KR820000740B1 - Process for preaprign penicillanic acid 1,1-dioxides - Google Patents

Abstract

Title compds. I (R1 = H, ester forming residue, carboxyl protective group) were prepd. by the reaction of 1,1-dioxide penicillanate and 3-phthalidyl chloride or -bromide, 4-crotonolacton-4-yl chloride or -bromide, -butyrolacton-4-yl chloride or -bromide, compd. II, or III(R3,R4 = H, C1-2 alkyl; R5 = C1-6 alkyl) at 0o-100oC in an inactive solvent. Thus, a mixt. of glacial acetic acid, KMnO4, H2O, and sodium salt of penicillanic acid was stirred at 5oC for 20 min and sodium bi sulfite added until disappearance of KMnO4 color, which was filtrated and adjusted to pH 1.7, extracted, and dried to give I (yield 78%).

Description

Method for preparing penicsilane acid 1,1-dioxide

The present invention relates to peniclanic acid 1,1-dioxide of the following general formula (I) which is a β-lactamase inhibitor and a pharmaceutically toxic base addition salt thereof.

Wherein R ¹ is selected from hydrogen, ester forming moieties that can be readily hydrolyzed in vivo, and conventional penicillin carboxy protecting groups.

Ester-forming residues that can be easily hydrolyzed in vivo refer to non-toxic ester residues that are readily degraded in mammalian blood or tissues to release the corresponding organic acid (the compound of formula (I) wherein R ¹ is hydrogen).

Representative examples of readily hydrolyzable ester forming moieties that can be used for R ¹ include alkanoyl oxymethyl of 3 to 8 carbon atoms, 1- (alkanoyl oxy) ethyl of 4 to 9 carbon atoms, 1 to 5 to 10 carbon atoms. -Methyl-1- (alkanoyloxy) ethyl, alkoxycarbonyloxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (5 to 8 carbon atoms) Alkoxycarbonyloxy) ethyl, 3-phthalidyl, 4-crotonolactonyl and r-butyrolactone-4-yl and the like.

Compounds of formula (I) wherein R ¹ is hydrogen or an ester forming moiety that can be readily hydrolyzed in vivo are useful as antimicrobial agents and to enhance the antimicrobial activity of β-lactam antibiotics.

Compounds of formula (I) wherein R ¹ is a penicillin carboxy protecting group are useful as chemical intermediates of compounds of formula (I) wherein R ¹ is hydrogen or an ester forming moiety that can be readily hydrolyzed in vivo.

Representative carboxy protecting groups are benzyl and substituted benzyl such as 4-nitrobenzyl and the like.

Peniclanic acid 1,1-dioxide and its esters which can be easily hydrolyzed in vivo are useful as antibacterial agents and also to enhance the effect of β-lactam antibiotics on β-lactamase producing bacteria. Derivatives of peniclanic acid 1,1-dioxide having a carboxy group protected with conventional penicillin carboxy protective groups are effective as intermediates of peniclanic acid 1,1-dioxide. Peniclanic acid 1-oxide and its esters are effective chemical intermediates for peniclanic acid 1,1-dioxide and esters thereof.

One of the best known and widely used antimicrobials is the so-called β-lactam antibiotic. This compound is characterized by having a nucleus composed of a 2-azetidinone (β-lactam) ring fused to thiazolidine or dihydro-1,3-thiazine.

When the nucleus contains a thiazolidine ring, the compound is generally penicillin. On the other hand, when the nucleus contains the dihydrothiazine ring, the compound is cephalosporin. Representative penicillins commonly used in the clinic are benzylphenicillin (penicillin G), phenoxymethylphenicillin (phenylcillin V) ampicillin and carbenicillin. Representative examples of cephalosporins are cephalotin, cephalexin and cefazoline.

However, although β-lactam antibiotics are widely used as useful chemotherapeutic agents, there are drawbacks that are inert to certain microorganisms, depending on the compound. In most cases, microorganisms with special resistance to β-lactam antibiotics produce -lactamase. β-lactamase is an enzyme that breaks down the β-lactam ring of penicillin and cephalosporin into a product that has no antibacterial action. However, depending on the substance, it has the ability to inhibit β-lactamase. When the β-lactamase inhibitor is used in combination with penicillin or cephalosporin, it enhances the antibacterial effect of penicillin or cephalosporin against certain microorganisms.

The antimicrobial effect of the β-lactamase inhibitor and the β-lac-antibiotic combination is considerably stronger than the sum of the antimicrobial effects of individual components.

1,1-dioxide, phenoxymethylphenicillin and its esters of benzylphenicillin are described in US Pat. Nos. 3,197,466 and 3,536,698 and described in the following paper by Gouldal et al. (See Tetrahedron Letters, No. 9 381 (1962).) Harrison et al. Described various penicillin 1,1-dioxides and 1-oxides in the following references, including methylphthalimidophenicylanate 1,1- Dioxide, methyl 6,6-phenylsilanate 1,1-dioxide, methyl penicillate 1α-oxide, 6,6-bromophenicylanic acid 1β-oxide and 6,6-dibromo-phenicylanic acid 1β- Oxides and the like. Journal of the Chevical Society (Londen) Perkin I, 1772 (1976).

The present invention provides novel compounds of the general formula (I) and pharmaceutically toxic base addition salts thereof.

Wherein R 'is selected from hydrogen, ester forming moieties that can be readily hydrolyzed in vivo, and conventional penicillin carboxy protecting groups.

