KR810002025B1 - Process for preparing penicillanic acid 1,1-dioxides - Google Patents

Abstract

Penicillanic acid 1,1-dioxides(I; R6 = H, ester group) were prepd. by oxidation of compd.(II; R1 = H, ester group, penicillin carboxylic protecting group), (III) or (IV). Thus, Na penicillanate was oxidized by KMnO4 in HOAc to give 78% compd. (I). The esters were obtained either by esterifying I (R = H) or by oxidizing the penicillanic acid esters. Compd. (I) potentiate the bactericidal activity of penicillins and cephalosporins. Thus, Staphylococcus aureus strains for which both ampicillin and I have min. inhibitory concns. of 200μg/ml are inhivited by a mixt. of 1.56μg/ml ampicillin with 3.12μg/ml I(R = H).

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.

Where

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

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

-부티로락톤-4-일 등이 있다.Representative examples of readily hydrolyzable ester forming moieties that can be used for R ¹ are alkanoyloxy methyl having 3 to 8 carbon atoms, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1 having 5 to 10 carbon atoms. -Methyl-1- (alkanoyloxy) ethyl, alkoxycarbonyl oxymethyl having 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4 to 7 carbon atoms, 1-methyl-1- (5 to 8 carbon atoms) Alkoxy carbonyloxy) ethyl, 3-phthalidyl, 4-crotonolacthonyl and

Butyrolactone-4-yl.

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-nitro benzyl and the like.

Peniclanic acid 1,1-dioxide and its esters which can be readily hydrolyzed in vivo are useful as antimicrobial 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 a conventional penicillin carboxy protecting group are effective as intermediates of peniclanic acid 1,1-dioxide.

Penicsilane 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 antibiotics. This compound is characterized by having a nucleus composed of a 2-azetidinone (β-lactam) ring fused to a thiazolidine or dihydro-1,3-thiazine ring.

The compound is generally penicillin when the nucleus contains a thiazolidine ring, while the compound is cephalosporin when the nucleus contains a dihydrothiazine ring. Representative penicillins commonly used in the clinic are benzyl penicillin (penicillin G), phenoxymethylpenicillin (penicillin 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 β-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-lactam antibiotic combination is much 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 by Guddal et al. In the following essay. 9 381 (1962).

Harrison et al. Described various penicillin 1,1-dioxides and 1-oxides in the following references, including methyl phthalimido penicillate 1,1-dioxide, methyl 6,6-dibromophenicylanate 1,1-dioxide, methyl penicilanate 1α-oxide, methyl penicilanate 1β-oxide, 6,6-dibromophenicylanic acid 1α-oxide and 6,6-dibromo-phenicylanic acid 1β-oxide Et al., Journal of the chemical Society (London) Perkin I, 1772 (1976).

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

Where

R ¹ 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 is characterized in that by oxidizing a compound of formula (II), (IIa) or (III) and then removing the carboxy protecting group if necessary, a pharmaceutically active compound of formula (Ia) It also relates to methods of preparing pharmaceutically harmless salts.

In the above formula,

R ⁶ is hydrogen or an ester moiety that can be readily hydrolyzed in vivo,

R ¹ is hydrogen, an esterogenic moiety that can be readily hydrolyzed in vivo or a conventional penicillin carboxy protecting group.

The present invention further relates to novel compounds of the following general formulas (II) and (III) and salts thereof.

In the above formula,

R ¹ is as described above.

The general formulas (II) and (III) are intermediates of the general formula (I) compounds.

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

In the compound of formula (IV), the linkage of the substituent to the annular nucleus indicates that the substituent is at the subplanar side of the annular nucleus. This coordination is called α-coordination.

In contrast, the linear representation of a substituent attached to this annular 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 position C-6 in the formula (V) is located at the bottom of the plane of the annular liquid. Desacetoxy cephalosporonic acid and 3-des acetoxymethyl cephalosporonic acid are represented by structural formulas (VI) and (iii), respectively.

4-crotono lactonyl and γ-butyrolactone-4-yl are represented by structural formulas (VII) 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 readily decomposes in vivo to release free carboxy groups (COOH).

That is, when the compound of formula (I), an ester-forming moiety, in which R ¹ is easily hydrolyzed in vivo, is exposed to the blood or tissue of a mammal, the compound of formula (I) in which R ¹ is hydrogen is readily 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).

In the above formula,

R ³ and R ⁴ are each selected from hydrogen and alkyl having 1 to 2 carbon atoms,

R ⁵ is alkyl having 1 to 6 carbon atoms.

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

When R ¹ is as described above, the general formula (I) compound may be prepared by oxidizing the general formula (II) or (III) compound.

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

When R ¹ oxidizes a compound of formula (II) or (III) as described above to the corresponding compound of formula (I) using a metal permanganate, the compound of formula (II) or (III) 0.5 to 5 molar equivalents, in particular 1 molar equivalent, 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 under 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. Indeed, 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 the solvent is removed by evaporation to separate it from manganese dioxide. In addition, the product is not separated from the solution at the end of the reaction but by the usual procedure of solvent extraction.

When R ¹ oxidizes a compound of formula (II) or (III) as described above to the corresponding compound of formula (I) using organic peroxy acid, ie peroxycarboxylic acid, the reaction is usually of formula (II) or (III) The compound is carried out by reacting about 1 to 4 molar equivalents, preferably 1.2 equivalents of oxidizing agent in an inert organic solvent.

Representative solvents are chlorinated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ethers such as diethylether, tetrahydrofuran and 1,2-dimethoxyethane.

The reaction is usually carried out at about -20 ° to about 50 ° C, preferably at about 25 ° C.

A reaction time of about 2 to about 16 hours at about 25 ° C. is commonly used. The product is separated by evaporating off the solvent in vacuo. The product is purified by conventional methods known in the art.

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

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

(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), benzyl hydryl groups, 2,2,2-trichloroethyl groups, t-butyl groups and phenacyl US Patent Nos. 3,632,850 and 3,197,466 UK Patent No. 1,051,985 Woodward et al, Journal of the Amercian Chemical Society, 88,852 (1966); Chauvette, Journal of Organic Chemistry, 36, 1259 (1971) Sheehan et al. Journal of Organic Chemistry 29, 2006 (1964) and published by phaCephalosporin and Penicillins, Chemistry and Biology ＂H, E. Flynn, Academic Press, Inc., 1972] Are considered and are typically removed.

