FI66003B - ANALOGIFICANT FARING FOR FRAMSTAELLNING AV EN THERAPEUTIC ANALYSIS OF PENICILLANSYRA-1,1-DIOXIDE AND DERIVATIVES - Google Patents

Description

RSF ^ l [β] (11) ULUTUSJ U UKISUU ^ A is * z jSff lJ 'υ utlAcgnincssiciiift ooUUo C (45) Fr-tortti ryS .-. Nelty ID CQ 1984 ^ T ^ (51) IC * .lfc? / tafcCL3 C 07 D 499/00 ENGLISH I—> FI N LAN D (21) ρ · * · "« μ * λ · «" »* · —ψμλμημολλ ^ 78i8oo. (22) Hak «inl $ ptM — AmBlailiig ^ ·· 06.06.78 (23) AtkupUvt — GlklglMiadat 06.06.78 (41) Tullut lulklMfcii —Mlvk offantNf 08.12.78

Patent * and registered (44) Nlhtivikaip * non fa kuaLJulkatoun pvm. -

Patent-och reglsterstyrelsen '/ Aiw5k »nutlndochutUkrUUupubiicuwd 30.04.84 (32) (33) (31) ttuoikuMt li | M priortMt 07.06.77 21.02.78 USA (US) 804320, 879381 (71) Pfizer Inc., 235 East 42nd Street , New York, New York, USA (72) Wayne Ernest Barth, East Lyme, Connecticut, USA (74) Oy Kolster Ab (54) Analog method for the treatment of therapeutically useful penis M 1 with acetic acid -1,1-dioxide and its derivatives - Analogiförfarande för framstä11 Ning av en therapeutiskt användbar penici1lansyra-1,1-dioxid och der ivat därav

The invention relates to an analogous process for the preparation of therapeutically useful penicillanic acid 1,1-dioxide or its esters of formula I

H -s. cft, I 1 I (I) J ------ N ......... 1

Ö "COOR

wherein R is hydrogen or an ester-forming, readily hydrolyzable residue in vivo, or a pharmaceutically acceptable salt thereof.

Penicillanic acid 1,1-dioxide and its readily hydrolyzable esters in vivo are useful as antibacterial agents 2 6 ό O O 3 as well as enhancers of several β-lactam antibiotics against many β-lactamase-producing bacteria.

One of the best known and most widely used groups of antibacterial agents comprises the so-called , Β-lactam antibiotics. These compounds are characterized in that their backbone contains a 2-azetidinone ring ((β-lactam) fused to either a thiazolidine or dihydro-1,3-thiazine ring. Examples of commonly used penicillins are benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), ampicillin and carbenicillin, typical examples of common cephalosporins, cephalosporins,

Although β-lactam antibiotics are widely used and accepted as valuable artificial therapeutic agents, their major drawback is that some of them are not active against certain microorganisms. It is believed that in many cases, the resistance of a particular microorganism to a particular β-lactam antibiotic depends on the β-lactamase produced by the microorganism. These are enzymes that break down the β-lactam ring of penicillins and cephalosporins to form compounds that do not have antibacterial activity. However, some agents have the ability to inhibit the action of β-lactamase, and when used as a β-lactamase inhibitor in combination with penicillin or cephalosporin, it enhances or enhances the antibacterial activity of penicillin or cephalosporin against certain microorganisms. When the combination of a β-lactamase inhibitor and a β-lactam antibiotic has a substantially higher antibacterial activity than the sum of the activities of the components, the antibacterial effect is considered to be enhanced.

The 1,1-dioxides of benzylpenicillin, phenoxymethylpenicillin, and some of these esters are described in U.S. Patent Nos. 3,197,466 and 3,536,698 to Guddal et al. in Tetrahedron Letters, No. 9 (1962) 381. Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976), CC · GG 3 have described several penicillin-1,1-dioxides , mm. methyl phthalimidopenicillanate 1,1-dioxide and methyl 6,6-dibromopenicillanate 1,1-dioxide.

As used herein, the term "ester-forming readily hydrolyzable group" refers to non-toxic ester groups that rapidly cleave in the blood or tissue of a mammal to give the free acid, i. a compound of Formula I wherein R is hydrogen. Such groups are known in penicillin chemistry, cf. e.g. DE-A-2 517 316. Typical examples of such readily hydrolysable ester-forming groups which R may represent are alkanoyloxymethyl having 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, alkanoyloxy) having 5 to 10 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) having 5 to 8 carbon atoms ) ethyl and 3-phthalidyl.

In Formula I, the dashed line with which the substituent is attached to the bicyclic backbone indicates that the substituent is below the level of the bicyclic backbone. Such a substituent is said to have the β-configuration. The incorporation of a substituent into the bicyclic backbone by a solid line indicates that the substituent is above the level of the backbone. This is called the / 3 configuration.

The process according to the invention for the preparation of the novel penicillanic acid 1,1-dioxide or its esters or their pharmaceutically acceptable salts is characterized in that a) oxidation of a compound of the formula II, III or IV * H ° 0 .____: / Sx / H3 HJ CH3 J - * - is, f [sh3 ° "COOR1 f N --- k 1

(II) 0 (III) ^ 00R

B

~ S S> CH3 (—Y> x I CH3 r — N -4, i

(IV) C00RX

65003 wherein R3- is hydrogen, an ester-forming group which is easily hydrolysable in vivo or a conventional protecting group for a penicillin carboxy group, and, if necessary, the carboxy group is protected, or

b) for the preparation of a compound of formula I wherein R is 3-phthalidyl or a group of formula X or XI

R3 q R3 0 'il 5 I II 5

-C-O-C-R -C-O-C-O-R

I 4 i and R R4 (X) (XI)

wherein R and R represent hydrogen or alkyl of 1 to 2 carbon atoms and R 3 is alkyl of 1 to 6 carbon atoms, the salt of penicillanic acid 1,1-dioxide is reacted with 3-phthalidyl chloride, 3-phthalidyl bromide, or a compound having is formula XII or XIII

R3 0 R3 0 'Hb 1 I 5

Q-C-O-C-Rb Q-C-O-C-O-R

R R

(XII) (XIII) wherein the Q is chlorine or bromine and R, R and R are as defined above, in a reaction-inert solvent at about room temperature, and if desired, the compound obtained is converted into a pharmaceutically acceptable salt.

Process variant a) can use a wide variety of oxidants used in the art to oxidize sulfoxides to sulfones. However, particularly suitable reagents are metal permanganates, such as alkali metal permanganates and alkaline earth metal permanganates, as well as organic peroxyacids, such as organic peroxycarboxylic acids. Suitable reagents include sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

6 500 3

When a compound of formula II or III having the same meaning as above is oxidized to the corresponding compound of formula I with metal permanganate, the reaction is usually carried out by treating a compound of formula II or III in a suitable solvent system with about 0.5 to about 5 molar equivalents, preferably about 1 molar equivalent of permanganate. A suitable solvent system is one that does not adversely affect the starting materials or the product, and water is usually used. If desired, a solvent which is miscible with water and does not affect the permanganate, e.g. tetrahydrofuran, can be added. The reaction is normally carried out at a temperature in the range of about -20 to 50 ° C, preferably about 0 ° C. At about 0 ° C, the reaction time is usually short, e.g., about one hour. Although the reaction may be carried out under neutral, basic or acidic conditions, it is most preferred to carry it out under substantially neutral conditions in order to avoid decomposition of the 3-lactam ring system of the compound of formula I. Thus, it is often advantageous to buffer the reaction medium close to the neutral point. The product is recovered by conventional methods. Any excess permanganate is usually decomposed with sodium bisulfite, and then, when the product has precipitated, is filtered. It is separated from the manganese dioxide by extraction into an organic solvent and evaporation of the solvent. If the product is dissolved at the end of the reaction, it is isolated by ordinary solvent extraction.

When a compound of formula II or III having the same meaning as above is oxidized to the corresponding compound of formula I with an organic peroxyacid, e.g. peroxycarboxylic acid, the reaction is usually carried out by treating a compound of formula II or III in a reaction-inert solvent with about 1 to about 4 molar equivalents. , preferably about 1.2 molar equivalents of oxidant. Suitable solvents include chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, and ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at about -20 to 50 ° C, preferably at about 25 ° C. At about 25 ° C, the reaction time is generally about 2 to about 16 hours. The product is usually isolated by removing the solvent in vacuo. The product can be purified by 6,600 3 by conventional methods known in the art.

When a compound of formula II or III is oxidized to a compound of formula I with an organic peroxyacid, it is sometimes advantageous to add a catalyst such as a manganese salt, e.g. inangane ethyl acetonate.

