HU180042B - Process for producing 2,2-dimethyl-pename-3-carboxylic acid-1,1-dioxide derivatives - Google Patents

Abstract

The invention relates to a method for increasing the efficacy of a pharmaceutical composition containing a beta-lactam antibiotic and a pharmaceutically acceptable carrier agent. According to the invention, the agent is supplemented with a selected penicillanic acid 1,1-dioxide derivative of the formula IA or a pharmaceutically acceptable salt thereof. In formula IA, R is either hydrogen or an ester-forming, readily in vivo hydrolysable radical, e.g. 3-phthalidyl, 4-crotonolactonyl or gamma-butyrolactone-4-yl. As an example of the beta-lactam antibiotic, mention may be made of 6- (2-phenylacetamido) penicillanic acid or 6- (2-phenoxyacetamido) penicillanic acid.

Description

The present invention relates to novel 2,2-dimethylpenam-3-carboxylic acid derivatives. More particularly, the present invention provides 2,2-dimethylpenam-3-carboxylic acid 2,2-dimethyl-penam-3-carboxylic acid and a readily hydrolyzable ester thereof which can be readily hydrolyzed in vivo as an antibacterial compound and several other β-lactam antibiotics. derivatives.

Β-lactam antibiotics are well known and widely used antimicrobial compounds. The compounds are characterized by a 2-azetidinone (β-lactam) ring fused to a thiazolidine or dihydro-1,3-thiazine ring. If the backbone contains a thiazolidine ring, the compound is a penicillin derivative, and if the backbone contains a di-hydrothiazine ring, the compound is referred to as cephalosporin. Examples of penicillins used in clinical practice include benzyl penicillin (penicillin G), phenoxymethyl penicillin (penicillin V), ampicillin and carbenicillin; commonly used cephalosporin derivatives include cephalotin, cephalexin and cefazoline.

Although widely used and widely recognized as valuable chemotherapeutic agents, β-lactam antibiotics have the disadvantage that some of their agents are ineffective against certain microorganisms.

The resistance of certain microorganisms to a particular β-lactam antibiotic is obviously due to the fact that the microorganism cleaves the β-lactam ring of the penicillins and cephalosporins with the β-lactamase enzyme they produce and the product produced by the hash180042 has no antimicrobial activity. Certain compounds have the ability to inhibit β-lactamase enzymes, and when used in combination with penicillin or cephalosporin, such a β-lactamase inhibitor compound enhances the antibacterial activity of penicillin or cephalosporin against certain microorganisms. An enhancement of the antibacterial activity is when the antimicrobial activity of a formulation containing a β-lactamase inhibitor compound and a β-lactamase-type antibiotic is significantly greater than the sum of the antibacterial activity of each component measured separately.

To date, numerous attempts have been made to produce penicillin derivatives resistant to β-lactamase. The results of these studies include, for example, methacillin, oxacillin, cloxacillin, dicloxacillin and floxacillin. However, these compounds are used clinically only against Gram positive bacteria and their action is much lower than, for example, benzylpenicillin or phenoxymethylpenicillin, which are commonly used in Gram positive infections. In addition, methacillin, oxacillin, cloxacillin, dicloxacillin, and floxacillin, in contrast to many other penicillins and cephalosporins, are inactive against gram-negative bacteria. The novel compounds of the present invention have the general antibacterial activity of penicillins and cephalosporins, both against Gram-positive and mipd-Gram-negative bacteria.

A number of β-lactamase inhibitors were tested by Tchaikovsky and co-workers (Antibiotics 13, 155 30 (1968)), but no compound with a corresponding effect was found other than methyl 1180042. However, benzylpenicillin-1,1-dioxide was completely ineffective.

Recent studies have shown that the β-lactam type compound produced by clavulanic acid, Sireptomyces clavuligerus, has been found to be a good β-lactamase inhibitor. However, this compound is chemically unstable. The compounds of the present invention are substantially more stable than clavulanic acid.

The present invention relates to novel penicillin derivatives which are useful as an antibacterial agent and also as a compound for inhibiting microbial β-lactamase enzymes. These novel penicillin derivatives are 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide derivatives and their readily hydrolyzable esters.

U.S. Patent Nos. 3,197,466 and 3,536,698, and Guddal et al., Tetrahedron Letters 9, 381 (1962), disclose 1,1-dioxide of benzylpenicillin and phenoxymethyl penicillin and esters thereof. Harrison et al., J. Med. of the Chemical Society (London), Perkin I, 1772 (1976)] discloses a number of penicillin-1,1-dioxide and 1-oxide, including methyl phthalimidopcnicillinate 1,1-dioxide, methyl 6,6-dibromopenicillinate, 1,1-dioxide, methyl-penicillinate-la-oxide, methyl-penicillinate-1-oxide, 6,6-dibromo-penicillanic acid-la-oxide and 6,6-dibromo-penicillanic acid-1-oxide.

The present invention is illustrated in formula I is 2,2-dimethyl-penam-3-carboxylic acid-l, l-dioxide-2,2-dimethyl-derivatives and pharmaceutically acceptable salts thereof, wherein R ^l is hydrogen, C 2-7 C 1 -C 4 alkanoyloxy-C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyloxy-C 1 -C 4 alkyl or 3-phthalidyl.

The compounds of formula I according to the invention have antibacterial activity and can be used to enhance the antibacterial activity of β-lactam antibiotics.

According to the invention, the compounds of the formula I are prepared by the following processes

a) a compound of the formula,, wherein X is> -S, = »SIIIi 0 or> S-0, and R ¹ is as defined above, or tetrahydropyranyl, benzyl, substituted benzyl, preferably p-nitrobenzyl , benzhydryl, 2,2,2-trichloroethyl, tert-butyl or phenacyl, by reaction with an oxidizing agent, preferably potassium permanganate or chloroperbenzoic acid, and if necessary to prepare compounds of formula I wherein R ^{1 is} hydrogen, the resulting 1,1- dioxide derivative, wherein R ¹ is tetrahydropyranyl, benzyl, substituted benzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl, phenacyl, splitting off the carboxyl-protecting group, or

b) for preparing compounds of formula I wherein R ¹ 3-phthalidyl, a salt compound of formula I, wherein ^R1 is hydrogen, in an inert solvent, is reacted with 3-or 3-ftalidilkloriddal ftalidilbromiddal at 0 ° to 100 ° C, or

c) for the preparation of compounds of formula I wherein R ^{1 is C} 2 -C 7 alkanoyloxy (C 1 -C 4) alkyl or C 1 -C 4 alkoxycarbonyloxy (C 1 -C 4) alkyl having the formula: a salt of a compound of formula I wherein R ^{1 is a} hydrogen atom, with an alkyl halide as defined above for R ¹ , in an inert solvent at a temperature of 0-100 ° C, and optionally reacting with a base of a compound of formula I wherein R * is hydrogen; .

The novel compounds of the above formulas I, II and III are referred to herein as derivatives of 2,2-dimethylpenam-3-carboxylic acid, Formula IVA.

In the formula IVA, the substituents linked to the bicyclic backbone by a dotted line represent the substituents located below the plane of the bicyclic backbone. These substituents are in the α-configuration. In contrast, with the drawn valence line, the substituents attached to the bicyclic backbone are located above the backbone plane. The latter have a β-configuration.

In the case where in formula I R ¹ is an ester-forming residue readily hydrolyzable in vivo, it is theoretically derived from an alcohol of formula R ¹ -OH, such as COOR ¹ group of formula I wherein one ester group. In addition, R ^{1 is} such that the -COOR ¹ group is readily cleaved in vivo when a free carboxyl group is formed. In other words, R ^{1 is} a group that when added to a mammalian blood or tissue, the compound of formula I (wherein R ^{1 is a} readily hydrolyzable ester-forming moiety) provides a compound of formula I wherein " hydrogen is.

Represented by the above R ¹ groups are well known in the penicillin chemistry. In most cases, they increase the absorption properties of the penic'llin derivative. In addition, the R ¹ group must be such that the compound is pharmaceutically acceptable and, when in vivo cleaved, releases a pharmaceutically acceptable product.

The process of the present invention provides compounds wherein R ^{1 is} preferably 3-phthalidyl or X and XI, wherein R ³ and R ^{4 are} hydrogen, methyl or ethyl, and wherein R ^{5 is} 1-4. C 1 -C 4 alkyl.

The compounds of formula I are prepared according to a preferred embodiment of the process of the invention by oxidizing the compounds of formula II or III. Known oxidizing agents used to oxidize sulfoxides to sulfonates are used for oxidation. The oxidation is preferably carried out with metal permanganates such as alkali metal permanganates, alkaline earth metal permanganates, organic peroxy acids such as organic peroxycarboxylic acids. Preferably, the reaction may be carried out with, for example, sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid or peracetic acid.

When the compound of formula II or III is oxidized using a metal permanganate to a compound of formula I, the reaction is preferably carried out in a reaction mixture with suitable solvents in the presence of 0.5 to 5 molar equivalents of the compound II or III and preferably 1 molar equivalent of permanganate. carried out.

The solvent used is a compound which does not react with either the starting materials or the product; such a solvent is water. Optionally, a water-miscible but inert inert solvent is added to the reaction mixture, preferably tetrahydrofuran.

