JPS6232754B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides methanediol in which one hydroxyl group of methanediol is esterified with hetacillin (or its p-hydroxy homolog) and the other hydroxyl group of methanediol is esterified with penicillanic acid 1,1-dioxide. bis-esters. These compounds have particular value in mammals as oral antibacterial agents against pinicillinase producing bacteria. They are effectively absorbed from the gastrointestinal tract. After absorption they are converted to give serum levels of ampicillin/amoxicillin and penicillanic acid 1,1-dioxide which are unusually long lasting. By virtue of its penicillinase inhibitory activity, the latter increases the activity of the former against penicillinase-producing bacteria. Compounds of the invention have previously been described in UK Patent Application No.
2044255 and US Pat. No. 4,244,951. Unexpectedly, the compounds of the present invention exhibit greatly increased serum half-lives of ampicillin/amoxicillin and penicillanic acid 1,1-dioxide compared to the parent compounds described in these references. Hetacillin (and its p-hydroxy congeners) has been described in the literature [Handcastle].
Long, J.Org.Chem.31, pages 897-899 (1966); Long, J.Chem.Soc.(C);
1920-1922 (1971)]. Esters of hetacillin (and its p-hydroxy congeners) have also been reported to be particularly convenient for use in oral dosing [von Daehne, U.S. Pat. No. 3,954,735, Sleezer et al. See also US Pat. No. 4,185,015), but these compounds are not known to be beta-lactamase inhibitors. The present invention provides a systematic wide range of formulas antibacterial agents, and pharmaceutically acceptable acid addition salts thereof. In the formula, Y is H or OH,
The imidazolidinone side chain is derived from alpha-aminophenyl acetic acid in the D-configuration. When Y is H, the compound is hetacillin (the acetonide of ampicillin) and the bis-ester of penicillanic acid 1,1-dioxide and methanediol. When Y is OH, the compound is the acetonide of amoxicillin and penicillanic acid 1.1
- bis-esters of dioxides. The expression "pharmaceutically acceptable acid addition salts" refers to hydrochloric, sulfuric, phosphoric, maleic, succinic, citric,
It is intended to include acids such as methanesulfonic acid, p-toluenesulfonic acid, and the like. Alternative methods for preparing the compounds of the invention are described in detail herein. The preferred method is because it is direct and gives high yields.
Reaction of acetone with ampicillin (or amoxicillin) and methanediol bis-ester of penicillanic acid 1,1-dioxide. The present invention also provides methods for treating infections by susceptible bacteria in mammals using the compounds alone or in admixture with other antimicrobial substances and/or pharmaceutically acceptable carriers or diluents. include. The preferred route of administration of the compounds of this invention is oral. This is because they are efficiently absorbed from the mammalian gastrointestinal tract. After absorption, they are converted to ampicillin (or amoxicillin) and penicillanic acid 1,1-dioxide, resulting in an extended serum half-life of these compounds. The imidazolidinone compounds of the present invention are readily prepared by a number of alternative methods. The preferred method is: The compound of formula () is simply left in acetone until the reaction is substantially complete and excess acetone is removed by evaporation. If an acid catalyst is present, use an acetone ketal (e.g. 2,2-dimethoxypropane) or an enol ether or ester derivative of acetone (e.g. 2-methoxypropene or 2-acetoxypropene) as the acetone bridge source. I can do it. Temperature is not critical; 0-50°C is satisfactory; ambient temperature may be used. In the second method, a compound of formula The carboxylate of the formula It is produced by reacting with a compound of
where Y is as defined above, M is a carboxylate-forming cation, and X is a good leaving group, e.g. chlorine, bromine, iodine, ( _C1 - _C4 )alkylsulfonyl It is an oxy group, a benzenesulfonyloxy group, or a toluenesulfonyloxy group. Although a variety of cations may be used to form the carboxylate salts in compounds of formula, commonly used salts are: alkali metal salts such as sodium and potassium salts; alkaline earth salts such as calcium and barium salts. Metal salts; trimethylamine, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, N-methylpyrrolidine, N・N'-dimethylpiperazine and 1.
tertiary amine salts such as 2,3,4-tetrahydroquinoline; and more recently quaternary ammonium salts such as tetrabutylammonium salts. The reaction between a compound of formula and a compound of formula typically involves contacting each reagent in a polar organic solvent at a temperature ranging from about 0° to about 80°C, and preferably from 25° to 50°C. Implemented by. The compounds of formula and are usually contacted in substantially equimolar proportions, but with an excess of either reagent, e.g.
