SE436206B - PENICILLANIC ACID-1,1-DIOXIDES WITH ANTIBACTERIAL EFFECTS - Google Patents

Description

7806628-9 produces β-lactamase. Substances of this latter kind are enzymes which cleave the β-lactam ring in the penicillins and cephalosporins, thereby forming products which do not have antibacterial activity. However, some substances have the ability to inhibit β-lactamase and when a β-lactamase inhibitor is used in combination with a penicillin or cephalosporin, it may increase or overcome the antibacterial efficacy of the penicillin or cephalosporin against certain microorganisms. It is believed that there is an increase in antibacterial efficacy when the antibacterial activity of a combination of an β-lactamase inhibitory substance and an β-lactam antibiotic is significantly greater than the sum of the antibacterial activities of the individual components. Accordingly, according to the present invention, there are provided certain novel chemical compounds which are novel individuals in a class of antibiotics known as penicillins which are useful as antibacterial agents. More specifically, these new nenicillin compounds are penicillanic acid 1,1-dioxides and some in vivo readily hydrolyzable esters thereof. I.

In addition, penicillanic acid 1,1-dioxide and its in vivo readily hydrolyzable esters are potent inhibitors of microbial β-lactamase. 1,1-Dioxides of benzylpenicillin, phenoxymethylpenicillin and certain esters thereof have been described in U.S. Pat. Nos. 3,197,466 and 3,536,698, and in an article by Guddal et al. in Tetrahedron Letters, No. 9, 381 (1962). Harrison and co-workers have in the Journal of the Chemical Society (London) Ä Perkin I, 1772 (1976), described a number of penicillin-1,1-dioxides and l-dioxides i.a. methylphthalimidopenicillanate-1,1-dioxide, methyl-6,6-dibromopenicillanate-1,1-dioxide, methylpenicillanate-1 (oxide, methylpenicillanate-1β-oxide, 6,6-dibromopenicillanic acid M-oxide and 6,6 Summary of the Invention: According to the invention there are provided novel compounds of the formula 7 H, "sf 'v - CH and pharmaceutically acceptable base salts thereof, in which formula R 1 is hydrogen, 3-phthalidyl, 4-crotonolactonyl, 1H-butyrolacton-4-yl, R 1 -C 10 R 11 or -co-E 6 -O-R 5 -R 11 in which formulas each of R 3 and R 4 is hydrogen or alkyl of 1-2 carbon atoms and R 5 is alkyl of 1-2 carbon atoms.

Compounds I, in which R1 is hydrogen or the indicated in vivo readily hydrolyzable ester-forming residue, are useful antibacterial agents and agents for enhancing the antibacterial activity of β-lactam antibiotics. Said compounds of formula I, in which R 1 is a penicillin carboxy protecting group, are useful as chemical intermediates for compounds of formula I, wherein R 1 is hydrogen or the in vivo readily hydrolysable ester-forming residue.

Typical carboxy-protected groups are benzyl and substituted benzyl, for example 4-nitrobenzyl.

In the preparation of the compounds I according to the invention, new compounds of the formula .15 pvaoseza-9 4 H fi v are used. . 'ß s mv.

N \ CH II) o; N ,,, ° 3 1 (_ COOR and - H, _, \ _ I 'I oss (III) N I _ fi), - Ks and salts thereof, in which formulas RW has the meaning given above. Said compounds II and III are intermediates of compounds I.

Detailed Description of the Invention: The invention relates to novel compounds I, In the present context reference is made to derivatives of penicillanic acid which fall within the structural formula A I H, g s * ams _ I i | cua av) o_ u 4 ,, coon - When the substituent fi in formula IV is stated to be attached to the bicyclic nucleus by means of a dashed line, this means that the substituent in question is below the plane of the bicyclic nucleus. Such a substituent is said to be in the α-configuration.

In contrast, a substituent attached to the bicyclic nucleus with a solid line is in the ß-configuration.

In the present context, reference is also made to certain derivatives of cephalosporanic acid which fall under the formula lvaossza-se S fli cuz-O-c-ca: (v) 0 z inches E !! COOH In formula V, the hydrogen atom at the carbon atom is in the 6-position below the plane of the bicyclic nucleus. The derived terms decacetoxycephalosporanic acid and 3-desacetoxymethylcephalosporanic acid are used to denote those of formulas VI and VII malignant structures: _ E 5, \, '3 5 0 “YLE pí, ~ C 3 0 _ coon _ coon' VI. v11 4-Crotonolactonyl and γ-butyrlacton-4-yl refer to structures VIII and IX. The wavy lines are intended to indicate each of two epimers and mixtures thereof: 7ø o 0 '. When R * 'in a compound of formula I is any of the indicated in vivo readily hydrolyzable ester-forming residues, the group is a group which may be derived from an alcohol of formula R1-OH, so that the group COOR1 in such a compound of formula I represents an ester group. In addition, R 1 is such that the COOR 1 group is readily cleaved in vivo, thereby forming the free carboxyl group COOH. This means that R1 is a group of such a type that when a compound of formula I, in which R1 is the ester-forming, in vivo readily hydrolysable residue, is exposed to mammalian blood or tissue, the veoesza-9 compound of formula I, wherein R1 is hydrogen, easily formed. The groups R1 are well known in the penicillin field. In most cases, they improve the absorption properties of the penicillin compound. In addition, R 1 should be such that it imparts pharmaceutically acceptable properties to a compound of formula I and it releases pharmaceutically acceptable fragments when cleaved in vivo.

As pointed out above, the groups R1 are well known and readily identified by those skilled in the art of penicillin. See, for example, West German Offenlegungsschrift 2,517,316.

Preferred groups represented by R1 are 3-phthalidyl, 4-crotonolactonyl and γ-butyrolactone-4-phyl.

The compounds of formula I, in which R1 has the meaning given above, can be prepared by oxidation of any of the compounds II or III, in which R1 has the meaning given above. For this purpose, a large number of the oxidizing agents known for the oxidation of sulfoxides to sulfones can be used. Particularly convenient oxidizing agents, however, are metal permanganate, such as alkali metal permanganate and permanganate of alkaline earth metals, as well as organic peroxyacids, such as organic peroxycarboxylic acids.

Suitable individual oxidizing agents include sodium permanganate, potassium permanganate, ecchlorperbenzoic acid and peracetic acid.

When a compound of formula II or III, wherein R1 is as defined above, is oxidized to the corresponding compound of formula I using a metal permanganate, 7 g, the reaction is usually carried out by treating the compound with formula I or II with between about 0.5 and about 5, preferably about 1 molar equivalent of the permanganate in a suitable solvent system. A suitable solvent system is one which does not react adversely with any of the starting materials or with the product and is usually used as the suitable solvent water. If desired, an additional solvent can be added which is miscible with water but which does not react with the permanganate, for example tetrahydrofuran. The reaction was normally carried out at a temperature between about -30 and about 50 ° C, preferably at about 0 ° C. At about 0 ° C, the reaction is normally substantially complete within a short time, for example one hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is preferred to operate under substantially neutral conditions in order to avoid decomposition of the β-lactam ring system in compound I.

It is t.o.m. often advantageous to buffer the pH of the reaction medium to a value close to neutrality. The product is extracted in a conventional manner. Any excess permanganate is usually decomposed using sodium bisulfite, whereupon the product is filtered off if it is not in solution.

It is separated from manganese dioxide by extraction into an organic solvent and the solvent is removed by evaporation. Alternatively, the isolation takes place by ordinary solvent extraction, if the product does not precipitate from the solution at the end of the reaction. When a compound of formula II or III, wherein R 1 is as defined above, is oxidized to the corresponding compound I using an organic peroxyacid, for example a peroxycarboxylic acid, the reaction is usually carried out by treating compound II or III with between about 1 and about H molar equivalents, preferably with about 1.2 equivalents of the oxidizing agent in a reaction-inert organic solvent. Typical solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction was normally carried out at a temperature between about -20 ° C and about 50 ° C, preferably at about 2 ° C. At about 35 ° C, reaction times between about 2 and about 16 hours are usually used. The product UT 7806528-9 I a is normally isolated by removing the solvent by evaporation in vacuo. The product can be purified in a conventional manner well known in the industrial area in question; When oxidizing a compound II or III to a compound I using an organic peroxyacid, it is sometimes advantageous to add such a catalyst as a manganese salt, for example manganese acetylacetonate. The compound I, wherein Rq is hydrogen, can also be obtained by removing the protecting group_R4 from a compound of formula I, wherein Rq is a penicillin carboxy protecting group. In this context, R q may be any carboxy protecting group conventionally used in the field of penicillin protection of the 5-position carboxy groups. The identity of the carboxy protection group is not of decisive importance. The only requirements for the carboxy protecting group R1 'are: (1) it must be stable during the oxidation of compound II or III; and (2) it must be possible to remove it from compound I under such conditions that the β-lactam remains substantially intact. Typical examples of useful groups include tetrahydropyranyl, benzyl, substituted benzyl (for example 4-nitrobenzyl), benzylhydryl, 2,2,2-trichloroethyl, t-butyl and phenacyl. See also U.S. Patent Nos. 5,652,850 and 5,196,466, British Patent Specification 1,041,985; Woodward et al., Journal of the American Chemical Society, 88, 852_ (1966); Chauvette, Journal of Organic Chemistry, 56, 1259, (19? 1); Sheehan et al., Journal.of Organic Chemistry, 29, 2006 (1964); and "Cephalosporin and Penicillins, Chemistry and Biology", edited by H. E. Flynn, Academic Press, Inc, 1972. The penicillin carboxy protecting group is removed in a conventional manner with due regard to the lability of the 3-lactam ring system.

Similarly, compounds of formula I, in which Rq has the meaning defined above, can be prepared by oxidation of a compound of formula 9 1aoss2a-9 where Rq has the meaning given above. This oxidation was carried out in exactly the manner described above for the oxidation of compound II or III with the only difference that twice as much oxidizing agent was usually used; Compounds of formula I, wherein Rq is an in vivo readily hydrolyzable, ester-forming residue, can be prepared directly by esterification of the compound of formula I, where X is hydrogen.