Similarly, the compound of formula (I) wherein R ¹ is as described above is prepared by oxidizing the following compound of formula.

Wherein R ¹ is as described above.

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

Formula (I) compounds wherein R ¹ is an ester forming residue 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 esterifying moiety but an appropriate method can be readily selected by one skilled in the art. A group of formulas (X) and (XI) wherein R ¹ is 3-phthalidyl, 4-crotonolactonyl, 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-crotonolactonyl halide, γ-butyrolactone-4-yl halide or general formula (XII) and It can be prepared by alkylating with (XIII) compound.

Wherein Q is halo and R ³ , R ⁴ and R ⁵ are as described above. “Hhalides” and “halogens” refer to derivatives of chlorine, bromine and iodine.

The reaction is carried out by dissolving a salt of the compound of formula (I) wherein R ¹ is hydrogen in a suitable 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 the 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, in halo compounds, iodide reacts more rapidly than bromide, which reacts more quickly 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 response time is usually about 1 to 24 hours.

Peniclanic acid 1α-oxide, a general formula (II) compound wherein R ¹ is hydrogen, is prepared by debromination of 6,6-dibromophenicylanic acid 1α-oxide. The debromination reaction is carried out by conventional hydrogenolysis. 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 in a hydrogen stream mixed with an inert diluent such as nitrogen or argon. Suitable solvents for the debromination reaction include lower alkanols such as methanol; Ethers 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. Hydrogen decomposition is at room temperature and atmospheric pressure to about 50p. s. i Usually performed under pressure.

Catalysts may be used in large quantities but are present in amounts up to 10% by weight relative to the dibromo compound relative to the dibromo compound. The reaction is usually obtained by filtering the compound of general formula (II), wherein R ¹ is hydrogen, usually after 1 hour, by removing the solvent in vacuo.

6,6-Dibromophenicylanic acid 1α-oxide is prepared by oxidizing 6,6-dibromo peniclanic acid to 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran for about 1 hour at 0 to 25 [deg.] C. See 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 the Chemical Society (London), (c) 2123 (1969).

Peniclanic acid 1β-oxide, which is a general formula (III) compound wherein R ¹ is hydrogen, 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. The solvent used here is chlorinated hydrocarbons such as chloroform and dichloromethane; 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.

-부티로락톤-4-일 및 R³, R⁴및 R⁵가 전술한 바와 같은 일반식(X) 및 (XI) 그룹중에서 선택된 경우 이들은 R¹이 수소인 일반식(II) 또는 (Ⅲ) 화합물을 3-프탈리딜 할라이드, 4-크로로노락토닐 할라이드, γ-부티로락톤-4-일 할라이드 또는 일반식(XII) 또는 (XⅢ)화합물로 알킬화시켜 제조할 수 있다. 반응은 페니실란산, 1,1-디옥사이드를 3-프탈리딜 할라이드, 4-크로로락토닐 할라이드, γ-부티로락톤-4-일 할라이드 또는 일반식(XII) 또는 (XIII)으로 에스테르화 시키는 전술한 바와 같은 동일한 방법으로 수행시킨다.R ¹ in vivo can be hydrolyzed in the general formula (II) an ester-forming residues readily from and (Ⅲ) compounds R ¹ is hydrogen in the general formula (II) or (Ⅲ) directly by esterification reaction from the compound Are manufactured. R ¹ is 3-phthalidyl, 4-chloroonolactonyl,

When butyrolactone-4-yl and R ³ , R ⁴ and R ⁵ are selected from the groups of the general formulas (X) and (XI) as described above, they are of the general formula (II) or (III) wherein R ¹ is hydrogen; The compounds may be prepared by alkylation with 3-phthalidyl halides, 4-chloroonolactonyl halides, γ-butyrolactone-4-yl halides or with general formula (XII) or (XIII) compounds. The reaction esterifies peniclanic acid, 1,1-dioxide with 3-phthalidyl halide, 4- chlorolactonyl halide, γ-butyrolactone-4-yl halide or general formula (XII) or (XIII) Is carried out in the same manner as described above.

In addition, the general formula (II) compound wherein R ¹ is an ester forming residue that can be easily hydrolyzed in vivo is prepared by oxidizing a suitable ester of 6,6-dibromo peniclanic acid followed by debromination. Esters of 6,6-dibromo peniclanic acid are prepared from 6,6-dibromophenicylanic acid by standard methods. Oxidation is carried out by oxidation of 6,6-dibromo peniclanic acid to 6,6-dibromo peniclanic acid 1α-oxide using 1 molar equivalent of 3-chloroperbenzoic acid, and debromination reaction. Is carried out in the manner described above for the debromination reaction of 6,6-dibromo peniclanic acid 1α-oxide.

Similarly, general formula (III) compounds, in which R ¹ is an ester forming moiety that can be readily hydrolyzed in vivo, are prepared by oxidizing the appropriate ester of peniclanic acid. The latter compound is prepared by esterifying peniclanic acid using standard methods.

Oxidation is oxidized as one molar equivalent of 3-chloroperbenzoic acid, which is carried out by the aforementioned method of oxidizing peniclanic acid to peniclanic acid 1β-oxide.

Formula (II) compounds, wherein R ¹ is a carboxy protective group, can be obtained in one of two ways. They are obtained simply by attaching a carboxy protecting group to peniclanic acid 1α-oxide.

It is also obtained as follows: (a) attaching a carboxy protecting group to 6,6-dibromophenic silane acid and (b) protecting the 6,6-dibromophenic carboxylic acid in 1 molar equivalent of 3-chloroperbenzoic acid. Is used to oxidize to protected 6,6-dibromophenicylanic acid 1a-oxide and (c) debrominated by hydrogenolysis of the protected 6,6-dibromophenicylanic acid 1α-oxide.

The general formula (III) compound wherein R ¹ is a carboxy protecting group is obtained simply by attaching a protecting group to peniclanic acid 1β-oxide. They are also obtained as follows.

(a) attach a carboxy protection group to the peniclanic acid,

(b) Protected peniclanic acid is oxidized as described above using 1 molar equivalent of 3-chloroperbenzoic acid.

