HU199465B - Process for producing new glycolamide esters and pharmaceutical compositions comprising same as active ingredient - Google Patents

Abstract

Prepn. of novel glycol-amide esters of general formula (I) and active acid adducts for pharmaceutical use. In formula (I), Z represents a -CH2= gp. or a nitrogen atom, R = 1-4C alkyl gp. or as in this case, an alkyl gp. substd. piperazino- or a CH2-NHR5 gp. substd. pyrrolidono-gp., where R5 = hydrogen atom or 1-4C alkyl gp.; R1 = hydrogen or fluorine atom or R and R1 combined, represent a -O-CH2-O- gp. R2 = R3 = 1-4C alkyl gps.; X = nitrogen atom or a =CR6 gp. where R6 = hydrogen or fluorine atom, R4 = 1-4C alkyl, 3-4C cycloalkyl or a 1-4C alkyl gp. substd. amino gp.; in this case a 6-10C aryl gp. or a gp. of general formula -CHR10-CR7R8R9, where R7, R8, R9 are identical or dissimilar, hydrogen and/or fluorine atoms; R10 = hydrogen atom or combined R10 and X represent a -CH2O-C= gp., and n = 1 or 2.

Description

The present invention relates to novel glycolamide esters of formula (I) having antibacterial activity and to pharmaceutical compositions containing the esters of formula (I).

Quinoline-3-carboxylic acids and analogues are known to be widely used in the treatment of bacterial diseases (Prog. Drug. Res. 1977, 21, 9, Antimicrobiol Agents and Chemotherapy 1980, 17, 103). The potency of the compounds, as known in vitro, due to their unfavorable pharmacokinetic properties, may not always be fully exploited (J. Antimicr. Chemother. 1984, 13, Suppl. B, 66, Eur. J. Clin. Microbiol. 1984, 3, 355, Fortschr. Antimicrob. Antineoplast. Chemother. 1984, 3, 695).

Surprisingly, it has now been found that the glycolamide esters of formula (I) according to the invention have a therapeutically advantageous pharmacokinetic property.

In the general formula (I), if

X = CH = n = 1,2

R = optionally substituted C, _ ₄ alkyl substituted piperazino

R = hatogénatom

R ₂ and R ₃ == C, - ₄ alkyl

R ₄ = C, _ ₄ alkyl, or C _3-4 cyclo, alkyl, or where

X = N atom then

R) ^ 2 (^ 3) R ₄ = C, _ ₄ alkyl

R 1 = hydrogen, n = 1 or 2.

The term C 1-4 alkyl means a straight or branched alkyl group. For example, methyl, ethyl, isopropyl, tert-butyl and the like.

The term C3-4cycloalkyl means, for example, methylcyclopropyl, cyclopropyl.

The term alkali metal is preferably sodium, lithium or potassium.

The term alkaline earth metal preferably refers to a calcium atom, a magnesium atom.

As used herein, the term halogen means chlorine, bromine, iodine.

According to the process of the present invention, the novel compounds of formula (I) may be prepared by reacting a compound of formula (II)

R ¹ , R ¹ , R ⁴ and X are as defined above, Y is an alkali metal, alkaline earth metal, or silver ion or an organic ammonium group) with a halide of formula (III)

R ^2, R ³ and n are as defined above and L is chlorine, bromine or iodine) is reacted.

The reaction is preferably carried out in a solvent. If desired, an excess of the halide of general formula (III) may also be used as the solvent. Preferred solvents include dipolar aprotic solvents such as ketones, preferably acetone, methylethylketone, nitriles, preferably acetonitrile, acid amides, preferably formamide, N, N-dimethylformamide, Ν, Ν-dimethylacetamide, sulfoxide, preferably dimethyl . The reaction may be carried out, if desired, in the presence of an aprotic solvent, such as a halogenated hydrocarbon, preferably dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, and a protic solvent such as alcohols or water, and mixtures thereof.