The esterification method to be applied can easily be determined by the person skilled in the art and of course depends on the nature of the ester-forming residue. If R4 is 5-phthalidyl, 4-crotonolactonyl, Xibutyrolacton-H-yl or a group of the formula X or XI, where R5, Du and H5 have the meanings given above, they can be prepared by alkylation of the compound of formula I , where Rq is hydrogen, with a Z-phthalidyl halide, a 4-crotonolactonyl halide, an X-butyrolacton-4-yl halide, a compound of the formula: 3 - Ra- R 0. a compound of Q'f _ ° - C '°' R R4 the formula Éê XII _ XIII 4 in which formulas Q is halogen and R5, R and H5 have the above an-. given meanings. By "halide" is meant chlorine, bromine and iodine derivatives. The reaction is conveniently carried out by dissolving a salt of the compound of formula I, wherein Rq is hydrogen, in a suitable, polar, organic solvent, for example N, N-dimethylformamide, then adding about one molar equivalent of the halide. When the reaction is substantially complete, the product is isolated by standard techniques. It is often sufficient to simply dilute the reaction medium with excess water and then extract the product into a water-immiscible organic solvent. The product is finally extracted by evaporating the solution. Commonly used salts of the starting material are alkali metal salts, such as sodium and potassium salts, and tertiary amine salts, such as triethylamine, K-ethylpiperidine, N, H-dimethylaniline and N-methylmorpholine salts. The reaction is carried out at a temperature between about 50 ° C and about 0 ° C and about 100 ° C, usually at about 25 ° C. The time for completion of the reaction varies depending on a number of factors, such as the concentrations and reactivity of the reactants.

Thus, among the halogen compounds, the iodides react faster than the bromides, which in turn react faster than the chlorides.

In fact, when using a chlorine compound, it is sometimes advantageous to add up to one molar equivalent of an alkali metal iodide. This speeds up the reaction. Taking into account all the above factors, it can be mentioned that reaction times of between about one and about 24 hours are usually applied.

Penicillanic acid-1a-oxide, i.e., the compound of formula II, wherein Rq is hydrogen, can be prepared by debromination of 6,6-dibromopenicillanic acid-1a-oxide. The debromination can be carried out using conventional hydrogenolysis techniques. Thus, a solution of 6,6-dibromopenicillanic acid la-oxide is stirred or shaken in the presence of a catalytic amount of a catalyst consisting of palladium on calcium carbonate and under an atmosphere of hydrogen or hydrogen mixed with an inert diluent, so such as nitrogen or argon. Suitable solvents for this debromination are lower alkanols, such as methanol; ethers such as tetrahydrofuran and dioxane; low molecular weight esters such as ethyl acetate and butyl acetate; water; and mixtures of these solvents. However, it is common to choose conditions under which the dibromo compound is soluble. The hydrogenolysis was usually carried out at room temperature and under a pressure between a value approximately corresponding to atmospheric pressure and about 0.55 MTa. The catalyst is usually present in an amount between about 10% by weight based on the dibromo compound and up to an amount corresponding to the amount by weight of bromine compound, although larger amounts may be used. The reaction usually takes about one hour, after which the compound of formula II, in which H4 is hydrogen, is simply filtered off and dried in vacuo. 6,6-Dibromopenicillanic acid-lee oxide is prepared by oxidizing 6,6-dibromopenicillanic acid with an equivalent of 5-chloroperbenzoic acid in tetrahydrofuran at 0-25 ° C for about one hour according to the procedure described by Harrison et al., Journal of the Chemical Society (London) Perkin I, 1772 (1976). 6,6-Dibromopenicillanic acid is prepared from 11 F-vaossza-9 according to Clayton, Journal of the Chemical Society (London), (C) 2125 (3369). > Penicillanic acid 13-oxide, i.e. the compound of formula III, wherein H1 is hydrogen, can be prepared by controlled oxidation of penioillanic acid. Thus, it can be prepared by treating penicillanic acid with one molar equivalent of 5-chloroperbenzoic acid in an inert solvent at about 0 ° C for about one hour. Typical useful solvents are chlorinated hydrocarbons such as chloroform and dichloromethane; ethers such as diethyl ether and tetrahydrofuran; and low molecular weight esters, such as ethyl acetate. and butyl acetate. The product is recovered in a conventional manner.

Penicillanic acid is prepared in the manner set forth in British Pat. Compounds of formulas II and III, wherein Rq is an in vivo readily hydrolyzable, ester-forming residue, can be prepared directly by conventional esterification of a compound of the formula 11 ener m, that is hydrogen. if rf] is α-phthalazine, fe- _crotonolactony1, X-butyrolacton-4-yl or a group of formula x or 3: 1, where iaf, al * een m5 have the same meanings, they may be prepared from the appropriate compound of formula II or III, wherein Rq is hydrogen, by alkylation with a 5-phthalidyl halide, 4-crotonolactonyl halide, an X-butyrolactone-4-yl-halide or a compound of formula XII or XIII. The reaction is carried out in exactly the same manner as indicated above with respect to esterification of penicillanic acid 1,1-dioxide with a 5-phthalidyl halide, an M-crotonolactonyl halide, a γ-butyrolactone-4- yl halide or a compound of formula XII or XIII.

Alternatively, the compounds of formula II, where H4 50 is an in vivo readily hydrolyzable ester-forming residue, can be prepared by oxidation of the appropriate ester of 6,6-dibromopenicillanic acid followed by debromination. The esters of 6,6-dibromopenicillanic acid are prepared from 6,6-dibromopenicillanic acid according to standard methods. The oxidation is carried out, for example, in the manner of oxidizing with a molar equivalent of 3-chlorobenzoic acid in the manner described above for the oxidation of 6,6-dibromopenicillanic acid to 6,6-dibromopenicillanic acid-1m oxide; and the debromination is carried out in the manner indicated above with respect to the debromination of 6,6-dibromopenicillanic acid-1a oxide. In a similar manner, the compounds of formula III, wherein Rq is an in vivo readily hydrolyzable ester-forming residue, can be prepared by oxidation of the appropriate ester of penicillanic acid. The latter compounds are readily prepared by oxidation of penicillanic acid according to standard methods. The oxidation is carried out, for example, by oxidizing with a molar equivalent of 5-perchlorobenzoic acid in the manner indicated above for the oxidation of penioillanic acid to penicillanic acid ~ lß-oxide. The compounds of formula II, wherein Rq is a carboxy-protecting group can be prepared in one of two different ways. Thus, they can be prepared by simply taking penicillanic acid-1a-oxide and attaching a carboxy-protecting group thereto.

Alternatively, they can be prepared by (a) linking a carboxy protecting group to 6,6-dibromopenicillanic acid, (b) oxidizing the protected 6,6-dibromopenicillanic acid to a protected 6,6-dibromopenicillanic acid-1a oxide using a molar equivalent of 5-chloroperbenzoic acid, (c) debrominates the protected 6,6-dibromopenicillanic acid-1a oxide by hydrogenolysis.

The compounds of formula III, wherein H4 is a carboxy-protecting group, can be prepared by simply binding a protecting group to penicillanic acid-lß-oxide. Alternatively, one can (a) bind a carboxy-protecting group to penicillanic acid, and (b) oxidize the protected penicillanic acid using a molar equivalent of 5-chloroperbenzoic acid in the manner indicated above. The compounds of formulas I, II and III, in which R is hydrogen, are acidic and form salts with basic compounds.

Such salts fall within the scope of the invention. These salts can be prepared according to standard methods. Thus, for example, the acidic and basic components may be contacted with each other, usually in a molar ratio of 1: 1, in an aqueous, non-aqueous or partially aqueous medium, as appropriate. It is recovered by filtration, precipitation with a non-solvent and filtration, evaporation of the solvent, or (in the case of aqueous solutions) by lyophilization. The extraction procedure applied depends on which is appropriate in an individual case. Basic compounds suitable for use in the formation of salts are both organic and inorganic, and examples may be mentioned ammonia, .alpha.-. hydrides and alkoxides, as well as hydroxides, carbonates, hydrides and alkoxides of alkaline earth metals.

Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine; secondary amines such as diethylamine, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo- [.5.5.Q] non-5-ene; hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonate such as potassium carbonate and sodium carbonate; bicarbonate such as sodium bicarbonate and potassium bicarbonate; and alkali metal salts of long chain fatty acids, such as sodium 2-ethylhexanoate. Preferred salts of compounds I, II and III are sodium, potassium and triethylamine salts.

As noted above, the compounds of formula I, wherein Rq is hydrogen or an in vivo readily hydrolyzable ester-forming residue, are moderate antibacterial agents. The in vitro activity of the compounds of formula I, where Rq is hydrogen, can be detected by determining its minimum inhibitory concentrations (MIG) in mcg / ml against a number of microorganisms. The procedure used is that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta. Pathologica et Hicrobiologia Scandinavia, Supp. 217, Sections A and B: 1-GO (1979)), at which uses brain-heart infusion agar (BHI agar) and the inoculation reproduction device. In culture culture tubes overnight, dilution was performed 100-fold for use as a standard inoculum (20,000-10,000 cells in approximately 0.002 ml are applied to the agar surface; 20 ml BHI agar / plate).

Twelve double dilutions of the test force were used with the first concentration of the test drug amounting to 230 mcg / hl. When inspecting the plates after 13 hours at š7 ° C, individual colonies are disregarded. The sensitivity (NIC) of the test organism is accepted as the lowest concentration of the compound, which can give complete inhibition of the growth when assessed with an unarmed eye. NIC values for penicillanic acid 1,1-dioxide against a number of microorganisms are summarized in Table I. Vaesszs-9 1 Q TABLE I Penicillanic acid 1,1-dioxide. In vitro antibacterial activity.

Microorganism _ NIC, meg / ml Staphylococcus aureus '100' Streptococcus faecalís 7200 Streptococcus pyogenes _ 100 Escherichia coli '50 Pseudomonas aeruginosa I' 200 Klebsiella pneumoniae - 50 Proteus mirabilís ', 100 Proteus morgani Å' 100 salmonella fi y 50 salmonella fi 50 salmonella fi Serratia marcescens ~ 100 Enterobacter aerogenes 25 Enterobacter clocae 0 100 Citrobacter freündíí 50: Providencia. -, 100 Staphylodoccus epidermís 0 200 Pseudomonas putida 0 _ 7200 Ilemophilus influenzae V v 50 Neissería gonorrhoeae '0,512 \ .71 -25 55 e' äsossza-s The compounds of formula I, where R? vivo readily hydrolyzable ester-forming residues are active as antibacterial agents in vivo. In determining such activity, acute experimental infection in mice is induced by intraperitoneal inoculation of the mice with a standard culture of the test organism suspended in a 5% porcine mucin. The severity of the infection is standardized so that the mice receive is hydrogen or a dose 1-10 times the IDIOO dose of the organism (LDloø is the smallest inoculum of the organism required for consistent killing of all the infected, untreated control animals). The test compound is administered to the infected mice according to a multiple dose regimen. At the end of the test, the activity of an association is assessed by counting the number of survivors among the treated experimental animals and the activity of an association is expressed as the percentage of live animals.

