HU184992B - Process for producing bis-esters of methandiol - Google Patents

Abstract

The present invention relates to a process for the preparation of a bis-ester of a methanediol of formula (I) with penicillanic acid, wherein Y is a hydrogen atom or a hydroxyl group and the imidazolidinone side chain is derived from the alpha-aminophenylacetic acid. The process according to the invention is characterized by (a) reacting a compound of formula (II) wherein Y is acetone; or (b) a salt of a carboxylic acid of formula (III) wherein Y is a radical of the formula and M is a sodium, potassium, calcium or barium, tertiary ammonium or quaternary ammonium cation (IV); wherein X 5 is chloro, bromo or iodo, C 1-4 alkanesulphonyloxy, benzenesulfonyloxy or toluenesulphonyloxy; or (c) reacting a salt of a carboxylic acid of formula V wherein M is as defined above with a compound of formula VI wherein Y and X are as defined above. 184992 -1-

Description

The present invention relates to a process for the preparation of 6 '- (2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl) penicillanoyloxymethyl penicillanate 1,1-dioxide. One hydroxyl group of methanediol is esterified with hetacillin and the other hydroxyl group of methanediol is esterified with penicillanic acid 1,1-dioxide. These compounds are particularly valuable against penicillinase producing bacteria when administered orally to mammals. They are well absorbed from the gastrointestinal tract. After absorption, they are converted to provide unusually long-lasting serum levels of ampicillin and penicillanic acid 1,1-dioxide. The latter's penicillinase inhibitory activity enhances the action of ampicillin on bacteria producing penicillinase.

The compound of the present invention is an acetonide derivative of the compounds described in British Patent 2,044,255 and U.S. Patent 4,244,951. The serum half-life of the compound of the invention for ampicillin and penicillanic acid 1,1-dioxide is much higher than that of the compounds described in these patents.

Hetacillin (and its p-hydroxy analog) has also been described in the literature by Handcastle et al., J. Org. Chem. 897-899. (1966)]; J. Chem. Soc., (C) 1920-1922. (1971)].

Esters of hetacillin (and its p-hydroxy analogue) are also reported to be particularly suitable for oral use: (von Daehne), U.S. Patent No. 3,954,735, see also Sleezer et al., U.S. Patent No. 4,185,015. however, the beta-lactamase inhibitory activity of these compounds was not known. The present invention relates to a broad-spectrum antibacterial compound of formula (I) and to pharmaceutically acceptable acid addition salts thereof.

The imidazolidinone side chain is derived from the D-form of alpha-aminophenylacetic acid. The compound is a bis ester of hetacillin (acetoflide of ampicillin) and penicillanic acid 1,1-dioxide with methanediol. The term "pharmaceutically acceptable acid addition salts" includes the salts formed with the following acids: hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, succinic acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like.

The preferred process for the preparation of the compounds of formula (I) according to the invention is the direct process which is very high yielding. In this process, the bis ester of methanediol with ampicillin and penicillanic acid is reacted with acetone.

The compound of formula (I), alone or in combination with other antibacterial agents and / or excipients conventionally used in pharmaceutical technology, is preferably administered orally as these are well absorbed from the gastrointestinal tract of mammals. After absorption, they are converted to ampicillin and penicillanic acid 1,1-dioxide, and as a result, these compounds have a long serum half-life.

The imidazolidinone compound of the present invention can be readily prepared by a variety of methods.

The preferred process is as follows:

The compound of formula (II) is allowed to stand in acetone until the reaction is substantially complete and then excess acetone is removed by evaporation. As the source of the acetone bridge, an acetone ketal (e.g., 2,2-dimethoxypropane) or an enol ether or ester derivative of acetone (e.g., 2-methoxypropene or 2-acetoxypropylene) may be used, provided that that an acidic catalyst is present. The temperature may be in the range of from O to 50 ° C, or may be carried out at room temperature.

In another process, the compound of formula (I) is prepared by reacting a salt of a carboxylic acid of formula (III) wherein

M is a cation forming a carboxylic acid salt, which is reacted with a compound of formula IV, wherein X is an easily leaving group such as chloro, bromo, iodo, C 1-4 alkylsulfonyloxy, benzenesulfonyloxy. or a toluenesulfonyloxy group. Various cations may be used to form salts of the carboxylic acid of formula (ΙΙΪ), but the salts commonly used are: alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and barium salts; tertiary amines such as trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, Ν, Ν'-dimethylpiperazine and , 2,3,4-tetrahydroquinoline.

The compounds of formula (III) and (IV) are generally polar; in an organic solvent at a temperature of 0 ° C to 80 ° C, preferably 25 ° C to 50 ° C. The compounds of formula (III) and (IV) are usually reacted in equimolar amounts, but excess of any of the reagents, for example ten times the amount of any of the reagents, may be used. A variety of solvents can be used, but a polar solvent is usually preferred as it speeds up the reaction. Solvents that solubilize the aetonide group, such as water or methanol, are preferably avoided. Suitable solvents include Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, hexamethylphosphoramide and acetone. Reaction times vary depending on a number of factors; Generally, reagents are reacted at 25 ° C for several hours, such as 12 to 24 hours. In the case where X is chlorine or bromine, it is preferable to add one molar equivalent of alkali metal iodide to the reaction mixture, as this will speed up the reaction.