If necessary, the penicillin carboxy protecting group is removed from the obtained compound. In this case, R1 can be any of the commonly used protecting groups for the carboxy group in the 3-position of penicillin. The type of protecting group is not critical. The only requirements for the protecting group R 1 are: (i) it must be stable during the oxidation of the compound of formula II or III, and (ii) it must be possible to remove it from the compound of formula I under conditions in which the β-lactam remains substantially unchanged. Examples of typical suitable protecting groups include tetrahydropyranyl, benzyl, substituted benzyl (e.g. 4-nitrobenzyl), benzhydryl, 2,2,2-trichloroethyl, tert-butyl and phenacyl. See also: U.S. Patent Nos. 3,632,850 and 3,197,466; GB Patent Publication 1,041,985 to Woodward et al., Journal of the American Chemical Society 88 (1966) 852; Chauvette, Journal of Organic Chemistry 36 (1971) 1259; Sheehan et al., Journal of Organic Chemistry 29 (1964) 2006; and "Cephalosporin and Penicillins, Chemistry and Biology", published by H.E. Flynn, Academic Press, Inc., 1972. The carboxy group protecting group of penicillin is removed in the usual manner, taking sufficient account of the instability of the β-lactam ring system.

When a compound of formula IV is used as a starting material in process variant a), the oxidation is carried out in the same manner as the oxidation of the compound of formula II or III described above, but usually using twice the amount of oxidant.

In process variant b), the reaction is suitably carried out by dissolving a salt of a compound of formula I in which R is hydrogen in a suitable polar organic solvent such as N, N-dimethylformamide and then adding about 1 molar equivalent of halide. When the reaction is substantially complete, the product is isolated in the usual manner. It is often sufficient to dilute the reaction mixture with excess water, to extract the product with a water-immiscible organic solvent and to recover the product by evaporation of the solvent. Commonly used starting material salts include alkali metal salts such as sodium and potassium salts, and salts of tertiary amines such as triethylamine, N-ethylpiperidine, Ν, Ν-dimethylaniline and N-methylmorpholine. The reaction is carried out at a temperature in the range of about 0 to 100 ° C, usually about 25 ° C. The reaction time depends on several different factors, such as the concentrations of the reactants and the reactivity. Of the halogen compounds, bromine compounds react faster than chlorine compounds. Thus, when using a chlorine compound, it is sometimes advantageous to add up to 1 molar equivalent of alkali metal iodide. This has the effect of increasing the reaction rate. In view of the above factors, the reaction times are generally about 1 to about 2 H hours.

Penicillanic acid-10-oxide, i.e. a compound of formula II wherein R 1 is hydrogen may be prepared by debromination of 6,6-dibromopenicillanic acid-IC 2 oxide. Debromation can be performed by a conventional hydrogenolysis method. In this case, 6,6-dibromo-penicillanic acid-1 (Xr-oxide) is mixed or shaken under a hydrogen atmosphere or in a mixture of hydrogen and an inert diluent gas such as nitrogen and argon with a catalytic amount of a palladium / calcium carbonate catalyst. Suitable solvents for use in such as methanol, ethers such as tetrahydrofuran and dioxane, lower esters such as ethyl acetate and butyl acetate, water, and mixtures of these solvents, and usually a solvent in which the dibromo compound is soluble is selected.Hydrogenolysis is usually carried out at room temperature under about 355 ° C pressure. is generally present from about 10% to about 100% by weight of the weight of the dibromo compound, although larger amounts may be used The reaction time is generally about one hour, after which the compound of formula II wherein R 1 is hydrogen is recovered simply by filtration and removal of the solvent in vacuo.

6,6-Dibromopenicillanic acid 1Ck oxide is prepared by oxidizing 6,6-dibromopenicillanic acid with 1 equivalent of 3-chlorobenzoic acid in tetrahydrofuran at 0-25 ° C for about one hour by the method described by Harrison et al., Journal of 8 65003 the Chemical Society (London) Perkin I, 1772 (1976). 6,6-Dibromo-penicillanic acid is prepared by the method described by Clayton, Journal of the Chemical Society (London), (C) 2123 (1969).

Penicillanic acid 1β-oxide, i. a compound of formula III wherein R 1 is hydrogen may be prepared by controlled oxidation of penicillanic acid. It can be prepared by treating penicillanic acid in an inert solvent at about 0 ° C with 1 molar equivalent of 3-chloroperbenzoic acid for about an hour. Typical solvents suitable for use include chlorinated hydrocarbons such as chloroform and dichloromethane, ethers such as diethyl ether and tetrahydrofuran. and lower esters such as ethyl acetate and butyl acetate. The product is isolated in the usual way.

Penicillanic acid is prepared as described in GB Patent Publication No. 1,072,108.

Compounds of formulas II and III having an ester-forming readily hydrolysable group in vivo may be prepared by conventional methods directly by esterification of compounds of formulas II and III with hydrogen. When R 1 is

. . 3 U

3-phthalidyl or a group of formula X or XI in which R, R and R are as defined above, they may be prepared by alkylation with a 3-phthalidyl halide, or a compound of formula XII or XIII, a suitable compound of formula II or III wherein R ^ is hydrogen. The reaction is carried out in exactly the same manner as the reaction of penicillanic acid 1,1-dioxide described above with a 3-phthalidyl halide or a compound of formula XII or XIII.

A compound of formula II having an ester-forming, easily hydrolysable group in vivo can also be prepared by oxidation of the appropriate 6,6-dibromopenicillanic acid ester followed by debromination. 6,6-Dibromopenicillanic acid esters are prepared from 6,6-dibromopenicillanic acid by standard methods. For example, the oxidation can be performed with one molar equivalent of 3-chloroperbenzoic acid in the same manner as described for the oxidation of 6,6-dibromopenicillanic acid to 6,6-dibromopenicillanic acid-10t oxide, and the debromination is performed as described above for 6,6-dibromopenicillanic acid X-oxide debromination.

Similarly, compounds of formula III wherein R 1 is an ester-forming, readily hydrolyzable group in vivo can be prepared by oxidation from the appropriate penicillanic acid ester.

9 65003

The latter compounds can be readily prepared by esterification of penicillanic acid by standard methods. The oxidation is carried out, for example, by oxidizing one molar equivalent of 3-chloroperbenzoic acid in the same manner as described for the oxidation of penicillanic acid to penicillanic acid 1H-oxide.

Compounds of formula II in which R 1 "is a carboxy protecting group can be prepared in two different ways. They can be prepared simply by attaching a carboxy protecting group to penicillanic acid 1-oxide. Alternatively, the preparation is carried out by (a) attaching a carboxy protecting group 6,6- dibromopenicillanic acid, (b) oxidizing the protected 6,6-dibromopenicillanic acid to the protected 6,6-dibromopenicillanic acid 10-oxide with 1 molar equivalent of 3-chloroperbenzoic acid, and (c) debrominating the hydrogenated 6,6-dibromophenyl-6,6-dibromo .

Compounds of formula III in which R 1 is a carboxy protecting group may be prepared simply by attaching a protecting group to penicillanic acid 1/3 oxide. Alternatively, they can be prepared by (a) attaching a carboxy protecting group to penicillanic acid, and (b) oxidizing the protected penicillanic acid with 1 molar equivalent of 3-chloroperbenzoic acid as described above.

The compounds of formula I containing hydrogen are acidic and form salts with basic substances.

These salts are also within the scope of the invention. Such salts may be prepared by conventional methods, such as by contacting the acidic and basic components with one another, usually in a molar ratio of 1: 1, in an aqueous or non-aqueous medium or in water. They are recovered by filtration, precipitation with a non-solvent and filtration, evaporation of the solvent or, in the case of aqueous solutions, lyophilization. Suitable basic substances for salt formation can be either organic or inorganic. These include, for example, ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxides. Examples of suitable bases include 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 tertiary amines. , N-methylmorpholine and 1,5-diazebicyclo [4.3.3] 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 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.

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

As mentioned above, the compounds of formula I having a hydrogen or ester-forming, easily hydrolysable group in vivo are moderately effective antibacterial agents. The in vitro activity of the compounds of formula I in which R * is hydrogen can be demonstrated by measuring the minimum inhibitory concentration (MIC) in μg / ml for various microorganisms. The method followed is that recommended by the International Collaborative Study on Antibiotic Sensitivity Testing (Ericsson and Sherris, Acta Pathologica et Microbiologica, Scan. Supp, 217, Sections A and B; 1-90, 1970). It uses brain-heart infusion agar (BHI agar) and an inoculation device. The contents of the overnight tubes are diluted 100-fold and used as standard inoculations (20,000 to 10,000 cells in about 0.002 ml; 20 ml BHI agar / dish) are applied to the agar surface. Test compounds are used in 12-fold dilutions, and the initial concentration of test compound is 200 μg / ml. Individual colonies are not counted when readings are made after 18 hours of incubation at 37 ° C. The MIC value for each test organism is the lowest concentration at which the compound can detectably completely inhibit the growth of the test organism. The MIC values of penicillanic acid 1,1-dioxide against several different microorganisms are shown in Table I.