Formulas (I), (II) and (III), wherein R ¹ is hydrogen, form salts with acidic and basic reagents. Such salts fall within the scope of the present invention. Such salts can be prepared by conventional techniques, if desired, with contact of the acidic and basic components in an aqueous, nonaqueous or partially aqueous medium, usually in a 1: 1 molar ratio.

They are recovered by filtration, precipitation with non-solvent, and filtration to evaporate the solvent or, if necessary, to freeze-dry. Basic reagents used for salt formation include both organic and inorganic and include ammonia, organic amines, alkali metal hydroxides, carbonate bicarbonates, hydrides and alkoxides and also alkaline earth 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 diethyl amine, morpholine pyrrolidine and piperidine; Tertiary amines such as triethylamine, N-ethylpiperidine, N-methylmorpholine and 1,5-diazabicyclo [4. 3. 0] non-5-ene, hydroxides such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; Alkoxides such as sodium ethoxide and potassium ethoxide; Hydrides such as calcium and sodium esters; Carbonates such as potassium carbonate and sodium carbonate; Noncarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal salts of higher fatty acids such as sodium 2-ethyl hexanoate.

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 esterifying moiety hydrolyzable 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 carried out using a brain heart infusion agar (BHI) and inoculation replicating with reference to: See International Collaborative Study on Antibiotic Sensitivity Testing (Ericcson and Sherris, Acta. Pathologica et Microbiologia Scandinav, Supp. 217, Sections A and B: 1-90 [1970]),

The overnight grown tubes 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 plates are 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 1 below.

TABLE 1

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 suspending mice in 5% pig gastricmucin and intraperitoneally inoculating mice with standard culture. The extent of infection is normalized so that mice get 1 to 10 times the LD100 dose of the microorganism. (LD100: Minimal 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 untested, 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 general formula (I) compounds 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 the compound is used topically, 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 diluents such as water, alkanols, glycols or mixtures thereof. In most cases it is appropriate to use a concentration of 0.1 to 10 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, for example Neisseria gonorrhoneae.

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. Carriers or diluents are selected according to the intended dosage form. For example, when administered orally, the antimicrobial penam compounds of the present invention are used in tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solutions and suspensions. The ratio of the active ingredient to the carrier depends on the chemical nature, solubility and stability and dose of the active ingredient. However, pharmaceutical compositions containing an antibacterial agent of formula (I) contain 20 to 95% of the 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 capsules for oral administration are lactose and polymer polyethylene glycols. When orally administered an aqueous suspension, the active ingredient is mixed with emulsifiers and suspending agents. If necessary, sweeteners and / or fragrances are added. For parenteral administration such as intramuscular injection, intraperitoneal injection, subcutaneous injection and intravenous injection, a sterile solution of the active ingredient is 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 prescribing physician determines the appropriate dosage for a particular person, which depends on the age and weight of the individual patient and on the nature and severity of the patient's condition. The compound of the present invention orally administers about 10 to 200 mg / kg of body weight per day, and parenteral administration uses about 10 to 400 mg / kg of 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 hydrolyzable in vivo are potent inhibitors of β-lactamase and are β for many microorganisms, particularly those that produce β-lactamase. Enhances the antimicrobial effects of lactam antibiotics (penicillins and cephalosporins). How the compound of Formula (I) enhances the effect of β-lactam antibiotics can be found by referring to the experiments measuring the MIC of the antibiotic alone and the compound of Formula (I) alone. These MIC'S are compared with the MIC value obtained when mixing antibiotic and compound of general formula (I). 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 the action. Combination MIC values are determined 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 2. Table 2 shows the 19 ampicillin-resistant strains of Staphylococcus aureus. The MIC of ampicillin and peniclanic acid 1,1-dioxide is 200 mcg / ml, respectively.

However, the MIC'S of ampicillin and peniclanic acid 1,1-dioxide is 1.56 and 3.12 mcg / ml, respectively. Ampicillin alone had a MIC of 200 mcg / ml for 19 strains of Staphylococcus aureus, while MIC was 1.56 mcg / ml when 3.212 mcg / ml of penicilanic acid 1,1-dioxide was present at different angles. reduced to ml.

Others in Table 2 show the enhancement of the antimicrobial effect of Ampicillin against 18 Ampicillin-resistant strains of C. cineupsis pneumoniae against Haemophilus influenza and 18 strains of Anaerobic Bacteroides prazilis. Tables 3, 4 and 5 show benzyl-penicillin (penicillin G) carbenicillin (α-carboxybenzyl penicillin) and cepazolin s aureus, h. Influenza K pneumoniae and Bacteroides pragilis strains show the enhancement of antimicrobial efficacy.

TABLE 2

TABLE 3

TABLE 4

TABLE 5

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 shown 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 starting treatment with the β-lactam antibiotic.

When peniclanic acid 1,1-dioxide or an ester thereof is used to enhance the effect of β-lactam antibiotics, it is administered in a formulation with a standard pharmaceutical carrier or diluent. The methods mentioned above for the use of peniclanic acid 1,1-dioxide or its esters as antibacterial agents can be used when co-administration 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 prescribing physician determines the dose to be used for humans, the ratio of the daily dose of peniclanic acid 1,1-dioxide or its esters and β-lactam antibiotics is usually 1: 3 to 3: 1. Furthermore, 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 penicylanic 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-amino-2-phenylacetamido) phenicylic acid,

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

6- (D-2-amino-2- [1,4-cyclohexadienyl] acetamido) phenoxysilane,

6- (1-aminocyclohexane carboxamido) phenicylic acid,

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

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

6- (D-2- [4-ethylpiperazin-2,3-dione 1-carboxamido] -2-phenyl acetamido) phenicylic acid.