-2180042

The reaction is usually carried out at a temperature of -20 ° C to 50 ° C, preferably 0 ° C. At 0 ° C, the reaction is usually carried out in a short time, e.g. in one hour. Although the reaction may be carried out under neutral, alkaline or acidic conditions, it is preferable to carry out the reaction under essentially neutral reaction conditions to avoid cleavage of the β-lactam ring of the compounds of formula I. It is often advantageous to adjust the pH of the reaction mixture to neutral with buffer.

The reaction product is isolated by known methods. The excess permanganate was decomposed with sodium bisulfite and the product was precipitated and collected by filtration. The product is separated from the magnesium oxide by shaking it in an organic solvent and then distilling off the solvent. If the product remains in solution at the end of the reaction, it is isolated by known solvent extraction.

In another preferred embodiment of the process according to the invention, the compounds of the formulas II and III are prepared with organic peroxyacid, e.g. peroxycarboxylic acid to form compounds of formula I. In this case, the reaction is carried out in a reaction mixture with a non-reactive organic solvent in the presence of 4 molar equivalents of the compound of formula II or III and preferably 1.2 equivalents of the oxidizing agent. Preferred solvents are chlorinated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane.

The reaction is generally carried out at a temperature of -20 ° C to 50 ° C, preferably at 25 ° C. At 25 ° C, the reaction time is 2-16 hours.

The product is generally isolated by removing the solvent by distillation under reduced pressure. The product may be purified by well known methods.

When the compound of Formula II or III is oxidized to a compound of Formula I by organic peroxyacid, the reaction mixture is preferably supplemented with a catalyst such as manganese salt such as manganese acetylacetonate.

Compounds of formula I wherein R ^{1 is} hydrogen may be prepared by cleavage of the R ¹ protecting group of a compound of formula I, optionally with a penicillin carboxylic acid protecting group.

The invention according to another preferred embodiment of the compounds of formula I, wherein R ¹ as defined hereinbefore, the preparation is carried out by a compound of structure shown in IV of structural formula: wherein R ¹ as defined above may be oxidized.

The oxidation reaction is carried out under similar reaction conditions to those described for the oxidation of compounds of formula II or ΠΙ, except that twice the amount of oxidizing agent is used.

According to the process of the present invention, compounds of formula I wherein R or R ^{1 are} hydrogen are esterified to produce compounds of formula I. The method chosen will, of course, depend on the nature of the ester-forming group and will not be difficult for one skilled in the art to select. In the case where R ^{13 is a} 3-phthalidyl group, or a group of the formula X or XI, wherein R ³ , R ⁴ and R ⁵ are as defined above, the compounds are of the formula I, wherein R or R ¹ hydrogen, alkylated; alkylation with, for example, 5 3-phthalidyl halide with a compound of Formula XII or XIII, wherein Q is halogen, and wherein R ³ , R ⁴ and R ⁵ are as defined above.

The term halide refers to chlorinated, brominated or iodinated derivatives.

The above reaction is carried out by dissolving the salt of the compound of formula I wherein R ^{1 is} hydrogen in a preferred polar organic solvent such as Ν, Ν-dimethylformamide and adding 15 molar equivalents of the halide. When the reaction is complete, the product is isolated by known methods. It is often preferable to dilute the reaction mixture with excess water and then extract the product with a water immiscible organic solvent, followed by distillation to remove the solvent. The starting salts are preferably alkali metal salts such as sodium or potassium salts, tertiary amine salts such as triethylamine, N-methylpiperidine, Ν, Ν-dimethylaniline or N-methylmorpholine salts.

The reaction is carried out at a temperature of 0 ° C to 100 ° C, generally 25 ° C.

The time needed for the reaction to complete is dependent on several factors, such as the concentration of the reagents or the reactivity of the reagents. For example, when tested for halogen, iodide reacts faster than bromide, which in turn reacts faster than chloride. It is often preferred to use chloride up to one molar equivalent of alkali metal iodide. This facilitates a rapid reaction. The reaction time varies from 1 hour to 24 hours, taking into account all of the above factors.

A compound of formula II wherein R ^{1 is} hydrogen, i.e., 2,2-dimethyl-penam-3-carboxylic acid la-oxide, according to a preferred embodiment of the process of the invention is 2,2-dimethyl-6,6-. is obtained by cleavage of bromine atoms of dibromopen-3-carboxylic acid la-oxide. Cleavage of the bromine atoms is accomplished by a known hydrogenolysis reaction. For example, a solution of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid-la45-oxide is treated with atmospheric hydrogen gas or a catalytic amount of calcium carbonate in hydrogen gas mixed with a non-reactive gas such as nitrogen or argon. stirring or shaking in the presence of a catalyst. The reaction mixture is preferably mixed with 50 lower alkanols such as methanol; ethers such as tetrahydrofuran or dioxane; low molecular weight esters such as ethyl acetate or butyl acetate; water or a mixture of the above. Preferably, the solvent in which the dibromo derivative 55 is soluble is selected. Hydrogenolysis is generally carried out at room temperature, at atmospheric pressure to 4.5 atmospheric pressure. The catalyst is generally added to the reaction mixture in an amount of from 10% to 100% based on the amount of the dibromo derivative, although larger amounts may be used.

The reaction usually takes about an hour. After completion of the reaction, the compound of formula II, wherein R ^{1 is} hydrogen, is isolated by filtration under reduced pressure.

2,2-Dimethyl-6,6-dibromopen-3-carboxylic acid la-oxide

-3180042 for the preparation of 2,2-dimethyl-6,6-dibromo penam-3-carboxylic acid an equivalent amount of 3-kIórperbenzoesavvai oxidizing reaction in tetrahydrofuran at a temperature between _O 0 C and 25 ° C for about one hour. The reaction was carried out according to Harrison et al., J. Med. Chemical Society (London), Perkin I, 1772, 1976). The preparation of 2,2-dimethyl-6,6-dibromopen-3-carboxylic acid is carried out according to the method of Clayton [J. Chemical Society (London); C, 2123.1969].

The compound of formula III wherein R * is hydrogen, i.e., 2,2-dimethyl-penam-3-carboxylic acid, is subjected to controlled oxidation to produce 2,2-dimethyl-penam-3-carboxylic acid-1-oxide. We proceed by a

2,2-Dimethyl-penam-3-carboxylic acid is reacted with 3-chloroperbenzoic acid in molar equivalents for one hour in a reaction mixture with a non-reactive solvent. Preferred solvents are chlorinated hydrocarbons such as chloroform or dichloromethane; ethers such as diethyl ether or tetrahydrofuran; or low molecular weight esters such as ethyl acetate or butyl acetate.

The product obtained is isolated by known methods.

A II and III compounds of the general formula 'wherein ^L R in vivo readily hic | rolizálódó ester-forming group, are prepared by the inclusion in Annex II or ΙΠ compounds wherein esterification in the formula ^R1 is hydrogen, by known methods. In the case where R * 3-phthalidyl or a group of formula X or XI wherein R ³ , R ⁴ and R ^{5 have} the meanings given above, the product is the corresponding compound of formula II or III wherein R ¹ hydrogen by alkylation. Alkylation is carried out with 3-phthalidyl halide or a compound of formula XII or ΧΙΠ.

The reaction is carried out exactly as described above for the esterification of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide with 3-phthalidyl halide or one of the compounds of formula XII or XIII.

For the preparation of compounds of Formula II from the group of II / The starting materials of the formula, wherein R ¹ in vivo easily hydrolyzable ester residue, 2,2-dibromo-6,6-dimethyl-penam-3-carboxylic acid ester with an appropriate oxidizing and then cleaving the bromine atoms from the compound thus obtained. The ester of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid is prepared from 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid by known methods. The oxidation is carried out, for example, with a molar equivalent of 3-chloroperbenzoic acid, as previously described for 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid, 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid. oxidation to la-oxide. Bromine cleavage is performed as described for bromination of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid la-oxide.

For the preparation of starting materials of formula III wherein R * in vivo is an easily hydrolyzable ester group, the appropriate ester of 2,2-dimethyl-penam-3-carboxylic acid is oxidized. The latter compound is prepared by known methods by esterification of 2,2-dimethylpenam-3-carboxylic acid. The oxidation is carried out, for example, with a molar equivalent of 3-chloropefenzoic acid, as previously described for the oxidation of 2,2-dimethyl-penafn-3-carboxylic acid to 2,2-dimethyl-penam-3-carboxylic acid-1-oxide.

There are two ways of preparing the compounds of formula II wherein R ^{1 is a} carboxyl protecting group. The compound may be prepared by coupling the protecting group to 2,2-dimethyl-penam-3-carboxylic acid la-oxide. However, it is also possible to (a) couple the carboxyl protecting group to 2,2-dimethyl-6,6-dibromopen-3-carboxylic acid; and (b) the molar equivalent of protected 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid into 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid la-oxide. oxidized; and (c) deprotecting the protected 2,2-dimethyl-6,6-dibromopenam-3-carboxylic acid? -oxide by hydrogenolysis.

For those compounds of formula III of the formula wherein ^R1 is a carboxyl protecting group, we are prepared by bonding the protecting group to the 2,2-dimethyl-penam-3-carboxylic acid L-β-oxide. However, in another preferred embodiment, it is possible to (a) link the carboxyl protecting group to 2,2-dimethylpenam-3-carboxylic acid; and (b) oxidizing the protected 2,2-dimethylpenam-3-carboxylic acid with a molar equivalent of 3-chloroperbenzoic acid as described above.