Table I

66003 11

Antibacterial activity of penicillanic acid 1,1-dioxide in vitro

MIC of the microorganism (μg / ml)

Staphylococcus aureus 100

Streptococcus faecalis> 200

Streptococcus pyogenes 100

Escherichia coli 50

Pseudomonas aeruginosa 200

Klebsiella pneumoniae 50

Proteus mirabilis 100

Proteus morgani 100

Salmonella typhimurium 50

Pasteurella multicida 50

Serratia marcescens 100

Enterobacter aerogenes 25

Enterobacter clocae 100

Citrobacter freundii 50

Providencia 100

Staphylococcus epidermis 200

Pseudomonas putida> 200

Hemophilus ingluenzae> 50

Neisseria gonorrhoeae 0.312 12 6: 3003 ..1. .

Compounds of formula I wherein R is hydrogen or an ester-forming, easily hydrolysable group in vivo are antibacterially active in vivo. To determine in vivo activity, mice are challenged by inoculation intraperitoneally with standard cultures of test organisms suspended in 5% porcine gastric mucosa. The infection is standardized so that the mice receive 1 to 10 times the LD ^ qq dose of the organism (LD ^ qq = the minimum inoculation number of the organism at which infected, untreated control animals die 100%). The test compound is administered to mice according to a multiple dosing regimen. At the end of the experiment, the activity of the compound is determined by counting the number of survivors of the treated animals and expressing the activity of the compound in% of the survival of the animals.

The in vitro antibacterial activity of the compound of formula I wherein R is hydrogen makes it a useful antimicrobial agent for industrial use, e.g. water treatment, mucus control, paint and wood preservation, as well as a disinfectant for topical use. When this compound is applied topically, the active ingredient is often preferably mixed with a non-toxic carrier such as a vegetable or mineral oil or a cream base. It may also be dissolved or dispersed in liquid diluents or solvents such as water, alkanols, glycols or mixtures thereof. In most cases, a suitable amount of active ingredient is from about 0.1% to about 10% by weight of the total composition.

. . 1

The activity of the compounds of formula I wherein R is hydrogen or an ester-forming, easily hydrolysable group in vivo makes them suitable for controlling bacterial infections in mammals, including humans, when administered orally or parenterally. The compounds can be used in humans to control harmful infections caused, for example, by strains of Neisseria gonorrhoeae.

For therapeutic use in mammals, especially humans, the compound of formula I or a salt thereof may be administered alone or in admixture with a pharmaceutically acceptable carrier! with a diluent. They can be administered orally or parenterally, i. intramuscularly, subcutaneously or intraperitoneally. The carrier or diluent is selected according to the route of administration. For oral administration, the antibacterial penam compound may be administered as tablets, capsules, lots, troches, powders, syrups, elixirs, aqueous solutions or suspensions, and the like, in accordance with standard pharmaceutical practice. The ratio of active compound to carrier will, of course, depend on the chemical nature, solubility and stability of the active compound as well as the intended dose. However, pharmaceutical compositions containing an antibacterial agent of formula I preferably contain from about 20% to about 95% of active ingredient. Carriers commonly used in the manufacture of tablets for oral use include lactose, sodium citrate and phosphoric acid salts. Various disintegrants such as starch, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. Capsules for oral use use, for example, lactose and high molecular weight ethylene glycols as diluents. In aqueous suspensions for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, sweetening and / or flavoring agents may also be added. For parenteral use, such as intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared, the pH of which is suitably adjusted and buffered. For intravenous use, the amount of solutes should be adjusted so that the product is isotonic.

As already indicated above, the antibacterial compounds of the invention can be used against organisms harmful to humans. The attending physician will ultimately determine the appropriate dose for the human patient, which will vary with the age, weight and individual response of the patient, as well as the severity of the patient's symptoms. The compounds of the invention are normally administered orally in doses of 10 to 200 mg / kg / day, and parenterally in doses of about 10 to 400 mg / kg / day. These are only guideline values that must be deviated from in some cases.

As mentioned above, the compounds of formula I, of which R 60003 is hydrogen or an ester-forming, easily hydrolysable group in vivo, are potent inhibitors of microbial β-lactamase and increase the antibacterial activity of β-lactam antibiotics (penicillins and cephalosporins). activity against microorganisms, especially those that produce β-lactamase. The potentiating effect of the β-lactam antibiotics of the compounds of formula I can be seen in experiments in which the antibacterial activity (MIC) of a particular antibiotic alone and the antibacterial activity (MIC) of a compound of formula I alone have been determined. These MIC values are then compared to the MIC value of the combination of antibiotic and compound of formula I. When the antibacterial potency of a combination is significantly greater than could have been inferred from the potencies of the individual compounds, this can be considered as an enhancement of activity. The MIC values of the combinations are measured by the method described by Barry and Sabath, Manual of Clinical Microbiology, edited by Lenette, Spaulding and Truant, 2nd edition, 1974, American Society for Microbiology.

The results of experiments showing that penicillanic acid po-1,1-dioxide increases ampicillin activity are shown in Table II. It can be seen from Table II that the MIC of ampicillin and penicillanic acid 1,1-dioxide for 19 ampicillin-resistant Staphylococcus aureus strains is 200 ug / ml. However, the MIC values of the combination of ampicillin and penicillanic acid 1,1-dioxide are 1.56 and 3.12 Mg / ml, respectively. That is, when ampicillin alone has an MIC of 200 pg / ml against 19 Staphylococcus aureus strains, its MIC decreases to 1.56 μg / ml in the presence of 3.12 μg / ml penicillanic acid 1,1-dioxide. The other experimental results in Table II show an increase in the antibacterial potency of ampicillin against 26 resistant Haemophilus influenzae strains, 18 resistant Klebsiella pneumoniae strains and 15 anaerobic Bacteroides fragiles strains. Tables III, IV and V show the increase in potency of benzylpenicillin (penicillin G), carbenicillin (X-carboxybenzylpenicillin and cefazoline) against microbial strains S. aureus, H. influenzae, K. pneumoniae and Bacteroides fragiles, respectively.

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Compounds of formula I in which R is hydrogen or an ester-forming, easily hydrolysable group in vivo enhance the antibacterial activity of β-lactam antibiotics in vivo. In other words, they reduce the amount of antibiotic required to protect mice after infection with otherwise lethal β-lactamase-producing bacteria.

. ... 1

The ability of compounds of formula I wherein R is hydrogen or an ester-forming, easily hydrolysable group in vivo to increase the activity of β-lactam antibiotics against β-lactamase-producing bacteria makes them valuable drugs to be administered in combination with β-lactam antibiotics for the treatment of bacterial infections. especially in humans. For the treatment of bacterial infections, a compound of formula I may be combined with a β-lactam antibiotic and both administered simultaneously. Alternatively, the compound of formula I may be administered separately during β-lactam antibiotic treatment. In some cases, it is preferred to administer a compound of formula I to a patient in advance of initiating β-lactam antibiotic treatment.

When penic acid 1,1-dioxide or a readily hydrolysable ester thereof is administered as a medicament for enhancing the efficacy of a β-lactam antibiotic, it is preferable to formulate it with conventional pharmaceutical carriers or diluents. The methods for preparing medicaments discussed above in connection with preparations of penicillan-1,1-dioxide or its ester are equally suitable for the preparation of a medicament in combination with a β-lactam antibiotic. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, a β-lactam antibiotic and penicillanic acid 1,1-dioxide or an in vivo readily hydrolysable ester thereof will normally contain from about 5% to about 80% of a pharmaceutically acceptable carrier.

When penicillanic acid -1,1-dioxide or its readily hydrolysable ester in vivo is used in combination with a β-lactam antibiotic, the sulfone can be administered orally or parenterally, i. intramuscularly, subcutaneously or intraperitoneally. Although the dose to be administered to a human patient is finally determined by the attending physician, the ratio of penicillanic acid 1,1-dioxide or its ester to β-lactam antibiotic in the daily dose is generally about 1: 3 to 3: 1. In addition, when penicillanic acid 1,1-dioxide or a readily hydrolyzable ester thereof is used in combination with a β-lactam antibiotic, the daily oral dose of each compound is normally about 10 to about 200 mg / kg and the daily parenteral dose of each is normally about 10 to about 400 mg / kg. These are only example values that may need to be deviated from in some cases.