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

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

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

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

6- (D- [3-methylsulfonylamidazolidin-2-one-1-carboxamido] -2-phenyl acetamido) -peniclanic acid,

6-([hexahydro-1H-azin-1-yl] methyleneamido) phenylanic acid, acetoxymethyl 6- (2-phenylacetamido) phenicilamate, acetoxymethyl 6- (D-2 -Amino-2-phenylacetamido) penicylanate,

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

Pivaloyloxymethylphenyl 6- (2-acetamido) phenylenate,

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) -penicylanate,

1- (ethoxycarbonyloxy) ethyl 6- (D-2-amino-2- [4-hydroxyphenyl] acetamido) -phenimalanate,

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] acet amido) phenicylic acid,

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

6- (2- [5-indanyloxycarbonyl] -2- [3-thienyl] acetamido) peniclanic 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-desacetoxymethyl cephalosporonic acid,

7- (2-cyanoacetamido) cephalosporic acid,

7- (D-2-hydroxy-2-phenylacetamido) -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 compound described above is effective when administered orally or parenterally, while the other is effective only when administered parenterally. Peniclanic acid 1,1-dioxide or its hydrolyzable esters in vivo requires a parenterally suitable complex formulation when used simultaneously with β-lactam antibiotics that are only effective for parenteral administration.

When peniclanic acid 1,1-dioxide or its esters are to be used in combination with β-lactam antibiotics effective for oral or parenteral use, co-formulations suitable for oral or parenteral administration can be prepared.

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. Oral administration and 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 recorded in number of wavelengths (cm ⁻¹ ). Nuclear magnetic resonance spectra (NMR) were measured at 60 MHz in a solution of deutero chloroform (CDCl ₃ ), pidutrodimethyl sulfoxide (DMSO-d ₆ ) or tuterium oxide (D ₂ O) and the peak position was tetramethylsilane Or ppm, which appears from sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The following abbreviations are used for the peak form.

S, singlet; d, doublet; t, triplet; f, quadruple; m, polyline,

Example 1

Peniclanic 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 peniclanate (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 passed through. To the aqueous filtrate add 1/2 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 afford 3.47 g of the title compound. The aqueous mother liquor is saturated with sodium chloride and further extracted with ethyl acetate. Ethyl acetate solution was evaporated to dryness in vacuo to afford 0.28 g of the title compound. The overall yield is therefore 3.75 g (78% yield). The NMR spectrum (DMSO-D ₆ ) of the product showed absorption at the following values.

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

Example 2

Benzyl penicilanate 1,1-dioxide

(24밀리몰)의 벤질 페니실라네이트를 75ml의 에탄올이 없는 클로로포름에 용해시켜 여기에 빙욕에서 질소기류하 4.78

의 85%의 순수한 3-클로로-과벤조산을 수분 간격으로 두번에 가한다. 빙욕에서 30분간 진탕을 계속하고 빙욕을 치우고 45분간 진탕한다. 반응 혼합물을 수용성 알칼리(pH8.5)로 세척하고 이어서 포화 염화나트륨으로 세척하고 진공에서 증발 건조시켜 7.05g의 잔류물을 얻는다. 이 잔류물은 벤질 페니실라네이트 1-디옥사이드와 벤질 페니실라네이트 1,1-디옥사이드 5.5 : 1의 혼합물이다.6.85

(24 mmol) benzyl penicillate was dissolved in 75 ml of ethanol-free chloroform, which was added to a nitrogen stream of 4.78 in an ice bath.

85% of pure 3-chloro-perbenzoic acid is added twice at intervals of minutes. Continue shaking for 30 minutes in the ice bath, remove the ice bath and shake for 45 minutes. The reaction mixture is washed with water soluble alkali (pH 8.5) followed by saturated sodium chloride and evaporated to dryness in vacuo to give 7.05 g of residue. This residue is a mixture of benzyl penicylanate 1-dioxide and benzyl penicylanate 1,1-dioxide 5.5: 1.

To a solution of 4.85 g of 5.5: 1 sulfoxide-sulfone mixture was stirred and dissolved in 50 ml of ethanol free chloroform, 3.2 g of 85% pure 3-chloroperbenzoic acid was added at room temperature under a nitrogen stream. The reaction mixture is shaken for 2.5 hours and diluted with ethyl acetate. The resulting reaction is added to water at pH 8.0 and the layers are separated. The organic phase is washed with water at pH 8.0 and then with saturated sodium chloride and dried using sodium sulfate. Evaporation of the solvent in vacuo affords 3.59 g of the title compound. NMR spectrum (CDCl ₃ ) of the product showed absorption at the following values.

1.28 (S, 3H), 1.58 (S, 3H), 3.42 (m, 2H), 4.37 (S, 1H), 4.55 (m, 1H), 5.18 (F, 2H, J = 12 Hz) and 7.35 (S, 5H) ppm.

Example 3

Peniclanic Acid 1,1-Dioxide

To a stirring solution of 8.27 g of benzyl penicillate 1,1-dioxide in a mixture of 40 ml of methanol and 10 ml of ethyl acetate is added 10 ml of water followed by the slow addition of 12 g of palladium on 5% calcium carbonate. The mixture is shaken for 40 minutes under 52p.s.i. under a hydrogen atmosphere and then filtered through a supersalm. The filter cake is washed with methanol, aqueous methanol solution, and the filtrate is added to the filtrate. The solution is collected and evaporated in vacuo to remove most of the organic solution and the residue is partitioned between ethyl acetate and water at pH 2.8. The ethyl acetate layer is removed and the aqueous phase is further extracted with ethyl acetate. Collect ethyl acetate solution, wash with saturated sodium chloride solution, dry using sodium sulfate and evaporate in vacuo. The residue is slurried in a 1: 2 mixture of ethyl acetate-ether to give 2.37 g of the title product. (Melting point 148-151 ° C.) The ethyl acetate-ether mixture is evaporated to yield 2.17 g of product.

Example 4

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 over 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 (in 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 5

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

A mixture of 0.654 g of peniclanic acid 1,1-dioxide, 0.42 ml of triethylamine, 0.412 g of 1-chloroethyl ethylcarbonate, 0.300 g of sodium bromide and 3 ml of 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 and once with saturated sodium chloride and dried over anhydrous sodium sulfate. Ethyl acetate is evaporated off in vacuo to yield 0.390 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 afford 150 mg of the title product (yield about 7%). The IR spectra of the product show absorption at 1805 and 1763 cm ⁻¹ . Spectrum (CDCl ₃ ) shows absorption at the following values. 1.43 (m, 12H), 3.47 (m, 2H), 3.9 (f, 2H, J = 7.5 Hz), 4.37 (m, 1H), 4.63 (m, 1H) and 8.77 (m, 1H) ppm.

Example 6

Benzyl penicillates, respectively, using equimolar amounts of benzylbromide and 4-nitrobenzyl bromide instead of chloromethyl pivalate. 1,1-dioxide and 4-nitro-benzylphenicylanate 1,1-dioxide are obtained.