More particularly the present invention relates to the leaves of peniclanic acid 1,1-dioxide with 3-phthalidyl chloride, 3-phthalidyl bromide, 4-crotonolactone-4-yl chloride, 4-crotonolactone-4-yl -Bromide, r-butyrolactone-4-ylchloride, r-butyrolactone-4-yl bromide or a compound of formula (XII) or (XIII), characterized in that The present invention relates to a method for preparing a pharmaceutically active compound.

Wherein Q is chloro or bromo and R ² is selected from 3-phthalidyl, 4-crotonolactonyl, r-butyrolactone-4yl and the following general formulas (X) and (XI).

Wherein R ³ and R ⁴ are each hydrogen or alkyl having 1 to 2 carbon atoms and R ⁵ is alkyl having 1 to 6 carbon atoms.

The compounds of the following formulas (II) and (III) and salts thereof are useful as intermediates.

The compounds of formulas (II) and (III) are intermediates of compounds of formula (I) wherein R 'is hydrogen.

The present invention relates to novel compounds of general formulas (I), (II) and (III), which are derivatives of peniclanic acid represented by the following structural formula (IV).

In the Structural Formula (IV) mixture, the linkage of the substituent to this cyclic nucleus indicates that the substituent is below the plane of the bicyclic nucleus. This coordination is called α-coordination. In contrast, the straight line representation of a substituent attached to the bicyclic nucleus indicates that the substituent is on top of the plane of the nucleus. This coordination is called β-coordination.

Also given by reference is a derivative of cephalosporranic acid of formula (V).

Hydrogen at the C-6-position in formula (V) is located at the bottom of the plane of this annular nucleus. Desacetoxycephalosporonic acid and 3-desacetoxymethylcephalosporonic acid are represented by structural formulas (VI) and (VII), respectively.

4-crotono lactonyl and 6-butyrolactone-4-yl are represented by the formulas (VIII) and (IX), respectively.

The wavy line represents each of the two epimers or a mixture thereof.

When R ¹ in the compound of formula (I) is an ester forming residue that can be easily hydrolyzed in vivo, it is derived from an alcohol of general formula R ¹ -OH, and COOR ¹ in such a compound represents an ester group.

Moreover, when R ¹ is as such, COOR ¹ is readily degraded in vivo to release free carboxy groups (COOH). That is, when the compound of general formula (I) which is an ester-forming residue which R ¹ is easily hydrolyzed in vivo is exposed to the blood or tissue of a mammal, the general formula (I) compound which R ¹ is hydrogen is easily produced. R ¹ group is well known in the penicillin art. In most cases they enhance the absorption properties of penicillin compounds.

In addition, R ¹ should impart pharmaceutically toxic properties to the compound of formula (I) and have the property of releasing toxic toxic fractions when degraded in vivo.

As above, the R ¹ group is well known and is readily identified by penicillin majors. See German Publication 2,517,316. Typical groups of R ¹ are 3-phthalidyl, 4-crotonolactonyl, γ-butyrolactone-4-yl and the following general formulas (X) and (XI).

Wherein R ³ and R ⁴ are each selected from hydrogen and alkyl having 1 to 2 carbon atoms and R ⁵ is alkyl having 1 to 6 carbon atoms.

However, preferred groups of R ¹ are alkanoyl oxymethyl having 3 to 8 carbohydrates, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, and 1-methyl-1- (alkanoyloxy) ethyl having 5 to 10 carbon atoms. , Alkoxycarbonyloxymethyl having 3 to 6 carbon atoms 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (alkoxycarbonyloxy) ethyl having 5 to 8 carbon atoms, 3-phthalidyl , 4-crotonolactonyl and γ-butyrolactone-4-yl.

Formula (I) compounds wherein R ¹ is hydrogen can be prepared by oxidizing compounds of Formula (II) or (III).

Various known oxidizing agents for the oxidation of sulfoxides to sulfones are used and particularly convenient reagents are metal permanganates, ie alkali metal permanganates and alkaline earth metal permanganates, and organic peroxyacids, ie organoperoxy carboxylic acids. Specific reagents are sodium permanganate, potassium permanganate, 3-chloroperbenzoic acid and peracetic acid.

When the compound of formula (II) or (III) is oxidized to the corresponding compound of formula (I) using metal permanganate, about 0.5 to 5 molar equivalents of permanganate, in particular 1 The molar equivalents are reacted in a suitable solvent system. Suitable solvent systems do not adversely interact with the starting materials or products and water is usually used. If necessary, a cosolvent, tetrahydrofuran, which is miscible with water but does not react with permanganate can be added. The reaction is carried out in the range of -20 to 50 ° C, preferably 0 ° C.

At 0 ° C. the reaction is completed within one hour. The reaction can be carried out in neutral, basic or acidic conditions, but is preferably carried out under almost neutral conditions to avoid degradation of the β-lactam ring of the general formula (I) compound. In practice, it is advantageous to make the pH of the reaction solvent nearly neutral. The product is obtained by conventional techniques. Excess permanganate is usually broken down using sodium bisulfite and the product is separated from the solvent by filtration. It is extracted with organic solvent and removed by evaporation of the solvent to remove it from manganese oxide. In addition, if not separated from the solution at the end of the reaction of the product is separated by the usual process of solvent extraction.

When the compound of formula (II) or (III) is oxidized to the corresponding compound of formula (I) using an organic peroxy acid, ie peroxycarboxylic acid, the reaction usually results in about 1 compound of formula (II) or (III). To 4 molar equivalents, preferably 1.2 equivalents of oxidant in an inert reaction organic solvent. Representative solvents are chlorinated hydrocarbons such as dichloromethane, chloromethane, chloroform and 1,2-dichloroethane, ethers such as diethylether, tetrahydrofuran and 1,2-dimethoxyethane. The reaction is usually carried out at about -20 ° C to about 50 ° C, preferably about 25 ° C. A reaction time of about 2 to about 16 hours at about 23 ° C. is commonly used. The product is separated by evaporation of the solvent under vacuum. The product is purified by conventional methods known in the art.