The compound of formula (I) is isolated by conventional means. When using a water miscible solvent, it is usually sufficient to dilute the reaction medium with a water immiscible solvent. The diluted reaction mixture was extracted with a saturated sodium chloride solution and then with water, dried and the solvent was evaporated. If a water immiscible solvent is used, dilution is usually sufficient! is omitted.

The compound of formula (I) may also be prepared according to the above process by reacting a compound of formula (V) wherein M is as defined above with a compound of formula (VI) wherein X is as defined above. The reaction conditions for compounds of formulas V and VI are the same as those described above for the reaction of compounds of formulas III and IV.

Compounds of formula (III) are known antibiotics and are prepared by methods already disclosed.

A compound of formula (IV) wherein X is as defined above is prepared by reacting a compound of formula (V).

-3184992 nos, wherein M is as defined above, is reacted with a compound of the formula X-CH ₂ -X 'where X and X' are each an easily cleavable group such as chloro, bromo, iodo, alkylsulfonyl oxy, benzenesulfonyloxy, toluenesulfonyloxy or chlorosulfonyloxy. The reaction is carried out under the same conditions as described above for the compound of formula (III) and the compound of formula (V), with the proviso that it is advantageous to use an excess of the compound X-CH ₂ -X '(e.g. ).

A compound of formula VI wherein X is as defined above is likewise a compound of formula III where M is as defined above and a compound of formula X-CH ₂ -X 'where X and X' are as defined above. - by reacting it. The reaction conditions are the same as described above for the reaction of the compound of formula V with the compound of formula X-CH ₂ -X '.

Compound (I) undergoes hydrolysis in aqueous medium to compound (II). Thus, the above methods for the preparation of the compound of formula (I) also represent an alternative synthesis of the compound of formula (II).

The invention also relates to the preparation of pharmaceutically acceptable acid addition salts of the compounds obtained by reacting an equivalent amount of the free base and the acid molecule, as described above, in an inert solvent (i.e., a solvent which is neither acetonide nor methanediol bis). hydrolysis or solvolysis of the ester). Acetone is a particularly preferred solvent. If the salt does not precipitate directly, it is isolated by concentration and / or addition of a solvent such as hexane or ether which is insoluble.

The compound of formula (I) has an antibacterial activity in vivo in mammals, and this activity is demonstrated by a standard procedure for penicillins. For example, the compound of formula (I) was administered to mice in which an acute infection of a standard culture of a pathogenic bacterium was induced by intraperitoneal inoculation.

The extent of infection was determined by administering to mice a dose of 1 to 10 times the LD ₁₀₀ (LD ₁₀₀ = the dose that kills the JOO / hr of control mice). At the end of the study, the activity of the compound was determined from the number of bacterial infected and surviving mice treated with the compound of formula (I). The compounds of formula (I) may be administered orally or subcutaneously.

Due to the efficacy of the compounds of the present invention, mammalian carcinogens, including humans, are capable of treating or controlling bacterial infections, either orally or parenterally. These compounds are useful for treating bacterial infections in humans. Compounds of formula (I) are degraded to ampicillin and penicillanic acid 1,1-dioxide after oral or parenteral administration to mammals. Penicillanic acid 1,1-dioxide then acts as a beta-lactamase inhibitor and enhances the antibacterial activity of ampicillin, for example, against penicillinase producing strains of Staphylococcus aureus or Escherichia coli.

The in vivo assay previously described may be used to determine whether a particular strain of Staphylococcus aureus or a particular strain of Escherichia coli is sensitive to the compound of formula (I). Alternatively, the minimum inhibitory concentration (MIC) of a 1: 1 mixture of ampicillin and penicillanic acid 1,1-dioxide may be measured. MIC is the “Study of Antibiotic Susceptibility Testing in International Collaboration” [Eriecson and Sherris, Acta Pathalogica et Mícrobiologia Scandinav, Suppl. 217, Section B: 64-68 (1971)], employing brain heart infusion (BHI) agar and a vaccine repetition construct. Cups left overnight are diluted 100-fold to be used as a standard inoculum. (20,000 to 10,000 cells in about 0.002 ml, placed on the agar surface; 20 ml BHI agar / dish.) 12-fold dilutions of the test compound were used at a starting drug concentration of 200 µg / ml. Individual colonies were not considered when the plates were read after 18 hours at 37 ° C. The lowest concentration capable of completely inhibiting growth, judged by the naked eye, was accepted as the susceptibility (MIC) of the test organism.

Because it is an object of the present invention to provide a single well-absorbable source of ampicillin and penicillanic acid 1,1-dioxide, the compounds of Formula I have also been characterized by serum levels in experimental animals such as laboratory rats. Starved rats at 20 mg / kg were administered orally with 6 '- (2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl) -penicobanyloxymethyl-penicillanate II-dioxide [(I) serum levels are shown in Table I below. In this study, 6 '- (2-amino-2-phenylacetamido) penicillanoyloxymethyl penicillanate 1,1-dioxide (Compound II) was used as a control in identical oral doses. Serum ampicillin levels were determined by the standard biological plate assay using Sarcina lutea 07A001 on agar. Pasteurella 59B010 on MH agar was used to determine penicillanic acid 1,1-dioxide. It is observed that the compound of formula (I) has a half-life of approx. 50% greater than the compound of formula II.