Example 7

Peniclanic Acid 1α-oxide

To 1.4 g of pre-soaked 5% calcium carbonate on 50 ml of water is added 1.39 g of benzyl 6,6-dibromophenicylanate 1α-oxide solution in 50 ml of tetrahydrofuran. The mixture had a hydrogen pressure of about 45p. s. shake at i and 25 ° C. for 1 hour and filter it. The filtrate is evaporated in vacuo to remove most of the tetrahydrofuran and the aqueous phase is extracted with ether. The ether extract is evaporated in vacuo to yield 0.5 g of material, which is mainly benzyl penicillate 1α-oxide.

The benzyl penicillate 1R-oxide is again mixed with 2.0 g of benzyl 6,6-dibromophenicylanate 1α-oxide and dissolved in 50 ml of tetrahydrofuran. The solution was added to palladium on 4.0 g of 5% calcium carbonate in 50 ml of water and the resulting mixture was brought about 45 p. s. Shake overnight at i and 25 ° C. The mixture is filtered and the filtrate is extracted with ether. The extract is evaporated in vacuo and the residue is purified by elution of chloroform on silica gel. 0.5 g of material is obtained.

The latter material is 28 ° C., about 45p. In si, soak for 2 hours with 0.50 g of palladium on 5% calcium carbonate in water-methanol (1: 1). In this case 0.50 g of 5% palladium on calcium carbonate was further added and 45p. s. i, the immersion reaction is continued at 25 ℃. The reaction mixture is filtered and extracted with ether to discard the extract. The residual aqueous phase is adjusted to pH1.5 and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulfate and evaporated in vacuo to yield 0.14 g of peniclanic acid 1α-oxide. NMR spectrum (CDCl ₃ ), DMSO-d ₆ showed absorption at the following values. The absorption bands in the IR spectrum (KBr disc) of 1.4 (S, 3H), 1.64 (S, 3H), 3.60 (m, 2H), 4.3 (S, 1H), and 4.54 (m, 1H) ppm products were 1795 and 1745 cm ^- appeared in one.

Example 8

Peniclanic Acid 1α-oxide

To 30 g of 1.0 g of pre-soaked 5% potassium carbonate on potassium carbonate is added a solution of 1.0 g of 6,6-dibromophenicylanic acid 1α-oxide.

The mixture was brought about 45 p under hydrogen atmosphere. s. In i., shake at 25 ° C. for 1 hour. The reaction mixture is filtered and the filtrate is concentrated in vacuo to remove methanol. The residue in the aqueous phase is diluted with an equal amount of water, adjusted to pH 7 and washed with ether. The aqueous phase is acidified to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried over sodium sulphate and evaporated in vacuo to give peniclanic acid 1α-oxide.

Example 9

Peniclanic Acid 1β-Oxide

2.58 g of 85% pure 3-chloroperbenzoic acid is added to a stirred solution of 2.65 g (12.7 mmol) of peniclanic acid in chloroform. After 1 hour the reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is dissolved in a small amount of chloroform. The solution is concentrated slowly until precipitation begins to form. At this point evaporation is stopped and the mixture is diluted with ether. The precipitate is filtered off, washed with ether and dried to yield 0.615 g of peniclanic acid 1β-oxide (melting point 140-143 ° C.). The absorption bands of the IR spectrum (CDCl ₃ solution) of the product are 1775 and 1720 cm ⁻¹ .

NMR spectrum (CDCl ₃ / DM SO-d ₆ ) showed absorption at the following values. 1.35 (s, 3H), 1.76 (s, 3H), 3.36 (m, 2H), 4.50 (s, 1H) and 5.05 (m, 1H) ppm.

NMR spectra showed that the product was about 90% pure.

The chloroform-ether mother liquor can be tested to see that it contains peniclanic acid 1β-oxide and some penicilanic acid 1α-oxide.

Example 10

Peniclanic acid 1α-oxide or penicilanic acid 1β-oxide are esterified with alkanoyloxy chloride according to Example 4 to obtain the following compounds, respectively.

Acetoxymethyl phenylsilanate 1α-cyoxide,

Propionyloxymethyl phenylsilanate 1α-oxide,

Pivaloyloxymethyl phenylsilanate 1α-oxide,

Acetoxymethyl peniclanate 1β-oxide,

Propionyloxymethyl peniclanate 1β-oxide,

Pivaloyloxymethyl peniclanate 1β-oxide,

Example 11

Penicillic acid 1α-oxide or penicilanic acid 1β-oxide is reacted with 3-bromophthalide, 4-bromocrotonolactone or 4-bromo-γ-butyrolactone to obtain the following compounds, respectively.

3-phthalidyl penicilanate 1α-oxide,

4-crotonolactonyl peniclanate 1α-oxide,

3-phthalidyl penicillate 1β-oxide,

4-crotonolactonyl penicilanate 1β-oxide, and

γ-butyrolactone-4-yl peniclanate 1β-oxide.

Example 12

Peniclanic acid 1α-oxide or penicilanic acid 1β-oxide is reacted with 1-chloroalkyl carbonate or 1- (alkanoyloxy) ethyl chloride according to Example 5 to obtain the following compounds, respectively.

1- (ethoxycarbonyloxy) ethyl peniclanate 1α-oxide,

Methoxycarbonyloxymethyl peniclanate 1α-oxide,

Ethoxycarbonyloxymethyl peniclanate 1α-oxide,

Isobutoxycarbonyloxymethyl peniclanate 1α-oxide,

1- (methoxycarbonyloxy) ethyl penicillate 1α-oxide,

1- (butoxycarbonyloxy) ethyl peniclanate 1α-oxide,

1- (acetoxy) ethyl penicillate 1α-oxide,

1- (butyryloxy) ethyl penicillate 1α-oxide,

1- (pivaloyloxy) ethyl penicillate 1α-oxide,

1- (ethoxycarbonyloxy) ethyl peniclanate 1β-oxide,

Methoxycarbonyloxymethyl peniclanate 1β-oxide,

Ethoxycarbonyloxymethyl peniclanate 1β-oxide,

Isobutoxycarbonyloxymethyl peniclanate 1β-oxide,

1- (methoxycarbonyloxy) ethyl peniclanate 1β-oxide,

1- (butoxycarbonyloxy) ethyl peniclanate 1β-oxide,

1- (acetoxy) ethyl penicillate 1β-oxide,

1- (butyryloxy) ethyl penicillate 1β-oxide, and

1- (pivaloyloxy) ethyl peniclanate 1β-oxide.