The compounds of formulas I, II and III, wherein R ^{1 is} hydrogen, are acids and thus form salts with bases. These salts are within the scope of the invention. Salts are prepared by known methods, for example by reacting acidic and basic compounds. The reaction is usually carried out in a 1: 1 molar ratio in aqueous, non-aqueous or partially aqueous reaction mixture. After the reaction, the salts are isolated by filtration, the product precipitated with a non-solvent by filtration, removal of the solvent, and use of aqueous solvents or aqueous solutions, such as freeze-drying.

The salt formation may be carried out with organic or inorganic bases such as ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides or alkoxides; and alkali-earth metal hydroxides, carbonates, hydrides or alkoxides. Of the above bases, primary amines such as n-propylamine, n-butylam, aniline, cyclohexylamine, benzylamine and octylamine are preferred; secondary amines such as diethylamine, morpholine, pyrrolidone and piperidine, N-methylmorphophin and 1,5-diazabicyclo [4.3.0] 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; carbonates such as potassium carbonate and sodium carbonate; bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal salts of long chain fatty acids such as sodium 2-ethylhexanoate are preferred.

Preferred salts of the compounds I, II and III are sodium, potassium and triethylamine salts.

As stated above, the compounds of the formula I according to the invention and their pharmaceutically acceptable salts have moderate potency antimicrobial activity. For a compound of formula I wherein R ^{1 is} hydrogen-4-

Atoms, the in vitro antibacterial activity can be characterized by the lowest growth inhibitory concentration of the compound against various microorganisms. The assay is recommended by the International Collaborative Study on Antibiotic Sensitivity Testing [Ericcson and Sherris, Acta Pathologica et Microbiologia Scandinav, Supp. 217, Chapters A and B, pp. 1-90. , 1970]. The measurement was performed with infusion agar and automatic inoculation. Cultures growing overnight were diluted 100-fold and inoculated with 0.002 ml of inoculum containing 10,000 to 20,000 cells in a 20 ml Petri dish. Twenty two-fold dilutions of the compound were assayed at an initial concentration of 200 μg / ml. The cultures were incubated for 18 hours at 37 ° C and the number of colonies was determined. The lowest concentration at which growth inhibition was observed was the lowest concentration at which growth was not observed with the naked eye.

The minimum growth inhibitory concentrations of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide tested against several microorganisms are given in Table 1.

Table 1

In vitro antimicrobial activity of penam-3-carboxylic acid 1,1-dioxide

Micro-organism Minimum growth inhibitory concentration (Hg / ml; Staphylococcus aureus 100 Streptococcus pyogenes 100 Streptococcus faecalis > 200 Escherichia coli 50 Pseudomonas aeruginosa 200 Klebsiella pneumoniae 50 Proteus mirabilis 100 Proteus morgani 100 Salmonella typhimurium 50 Pasteurella multocida 50 Serratia marcescens 100 Enterobacter aerogenes 25 Enterobacter clocae 100 Citrobacter freundii 50 Providence 100 Staphylococcus epidermis 200 Pseudomonas putida > 200 Hemophilus influenza > 50 Neisseria gonorrhoeae 0.312

The compounds of the formula I according to the invention and their salts also exhibit antimicrobial activity in vivo. To investigate this effect, acute experimental infection was induced in mice by intraperitoneal vaccination. Infection was performed with a standardized culture of the test microorganism suspended in porcine gastric mucin. Infection was standardized by administering to mice a 10-10 fold dose of LD _{) 00} from each microorganism. LD ₁₀₀ represents the minimum amount of inoculum required to kill 100% of untreated control mice. The test compound was administered in multiple doses to the experimental animals. At the end of the study, the activity of the test compound was characterized by the number of surviving animals; activity of a given compound is expressed as a percentage of surviving animals.

I according to the invention are compounds wherein in formula R ¹ hid5 rogénatom, have in vitro antibacterial activity, and this allows the use of industrial antimicrobial composition as compounds such as yíz treatment of the sludge bacteria content for controlling the toner and for the treatment of wood and for the preparation of topical disinfectants. When the compound of the invention is applied topically, it is often preferable to mix the active ingredient with a non-toxic carrier such as vegetable or mineral oils or a cream. The active ingredient may be dissolved or dispersed in a liquid diluent or solvent such as or mixtures thereof. In most cases, the active ingredient is used in an amount of from 0.1% to 10% by weight of the total composition.

The in vivo biological activity of the compounds of the formula I and their salts allows the compounds to be used orally or parenterally for the treatment of bacterial infections in mammals, including man. The compounds of the present invention are particularly useful for treating infections in humans caused by bacteria susceptible to these compounds, such as strains of Neisseria gonorrhoeae.

When used in the therapeutic treatment of mammals, in particular humans, the compounds of formula I or salts thereof are administered alone or in combination with pharmaceutically acceptable carriers or diluents. The composition may be administered orally or parenterally, i.e. intramuscularly, subcutaneously, or intraperitoneally. The vehicle or diluent will be determined by the route of administration. For example, when the composition is to be administered orally, the antibacterial penam 40 of the present invention is administered in tablets, capsules, lozenges, powder formulations, syrups, elixirs, aqueous solutions or suspensions, according to standard pharmaceutical practice. The amount of active ingredient in the carrier 45 will of course depend on the chemical nature, solubility and stability of the active ingredient, and will depend on the active ingredient content of the composition. Pharmaceutical compositions containing the antimicrobial compounds of formula IA of the present invention generally contain from about 2% to about 95% of the active ingredient. In the case of tablets for oral administration, the carrier may be, for example, salts of lactose, sodium nitrate and phosphoric acid. Various other active ingredients may be used, such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate or talc. In the case of capsules for oral administration, diluents include lithose and high molecular weight polyethylene glycols. If an aqueous suspension is to be used for oral administration, the active ingredient is combined with an emulsifying and suspending agent. Optionally, a sweetening and / or perfuming agent may be added.

For parenteral administration, i.e., intramuscular, intraperitoneal, subcutaneous or intravenous administration, the

Sterile solutions of the -511 active compound are prepared, the pH of the solutions is preferably adjusted, or buffered. For intravenous administration, a composition is prepared which is isotonic.

As stated above, the antibacterial compounds of the present invention can be used to treat infections in humans caused by microorganisms sensitive to the compounds. The prescribing physician will determine the dosage required for a particular patient, which will depend upon the age, weight, individual response of the individual patient and the nature and severity of the patient's symptoms. The compounds of the present invention are generally administered orally at daily doses ranging from 10 mg to 200 mg / kg body weight. For parenteral administration, 10 mg to 400 mg of active ingredient per day and per kilogram of body weight are used. These data are for illustrative purposes only and in some cases may be outside the required dosage range. 20

The compounds of the formula I and their salts according to the invention significantly inhibit the activity of microbial β-lactamase enzymes and enhance the antibacterial activity of β-lactam antibiotics (penicillins and cephalosporins) against a wide variety of microorganisms, in particular β-lactamase enzymes. . The potency of β-lactam antibiotics to enhance the activity of β-lactam antibiotics of the present invention can be demonstrated by assaying the lowest growth inhibitory concentrations of the test antibiotic alone, and by determining the lowest growth inhibitory concentration of a compound of formula IA alone. These values are then compared to the lowest growth inhibitory concentrations obtained with the combination of the particular antibiotic and the compound of formula I. In the case where the antibacterial activity of the composition containing the two compounds is significantly greater than that which could be predicted from the individual activity of each of the components, this is an enhancement. Minimum growth inhibitory concentrations of multi-compound combinations were determined by the Barry and 10 Sabath Methods (Manual of Clinical Microbiology, published by Lenette, Spaulding and Traunt, 2nd Edition, 1974, American Society for Microbiology).

Table 2 shows the results of experiments demonstrating that 2,2-di15 methyl penam-3-carboxylic acid 1,1-dioxide enhances the biological activity of ampicillin. Table 2 shows that the lowest growth inhibitory concentration of ampicillin and 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide is 19 μg / ml against 19 ampicillin-resistant Staphylococcus aureus strains. However, mixtures of ampicillin and 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide have a minimum growth inhibitory concentration of 1.56 μg / ml and 3.12 μg / ml. In other words, while the lowest growth inhibitory concentration of ampicillin against 19 strains of Staphylococcus aureus is 200 μg'ml, in the presence of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide it is 3,12 μg / ml. the minimum growth inhibitory concentration is reduced to 1.56 μg / ml. Other data in Table 2 show that the antimicrobial activity of ampicillin against 30 ampicillin-resistant strains of Haemophilus influenzae, 18 ampicillin-resistant strains of Klebsiella pneumoniae and 15 anaerobic strains of Bacterides fragilis is enhanced in the presence of a compound of the invention.