The reaction can be carried out over a wide temperature range. At higher temperatures, shorter reaction times may be used. At temperatures above the boiling point of the particular solvent, the reaction is carried out in a closed system. The reaction is preferably carried out at a temperature in the range of 20 to 200 ° C.

The molar ratio of reacting compounds of formula (II) and (III) is preferably in the range of 1: 1-5. The resulting compound of formula (I) can be isolated from the reaction mixture in a manner known per se. For example, the solvent may be distilled off under reduced pressure and the residue crystallized from a suitable solvent. Alternatively, the reaction mixture is diluted with water and the resulting compound of formula (I) is extracted from the aqueous solution with an organic solvent immiscible with water.

The compounds of formula (II) and (III) used as starting materials are partially known or may be prepared from known compounds by methods known per se.

The compounds of formula (I) may be used in medicine in the form of compositions containing the active ingredient and inert solid or liquid organic or inorganic carriers. The formulations are prepared by methods well known in the art of pharmaceutical manufacture. The compounds of the formula I are useful in the treatment of diseases of both human and veterinary origin, preferably of bacterial origin.

The compositions may be formulated for oral or parenteral administration, e.g. in the form of tablets, dragees, capsules, lozenges, powder mixtures, aqueous suspensions or solutions or injectable solutions or syrups. The formulations may contain suitable solid diluents or carriers, or a sterile aqueous solvent or non-toxic organic solvent. Sweetening or flavoring agents may be added to the compositions for oral administration.

Tablets for oral administration may be formulated as carriers, e.g. lactose, sodium citrate, calcium carbonate, and disintegrants (eg starch, alginic acid), lubricants (eg talc, sodium lauryl sulfate, magnesium stearate). The carrier for the capsules may be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying or suspending agents. The organic solvent slurry diluent is ethanol, glycerol, chloroform, and the like. may.

Formulations for parenteral administration may be formulated as a suspension in a suitable medium (e. G., Peanut oil, sesame oil, polypropylene glycol, or water). Injection formulations may be administered intramuscularly or intravenously or subcutaneously. Injectable solutions are preferably formulated in an aqueous medium and the pH is adjusted to a suitable level. The solutions may be prepared in isotonic saline or glucose solution if necessary.

The active ingredient content of the pharmaceutical compositions may vary within wide limits and may range from 0.005% to 90%.

The daily dosage of active ingredient may vary within wide limits and will depend upon the severity, age, weight, formulation of the active ingredient, and activity of the patient. For oral administration, the daily dose is generally between 0.05 and 150 mg / kg, and for inhalation or intravenous administration, it is usually between 0.001 and 50 mg / kg, once or several times a day. The above information is for guidance purposes only and may vary both upwards and downwards depending on the requirements of the case and the physician's instructions.

The following examples further illustrate the process without limiting the invention to the examples.

EXAMPLES

1.) 9.3 g of 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid are dissolved in ethanol containing 100 ml of potassium hydroxide and the solvent is distilled off under reduced pressure. The residue was dissolved in 100 ml of dimethylformamide and added to the solution

5.5 ml of 2-chloro-N, N-diethylacetamide are added. The reaction mixture was reacted at 60 ° C and after 8 hours the reaction mixture was poured into 100 ml of water. The aqueous reaction mixture was extracted three times with dichloromethane. The combined organic solution dried over magnesium sulfate was evaporated. The residue was crystallized from ethyl acetate (10.5 g (Ν ', Ν'-diethylcarbamoylmethyl) -1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate). mp 149-151 ° C.

Analysis calculated for C ₁₈ H ₂₃ N ₃ O ₄ : C, 64.33; H, 7.30; N, 13.24. Found: C, 64.45; C, 7.22; N, 13.20%

2.) 5.67 g of 1-ethyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and

Starting from 2.4 ml of 2-chloro-N, N-diethylacetamide and working as in the first example, 6.3 g of (Ν ', Ν'-diethylcarbamoylmethyl) - (1 -ephyl-6-fluoro- 7-piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylate) is obtained, m.p. 200-202 ° C.