The in vitro antibacterial activity of the compound of formula I, where R1 is hydrogen, makes the compound useful as an industrial antimicrobial agent, for example for water treatment, sludge control, preservation of paint and wood as well as for topical application as a disinfectant. When applied topically to the compound, it is often convenient to mix the active ingredient with a non-toxic carrier, for example, a vegetable oil or a mineral oil or an emollient ointment. It can also be dissolved or dispersed in liquid diluents or solvents, such as water, alkanols, glycols or mixtures thereof. In most cases, it is advisable to use concentrations of the active ingredient between about 0.1 and about 10% by weight, based on the whole mixture.

The in vivo activity of the compounds of formula I, wherein Rq is hydrogen or an in vivo readily hydrolysable ester-forming residue, makes the compounds suitable for controlling bacterial infections in mammals, including humans, by administering orally or parenterally. The compounds can be used to control infections in humans caused by susceptible bacteria, for example strains of Neisseria gonorrhoeae.

In the therapeutic treatment of mammals, especially humans with a compound I or a salt thereof, the compound may be administered alone or in admixture with pharmaceutically acceptable carriers or diluents. They can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected according to the mode of administration referred to. For example, when performing oral administration, an antibacterial penam compound may be used as hereinbefore invention in the form of tablets, capsules, candies, lozenges, powders, syrups, elixirs, aqueous solutions, suspensions, etc., all in accordance with standard pharmaceutical practice.The final ratio of active ingredient carrier depends, of course, on the chemical nature, solubility of the active ingredient and stability as well as the intended dose Pharmaceutical preparations containing an antibacterial compound of formula I in however, it usually contains between about 20% and about 95% of active ingredient. Tablets for oral use include those carriers which are commonly used for this purpose, for example lactose, sodium citrate and salts of phosphoric acid. Various disintegrating ingredients, such as starch, and lubricants, such as magnesium stearate, sodium lauryl sulfate and talc, are usually included in the tablets. For oral administration in the form of capsules, lactose and high molecular weight polyethylene glycols were used as diluents. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners and / or flavors may be added. For parenteral administration involving intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared and the pH of the solutions is suitably adjusted and buffered. For intravenous use, the total concentration of all dissolved constituents should be adjusted so that the preparation becomes isotonic.

As noted above, the antibacterial agents of the present invention are useful for treating humans against susceptible organisms. The patient ultimately determines the appropriate dose for a given patient and this can be expected to vary with the patient's age, body weight and sensitivity as well as with the nature and severity of the symptoms. The compounds of the invention are normally administered orally in ._35 k !! O 55 1. 'ga' raosszs-s doses between about 10 and about 200 mg / kg body weight and day and parenterally in doses between about 10 and about 400 mg / kg body weight and day. These figures are given only as examples and in in some cases it may be necessary to select doses outside the said limits.

However, as noted above, the compounds of formula I, wherein 31 is hydrogen or an in vivo readily hydrolysable ester-forming residue, are potent inhibitors of microbial 3-lactamases and they increase the antibacterial efficacy of β-lactan antibiotics (penicillins and cephalosporins) against many microorganisms. especially those that produce a β-lactamase. How said compounds I increase the efficacy of a β-lactam antibiotic can be demonstrated by experiments in which the NIC of a given antibiotic alone and a compound I alone are determined. These values for NIC are then compared with MIC values obtained with a combination of the antibiotic in question and the compound of formula I. When the antibacterial efficacy of the combination is significantly greater than would have been expected based on the efficiencies of the individual components, this is considered to mean a strengthening of the activity. The NIC values for the combinations are determined according to the method described by Barry and Sabath in the "Manual of Clinical Microbiology", Ienette, Spaulding and Truant, 2nd edition, 1974, American Society for Microbiology. Table II summarizes the results of experiments showing that penicillanic acid 1,1-dioxide increases the effectiveness of apicillin. The results summarized in Table II show that the mean NIC of ampicillin and penicillanic acid 1,1-dioxide against 19 ampicillin-rich strains of Staphylococcus aureus is 200 mg / ml. However, the combination of ampicillin and penicillanic acid 1,1-dioxide gives an average MIC of 1.56 resp. 3.12 meg / ml. In other words, although the ampicillin has an average NIC of 200 mg / ml compared to 19 strains of Staphylococcus aureus, its average NIC is reduced to 1.56 mg / ml in the presence of .12 mcg / nl of penicillanic acid-1,1 -dioxide. The other data in Table II show the increase in the antibacterial efficacy of anpicillin against 26 ampicillin-resistant strains of Haemophilus influenzae, 18 ampicillin-resistant strains of 4A. vsossza-9 18.

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Go fl ßö flfl näo fi ïp fi æn fl m unæß fl m _ fi_ uHxo «ø | H.H | | @ ~ @ o www oHz w fifl pp fl qmsoøww OH: w fifi pp fi nwsonww UH: w flfi pp fl qweo fl ww Hm »q <sm fl nwwnoops fi z .wø» fi> fi uxm m flfi w fi mwuxmn fi unm wvm m flfi om flflfl om flflfl om. Ä H fi mnmë wß.o ~ H, m om. om m fi w fiflfl wwnw wwø fl onmpomm m ~, @ om oß oo: ^ w fi. mß fi qoszwnm m flfi o fl wpw fi m mß.ø @ m.o oo fi mm.w. mm ww fi qw fifi wn fi w flflfl nnoswmm mm.w mm.w oom m.mH om mømn fi m msoooøo fi hnmmvw T fifl o fi @ »fi.fi | Go f pm flfl ßëoß f p f wnøø uhmßco _ @ f »0FL @ | H.H1 | HMX www OH: w flfi pp al nmeoawø .UHS w fifl pp al qwsonwo UH w fifi SSP access nweonwø Hmpn al sw al qmwhocpß fl z .wcp al w fi wuø ø flfl u al nouxm flfi PNM muwn fififlfi o fifl onnøx now access the m x @> n fl ^ wsov fi mo fl @ | H fi | The compounds of formula I, wherein 14 is hydrogen or an in vivo readily hydrolyzable ester-forming residue, increase the antibacterial efficacy of 2-lactam antibiotics in vivo. This means that they lower it. the amount of antibiotic required to protect the mice against an otherwise lethal inoculum of certain 2-lactamase-producing bacteria. The compounds of formula I, wherein Rq is hydrogen or an in vivo readily hydrolyzable ester-forming residue, are capable of increasing the efficacy of an E-lactam antibiotic against gent lactam-producing bacteria make them valuable for administration with E-lactam antibiotics in the treatment of bacterial infections in mammals, especially humans. In the treatment of a bacterial infection, said compound I may be mixed with a β-lactam antibiotic, whereby they both agents will be administered simultaneously. Alternatively, said compound I may be administered as a separate agent during the treatment with a β-lactamanti biotics. In some cases it is advantageous to administer to the patient the compound I before the -first treatment with a β-lactam antibiotic; When using penicillanic acid 1,1-dioxide or an in vivo easily hydrolyzable ester thereof to increase the effectiveness of β-lactam antibiotic, it is preferably administered in admixture with standard pharmaceutical carriers or diluents. The above methods of preparation for the use of penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzable ester thereof as a single antibacterial agent can be used when co-administration with another 3-lactam antibiotic is intended. A pharmaceutical preparation containing a pharmaceutically acceptable carrier, a 2-lactam antibiotic and penicillanic acid 1,1-dioxide or an easily hydrolysable ester thereof normally contains between about 5% and about 5% by weight of the pharmaceutically acceptable carrier. When using penicillanic acid 1,1-dioxide or an in vivo easily hydrolyzable ester thereof in combination with another β-lactam antibiotic, the sulfone can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intraperitoneally. Although the physician ultimately determines the dose for a patient, the ratio between the daily doses of penicillanic acid 1,1-dioxide or ester thereof and §-lactate1- 50 7806628-9 M, antibiotic is normally between about 1: 5 and about Bél. In addition, the daily oral dose for each component, when using penicillanic acid 1,1-dioxide or an in vivo readily hydrolyzable ester thereof in combination with other β-lactam antibiotics, is normally between about 10 and about 200 mg / kg body weight and the daily parenteral dose for each of the components is normally between about 10 and about 400 mg / kg body weight. These figures are given as examples only and in some cases it may be necessary to choose doses outside these limits.

