFMQ), oxilicic acid and nalidixic acid

Minimum inhibitory concentrations Ο.ί « acid Test microorganism 0.4 ml 0.4 lü 0.4 2 Gram negative bacteria DFMQ Oxolinic Acid Nalidixine 0.4 2 SaI. typhl (02A) «* <0.08 2 SaI. typhi (02B) 2 2 Sal.typhosa (02D) 2 0.4 2 SaI. typhirauriun (03A) 0.4 <0.08 > 10 SaI. typhinuriun (02C) <0.08 0.4 10 SaI. typhir.uriun (03K) 0.4 2 2 SaI. qallir.arun (04C) 0.4 10 > 10 SaI. gallinarum (04D) <0.08 0.4 > 10 Sal.choleraesuis (18F) 2 0.4 > 10 Shiq. dysenteriae (27A) 0.4 0.4 2 E. coli (06C) <0.08 0.4 10 E. eoli (061) 0.4 2 10 E. coli (06J) 2 0.4 10 E. coli (06K) 10 2 10 E. coli (06L) 0.4 2 2 j E. coli (06M) 0.4 10 E. coli (06S) 0.4 > 10 ^! E. coli (06V) 0.4 E. coli (06X) 0.4 E. coli (06-23) 0.4 2 2

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Table 1 (cont.)

Test microorganism Minimum inhibitory concentration, µg / ml 2
0.4
10
<0.08
2
2 10
2
2
> io
> io DFMQ Oxolinic Nalldixic Acid 10 > io E. coli (06-2D)
E. coli (06-2F)
E. coli (06-2L)
E. coli (06-2M)
Aeruginosa (113)
Pseud. Aeruginosa (HC) 2
0.4
10
<0.08
10
2 10 > io Pseud. Aeruainosa (HD) 10 2 > io Pseud. Aeruqinosa (HG) 10 2 > 10 Pseud.aeruginosa (HI) 2 2 > io Pseud.aeruginosa (HJ) 10 <0.08 2 Proteus vulgaris (14P) 2 Proteus sp. <0.08 0.4 2 Adhesive, asrobacter (20F) 2 <0.08 2 Ser. raarcescens (22) 0.4 Aero, cloacae (39Λ) <0.08 <0.08 0.4 Gram-Positive Bacteria: 0.4 2 Bac. subtilis (07A) <0.08 <0.08 10 Staph. aurous (03?) 0.4 Strep, pyogercos (10V) <0.08

25 "» brain-heart infusion broth, incubated for 20 hours at 37 ° C.

«« These numbers identify the respective type and the Origin of the microorganisms.

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B. In vivo

• 49 *

1) Escherichla coil (mouse infections)

Female white mice weighing approximately 20 g were infected by intraperitoneal injection with such numbers of Escherichia coli cells that the dose would be lethal to 85-100% of the animals within 3 days of infection. Groups of 12 infected mice each received orally by intubation the compound suspended in water at a dose of 40, 20, 10 and 5 mg / kg at the time of infection and again 4 hours after the time of infection. The mice were observed for 72 hours, after which the test was discontinued. The effective dose to rescue 50% of the mice (ED, -,.) Was calculated according to the Reed-Muench method (LJReed and H.Muench, "A Single Method of Estimating 50% Endpoints ¹¹ , Am. J. Hygiene 27 (1938) 493-497) The results are given in Table 2.

2) Staphylococcus aureus (mouse infections)

The same method as for Escherichla coli was used, with the difference that the concentrations of the compound were 400, 200, 100 and 50 mg / kg. The ED-Q values are given in Table 2.

Table 2

Effects of 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid on mouse infections with Escherichia coli and Staphylococcus aureus

ED ₅₀ * mg / kg

Escherichia coll Staphylococcus aureus

30 9.9 149

• Reed Muench

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C. General pharmacological studies

method

Female white mice that had been had for 17 to 24 hours! fasted and had a weight of 16-20 g, ι or rats of 70-90 g each received the test connection ^! manure (or comparative compound) orally at a dose of 0, 4, 12, 36, 108 or 324 mg / kg. The mice were '0.5, 2, 5 and 24 hours after the administration of the _; Observed by means of the number of surviving animals, signs of ataxia, loss of the vertical rod, hypothermia or hyperthermia, agitation and irritability during handling, and loss of appetite (anorexia). The rats were observed in the same manner 1, 2, 4, 6 and 24 hours after administration of the agent, but the anorexia test was not performed.

I was leading.

Ataxia: The mouse or rat was placed upright on the work table, looking away from the observer. Disturbance of the coordination of movements, manifested in abnormal gait or lack of accuracy in deliberate movements, represented ataxia.! Mice that did not walk or walk spontaneously were easily nudged.