It is advantageous to have a manganese salt catalyst such as manganese acetyl acetonate when the compound of formula (II) or (III) is oxidized to the compound of formula (I) using organic peroxy acid.

The compound of formula (I) wherein R ¹ is hydrogen can be obtained by removing the protecting group R ¹ from the compound of formula (I) wherein R ¹ is a penicillin carboxyprotecting group. Wherein R ¹ is a carboxyprotective group commonly used in the penicillin field to protect the carboxy group at the 3-position. The carboxy protection group is not critical. The requirements of the carboxy protection group R ¹ are as follows.

(i) be stable when oxidizing the compound of formula (II) or (III)

(ii) be able to be removed from the compound of formula (I) under conditions in which the β-lactam is not damaged. Representative examples used include tetrahydropyranyl groups, benzyl groups, substituted benzyl groups (eg 4-nitrobenzyl), benzylhydryl groups, 2,2,2-trichloroethyl groups, t-butyl groups and phenacyl Group. [See, US Pat. Nos. 3,632,850 and 3,197,466, UK Pat. No. 1041,985 Woodward et al. , Journal of the American Chemical Society, 88,852 (1966); Chauvette, Journal of Organic Chemistry, 36, 1259 (1971); Sheehan et al., Journal of Organic Chemistry, 29, 2006 (1964); and “Cephalosporin and Penicillins, Chemistry and Biology” edited by H. E. Flynn, Academic Press, Inc., 1972].

Penicillin carboxy protection groups are typically removed in consideration of the instability of the β-lactam ring system. Likewise, a compound of formula (I) wherein R ¹ is hydrogen is prepared by oxidizing the following general compound.

In this case, the same method as for oxidizing the compound of formula (II) or (III) is carried out.

Formula (I) compounds wherein R ¹ is an ester forming moiety that can be readily hydrolyzed in vivo can be prepared directly by esterifying compounds of Formula (I) wherein X is hydrogen. The particular method chosen will depend upon the structure of the ester forming moiety but an appropriate method can be readily selected by one skilled in the art.

A group of general formulas (X) and (XI) wherein R ¹ is 3-phthalidyl, 4-chloronolactonyl, γ-butyrolactone-4-yl and R ³ , R ⁴ and R ⁵ are as described above When selected from these, they may be selected from compounds of formula (I) wherein R ¹ is hydrogen, 3-phthalidyl halide, 4-chloronotactonyl halide, γ-butyrolactone-4-yl halide or formula (XII) and ( XIII) can be prepared by alkylation with a compound.

Wherein Q is halo and R ³ , R ⁴ and R ⁵ are as described above. "Halide" and "halo" refer to chlorine, bromine and derivatives of iodine. The reaction is carried out by dissolving a salt of the compound of formula (I) wherein R ¹ is hydrogen in an appropriate polar organic solvent, N, N-dimethylformamide, and then adding about 1 molar equivalent of halide. When the reaction is complete the product is separated by standard methods.

At this time, the reaction solvent is diluted with excess water, the product is extracted with a water immiscible organic solvent, and the solution is evaporated to recover the product. Commonly used salts of starting materials are alkali metal salts such as sodium and potassium salts and tertiary amine salts such as triethylamine, N-ethylpiperidine, N, N-dimethylaniline and N-methylmorpholine salts. The reaction is carried out at 0 ° to 100 ° C, usually about 25 ° C. The time taken to complete the reaction depends on several factors: the concentration of the reactants and the degree of reactivity. Thus, iodide in halo compounds reacts more rapidly than bromide, which reacts faster than chloride. In practice, it is sometimes advantageous to add up to 1 molar equivalent of alkali metal iodide when using chloro compounds. This has the effect of promoting the reaction. Considering all the above factors, the reaction time is usually about 1 to 24 hours.

Peniclanic acid 1α-oxide, which is a general formula (II) compound, is prepared by debromination of 6,6-dibromophenicsilane 1α-oxide. The debromination reaction is carried out by conventional hydrolysis. Thus, a solution of 6,6-dibromophenicylanic acid 1α-oxide is shaken in the presence of a catalytic amount of palladium on calcium carbonate under a hydrogen stream or under a hydrogen stream combined with an inert diluent such as nitrogen or argon. Suitable solvents for the debromination reaction include lower alkanols such as methanol ether, ie tetrahydrofuran and dioxane; Lower esters such as ethyl acetate and butyl acetate; water; And mixtures thereof. However, it is common to select conditions under which the dibromo compound can be dissolved. Hydrolysis is usually carried out at room temperature and under atmospheric pressure or about 50 psi pressure. A large amount of catalyst may be used but is present in a weight percentage of 10% to the same amount as the dibro compound for the dibromo compound. The reaction is usually obtained by filtering the compound of general formula (II) after removing the solvent in vacuo after 1 hour.

6,6-dibromophenicylanic acid 1-α-oxide is prepared by oxidizing 6,6-dibromophenicylanic acid to 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran at 0 to 25 ° C. for about 1 hour. Harrison et al., Journal of the Chemical Society (London) Perkin I 1772 (1976).

6,6-Dibromophenic silane acid is prepared by the method of Clayton in the following reference.

See Journal of Chemical Society (London), (c) 2123 (1969).