Typical 3-lactam antibiotics with which penicillanic acid 1,1-dioxide and in vivo readily hydrolyzable esters thereof can be co-administered are: 6- (2-phenylacetamido) penicillanic acid, 6- (2-phenoxyacetamido) penicillanic acid, 6- ( 2-phenylpropionamido) penicillanic acid, 6- (D-2-amino-2-phenylacetamido) penicillanic acid, 6- (D-2-amino-2-Z-hydroxyphenyl-7-acetamido) penicillanic acid, 6 ~ (D-2-amino-2 -Z1,4-cyclohexadienyl-7-acetamido) penicillanic acid, 6- (1-aminocyclohexanecarboxamido) penicillanic acid, G- (2-carboxy-2-phenylacetamido) penicillanic acid, 6- (2-carboxy-2- [ε-thienyL7acetanamic acid) D-2- [α-Ethylpiperazine-2,5-dione-1-carboxamide] -2-phenylacetamido) penicillanic acid,. 6- (D-2- [α-hydroxy-1,5-naphthyridine-ε-carboxamide] -2-phenylacetamido) -penicillanic acid, 6- (D-2-sulfo-2-phenylacetamido) penicillanic acid, 6- (D -2-sulfoamino-2-phenylacetamido) penicillanic acid, e- (n-eschemidazoliainsz-one-carboxamide / α-α-phenylacetamia; penicillanic acid, e- (n-z-ethylisufonylimiaazolidine-z-one-1-carboxylacido) ) -penicillanic acid, G - ([hexahydro-1H-azepin-1-ylmethyleneamino) penicillanic acid, acetoxymethyl 6- (2-phenylacetamido) penicillanate, acetoxymethyl-6-CD-2-amino-2-phenylacetamido) penicylimanate, acetoxyl - (D-2-amino-2- [α-hydroxyphenyl] acetamido) penicillanate, pivaloyloxymethyl 6- (2-phenylacetamido) penicillanate, pivaloyloxymethyl 6- (D-2-amino-2-phenylacetamido) penicillanimate, pivaloylloanate 6- (D-2-Amino-2- [α-hydroxyphenylphacetamido) -β-bo 'phosphorylsicnicillanate, 1- (ethoxycarbonyloxy) ethyl] -6- (2-phenylacetamido) penicillanate, 1- (otoxycarbonyloxy) ethyl G- (D-2-amino-2-phenylacetamido) -penicillanate, 1- (ethoxycarbonyloxy) ethyl-6- (D-2-amino-3-1'-hydroxyphenyl] -acetamido) -penioillanate, d 3-F: id1 idyl-α- (2-renylacetamido) penicillanate, -phthalidyl-5- (D-2-amino-2-phenylacetamido) penicillanate, -phthalidyl-6- (D-2-amino-2-11- hydroxyphenylacetamino) penicillanate, 1- (2- (2-phenoxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-tolyloxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-β-indanyloxycarbonyl] -2-phenyla penicillanic acid, do- (2-phenoxycarbonyl-2- [E-thienyl7acetamido) penicillanic acid, 6- (2-tolyloxycarbonyl-2- [E-thienyl7acetamido) penicillanic acid, 6- (2- [E-indanyloxycarbonyl7-2-β-thienyl7acetamido ) penicillanic acid, e 6- (2,1-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) penicillanic acid, 7- (2- [E-thienylphacetamido) cephalosporanic acid, 7- (2-11-tetrazolyl; 7-Acetamido-5- (2-β-methyl-1-1.5,--α-diazolyl-7-thiomethyl) -β-desacetoxymethylcephalosporanoic acid, β- (D-2-amino-2-phenylacetamido) -acetoxicephalosporanic acid, α-methoxy-7- (2- [E-thienyl] acetamido) -5 = carbamoyloxymethyl-5-desacetoxymethyl-cephalosporanic acid, d 7- (2-cyanoacetamido) cephalosporanic acid - (D-2-hyaroxy-2-phenylacetamido) -3- (5- / ï-methyltecrazo1yi7-thiomet yl) -5-desacetoxymethylcephalosporanic acid, 7- (3- [β-pyridylticphacetamido) cephalosporanic acid, “- (D-2-amino-2-11,4-cyclohexadienylphacetamido) cephalosporanic acid, T- (D-2-amino-2-phenylacetamido ) cephalosporanic acid, and pharmaceutically acceptable salts thereof. It will be apparent to those skilled in the art that some of the β-lactam compounds listed above are effective in oral or parenteral administration, whereas others are effective only in parenteral administration. Where penicillanic acid 1,1-dioxide or an in vivo readily hydrolysable ester thereof is to be used concomitantly (ie mixed with a 3-lactamanti-biotic which is effective only in parenteral administration, a combined preparation suitable for vaoseza is of course required). When the penicillanic acid 1,1-dioxide or its ester is to be used simultaneously (mixed) with a β-lactam antibiotic, which is effective both orally and parenterally, combinations such as In addition, it is possible to administer the preparations of the penicillanic acid 1,1-dioxide or the ester thereof orally and at the same time to administer another 2-lactam antibiotic parenterally; It is also possible to administer the preparations of penicillanic acid. 1,1-dioxide or its ester parenterally and at the same time administering another β-lactam antibiotic orally. The following examples illustrate the invention. . IR spectra have been determined using potassium bromide tablets (KBr disks) or suspensions in nujol, and diagnostic absorption bands are given in weight (cm_1). NMR spectra have been determined at 60 HHz for solutions in deuterochloroform ((CÉCl2), perdeutero-dimethylsulfozide (DHSO-de) or deuterium oxide / (D20) and the maximum positions are given in parts per million (ppm) below the signal for tetramethylsilane or sodium -2,2-dimethyl> 2-silapentane-5-sulfonate The following abbreviations for the shape of the signals were used: s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet. <Example 1: Penicillanic acid-1, A dioxide A solution of 6.51 g (41 mmol) of potassium permanganate in 150 ml of water and 4.95 ml of glacial acetic acid, which had been cooled to about 5 ° C, was added to a cold (about 5 ° C) solution. of 4.58 g (21 mmol) of sodium salt of penicillanic acid in 50 ml of water, the mixture was stirred at about 5 ° C for 20 minutes, then the cooling bath was removed Solid sodium bisulfite was added until the color of the potassium permanganate disappeared, then the mixture was filtered To the aqueous filtrate was added a saturated sodium chloride solution in an amount corresponding to half the volume of the filtrate. glue, after which the pH was adjusted to 1.7. The acidic solution was extracted with ethyl acetate, the extracts were dried and evaporated in vacuo to give 5.47 g of the title product (the title product or title compound is hereinafter referred to as the title or compound of the title).

The aqueous mother liquor was saturated with sodium chloride and further extracted with ethyl acetate. The ethyl acetate solution was dissolved in vacuo and evaporated in vacuo to give an additional 0.28 g of product. Accordingly, the total yield was 3.75 g (78%). fHR spectrum (DNSO-do) for the product showed absorptions at 1.40 (S, 5Hj, 1.50 (S, 5H), 5.15 (d of duplicate 1H, J4 = 16 Hz, J2 = 2 Hz), 5.85 (d of doublets, 1H, J4 = 16 Hz, J1 = 4Hz), 422 (s, 1H) and 5.05 (d of aublets, 1a, Jq_ = 4 Hz, J? = 2 Hz) ppm.s Example 2: Benzylpenicillanate-1,1-dioxide A solution of 6.85 g (24 mmol) of benzylpenicillanate in 75 ml of ethanol-free chloroform was stirred under nitrogen in an ice bath and added with a portion consisting of 4.78 g of an 85% pure_5-chloroperbenzoic acid and several minutes later with a second equal portion Stirring was continued for 50 minutes in the ice bath and then for 45 minutes without external cooling.The reaction mixture was washed with an aqueous solution of alkali (pH 8.5) and then with a saturated solution of sodium chloride, then dried and evaporated in vacuo to give 7.05 g of a residue which on examination was found to be a mixture of benzylpenicillanate-1-oxide and benzylpenicillanate-1,1-dioxide in the proportions ratio, 51- 'i A solution of 4.85 g of the above mixture of sulfoxide and sulfone in the ratio of 5.521 in 50 ml of ethanol-free chloroform was added under nitrogen 5.2 g of an 85% pure 5-chloroperbenzoic acid at room temperature. The reaction mixture was stirred for 2.5 hours, then diluted with ethyl acetate.

The mixture thus obtained was added to water at pH 8.0, whereupon the phases were separated. The organic phase was washed with water at 5.0 DEG C. and then with a saturated solution of sodium chloride, then dried over sodium sulfate. Evaporation of the solvent in vacuo gave 5.59 g of the title compound. The HNR spectrum of the product (in CDCl 3) showed absorptions at 1.28 (s, 5H), 1.58 (s, ZH), 5.42 (m, 2H), 4.3? (S, 1H), 4.55 (m, 1H), 5.15 (q, en, J = 12 Hz) and 7.55 (s, EE) ppm. Example 5: Ycnicillanic acid-1,1-dioxide. A solution of 8.27 g of benzylpenicillanate-1,1-dioxide in a mixture of 40 ml of methanol and 10 ml of ethyl acetate was slowly added with 10 ml of water and then with 12 g of palladium on potassium carbonate. The mixture was shaken under a nitrogen atmosphere at 558.5 KTa for # 0 minutes, \ J1 - lay 'reossze-s f, then filtered through SUPERCEIf (a diatomaceous earth). The filter cake was washed with methanol and then with aqueous methanol, after which the washings were added to the filtrate. The combined solution was evaporated in vacuo to remove the majority of organic solvents, then the residue was partitioned between ethyl acetate and water at pH 2.8. The ethyl acetate phase was removed and the aqueous phase was subjected to further extraction with ethyl acetate. The combined ethyl acetate solutions were washed with a saturated sodium chloride solution, dried over sodium sulfate and then evaporated in vacuo. The residue was slurried in a mixture of ethyl acetate and ether in a ratio of 1: 2 to give 2.57 g of the title product, m.p. 145 DEG-115 DEG C. The ethyl acetate-ether blazap evaporated to give a further 2.17 g of product. . Example 4; Pivaioyloxymethyl-penieillanate-1ioxide. 0.615 g (2.4l mmol) of penicillanic acid 1,1-dioxide in 2 ml of N, N-di4 methylformamide were added 0.215 g (2.5O mmol) of diisopropylethylamine and then 0.565 ml of chloromethyl pivalate. The reaction mixture was stirred at room temperature for 24 hours and then diluted with ethyl acetate and water. The ethyl acetate phase was separated and washed three times with water and once with a saturated solution of sodium chloride. The ethyl acetate solution was then dried using anhydrous sodium sulfate and evaporated in vacuo to give 0.700 g of the title product, a solid, m.p. The NHR spectrum of the product (in CDCIB) showed absorptions at 1.27 (s,? H), 1.4? (s, EH), 1.62 (S, BH), 5.52 (m, 23), 4.47 (s, 1H), 4.70 (m, 1n), 5.75 (d, 1H, J = 6.0 Hz) and 5.93- (d, in, J = 6.0 Hz). in Example 5: The procedure described in Example 4 was repeated with the modification that the pivaloyloxymethyl chloride used in Example 4 was exchanged for an equimolar amount of aethoxymethyl chloride, propionyloxymethyl chloride and hexanoyloxymethyl chloride to give: acetoxymethyl] -penioillanate-1,1-dioxide, propionyloxymethyl-penicillanate-1,1 = dioxide and hexanoyloxymethyl-penicillanate-1,1-dioxide.

Example 62 E-Phthalidyl penicillanate-1,1-dioxide. To 0.785 g of a few vaoeezs-9 (3.56 mmol) penicillanic acid 1,1-dioxide in 5 ml of N, N-dimethylformamide was added 0.47 ml of triethylamine and then 0.715 5-bromophthalide. The reaction mixture was stirred for 2 hours at room temperature and then diluted with ethyl acetate and water. The pH of the aqueous phase was raised to 7.0 and the phases were separated. The ethyl acetate phase was washed first with water and then with a saturated sodium chloride solution, after which it was dried using sodium sulfate. The ethyl acetate solution was evaporated in vacuo to give the title product as a white foam as an evaporation residue. The INR spectrum of the product (in CDCl 3) showed absorbances at 1.47 (s, GH), 5.45 (m, 1H), 4.45 (s, 1H), 4.62 (m, 1H), 7 , 40 and 7.47 (2 singlets, 1H) and 7.75 (m, 4H) ppm. The procedure described above was repeated with the change that 5-bromophthalide is exchanged for 4-bromochrotonolactone resp. 4-bromo-X-butyrolactone to give: M-crotonolactonyl penicillanate-1,1-dioxide and X-butyrolacton-4-yl penicillanate.

Example 71 1- (Ethoxycarbonyloxy) ethyl penicillanate 1,1-diol.

A mixture of 0.654 g of penicillanic acid 1,1-dioxide, 0.42 ml of triethylamine, 0.412 g of 1-chloroethyl ethyl carbonate, 0.500 g of sodium bromide and 5 ml of N, N-dimethylformamide was stirred at room temperature for 6 days. The mixture was then worked up by diluting with ethyl acetate and water, after which the pH was adjusted to 8.5. The ethyl acetate phase was separated, washed three times with water and then once with a saturated sodium chloride solution, after which it was dried using anhydrous sodium sulfate. The ethyl acetate was removed by evaporation in vacuo to give 0.590 g of the title product as an oil.