Typical β-lactam antibiotics that can be co-administered with penicillanic acid 1,1-dioxide or its in vivo hydrolysable esters include the following 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-A-hydroxyphenyl] -7-acetamido) penicillanic acid, 6- (D-2-amino-2- / “1,4-Cyclohexadienyl-acetamido) penicillanic acid, 6- (1-aminocyclohexanecarboxamido) penicillanic acid, 6- (2-carboxy-2-phenylacetamido) penicillanic acid, 6- (2-carboxy-2 - [? 3-thienyl] acetamido) 6- (D-2- [4-ethylpiperazine-2,3-dione-1-carboxamido] -2-phenylacetamido) -penicillanic acid, 6- (D-2-A-hydroxy-1,5-naphthyridine-3-carboxamido-7 2-Phenylacetamido) penicillanic acid, 6- (D-2-sulfo-2-phenylacetamido) penicillanic acid, 6- (D-2-sulfoamino-2-phenylacetamido) penicillanic acid, 6- (D-2-Zimidazolidin-2-one -1-carboxamido-2-phenylacetam ido) penicillanic acid, 6- (D-Z'3-methylsulfonylimidazolidin-2-one-1-carboxamido-2-phenylacetamido) penicillanic acid, 6- (Zhexahydro-1H-azepin-1-yl-methyleneamino) penicillanic acid, acetoxymethyl 6- (2-phenylacetamido) penicillanate, acetoxymethyl 6- (D-2-amino-2-phenylacetamido) penicyanate, n 6: 500 3 acetoxymethyl-6- (D-2-amino-2- [4-hydroxyphenyl] acetamide) -do) penicillanate, pivaloyloxymethyl 6- (2-phenylacetamido) penicillanate, pivaloyloxymethyl 6- (D-2-amino-2-phenylacetamido) penicillanate, pivaloyloxymethyl-6- (D-2-amino-2-A- hydroxyphenyl 117-acetamido) penicillanate, 1- (ethoxycarbonyloxy) ethyl 6- (2-phenylacetamido) penicillanate, 1- (ethoxycarbonyloxy) ethyl 6- (D-2-amino-2-phenylacetamido) penicillanate , 1- (ethoxycarbonyloxy) ethyl 6- (D-2-amino-2-N-hydroxy-phenyl) acetamido) penicillanate, 3-phthalidyl-6- (2-phenylacetamido) penicillanate, 3-phthalidyl-6- (D- 2-amino-2-phenylacetamido) penicillanate, 3-phthalidyl-6- (D-2-Amino-2-A-hydroxyphenyl) acetamido) penicillanate, 6- (2-phenoxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-tolyloxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-75 -indanyloxycarbonyl-2-phenylacetamido) penicillanic acid, 6- (2-phenoxycarbonyl-2-A-thienyl) acetamido) penicillanic acid, 6- (2-tolyloxycarbonyl-2-Z'3-thienyl] acetamido) penicillanic acid 2-A-Indanyloxycarbonyl-2 - [(3-thienyl) acetamido) -penicillanic acid, 6- (2,2-dimethyl-5-oxo-η 4 -phenyl-1-imidazolidinyl) penicillanic acid, 7- (2-Z (2-thienyl) acetamido) cephalosporanic acid, 7- (2- [71-tetrazolyl] acetamido) -3- (2-N-methyl-1,3,4-thiadiazolylthiomethyl) -3-deacetoxymethylcephalosporanic acid, 7- (D-2-amino -2-phenylacetanoic acid) deacetoxycephalosporanic acid, 22,600,37-o (.-Methoxy-7- (2- [2-thienyl] acetamido) -3-carbamoyloxymethyl-3-deacetoxymethylcephalosporanic acid, 7- (2-cyanoacetamido) ) cephalosporanic acid, 7- (D-hydroxy-2-phenylacetamido ) -3- (5H-methyltetrazolyl) thiomethyl) -3-deacetoxymethylcephalosporanic acid, 7- (2-N-pyridylthioacetamido) cephalosporanic acid, 7- (D-2-amino-2-Z'-1,4-cyclohexyleneaminoacetamido) ) cef alosporanic acid, 7- (D-2-amino-2-phenylacetamido) cephalosporanic acid, and pharmaceutically acceptable salts thereof.

It will be apparent to one skilled in the art that some of the aforementioned β-lactam compounds are effective for oral or parenteral administration, while others are effective only when administered parenterally. When penicillanic acid 1,1-dioxide or an in vivo hydrolysable ester thereof is co-administered (i.e. in combination) with a β-lactam antibiotic that is active only when administered parenterally, the combination product must be formulated for parenteral administration. When penicillanic acid 1,1-dioxide or an ester thereof is co-administered (i.e., in combination) with a β-lactam antibiotic that is active both orally and parenterally, the combination may be formulated for both oral and parenteral administration. In addition, it is possible to administer preparations containing penicillanic acid 1,1-dioxide or an ester thereof orally at the same time as the β-lactam antibiotic is administered parenterally; it is also possible to administer the preparation containing penicillanic acid 1,1-dioxide or an ester thereof parenterally while administering the β-lactam antibiotic preparation orally.

The following examples illustrate the invention. Infrared spectra (IR spectra) were measured as KBr disks or Nujol alloy, and characteristic absorption sites are reported as wavenumbers (cm). Nuclear magnetic resonance (NMR) spectra were measured at 60 MHz in deuterochloroform (CDCl 3), perdeuterodimethylsulfoxide (DMSO-d 6) or deuterium oxide (D 2 O) solutions, and the location of the peaks is reported in parts per million (ppm) of tetramethylsilane. or sodium 2,2-dimethyl-2-silanepentane-5-sulfonate.

23 60003

Abbreviations are used for peak shapes: s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet.

Example 1

Of penicillanic acid 1,1-dioxide

To a solution of 6.51 g (41 mmol) of potassium permanganate in 130 mL of water and 4.95 mL of glacial acetic acid was added a cold (about 5 ° C) solution of 4.58 g (21 mmol) of cold vinegar at about 5 ° C. ) 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 to the solution until the color of the potassium permanganate had disappeared, and the mixture was filtered. The aqueous filtrate was added to half the volume of saturated sodium chloride solution, and 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 3.47 g of the title compound. The aqueous mother liquor was saturated with sodium chloride and extracted again with ethyl acetate. The ethyl acetate solution was dried and evaporated to dryness in vacuo to give a further 0.28 g of the title product. The total yield was thus 3.75 g (78%). The NMR spectrum of the compound (DMSO-d 6) showed absorptions: 1.40 (s, 3H), 1.50 (s, 3H), 3.13 (doublet d, 1H, J 1 = 16 Hz, J 2 = 2 Hz), 3.63 (doublets d, 1H, J1 = 16 Hz, J2 = 4 Hz), 4.22 (s, 1H) and 5.03 (doublets d, 1H, J1 = 4 Hz, J2 = 2 Hz) ppm.

Example 2

Benzylpenicillanate 1,1-dioxide To a stirred solution of 6.85 g (24 mmol) of benzylpenicillanate in 75 ml of ethanol-free chloroform in an ice bath was added a total of 4.78 g of 85% pure nitrogen in two portions over several minutes under nitrogen. 3-chloro-acid was. Stirring in an ice bath was continued for 30 minutes and then without external cooling for another 45 minutes. The reaction mixture was washed with aqueous alkali solution (pH 8.5), then saturated sodium chloride solution and dried and evaporated in vacuo to give 7.05 g of residue. Upon examination, the residue was found to be a 5.5: 1 mixture of benzylpenicillanate-1-oxide and benzylpenicillanate-1,1-dioxide.

24 66003

To the above 5.5: 1 sulfoxide-sulfone mixture (4.85 g) in 50 ml of ethanol-free chloroform was added 3.2 g of 85% pure 3-chloroperbenzoic acid under nitrogen at room temperature with stirring. The reaction mixture was stirred for 2.5 hours, then diluted with ethyl acetate. The resulting mixture was added to water (pH 8) and the layers were separated. The organic phase was washed with water (pH 8), then saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave 3.59 g of the title compound. The NMR spectrum had absorbances: 1.28 (s, 3H), 1.58 (s, 3H), 3.42 (m, 2H), 4.37 (s, 1H), 4.55 (m, 1H) , 5.18 (q, 2H, J = 12 Hz) and 7.35 (s, 5H) ppm.