Table 2

Effect of penam-3-carboxylic acid 1,1-dioxide on the antimicrobial activity of amplicillin

Micro-organism Number of strains Minimum growth inhibitory concentration of ampicillin Minimum growth inhibitory concentration of penam-3-carboxylic acid -1,1-dioxide (µg / ml) Minimum growth inhibitory concentration (pg / ml) of ampicillin and penam-3-carboxylic acid 1,1-dioxide ampicillin penam-3-carboxylic acid-l, l-dioxide Staphylococcus aureus 19 200 200 1.56 3.12 Haemophilus influenza 26 200 > 200 0.78 3.12 Klebsiella pneumoniae 18 > 400 50 6.25 6.25 Bacteroides fragilis 15 50 50 1, 1.56 0.78

Table 3

Effect of penam-3-carboxylic acid 1,1-dioxide on penicillin G antimicrobial activity

Micro-organism Number of strains Reduced growth inhibitory concentration of penicillin G1 (Rg / ml) Minimum growth inhibitory concentration of penam-3-carboxylic acid, l-dioxide (μβ / ιηΐ) Minimum growth inhibitory concentration of penicillin G and penam-3-carboxylic acid 1,1-dioxide (gg / ml) penicillin G penam-3-carboxylic acid-l, l-dioxide Staphylococcus aureus 20 200 200 3.12 6.25 Haemophilus influenza 25 50 100 0.78 1.56 Klebsiella pneumoniae 24 400 50 25 12.5 Bacteroides fragilis 15 25 50 1.56 0.39

-613

Table 4

Effect of penam-3-carboxylic acid 1,1-dioxide on the antimicrobial activity of carbenicillin

Micro-organism Number of strains Minimum growth inhibitory concentration of carbenicillin (μδ / ηιΐ) Minimum growth inhibitory concentration of penam-3-carboxylic acid 1,1-dioxide (g / ml) Minimum growth inhibitory concentration of carbenicillin and penam-3-carboxylic acid 1,1-dioxide (g / ml) Carb penam-3-carboxylic acid-1,1-dioxide Staphylococcus aureus 20 12.5 200 6.25 6.25 Haemophilus influenza 25 6.25 100 0.39 0.78 Klebsiella pneumoniae 16 > 400 50 50 6.25 Bacteroides fragilis 15 50 50 3.12 0.78

Table 5

Effect of penam-3-carboxylic acid 1,1-dioxide on the antimicrobial activity of cefazoline

Micro-organism Number of strains Minimum growth inhibitory concentration of cefazoline Minimum growth inhibitory concentration of pengm-3-carboxylic acid 1,1-dioxide (μΒ, / ΓηΙ) Minimum growth inhibitory concentration of cefazoline and penam-3-carboxylic acid 1,1-dioxide (g / ml) cefazolin penam-3-carboxylic acid-l, l-dioxide Staphylococcus aureus 20 0.78 200 0.2 25 Haemophilus influenza 25 25 200 3.12 0.20 Klebsiella pneumoniae 3 100 50 6.25 25 Bacteroides fragilis 15 200 50 6.25 6.25

Tables 3, 4 and 5 show the antimicrobial potency enhancement of benzyl penicillin (penicillin G), carbenicillin (α-carboxybenzyl penicillin) and cefazoline in Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae and Bacteroides frag. opposite.

The compounds of the formula I and their salts produced by the process of the present invention enhance the antibacterial activity of β-lactam antibiotics in vivo. This means that they reduce the amount of antibiotic needed to cure mice infected with bacteria that otherwise produce lethal β-lactamase.

The fact that the compounds of the formula I according to the invention and their salts increase the efficacy of β-lactam-type antibiotics against β-lactamase-producing bacteria means that they can be used very advantageously in infecting mammals, especially humans. treatment with β-lactam antibiotics. In the treatment of bacterial infections, the compound of formula IA of the present invention may be admixed with the β-lactam antibiotic and the two agents administered together. Alternatively, the compound of formula IA of the present invention may be administered simultaneously with, but separately, the β-lactam antibiotic during treatment. In some cases, it is preferable to first administer a compound of formula IA of the present invention and then administer the β-lactam antibiotic.

When used to enhance the effect of the β-lactam antibiotic of the present invention comprising 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide or a readily hydrolyzable ester group thereof, it is used with standard pharmaceutical diluents or carriers. mixed. A one-component antimicrobial composition containing 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or an ester derivative thereof which is readily hydrolyzable in vivo, is co-administered with the other β-lac35 support type antibiotic as described above. Formulations containing a pharmaceutically acceptable carrier, a β-lactam antibiotic and the

They contain 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide, or an ester derivative or a salt thereof which is readily hydrolysable, and generally contain from 5% to 80% of a pharmaceutically acceptable carrier.

When the 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or its readily hydrolyzable ester derivative thereof is used in combination with another β-lactam an50 tibiotic, the preparation is administered orally or parenterally, that is, intramuscular, subcutaneous or intraperitoneal administration. Although the dosage to be administered to a patient is determined by the attending physician, the amount of 2,2-dimethylpenam-3-carboxylic acid 1,155-dioxide or its ester derivative or salt thereof is proportional to the amount of the β-lactam antibiotic, like 1: 3 to 3: 1. Further, when the 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or an ester derivative or salt thereof of the present invention is administered in combination with another β-lactam antibiotic, the daily oral formulation of both It is present in an amount of from 10 mg to 200 mg per kilogram body weight of the ingredient. If the formulation containing the two antibiotics is administered parenterally daily, the two antibiotics will

It is present in amounts of 10 mg to 400 mg per -715 grams. These data are illustrative, and in some cases it may be necessary to administer amounts outside this range. The following describes some of the β-lactam antibiotics administered in combination with the 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or the esters or salts thereof of the present invention: 6- (2-phenylacetamido) -2,2-Dimethyl-penam-3-carboxylic acid, 6- (2-phenoxyacetamido) -2,2-dimethyl-penam-3-carboxylic acid, 6- (2-phenyl-propionamide) -2,2 dimethyl-penam-3-carboxylic acid,

6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D-2-amino-2- [l, 4-cyclohexadienyl] acetamido-2,2-dimethyl-penam-3-carboxylic acid,

6- (l-amino-cyclohexane-carboxamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (2-carboxy-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (2-carboxy-2- [3-thienyl] acetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D-2- [4-Ethyl-piperazine-2,3-dione-1-carboxamido] -2-phenyl-acetamido) -2,2-dimethyl-penam-3-carboxylic acid, 6- (D-2 - [4-Hydroxy-1,5-naphthyridine-3-carboxamido] -2-phenylacetamido) -2,2-dimethylpenam-3-carboxylic acid, 6- (D-2-sulfo-2-phenylacetamide) ) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D-2-sulfoamino-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D-2- [imidazo1idin-2-one-l-carboxamido] -2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (D- [3-methylsulfonyl-imidazolidin-2-one-1-carboxylic acid] -2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6 - ([hexahydro-lH-azepin-l-yl] methylene-amino) -2,2-dimethyl-3-carboxylic acid,

6- (2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid acetoxymethyl ester,

6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid acetoxymethyl ester,

6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) -2,2-dimethyl-PCNA-3-carboxylic acid-acetoxy-mctilészter,

6- (2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid pivaloyloxymethyl ester,

6- (D-2-amino-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid pivaloyloxymethyl ester,

6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) -2,2-dimethyl-penam-3-carboxylic acid pivaloyloxymethyl ester,

6- (2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid, l- (ethoxy-carbonyloxy) ethyl ester,

6- (D-2-Amino-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid 1- (ethoxycarbonyloxy) * ethyl ester, δ- (D-2-amino-2) - [4-Hydroxyphenyl] -acetamido-2,2-dimethyl-penam-3-carboxylic acid 1- (ethoxycarbonyloxy) -ethyl ester, 6- (2-phenylacetamido) -2,2-dimethyl-penam -3-Carboxylic acid -3-phthalidyl ester, 6- (D-2-amino-2-phenylacetamido) -2,2-dimethylpenam-3-carboxylic acid 3-phthalyl ester,

6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) -2,2-dimethyl-penam-3-carboxylic acid 3-phthalidyl,

6- (2-phenoxycarbonyl-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (2-tolyloxy-carbonyl-2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (2- [5-carbonyl-indanyl-oxy] -2-phenylacetamido) -2,2-dimethyl-penam-3-carboxylic acid,

6- (2-Phenoxy-carbonyl-2- [3-thienyl] -acetamido) -2,2-dimethyl-penam-3-carboxylic acid, 6- (2-tolyloxycarbonyl-2- [3-thienyl] -acetamide ) -2,2-Dimethyl-penam-3-carboxylic acid, 6- (2- [5-indanyloxycarbonyl] -2- [3-thienyl] -acetamido) -2,2-dimethyl-penam-3- carboxylic acid, 6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) -2,2-dimethyl-penam-3-carboxylic acid, and pharmaceutically acceptable salts of the compounds described above.

As is known to those skilled in the art, the above β- _f

Some of the lactam-type compounds are effective when administered orally or parenterally, while other compounds are effective only when administered parenterally. When the 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide or its ester or salt of the present invention is administered only with a parenteral β-lactar antibiotic, the parenteral preparation we have to produce. When the 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or its ester or salt thereof is co-administered with an orally or parenterally administered β-lactam antibiotic, both orally and parenterally can be formulated.

However, it is also possible to administer the 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide or an ester or salt thereof according to the invention orally, while the other β-lactam antibiotic is administered parenterally; Alternatively, the 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide of the invention, or an ester or salt thereof, may be administered parenterally while the other β-lactam antibiotic is administered orally.

The invention is further illustrated by the following examples.