This product was combined with an approximately equal amount of a similar material from a similar experiment. The combined product was dissolved in chloroform and 1 ml of pyridine was added. The mixture was stirred at room temperature overnight, after which the chlorine form was read off by evaporation in vacuo. The evaporation residue was partitioned between ethyl acetate and water at room temperature. The separated and dried ethyl acetate was then evaporated in vacuo to give 150 mg of the title product (yield about 7%). IR spectrum (film) of the product showed absorptions at 1805 and 1765 cm -1 q. NHR spectrum (CDCl 3) 50 'feoesza-e in exhibited mbsmmpmimmons at 1.45 (m, 1211), 5.47 (m, a ), 5.9 (q, 211.1 -. ~ M5 sz), 4.37 (m, m), 4.65 (m, m) and 6.77 (m, 13) ppm- in Example 8: The procedure described in Example 7 was repeated with the modification that polychloroethylethyl carbonate was exchanged for an equilibrium manganese of suitable: i-kiomalkyl-alkylcambonam, 1- (alicoamoxyloxy) ethyl chloride or 1-methyl-1- (alkanoyloxy) ethyl chloride status of the following compounds: 7 methoxycarbonyloxymethyl-penicillanate-1,1-dioxide, ethoxycarbonyloxymethyl-penicillanate-1,1-dioxide, isobutoxycarbonyloxymethyl-penicillanate-1,1-dioxide, 1- (methoxycarbonylo-penicillate) } 1- (butoxycarbonyloxy) ethyl penicillanate-1,1-dioxide, 1- (acetoxy) ethyl penicillanate-1,1-dioxide, 1- (butyryloxy) ethyl penicillanate-1,1-dioxide, 1- (pivaloyloxy ) ethyl penicillanate 1,1-dioxide, 1- (hexanoyloxy) ethyl penicillanate-1,1-dioxide, 1-methyl-1- (acetoxy) ethyl penicillan at-1,1-dioxide and 1-methylfl- (isobutyryloxy) ethyl penicillanate-1,1-dioxide. Example Gel Q: The procedure described in Example 4 was repeated, but the chloromethyl pivalate was exchanged for an equimolar amount of benzyl bromide and 4-nitrobenzyl bromide, respectively, to give benzylpenicillanate-1,1-dioxide and 4-nitrobenzylpenicillanate-1,1-dioxide.

Example 10: Penicillanic acid-1a oxide. To 1.4 g of 5% palladium on calcium carbonate (prehydrated) in 50 ml of water was added a solution of 1.59 g of benzyl-6,6-dibromopenicillanate-1a-oxide in 50 ml of tetrahydrofuran. The mixture was shaken for one hour in a hydrogen atmosphere with a pressure of about 510 kPa and a temperature of 25 ° C, after which it was filtered. The filtrate was evaporated in vacuo to remove the major amount of tetrahydrofuran, then the aqueous phase was extracted with ether. The ether extracts were evaporated in vacuo to give 0.5 g of a material which was found to be largely benzylpenicilanate-1a-oxide. The above benzylpenicillanate-1a oxide was combined with an additional 2.0 g of benzyl-6,6-dibromopenicilanate-1a oxide and dissolved in 50 nl of tetrahydrofuran. the solution was added to 4.0 g of 5% palladium on calcium carbonate in 50 ml of water and the resulting mixture was shaken overnight at 25 ° C in a hydrogen atmosphere with a pressure of about 310 kPa. The mixture was filtered and the BO y, p 7806628-9 filtrate was extracted with ether. The extracts were evaporated in vacuo and the evaporation residue was purified by chromatography on silica gel. The elution was performed with chloroform. This gave 0.50 g of material; The latter material was hydrogenated at about 510 kPa and ° C in water-methanol, (1: 1) with 0.50 g of 5% palladium on calcium carbonate for two hours. Then an additional 0.50 g% palladium on calcium carbonate was added and hydrogenation was continued at 510 kPa and 25 ° C overnight. The reaction mixture was filtered, extracted with ether and the extracts discarded. The residual aqueous phase was adjusted to pH 1.5, then extracted with ethyl acetate. The ethyl acetate extracts were dried (Na 2 SO 4) and then evaporated in vacuo to give 0.14 g of penicillanic acid 1a-oxide. NHR spectrum (CDCl 3 / DMSO-d 6) showed fisorptions at 1.4 (s, EH), 1.64 (s, BH), 5.60 cm 2, EH), 4.5 is, 1H) and 4.54 (m, 1H) ppm. The IR spectrum of the product (KSR disc) showed absorptions at 1795 and 1745 cm -1. Example 11: Penicillanic acid-1a-oxide. To 1.0 g of 5% palladium on calcium carbonate (prehydrated) in 30 ml of water was added a solution of 1.0 g of 6,6-dibromopenicillanic acid-1a-oxide. The mixture was shaken under an atmosphere of hydrogen at a pressure of about 510 kPa and a temperature of 25 ° C for one hour. the leakage mixture was then filtered and the filtrate was evaporated in vacuo to remove the methanol. The remaining aqueous phase was diluted with an equal volume of water, adjusted to pH 7 and washed with ether. The aqueous phase was then acidified to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate extracts were dried (Ka 2 SO 4) and evaporated in vacuo to give penicillanic acid 1m-oxide.

Example 12: Penicillanic acid-1S oxide. To a stirred solution of 2.65 g of 12.7 mmol) of penicillanic acid in chloroform at 0 ° C was added 2.58 g of 853 pure 5-chloroperbenzoic acid. After one hour, the reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in a small amount of chloroform. the solution was concentrated slowly until a precipitate began to form. At this time, evaporation was stopped and the mixture was diluted with ether. The precipitate was filtered off, washed with ether and dried, yielding 0.615 g of peniolylanic acid 12-oxide having a melting point of 140 DEG-145 DEG. The IR spectrum of the product \ n 55 vaossze-s in (CHCl 3 solution) showed absorptions at 1775 and 1720 cm -1.

High spectrum (CDCl 3 / DMSO-d 6) showed absorptions at 1.55 (s, 3: a), 1.76 (s, 5H), 5.56 (m, an), uxoecs, 1H-) and 5.05 ( m, lä) ppm. The NHR spectrum showed that the product was approximately 90% pure.

Examination of the chloroform ether ether liquor showed that it contained an additional amount of penicillanic acid-low oxide and also a small amount of penicillanic acid-1a-oxide. § §m29l_lâ: By esterification of penicillanic acid-1a-oxide or, where applicable, penicillanic acid ~ 13Eoxide with the required alkanoyloxychloride in the manner set forth in Example 5, the following compounds were obtained: in acetoxymethyl fl penicillanate-la-oxide propionyloxyl oxide, pivaloyloxymethyl-penicillanate-1a-oxide, acetoxymethyl-penicillanate-oxide, propionyloxymethyl-penicillanate-13-oxide and pivaloyloxymethyl-penioillanate-B-oxide. Example 14: Reaction of penicillanic acid-1a-oxide or penicillanic acid-1β-oxide with 3-bromophthalide or, where appropriate, 4-bromocrotonolactone or 4-bromofibutyrolactone gave the following compounds: _. -phthalidyl-penicillanate-1α-oxide, α-crotonolactonyl-penicillanate-lae oxide, z-phthalyl-penicillanate-1β-oxy, ε-crotonolactonyl-penicillanate-oxide and 1-butyrolactone-4-yl-penicillanate-1β-oxide. Example: By reacting penicillanic acid-1a-oxide or, where appropriate, penicillanic acid-1β-oxide with the required 1-chloro-alkyl-alkyl carbonate or 1- (alkanoyloxy) ethyl chloride in the manner set forth in Example 7, the following compounds were obtained: 1- (ethoxycarbonyloxy) ethyl penicillinate-1-oxide, methoxycarbonyloxymethyl-penicillanate flax oxide, ethoxycarbonyloxymethyl-penicillanate-1-oxide, isobutoxycarbonyloxymethyl-penicillanate-1a-oxide, 1- (methoxycarbyl-oxy-bromoxyl) ) ethyl penicillanate-1a-oxide, 1- (aethoxy) ethyl-penicillananate-1a-oxide, 1- (butyryloxy) ethyl-penicillanate-1a-oxide, 1- (piva10; .-: QX:) asylum-penis: lianate-1α-oxia, N- (_) 7: (ethoxycarbonyloxy) ethyl penicillanate-13-oxide methoxycarbonyloxymethyl penicillanate-12-oxide; ethoxycarbonyloxymethylpenicillanate-13-oxide, isobutoxycarbonyloxymethyl-penicillanate-13-oxide, 1- (methoxycarbonyloxy) ethyl-penicillanate-1B-oxide, 1- (butoxycarbonyloxy) ethyl-penicillanate-1-oxy-oxide, 1β-oxide; , J- (butyryloxy) ethyl penicillanate-1β-oxide and 1- (pivaloyloxy) ethyl-penicillanate-1β-oxide.

Example 16: By reacting penicillanic acid 11a-oxide and penicillanic acid-13-oxide with benzyl bromide in the manner set forth in Example 4, benzylpenicillanate-1a oxide and benylpenicillanate l13-oxide, respectively, were obtained.

The same method was obtained by reacting penicillanic acid-1m oxide and penicillanic acid-1β-oxide with 4-nitrobenzyl bromide in the manner set forth in Example 4, 4-nitrobenzyl-penicillanate-1a-oxide and 4-nitrobenzyl-penicillanate-13-oxide, respectively.

Example 17: Penicillanic acid 1,1-dioxide. To 2.1? g (10 mmol) of penicillanic acid-1a-oxide in 30 ml of ethanol-free chloroform at about 0 ° C was added 1.73 g (10 mmol) of 5-chloroperbenzoic acid. The mixture was stirred for one hour at about 0 ° C and then for a further Bu hours at 25 ° C. The filtered reaction mixture was evaporated in vacuo to give penicillanic acid 1,1-dioxide.