Peniclanic acid 1β-oxide, which is a general formula (III) compound, is prepared by oxidizing peniclanic acid. Thus, peniclanic acid is prepared by treating with 1 molar equivalent of 3-chloroperbenzoic acid in an inert solvent at 0 ° C for 1 hour. Solvents used here are chlorinated hydrocarbons such as chloroform and chloromethane, ethers such as dimethyl ether and tetrahydrofuran and lower esters such as ethyl acetate and butyl acetate. The product is obtained by conventional methods.

Peniclanic acid is prepared by the method described in British Patent No. 1,072,108.

Formulas (I), (II) and (III), wherein R ¹ is hydrogen, form salts with acidic and basic reagents. Such salts may be prepared by conventional techniques, if desired, with contact of the acidic and basic components, usually in a 1: 1 molar ratio, in aqueous, non-aqueous or partially aqueous media. They are recovered by filtration, precipitation with non-solvent, and filtration to evaporate the solvent or, if necessary, to lyophilize if necessary. Basic reagents used for salt formation are organic and inorganic, and include ammonia organoamine alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides and also alkali metal hydroxides, carbonates, hydrides and alkoxides. Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine and octylamine, secondary amines such as diethylamine, morpholine, pyrroli Dine and piperidine, tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4,3,0] non-5-ene, hydroxy 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 higher fatty acids such as sodium 2-ethylhexanoate.

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

As described above, the general formula (I) compound wherein R ¹ is hydrogen or an ester-forming moiety in vivo is a common antimicrobial agent. In vivo activity of a compound of formula (I) wherein R ¹ is hydrogen can be known by measuring the minimum inhibitory concentration (MIC'S) (mcg / ml) for various microorganisms. The subsequent process is performed using a brain heart injection agar (BHI) and the inoculation replicating apparatus with reference to: See International Collaborative Study on Antibiotic Senisi-tivity Testing (Ericcson and Sherris, Acta, Pathologicaet Microbiologia Scandinav, Supp. 217, Sections A and B: 1-90 [1970].

Overnight grown tubs are diluted 100-fold for use as standard inoculum. (20,000 to 10,000 cells in 0.002 ml are placed on the agar surface. 20 ml BHI agar / dish). A 12 × 2 dilution of the test compound is used and the initial concentration of the test drug is 200 mcg / ml. Single colonies are discarded when folate is read after 18 hours at 37 ° C. The sensitivity of the test microorganism (MIC) is recognized as the lowest concentration of compound that can completely inhibit growth upon visual observation. The MIC values of peniclanic acid 1,1-dioxide for various microorganisms are shown in Table I below.

TABLE I

Formula (I) compounds wherein R ¹ is hydrogen or an ester forming moiety hydrolyzable in vivo, act as antibacterial agents in vivo. When measuring this action, acute experimental infection is produced by inoculating mice intraperitoneally with a culture cultured in a standard culture by suspending the mice in 5% of gastric mucin. The extent of infection is normalized by mice inoculating 1-10 times the LD ₁₀₀ dose of microorganisms. (LD ₁₀₀ : minimum inoculation of microorganisms required to kill 100% of infected and untreated control mice) The test compound is administered to infected mice using several doses. At the end of the test the activity of the compound is assessed by counting the number of survivors in the treated animals and expressing the activity of the compound as a percentage of surviving animals.

In vivo antimicrobial activity of compounds of formula (I) wherein R ¹ is hydrogen is effective as an industrial antimicrobial agent for topical application as water treatment, mucus control, color preservation and wood preservation or preservative. When using this compound for topical application, the active ingredient is conveniently used in admixture with nontoxic carriers such as vegetable oils or mineral oils or emollient creams. Similarly it is dissolved or dispersed in liquid diluents such as water, alkanols, glycols or mixtures thereof. In most cases it is appropriate to use a concentration of 0.1 to 1 percent (weight) of the active ingredient.

The in vivo action of the compound of formula (I), wherein R ¹ is hydrogen or a hydrolyzable ester forming moiety, is suitable for controlling bacterial infection in mammals upon oral or parenteral administration. The compounds are used for the control of infections caused by bacteria susceptible to the human body, such as Neisseria gonorrhoeae.

When the compound of formula (I) or a salt thereof is used for therapeutic treatment in a mammal, in particular a human body, the compound may be administered alone or mixed with a pharmaceutically toxic carrier or diluent. They are administered orally or parenterally, i.e. subcutaneously, intramuscularly or intraperitoneally. The carrier or diluent is selected according to the intended dosage form. For example, when administered orally, the antimicrobial penam compound of the present invention is used in tablets, capsules, lozenge troches, powders, syrups, elixirs, aqueous solutions and suspensions. The ratio of the active ingredient to the carrier depends on the chemical property solubility, stability and dose of the active ingredient. However, pharmaceutical compositions containing an antimicrobial agent of formula (I) contain 20% to 95% active ingredient.

Carriers commonly used in oral tablets include salts of lactose, sodium, citrate and phosphoric acid.

Disintegrants such as starch and lubricants such as magnesium stearate, sodium lauryl sulfate and talc are commonly used in tablets. Useful diluents in oral capsules are lactose and polymer polyethylene glycols.

When orally administered an aqueous suspension, the active ingredient is mixed with emulsifiers and suspending agents. If necessary, sweetening and / or fragrances are added. In the case of parenteral administration for intramuscular injection, intraperitoneal injection, subcutaneous injection, sterile solutions of the active ingredient are generally prepared, and the pH of the solution is appropriately adjusted to be a buffer solution. When used intravenously, the total concentration of the solute is prepared by isotonicity.