Example 3

Of penicillanic acid 1,1-dioxide

To a stirred solution of 8.27 g of benzylpenicillanate-1,1-dioxide in a mixture of methanol (40 ml) and ethyl acetate (10 ml) was slowly added 10 ml of water and then 12 g of% palladium / calcium carbonate. The mixture was shaken under a hydrogen atmosphere at 360 kPa for 40 minutes, filtered through supercel (diatomaceous earth). The filter cake was washed with methanol and aqueous methanol, and washings were added to the filtrate. Most of the solvent was evaporated from the combined solutions in vacuo and the residue partitioned between ethyl acetate and water (pH 2.8). The ethyl acetate layer was removed and the aqueous phase was further extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was slurried in a 1: 2 mixture of ethyl acetate and ether to give 2.37 g of the title compound, m.p. 148-151 ° C. The ethyl acetate-ether mixture was evaporated to give an additional 2.17 g of product.

Example 4

Pivaloyloxymethylpenicillanate 1,1-dioxide To 0.562 g (2.41 mmol) of penicillanic acid 1,1-dioxide in 2 ml of Ν, Ν-dimethylformamide was added 0.375 g (2.90 mmol) of diisopropylethylamine, and then 0.360 n \ l chloromethyl pi-valate. The reaction mixture was stirred at room temperature for 24 hours under CCl 3, then diluted with ethyl acetate and 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 dried over sodium sulfate and evaporated in vacuo to give 0.700 g of the title product as a solid, m.p. 103-104 ° C. The NMR spectrum of the product (CDCl 3) showed absorbances: 1.27 (s, 9H), 1.47 (s, 3H), 1.62 (s, 3H), 3.52 (m, 2H), 4, 47 (s, 1H), 4.70 (m, 1H), 5.73 (d, 1H, J = 6.0 Hz) and 5.98 (d, 1H, J = 6.0 Hz).

Example 5

Asetoksimetyyllpenlsillanaatti-1,1-dioxide

However, the procedure of Example 4 was repeated using an equimolar amount of acetoxymethyl chloride instead of the pivaloyloxymethyl chloride used therein to give the title product, yield 56%, m.p. 138-141 ° C. The NMR spectrum of the product (in CDCl 3) showed absorbances at 1.45 (s, 3H), 1.65 (s, 3H), 2.10 (s, 3H), 3.45 (d, 2H, J = 3). Hz), 4.40 (s, 1H), 4.50 <t, 1H, J = 3 Hz) and 5.75 (q, 2H, J = 5 Hz) ppm from the tetramethylsilane used as an internal standard.

Acetoxymethyl perricillanate 1,1-dioxide was also prepared from sodium penicillanate 1,1-dioxide and acetoxymethyl libromide in dimethyl sulfoxide as described in Example 4, yield 29%. After chromatography, the product m.p. was 143-144 ° C. Its IR spectrum (KBr tablet) had absorbances at 1750, 1300, 1150, 1040, 990 and 825 cm-1 and its NMR spectrum (DMSO-d 6) at 1.00 (s, 3H), 1.15 (s, 3H), 1.75 (s, 3H), 2.95 (q, 1H), 3.15 (q, 1H), 4.05 (s, 1H), 4.80 (q, 1H), and 5 .40 (q, 2H) ppm from the tetramethylsilane used as an internal standard.

Example 6 3-Phthalidylpenicillanate 1,1-dioxide To 0.783 g (3.36 mmol) of penicillanic acid 1,1-dioxide in 5 ml of Ν, Ν-dimethylformamide was added 0.47 ml of triethylamine and then 0.715 g of 3 -bromiftalidia. The reaction mixture was stirred for two hours at room temperature, then diluted with ethyl acetate and water. The pH of the aqueous phase was adjusted to 7.0 and the layers were separated. The ethyl acetate layer was washed successively with water and saturated sodium chloride solution, and dried over sodium sulfate. The ethyl acetate solution was evaporated in vacuo to give the title compound as a white foam.

The NMR spectrum of the product (CDCl 3) had absorbances: 1.47 (s, 6H), 3.43 (m, 1H), 4.45 (s, 1H), 4.62 (m, 1H), δ , 40 and 7.47 (2 singlets, 1H) and 7.73 (m, 4H) ppm.

Example 7 1- (Ethoxycarbonyloxypethylpenicillanate-1,1-dioxide

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, 0.300 g of sodium bromide and 3 ml of N, N-dimethylformamide was stirred at room temperature for six days. The mixture was then diluted with ethyl acetate and water, the pH was adjusted to 8.5. The ethyl acetate layer was separated, washed three times with water and once with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The ethyl acetate was evaporated in vacuo to give 0.390 g of the title compound as an oil.

The product obtained above was combined with approximately the same amount of the corresponding material obtained in the corresponding experiment. The combined product was dissolved in chloroform, and 1 ml of pyridine was added to the solution. The mixture was stirred at room temperature overnight, then the chloroform was evaporated in vacuo. The residue was partitioned between ethyl acetate and water (pH 8). The ethyl acetate layer was separated, dried and evaporated to dryness in vacuo to give 150 mg of the title compound (yield about 75%). The IR spectrum (film) of the product had absorptions: 1805 and 1763 cm. The NMR spectrum (CDCl 3) had absorbances: 1.43 (m, 12H), 3.47 (m, 2H), 3.9 (q, 2H, J = 7.5 Hz), 4.37 (m, 1H), 4.63 (m, 1H) and 6.77 (m, 1H) ppm.

Example 8

Metoksikarbonyylioksimetyylipenisillanaatti-1,1-dioxide

A mixture of 3.08 ml of methyl chloroformate in 50 ml of deoxygenated carbon tetrachloride was stirred and bubbled through a vigorous stream of chlorine gas under a nitrogen atmosphere. The reaction mixture was then irradiated for 10 minutes with light having a wavelength of 3500 A. The carbon tetrachloride solution was cooled to -10 ° C and 1.62 ml of methanol was added thereto. A solution of 11.87 ml of diisopropylethylamine in 10 ml of carbon tetrachloride was then added dropwise to the mixture.

27 6 5 0 0 3

The reaction mixture was allowed to slowly warm to room temperature and stirring was continued for 45 minutes. The solvent was removed by evaporation in vacuo, followed by the addition of a solution of 6.24 g of penicillanic acid 1,1-dioxide and 4.62 ml of diisopropylethylamine in 60 ml of Ν, Ν-dimethylformamide. Stirring was continued for 24 hours, after which water and dichloromethane were added to the mixture. The pH was adjusted to 4.0 and the phases were separated. The aqueous phase was extracted with dichloromethane, after which the dichloromethane solutions were combined and washed first with water at pH 3.0 and then with water without pH adjustment. The dried dichloromethane solution was evaporated in vacuo to an oil which crystallized after treatment with ether. 1.94 g of the title product were obtained, m.p. 124-126 ° C. The NMR spectrum (CDCl 3) had absorbances at 1.43 (s, 3H), 1.61 (s, 3H), 3.44 (m, 2H), 3.85 (s, 3H), 4.39 ( s, 1H), 4.59 (m, 1H) and 5.78 (q, 2H) ppm from the tetramethylsilane.

Example 9

Butoksikarbonyylioksimetyylipenisillanaätti-I, 1-dioxide

A mixture of 3.08 ml of methyl chloroformate in 50 ml of deoxygenated carbon tetrachloride was stirred and bubbled with a strong stream of chlorine gas. The reaction mixture was then irradiated for 7 minutes with light having a wavelength of 3500 A. The reaction mixture was purged with nitrogen and then irradiated for another 10 seconds. The resulting solution was cooled to about -10 ° C and 3.48 ml of n-butanol was added. A solution of 8.6 ml of diisopropylethylamine in 10 ml of dichloromethane was then added dropwise to the mixture. The cooling bath was removed and stirring was continued for one hour. The dichloromethane was removed in vacuo, followed by the addition of a solution of 3.07 g of penicillanic acid 1,1-dioxide and 2.27 ml of diisopropylethylamine in about 500 ml of Ν, Ν-dimethylformamide. Stirring was continued for 18 hours, after which water and dichloromethane were added to the mixture. The phases were separated and the aqueous phase was extracted with dichloromethane. The dichloromethane solutions were combined and washed with water, dried and evaporated to give the crude product.

66003 28

The NMR spectrum of the obtained crude product indicated that the reaction was incomplete. Thereafter, the crude product was dissolved in any N, N-dimethylformamide, and 1.165 g of penicillanic acid 1,1-dioxide and 0.86 ml of diisopropylethylamine were added to the mixture. The mixture was stirred overnight and the product was isolated as before. It was found that the reaction was still incomplete, so the obtained product was redissolved 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 mixture. The mixture was stirred overnight and the product was isolated again as before. 4.6 g of crude product were obtained.