Example 13: The procedure described in Example 17 was repeated but the penicilic acid-1G oxide was exchanged for: penicillanic acid II-oxide, 1ethoethoxymethyl-penicillanate-1α-oxide, propionyloxymethyl-penicillanate-1α-oxide, pivaloyoxymethyl-1-penicillanate , acetoxymethyl-penicillanate-1-oxide, propionyloxymethyl-penicillanate-13-oxide, pivaloyloxymethyl-penicillanate-1β-oxide, E-phthalidyl-penicillanate-1α-oxide, Z-phthalidyl-penicillanate-12-oxide, 1- (ethoxy) ethyl penicillanate-1a-oxide, methoxycarbonyloxymethyl-penicillanate-1a-oxide, ethoxycarbonyloxymethyl-penicillanate-1a-oxide, isob toxicarbonyloxynethyl-penicillanate-1a-oxide, 1- (methoxycerbonyloxy) -N-1-laicyl 1- (butoxycarbononyloxy) ethyl-penicillanate-1a-oxide, 1- (acetoxy) ethyl-penicillanate-la-oxide, 1- (butyryloxy) ethyl-penicillanate-la-oxide oxide, 1- (pivaloyloxy) ethyl penicillanate-1a-oxide, 1- (ethoxycarbonyloxy) ethyl-penicillanate-13-oxide, methoxycarbonyloxymethyl-penicillanate-134 oxide, ethoxycarbonyloxymethyl-penicillanate-13-oxyacid bonyloxymethyl penicilanate-15-oxide, 1- (methoxycarbonyloxy) ethyl-penicilanate412-oxide; 1- (butoxycarbonyloxy) ethyl penicillanate-13-oxide, 1- (acetoxy) ethyl-penicillanate-1S-oxide, 1- (butyryloxy) ethyl-penicillanate-1S-oxide and 1- (pivaloyloxy) ethyl-penicillanate-13- The following were obtained: penicillanic acid 1,1-dioxide, acetoxymethyl-penicillanate-lil dioxide, propionyloxymethyl-penicillanate-1,1-dioxide, pivaloyoxymethyl-penicillanate-1,1-dioxide, acetoxymethyl-penicillan-1,1-dioxide , propionyloxymethyl-penicillanate # 1,1-dioxide, pivaloyloxymethyl-penicillanate-1,1-dioxide, -phthalidyl-penicillanate-1,1-dioxide, '-phthalidyl-penicillanate-1,1-dioxide, 1- (e-oxycarbonyloxylate 1,1-aioxia, methoxycarbonyloxymethyl penicillanate-1,1-dioxide, ethoxycarbonyloxymethyl-penicillanate-1,1-dioxide, isobutoxycarbonyloxymethyl-penicillanate-1,1-dioxide, 1- (methoxycarbonyloxy-1-yl) -lyl-ethyl-ethyl dioxide, 1- [1-butoxycarbonyloxynethyl-penicillanate-1,1-dioxide, 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 1- (butyryloxy) ethyl-penicillanate-1,1-dioxide, 1- (pivaloyloxy) ethyl] -penicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethyl-penicillin nat-1,1-dioxide, netoxycarbonyloxymethyl-penicillanate-1,1-dioxide, ethoxycarbonyloxymethyl-penicillanate-1,1-dioxide, isobutoxycarbonyloxymethyl-penicillanate-1,1-dioxyl, 1- (methicyl) dioxy-1- (methicyl) dioxy butoxycarbonyloxy) ethyl 1-penicillanate-1,1-dioxide, 1- (acetoxy) ethyl-penicillanate-1,1-dioxide, 7- (butyryloxy) ethyl-penicillanate-1,1- dioxide and 1- (pivaloyloxy) ethyl penicillanate-1,1-dioxide.

Example 12: By oxidation of benzylpenicillanate-1a-oxide and benzylpenicillanate-13-oxide with 5-chloroperbenzoic acid in the manner set forth in Example 17, benzylpenicillanate-1,1-dioxide was obtained in each case. .

Few similar methods were obtained by oxidizing N-nitrobenzyl-penicillanate-1α-oxide and 4-nitrobenzylpenicillanate-13-oxide with 3-chloropertenzoic acid as in Example 17 4-nitro-benzyl-penicillanate-1,1-dioxide.

Example 20: Penicillanic acid ~ 1,1-dioxide. By hydrogenolysis of 4-nitrobenzyl penicillanate-1,1-dioxide in the manner set forth in Example 5, penicillanic acid 1,1-dioxide was obtained.

Example 21: Hatrium penicillanate-1,1-dioxide. To a stirred solution of 52.75 g (0.4 mol) of penicillanic acid 1,1-dioxide in 450 ml of ethyl acetate was added a solution of 25.7 g of sodium 2-ethylhexanoate (0.155 mol) in 200 ml of ethyl acetate. The solution thus obtained was stirred for one hour, after which a further 10% excess of sodium 2-ethylhexanoate in a small volume of ethyl acetate was added. The product immediately began to precipitate. Stirring was continued for 50 minutes, after which the precipitate was filtered off. It was washed first with ethyl acetate, then with a 1: 1 mixture of ethyl acetate and ether and finally with ether. The solid was dried over phosphorus pentoxide for about 16 hours at 2 ° C and about 0.1 mmHg. He obtained 56.8 g of the title compound of the sodium salt of the present example contaminated with a small amount of ethyl acetate. The ethyl acetate content was reduced by heating the product in vacuo at 100 ° C for three hours. The IR spectrum of this final product (K3r disk) showed the absorption at 1736 and 1608 cm-4. NHR spectrum (D 2 O) showed absorptions at 1.43 (s, EH), 1.62 (s, BH), 3.35 (d of doublets, 1H, J1 = 1GHz, J2 = 2Hz), 5, 70 (d of doublets, E, J1 = 16Hz, J2 = kHz), 4.2E (s, 1H) od: 5.05 (d of doublets, lfl, J1 = 4Hz, Jq = 2nd) ppm. The sodium salt given in the title of the present example can also be prepared using acetone instead of ethyl acetate.

Example 22: Penicillanic acid 1,1-diol. To a mixture of .6OG ml of water and 289 ml of glacial acetic acid was added portionwise š *?, 5 g * -25 55 'rsoeaza-s i, potassium permanganate. The mixture was stirred for 15 minutes, then cooled to 0 ° C and added with stirring to a mixture prepared from evo g penicillanic acid, zoo m 1 ar-Naon 'and 2. # 00 ml of water (at 7.2) and then cooled to 8 ° C. The temperature rose to 155 ° C during said addition. The temperature of the mixture thus obtained was lowered to 5 ° C and stirring was continued for 50 minutes. To the reaction mixture was then added 142.1 g of sodium bisulfite in portions over 10 minutes.

The mixture was stirred for 10 minutes at 10 ° C and then added with 100 g of SUPERCEI (a diatomaceous earth). After stirring for an additional 5 minutes, the mixture was filtered. To the filtrate was added 4.0 liters of ethyl acetate, after which the pH of the aqueous phase was lowered to 1.55 using 6N-HCl. The ethyl acetate phase was removed and combined with several additional ethyl acetate extracts. The combined organic phases were washed with water, dried (HgSO 4) and evaporated to near dryness in vacuo.

The slurry thus obtained was stirred with 700 nl of ether at 10 ° C for 20 minutes, after which the solids were filtered off.

He thus obtained 52.6 g (26% yield) of the title compound, m.p. 154-155.5 ° C (dec.).

Example 25: Pivaloyloxymethyl penicillanate-1,1-dioxide. To a solution of 1.25 g of pivaloyloxymethyl penicillanate in 40 ml of chloroform cooled to about -15 ° C was added 0.8 5-chloroperbenzoic acid.

The mixture was stirred at about -15 ° C for 20 minutes, after which its temperature was allowed to rise to a value corresponding to room temperature. NHR analysis of the solution thus obtained showed that it contained both the 1α and 13 oxide.

The chloroform solution was concentrated to about 20 ml and then added with an additional 0.5-8 chloroperbenzoic acid.

The mixture thus obtained was stirred overnight at room temperature, after which the entire amount of solvent was removed by evaporation in vacuo. The residue was dissolved in about 4 ml of dichloromethane and 0.4 g of 5-chloroperbenzoic acid was added. The mixture was stirred for 5 hours, after which the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water at pH 6.0 and sodium bisulfite was added until a test for the presence of peroxides was negative.

The pH of the aqueous phase was raised to 8.0 and the phases were separated. The organic phase was washed with brine, dried | c 76066284 using anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in ether and reprecipitated by the addition of hexane. The solid thus obtained was recrystallized from ether to give 0.357 S of the title compound.

The NFÉ spectrum of the product (CDCl5) showed absorptions at 1.25 (S, 95), 1.50 (S, 5H), 1.67 (S, šï), 5.23 (m, 2H) 4.45 ( S, 13), 5.25 (m, 13) and 5.78 (m, _H> PPU- Example 24: 1-Phthalidylphenicillanate-1,1-dioxide To a solution of 1 mg of 3-phthalidyl-penicillanate in 5 0.430 g of chloroperbenzoic acid was added at about 10 DEG C. The mixture was stirred for 50 minutes, then an additional 0.515 g of 5-chloroperbenzoic acid was added, the mixture was stirred for 4 hours at room temperature, then the solvent was removed by evaporation in vacuo and the residue was partitioned between water at pH 6.0 and sodium bisulfite were added to decompose the remaining peracid, the aqueous phase pH was raised to 8.8 The eases were separated and the organic phase was evaporated in vacuo to give the rubril compound as a foam. (CDCl 3) showed absorptions at 1.62 (m, GH), 3.5 (m, en), H 52 (p, m), 5.23 (m, 12 :) and fi nêö (m, SH) ppm. Example Ef: 2.2.2 ~ Tricyclethyl -penicillanate-1,1-dioxide. To 100 mg of 2,2,2-trichloroethyl penicillanate in a small volume of chloroform was added SO mg of 5-chloroperbenzoic acid and the mixture was stirred for 50 minutes. An examination of the reaction product at this time showed that it consisted mainly of sulfoxide (ïñš spectrum (CDCl 3), showed absorptions at 1.6 (s, BH), 1.77 (S, 55). 3158 (m , BH), 4 »C5 (S, 15), 4.85 (w,» HJ ash 5.3? (M, IE * ppm). Additional «1CC mg of 3-chloroperbenzoic acid was added and the mixture was stirred overnight. The solvent was removed then, by evaporation in vacuo and the evaporation residue, partitioned between ethyl acetate and water at a temperature of 0 DEG C. A sufficient amount of sodium bisilphite was added to alter the excess peracid, then raised to 3.5 DEG C. the organic phase was separated, washed with brine and dried over brine. - Dec. By evaporation in vacuo 55 mg of the title product were obtained. Níš spectrum (Cïülz) showed abscretions at 1.53 (s, fine), new: (s, 3rd), 5, '+ 7 '(1.1, 2: 1), rm »(e,. ;; 2: ._ (m, 1: e) - sen 4.8 fm, EH) ppm.