Table I

Serum levels (mcg / ml) after oral administration of 20 mg / kg in fasted rats

Time (Minutes) Compound of Formula I Compound II ampicillin Penicillán- acid 1,1- -dioxide ampicillin Penicíllán- acid 1,1- -dioxld 15 1.46 1.04 3.01 1.80 30 1.42 1.27 2.60 2.07 60 0.88 0.75 1.09 0.62 90 0.57 0.40 0.50 0.16 120 0.45 0.24 0.35 0.09 180 0.26 0.14 0.14 0.04 240 0.11 0.06 0.06 0.03 Half-life (Minutes) 60.70 49.10 39.26 35.60

When the antibacterial compound of the present invention is administered to a mammal, especially a human, the compound may be administered alone or in admixture with other antibiotics and / or excipients conventionally used in pharmaceutical technology.

-4184992

The excipients are selected according to the mode of application. For example, for oral administration, the compound may be in the form of tablets, capsules, dragees, pills, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. The ratio of active ingredient to vehicle will, of course, also depend on the chemical nature, solubility and stability of the active ingredient, and the intended dosage. Commonly used carriers for oral tablets include salts of lactose, sodium citrate and phosphoric acid. Various disintegrants such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are generally included in the tablets.

Diluents for oral capsules include lactose and high molecular weight polyethylene glycols, e.g. polyethylene glycols of molecular weight from 2000 to 4000. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening and / or flavoring agents may be added.

As noted above, the antibacterial compounds of the present invention are useful in human medicine and the daily dose used is not significantly different from the daily dose of other penicillin antibiotics used in therapy. The 25 individual doses are determined by the physician and are expected to vary with the patient's age, weight and response to the drug, as well as the nature and severity of the patient's symptoms. The compounds of the present invention may be administered orally and parenterally, from about 5 to about 5 times. In doses up to 100 mg / kg body weight / day, usually in divided doses. In some cases it may be necessary to use doses outside this dose range.

The invention is illustrated by the following example. However, the invention is not limited to the details of the examples.

Example '- (2,2-Dimethyl-4-phenyl-5-imidazolidinon-1-yl) penicillanoyloxymethyl penicillanate 1,1-dioxide

Compound of Formula I

The method

6 '- (2-Amino-2-phenylacetamido) penicillanoyloxymethyl penicillanate 1,1-dioxide (594 mg, 1 mmol) was mixed with acetone (30 mL) at room temperature. After 66 hours, the reaction mixture was evaporated to dryness in vacuo to give the title product in essentially quantitative yield (m.p. 115-125 °) with decomposition; Proton NMR (CDC1 ₃₎ delta 1.3-1.7 (18H; three pairs of geminal methyl), 3.4 (2H; C-6 _CH2), 4.2-4.7 (5H; C-3 , C-7, C-3 ', C-6' and 5 C-7 'CH), 5.5 (1H, side chain CH), 5.8 (2H, -OCH ₂ O-), 2.3 ( 5 H, aromatic) (ppm).

Method B.

214 mg (0.5 mmol) of potassium hetacillin (III), M is a potassium cation, suspended in 5 ml of dimethylformamide. Methyl iodide penicillanate 1,1-dioxide (Compound IV, X is iodine, Belgian Patent 883 299, 187 mg, 0.5 mmol) is added in one portion. The reaction mixture is stirred for 1.5 hours at room temperature (during which time it is completely soluble), then 100 ml of ethyl acetate are added and the mixture is extracted first with 50 ml of saturated sodium chloride solution, 50 ml of water and again 50 ml of sodium chloride solution. . The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo. The resulting oily residue was dried under a stream of dry nitrogen to give the title product as a dry powder (190 mg, 60%) based on proton nuclear magnetic resonance spectrum and thin layer chromatography (silica gel, 95; 5 methylene chloride: methanol, phosphomolybdene). ) and is identical to the product obtained by Method A.

Claims (1)

A patent claim A process for the preparation of the 6 '- (2,2-dimethyl-4-phenyl-5-imidazolazinon-1-yl) penicillanoyloxymethyl penicillanate 1,1-dioxide of formula I wherein the imidazolidinone side chain is D-form of alpha-aminophenylacetic acid, characterized in that a) reacting a compound of formula II with acetone; obsession b) a salt of a carboxylic acid of formula III wherein M is a cation of sodium, potassium, calcium or barium, tertiary ammonium, with a compound of formula IV, wherein: - X 45 is chloro, bromo or iodo, C 1-4 alkanesulfonyloxy, benzenesulfonyloxy or toluenesulfonyloxy; obsession c) reacting a salt of a carboxylic acid of formula (V) wherein M is as defined above with a compound of formula (VI) wherein X is as defined above.