This crude product was purified by silica gel column chromatography to give 0.19 g of the title product. The NMR spectrum (CDCl 3) showed absorbances at 0.98 (t, 3H), 1.45 (s, 3H), 1.63 (s, 3H), 1.55 (m, 4H), 3, Δ (m, 2H), 4.23 (t, 3H, J = 6.8 Hz), 4.45 (s, 1H), 4.65 (m, 1H) and 5.85 (q, 2H) ppm in the subfield of tetramethylsilane.

Example 10

Penicillanic acid 1Λ-oxide To 1.4 g of prehydrated 5% palladium / calcium carbonate in 50 ml of water was added a solution of 1.39 g of benzyl 6,6-dibromopenicillanate-1Λ-oxide in 50 ml of tetrahydrofuran. The mixture was shaken under a hydrogen atmosphere at 310 kPa at 25 ° C for 1 hour, then filtered. Most of the tetrahydrofuran was evaporated from the filtrate in vacuo and the aqueous phase was extracted with ether. The ether extract was evaporated in vacuo to give 0.5 g of a substance consisting mainly of benzylpenicillanate-10 (-oxide).

The benzylpenicillanate-106-oxide obtained above and an additional 2.0 g portion of benzyl 6,6-dibromopenicillanate-1α-° xide were combined and dissolved in 50 ml of tetrahydrofuran. The solution was added to 4.0 g of 5% palladium / calcium carbonate in 50 ml of water, and the resulting mixture was shaken under a hydrogen atmosphere at a pressure of about 310 kPa at 25 ° C overnight. The mixture was filtered, the filtrate was extracted with ether. The extract was evaporated in vacuo, and the residue was purified by chromatography on silica gel, eluting with chloroform. 0.50 g of product is obtained, which is hydrated for two hours at a hydrogen pressure of about 310 kPa at 250 [deg.] C. in a water-methanol mixture (1: 1) in the presence of 5% palladium / calcium carbonate (0.50 g). A further 0.50 g portion of 5% palladium / calcium carbonate was then added and the hydrogenation was continued at 310 kPa at 25 ° C overnight. The reaction mixture was filtered, extracted with ether and the extracts discarded. The pH of the aqueous phase was adjusted to 1.5 and then extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and evaporated in vacuo to give 0.14 g of penicillanic acid 1 * X-oxide. The NMR spectrum (CDCl 3 / DMSO-d 6) showed absorbances: 1.4 (s, 3H), 1.64 (s, 3H), 3.60 (m, 2H), 4.3 (s, 1H) and 4 , 54 (m, 1 H) ppm. The IR spectrum (KBr disc) of the product had absorbances: 1795 and 1745 cm

Example 11

Penicillanic acid 1H-oxide To 1.0 g of prehydrated 5% palladium / calcium carbonate in 30 ml of water was added a solution of 1.0 g of 6,6-dibromo-penicillanic acid KX-oxide in methanol. The mixture was shaken under a hydrogen atmosphere at a pressure of about 310 kPa at 25 ° C for one hour. The reaction mixture was then filtered and the filtrate was evaporated to remove methanol. The aqueous phase was diluted with an equal volume of water, the pH was adjusted to 7 and the solution was extracted with ether. The aqueous phase was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and evaporated to dryness to give penicillanic acid 1 ° (oxide).

Example 12

Penis illanoic acid 1 / b-oxide

To a stirred solution of 2.65 g (12.7 mmol) of penicillanic acid in chloroform was added 2.58 g of 85% pure 3-chloroperbenzoic acid at 0 ° C. After 1 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 slowly concentrated until a precipitate began to form. At this point, evaporation was stopped and the mixture was diluted with ether. The precipitate was filtered, washed with ether and dried to give 0.615 g of penicillanic acid 1/3 oxide, m.p. 140-143 ° C. The IR spectrum (CHCl 3 solution) had absorbances: 1775 and 1720 cm -1. The NMR spectrum (CDCl 3 / DMSO-d 6) had absorbances: 1.35 (s, 3H), 1.76 (s, 3H), 3.36 (66003 (m, 2H), 4.50 (s, 1H)). and 5.05 (m, 1H) ppm. Based on the NMR spectrum, the product was about 90% pure.

When the chloroform-ether mother liquor was examined, it was found that it still contained penicillanic acid-1 ytf-oxide and some penicillanic acid-1 (»(-oxide.

Example 13

Penicillanic acid 1,1-dioxide To 2.17 g (10 mmol) of penicillanic acid 1-oxide in 30 ml of ethanol-free chloroform at about 0 ° C was added 1.73 g (10 mmol) of 3-chloroperbenzoic acid. The mixture was stirred for 1 hour at about 0 ° C and then for another 24 hours at 25 ° C. The reaction mixture was filtered and evaporated in vacuo to give penicillanic acid 1,1-dioxide.

Example 14

However, the procedure of Example 13 was repeated using the following compounds instead of penicillanic acid 1-oxide: penicillanic acid 1 - (4-oxide, acetoxymethylpenicillanate 1 - [(oxide), pivaloyloxymethylpenicillanate-1-oxide, acetoxymethylpenicillanimino-1-oxyoxenic oxide, 3-phthalidylpenicillanate-10 - (oxide, 3-phthalidylpenicillanate-1/3-oxide, 1- (ethoxycarbonyloxy) ethylpenicillanate-1- oxide, methoxycarbonyloxymethylpenicillanate 1/3 oxide, The following compounds were obtained, respectively: penicillanic acid 1,1-dioxide, acetoxymethylpenicillanate-1,1-dioxide, pivaloyloxymethylpenicillanate-1,1-dioxide, 1,1-dioxide, acetoxymethylmethyl 1,1-dioxide, 3-phthalidylpenicillanate 1,1-dioxide, 3-phthalidylpenicillanate 1,1-dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanate 1,1-dioxide, 31 C'j 00 3 methoxycarbonyloxymethylpenicillanate-1,1-dioxide, 1- (ethoxycarbonyloxy) ethylpenicillanate-1,1-dioxide, methoxycarbonyloxymethylpenicillanediol

Example 15

Oxidation of benzylpenicillanate-10-oxide and benzylpenicillanate-1β-oxide with 3-chloroperbenzoic acid by the method described in Example 13 gave benzylpenicillanate-1,1-oxide in each case.

Example 16

Penicillanic acid 1,1-dioxide Hydrogenolysis of 4-nitrobenzylpenicillanate-1,1-dioxide by the method of Example 3 gives penicillanic acid 1,1-dioxide.

Example 17

Of sodium 1,1-dioxide

To a stirred solution of 32.75 g (0.14 mmol) 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. ethyl acetate. The resulting solution was stirred for 1 hour, then an additional 10% excess of sodium 2-ethylhexanoate in a small amount of ethyl acetate was added. The product immediately began to precipitate. Stirring was continued for 30 minutes, then the precipitate was filtered. It was washed successively with ethyl acetate, 1: 1 ethyl acetate-ether and ether. The solid was dried over phosphorus pentoxide at about 0.1 mmHg for 16 hours at 25 ° C to give 36.8 g of the title compound with some ethyl acetate as an impurity. The ethyl acetate content was reduced by heating at 100 ° C under vacuum for three hours. The IR spectrum of the final product (KBr disks) had absorbances: 1786 and 1608 cm -1. The NMR spectrum (D 2 O) had absorbances: 1.48 (s, 3H), 1.62 (s, 3H), 3.35 (doublet d, 1H, -16 Hz, J 2 = 2 Hz), 3.70 ( ppm of doublets d, 1H, = 16 Hz, = 4 Hz), 4.25 (s, 1H) and 5.03 (doublets of d, 1H, = 4 Hz, = 2 Hz).

The title sodium salt can also be prepared using acetone instead of ethyl acetate.

66003

Example 18

Penis illanic acid-1,1-dioxide

To a mixture of 7,600 ml of butter and 289 ml of ice was added portionwise 379.5 g of potassium permanganate. The mixture was stirred for 15 minutes, then cooled to 0 ° C. A mixture prepared by 270 g, cooled to 8 ° C, was then added thereto. of the acid, 260 ml of 4N sodium hydroxide and 2400 ml of water (pH 7.2). During the addition, the temperature rose to 16 ° C. The temperature of the mixture was lowered to 3 ° C and stirring was continued for 30 minutes. 142.1 g of sodium bisulfite were added portionwise over 10 minutes to the reaction mixture. The mixture was stirred at 10 ° C for 10 minutes, then 100 g of supercel (diatomaceous earth) was added. After stirring for 5 minutes, the mixture was filtered. To the filtrate was added 4.0 liters of ethyl acetate, and the pH of the aqueous phase was lowered to 1.55 with 6N hydrochloric acid. The ethyl acetate layer was separated and combined with several other ethyl acetate extracts. The combined extracts were washed with water, dried over magnesium sulphate and evaporated to near dryness in vacuo.