Example 25: L-Hydrobenzylenicillanate-1,1-dioxide. A solution of 4-nitrobenzyl penicillanate in chloroform was cooled to about 15 DEG C. and an equivalent of 3-chloroperbenzoic acid was added. The reaction mixture was stirred for 20 minutes. Examination of the reaction mixture at this time by NMR spectroscopy showed that it contained 4-nitrobenzyl-penicillanate-1-oxide. an additional equivalent of 5-chloroperbenzoic acid was added and the reaction mixture was stirred for H hours. At this time, another equivalent of 5-chlorobenzoic acid was added and the reaction mixture was stirred overnight. The solvent was removed by evaporation and the evaporation residue was partitioned between ethyl acetate and water at pH 8.5. The ethyl acetate phase was separated, washed with water, dried and evaporated to give the crude product. This was purified by chromatography on silica gel, eluting with a 1: 4 mixture of ethyl acetate and chloroform.

The NHR spectrum of the product (ÖDCl 3) showed absorptions of 1.55 (s, an), 1.53 (s, 5: 1), 5.45 (m, aa), 4.42 (s, m), f, 5s (m, n), 5.50 (s, 2nd) and 7.85 (q, un) ppm.

Example 2T: Penicillanic acid ~ 1,1-dioxide. To 0.54 g of 4-nitrobenzyl penicillanate-1,1-dioxide in 50 ml of methanol and 10 ml of ethyl acetate was added 0.54 g of 10% palladium on carbon. The mixture was then shaken under an atmosphere of hydrogen at a pressure of about 545 ° C until the hydrogen uptake subsided. The reaction mixture was filtered and the solvent was evaporated, then the residue was partitioned between ethyl acetate and water at 8.5 p. The aqueous phase was removed, new ethyl acetate was added and the pH was adjusted to 1.5. The ethyl acetate phase was separated, washed with water and dried, then evaporated in vacuo.

He thus obtained 0.168% of the title compound as a crystalline solid.

Example 28: Phenicillanic acid 1,1-dioxide. A solution of 512 mg of 4-nitrobenzyl penicillanate-1,1-dioxide in a mixture of 5 ml of acetonitrile and 5 ml of water was cooled to 0 ° C with stirring. then a solution of 484 mg of sodium dithionite in 1.4 ml of 1,03-NaOH was added portionwise over several minutes. The reaction mixture was stirred for a further 5 minutes and then diluted with ethyl acetate and water at 8.5. The ethyl acetate phase was removed and evaporated in vacuo to give 500 mg of starting material. New ethyl acetate was added to the aqueous \ .T! \ N O J! in the 7-806628-9 phase and on was adjusted to 1.5. The ethyl acetate was removed, dried and evaporated in vacuo to give 50 mg of the title compound.

Example 29: 1-Methyl-1- (acetoxy) ethyl penicillanate-1,1-dioxide.

To 2.55 g of penicillanic acid 1,1-dioxide in 5 ml of R, N-dimethylformamide was added 1.9 ml of ethyldiisopropylamine followed by dropwise addition of 1.3? g of 1-methyl-1- (acetoxysethyl chloride at about 20 ° C.

The mixture was stirred at room temperature overnight and then diluted with ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with water at pH 9. The ethyl acetate solution was then dried (Na 2 SO 4) and evaporated in vacuo to give as evaporation residue 1.65 g of crude product as an oil. This solidified on standing in the refrigerator, after which recrystallization was carried out in a mixture of chloroform and ether. He obtained a material with a melting point of 90-92 ° C.

NHR spectrum of the crude product (CEC1-) showed absorptions At 1.5 (S, 5H) »1.62 (S, 33)» 1135 (S, 55) »1.95 (S, BH), 2.07 ( Sa (ms-gina A35 (S, 1.31) šCh LHS? (Ma l fi) ppm 'Example 59: The procedure described in Example 29 was repeated but the 1-methyl-1- (acetoxy) ethyl chloride was replaced with the appropriate 1-methyl-1- (alkanoyloxy) -ethyl chloride for the preparation of the following compounds: in 1-methyl-1- (propionyloxyDethyl-penicillanate-1,1-dioxide, I-methyl-1- (pivaloyloxy) ethyl-penicillanate-1,1-dioxide and 1-methyl-1- (hexanoyloxy) ethyl-penicillanic acid 1,1-dioxide.

Example 21: Penicillanic acid 1,1-dioxide. To a stirred solution of 1.78 .mu.l of penicillanic acid in water of 7.5 was added 1.4 ml of a 40 .mu.l peracetic acid and 50 minutes later an additional 3.94 ml of 40 .mu.g of peracetic acid. The reaction mixture was stirred for E days at room temperature and then diluted with ethyl acetate and water. Solid sodium bisulfite was added to decompose the excess peracid, then adjusted to 1.5. The ethyl acetate phase was separated, dried (Ha, SO 3) and evaporated in vacuo. The residue consisted of a 5: 2 mixture of penicillanic acid 1,1-dioxide and penicillanic acid I-oxide.

Example 32: Fivaloyloxynethyl penicillanate 1,1-dioxide. A stirred solution of H95 mg of pivaloyloxymethyl penicillanate oxide in 5 ml of ethyl acetate was cooled to about -15 ° C and added with 5 mg of manganese acetylacetonate. To the thus obtained dark brown mixture was added 0.89 ml of a 40% peracetic acid in small amounts over the course of several minutes. After 40 minutes, the cooling bath was removed and the mixture was stirred at room temperature for days. The mixture was diluted with ethyl acetate and water at pH 8.5 and the ethyl acetate phase was separated, dried and evaporated in vacuo. He thus obtained 178 mg of a material which, by NNE spectroscopy, was found to be a mixture of pivaloyloxymethyl-penicillenate-1,1-dioxide and pivaloyloxymethyl-1 - 1 CJ \ N \ J1 penicillanate-1-oxide. . The above materials were dissolved in ethyl acetate and oxidized using 0.9 ml of peracetic acid and 5 mg of manganese acetyl acetonate as described above using a reaction time of 16 hours. The reaction mixture was then worked up as above and 186 mg of pivaloyloxymethyl penicillanate-1,1-dioxide were obtained. Preparation Method A: 6.6-Dibromopenicillanic acid 11-oxide.

This compound is prepared by oxidizing 6,6-dibromopenicillanic acid with 1 equivalent of 5-chloroperbenzoic acid in tetrahydrofuran at C-25 ° C for about one hour according to the procedure described by Harrison and co-workers in the Journal of theeChemical Society (london) Perl-cin I, 1772 (1976).

Preparation method B: Benzyl-6.G-dibromopenicillanate.

To a solution of 54 Q (0.65 mol) of 6.6 dibromopenicillanic acid in E50 ml of N, N-dimethylacetamide was added 22.9 ml (0.65 mol) of triethylamine and the solution was stirred for 40 minutes. Benzyl bromide (19.6 ml; 0.165 mol) was added and the resulting mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered off and the filtrate was added to 1500 ml of ice water adjusted to pH 2. The mixture was extracted with ether and the extracts were washed first with a saturated sodium bicarbonate solution, then with water and finally with brine.

The dried (HQSOQ) ether solution was evaporated in vacuo to give a pale gray-yellow solid which was recrystallized from isopropanol. This gives 73 g of 95% yield of the title compound, m.p. IE spectrum (ïšr disk) showed absorptions at 17? 5 and 1740 cm_ ''. ~ r_-v- \ ïlš spectrum (CïCl2) showed absorptions at 1.53 (s, 5n ,, \ w IQ \ fl \ N \ .J '| Ifiltrerades.? 8 ° 6628'9 »__-“ laf- 'ÖÜ (59 Z) s 4:50 (51: ina (S1 2109 (sa IH) and fi ašï (S1 53) PPÜ- “framing process C: Benzyl-E, 6-dibromopicnicillanate-ld-oxide. To a while stirring solution of 15.4 g (0.05 mol) of benzyl 6,6-dibromopenicillanate in 200 ml of dichloromethane was added a solution of 6.12 g (0.0 mol) of 5-chloroperbenzoic acid in 100 ml of dichloromethane at a temperature of about 0 Stirring was continued for 3.5 hours at about 0 ° C, after which the reaction mixture was filtered. The filtrate was washed first with a 5% sodium bicarbonate solution and then with water, then dried (Ha 3 SO 4). 12.5 3 g of the title product were obtained in the form of an oil, the oil was solidified by trituration under ethylene and it was filtered off to give 10.5 g of benzyl-6,6-dibromopenicilyla as a solid. spectrum (HCIÄ)? §0 cm'1. F13 spectrum for nat- 1-.x-oxide in exhibited absorptions at 1800 and the product (CDCl 3) exhibited absorptions at 1.3 (s, EH), 1.5 (S, 55), 5 (S1 1H) 1 5.15 (S1 33 ), 5.3 (S, 13) and 7.5 (S, 5H) ppm.

Preparation procedure L: 4-Nitrobenzyl penicillanate. By reacting the triethylamine salt of penicillanic acid with 4-nitrobenzyl bromide in the manner indicated above under the heading Preparation Procedure B, 4-nitrobenzyl penicillanate was obtained. Preparation procedure E: 2,2,2-Trichloroethyl penicillanate. to -03 mg of penicillanic acid in 10 ml of dichloromethane was added 2 ng of diisopropylcarbodiimide and then 0.19 ml of 2,2,2-trichloroethanol.

The mixture is stirred overnight, after which the solvent is removed by evaporation in vacuo. The seed was purified by flash chromatography using silica gel as adsorbent and chloroform as eluent.

Preparation procedure F: 5-Phthalidyl penicillanate. To a solution of 506 mg of penicillanic acid in 2 ml of N, L-dimethylformamide was added 0.76 ml of diisopropylethylamine and then F55 mg of 5-ethylethyl bromide. The mixture was stirred overnight and then diluted with ethyl acetate and water. The pH was adjusted to š.0 and the phases were separated. The organic phase was washed with water and then with water at pH 8.0, after which it was dried using anhydrous sodium sulfate. The dried ethyl acetate solution was evaporated in vacuo to give 715 mg of the title compound. 7§Û6628'9 5: L ester in the form of an oil. NHR spectrum (CDCl 3) showed absorptions at 1, e2 (m, GH), 5.3 (m, za), 4.52 (E, 1 :), 5, :: (m, ie, and 7.65 (m, 521). The mixture was stirred overnight and then diluted with ethyl acetate and water, the organic phase was separated and washed first with water at pH 5.0 and then with water at pH 8.0 The ethyl acetate solution was dried (Na 2 SO 4) and evaporated then in vacuo to give pivaloyloxymethyl-6,6-dibromopenicillanate as an amber oil (Z, 1, g) which slowly crystallized. The latter ester was dissolved in 100 ml of methanol, whereupon 5.1 g of palladium on carbon and 1.51 g of potassium bicarbonate in 20 ml of water were added, the mixture was shaken under hydrogen at atmospheric pressure until the hydrogen uptake subsided, the reaction mixture was filtered and the ethanol was evaporated by evaporation in vacuo. The residue was partitioned between water and ethyl acetate at pH 8, after which the organic phase was separated. The latter was dried (Ka 2 SO 4) and evaporated in vacuo to give 1.25 g of the title compound. NH spectrum (CDCl 3) showed absorptions at 1.2; (S, 9H), 1.5 (s, 5H), 1.67 (S, 5H), 5.5s (m, 1H), 25 (m, 1H) and 5.78 (m, 2H) ppm .