Example 13

Peniclanic acid 1α-oxide and peniclanic acid 1β-oxide are reacted with benzyl bromide according to Example 4 to obtain benzyl penicillate 1α-oxide and benzyl penicillate 1β-oxide, respectively.

Similarly, peniclanic acid 1α-oxide and penicilanic acid 1β-oxide were reacted with 4-nitrobenzyl bromide according to Example 4 to give 4-nitrobenzyl penicilanate 1α-oxide and 4-nitrobenzyl penicilanate 1β- Oxides are obtained respectively.

Example 14

Peniclanic Acid 1,1-Dioxide

To 1.17 g (10 mmol) of 3-chloroperbenzoic acid at about 0 ° C. is added to 2.17 g (10 mmol) of peniclanic acid 1α-oxide in 30 ml of ethanol-free chloroform. The mixture is stirred at about 0 ° C. for 1 hour and again at 25 ° C. for 24 hours. The filtered reaction mixture is evaporated in vacuo to give peniclanic acid 1,1-dioxide.

Example 15

Instead of peniclanic acid 1α-oxide, the method of 14 is repeated using the following.

Peniclanic acid 1β-oxide,

Acetoxymethyl penicilanate 1α-oxide,

Propionyloxymethyl peniclanate 1α-oxide,

Fibaroioxymethyl peniclanate 1α-oxide,

Acetoxymethyl peniclanate 1β-oxide,

Propionyloxymethyl peniclanate 1β-oxide,

Fibaroyloxymethyl peniclanate 1β-oxide,

3-phthalidyl penicilanate 1α-oxide,

3-phthalidyl penicillate 1β-oxide,

1- (ethoxycarbonyloxy) ethyl peniclanate 1α-oxide,

Methoxycarbonyloxymethyl peniclanate 1α-oxide,

Ethoxycarbonyloxymethyl peniclanate 1α-oxide,

Isobutoxycarbonyloxymethyl peniclanate 1α-oxide,

1- (methoxycarbonyloxy) ethyl penicillate 1α-oxide,

1- (butoxycarbonyloxy) ethyl peniclanate 1α-oxide,

1- (acetoxy) ethyl penicillate 1α-oxide,

1- (butyryloxy) ethyl penicillate 1α-oxide, and

1- (pivaloyloxy) ethyl peniclanate 1α-oxide.

1- (ethoxycarbonyloxy) ethyl peniclanate 1β-oxide,

Methoxycarbonyloxymethyl peniclanate 1β-oxide,

Ethoxycarbonyloxymethyl peniclanate 1β-oxide,

Isobutoxycarbonyloxymethyl peniclanate 1β-oxide,

1- (methoxycarbonyloxy) ethyl peniclanate 1β-oxide,

1- (butoxycarbonyloxy) ethyl peniclanate 1β-oxide,

1- (acetoxy) ethyl penicillate 1β-oxide,

1- (butyryloxy) ethyl penicillate 1β-oxide

1- (Pivaroyloxy) ethyl penicillate 1β-oxide.

This provides each of the following compounds.

Peniclanic acid 1,1-dioxide,

Acetoxymethyl penicilanate 1,1-dioxide,

Propionyloxymethyl peniclanate 1,1-dioxide,

Pivaloioxymethyl peniclanate 1,1-dioxide,

Acetoxymethyl penicilanate 1,1-dioxide,

Propionyloxymethyl peniclanate 1,1-dioxide,

Fibaroyloxymethyl peniclanate 1,1-dioxide

3-phthalidyl penicillate 1,1-dioxide,

3-phthalidyl penicillate 1,1-dioxide,

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

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- (Pivaroyloxy) ethyl penicillate 1,1-dioxide.

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

Methoxycarbonyloxymethyl peniclanate 1,2-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- (fibaroyloxy) ethyl penicillate 1,1-dioxide,

Example 16

Benzyl penicylanate-1α-oxide and benzyl penicilanate 1β-oxide are oxidized with 3-chloroperbenzoic acid according to Example 14 to obtain benzyl penicilanate 1,1-dioxide in each case.

Similarly, 4-nitrobenzyl penicillate 1α-oxide and 4-nitrobenzyl penicilanate 1β-oxide were oxidized according to Example 14 with 3-chloroperbenzoic acid to form 4-nitrobenzyl penicillate 1,1-dioxide. Get

Example 17

Peniclanic Acid 1,1-Dioxide

4-nitrobenzyl penicilanate 1,1-dioxide was hydrolyzed according to Example 3 to obtain penicilanic acid 1,1-dioxide.

Example 18

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 mmHg of phosphorus pentoxide for 25 ° C. for 16 hours to give 36.8 g of the titled 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 disk) 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 = 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 = 2 Hz) ppm.

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

Example 19

Peniclanic 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 2400 ml of water (pH 7.2) cooled to 8 ° C. 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 again for 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 title compound. Melting point 154 to 155.5 ° C. (decomposition)

Example 20

Pivaloyloxymethyl peniclanate 1,1-dioxide

A solution of 1.25 g of pivaloyloxymethyl penicillate in 40 ml of chloroform is cooled to −15 ° C. and 0.8 g of 3-chloroperbenzoic acid is added thereto. The mixture is stirred at about −15 ° C. for 20 minutes and the temperature is raised to room temperature. The resulting solution contains both 1α- and 1β-oxides by NMR analysis.

Concentrate the chloroform solution to approximately 20 ml and add 0.8 g of 3-chloroperbenzoic acid. The mixture is stirred overnight at room temperature and the solvent is evaporated off in vacuo. The residue is redissolved in about 4 ml of dichloromethane and 0.4 g of 3-chloroperbenzoic acid is added. The mixture is stirred for 3 hours and the solvent is evaporated off in vacuo. The residue is partitioned between ethyl acetate and water at pH 6.0 and sodium bisulfite is added until the peroxide is free. The pH of the aqueous phase is raised to 8.0 and the layers are separated. The organic layer is washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in ether and reprecipitated by adding hexanes.