As mentioned above, the antimicrobial agents of the present invention are effective in the human body for susceptible organisms. The prescriber will determine the appropriate dose for a particular person, depending on the age and weight of the individual patient and on the nature and triangle of the patient's condition.

The compound of the present invention orally administers about 10 to 200 mg / kg body weight per day and parenteral administration uses about 10 to 400 mg / kg body weight per day. This figure is illustrative only and in some cases may be used beyond this limit.

However, as described above, compounds of formula (I) wherein R ¹ is hydrogen or an ester-forming moiety that is hydrolysable in vivo are potent inhibitors of β-lactamase and are effective against many microorganisms, in particular those producing β-lactamase. Enhances the antimicrobial effects of β-lactam antibiotics (penicillins and cephalosporins).

How the compound of Formula (I) enhances the effect of β-lactam antibiotics can be seen by reference to experiments measuring MIC of antibiotics alone and of Formula (I) alone. These MIC's are compared with the MIC values obtained when the antibiotic and the compound of formula (I) are mixed. When the antimicrobial efficacy of the combination is significantly greater than the combined efficacy of the individual compounds, this is considered to be an enhancement of action. The MIC value of the composite is measured by the method of the following reference.

Barry and Sabath in “Manual of Clinical Microbiology”, edited by Lenette Spaulding and Truant, 2nd edition, 1974, American Society for Microbiology

The results of experiments showing that peniclanic acid 1,1-dioxide enhances the effects of ampicillin are reported in Table II. Table II shows the 19-ampicillin-resistant strain of Staphylococcus aureus, with MICs of ampicillin and peniclanic acid 1,1-dioxide being 200 mcg / ml, respectively. However, the MIC's of ampicillin and peniclanic acid 1,1-dioxide were 1.56 and 3.12 mcg / ml, respectively. Considered at different angles, this indicates that ampicillin alone has a MIC of 200 mcg / ml for 19 strains of Staphylococcus aureus, whereas MIC is 1.56 mcg when 3.12 mcg / ml of penicilanic acid 1,1-dioxide is present. decreases to / ml.

Others in Table II show the enhancement of the antimicrobial effect of ampicillin against 26 ampicillin resistant strains to Haemophilus influenzae and 18 ampicillin resistant strains to Klebsiella pneumoniae and 15 strains of basic Bacteroides prazilis.

Tables III, IV and V show benzyl-penicillin (penicillin G) carbenicillin (α-carboxybenzyl penicillin) and cefazolin's aureus, H. enfluenza, K pneumoniae and bacteroides pragillis strains. It shows the improvement of antimicrobial effect against.

TABLE II

TABLE III

TABLE IV

TABLE V

Formula (I), wherein R ¹ is hydrogen or an ester forming moiety that can be readily degraded in vivo, enhances the antimicrobial activity of β-lactam antibiotics in vivo. That is, the dose of antibiotics required to protect mice against lethal inoculation of β-lactamase producing bacteria is reduced.

The ability of β-lactam antibiotics to enhance the effect of β-lactam antibiotics on β-lactamase-producing bacteria of the compound of formula (I), wherein R ¹ is hydrogen or an ester-forming residue hydrolyzable in vivo, has been found to be β- in the treatment of mammals, especially humans. It is valuable when co-administered with lactam antibiotics. In the treatment of bacterial infections, the general formula (I) compound is mixed with β-lactam antibiotics and the two agents are administered simultaneously. In addition, the compound of formula (I) may be administered as a separate agent during treatment with β-lactam antibiotics. In some cases, it may be advantageous to pre-administer the compound of formula (I) before initiation of treatment with β-lactam antibiotics.

When peniclanic acid 1,1-dioxide or its esters are used to enhance the effect of β-lactam antibiotics, they are administered in the form of standard pharmaceutical carriers or diluents. The previously mentioned method for the use of peniclanic acid 1,1-dioxide or its esters as an antimicrobial agent can be used when co-administering with other β-lactam antibiotics. Pharmaceutically toxic carriers, pharmaceutical compositions consisting of β-lactam antibiotics and peniclanic acid 1,1-dioxide or esters thereof will contain from 5 to 80% (by weight) of pharmaceutically toxic carriers.

When using peniclanic acid 1,1-dioxide or esters thereof in admixture with other β-lactam antibiotics, sulfone is administered orally or parenterally, such as intramuscular, subcutaneous or intraperitoneal injection. Although the prescriber determines the dose to be used for humans, the ratio of one dose of penicilanic acid 1,1-dioxide or its esters to β-lactam antibiotics is usually 1: 3 to 3: 1.

Additionally, when peniclanic acid 1,1-dioxide or its esters are mixed with other β-lactam antibiotics, the daily oral dose of each component is about 10 to 200 mg / kg body weight and the daily parenteral dose is kg About 10 to 400 mg per sugar. This number is just an explanation and can be out of this range when necessary.