The infrared absorption spectra were determined on KBr tablets or in Nujol, the absorption maxima are reported in wave lengths (cm ^-1), the nuclear magnetic resonance spectrum of 60 MHz were measured in deuterochloroform (CDC1 _3), perdeutero dimethyl sulfoxide (DMSO-d ₆₎ or in deuterium oxide (D ₂ O); the maximum is given in parts per million parts (ppm) relative to tetramethylsilane or sodium 2,2-dimethylsilapentane-5-sulfonate.

Example 1

Preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide

A solution of potassium permanganate (6.51 g, 41 mM) in 130 ml of water and 4.95 ml of glacial acetic acid was cooled to 5 ° C, then dissolved in 4.58 g (21 mM) of water (50 ml) and cooled to 5 ° C. Sodium salt of 2-dimethyl-penam-3-carboxylic acid is added. After stirring at 5 ° C for 20 minutes, the cooling bath was removed. Solid sodium bisulfite was added until the color of the potassium permanganate

-817

disappear after filtration of the reaction mixture. Saturated sodium chloride solution corresponding to half the original volume was added to the aqueous filtrate and the pH was adjusted to 1.7. The resulting acidic solution is extracted with ethyl acetate. The extract was dried and distilled under reduced pressure to give 3.47 g of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide as a distillation residue. The aqueous mother liquor was saturated with sodium chloride and extracted once more with ethyl acetate. The ethyl acetate solution was dried and distilled under reduced pressure to give 0.28 g of product as a distillation residue. The product is also 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide. A total of 3.75 g (78%) of product is obtained.

The compound has magnetic magrezonanciaspektruma _(DMSO-d6): 1.40 (s, 3H); 1.50 (singlet, 3H); 3.13 (doublet, 1H, J = 16 Hz, J ₂ : 2 Hz); 3.63 (doublet, 1H, Jj: 16 Hz, J ₂ : 4 Hz); 4.22 (singlet path, 1H) and 5.03 (doublet, 1H, Jp 4 Hz, J ₂ : 2 Hz) ppm.

Example 2

Preparation of 2,2-dimethylpenam-3-carboxylic acid benzyl ester 1,1-dioxide in ml ethanol-free chloroform under nitrogen and in an ice bath 6.85 g (24 mM) of 2,2-dimethylpenam-3-carboxylic acid Benzyl ester is dissolved and 4.78 g of 85% pure 3-chloroperbenzoic acid are added in two portions (several minutes between each addition). Stirring was continued for 30 minutes in an ice bath and then for another 45 minutes without external cooling. Wash the reaction mixture with aqueous pH 8.5, repeat the wash with saturated sodium chloride, then dry and distill under reduced pressure. 7.05 g of product are obtained as a distillation residue. The product obtained was found to contain 5.5: 1 2,2-dimethyl-penam-3-carboxylic acid benzyl ester 1-oxide and 2,2-dimethyl-penam-3-carboxylic acid benzyl ester 1,1-dioxide in a ratio of 5.5: 1.

Dissolve 4.85 g of the above 5.5: 1 sulfoxide sulfone mixture in 50 ml of ethanol-free chloroform and add 3.2 g of 85% pure 3-chloroperbenzoic acid under stirring at room temperature under nitrogen. The reaction mixture was stirred for 2.5 hours and then diluted with ethyl acetate. The resulting mixture was added to water at pH 8.0 and the two layers were separated. Wash the organic solvent phase with water, pH 8.0, then brine, then dry over sodium sulfate. Removal of the solvent under reduced pressure gave 3.59 g of 2,2-dimethyl-penam-3-carboxylic acid benzyl ester 1,1-dioxide.

The nuclear magnetic resonance spectrum of the compound obtained (CDC1 _3): 1.28 (s, 3H); 1.58 (singlet, 3H); 3.42 (multiplet, 2H); 4.37 (singlet, 1H); 4.55 (multiplet, 1H); 5.18 (quartet, 2H, J: 12Hz) and 7.35 (singlet, 5H) ppm.

Example 3

Preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide in a mixture of methanol / ml of ethyl acetate (8.27 g)

2,2-Dimethyl-penam-3-carboxylic acid benzyl ester 1,1-dioxide was dissolved and water (10 ml) was slowly added, followed by 12 g of 5% palladium-on-calcium carbonate catalyst. The reaction mixture was shaken for 40 minutes under about 4 atmospheric hydrogen and then filtered in the presence of 5 Supercial (diatomaceous earth) filtration aids. Wash the filter residue with methanol, repeat the wash with aqueous methanol, and add the washings to the filtrate. The mixture is distilled under reduced pressure to remove most of the organic solvent. The distillation residue was dissolved in a mixture of ethyl acetate and water at pH 2.8. The ethyl acetate layer was separated and the aqueous phase was extracted once more with ethyl acetate. The ethyl acetate extracts were combined, washed with a saturated sodium chloride solution, dried over sodium sulfate, and the solvent removed under reduced pressure. The product obtained as a distillation residue was suspended in ethyl acetate: ether (1: 2) to give 2.37 g of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxo20 m.p. 148-151 ° C. The ethyl acetate-ether mixture was distilled off to give 2.17 g of product as a distillation residue.

Example 4

Preparation of 2,2-Dimethylpenam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide

In 2 ml of N, N-dimethylformamide 0.615 g (2.41 mM)

2,2-Dimethyl-penam-3-carboxylic acid 1,1-dioxide was dissolved and 0.215 g (2.50 mM) of diisopropylethylamine was added followed by 0.365 ml of chloromethyl pivalate. After stirring at room temperature for 24 hours, the reaction mixture was diluted with ethyl acetate (35 mL) water. The ethyl acetate layer was separated and washed three times with water and once with saturated sodium chloride solution. The ethyl acetate solution was then dried over sodium sulfate and then distilled under reduced pressure. The residue was distilled to give a solid, m.p. 103-104 ° C, identical to 2,2-dimethylpenam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) of the prepared compound: 1.27 (singlet, 9H); 1.47 - 45 (singlet, 3H); 1.62 (singlet, 3H); 3.52 (mujplet, 2H); 4.47 (singlet, 1H); 4.70 (multiplet, 1H); 5.73 (doublet, 1H, J: 6.0 Hz) and 5.98 (doublet, 1H, J: 6.0 Hz).

Example 5

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 3-phthalidyl ester 1,1-dioxide

In 5 ml of N, N-dimethylformamide was dissolved 0.783 g (3.36 mM) of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide, 0.47 ml of triethylamine and 0.715 g of 3-bromophthalide were added. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and water. The pH of the aqueous phase is adjusted to 7.0 60 and the two layers are separated. Wash the ethyl acetate solution first with water and then with saturated sodium chloride solution, then dry with sodium sulfate. Ethyl acetate was removed by distillation under reduced pressure to give a white foam as a distillation residue. The pre-919

claimed to be identical to '2,2-ditiethyl-sofafh-3-carbone-3-phthalidyl ester-D1-oxide.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) of the prepared compound: 1.47 (singlet, 6H); 3.43 (multiplet, 1H); 4.45 (singlet, 1H) 4.62 (multiplet, 5 1H); 7.40 and 7.47 (1H) and 7.73 (multiplet, 4H) ppm.

The above procedure is repeated, except that 4-bromocortotolactone lactide and 4-bromo-Y-butyrolactone are used in place of 3-bromophthalide to give the following compounds, respectively:

2,2-Dimethyl-penarn-3-carbonazole-4-crotonolactone ester 1,1-dioxide and

2.2-Dimethyl-penam-3-carboxylic acid Y-butyrolacton-4-yl ester 1,1-dioxide.

^: 15

Example 6 - · -

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 1-ethoxycarbonyl-oxo-ethyl 1,1-dioxide in 20 ml of N, N-dimethylformamide, 0.654 g 2 2-Dimethyl-penam-3-carboxylic acid 1,1-dioxide was dissolved and 0.42 ml of triethylamine, 0.412 g of 1-chloroethyl ethyl carbonate and 0.300 g of sodium bromide were added, followed by heating at room temperature for 6 days. stir the reaction mixture. Ethyl acetate and water were added and the pH adjusted to 8.5. The ethyl acetate layer was separated, washed three times with water and once with saturated sodium chloride solution. The mixture was dried over sodium sulfate. Distillation under reduced pressure removed the azeethyl acetate to give a distillation residue of 0.390 g of oily product 2,2-dimethyl-penam-3-carboxylic acid 1-ethoxycarbonyloxy-1,1-dioxide.

The product thus obtained is mixed with approximately the same amount of the same product obtained in another experiment. The mixed material was dissolved in chloroform and 1 ml of pyridine was added. After stirring overnight at room temperature, the chloroform was removed under reduced pressure. Ethyl acetate and pH 8.0 water were added to the distillation residue. The ethyl acetate solution was separated and then distilled under reduced pressure. The residue was obtained by distillation to yield 150 mg (7% yield) of 2,2-dimethyl-penam-3-carboxylic acid 1- (ethoxycarbonyloxy) ethyl ester 1,1-dioxide. "

In the infrared absorption spectrum of the prepared compound, the absorption maxima at 1805 and 1763 cm ^-1 are seen.

Nuclear Magnetic Resonance Spectrum of the prepared compound in deuterium chloroform: 1.43 (multiplet, 12H); 3.47 (multiplet, 2H): 3.9 (quartet, 211, J: 7.5 Hz); 4.37 (multiplet, 1H); 4.63 (multiplet, 1H) and 6.77 (multiplet, 1H) ppm.