The resulting solid is recrystallized from ether to afford 0.357 g of the title compound.

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

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 21

3-phthalidyl penicillate 1,1-dioxide

To a solution of 713 mg of 3-phthalidyl penicillate in 3 ml of chloroform is added 0.430 g of 3-chloroperbenzoic acid at about 10 ° C.

The mixture is stirred for 30 minutes and again 0.513 g of 3-chloroperbenzoic acid is added. The mixture is stirred at rt for 4 h and the solvent is evaporated off in vacuo. The residue is decomposed between ethyl acetate and water at pH 6.0 and sodium bisulfite is added to decompose the residual peracid. The pH of the aqueous phase is adjusted to 8.8. The layers are separated and the organic phase is evaporated in vacuo. The title compound is then obtained in the form of bubbles.

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

1.62 (m, 6H), 3.3 (m, 2H), 4.52 (p, 1H), 5.23 (m, 1H) and 7.63 (m, 5H) ppm.

Example 22

2,2,2-trichloroethyl menislanate 1,1-dioxide

To 100 mg of 2,2,2-trichloroethyl penicillate in a small amount of chloroform is added 50 mg of 3-chloroperbenzoic acid and the mixture is stirred for 30 minutes. Testing of the reaction product showed that most of these were sulfoxides. The absorption band of (NMR spectrum (CDCl ₃ )) is as follows.

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.

100 mg of 3-chloroperbenzoic acid is further added and the mixture is stirred overnight. The solvent is evaporated off in vacuo and the residue is partitioned between ethyl acetate and water at pH6.0. Sufficient sodium bisulfite is added to break down excess peracid and raise the pH to 8.5. The organic phase is separated, washed with brine and dried. Evaporation in vacuo afforded 65 mg of the title product. The absorption band of the MR spectrum (CDCl ₃ ) is as follows.

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 23

4-nitrobenzyl penicilanate 1,1-dioxide

The solution of 4-nitrobenzyl penicilanate in chloroform is cooled to about 15 ° C. and 1 equivalent of 3-chloroperbenzoic acid is added.

The reaction mixture is stirred for 20 minutes. The reaction mixture is then tested with hex resonance spectrospoke to show that it contains 4-nitrobenzyl penicillate 1-oxide. Further, 1 equivalent of 3-chloroperbenzoic acid is added, and the reaction mixture is stirred for 4 hours.

At this time, 1 equivalent of 3-chloroperbenzoic acid is added and the reaction mixture is stirred overnight. The solvent is evaporated off and the residue is partitioned between ethyl acetate and water at pH8.5. The ethyl acetate layer is separated, washed with water and evaporated to dryness to afford crude product. The crude product is eluted with a 1: 4 mixture of ethyl acetate / chloroform and purified by chromatography on silica gel.

The absorption band of the NMR spectrum (CDCl ₃ ) of the product is as follows.

1.35 (S, 3H), 1.58 (S, 3H), 3.35 (m, 2H), 4.42 (S, 1H), 4.58 (m, 1H), 5.30 (S, 2H) and 7.83 (q, 4H) ppm.

Example 24

Peniclanic Acid 1,1-Dioxide

0.54 g of 10% palladium on carbon is added to 0.54 g of 4-nitrobenzyl penicillate 1,1-dioxide in 30 ml of methanol and 10 ml of ethyl acetate. 50p of the mixture. s. i. Under pressure hydrogen stream, shake until the end of hydrogen introduction. The residue is partitioned between ethyl acetate and water at pH8.5 and the water layer is removed. Fresh ethyl acetate is added and the pH adjusted to 1.5. The ethyl acetate layer is recovered, washed with water, dried and evaporated in vacuo. 0.168 g of the title compound is obtained as a crystal solid.

Example 25

Peniclanic Acid 1,1-Dioxide

A solution containing 512 mg of 4-nitrobenzyl penicillate 1,1-dioxide in 5 ml of acetonitrile and 5 ml of water mixture was cooled to 0 ° C. and 484 mg of sodium dithionite in 1.4 ml of 1.0-N sodium hydroxide. The solution of was added in small portions over several minutes. The reaction mixture is further stirred for 5 minutes and diluted with ethyl acetate and water at pH 8.5. The ethyl acetate layer was recovered and evaporated in vacuo to yield 300 mg of starting material. Fresh ethyl acetate is added to the aqueous phase and the pH is adjusted to 1.5. Ethyl acetate is recovered, dried and evaporated in vacuo to yield 50 mg of the title compound.

Example 26

Peniclanic Acid 1,1-Dioxide

1.46 g of 40% of acetic acid and acetic acid are added to 1.78 g of a mixture of peniclanic acid (pH 7.5) in water, followed by 2.94 ml of 40% of peracetic acid after 30 minutes. The reaction mixture is stirred for 3 days at room temperature and diluted with ethyl acetate and water.

Solid sodium bisulfite is added to adjust the excess pH to pH 1.5. The ethyl acetate layer was recovered, dried over Na ₂ SO ₄ and evaporated in vacuo. The residue is a 3: 2 mixture of peniclanic acid 1,1-dioxide and peniclanic acid 1-oxide.

Example 27

Fibaroyloxymethyl peniclanate 1,1-dioxide

A stirred solution of 595 mg of pivaloyloxymethyl penicillate in 5 ml of ethyl acetate is cooled to about −15 ° C. and 5 mg of manganese acetyl acetonate is added. To the dark brown mixture thus obtained is added 0.89 ml of 40% and acetic acid in small portions over several minutes. After 40 minutes the cooling bath is removed and the mixture is stirred at ambient temperature for 3 days. The mixture is diluted at pH 8.5 with ethyl acetate and water, the ethyl acetate layer is recovered, dried and evaporated in vacuo. This yields 178 mg of material, which is a mixture of pivaloyloxy methyl penicillate 1,1-dioxide and pivaloyloxymethyl penicillate 1-oxide according to NMR spectroscopy.

The material is dissolved in ethyl acetate and reoxidized for 16 hours using 0.9 ml of peracetic acid and 5 mg of manganese acetylacetonate. The reaction mixture is treated as above to yield 186 mg of pivaloyloxymethyl penicillate 1,1-dioxide.