The resulting broth was stirred in 700 mL of ether at 10 ° C for 20 minutes, then the solid was filtered off. There was thus obtained * 82.6 g (26% yield) of the title compound, m.p. 154-155.5 ° C (decomposes).

Example 19

To a solution of pivaloyloxymethyl penicillanate 1,1-dioxide cooled to -15 ° C with 1.25 g of pivaloyloxymethylpenicillanate in 40 ml of chloroform was added 0.8 g of 3-chloroperbenzoic acid. The mixture was stirred at about -15 ° C for 20 minutes, then allowed to warm to room temperature. The NMR spectrum showed that the resulting solution contained both 1 ° oxide and 1/3 oxide.

The chloroform solution was evaporated to about 20 ml, and a further 0.8 g of 3-chloroperbenzoic acid was added. This mixture was stirred overnight at room temperature, then the solvent was evaporated in vacuo. The residue was dissolved in about 4 ml of dichloromethane, and 0.4 g of 3-chloroperbenzoic acid was added to the solution. The mixture was stirred for three hours, then the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate and water (pH 6.0), and sodium bisulfite was added to the aqueous phase until the disappearance of peroxides was experimentally observed. The pH of the aqueous phase was raised from 66003 33 to 8.0, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was dissolved in ether and reprecipitated by the addition of hexane. The resulting solid was recrystallized from ether to give 0.357 g of the title compound.

The NMR spectrum of the compound (CDCl 3) had absorbances: 1.23 (s, 9H), 1.50 (s, 3H), 1.67 (s, 3H), 3.28 (m, 2H), 4.45 (s, 1H), 5.25 (m, 1H) and 5.78 (m, 2H) ppm.

Example 20 3-Phthalidyl penicillanate 1,1-dioxide

To a solution of 713 mg of 3-phthalidylpenicillanate in 3 ml of chloroform was added 0.430 g of 3-chloroperbenzoic acid at about 10 ° C. The mixture was stirred for 30 minutes and then an additional 0.513 g of 3-chloroperbenzoic acid was added. The mixture was stirred for a further four hours at room temperature, then the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water (pH 6.0) and sodium bisulfite was added to decompose the remaining peracid. The pH of the aqueous phase was adjusted to 8.8. The layers were separated and the organic phase was evaporated in vacuo. The title compound was obtained as a foam. The NMR spectrum (CDCl 3) had absorbances: 1.62 (m, 6H), 3.3 (m, 2H), 4.52 (p, 1H), 5.23 (m, 1H) and 7.63 ( m, 5H) ppm.

Example 21 2,2,2-Trichloroethylpenicillanate-1,1-dioxide To 100 mg of 2,2,2-trichloroethylpenicillanate in a small amount of chloroform was added 50 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 30 minutes. Examination of the reaction product at this stage showed that it was predominantly sulfoxide (NMR spectrum (CDCl 3) had absorptions: 1.6 (s, 3H), 1.77 (s, 3H), 3.38 (m, 2H ), 4.65 (s, 1H), 4.85 (m, 2H) and 5.37 (m, 1H) ppm). An additional 100 mg of 3-chloroperbenzoic acid was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water (pH 6.0). The excess peracid was decomposed by the addition of sufficient sodium bisulfite, then the pH was raised to 8.0. The organic phase was separated, washed with brine and dried. Evaporation in vacuo gave 65 mg of the title compound. The NMR spectrum (CDCl 3) had absorbances: 1.53 (s, 3H), 1.72 (s, 3H), 3.47 (m, 2H), 4.5 (s, 1H), 4.6 ( m, 1H) and 4.8 (m, 2H) ppm.

Example 22 4-Nitrobenzylpenicillanate 1,1-dioxide 3 * 60003

To a chloroform solution of 4-nitrobenzylpenicillanate cooled to about 15 ° C was added 1 equivalent of 3-chloroperbenzoic acid. The reaction mixture was stirred for 20 minutes. Examination of the reaction mixture by NMR at this stage revealed that it contained 4-nitrobenzylpenicillanate-1-oxide. An additional 1 equivalent of 3-chloroperbenzoic acid was added and the reaction mixture was stirred for four hours. At this time, 1 equivalent of 3-chloroperbenzoic acid was added again and the reaction mixture was stirred overnight. The solvent was removed by evaporation and the residue partitioned between ethyl acetate and water (pH 8.5). The ethyl acetate layer was separated, washed with water, dried and evaporated to give the crude product. It was purified by chromatography on silica gel eluting with ethyl acetate / chloroform 1: 4.

The NMR spectrum of the product (CDCl 3) had absorbances: 1.35 (s, 3H), 1.58 (s, 3H), 3.45 (m, 2H), 4.42 (s, 1H), 4.58 ( m, 1H), 5.30 (s, 2H) and 7.83 (q, 4H) ppm.

Example 2 3

Penicillanic acid 1,1-dioxide To 0.54 g of 4-nitrobenzylpenicillanate 1,1-dioxide in 30 ml of methanol and 10 ml of ethyl acetate was added 0.54 g of 10% palladium on carbon. The mixture was shaken under a hydrogen atmosphere at a pressure of about 345 kPa until hydrogen bonding ceased. The reaction mixture was filtered and the solvent was removed by evaporation. The residue was partitioned between ethyl acetate and water (pH 8.5) and the aqueous layer was separated. A new portion of ethyl acetate was added and the pH was adjusted to 1.5. The ethyl acetate layer was removed, washed with water and dried and evaporated in vacuo. 0.168 g of the title compound was obtained as crystals.

35 6 5 0 0 3

Example 24

Penicillanic acid 1,1-dioxide To a stirred solution of 512 mg of 4-nitrobenzylpenicillanate-1,1-dioxide cooled to 0 ° C in a mixture of acetonitrile (5 ml) and water (5 ml) was added portionwise over several minutes. containing 485 mg of sodium dithionite in 1.4 ml of 1.0 N sodium hydroxide. The reaction mixture was stirred for an additional five minutes, then diluted with ethyl acetate and water (pH 8.5). The ethyl acetate layer was separated and evaporated in vacuo to give 300 mg of starting material. A new portion of ethyl acetate was added to the aqueous phase and the pH of the aqueous phase was adjusted to 1.5. The ethyl acetate layer was separated, dried and evaporated in vacuo to give 50 mg of the title compound.

Example 25 1-Methyl-1- (acetoxy) ethylpenicillanate 1,1-dioxide To 2.33 g of penicillanic acid 1,1-dioxide in 5 ml of N, N-dimethylformamide was added 1.9 ml of ethyldiisopropylamine. and then dropwise at about 20 ° C 1.37 g of 1-methyl-1- (acetoxy) ethyl chloride. The mixture was stirred at room temperature overnight, then ethyl acetate and water were added. The layers were separated and the ethyl acetate layer was washed with water (pH 9). The ethyl acetate layer was dried over sodium sulfate and evaporated in vacuo to give 1.65 oily crude product. When standing in the refrigerator, the oil crystallized. It was recrystallized from a mixture of chloroform and ether to give the product, m.p. was 90-92 ° C.

The NMR spectrum of the crude product (CDCl 3) had absorbances: 1.5 (s, 3H), 1.62 (s, 3H), 1.85 (s, 3H), 1.93 (s, 3H), s, 07 (s, 3H), 3.43 (m, 2H), 4.3 (s, 1H) and 4.57 (m, 1H) ppm.

Example 26

Of penicillanic acid 1,1-dioxide

To a stirred solution of 1.78 g of penicillanic acid in water (pH 7.5) was added 1.46 ml of 40% peracetic acid and then after 30 minutes a further 2.94 ml of 40% peracetic acid was added. . The reaction mixture was stirred for three days at room temperature, then ethyl acetate and water were added thereto. Solid sodium bisulfite was added to decompose the excess peracid, then the pH was adjusted to 1.5. The ethyl acetate layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was a 3: 2 mixture of penicillanic acid 1,1-dioxide and penicillanic acid 1-oxide.