Representative β-lactam antibiotics co-administered with peniclanic acid 1,1-dioxide and its hydrolyzable esters in vivo are as follows:

6- (2-phenylacetamido) phenicylic acid,

6- (2-phenoxyacetamido) phenic silane,

6- (2-phenylpropionamido) phenic carboxylic acid,

6- (D-2-amino-2-phenylacetamido) phenic carboxylic acid,

6- (D-2-amino-2- [4-hydroxyphenyl] acetamido peniclanic acid,

6- (D-2-amino-2- [1,4-cyclohexadienyl] acetamido peniclanic acid,

6- (1-aminocyclohexanecarboxamido) phenicylic acid,

6- (2-carboxy-2-phenylacetamido) phenic carboxylic acid,

6- (2-carboxy-2- [3-diphenyl] acetamido) phenic carboxylic acid,

6- (D-2- [4-ethylpiperazine-2,3-dione-1-carboxamido] -2-phenylacetamido) phenylanic acid,

6- (D-2- [4-hydroxy-1,5-naphthyridine-3-carboxamido] -2-phenylacetamido) -phenylanic acid,

6- (D-2-sulfo-2-phenylacetamido) phenoxysilane,

6- (D-2-sulfoamino-2-phenylacetoamido) phenylanic acid,

6- (D- [2-imidazolidin-2-one-1-carboxamido] -2-phenylacetamido) phenylanic acid,

6- (D- [3-methylsulfonylimidazolidin-2-one-1-carboxamido] -2-phenylacetamido) -peniclanic acid,

6-([hexahydro-1H-azin-1-yl] methyleneamino) phenicylic acid,

Acetoxymethyl 6- (2-phenylacetamido) penicylanate,

Acetoxymethyl 6- (D-2-amino-2-phenylacetamido) pheniclanate,

Acetoxymethyl 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) phenylanate,

Pivaloyloxymethyl 6- (2-phenylacetamido) pheniclanate,

Pivaloyloxymethyl 6- (D-2-amino-2-phenylacetamido) -penicylanate,

Pivaloyloxymethyl 6- (D-2-amino-2- [4-hydroxyphenyl) acetamido) penicylanate,

1- (ethoxycarbonyloxy) ethyl 6- (2-phenylacetamido) pheniclanate,

1- (ethoxycarbonyloxy) ethyl 6- (D-2-amino-2-phenylacetamido) -phenisalanate,

1- (ethoxycarbonyloxy) ethyl 6- (D-2-amino-2-4-hydroxy phenyl acetamido) -penicylanate,

3-phthalidyl 6- (2-phenylacetamido) penicylanate,

3-phthalidyl 6- (D-2-amino-2-phenylacetamido) phenylanate,

3-phthalidyl 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) phenylanate,

6- (2-phenoxycarbonyl-2-phenylacetamido) phenic carboxylic acid,

6- (2-tolyloxycarbonyl-2-phenylacetamido) phenoxysilane,

6- (2- [5-indanyloxycarbonyl] -2-phenylacetamido) phenoxysilane,

6- (2-phenoxycarbonyl-2- [3-thienyl] acetamido) phenic carboxylic acid,

6- (2-tolyloxy-2- [3-thienyl] acetamido) phenylanic acid,

6- (2- [5-indanyloxycarbonyl) -2- [3-thienyl] acetamido) phenylanic acid,

6- (2,2-dimethyl-5-oxo-4-phenyl-1-imidazolidinyl) phenoxysilane,

7- (2- [2-thienyl] acetamido) cephalosporic acid,

7- (2- [1-tetrazolyl] acetamido-3- (2- [5-methyl-1,3,4-thiadiazolyl] thiomethyl) -3-desacetoxymethyl cephalosporonic acid ,

7- (D-2-amino-2-phenylacetamido) desacetoxy cephalosporonic acid,

7-α-methoxy-7- (2- [2-thienyl] acetamido) -3-carbamoyloxymethyl-3-desacetoxymethylcephalosporanic acid,

7- (2-cyanoacetamido) cephalosporic acid,

7- (D-2-hydroxy-2-phenyl acetamido) -3- (5- [1-methyltetrazolyl] thiomethyl) -3-desacetoxymethylcephalosporanic acid,

7- (2- [4-pyridylthio] acetamido) cephalosporanic acid,

7- (D-2-amino-2- [1,4-cyclohexadinyl] acetamido) -cephalosporonic acid,

7- (D-2-amino-2-phenylacetamido) cephalosporonic acid and its pharmaceutically harmless salts.

The β-lactam compounds described above are effective when administered orally or parenterally, while others are only effective when administered parenterally. Peniclanic acid 1,1-dioxide or its hydrolyzable esters in vivo will require parenteral suitable formulations when used simultaneously with β-lactam antibiotics that are effective only for parenteral administration.

Penicsilane acid 1,1-dioxide or esters thereof may be prepared in combination with a β-lactam antibiotic effective for oral or parenteral use simultaneously with a preparation suitable for oral or parenteral administration.

In addition, it is possible to orally administer a preparation of peniclanic acid 1,1-dioxide or an ester thereof and at the same time parenteral administration of other β-lactam antibiotics. Once administered, other β-lactam antibiotics may be administered orally.

The following examples are provided for illustrative purposes only.

Infrared (IR) spectra are measured as potassium bromide (KBr) disks or nujol mulls and the absorption bands are reported in number of wavelengths (cm ⁻¹ ). Nuclear magnetic resonance spectra (N MR) were measured at 60 MHz in a solution of dutrochloroform (CDCl ₃ ), perdutrodimethyl sulfoxide (DMSO-d ₆ ) or deuterium oxide (D ₂ O) and the peak position was tetramethyl It is expressed in ppm which appears from silane or sodium 2,2-dimethyl-2-silapentin-2-sulfonate. Use the following abbreviations for the peak form:

s: single line, d: double line, t: triplet, q: quadruple, m: multiplet.

Example 1

[Phenylanic Acid 1,1-Dioxide]

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 cooled to about 5 ° C. to a solution of 4.58 g (21 mmol) of sodium salt of penicilanic acid (about 5 ° C.) in 50 ml of water. Add. The mixture is stirred at about 5 ° C. for 20 minutes and then the cooling bath is removed. Solid sodium bisulfite is added until the color of potassium permanganate disappears and the mixture is filtered. To the aqueous filtrate add ½ volume of saturated sodium chloride solution and adjust the pH to 1.7.