Production Example A

6,6-dibromophenicylanic acid 1α-oxide

The title compound is prepared by oxidizing 6,6-dibromophenic carboxylic acid in 1 equivalent of 3-chloroperbenzoic acid in tetrahydrofuran for about 1 hour at 0 ° C. to 25 ° C. according to the Harrison method of the following reference. of the Chemical Society (London) Perkin I, 1772 (1976).

[Manufacture example B]

Benzyl 6,6-dibromophenicylanate

22.9 ml (0.165 mol) of triethylamine are added to a solution of 54 g 0.165 mol of 6,6-dibromophenicsilane acid in 350 ml of N, N-dimethylacetamide and the solution is stirred for 40 minutes. Benzyl bromide (19.6 ml, 0.165 mol) is added and the resulting mixture is stirred for 48 hours at room temperature. Precipitated triethylamine hydrobromide is filtered and the filtrate is added to 1500 ml of ice water and the pH is adjusted to 2. The mixture is extracted with ether and the extract is washed successively with saturated sodium bicarbonate, water and brine. The ether solution dried over magnesium sulfate was evaporated in vacuo to give a white solid which was recrystallized from isopropanol to give 70.0 g (95% yield) of the title compound (melting point 75-76 ° C.).

The absorption bands of the IR spectrum (KBr disk) are 1795 and 1740 cm ⁻¹ . The absorption band of the NMR spectrum (CDCl ₃ ) is as follows.

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.

Production Example C

Benzyl 6,6-dibromophenicylanate 1α-oxide

A solution of 6.12 g (0.03 moles) of 3-chloroperbenzoic acid in 100 ml of dichloromethane at about 0 ° C. in a stirred solution of 13.4 g (0.03 moles) of benzyl 6,6-dibromo-penicilanate in 200 ml of dichloromethane Add. Stirring was continued at about 0 ° C. for 1.5 hours and then the reaction mixture was filtered. The filtrate is washed successively with 5% sodium bicarbonate and water and dried over sodium sulfate. The solvent is evaporated off in vacuo to give 12.5 g of the title product as an oil. The oil phase is solidified by treating as ether. Filtration yields 10.5 g of benzyl 6,6-dibromophenicylanate 1α-oxide as a solid.

IR spectra (CHCl ₃ ) showed absorption at 1800 and 1750 cm ⁻¹ . NMR spectrum (CDCl ₃ ) of the product showed absorption at the following values. 1.3 (s, 3H), 1.5 (s, 3H), 4.5 (s, 1H), 5.18 (s, 2H), 5.2 (s, 1H) and 7.3 (s, 5H) ppm.

Preparation Example D

4-nitrobenzyl penicillate

Triethylamine salt of penicilanic acid is reacted with 4-nitro-benzylbromide according to the procedure of Preparation Example B to obtain 4-nitrobenzyl penicilanate.

Production Example E

2,2,2-trichloroethyl penicillate

To 403 mg of peniclanic acid in 10 ml of dichloromethane are added 25 mg of diisopropyl carbodiimide followed by 0.19 ml of 2,2,2-trichloroethanol. The mixture is stirred overnight and the solvent is evaporated off in vacuo.

The crude product is purified by column chromatography using silica gel as adsorbent and chloroform as eluent.

[Manufacture example F]

3-phthalidyl penicillate

0.476 ml of diisopropylethylamine is added to a solution of 506 mg of peniclanic acid in 2 ml of N, N-dimethylformamide followed by 536 mg of 3-phthalidyl bromide. The mixture is stirred overnight and diluted with ethyl acetate and water. The pH is adjusted to 3.0 and the layers are separated. The organic layer is washed with water and water at pH 8.0 and dried using anhydrous sodium sulfate. The dried ethyl acetate solution is evaporated in vacuo to give 713 mg of the title ester as an oil.

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

1.62 (m, 6H), 3.3 (m, 2H), 4.52 (s, 1H), 5.23 (m, 1H) and 7.63 (m, 5H).

[Manufacture example G]

Pivaloyloxymethyl penicilanate

To 3.588 g of 6,6-dibromophenicylic acid in 10 ml of N, N-dimethylformamide, 1.8 ml of diisopropylethylamine is added followed by 1.40 ml of chloromethyl pivalate. The mixture is stirred overnight and diluted with ethyl acetate and water. The organic layer is recovered and washed successively with water at pH 3.0 and water at pH 8.0. Ethyl acetate solution was dried over sodium sulfate and evaporated in vacuo to give pivaloyloxy-methyl 6,6-dibromo penicilanate as amber oil (3.1 g), which slowly crystallized.

The ester is dissolved in 100 ml of methanol and 3.1 g of 10% palladium on carbon and 1.31 g of calcium bicarbonate in 20 ml of water are added. The mixture is shaken under hydrogen stream at atmospheric pressure until hydrogen introduction is complete. The reaction mixture is filtered and methanol is evaporated off in vacuo. The residue is partitioned between water at pH 8 and ethyl acetate and the organic layer is recovered.

The organic layer is dried over sodium sulfate and evaporated in vacuo to yield 1.25 g of the title compound.

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

1.23 (s, 9H), 1.5 (s, 3H), 1.67 (s, 3H), 3.28 (m, 2H), 4.45 (s, 1H), 5.25 (m, 1H) and 5.78 (m, 2H) ppm.

Production Example H

4-nitrobenzyl penicillate

2.36 g of 4-nitrobenzyl bromide is added dropwise at about 20 ° C. to a stirred solution of 2.14 g of peniclanic acid and 2.01 ml of ethylisopropylamine in 10 ml of N, N-dimethylformamide. The mixture is stirred at ambient temperature overnight and diluted with ethyl acetate and water. The layers are separated and the ethyl acetate layer is washed with water at pH 2.5 followed by water at pH 8.5. The ethyl acetate solution is dried over sodium sulfate and evaporated in vacuo to afford 3.36 g of the title compound.

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

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 (g, 4H) ppm.

Claims (1)

A process for preparing a compound of formula (Ia) or a salt thereof, characterized by oxidizing a compound of formula (II), (IIa) or (III).

In the above formula, R ⁶ is hydrogen or an ester moiety that can be readily hydrolyzed in vivo, R ¹ is hydrogen, an ester forming residue that can be readily hydrolyzed in vivo, or a conventional penicillincarboxy protecting group.