Preparation method H: 4-Nitrobenzyl penicillanate. To a stirred solution of 2.14 g of penicillanic acid and 2.01 ml of ethyldiisopropylamine in 10 ml of N, H-dimethylformamide was added dropwise 2.56 g of 4-nitrobenzyl bromide at about 2 ° C. The mixture was stirred at room temperature overnight and then diluted with ethyl acetate and water. The phases were separated and the ethyl acetate phase was washed with water at pH 2.5 and then with the water at 5.5. The ethyl acetate solution was dried (Ea 2 SC 2) and evaporated in vacuo to give 5.56-5 of the title compound as an evaporation residue.

KAR spectrum of the product (in Ciß showed absorption (m1 Ein »14x56 '(S, 1) ions at 1.45 (S, 55), 1, es (S, 5H), 5 (q, 43) ppm .lñ), 5.25 cm -1, 1H :, 5.25 (s, EH) and?, 3 ø flfi 50 55 40 7806628 -9 41 Example 55: Me fi oxide carbononyloxy-penicillanate-1,1-dioxide A rapid chlorine gas stream was bubbled through a stirring solution of 5.08 ml of methyl chloroformate in 50 ml of carbon tetrachloride (liberated from oxygen) under a nitrogen atmosphere.This reaction mixture was then irradiated with light having a wavelength of 5500Å for 10 minutes.The carbon tetrachloride solution was then cooled to -10 ° C and was added with 1.62 ml of methanol, then 11.87 ml of diisopropylethylamine in 10 ml of carbon tetrachloride were added dropwise, the temperature of the reaction mixture was allowed to rise slowly to room temperature and stirring was continued for 45 minutes.

The solvent was removed by evaporation in vacuo, then a solution of 6.24 g of penicillanic acid 1,1-dioxide and 4.62 ml of diisopropylethylamine in 60 ml of N, N-dimethylformamide was added. Stirring was continued for 24 hours after which time water and dichloromethane were added. The pH was adjusted to 4.0 and the phases were separated.

The aqueous phase was further extracted with dichloromethane, the dichloromethane phases were combined and washed with pH 5.0 water and then with water whose pH was not adjusted. The dried dichloromethane solution was evaporated in vacuo to give an oil as an evaporation residue. This solidified when treated with ether. This gave 1.94 g of the title compound of the present example, m.p. 124-126 ° C. NHR spectrum (CDCl 3) showed absorbances via 1.45 (s, an), 1.61 (s, 5H), 5.44 (m, an), 3.85 (s, sH) 4.59 ( s, 1H), 4.59 (m, 1H) and 5.78 (q, 2H) ppm, in the range below for tetramethylsilane. in Example 54: Butoxycarbonyloxymethyl penicillanate-1,1-dioxide. A fast stream of chlorine gas was bubbled through a stirred solution of 5.08 ml of methyl chloroformate in 50 ml of carbon tetrachloride (which was freed from oxygen). This reaction mixture was then irradiated with light having a wavelength of 5500 Å for 7 minutes. The reaction mixture was purged with nitrogen and then irradiated for a further 10 seconds. The solution thus obtained was cooled to about -10 ° C, then 5.48 ml of n-butanol was added. Then 8.6 ml of diisopropylethylamine in 10 ml of dichloromethane were added dropwise.

The cooling bath was removed and stirring was continued for one hour.

The dichloromethane was removed in vacuo and 5.07 g of penicillanic acid 1,1-dioxide and 2.27 ml of diisopropylethylamine in about 50 ml of N, N-dimethylformamide were added. Stirring was continued for 18 hours, after which water and dichloromethane were added. The phases 10% @ 6628-9 42 were separated and the aqueous phase was further extracted with dichloromethane. The combined dichloromethane solutions were washed with water, dried and evaporated to give the crude product. Analysis of the crude product by NMR spectroscopy revealed that the reaction was incomplete. Accordingly, the crude product was dissolved in 5 ml of N, N-dimethylformamide and 1.165 g of penicillanic acid 1,1-dioxide and 0.86 ml of diisopropylethylamine were added to the solution.

The mixture was stirred overnight and the product was isolated as above. The reaction was still incomplete, so the product was redissolved in 5 ml of N, N-dimethylformamide and 1,65 g of penicillanic acid 1,1-dioxide and 0.86 ml of diisopropylethylamine were added to the solution. The mixture was stirred overnight and the product was isolated as above. . This gave 4.6 g of crude product. The crude product was purified by column chromatography on silica gel to give 0.19 g of the title compound of the present example. NMR Spectrum QCDCl 3 showed absorbances at 0.98 (t, 5H), 1.45 (s, 5H), 1.65 (s, EH), 1.55 (m, 4H>, 5.5 (m, 2H>, 4.25 (δ, BH, J = 6.8 Hz>? 4.45 (s, in), 4.65 (m, 1H} and 5.85 (q, 2H) ppm, in the range below tetramethyl- Example 55: Acetoxymethyl-penicillanate-1,1-dioxide. 1500, 1150, 100 ° C, 99o and 825 cm -1. NHR spectrum 1 Dmso-as showed absorbances at 1.0 (s, 5H), 1.15 (s, 5H), 1.75 (s, 5H), 2.95 (q, 1H), 5.15 (q, 1H), 4.05 (8, 1H), 4.80 (q, 1H) and 5.40 (q, 2H) ppm, in the range below tetramethylsilane NMR spectrum in CDCl 3 showed absorbances at 1.45 (s, EH), 1.65 (s, EH), 2.10 (s, 5H), 5.45 (d, 2H), 4.40 (s , 1H) 4.50 (t, 1H) and 5.75 (q, 2H) ppm, in the range below tetramethylsilane. 7806-628 -9 43 fimnnel 5 ": Pivaloyloxymethylpenicillanate, 1-Dioxide. To 0.55? 2.41 mmol) of nenicillanic acid-1,1-dioxide in 9 ml of N, fl-methylformamide was added 0.5 (2.90 mmol) of diisonronethylethylamine and then 0.0 ml of chloromethyl pivalate. The reaction mixture is stirred at room temperature for 24 hours then diluted with ethyl acetate and water.

The ethyl acetate phase was delayed and washed three times with water and a vinegar with a saturated sodium chloride solution. The ethyl acetate solution was then dried using anhydrous sodium sulfate and evaporated in vacuo to give 0.700 g of the title compound as a solid, m.p. 103 DEG-10 DEG. The UMR ~ spectrum of the product (in CDCl 3) showed absorbances via 1.20 (S, 91), 1.4? (S, an), 1.t2 (S, any 5.52 (m, gu), 4.4? (S, ln), 4.70 (m, 1H); 5.5 (a, 1H, J = e, o Hz), and%, G8 (a, la, J = e, o Hz).

Example 57: Acetoxymethylpenicillenate-1,1-dioxide. The procedure described in Example 55 was repeated, but the pivaloyloxymethyl chloride was exchanged for one equimolar month of acetoxymethyl chloride. This gave acetoxymethylpenicillanate-1,1-dioxide in 56% yield, m.p. 158-14300. IïR ~ vj * “trur for this product (in ODCl2) undisputed absorptions at 1.45 (S, SH), 1.65 (s, šU); 2.10 (S, δ), 5.4e (d, QH, J = 5 Hz), 4.40 (5, 1fl); 4.50 (t, ln, J = 5 dz); and 5.75 (o, EH, J = 5 Hz) ppm in the range below inner tetramethylsilane.

Acetoxymethyl penicillanate-1,1-dioxide was also prepared in 99% yield of sodium penicillanate-1,1-dioxide and acetoxymethyl bromide, in dimethyl sulfoxide as in Example 3 '. After chromatography, the product had a melting point of 147 ~ 14M ° C. Its IR spectrum in a KBr disk showed absorptions at 1750, 1300, 1150, 1040, 990 and 825 cm -1. NMR Spectrum in DhSO 4 -declosed absorptions at 1.00 (s, BH), 1.15 (s, 5H); 1, e (Q, 5fl); 2.95 (~, 1n); 5.15 (q, 1a); n, o = (S, 1H); 4.80 (0.1) and 5.40 (n, 20) ppm in the range below inner tetramethylsilane.

Claims (7)

10 15 20 25 g 'resande -9 HH Patent claim Compounds of the general formula: 13 ° E '. yl, u Ra o 'R3 o I II I II acoc-RS or -coco-RS I _ IR "o R" in which formulas each of Ra and R "is hydrogen or alkyl having 1-2 carbon atoms and R5 is alkyl of 1-6 carbon atoms. _ ' A compound according to claim 1, n i m 1 i g e n penicillanic acid-1,1-dioxide, i.e. R1 in the general formula I is hydrogen. A compound according to claim 1, n i m l i g e n sodium penicillanate fl 1,1-dioxide, i.e. a pharmaceutically acceptable base salt of compound I, in which the cation is sodium. Compounds according to claim 1, characterized in that R1 has the formula Ra o I ll -c-o-c-RS I Rlæ wherein Ra and R 'are each hydrogen. A compound according to claim 4, namely pivaloyloxymethyl-penicillanate-1,1-dioxide, i.e. R 5 is t-butyl. Compounds according to claim 1, in that R 1 has the formula k e n n e - t e c k n a d e 7 .. Hg 806628 9 Ra o I ll -c-o-c-o-R fi I RI »wherein Ra and R A compound according to claim 6, wherein 1- (ethoxycarbonyloxy) ethyl penicillanate-lf1 dioxide, i.e. R 5 is ethyl. SUMMARY OF THE INVENTION The invention relates to novel penicillanic acid 1,1-dioxides of the formula a ° E '3 CH3 IE C213 - cooal and pharmaceutically acceptable base salts thereof, in which formula R1 is hydrogen, 3-phthalidyl, 4-crotonolactonyl,' T-butyrolactone- 4-yl, Ra O R fl OI II "ç" 0 "C-Rs or -é-O ~ ë-O-RS R * in which formulas each of R 3 and R 4 are hydrogen or alkyl of 1-2 carbon atoms and R 5 is alkyl of 1-6 carbon atoms. The new compounds are useful as antibacterial agents and for increasing the efficacy of multifasc-lactam antibiotics against a variety of β-lactamase-producing bacteria.