Example 7 ........

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid la oxide: m.p. .... // - / /; ./// .. 60

- 1.4 g of previously hydrogenated palladium catalyst containing 5% palladium in 50 ml of water are suspended in 1.39 'g of 2,2-dimethyl-6,6-dichromo-3-carboxylic acid in 50 ml of tetrahydrofuran. benzyl ester la-oxide is added. "About four" 65 "spherical bridgehead gaze is shaken with"2'5" ^d . The tetrachloride was removed by distillation of the filtrate under reduced pressure, and the remaining aqueous phase was extracted with ether. Distillation under reduced pressure removes gas from the ethereal extracts, yielding '03 g of product as a distillation residue. ' It consists predominantly of 2,2-dimethylperiamine-3-arbone band benzylesterol-la-oxido. ^J

Benzyl ester of 2,2-dimethylphenam-3-carbonyl ester la-oxide. 2.0 g of benzyl ester of 2,2,2-dimethyl-6,6-dibromo-3-carboxylic acid. -la-oxide, the mixture is dissolved in 50 ml of tetrahydrofuran. 4.0 g of 5% palladium-on-calcium calcium carbonate is added to the solution along with 50 ml of water, and the reaction mixture thus obtained is placed under an atmosphere of about 4 atmospheres / pressures of Citrate Patride. Shake at 25 [deg.] C. for four nights. After filtration over ether, the filtrate was extracted with ether. Distillation under reduced pressure of the extract and purification of the residue by chromatography on silica gel with chloroform gave 0.50 g of product.

This product was hydrogenated with 5% palladium-on-palladium chloride calcine in hydrogen gas at about 4 atmospheres in a 1: 1 mixture of water and methanol for 2 hours. After the reaction time, an additional 0.50 g of palladium calcium carbonate catalyst containing 5% palladium was added to the reaction mixture, followed by hydrogenation at 25 ° C overnight at 25 ° C. The reaction mixture was filtered and then extracted with ether to quench the extracts. The aqueous solution was adjusted to pH 1.5 and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over anhydrous silica and distilled under reduced pressure to give 0.14 g of 2,2-dimethyl-penam-3-carboxylic acid la-oxide.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ ) (DMSO-d _g ): 1.4 (singlet. 3T1); 1.64 (singlet, 3H); 3.60 (multiplet, 2H); 4.3 (untrained, 1H) and 4.54 (mu / ml / 1H) ppm, '

The infrared absorption spectrum of the compound obtained examined káliumbrornid tablet shown in the wavelengths of 1795 and 1745 ^cm-1 absorption maxima;

Example 8 '• /: 1 J' JI. : / i iUArOUi ').' «/ ·. . Λ t i; TV.

Preparation of 2,2-Dimethyl-pen'ahS-3-carboxylic acid-1-β-oxide

2.65 g (12.7 m'M) of 2,2-dimethylpenam-3-carboxylic acid are dissolved in chloroform and then 2.58 g of 85% purity of 3-chlorobenzoate are added under stirring at 0 ° C ^; Saturate is added to the solution. After one hour, the filtrate is filtered and the filtrate is distilled under reduced pressure. Dissolve the distillation residue in a small amount of chloroform and slowly concentrate the solution until a precipitate begins to separate from the solution. Then the distillation is complete and the mixture is diluted again. The precipitate was filtered off, washed with ether and dried to give 0.615 g of 2,2-dimethylpenam-3-carbohydrate-1-β-oxide m.p. 140-143 ° C.

The compound prepared was tested in chloroform solution

In the infrared absorption spectrum of -1021, absorption maxima are observed at 1775 and 1720 cm ^-1 .

The product obtained by nuclear magnetic resonance spectrum (CDCl₃ / _DMSO-d6): 1.35 (s, 3H); 1.76 (singlet, 3H); 3.36 (multiplet, 2H); 4.50 (singlet, 1H) and 5.05 (multiplet, 1H) ppm. The nuclear magnetic resonance spectrum indicates that the product obtained is about 90% pure.

According to a study of the mother liquor in chloroform ether, it contained an additional amount of 2,2-dimethylpenam-3-carboxylic acid l-5-oxide in addition to 2,2-dimethylpenam-3-carboxylic acid la-oxide.

Example 9

Preparation of 2,2-Dimethylpenam-3-carboxylic acid 1,1-dioxide sodium salt

32.75 g (0.14 M) of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide are dissolved in 450 ml of ethyl acetate, followed by stirring with 25.7 g (0.155 M) of sodium in 200 ml of ethyl acetate. 2-Ethylhexanoate was added to the solution. After stirring for one hour, a solution of 10% excess sodium 2-ethylhexanoate in a small amount of ethyl acetate was added. At this point, the product precipitates out of solution immediately. Stirring was continued for a further 30 minutes and then the precipitate was removed by filtration. The precipitate was washed with ethyl acetate, ethyl acetate / ether 1: 1 and finally ether. The product is then dried over phosphorus pentoxide for 16 hours at 25 ° C and 0.1 mm Hg. This gives 36.8 g of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide sodium salt contaminated with a small amount of ethyl acetate. The product was heated at 100 ° C under reduced pressure for 3 hours to remove ethyl acetate.

The absorption spectrum of the obtained product in the infrared absorption spectrum of potassium bromide was observed at 1786 and 1608 cm ^-1 .

The compound has a nuclear magnetic resonance spectrum in deuterium oxide of 1.48 (singlet, 3H); 1.62 (singlet, 3H); 3.35 (1H, Jj: 16 Hz, J ₂ : 2 Hz); 3.70 (1H, Jp 16 Hz, J ₂ ; 4 Hz); 4.25 (s, 1H) and 5.03 (1H, Jj: 4 Hz, _J2 2 Hz) ppm.

The sodium salt may also be prepared by using acetone instead of ethyl acetate in the above process.

Example 10

Preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide

Water (7600 ml) and glacial acetic acid (289 ml) were added and potassium permanganate (379.5 g) was added portionwise. The mixture was stirred for 15 minutes and then cooled to 0 ° C. 2,2-Dimethyl-penam-3-carboxylic acid (270 g, 260 ml) in 4N sodium hydroxide solution (2400 ml) in water (pH 7.2) was added at 8 ° C. During the addition, the reaction temperature rises to 15 ° C. The resulting reaction mixture was cooled to 5 ° C and stirred for 30 minutes. Sodium bisulfite (142.1 g) was then added portionwise over 10 minutes.

After stirring for 10 minutes at 10 ^° C, 100 g of Supercel (diatomaceous earth) filter aid are added. The suspension was stirred for an additional 5 minutes and then filtered. Ethyl acetate (4.0 L) was added to the filtrate and the aqueous phase was adjusted to pH 1.55 with 6N hydrochloric acid.

The ethyl acetate phase is then removed and the ethyl acetate solutions are combined after further ethyl acetate extractions. This organic solvent solution was washed with water, dried over magnesium sulfate and evaporated to near dryness under reduced pressure. The resulting slurry was added to 700 ml of ether and stirred at 10 ° C for 20 minutes. The precipitated solid is isolated by filtration. This gave 82.6 g (26%) of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide melting at 154-155.5 ° C.

Example 11

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide To 1 ml of chloroform was added pivaloyloxymethyl ester of 2,2-dimethyl-penam-3-carboxylic acid. , the solution is cooled to -15 ° C and 0.8 g of 3-chloroperbenzoic acid is added. Stir the reaction mixture at -15 ° C for 20 minutes and then allow to warm to room temperature. The solution thus obtained contains both 1 z and 1 β-oxide according to nuclear magnetic resonance spectroscopy.

The above chloroform solution is concentrated to a volume of about 20 ml and an additional 0.8 g of 3-chloroperbenzoic acid is added. The reaction mixture was stirred overnight at room temperature and then distilled under reduced pressure to remove the solvent. The distillation residue was dissolved in 4 ml of dichloromethane and 0.4 g of 3-chloroperbenzoic acid was added. After stirring for 3 hours, the solvent was distilled off under reduced pressure. The resulting distillation residue was suspended in a mixture of ethyl acetate and water at pH 6.0, and then sodium bisulfite was added until the reaction mixture was found to be free of peroxide. The pH of the aqueous phase is adjusted to 8.0 and the two phases are separated. The organic solvent solution was washed with brine, dried over sodium sulfate, and then distilled under reduced pressure. The product obtained by distillation was dissolved in ether and precipitated by addition of hexane. The separated solids were crystallized from ether to give 0.357 g of 2,2-dimethyl-1-penam-3-carboxylic acid pivaloyloxymethyl ester 1,1-dioxide.

Nuclear Magnetic Resonance Spectrum of the prepared compound in deuterium chloroform solution: 1.23-55 (singlet, 9H); 1.50 (singlet, 3H); 1.67 (singlet, 3H); 3.28 (multiplet, 2H); 4.45 (singlet, 1H); 5.25 (multiplet, 1H) and 5.78 (multiplet, 2H) ppm.