Up to a 10-fold excess can be used. It is generally advantageous to use relatively polar solvents, either because a greater number of solvents can be used or because they have the effect of speeding up the reaction. It is preferred to avoid solvents such as water or methanol that can solvolyze the acetonide group. Typical solvents that can be used include N.N-dimethylformamide,
Included are N.N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, dimethylsulfoxide, hexamethylphosphoramide and acetone. When quaternary ammonium salts are used in the preparation of the compounds of the invention, the latter are suitable solvents. Reaction times will vary depending on many factors, but reaction times of several hours at about 25° C., for example 12 to 24 hours, are commonly used. When X is chlorine or bromine, it is sometimes advantageous to add up to about 1 molar equivalent of alkali metal iodide, which has the effect of speeding up the reaction. Compounds of formula are isolated as is conventional practice. When a water-miscible solvent is used, it is usually sufficient to dilute the reaction medium with a water-immiscible solvent. The diluted reaction mixture was extracted with brine and water and dried.
The product is then recovered by solvent evaporation. When a water-immiscible solvent is used, it is usually sufficient to omit the dilution step. A variation of the above method for producing a compound of formula A compound with the formula This includes reactions of compounds. where M and X are as defined above. The reaction conditions for the reaction between () and () are as described above for the reaction between () and (). Compounds of formula are known antibiotics and are prepared by published methods. Compounds of formula X- _CH2 -X' (X and
X' is each a good leaving group, e.g. chlorine, bromine,
iodine, an alkylsulfonyloxy group, a benzenesulfonyloxy group, a toluenesulfonyloxy group or a chlorosulfonyloxy group). Excess of compound of formula X- _CH2 -X' (e.g.
except that it is preferred to use a 4-fold excess).
The same conditions described above for the reaction of compounds of formula with compounds of formula are used for this reaction. Similarly, a compound of formula X
_-CH2 -X', where X and X' are as defined above, by reaction with a compound. The conditions used are that a compound of formula X- _CH2-
This is the same as described for the reaction of X' with the compound. The compound of the present invention (formula) is hydrolyzed in an aqueous system to a compound of formula. Thus, the alternative routes to compounds of formula described above also provide alternative synthetic routes to compounds of formula. The pharmaceutically acceptable acid addition salts of the compounds of this invention are prepared in a solvent that is inert to the reaction (i.e., a solvent that will not lead to hydrolysis or solvolysis of either the acetonide or the methanediol bis-ester). , by reacting the free base form with one molar equivalent of an acid such as those defined above. Acetone is particularly suitable as a solvent for this purpose. When the salt does not settle directly,
It is isolated by concentration and/or addition of a non-solvent such as hexane or ether. The compounds of formula have in vivo antibacterial activity in mammals, which activity can be demonstrated by standard techniques for penicillin compounds. For example, a compound of formula is administered to acutely infected mice by intraperitoneal inoculation with a standardized pathogen culture. The severity of the infection is
Mice are standardized to receive LD ₁₀₀ 1 to 10 times (minimum inoculation required to consistently kill 100 percent of control mice throughout LD ₁₀₀ ). At the end of this test, the activity of this compound was challenged by bacteria, which also received a compound of formula
Evaluated by counting the number of survivors. Compounds of formula can be administered orally (p, o.) and subcutaneously (sc.
) can be administered by both routes. Because of the in vivo activity of the antimicrobial compounds of the invention, they are suitable for controlling bacterial infections in mammals, including humans, by both oral and parenteral modes of administration. These compounds are useful in controlling infections caused by sensitive bacteria in human patients. The compound of formula decomposes into ampicillin (or amoxicillin) and penicillanic acid 1,1-dioxide after administration to a mammalian patient by both oral and parenteral routes. Penicillanic acid 1,1-dioxide then increases the antibacterial effect of ampicillin (or amoxicillin) against beta-lactamase producing strains. To determine whether a particular Staphylococcus aureus or E. coli strain is sensitive to a compound of formula, the in vivo tests described above can be used. Alternatively, the minimum inhibitory concentration (MIC) of a 1:1 mixture of ampicillin (or amoxicillin) and penicillanic acid 1,1-dioxide can be determined. This MIC is based on the International Collaborative Research on Antibiotic Sensitivity Testing.
Collaborative Study on Antibiotic Sensitivity
[Ericcson and Sherris,
Acta . Pathologica et Microbiologia
Scandinav. Supplement 217, Section B: 64-68 (1971)] using brain heart infusion (BHI) agar and a repeat inoculation device. Overnight growth tubes were grown using a standard inoculum (approximately 20,000−2 in 0.002 ml).