Example 27

Pivaloyloxymethylpenicillanate 1,1-dioxide To a stirred solution of 595 mg of pivaloyloxymethylpenicillanate-1-oxide in 5 ml of ethyl acetate cooled to about -15 ° C was added 5 mg of manganese acetylacetonate. To the resulting dark brown mixture was added 0.89 ml of 40% peracetic acid in small portions over several minutes. After 40 minutes, the cooling bath was removed and the mixture was stirred at room temperature for three days. Ethyl acetate and water (pH 8.5) were added to the mixture and the ethyl acetate layer was separated, dried and evaporated in vacuo. 178 mg of product were obtained, which according to NMR spectrum was a mixture of pivaloyloxymethylpenicillanate-1,1-dioxide and pivaloyloxymethylpenicillanate-1-oxide.

The obtained product was dissolved in ethyl acetate and reoxidized as described above with 0.9 ml of peracetic acid and 5 mg of manganese acetylacetonate with a reaction time of 16 hours. Further work-up of the reaction mixture was carried out in the same manner as above to give 186 mg of pivaloyloxymethyl penicillanate t-1,1-dioxide.

Preparation A

6,6-dibromopenicillanic-1 <^ - oxide

The title compound is prepared by oxidizing 6,6-dibromopenicillanic acid with 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0-25 ° C for about one hour by the method of Harrison et al., Journal of the Chemical Society (London) Perkin I, 1772 ( 1976) have described.

65003 37

Preparation B

Benzyl 6,6-dibromopenicillanate

To a solution of 54 g (0.165 moles) of 6,6-dibromopenicillanic acid in 350 ml of N, N-dimethylacetamide was added 22.9 ml (0.165 moles) of triethylamine, and the solution was stirred for 40 minutes. To the solution was added benzyl bromide (19.6 mL, 0.165 mol), and the resulting mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered and the filtrate was added to 1,500 ml of ice water (pH 2). The mixture was extracted with ether, the extracts washed successively with saturated sodium bicarbonate solution, water and brine, dried over mangesium sulphate and evaporated in vacuo to give an off-white solid which was recrystallised from isopropanol. 70.0 g (95% yield) of the title compound were obtained, m.p. 75-76 ° C. The IR spectrum -1 (KBr disk) had absorbances: 1795 and 1740 cm. The NMR spectrum (CDCl 3) had absorbances: 1.53 (s, 3H), 1.58 (s, 3H), 4.50 (s, 1H), 5.13 (s, 2H), 5.72 (s 1H) and 7.37 (s, 5H) ppm.

Preparation C

Benzyl 6,6-dibromopenicillanate-1α oxide

To a stirred solution of 13.4 g (0.03 moles) of benzyl 6,6-dibromopenicillanate in 200 mL of dichloromethane was added at about 0 ° C a solution of 6.12 g (0.03 moles) of 3-chloroethane. -perperbenzoic acid in 100 ml of dichloromethane. Stirring was continued for 1.5 hours at about 0 ° C, then the reaction mixture was filtered. The filtrate was washed successively with 5% sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo to give 12.5 g of the oily title product. The oil was crystallized by trituration in ether. Filtration of the crystals gave 10.5 g of benzyl 6,6-dibromopenicillanate-10 (oxide). The NMR spectrum of the product (CDCl 3) had absorbances: 1.3 (s, 3H), 1.5 (s, 3H), 4 , Δ (s, 1H), 5.18 (s, 2H), 5.2 (s, 1H) and 7.3 (s, 5H) ppm.

65003

Preparation D

4-nitrobentsyylipenisillanaatti

Reaction of the triethylamine salt of penicillanic acid with 4-nitrobenzyl bromide by the method described in Preparation B gives 4-nitrobenzylpenicillanate.

Preparation E

2,2,2-Trichloroethylpenicillanate To 403 mg of penicillanic acid in 10 ml of dichloromethane was added 25 mg of diisopropylcarbodiimide and then 0.19 ml of 2,2,2-trichloroethanol. The mixture was stirred overnight, then the solvent was evaporated in vacuo. The crude product was purified by chromatography on a silica gel column, eluting with chloroform.

Preparation F

3-ftalidyylipenisillanaatti

To a solution of 508 mg of penicillanic acid in 2 ml of N, N-dimethylformamide was added 0.476 ml of diisopropylethylamine and then 536 mg of 3-phthalidyl bromide. The mixture was stirred overnight, then ethyl acetate and water were added, and the pH was adjusted to 3.0. The layers were separated, the organic layer was washed with water and then water adjusted to pH 8.0, dried over anhydrous sodium sulfate and evaporated in vacuo to give 713 mg of the oily title product. The NMR spectrum (CDCl 3) had absorbances: 1.62 (m, 6H), 3.3 (m, 2H), 4.52 (s, 1H), 5.23 (m, 1H) and 7.63 (m , 5H).

Preparation G

Pivaloyloxymethylpenicillanate To 3.588 g of 6,6-dibromopenicillanic acid in 10 ml of N, N-dimethylformamide was added 1.8 ml of diisopropylethylamine and then 1.40 ml of chloromethyl pivalate. The mixture was stirred overnight, then ethyl acetate and water were added. The organic layer was separated and washed successively with water (pH 3.0) and water (pH 8.0). The ethyl acetate solution was dried over sodium sulfate and evaporated in vacuo to give 3.1 g of pivaloyl 65003 hydroxymethyl 6,6-dibromopenicillanate as an amber oil which slowly crystallized.

The ester obtained above was dissolved in 100 ml of methanol, and 3.1 g of 10% palladium / carbon and 1.31 g of potassium carbonate in 20 ml of water were added to the solution. The mixture was shaken in a hydrogen atmosphere under normal pressure until hydrogen bonding ceased. The reaction mixture was filtered and the methanol was evaporated in vacuo. The residue was partitioned between water and ethyl acetate at pH 8, the organic layer separated, dried over sodium sulphate and evaporated in vacuo to give 1.25 g of the title compound. NMR spectrum (CDCl 3) had absorbances: 1.23 (s, 9H), 1.5 (s, 3H), 1.67 Cs, 3H), 3.28 (m, 2H), 4.45 ( s, 1H), 5.25 (m, 1H) and 5.78 (m, 2H) ppm.

Preparation H

4-nitrobentsyylipenisillanaatti

To a stirred solution of 2.14 g of penicillanic acid and 2.01 ml of ethyldiisopropylamine in 10 ml of N, N-dimethylformamide was added dropwise at about 20 ° C 2.36 g of 4-nitrobenzyl bromide. The mixture was stirred at room temperature overnight, then ethyl acetate and water were added. The layers were separated and the ethyl acetate layer was washed with water (pH 2.5) and water (pH 8.5). Ethyl acetate layer Dried over sodium sulfate and evaporated in vacuo to give 3.36 g of the title compound.

The NMR spectrum (CDCl 3) had absorbances: 1.45 (s, 3H), 1.68 (s, 3H), 3.32 (m, 2H), 4.50 (s, 1H), 5.23 ( m, 1H), 5.25 (s, 2H) and 7.85 (q, 4H) ppm.

Claims (3)

65003 40 An analogous process for the preparation of a therapeutically useful penicillanic acid 1,1-dioxide or its esters of formula I; J ------ n: COOR wherein R is hydrogen or an ester-forming, easily hydrolysable group in vivo, or for the preparation of these pharmaceutically acceptable salts, characterized in that a) a compound of formula JI, III or IV is oxidized; H 0: Sv * \ CHo I -...... f S · '6 S.,. CH 'γη I;' 3. 1 ..... N -...... 3! i 'CH. λ i N -.i 3 tOOR1 0 v Ri (id (ui) C00R HS \ CH3! I 'CH. - N - 1. 3 (IV) COOR1 where R · * "is hydrogen, ester-forming, easily hydrolysable in vivo a group or a conventional protecting group for a penicillin carboxy group, and optionally removing the protecting group for the carboxy group, or b) to prepare a compound of formula I wherein R is 3-phthalidyl or a group of formula X or XI R3 0 R3 0 i |! E. i | j C -COCR -COCOR 1 4 14 RR (X) (XI) 41 06003. 3 4 .. wherein R and R represent hydrogen or alkyl having 1 to 2 carbon atoms and R is alkyl having 1 to 6 carbon atoms, penicillanic acid The 1,1-dioxide salt is reacted with 3-phthalidyl chloride, 3-phthalidyl bromide, or a compound of formula XII and XIII R3 0 R3 0 f!] 5 (| 1 5 QCOCR QCOCOR 14. U R R (XII) (XIII) 3 4 5 wherein Q is chlorine or bromine or R, R and R are as defined above, in a reaction inert solvent at about room temperature, and if desired the resulting compound is converted into a pharmaceutically acceptable salt. Process according to Claim 1, characterized in that R and R 1 represent hydrogen. Process according to Claim 1 (b), characterized in that R is pivaloyloxymethyl. 42 66003