Example 12

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 3-phthalidyl ester-1,1-dioxide 7 ml of 2,2-dimethyl-penam-3-carboxylic acid 3-phthalidyl ester were dissolved in 10 ml of chloroform. hőmér11

After cooling to -1123, 0.430 g of 3-chloroperbenzoic acid was added. After stirring for 30 minutes, 3-chloroperbenzoic acid (0.513 g) was added. Stirring is continued for 4 hours at room temperature and the reaction mixture is distilled under reduced pressure. To the distillation residue was added a mixture of ethyl acetate and water at pH 6.0, and then sodium bisulfite was added until the total amount of unreacted peracid decomposed. The pH of the aqueous phase is then adjusted to 8.8. The organic and aqueous phases are separated and the organic solution is distilled under reduced pressure. The residue obtained by distillation gave a foamy product which was identical to 2,2-dimethyl-1-penam-3-carboxylic acid 3-phthalidyl ester 1,1-dioxide.

The nuclear magnetic resonance spectrum of the prepared compound in deuterium chloroform is 1.62 (multiplet, 6H); 3.3 (muplet, 2H); 4.52 (1H); 5.23 (multiplet, 1H) and 7.63 (multiplet, 5H) ppm.

Example 13

Preparation of 2,2-Dimethylpenam-3-carboxylic acid 2,2,2-trichloroethyl ester 1,1-dioxide

A solution of 2,2-dimethylpenam-3-carboxylic acid 2,2,2-trichloromethyl ester (100 mg) in a small amount of chloroform was added and 3 mg of 3-chloroperbenzoic acid was added. Stir the reaction mixture for 30 minutes. According to analytical tests, the reaction mixture contained almost all the sulfoxide. [Nuclear Magnetic Resonance Spectrum (CDCl3): 1.6 (singlet, 3H); 1.77 (singlet, 3H); 3.38 (multiplet, 2H); 4.65 (singlet, 1H); 4.85 (multiplet, 2H) and 5.37 (multiplet, 1H) ppm.] 100 mg of 3-chloroperbenzoic acid are added and the mixture is stirred overnight. The solvent was removed by distillation under reduced pressure, and a mixture of ethyl acetate and water (pH 6.0) was added to the residue. Sufficient sodium bisulfite was added to decompose the unreacted peracid and the pH was adjusted to 8.5. The organic solvent solution was separated, washed with brine and dried. Distill the solution under reduced pressure to give 65 mg of 2,2-dimethyl-penam-3-carboxylic acid 2,2,2-trichloroethyl ester 1,1-dioxide as a distillation residue.

The nuclear magnetic resonance spectrum of the compound obtained in deuterium chloroform was 1.53 (singlet, 3H); 1.72 (singlet, 3H); 3.47 (multiplet, 2H); 4.5 (singlet, 1H); 4.6 (multiplet, 1H) and 4.8 (multiplet, 2H) ppm.

Example 14

Preparation of 2,2-Dimethylpenam-3-carboxylic acid 4-nitrobenzyl ester 1,1-dioxide

2,2-Dimethyl-penam-3-carboxylic acid 4-nitrobenzyl ester is dissolved in chloroform, the solution is cooled to 15 ° C and an equivalent amount of 3-chloroperbenzoic acid is added. Stir the reaction mixture for 20 minutes. The reaction mixture then contained 2,2-dimethylpenam-3-carboxylic acid 4-nitrobenzyl ester 1-oxide by nuclear magnetic resonance spectroscopy. An additional 1 equivalent of 3-chloroperbenzoic acid was added and stirring continued for 4 hours.

An additional equivalent amount of 3-chloroperbenzoic acid was added and stirring was continued overnight. The solvent was removed and the residue was treated with a mixture of ethyl acetate and water at pH 8.5. The ethyl acetate solution was separated, washed with water, dried and then distilled to give the crude product as a distillation residue. This was purified by silica gel column chromatography eluting with ethyl acetate / chloroform (1: 4).

The magnetic resonance spectrum of the prepared compound in deuterium chloroform was 1.35 (singlet, 3H); 1.58 (singlet, 3H); 3.45 (multiplet, 2H); 4.42 (singlet, 1H); 4.58 (multiplet, 1H); 5.30 (singlet, 2H) and 7.83 (quartet, 4H) ppm.

Example 15

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 1-methyl-1- (ace20-toxic) ethyl ester-1,1-dioxide in ml N, N-dimethylformamide 3-Carboxylic acid 1,1-dioxide was dissolved in ethyl diisopropylamine (1.9 ml) at 20 ° C followed by dropwise addition of 1.37 g of 1-methyl-1- (acetoxy) ethyl chloride in 25 drops. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated and the ethyl acetate solution was washed with water at pH 9. The ethyl acetate solution was then dried over sodium sulfate and distilled under reduced pressure. 1.65 g of crude product are obtained in the form of an oily distillation residue. The oily product was solidified in a refrigerator and then crystallized from chloroform / ether to give 2,2-dimethyl-penam-3-carboxyl-v-1-methyl-1- (acetoxy) ethyl ester as a melting point at 90-92 ° C. -1,1-dioxide.

The crude product has the following nuclear magnetic resonance spectrum in deuterium chloroform: 1.5 (singlet, 3H); 1.62 (singlet, 3H); 1.85 (singlet, 40 3H); 1.93 (singlet, 3H); 2.07 (singlet, 3H); 3.43 (multiplet, 2H); 4.3 (singlet, 1H) and 4.57 (multiplet, 1H) ppm.

Example 16

Preparation of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester

In 350 ml of N, N-dimethylacetamide was dissolved 54 g (0.165 M) of 2,250-dimethyl-6,6-dibromopen-3-carboxylic acid, 22.9 ml (0.165 M) of triethylamine was added and the mixture was stirred for 40 minutes. the reaction mixture. Benzyl bromide (19.6 mL, 0.165 M) was added and the mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was removed by filtration, and the filtrate was poured into 1500 ml of ice water of pH 2. The mixture was extracted with ether, and the extract was washed with saturated aqueous sodium bicarbonate, water, and brine. The 60 ether solution was then dried over magnesium sulfate and distilled under reduced pressure. The residue was distilled to give an off-white product which was crystallized from isopropanol. This gave 70.0 g (95% yield) of product, m.p. 75-76 ° C, identical to the benzyl ester of 2,2-dimethyl-6,6-dibromopen-365-carboxylic acid.

-1 225

In the infrared absorption spectrum studied in potassium bromide, absorption maxima are observed at 1795 and 1740 cm ^-1 .

Nuclear Magnetic Resonance Spectrum of the prepared compound in deuterium chloroform is as follows: 1.53 (singlet, 3H); 1.58 (singlet, 3H); 4.50 (singlet, 1H); 5.13 (singlet, 2H); 5.72 (singlet, 1H) and 7.37 (singlet, 5H) ppm.

Example 17

Preparation of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester la-oxide

Dissolve 13.4 g (0.03 M) of 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester in 200 ml of dichloromethane and stir with 6.12 g (0.03 M) in 100 ml of 3-chloroperbenzoic acid dissolved in dichloromethane was added at 0 ° C. Stirring was continued for 1.5 hours at the same temperature and the reaction mixture was filtered. The filtrate was washed with 5% sodium bicarbonate solution, followed by water, and then dried over sodium sulfate. The solution is distilled under reduced pressure to give 12.5 g of 2,2-dimethyl-6,6-dibromopen-3-carboxylic acid benzyl ester la-oxide as an oily distillation residue.

The oily product is crystallized from ether. After completion of the crystallization process, the suspension is filtered to give 10.5 g of the solid product 2,2-dimethyl-6,6-dibromo-penam-3-carboxylic acid benzyl ester la-oxide.

The absorption spectrum of the prepared compound in the chloroform solution showed an infrared absorption at the following wavelengths: '1800 and 1750 cm ^-1 '.

The product has a nuclear magnetic resonance spectrum in deuterium chloroform as follows: 1.3 (singlet, 3H); 1.5 singlet, 3H); 4.5 (singlet, 1H); 5.18 (singlet, 2H); 5.2 (singlet, 1H) and 7.3 (singlet, 5H) ppm.

Example 18

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 3-phthalidyl ester In ml, N, N-dimethylformamide, 506 mg of 2,2-dimethyl-penam-3-carboxylic acid were dissolved in 0.476 ml of diisopropylethylamine followed by 536 mg of phthalidyl bromide is added. After stirring overnight, the reaction mixture was diluted with ethyl acetate and water. Set the ρΗ of the mixture to 3.0 and separate the two phases. The organic solution was washed with water, then with water at pH 8.0, and then dried over sodium sulfate. The anhydrous ethyl acetate solution was distilled under reduced pressure to give the desired ester as an oily distillation residue (713 mg).

The nuclear magnetic resonance spectrum of the prepared compound in deuterium chloroform is 1.62 (multiplet, 6H); 3.3 (multiplet, 2H); 4.52 (singlet, 1H); 5.23 (multiplet, 1H) and 7.63 (multiplet, 5Tf) ppm.

Example 19

Preparation of pivaloyloxy-5-methyl-2,2-dimethyl-penam-3-carboxylate In ml of N, N-dimethylformamide, 3,588 g of 2,2-dimethyl-6,6-dbromopen-3-carboxylic acid was dissolved in 1 ml. 8 ml of diisopropylethylamine followed by 1.40 ml of chloromethyl-pi10 valate. After stirring overnight, the reaction mixture was diluted with ethyl acetate and water. The organic solvent layer was separated, washed with water at pH 3.0 and then with water at pH 8.0. The ethyl acetate solution was then dried over sodium sulfate and then distilled under reduced pressure, after which 2,2-dimethyl-6,6-dibromopenam-3-carboxylic acid pivaloyloxylate, which slowly crystallized out as a distillation residue, was obtained as an amber oil (3.1 g). we get.