Analysis for C ₂₂ H ₂ O ₄ Calculated 9FN ₄ O: C = 61.24%, H 6.54%, N 12.99%

F, 4.40; Found: C, 61.33; H, 6.61; N, 13.07.

F = 4.39%;

3.) 3.33 g of 1-ethyl-6-fluoro-7- (N'-methyl) piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 6.9 g of freshly calcined potassium The carbonate was stirred in 100 mL of acetone and 11 mL of 2-chloro-N, N-diethylacetamide was added to the reaction mixture. The reaction mixture was heated at reflux for 8 hours. After cooling, the acetone is distilled off under reduced pressure. The residue was dissolved in water (50 mL) and extracted with dichloromethane (50 mL) three times. The combined organic solution, dried over magnesium sulfate, was evaporated. The residue was crystallized from 30 ml of dichloromethane and 50 ml of diethyl ether to give 3.96 g (88%) of (N ', N'-diethylcarbamoylmethyl) - (1-ethyl-6-fluoro-7- (N)). (methyl) piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylate), m.p. 178-179 ° C. Analysis calculated for C ₂₃ H ₃ FN ₄ O ₄ : C, 61.86; H, 7.00; N, 12.55.

F, 4.26. Found: C, 61.42; H, 7.15; N, 12.34.

F = 4.21%;

4.) 2 g of 1-cyclopropyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

Starting from 2.1 g of potassium carbonate and 2.42 ml of 2-chloro-Ν, diet-diethylacetamide, working as in Example 3, 2.17 g of (N ', N'-diethylcarbamoylmethyl) - (1 cyclopropyl-6-fluoro-7-piperazino-4-oxo-1,4-dihydroquinoline-3-carboxylate), m.p.

Analysis calculated for C ₂₃ H ₂₉ FN ₄ O ₄ : C, 62.14; H, 6.58; N, 12.61.

F, 4.27; Found: C, 62.01; H, 6.71; N, 12.39.

F = 4.19%;

Presentation examples

5.) Composition of prolonged-release tablets containing 400 mg of active ingredient (based on 100 tablets)

Example 2 40.0 g

CMC-Na 4.5 g

Lactose 5.0 g

Gypsum 48.5 g

Stearic acid 5.0 g

Mg stearate 0.7 g

Talkum 1.4 g

Distilled water gives 100.0 g

6.) Adult suppository containing 100 mg of active ingredient (based on 100 suppositories)

Example 2 10.0 g

Tagat R 1 15.0 g

Softisan 378 15.0 g

Witepsol H 32 ad 300.0 g

-4HU 199465 Β

Claims (4)

1.) A process for preparing the esters of formula I wherein: X represents = CH 5 n = 1, 2 R = optionally substituted C, _ ₄ alkyl substituted piperazino R [= halogen Rj and RjbC1-4 alkyl ¹⁰ R ₄ = C, _ ₄ alkyl or C ₃ _ ₄ cycloalkyl group, or when X = N, then R) R 2 (R 3) R 4 = O, -4 alkyl R 1 = hydrogen and 15 n = 1 or 2, characterized in that a compound of the formula (II) - in which R, R ¹ , R ⁴ and X are as defined above and Y is an alkali metal - ²⁰ alkali earth metal, or a silver ion or an organic ammonium group (III) halide of the formula - is reacted with - wherein R ^2, R ³ and n are as defined above and L is chlorine, bromine, or iodine. 2.) The l. A process according to claim 1, wherein the reaction of a compound of formula (II) and (III) wherein R, R ¹ , R ² , R ³ , R ⁴ , X, Y, L, and n are as defined in claim 1. above in the presence of a solvent. 3. A process according to claim 2 wherein the solvent is a dipolar aprotic or protic solvent or an excess of the compound of formula (III). 4. A process for the preparation of a pharmaceutical composition, which comprises as an active ingredient a compound of formula (I) according to claim 1, wherein R, R ¹ , R ² , R ³ , R ⁴ , X and n are as defined in claim 1. and pharmaceutically acceptable excipients which are formulated according to the known pharmaceutical technology.