Vertical stick: The mouse or rat was waved by the tail with its head pointing down at a > 30.5 cm long vertical stick covered with adhesive tape and 12.7 mm in diameter (25.4 mm in rats ) would have. The inability to take the baton '■ with his front paws, or _slipping; Inability to move after bumping represented loss of the vertical rod. '

Body temperature: The rectal temperatures of the mice and rats were measured with a KC-1 thermocouple probe. Temperatures with more than two standard

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deviations below the mean temperature of the comparison animals treated only with the carrier Hypothermia represents while temperatures are greater than, two standard deviations above the mean as> Hyperthermia. ;

Agitation and irritability; Increased spontaneous motility, running and jumping before grasping were noted as excitement. After grasping, jumping, fighting, biting, and squeaking were noted as irritability.

Anorexia: After the test period of 0.5 hours, each mouse in a bright individual room from the material of polymethyl methacrylate ( "Lucite") (13.3 χ χ 12.7 12.7 cm) with a wire mesh floor having a mesh of 0.64 was' χ 0.64 cm transferred. In each cage was a piece of a black stick made of "Lucite" (13 cm 1.2 cm 1.2 cm) with 10 individual wells (0.8 cm 'diameter), each 0.05 ml 50% contained sweetened condensed milk. 30 minutes later, the number of servings of milk consumed was counted. Five mice can ^: - drink a maximum of 50 servings (2.5 ml of milk) per drug. Fifteen or fewer servings of milk consumed by five mice was considered anorexia.

Results;

An ED ₅₀ , the calculated dose at which 50% of the test animals responded, was calculated for each described parameter for the compound according to the invention and the standard medicaments. The ED ^ Q i

are listed in Tables 3 and 4.

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Table 3

General pharmacological experiments with 1-difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (DFMQ), oxolinic acid and nalidixic acid in mice

link

Animal number Mortality 24 hours. ED ₅₀ values

Ataxia Senkr. Ano- Hypo- HyperStab rexie ther- thermie mie

Excitement

DFMQ

Mouse> 450. > 450. > 45O. > 450. > 450. > 450. > 450. > 450.

Cxolinic acid

mouse

> 450. 3.2 4.5 21. > 450. > 450.

8. 36.

Nalidixic acid mouse

10

> 450.

150, 187, 180, 187. > 450. > 450. > 450.

cn ■ ο oo

Tabel

General pharmacological experiments with 1-difluoromethyl-6,7-methylenedioxy-1, 4-dihydro-4- oxo-3-quinolinecarboxylic acid (DFMQ), oxolinic acid and nalidixic acid in rats

link

Animal number Mortality 24 hours

ED ₅₀ values

Ataxia Senkr. Ano- hypo- hyper-excitable-irritable-rod rexie ther- therm mie mie

O (O OO U)

DFMQ

Oxolinic acid

Rat 5> 324. > 324. > 324.

Rat 5> 324.

97, 187.

> 324.> 324. > 324. > 324

> 324- 121. 62.> 324.

Nalidixic acid rat 5> 324. 187. 360. -> 324.> 324. > 324. > 324.

Claims (8)

Claims and independently for C.-C ~ -alkyl radicals and η for 2 or 3 stand, and their pharmaceutically acceptable salts. 2) 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. 3) 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-S-quinolinecarboxylic acid N, N-diethylaminoethyl ester. 4) 1-Difluoromethyl-6,7-methylenedioxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid S-CNjN-dimethylaminoJ-n-propyl- • ester. 5) Process for the preparation of compounds of the formula C-O-R Il CFaH where R is hydrogen or - (CH. R ^ and R- are independently C, -C - alkyl radicals and η is 2 or 3, and their pharmaceutically acceptable salts, i characterized in that a compound of the ; formula 709835/0731 ORIGINAL INSPECTED COOR ₃ CP ₂ H wherein R _{3 is} -CH ₃ , -C ₃ H ₅ or -C ₃ H ₇ , hydrolyzed in dilute acid, and the product then optionally first with PCl ₅ and then in an inert solvent with a compound of the formula R-. HO- (CH ₂ ) _n -N brings together. 6) compounds of formula COX CFaH
wherein X is OCH ₃ , -OC ₂ H ₅₁ -OC ₃ H ₇ or -Cl. 7) Process for the preparation of compounds according to claim 6, characterized in that a compound of the formula COOR3 wherein R _{3 is} CH ₃ , C ₂ H ₅ or C ₃ H ₇ stands, merges with the remainder of CFp in an aprotic solvent, then optionally hydrolysed in dilute acid and brought into contact _{with PCl 5.} 709835/0731 8) Pharmaceutical preparations containing a compound according to claim 1 to 4 and a pharmaceutical ι harmless carrier. 709036/0731