The acidic solution is extracted with ethyl acetate. The extract is evaporated to dryness in vacuo to give 3.47 g of the title compound. The aqueous mother liquor is saturated with sodium chloride and further extracted with ethyl acetate. The ethyl acetate solution is evaporated to dryness in vacuo to afford 0.28 g of the title compound. The overall yield is therefore 3.75 g (78% yield).

NMR spectrum (DMSO-d ₆ ) of the product showed absorption at the following values.

1.40 (s, 3H), 1.50 (s, 3H), 3.13 (dofd's, 1H, J ₁ = 16Hz, J ₂ = 2Hz), 3.63 (dof d's, 1H, J ₁ = 16Hz, J ₂ = 4 Hz), 4.22 (s, 1 H) and 5.03 (dof's, 1 H, J ₁ = 4 Hz, J ₂ = 2 Hz) ppm.

Example 2

[Pivaloyloxymethyl peniclanate 1,1-dioxide]

0.215 g (2.50 mmol) of diisopropylethylamine is added to 0.615 g (2.41 mmol) of peniclanic acid 1,1-dioxide in 2 ml of N, N-dimethylformamide followed by 0.365 ml of chloromethyl pivalate. do. The reaction mixture is stirred for 24 hours at room temperature and diluted with ethyl acetate and water. The ethyl acetate layer is separated and washed three times with water and once with saturated solution of sodium chloride. The ethyl acetate solution is dried using anhydrous sodium sulfate and evaporated in vacuo to give 0.700 g of the title product as a solid. Melting point 103-104 캜

The NMR spectrum (CDCl ₃ ) of the product showed absorption at the following values.

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 3

The process of Example 2 is repeated using equimolar amounts of acetoxy methyl chloride, propionyloxymethyl chloride and hexanoyloxymethyl chloride instead of pivalo oxymethyl chloride to give the following respectively.

Acetoxymethyl penicillate 1,1-dioxide, propionyl oxymethyl penicillate 1,1-dioxide and hexanoyloxymethyl penicillate 1,1-dioxide.

Example 4

[3-phthalidyl penny silanate 1,1-dioxide]

To a solution of 5 ml of N, N-dimethylformamide containing 0.783 g (3.36 mmol) of peniclanic acid 1,1-dioxide was added 0.47 ml of triethylamine followed by 0.715 g of 3-bromophthalide. do. The reaction mixture is stirred at room temperature for 2 hours and diluted with ethyl acetate and water. The pH of the aqueous phase is raised to 7.0 and the layers are separated. The ethyl acetate layer is washed successively with water and sodium chloride bleach and dried using sodium sulfate. The ethyl acetate solution is evaporated in vacuo to afford the title compound as a white bubble.

NMR spectrum (CDCl ₃ ) showed absorption at the following values.

1.47 (s, 6H), 3.43 (m, 1H), 4.45 (s, 1H), 4.62 (m, 1H), 7.40 and 7.47 (2s, 1H) and 7.73 (m, 4H), ppm

This process is repeated using 4-bromocrotononolactone and 4-bromo-γ-butyrolactone instead of 3-bromophthalide to give the following respectively.

4-crotonolactonyl penicilanate 1,1-dioxide, γ-butyrolactone-4-yl penicilanate.

Example 5

[1- (Ethoxycarbonyloxy) ethyl peniclanate 1,1-dioxide]

A mixture of 0.654 g phenylsilane acid 1,1-dioxide, 0.42 ml triethylamine, 0.412 g 1-chloroethyl ethylcarbonate 0.300 g sodium bromide and 3 ml N, N-dimethylformamide was added at room temperature. Stir for days. Then dilute with ethyl acetate and water and adjust the pH to 8.5. The ethyl acetate layer is separated, washed three times with water, once with saturated sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated off in vacuo to yield 0.309 g of the title product as an oil.

The product is mixed with about the same amount of similar material. The combined products are dissolved in chloroform and 1 ml pyridine is added. The mixture is stirred overnight at room temperature and the chloroform is then evaporated off in vacuo. The residue is partitioned between ethyl acetate and water at pH8. Separately dried ethyl acetate was evaporated in vacuo to yield 150 mg of the title product (yield about 7%). IR spectra of the product show absorption at 1805 and 1763 cm ⁻¹ .

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 6

Using the same amount of 1-chloro alkyl alkylcarbonate, 1- (alkanoyloxy) ethyl chloride or 1-methyl-1- (alkanoyloxy) ethyl chloride instead of 1-chloro ethyl ethylcarbonate, the following compounds were prepared according to Example 5 Create

Methoxycarbonyloxymethyl peniclanate 1,1-dioxide,

Ethoxycarbonyloxymethyl peniclanate 1,1-dioxide,

Isobutoxycarbonyloxymethyl peniclanate 1,1-dioxide,

1- (methoxycarbonyloxy) ethyl peniclanate 1,1-dioxide,

1- (butoxycarbonyloxy) ethyl peniclanate 1,1-dioxide,

1- (acetoxy) ethyl penicillate 1,1-dioxide,

1- (butyryloxy) ethyl penicillate 1,1-dioxide,

1- (pivaloyloxy) ethyl penicillate 1,1-dioxide,

1- (hexanoyloxy) ethyl peniclanate 1,1-dioxide,

1-methyl-1- (acetoxy) ethyl penicilanate 1,1-dioxide and

1-methyl-1- (isobutyryloxy) ethyl penicilanate 1,1-dioxide.