The ester thus prepared is dissolved in 100 ml of methanol, then 20 g of 3.1 g of 10% palladium-on-carbon palladium catalyst and 1.31 g of 20 ml of potassium bicarbonate in water are added. Under atmospheric pressure, hydrogen is shaken until the uptake of hydrogen ceases. The reaction mixture is filtered and the methanol is removed by distillation under reduced pressure. Water (pH 8.0) and ethyl acetate were added to the distillation residue and the organic solvent phase was separated. This was dried over sodium sulfate and distilled under reduced pressure, followed by distillation as a residue.

1.25 g of pivaloyloxymethyl ester of 2,2-dimethylpenam-3-carboxylic acid are obtained.

Nuclear Magnetic Resonance Spectrum of the product prepared in deuterium chloroform is as follows: 1.23 (singlet, 9H); 1.5 (singlet, 3H); 1.67 (singlet, 3H); 3.28 (multiplet, 2H); 4.45 (singlet, 1H);

5.25 (multiplet, 1H) and 5.78 (multiplet, 2H) ppm.

Example 20

Preparation of 2,2-Dimethyl-penam-3-carboxylic acid 4-nitrobenzyl ester To a solution of N, N-dimethylformamide in ml was added 2.14 g of 2,2-dimethyl-penam-3-carboxylic acid and 2.01 ml of ethyl diisopropylamine. and 2.36 g of 4-nitrobenzyl bromide are added dropwise with stirring at 20 ° C. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate and water. The two phases were separated and the ethyl acetate solution was washed with water at pH 2.5 and then at pH 8.5. The ethyl acetate solution was dried over sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was 3.36 g

2,2-Dimethyl-penam-3-carboxylic acid 4-nitrobenzyl ester is obtained.

The nuclear magnetic resonance spectrum of the compound obtained in deuterium chloroform was 1.45 (singlet, 3H); 1.68 (singlet, 3H); 3.32 (multiplet, 2H); 4.50 singlet, 1H); 5.23 (multiplet, 1H);

5.25 (singlet, 2H) and 7.85 (quartet, 4H) ppm.

Claims (13)

A process for the preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide derivatives of formula I and pharmaceutically acceptable salts thereof, wherein R ^{1 is} hydrogen, C 2 -C 7 alkanoyloxy-. C1-C4-alkyl, C1-C4-alkoxycarbonyloxy-C1-C4-alkyl or 3-phthalidyl, characterized in that a) a compound of formula IIA wherein X is>S,> S ™ * vO or = -S- ^ O and R is the same as R ¹ above or tetrahydropyranyl, benzyl, substituted benzyl, preferably p-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, tert-butyl or phenacyl, by reaction with an oxidizing agent, preferably potassium permanganate or chloroperbenzoic acid, and if necessary to prepare compounds of formula I wherein R ^{1 is} hydrogen; 1,1-dioxide derivative, wherein R ¹ is tetrahydropyranyl, benzyl, substituted benzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl, phenacyl, splitting off the carboxyl-protecting group, or the formula b) for preparing compounds of formula I wherein ^R! 3-phthalidyl, a salt of a compound of formula I wherein R ^{1 is} hydrogen, in an inert solvent at 0-100 ° C, with 3-phthalidyl chloride or 3-phthalidyl bromide, or c) for the preparation of compounds of formula I wherein R ^{1 is C} 2 -C 7 alkanoyloxy (C 1 -C 4) alkyl or C 1 -C 4 alkoxycarbonyloxy (C 1 -C 4) alkyl, a compound of formula I a salt of a compound of Formula I wherein R ^{1 is} hydrogen, an alkyl halide of any ^{one of} the meanings of R ¹ , in an inert solvent at a temperature of 0-100 ° C, and optionally forming a pharmaceutically acceptable salt of a compound of Formula I (Priority: June 6, 1978) Process for the preparation of process a) according to claim 1, for the preparation of 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide derivatives of the formula I and their pharmaceutically acceptable salts, wherein R ^{1 is a} hydrogen atom. characterized in that a compound of formula IIA wherein X is> S, o or> S-4 O and ^R1 is hydrogen, tetrahydropyranyl, benzyl, substituted benzyl group, preferably p-nitrobenzyl, benzhydryl, 2,2,2-trichloroethyl, t-butyl, phenacyl, an oxidizing agent, and then reacting the resulting formula I - wherein R ¹ is the 1,1-dioxide derivative as defined above, when R ^{1 is} other than hydrogen, is cleaved with a carboxyl protecting group and, if desired, reacting a compound of formula I wherein R ^{1 is} hydrogen with a base to form a pharmaceutically acceptable salt. (Priority: June 7, 1977) 3. A process for the preparation of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide derivatives of the formula I according to claim 1, wherein R ^{1 is C} 2-7 alkanoyloxymethyl, C 1-7 -alkanoyloxy-ethyl, C 1-4 -alkoxycarbonyloxymethyl, C 1-4-1- - (alkoxycarbonyloxy) ethyl or 3-phthalidyl, characterized in that a) thus reacting a compound of formula IIA, wherein X = »S,> Swvw o or> S- ^ O, and R ^{1 is} reacted with an oxidizing agent as defined above, or b) for preparing compounds of formula I wherein R 3 ^1-phthalidyl group, a salt of compound of formula I, wherein ^R1 is hydrogen, in an inert solvent at temperatures from 0 to 100 ° C, 3-or 3-ftalidilkloriddal ftalidilbromiddal reacted. (Priority: February 21, 1978) A process for the preparation of 2,2-dimethyl-penam-3-carboxylic acid 1,1-dioxide derivatives of the formula I according to claim 1, wherein R ^{1 is C} 2-7 alkanoyloxy- (1- C 4 -C 4 alkyl or C 1 -C 4 alkoxycarbonyloxy (C 1 -C 4) alkyl, characterized in that (a) reacting a compound of Formula IIA wherein X is -S-, 3 = -Swvw O, or> 8,4 O, and R ^{1 is} reacted with an oxidizing agent as described above, or b) a salt of a compound of formula I wherein R ^{1 is} hydrogen, reacted with an alkyl halide as defined above for R ^{1 in an} inert solvent at a temperature from 0 ° C to 100 ° C. (Priority: June 6, 1978) 5. A process according to claim 1, wherein the oxidizing agent is an alkali metal permanganate, an alkaline earth metal permanganate or an organic peroxyacid. (Priority: June 6, 1978) 6. Process a) mode of implementation according to claim 1, characterized in that a II A compound of formula wherein X is> SWV ^ O or O group and R ¹ as defined in claim 1, meaning, the reaction mixture in a non-reactive solvent - 20 ° C is oxidized at 50 ° C with 0.5 to 5 molar equivalents of alkali metal permanganate or alkaline earth metal permanganate. (Priority: June 6, 1978) 7. A process for the preparation of process a) according to claim 1, characterized in that a compound of formula IIA wherein X = S'-X'O or> S- <O and R ^{1 has} the meaning given in claim 1 , in a reaction mixture with a non-reactive organic solvent is oxidized at a temperature of -20 ° C to 50 ° C with 1 to 4 molar equivalents of organic peroxyacid. (Priority: June 6, 1978) 8. A process according to claim 1, wherein X is -S- and R is -20 ° C to 50 ° C in a non-reactive solvent as defined in claim 1. at a temperature between 1 and 10 molar equivalents of alkali metal permanganate or alkaline earth metal permanganate. (Priority: June 6, 1978) 9. The process of claim 1, wherein a compound of formula IVA wherein X is -S- and R is -20 ° C to 50 ° C in a non-reactive organic solvent as defined in claim 1 At a temperature of from C to 2, 8 molar equivalents of organic peroxyacid are oxidized. (Priority: June 6, 1978) 10. A process according to claim 4 for the preparation of a compound of formula I. wherein R 2 is C 7 -C 7 alkanoyloxymethyl, wherein the compound of formula I wherein R ^{1 is} hydrogen is reacted with C 2 -C 7 alkanoyloxymethyl halide. (Priority: June 6, 1978) 11. A process according to claim 4 for the preparation of a compound of formula 1 wherein R is a pivaloyloxymethyl group, wherein the compound of formula I wherein R ^{1 is} hydrogen is reacted with pivaloyloxymethyl halide. (Priority: June 6, 1978) 12. A process for enhancing the efficacy of a pharmaceutical composition comprising a β-lactam antibiotic and a pharmaceutically acceptable carrier, characterized in that the composition is a 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide derivative of general formula I or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} as defined in claim 1. (Priority: 5 June 6, 1978) 13. A process for the preparation of a pharmaceutical composition, wherein a pharmaceutically acceptable carrier is an effective antimicrobial agent according to any one of claims 1-10. The 2,2-dimethylpenam-3-carboxylic acid 1,1-dioxide derivative of the formula I obtained according to any one of claims 1 to 3, wherein R is 1-3. or a pharmaceutically acceptable salt thereof. (Priority: June 6, 1978)