10000 cells are placed on the agar surface: BHI agar 20
diluted 100 times for use as ml/dish). Twelve 2-fold dilutions of test compound are used with an initial concentration of test drug of 200 mcg/ml. One colony is ignored when reading the plate after 18 hours at 37°C. The susceptibility (MIC) of the test bacteria is taken as the lowest concentration of the compound that can completely inhibit growth when judged visually. Since the purpose of the present invention is to provide a single, well-absorbed source of ampicillin/amoxicillin and penicillanic acid 1,1-dioxide in the serum, the compounds of the present invention may also be used in laboratory rats. Determination of serum levels of these induced compounds in experimental animals such as 20mg/Kg of penicillanic acid 6'-(2,2-dimethyl-4-phenyl-5-imidazolidinone-1-
The serum level results in fasted rats following oral administration of penicillanoyloxymethyl 1,1-dioxide are shown in Table 1. In this study, the same oral dose of penicillanic acid 6'-(2-amino-2-phenylacetamide)penicillanoyloxymethyl 1,1-dioxide (,Y=H)
was used as a control. Ampicillin blood levels were determined by standard plate bioassay using Sarcina Lutea 07A001 on Seed agar. Pasteurella 59B010 on MH agar was used for the determination of penicillanic acid 1,1-dioxide. The half-life of a compound (Y=H) is
It can be seen that this is an improvement of approximately 50% compared to =H).

When the antimicrobial compound of the invention is used in mammals, particularly humans, the compound can be administered alone or it can be administered in combination with other antibiotics and/or a pharmaceutically acceptable carrier or diluent. Can be mixed with. The carrier or diluent described above is selected based on the intended mode of administration. For example, when considering suitable oral modes of administration, the antimicrobial compounds of the present invention can be formulated into tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like, according to standard pharmaceutical practice. It can be used in the form of something similar to. The ratio of active ingredient to carrier will, of course, depend on the chemical nature, solubility and stability of the active ingredient, as well as the intended dosage. In the case of tablets for oral use, commonly used carriers include lactose, sodium citrate and salts of phosphoric acid. Various leavening agents such as starch, and leavening agents such as magnesium stearate, sodium lauryl sulfate and talc,
Commonly used in tablets. For oral administration in capsule form, useful diluents include lactose and high molecular weight polyethylene glycols, such as
polyethylene glycol from 4000 to 4000.
When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweeteners and/or flavors can be added. As previously pointed out, the antimicrobial compounds of the present invention are
The daily dosages to be useful and used in human patients will not differ significantly from other clinically used penicillin antibiotics. The prescribing physician will ultimately determine the appropriate dosage for a given human patient, but this will depend on the individual patient's age, weight, and response, as well as the nature and severity of the patient's symptoms. It can be expected that this will vary depending on gender. The compounds of this invention will normally be administered at about 5 to about 100 mg per kilogram of body weight per day.
It will be used orally and parenterally, usually in divided doses. In some cases it may be necessary to use dosages outside this range. The invention is illustrated by the following examples.
However, it must be understood that the invention is not limited to the specific details of this embodiment. Example Penicillanic acid 6'-(2,2-dimethyl-4-phenyl-5-imidazolidinon-1-yl)-
Penicillanoyloxymethyl 1,1-dioxide (,Y=H) Method A Penicillanic acid 6'-(2-amino-2-phenylacetamide)penicillanoyloxymethyl 1,1
-dioxide (, Y=H; 594 mg, 1 mmol) was stirred in 30 ml of acetone at room temperature. After 66 hours, the reaction mixture was evaporated to dryness in vacuo to give an virtually quantitative yield of the title product [mp 115-125 (decomposition): pnmr ( _CDCl3 ) delta
1.3−1.7 (18H; 3 pairs of gem-dimethyl groups), 3.4
(2H; C-6 CH ₂ ) 4.2-4.7 (5H; C-3, C
-7, C-3', C-6' and C-7'CH), 5.5
(1H. side chain CH), 5.8 (2H, −OCH ₂ O−) and 2.3
(5H. aromatic hydrocarbons) ppm]. Under the same conditions, penicillanic acid 6′-[2-amino-2-( p -hydroxyphenyl)acetamide]
Penicillanoyloxymethyl 1,1-dioxide (,Y=OH) is penicillanic acid 6'-[2,2-
Dimethyl-4-( p -hydroxyphenyl)-5-
imidazolidinone-1-yl)penicilanoyloxymethyl 1,1-dioxide (, Y=OH)
can be changed to Method B Potassium hetacillin (, Y=H, M=K;
214 mg, 0.5 mmol) were suspended in 5 ml of dimethylformamide. Iodomethyl penicillanate 1,1-dioxide (X=I; Belgian Patent No. 883299; 187 mg, 0.5 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1.5 hours (by which time complete dissolution had occurred), then quenched with 100 ml of ethyl acetate and extracted successively with 50 ml of brine, 50 ml of water, and 50 ml of brine. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed 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%), which showed its pnmr and tlc mobility (silica gel, 95:5 methylene chloride:methanol, Phosphorous molybdic acid spray/
heat) to that of the same product prepared in Method A above.

Claims (1)

[Claims] 1 formula wherein Y is H or OH and the imidazolidinone side chain is derived from the D form of alpha-aminophenyl acetic acid; and pharmaceutically acceptable acid addition salts thereof. 2. The compound according to claim 1, wherein Y is H. 3. A compound according to claim 1, wherein Y is OH.