Example 7

Sodium Penicillate 1,1-Dioxide

To a stirred solution of 32.75 g (0.14 mole) of peniclanic acid 1,1-dioxide in 450 ml of ethyl acetate is added a solution of 25.7 g of sodium 2-ethylhexanoate (0.155 mole) in 200 ml of ethyl acetate. The resulting solution is stirred for 1 hour and further 10% excess sodium 2-ethyl hexanoate in a small amount of ethyl acetate is added. The product precipitates immediately. Stirring is continued for 30 minutes and the precipitate is filtered off. It is washed successively with ethyl acetate, 1: 1 ethyl acetate-ether and ether. The solid is dried at about 0.1 mm Hg of phosphorus pentoxide for 25 hours at 25 ° C. to obtain 36.8 g of the title sodium salt contaminated with a small amount of ethyl acetate. The ethyl acetate content is reduced by heating to 100 ° C. for 3 hours in vacuo. The absorption bands of the IR Spectrum (KBr) disc of the final product are 1786 and 1608 cm ⁻¹ .

NMR spectrum (D ₂ O) showed absorption at the following values:

1.48 (s, 3H), 1.62 (s, 3H), 3.35 (d of d's, 1H, J ₁ = 16 Hz, J = 2 Hz), 3.70 (d of d's, 1H, J ₁ = 16 Hz), J ₂ = 4 Hz), 4.25 (s, 1 H) and 5.03 (d of d's, 1 H, J ₁ = 4 hz J = 2 Hz).

The title sodium salt is prepared using acetone instead of ethyl acetate.

Example 8

[Phenylanic Acid 1,1-Dioxide]

To a mixture of 7600 ml of water and 289 ml of glacial acetic acid is added 379.5 g of potassium permanganate in small portions. The mixture is stirred for 15 minutes and then cooled to 0 ° C. To this was added a mixture of 270 g of peniclanic acid 260 ml of 4N sodium hydroxide and a mixture cooled to 8 ° C. prepared from 2400 ml of water pH 7.2 with stirring. The temperature rises to 15 ° C. when the mixture is added. The temperature of the resulting mixture is lowered to 5 ° C. and stirring continued for 30 minutes. To the reaction mixture is added 142.1 g of sodium bisulfite in small portions for 10 minutes. The mixture is stirred at 10 ° C. for 10 minutes and 100 g of supercell (diatomaceous earth) are added. After stirring for another 5 minutes, the mixture is filtered. 4.0 L of ethyl acetate is added to the filtrate and the pH of the aqueous phase is lowered to 1.55 with 6N hydrochloric acid. Recover the ethyl acetate layer and combine with ethyl acetate extract. The combined organic layers are washed with water, dried over MgSO ₄ and evaporated in vacuo. The slurry thus obtained is stirred with 700 ml of ether at 10 ° C. for 20 minutes and the solids are collected by filtration. This gives 82.6 g (26% yield) of the siege compound. Melting point 154 to 155.5 ° C. (decomposition)

Example 9

[1-Methyl-1- (acetoxy) ethyl penicillate 1,1-dioxide]

1.9 ml of ethyldiisopropylamine is added to 2.33 g of peniclanic acid 1,1-dioxide in 5 ml of N, N-dimethyl formamide followed by about 1.37 g of 1-methyl-1- (acetoxy) ethyl chloride. Add dropwise at 20 ° C. The mixture is stirred overnight at ambient temperature and the mixture is diluted with ethylacetate and water. The layers are separated and the ethyl acetate layer is washed with water at pH9. The ethyl acetate solution is dried over sodium sulfate and evaporated in vacuo to yield 1.65 g of crude product as an oil. When the oil is left in the refrigerator it solidifies and recrystallizes from a mixture of chloroform and ether to give a material having a melting point of 90 to 92 ° C.

NMR spectrum (CDCl ₃ ) of the crude product showed absorption at the following values.

1.5 (s, 3H), 1.62 (s, 3H), 1.85 (s, 3H), 1.93 (s, 3H), 2.07 (s, 3H), 3.43 (m, 2H), 4.3 (s, 1H) and 4.57 (m, 1H) ppm

Example 10

The process of Example was repeated using 1-methyl-1- (alkanoyloxy) ethyl chloride instead of 1-methyl-1- (acetoxy) ethyl chloride to obtain the following compounds, respectively.

1-methyl-1- (propionyloxy) ethyl penicillate 1,1-dioxide,

1-methyl-1- (pivaloyloxy) ethyl penicilanate 1,1-dioxide and 1-methyl-1- (hexanoyloxy) ethyl peniclanic acid 1,1-dioxide,

Claims (1)

Salts of peniclanic acid 1,1-dioxide were substituted with 3-phthalidyl chloride, 3-phthalidyl bromide, 4-crotonolactone-4-yl chloride, 4-crotonolactone-4-yl bromide, γ-buty Rolactone-4-yl chloride, r-butyrolactone-4-yl bromide, or a compound of the following general formula (XII) or (XIII) in an inert solvent at a temperature of 0 to 100 ° C. To prepare a compound of ′).

Wherein Q is chloro or bromo and R ⁷ is selected from 3-phthalidyl, 4-crotonolactonyl, r-butyrolactone-4-yl and the following general formulas (X) and (XI).

Wherein R ³ and R ⁴ are each hydrogen or alkyl having 1 to 2 carbon atoms and R ⁵ is alkyl having 1 to 6 carbon atoms.